Chronic Atrial and Ventricular Pacing in the Mouse Circ. Heart Fail. (IF 5.684) Pub Date : 2019-02-15 Marcus Ståhlberg, Ryo Nakagawa, Djahida Bedja, Guangshuo Zhu, Brian L. Lin, Amir Saberi, Dong I. Lee, David A. Kass
Background:The mouse is the most widely used mammal in experimental biology. Although many clinically relevant in vivo cardiac stressors are used, one that has eluded translation is long-term cardiac pacing. Here, we present the first method to chronically simulate and simultaneously record cardiac electrical activity in conscious mobile mice. We then apply it to study right ventricular pacing induced electromechanical dyssynchrony and its reversal (resynchronization).Methods and Results:The method includes a custom implantable bipolar stimulation and recording lead and flexible external conduit and electrical micro-commutator linked to a pulse generator/recorder. This achieved continuous pacing for at least 1 month in 77% of implants. Mice were then subjected to cardiac ischemia/reperfusion injury to depress heart function, followed by 4 weeks pacing at the right ventricle (dyssynchrony), right atrium (synchrony), or for 2 weeks right ventricle and then 2 weeks normal sinus (resynchronization). Right ventricular pacing–induced dyssynchrony substantially reduced heart and myocyte function compared with the other groups, increased gene expression heterogeneity (>10 fold) comparing septum to lateral walls, and enhanced growth and metabolic kinase activity in the late-contracting lateral wall. This was ameliorated by restoring contractile synchronization.Conclusions:The new method to chronically pace conscious mice yields stable atrial and ventricular capture and a means to dissect basic mechanisms of electromechanical physiology and therapy. The data on dyssynchrony and resynchronization in ischemia/reperfusion hearts is the most comprehensive to date in ischemic heart disease, and its similarities to nonischemic canine results support the translational utility of the mouse.
Stem Cell and Left Ventricular Assist Device Combination Therapy Circ. Heart Fail. (IF 5.684) Pub Date : 2019-02-14 Gregor Poglajen, Igor D. Gregoric, Rajko Radovancevic, Bojan Vrtovec
Ventricular assist device (VAD) technology has evolved significantly over the past decades and currently represents one of the most important treatment strategies for patients with advanced chronic heart failure. There is increasing evidence that in selected patients undergoing long-term VAD support, improvement of myocardial structure and function may occur. However, there seems to be a significant discrepancy between structural and functional recovery of the failing myocardium, as only a small fraction of VAD-supported patients demonstrate reverse structural remodeling and eventually reach clinically significant and stable, functional improvement. More recently, cell therapy has gained a growing interest in the heart failure community because of its potential to augment reverse remodeling of the failing myocardium. Although theoretically the combination of long-term VAD support and cell therapy may offer significant advantages over using these therapeutic modalities separately, it remains largely unexplored. This review aims to summarize the current state of the art of the effects of VAD support and cell therapy on the reverse remodeling of the failing myocardium and to discuss the rationale for using a combined treatment strategy to further promote myocardial recovery in patients with advanced chronic heart failure.
Mitochondrial Morphology, Dynamics, and Function in Human Pressure Overload or Ischemic Heart Disease With Preserved or Reduced Ejection Fraction Circ. Heart Fail. (IF 5.684) Pub Date : 2019-02-12 Antoine H. Chaanine, Lyle D. Joyce, John M. Stulak, Simon Maltais, David L. Joyce, Joseph A. Dearani, Katherine Klaus, K. Sreekumaran Nair, Roger J. Hajjar, Margaret M. Redfield
Background:The FOXO3a (forkhead box O3a)-BNIP3 (B-cell lymphoma 2/adenovirus E1B 19kDa interacting protein 3) pathway modulates mitochondrial dynamics and function and contributes to myocardial remodeling in rodent models of heart failure. We sought to investigate the expression of this pathway along with the expression of mitochondrial biogenesis (PGC-1α [peroxisome proliferator-activated receptor-γ coactivator-1α]), dynamics (DRP-1 [dynamin-related protein 1], OPA-1 [optic atrophy 1], and MFN 2 [mitofusin 2]), and oxidative phosphorylation (citrate synthase and electron transport chain complexes) markers and COX IV (cytochrome C oxidase) activity in myocardium from patients with valvular or ischemic heart disease and heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF).Methods and Results:Subepicardial left ventricular biopsies (10×1×1 mm3) were obtained at aortic valve replacement (HFpEFAVR, n=5; and HFrEFAVR, n=4), coronary artery bypass grafting (HFpEFCABG, n=5; and HFrEFCABG, n=5), or left ventricular assist device implantation (HFrEFLVAD, n=4). Subepicardial biopsies from patients with normal left ventricular function (n=2) and from donor hearts (n=3) served as controls (normal). Relative to normal, mitochondrial fragmentation and cristae destruction were evident, and mitochondrial area was decreased in HFpEF; 1.00±0.09 versus 0.71±0.08; P=0.016. These mitochondrial morphological changes were more pronounced in HFrEF (0.54±0.06); P=0.002 HFpEF versus HFrEF. BNIP3 (monomer+dimer) expression was increased in HFpEF (3.99±2.44) and in HFrEF (5.19±1.70) relative to normal; P=0.004 and P<0.001, respectively. However, BNIP3 monomer was increased in HFrEF (4.32±1.43) compared with normal (0.99±0.06) and HFpEF (1.97±0.90); P=0.001 and 0.004, respectively. The HFrEF group uniquely showed increase in DRP-1 expression (1.94±0.38) and decreases in PGC-1α expression (0.61±0.07) and COX IV activity (0.70±0.10) relative to normal; P=0.013, P<0.001, and P<0.001, respectively, with no significant change in electron transport chain complexes expression.Conclusions:These findings in human myocardium confirm studies in rodents where contractile dysfunction is associated with activation of the FOXO3a-BNIP3 pathway and altered mitochondrial dynamics, biogenesis, and function.
Optimal Hemodynamics During Left Ventricular Assist Device Support Are Associated With Reduced Readmission Rates Circ. Heart Fail. (IF 5.684) Pub Date : 2019-02-01 Teruhiko Imamura, Valluvan Jeevanandam, Gene Kim, Jayant Raikhelkar, Nitasha Sarswat, Sara Kalantari, Bryan Smith, Daniel Rodgers, Stephanie Besser, Ben Chung, Ann Nguyen, Nikhil Narang, Takeyoshi Ota, Tae Song, Colleen Juricek, Mandeep Mehra, Maria Rosa Costanzo, Ulrich P. Jorde, Daniel Burkhoff, Gabriel Sayer, Nir Uriel
Background:Left ventricular assist device (LVAD) therapy improves the hemodynamics of advanced heart failure patients. However, it is unknown whether hemodynamic optimization improves clinical outcomes. The aim of this study was to investigate whether hemodynamic optimization reduces hospital readmission rate in LVAD patients.Methods and Results:LVAD patients undergoing an invasive hemodynamic ramp test were prospectively enrolled and followed for 1 year. LVAD speed was optimized using a ramp test, targeting the following goals: central venous pressure <12 mm Hg, pulmonary capillary wedge pressure <18 mm Hg, and cardiac index >2.2 L/(min·m2). The frequency and cause of hospital readmissions were compared between patients who achieved (optimized group) or did not achieve (nonoptimized group) these goals. Eighty-eight outpatients (median 61 years old, 53 male) underwent ramp testing 236 days after LVAD implantation, and 54 (61%) had optimized hemodynamics after LVAD speed adjustment. One-year survival after the ramp study was comparable in both groups (89% versus 88%). The total hospital readmission rate was lower in the optimized group compared with the nonoptimized group (1.15 versus 2.86 events/y, P<0.001). This result was predominantly because of a reduction in the heart failure readmission rate in the optimized group (0.08 versus 0.71 events/y, P=0.016).Conclusions:LVAD patients, in whom hemodynamics were optimized, had a significantly lower rate of hospital readmissions, primarily because of fewer heart failure admissions. These findings highlight the importance of achieving hemodynamic optimization in LVAD patients.
Correction to: Novel Model to Predict Gastrointestinal Bleeding During Left Ventricular Assist Device Support: The Utah Bleeding Risk Score Circ. Heart Fail. (IF 5.684) Pub Date : 2019-02-01
In the article by Yin et al, “Novel Model to Predict Gastrointestinal Bleeding During Left Ventricular Assist Device Support: The Utah Bleeding Risk Score,” which appeared in the November 2018 issue of the journal (Circ Heart Fail.2018;11:e005267), a correction is needed. The name of the fifth author should read “Iosif Taleb, MD,” not “Iosef Taleb, MD.” The authors regret this error. This correction has been made to the current version of the article, which is available at https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.118.005267.
Characteristics of Acute Heart Failure Hospitalizations Based on Presenting Severity Circ. Heart Fail. (IF 5.684) Pub Date : 2019-01-11 Kishan S. Parikh, Shubin Sheng, Bradley G. Hammill, Clyde W. Yancy, Gregg C. Fonarow, Adrian F. Hernandez, Adam D. DeVore
BACKGROUND:Hospitalizations for acute heart failure (HF) are significant events with downstream implications for patients, as well as healthcare systems and payers. However, from anecdotal experience, both hospitalization and postdischarge courses vary significantly based on severity of presenting decompensation.METHODS AND RESULTS:We compared patient and hospitalization characteristics, resource utilization, and associated outcomes, among modern era acute HF patients enrolled in the GWTG–HF (Get With the Guidelines–Heart Failure) registry between 2011 and 2016, by varying severity of their acute HF. Among over 165 000 hospitalizations included in our analysis, 2% were considered high-risk and 32% intermediate-risk for in-hospital mortality, similar to findings from 15 years prior. Further, the 1-year mortality rate was 40% among Medicare beneficiaries in GWTG–HF who survived to hospital discharge.CONCLUSIONS:The long-term outcomes among acute HF survivors remain poor and, in the context of an increasing HF burden, warrant further study of postdischarge management strategies including inpatient-to-clinic transitions and ambulatory HF systems-based care.
Standardized Psychosocial Assessment Before Left Ventricular Assist Device Implantation Circ. Heart Fail. (IF 5.684) Pub Date : 2019-01-09 Brett W. Sperry, Asad Ikram, Paulino A. Alvarez, Antonio L. Perez, Kay Kendall, Eiran Z. Gorodeski, Randall C. Starling
Background:Before consideration of advanced cardiac therapies, guidelines recommend a comprehensive multidisciplinary examination, including psychosocial assessment. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) has emerged as a highly reproducible tool to assess for psychosocial impairment and is associated with negative medical and psychosocial outcomes after transplantation. We sought to assess the association between SIPAT and outcomes after left ventricular assist device.Methods and Results:We evaluated 128 patients implanted with a first left ventricular assist device at the Cleveland Clinic from 2013 to 2017 who underwent a prospectively collected quantitative psychosocial assessment using SIPAT. Several survival analyses were performed testing the association between SIPAT score and mortality, first adverse event (defined as hospitalization, device exchange, or death), and recurring adverse events after multivariable adjustment. Median SIPAT score was 14 (interquartile range, 9.5–22.5), with higher values (representing more impairment) seen in patients implanted as destination therapy. After a median follow-up of 349 (interquartile range, 178–684) days, there were 319 adverse events (18 deaths, 10 device exchanges, and 291 readmissions) with 2.5±2.4 events per patient. Higher preimplant SIPAT scores were not associated with mortality (P=0.764) or time to a first adverse event (P=0.589) but were associated with cumulative adverse events (hazard ratio, 1.31; 95% CI, 1.09–1.58; P=0.005 per Δ10 in score). In addition, SIPAT was associated with days alive outside of the hospital (P=0.016).Conclusions:A standardized assessment of psychosocial impairment after left ventricular assist device using the SIPAT score was not associated with mortality or time to first adverse event but was associated with cumulative adverse cardiac events. This score may provide insight when structuring mitigation strategies for high-risk patients and should be further tested in a prospective multicenter study.
Of Parachutes and Heart Pumps Circ. Heart Fail. (IF 5.684) Pub Date : 2019-01-09 Eric D. Adler
See Article by Sperry et al Left ventricular assist devices (LVADs) have revolutionized the treatment of advanced heart failure. Numerous clinical trials using LVADs unequivocally demonstrate that they improve mortality, morbidity, and quality of life. Patients that received the latest generation of LVADs had a survival of ≈85%, which rivals heart transplant, the gold standard for advanced heart failure.1 Furthermore, objective measurements of quality of life and depression are significantly improved in LVAD patients in comparison to end-stage heart failure patients.2 Like transplant, it is generally accepted that the postoperative, life-long burden of care for LVAD patients is high. LVADs are unlike almost any other long-term therapeutic used in modern health care. Patients need to physically carry around the device and batteries with a total weight of 10 to 14 lbs. They require maintaining an electric charge via either battery or wall charger and being vigilant monitoring for alarms that may signal malfunction of the device. They require dressing changes at the electric driveline exit site which vary in frequency from daily to weekly and need to adhere to a pharmacological regimen that almost always includes vitamin K antagonists, which of themselves require significant monitoring. Hence, these patients generally have frequent physician visits to monitor their status. And despite strict adherence patients still may have complications, including gastrointestinal bleeding, stroke, and infection, all of which may increase care requirements and hospitalizations. Given the overall burden of care, it has been generally accepted that the psychosocial assessment is critical for LVAD candidates. This assessment is performed to ensure implanted patients will have optimal long-term outcomes and is especially relevant given the high demands and high cost of these devices. Accrediting bodies such as the Medicare Joint Commission as well as guidelines published by the International Society for Heart Lung Transplant place a heavy emphasis on the psychosocial assessment.3 Though it is somewhat intuitive that psychosocial factors are essential to the outcome of LVAD patients, little to no objective evidence has demonstrated their significance. Unfortunately, the psychosocial assessment is difficult and remains mostly subjective. As such many hours in selection meetings across the country are spent debating the psychosocial evaluation of LVAD and transplant patients. These discussions frequently consist of a subjective assessment of the patient and her/his caregiver’s ability to manage after the LVAD and or transplant. These are commonly heated discussions between various members of the team all of whom are doing their best to predict the ability of the patient and caregiver to comply with their prescribed regimen and thrive with mechanical circulatory support. The Stanford Integrated Psychosocial Assessment Tool (SIPAT) was developed in a population of solid organ transplant patients to help objectify and standardize the transplant evaluation process.4 It includes 18 questions surrounding 4 psychosocial domains (readiness level, social support system, psychological stability, and substance abuse) which are assessed and scored.4 High SIPAT scores correlate with posttransplant morbidity (rejection episodes, readmissions, infections, psychiatric decompensation, and support system failure), but not with mortality, organ failure, or nonadherence.5 Of note, only a small fraction of the patients included in this study were heart transplant recipients (36 of the 217).5 A subsequent larger study of SIPAT in the heart transplant population had found no associations with clinical outcomes of 1-year survival, rejection episodes, or readmissions.6 Despite some shortcomings, the SIPAT remains a reproducible, rapid, and quantitative measure of psychosocial risk to assist with the evaluation of transplant patients. In this issue of Circulation: Heart Failure, Sperry et al7 present their experience using the SIPAT in LVAD patients. In this retrospective study, they provide data on 128 patients implanted with an LVAD for destination therapy (n=63) or bridge to transplant (n=65) at a single academic institution, all of whom had preoperative SIPAT scores calculated. The SIPAT was slightly modified, as it included questions specifically related to knowledge of the LVAD. Associations between SIPAT scores and adverse events such as hospitalization, device exchange, or death were evaluated. Over a period of nearly a year, 319 adverse events occurred, mainly consisting of readmissions (n=281) followed by fatalities (n=18) and device exchanges (n=10). Patients were censored at the time of transplant or last follow-up. These adverse events were cumulatively more common in those with higher SIPAT (hazard ratio 1.31). SIPAT did not predict time to the first event, but higher SIPAT scores were associated with fewer days alive outside the hospital. It is unclear if SIPAT specifically predicted mortality, it seems the study was not powered adequately to examine this variable in of itself. The authors should be commended for completing this important preliminary study, especially given the increasing use of LVADs worldwide. As the authors suggest, the findings indicate the utility of SIPAT in this patient population. Of note, the one prior study of SIPAT in LVAD did not show an association between SIPAT and outcomes, albeit it was a small retrospective study in which I (Dr Adler) was an author.8 The differences in outcomes are likely attributable to the larger data set used by Sperry et al,7 though regional and institutional differences may explain some of the findings and remind us that Sperry findings may not be universally applicable. The predictive value of a high SIPAT score in Sperry study was relatively modest (hazard ratio 1.31), suggesting that further modification of the score may be beneficial. There are fundamental differences in psychosocial requirements for LVAD patients and transplant patients. For example, it seems likely that a modified score including an objective assessment of the patient and caregiver’s comprehension of the LVAD would improve the ability of the test to predict readmissions. The authors correctly recognize this study suffers from all the limitations of a retrospective study, and as such suggest that a larger prospective study be completed. Though this seems like the obvious next step in the evaluation of the tool, is it necessary? In the era of evidence-based medicine, there is clearly a temptation to standardize and critically evaluate every aspect of decision-making. But as suggested in the groundbreaking systematic meta-analysis of parachutes in the BMJ in 2003, not all fields of medicine need or require evidence-based studies.9 In the case of the SIPAT, too much objectification of this largely subjective assessment has the risk of undermining the value of a thorough, comprehensive psychosocial evaluation. Furthermore, any test of SIPAT is likely limited by selection bias, namely that patients with high SIPAT scores are likely to be excluded from the therapy in any study. In their excellent discussion, the authors suggest that the SIPAT provides a starting place for the psychosocial assessment, and one that needs to be placed into the context of other factors, both social and medical. For example, does a SIPAT of 30 portend the same risk in an otherwise healthy 25-year-old with heart failure as a frail octogenarian with multiple comorbidities? Ultimately, the best use of the SIPAT may be as a quality metric for a program to gauge globally the degree of psychosocial risk they are taking. As LVAD technology improves and costs decrease, it is likely the psychosocial evaluation will become a less-critical element of the preoperative assessment. For example, significantly less psychosocial assessment is advocated for patients receiving automated internal cardiac defibrillators, because they place a smaller burden on patients and caregivers and are not associated with frequent readmissions. Ultimately, we are still waiting for the set it and forget it LVAD; one that obviates the need for significant psychosocial assessment. Until that time point, our LVAD team will continue to spend countless hours hearing about the life stories of our patients, essentially peering into the crystal ball and trying our best to predict the future. Dr Adler is a consultant for Medtronic and Abbott. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Endothelial Leptin Receptor Deletion Promotes Cardiac Autophagy and Angiogenesis Following Pressure Overload by Suppressing Akt/mTOR Signaling Circ. Heart Fail. (IF 5.684) Pub Date : 2019-01-09 Rajinikanth Gogiraju, Astrid Hubert, Jörg Fahrer, Beate K. Straub, Moritz Brandt, Philip Wenzel, Thomas Münzel, Stavros Konstantinides, Gerd Hasenfuss, Katrin Schäfer
Background:Cardiac remodeling is modulated by overnutrition or starvation. The adipokine leptin mediates energy balance between adipose tissue and brain. Leptin and its receptors are expressed in the heart.Methods and Results:To examine the importance of endothelial leptin signaling in cardiac hypertrophy, transverse aortic constriction was used in mice with inducible endothelium-specific deletion of leptin receptors (End.LepR-KO) or littermate controls (End.LepR-WT). End.LepR-KO was associated with improved left ventricular function (fractional shortening, 28.4% versus 18.8%; P=0.0114), reduced left ventricular dilation (end-systolic inner left ventricular diameter, 3.59 versus 4.08 mm; P=0.0188) and lower heart weight (133 versus 173 mg; P<0.0001) 20 weeks after transverse aortic constriction. Histology and quantitative polymerase chain reaction analysis confirmed reduced cardiomyocyte hypertrophy. STAT3 (signal transducer and activator of transcription) activation was reduced, and Akt (protein kinase B) and mTOR (mammalian target of rapamycin) phosphorylation after transverse aortic constriction were blunted in End.LepR-KO hearts. Elevated LC3 (microtubule associated protein 1 light chain 3)-I/-II conversion (P=0.0041) and increased (LC3II-positive) endothelial cells (P=0.0042) in banded hearts of End.LepR-KO mice suggested improved cardiac angiogenesis because of activated autophagy. Microscopy confirmed autophagosome accumulation after genetic or small interfering RNA-mediated LepR downregulation. Enhanced sprouting angiogenesis was observed in endothelial cells (P<0.0001) and aortic rings (P=0.0060) from End.LepR-KO mice, and murine and human endothelial sprouting angiogenesis was reduced after mTOR inhibition using rapamycin or autophagy inhibition using 3-methyladenine. Banded End.LepR-KO mouse hearts exhibited less apoptosis (P=0.0218), inflammation (P=0.0251), and fibrosis (P=0.0256). Reduced endothelial autophagy was also observed in myocardial biopsies of heart failure patients with cardiac fibrosis.Conclusions:Our findings suggest that endothelial leptin signaling contributes to cardiac fibrosis and functional deterioration by suppressing endothelial autophagy and promoting endothelial dysfunction in a chronic pressure overload model.
Reserve of Right Ventricular-Arterial Coupling in the Setting of Chronic Overload Circ. Heart Fail. (IF 5.684) Pub Date : 2019-01-08 Khodr Tello, Antonia Dalmer, Jens Axmann, Rebecca Vanderpool, Hossein A. Ghofrani, Robert Naeije, Fritz Roller, Werner Seeger, Natascha Sommer, Jochen Wilhelm, Henning Gall, Manuel J. Richter
Background:Right ventricular (RV) maladaptation and failure determine outcome in pulmonary hypertension. The adaptation of RV function to loading (RV-pulmonary arterial coupling) is defined by a ratio of end-systolic to arterial elastances (Ees/Ea). How RV-pulmonary arterial coupling relates to pulmonary hypertension severity and onset of RV failure (defined by excessive volume increase and ejection fraction [EF] decrease) is not exactly known.Methods and Results:We performed cardiac magnetic resonance (CMR) imaging within 24 hours of a diagnostic right heart catheterization and invasive measurement of RV pressure-volume loops in 42 patients with pulmonary hypertension. Median (interquartile range) Ees and Ea were 0.49 (0.35–0.74) and 0.74 (0.45–1.04) mm Hg/mL, respectively; Ees/Ea was 0.73 (0.47–1.07). End-diastolic elastance (Eed) was 0.14 (0.06–0.24) mm Hg/mL. RV EF was 39±13%. End-systolic volume and end-diastolic volume/body surface area (BSA) were 62 (45–101) and 104 (83–143) mL/m2, respectively. Ees/Ea decreased with increasing RV end-diastolic volume/BSA, mass/BSA, and pulmonary arterial stiffness, and with decreasing EF, from 0.89 to 1.09 in the least impaired tertiles to 0.55 to 0.61 in the most impaired tertiles. Eed increased with increasing RV mass/BSA, end-diastolic volume/BSA, and T1 mapping and with decreasing EF. Receiver operating characteristic analysis identified an Ees/Ea cutoff of 0.805 associated with onset of RV failure defined by increased RV volumes with EF <35%.Conclusions:RV-pulmonary arterial coupling (Ees/Ea) has considerable reserve, from normal values of 1.5–2 to <0.8, and has the ability to detect pending RV failure in patients with pulmonary hypertension.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT03403868.
Coupling Right Ventricular–Pulmonary Arterial Research to the Pulmonary Hypertension Patient Bedside Circ. Heart Fail. (IF 5.684) Pub Date : 2019-01-08 Steven Hsu
See Article by Tello et al Over the last decade, there has been increasing appreciation for the importance of right ventricular (RV) coupling to the pulmonary arterial (PA) circulation. This relationship, so-called RV-PA coupling, is an application of the left-sided ventriculo-arterial coupling first described in the 1980s.1 Whether it refers to the left or right, coupling describes the energy transfer between ventricular contractility and arterial afterload. Ventricular contractility is well characterized by end-systolic elastance (Ees), a load-independent measure of systolic function. Arterial afterload, on the other hand, can be thought of in terms of net vascular stiffness. Sunagawa et al1,2 created a term in 1983 called effective arterial elastance (Ea), which encapsulates net stiffness by combining mean and pulsatile loading to yield a lumped parameter that reflects the load imposed upon the ventricle. An important breakthrough came in 1992 when Kelly et al3 found in humans that end-systolic pressure divided by stroke volume accurately represented Ea across a wide afterload range. Because Ea is conveniently measured using the same units as Ees, this allows the ratio of Ees to Ea to become a unit-less value that encapsulates ventriculo-arterial coupling. The ideal Ees/Ea ratio is estimated to be 1.0 to 2.0.2 This ratio is seen in the healthy RV-PA unit and remains preserved even in the early phases of pulmonary hypertension (PH) because compensatory RV hypertrophy leads to an increase in RV Ees that matches increasing Ea. It is only with progressive RV decompensation that RV Ees begins to fall, Ees/Ea declines, and the RV-PA unit becomes uncoupled.4 RV-PA coupling is often talked about in academic circles and carefully measured in animal and human experimental studies of PH. Coupling can describe RV compensation not only in group I PH but also in PH secondary to a range of left-sided cardiac conditions. Its importance has risen alongside increasing recognition of the pivotal role that the RV plays in many cardiopulmonary conditions. But when was the last time any of us talked to a patient or clinical colleague about coupling? “Great news, your coupling ratio is 1.5!” Despite its common use in the literature and its ability to describe the full range of RV-PA performance, there is a surprising lack of correlation between coupling, as measured by Ees/Ea, and more clinically utilized parameters of RV dysfunction, such as RV dilation or RV ejection fraction (RVEF). This leads to an unfortunate disconnect between the research and clinical applications of RV-PA coupling. In this issue of Circulation: Heart Failure, Tello et al5 lay out a much-needed blueprint that relates RV-PA coupling to more clinically accessible measures of RV performance in PH. In their study, they prospectively obtain pressure-volume loop measurements alongside right heart catheterization and cardiac magnetic resonance imaging in 42 human patients with PH. In this cohort, the PH patients with more severe disease demonstrated predictable increase in RV mass and end-diastolic volume , decrease in RVEF, as well as worsening PA stiffness, capacitance, and distensibility. Ees/Ea showed progressive decline alongside worsening RV end-diastolic volume, mass, and RVEF. By mapping out Ees/Ea across tertiles of each parameter, the authors show that Ees/Ea maintains a ratio of 0.89:1.09 in PH patients with compensated RVs (best tertile), drifts to 0.58:0.70 in early RV decompensation (middle tertile), and falls to 0.56:0.61 in the most decompensated tertile. Little is known about the clinical relevance of Ees/Ea, and so by using receiver operator curve analysis, the authors show that an Ees/Ea of <0.805 best predicted a cardiac magnetic resonance RVEF of <35%, the latter being an established indicator of RV decompensation in PH. Last, they show that RV stroke volume divided by end-systolic volume, a measure readily attainable from cardiac magnetic resonance, is at least as good at predicting RVEF <35% as Ees/Ea, if not better. Using pressure-volume loops, the authors also calculate single-beat end-diastolic elastance (Eed), a coefficient of diastolic stiffness attainable from RV pressure-volume data. Eed indexes RV diastolic dysfunction, increases with diastolic stiffness, and has been shown to be predictive of outcomes in PH.6,7 The authors show that Eed increases alongside worsening RV mass, volume, and ejection fraction, as well as worsening T1 mapping of RV fibrosis. Interestingly, Eed trends upward just as RV mass and end-diastolic volume increase and Ees/Ea declines, illustrating just how tightly interwoven coupling, mass, dilation, and diastolic dysfunction are in PH.5 RV Ees/Ea has been widely used in research; its clinical validity has generally been assumed. The current study thus does an important job of validating Ees/Ea, and even Eed, against multiple established clinical benchmarks of RV decompensation. Second, the authors verify that Ees/Ea maintains coupling at ≈1.0 in early PH and show us that Ees/Ea has to fall below 0.8 before we see RV dilation and overt worsening of RV systolic function. These values help us to understand the range of Ees/Ea in the context of known clinical markers of RV decompensation. Tello et al5 thus provide a much-needed link between the growing body of RV-PA coupling research to the bedside assessment of RV function in PH. One fly in the ointment, however, is the single-beat method by which Ees/Ea was determined. Ees is traditionally measured by altering RV preload, obtaining a family of pressure-volume loops, and measuring the slope of multiple end-systolic pressure points. This is known as the multi-beat method. The single-beat method determines Ees without need for filling changes to the RV. It was originally proposed by Sunagawa et al8 and Senzaki et al9 in the left ventricle and shown to be practical for the RV by Brimioulle et al.10 The single-beat method extrapolates a theoretical pressure of isovolumic contraction (Pisovol) and combines that with the end-systolic pressure point to calculate Ees. It should be noted that although RV Pisovol has been validated in animal models, it has not been validated in humans with severe PH,4 and a recent study failed to show correlation between single-beat and multi-beat measures of Ees in a human cohort with and without PH.11 That said, both methodologies, on the whole, capture the same overall relationship of RV contractility to PA afterload, and Ea is measured the same either way. Also, the current study may help to bolster the validity of single-beat Ees/Ea by relating it to well-established metrics of RV decompensation. Now that we have a blueprint with which to understand the clinical implications of Ees/Ea, where do we go from here? More work needs to be done to link Ees/Ea to the bedside. Despite its common use in research, Ees/Ea has never been shown to predict outcomes in PH patients. Does Ees/Ea even predict clinical events? It would be a much more relevant parameter if so. Also, the current study shows that readily available clinical metrics of RV performance serve as an adequate surrogate for reduced Ees/Ea. But is there perhaps a role for Ees/Ea in identifying early uncoupling in PH patients? Ees does remain a very sensitive measure of RV systolic function and captures declining RV contractility well before right heart catheterization or cardiac magnetic resonance can detect.12,13 RV dilation, stroke volume/end-systolic volume, and reduced RVEF all capture the uncoupled RV, and so perhaps Ees/Ea can be better put to use in capturing earlier RV disease. Now that we are guided by Tello et al5 with a more robust clinical framework for RV-PA coupling, future studies in the field will hopefully provide more context and utility to the bedside application of Ees/Ea. None. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. Guest Editor for this article was Ryan J. Tedford, MD.
Thyroid Dysfunction in Heart Failure and Cardiovascular Outcomes Circ. Heart Fail. (IF 5.684) Pub Date : 2018-12-14 Lakshmi Kannan, Pamela A. Shaw, Michael P. Morley, Jeffrey Brandimarto, James C. Fang, Nancy K. Sweitzer, Thomas P. Cappola, Anne R. Cappola
Background:The effects of thyroid dysfunction in patients with preexisting heart failure have not been adequately studied. We examined the prevalence of thyroid dysfunction and associations with cardiovascular outcomes in a large, prospective cohort of outpatients with preexisting heart failure.Methods and Results:We examined associations between thyroid dysfunction and New York Heart Association class, atrial fibrillation, and a composite end point of ventricular assist device placement, heart transplantation, or death in 1365 participants with heart failure enrolled in the Penn Heart Failure Study. Mean age was 57 years, 35% were women, and the majority had New York Heart Association class II (45%) or III (32%) symptoms. More severe heart failure was associated with higher thyroid-stimulating hormone (TSH), higher free thyroxine (FT4), and lower total triiodothyronine (TT3) concentrations (P<0.001 all models). Atrial fibrillation was positively associated with higher levels of FT4 alone (P≤0.01 all models). There were 462 composite end points over a median 4.2 years of follow-up. In adjusted models, compared with euthyroidism, subclinical hypothyroidism (TSH 4.51–19.99 mIU/L with normal FT4) was associated with an increased risk of the composite end point overall (hazard ratio, 1.82; 95% CI, 1.27–2.61; P=0.001) and in the subgroup with TSH ≥7.00 mIU/L (hazard ratio, 3.25; 95% CI, 1.96–5.39; P<0.001), but not in the subgroup with TSH 4.51–6.99 mIU/L (hazard ratio, 1.26; 95% CI, 0.78–2.06; P=0.34). Isolated low T3 was also associated with the composite end point (hazard ratio, 2.12; 95% CI, 1.65–2.72; P<0.001).Conclusions:In patients with preexisting heart failure, subclinical hypothyroidism with TSH ≥7 mIU/L and isolated low T3 levels are associated with poor prognosis. Clinical trials are needed to explore therapeutic effects of T4 and T3 administration in heart failure.
Pulmonary Production of Soluble ST2 in Heart Failure Circ. Heart Fail. (IF 5.684) Pub Date : 2018-12-13 Domingo A. Pascual-Figal, Maria T. Pérez-Martínez, Maria C. Asensio-Lopez, Jesús Sanchez-Más, Maria E. García-García, Carlos M. Martinez, Miriam Lencina, Ruben Jara, James L. Januzzi, Antonio Lax
Background:Serum concentrations of ST2 (interleukin-1 receptor-like 1) represent a meaningful prognostic marker in cardiac diseases. Production of soluble ST2 (sST2) may be partially extracardiac. Identification of sST2 sources is relevant to design strategies for modulating its signaling.Methods and Results:An experimental model of ischemic heart failure was used. sST2, membrane-bound ST2 (ST2L), and IL-33 were measured in lungs, heart, kidney, and liver by quantifying mRNA and protein expression in tissue samples obtained at different times (1, 2, 4, and 24 weeks). Primary human type II pneumocyte cell cultures were subjected to strain. sST2 was measured in samples of bronchial aspirate and serum obtained from patients treated with invasive respiratory support. In the experimental model, sST2 increased significantly from the first week in both lungs and myocardium, whereas ST2L/IL-33 response was unfavorable in lungs (decrease) and favorable in myocardium (increase). No changes were observed in liver and kidneys. ST2 immunostaining was intensely observed in alveolar epithelium, and sST2 was secreted by primary human type II pneumocytes in response to strain. sST2 levels in lung aspirates were substantially higher in the presence of cardiogenic pulmonary edema (median, 228 [interquartile range, 28.4–324.0] ng/mL; P<0.001) than bronchopneumonia (median, 5.5 [interquartile range, 1.6–6.5]) or neurological disorders (median, 2.9 [interquartile range, 1.7–10.1]), whereas sST2 concentrations in serum did not differ.Conclusions:The lungs are a relevant source of sST2 in heart failure. These results may have implications for the progression of disease and the development of therapies targeting the ST2 system in patients with heart failure.
ST2 in Heart Failure Circ. Heart Fail. (IF 5.684) Pub Date : 2018-12-13 Antoni Bayés-Genis, Arantxa González, Josep Lupón
See Article by Pascual-Figal et al From the heart, impurities or ‘sooty vapors’ are carried back to the lung by way of the pulmonary artery, to be exhaled to the outer air. —Leonardo Da Vinci, 1452–1519 Before getting to the central point of this editorial commentary, we wish to clarify an error that appears repeatedly in the literature which is that the alias ST2 refers to the gene for IL1RL1 (interleukin-1 receptor-like 1; GeneID: 9173), found on chromosome 2, and a major player in immune and inflammatory responses. This ST2 must not be confused with suppression of tumorigenicity 2 (GeneID: 6761), which is an entirely different gene that is located on chromosome 11, in a region that represents a putative locus associated with various forms of cancer. The circulating ST2 discussed here, the product of the gene IL1RL1, is measured in heart failure (HF), and is essentially a marker of inflammation and stretch, although it also signals the presence and severity of adverse cardiac remodeling and tissue fibrosis. Multiple researchers have measured soluble ST2 (sST2; hereafter referred to simply as ST2) in HF in different settings over the past decade, building robust and reproducible evidence of its value for prognostication in HF, both in addition to and independently of other established markers.1 ST2 is included in the 2017 American College of Cardiology/American Heart Association guidelines for additive risk stratification of patients with acute and chronic HF. Furthermore, ST2 immunoassays are approved for clinical use by the US Food and Drug Administration and have received the Conformitè Europèenne mark. However, despite its approval and the growing use of ST2 by practicing clinicians, issues related to its pathobiology remain incompletely understood, including the production of circulating ST2 in cardiac and extracardiac tissues. Early in vitro findings showed load induction of ST2 mRNA in neonatal rat cardiac myocytes,2 and it was thus presumed that circulating ST2 in cardiovascular disease was exclusively myocardial in origin. These data, reported over 15 years ago from the laboratory of Richard T. Lee in Boston, stimulated ST2 research in the cardiovascular field and are nicely summarized by Kakkar and Lee.3 Briefly, alternative splicing generates multiple ST2 isoforms, including a transmembrane form (ST2 ligand or ST2L) and a soluble circulating form (sST2 or ST2) that is a valuable biomarker. Both ST2L and ST2 are expressed by cardiomyocytes and cardiac fibroblasts in response to mechanical stress, and both isoforms bind to IL-33 (interleukin-33). IL-33 is also induced by cellular stretch, and apparently protects against fibrosis and hypertrophy in mechanically strained tissues via activation of MyD88 (myeloid differentiation primary response gene 88), IRAK (interleukin-1 receptor-associated kinase), and ERK (extracellular signal-regulated kinase), and ultimately NF-κB (nuclear factor-κB). In in vitro and in vivo models, ST2L transduces the effects of IL-33, while excess circulating ST2 leads to cardiac fibrosis and remodeling and ventricular dysfunction. It is proposed that circulating ST2 acts as a decoy receptor for IL-33, such that high levels of soluble ST2 block the favorable effects of IL-33 by limiting activation of the cascade triggered by the IL-33/ST2L interaction (Figure). Thus, higher levels of circulating ST2 are associated with increased myocardial fibrosis, adverse cardiac remodeling, and worse cardiovascular outcomes.4 Figure. Schematic of the ST2 axis in health and disease. In cardiovascular (CV) health, sST2 (soluble interleukin-1 receptor-like 1) production by endothelium and the lungs is low, which permit IL-33 (interleukin-33)/ST2L (transmembrane interleukin-1 receptor-like 1) interaction at the cardiomyocyte level, which leads to activation of a cardioprotective cascade by activation of diverse intracellular kinases and factors. In heart failure, sST2 production by endothelium and the lungs is upregulated, and sST2 binds IL-33 as a decoy receptor limiting activation of the cardioprotective cascade in the cardiomyocyte triggered by the IL-33/ST2L interaction. ERK indicates extracellular signal-regulated kinase; IRAK, interleukin-1 receptor-associated kinase; JNK, c-Jun N-terminal kinases; LA, left atrium; LV, left ventricle; MYD88, myeloid differentiation primary response gene 88; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; and TRAF-6, tumor necrosis factor receptor-associated factor-6. Recent evidence suggests a disconnect between tissue-based and circulating ST2 concentrations, and some findings indicate possible extracardiac ST2 protein production. Bartunek et al5 first demonstrated that adult human myocardium is a weak source of increased soluble ST2 in pressure overload hypertrophy and congestive cardiomyopathy. They observed that ST2 mRNA levels were not significantly increased in myocardial biopsies from human hearts, prompting investigation of ST2 protein production in extramyocardial nonmyocyte cell types, which revealed ST2 protein secretion from human venous and arterial endothelial cells (Figure).5 In a later study, Demyanets et al6 found that human macrovascular (aortic and coronary artery) and heart microvascular endothelial cells express specific mRNA for soluble ST2, and are a source of ST2 protein. Moreover, recent data indicate that soluble ST2 plays a modulatory role in obesity-associated vascular remodeling.7 In the current issue of Circulation: Heart Failure, Pascual-Figal et al8 present the first data indicating the production of soluble ST2 protein by organs other than the heart and vessels. Using an experimental model of HF (permanent left anterior descending occlusion in a rat model), they measured soluble ST2 mRNA in lung, kidney, and liver tissue samples obtained at prespecified time-points. The liver and kidneys did not participate in ST2 production during any of the studied periods. In contrast, the lungs exhibited significant upregulation of soluble ST2 mRNA. The authors also identified an association between increased alveolus thickness and upregulation of soluble ST2, suggesting a relationship between the degree of pulmonary congestion and ST2 production. Furthermore, ST2 protein was detected in alveolar epithelium and secreted by type II pneumocytes in response to cellular strain. Although their report did not establish causality, which is an acknowledged limitation, the results support that the lungs are a relevant source of soluble ST2 in HF.8 The presently available data suggest that the myocardium may not be the main source of circulating ST2. Indeed, soluble ST2 level appears to be heavily influenced by dynamic contributions of the lungs and the vascular endothelium. This indicates that ST2, rather than being specific for indices of cardiac remodeling, may reflect heart-lung-vasculature health status beyond cardiac function. In response to alterations in hemodynamic and inflammatory status, the lungs and the vascular endothelium may emerge as the main sources of elevated soluble ST2 levels in HF (Figure). These data further imply that soluble ST2 may be a surrogate of congestion in HF. Congestion can manifest as venous (systemic) congestion or as pulmonary congestion, which is the main cause of dyspnea in HF. Pulmonary congestion in HF primarily results from elevated left ventricular filling pressure and frequently coexists with venous congestion and fluid retention. In clinical practice, congestion is difficult to evaluate, and such assessment is commonly considered unreliable because of substantial interobserver variability. In terms of using ST2 as a biomarker in acute and chronic HF—both of which include variable degrees of pulmonary and venous congestion—a rise in ST2 levels (which is much greater in acute HF) provides important prognostic information.4 Further research combining ST2 with congestion scores, lung ultrasound, bioimpedance or other congestion biomarkers may better characterize the value of ST2 and congestion in HF. In conclusion, in their recent study, Pascual-Figal et al8 demonstrate that the lungs seem to be a main source of ST2 protein production. This may impact the interpretation of data from clinical studies using soluble ST2 measurement and may open a new avenue for the modulation of ST2 expression as a potential therapeutic target in HF. Dr Bayés-Genis was supported by grants from the Ministerio de Educación y Ciencia (SAF2017-84324-C2-1-R), Fundació La MARATÓ de TV3 (201502, 201516), Centro de Investigación Biomédica en red (CIBER) Cardiovascular (CB16/11/00403), and AdvanceCat 2014–2020. Dr González was supported by CIBER Cardiovascular (CB16/11/00483) and the European Commission (HOMAGE project 2012–305507). Dr Bayés-Genis received board membership fees and travel expenses from Novartis and Roche Diagnostics and reports a relationship with Critical Diagnostics. Dr Lupón reports lecture honoraria from Roche Diagnostics and a relationship with Critical Diagnostics. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Increased Cardiac Uptake of Ketone Bodies and Free Fatty Acids in Human Heart Failure and Hypertrophic Left Ventricular Remodeling Circ. Heart Fail. (IF 5.684) Pub Date : 2018-12-12 Gabor Voros, Joris Ector, Christophe Garweg, Walter Droogne, Johan Van Cleemput, Nele Peersman, Pieter Vermeersch, Stefan Janssens
Background:Deranged energy metabolism contributes to the pathophysiology of heart failure (HF). Recent studies showed diminished free fatty acid (FFA) oxidation in experimental HF models with a shift towards oxidation of ketone bodies. However, conflicting clinical data on FFA metabolism and limited knowledge on ketone body metabolism in human HF mandate additional metabolic profiling studies. We, therefore, investigated cardiac uptake of FFAs and ketone bodies (β-hydroxybutyrate and acetoacetate) in patients with HF with reduced ejection fraction (HFrEF) or with aortic stenosis (AS)–induced left ventricular hypertrophy. We hypothesized that FFA oxidation is impaired in HFrEF and in AS and results in decreased concentrations of free carnitine, the necessary carrier for mitochondrial entry of activated FFAs, and in accumulation of metabolic intermediates.Methods and Results:We collected arterial and coronary sinus blood samples in patients with HFrEF (n=15), in AS patients with preserved systolic function (n=15), and in control patients (n=15). Plasma concentration gradients across the heart show significantly greater uptake of ketone bodies in patients with HFrEF than in controls. Patients with AS show significantly increased uptake of β-hydroxybutyrate and FFAs. Free carnitine concentration and concentration gradients of intermediates of FFA oxidation were comparable between groups.Conclusions:In conclusion, our results show significantly increased cardiac uptake of ketone bodies in patients with stable HFrEF and AS and increased uptake of FFAs in AS compared with control patients. The lack of myocardial release of acyl-carnitine species or change in free carnitine uptake suggests no impairment of FFA oxidation.
Hungry Hearts Circ. Heart Fail. (IF 5.684) Pub Date : 2018-12-12 Edoardo Bertero, Vasco Sequeira, Christoph Maack
See Article by Voros et al To maintain its intense energy requirements, the heart continuously transforms chemical energy obtained from circulating substrates into mechanical work via an efficient metabolic machinery. Under normal conditions, fatty acids (FA) provide 70% of the fuel requirements to the heart, with the remaining 30% resulting from glucose oxidation. In heart failure (HF), the 3 fundamental steps of cardiac energy metabolism are deranged, that is, substrate uptake, oxidative phosphorylation, and shuttling of energy from mitochondria to the cytosol. Although this metabolic remodeling is a heterogeneous process, which varies largely depending on the stage and the cause of cardiac dysfunction, it is generally accepted that in HF, mitochondrial oxidative metabolism is impaired, which is accompanied by decreased reliance on FA oxidation for ATP production and a mismatch between enhanced glycolytic rates and decreased glucose oxidation in mitochondria.1 Based on proteomic and metabolomic evidence, 2 groups independently proposed that ketone bodies may become a predominant source of energy in the failing heart.2,3 In the current issue of Circulation: Heart Failure, Voros et al4 measured concentration gradients of ketone bodies and FA between arterial and coronary sinus blood samples obtained from patients with HF with reduced ejection fraction or aortic stenosis (AS)–induced cardiac hypertrophy.4 The control group consisted of individuals without structural cardiac disease undergoing catheter ablation for atrial arrhythmias. Both HF with reduced ejection fraction and AS patients displayed a marked increase in ketone bodies concentration gradients, suggesting increased uptake, whereas the FA gradient across (and therefore, uptake into) the heart was increased exclusively in the AS group. Although this confirms previous evidence that myocardial ketone body utilization is increased in patients with HF, the study represents an important addition to the field in that it investigates substrate uptake also in individuals with cardiac hypertrophy but without failure, a subgroup of patients which has not been characterized in this respect to date. Ketone bodies are produced from acetyl-CoA in the liver and released into the bloodstream to provide extra-hepatic tissues with a substrate for ATP production during prolonged fasting or starvation. In fact, starvation is associated with a predominance of glucagon over insulin signaling, which stimulates gluconeogenesis and thereby depletes Krebs cycle intermediates in the liver, diverting acetyl-CoA toward synthesis of ketone bodies. In end-stage HF, neurohormonal activation enhances mobilization of FA from adipose tissue,5 and peripheral tissues become resistant to insulin activity.6 Together, these processes promote ketogenesis and increase circulating levels of ketone bodies in HF patients.3,7 Because ketone bodies availability is a key determinant of their uptake and utilization in the myocardium, it has been proposed that perturbed metabolism in extracardiac tissues contributes to metabolic remodeling in the failing heart. In agreement with previous studies,7 Voros et al4 observed a mild increase in arterial levels of ketone bodies and an increase in their myocardial extraction in both HF with reduced ejection fraction and AS patients. Intriguingly, the increased cardiac uptake of ketone bodies in patients with compensated hypertrophy is corroborated by the observation that enzymes involved in ketone bodies oxidation are upregulated in mice with pressure overload–induced cardiac hypertrophy before the development of overt HF.2 Although it remains unclear whether a metabolic shift towards ketone bodies oxidation in the failing human heart is an adaptive or maladaptive response, experimental evidence argues in favor of the former. Because the energy yield from β-hydroxybutyrate oxidation is higher than of FA (but not of glucose), ketone bodies may represent a more oxygen-efficient substrate for the energetically starved heart.8 Furthermore, cardiac-specific deletion of one of the key enzymes of ketone bodies oxidation does not result in a pathological phenotype at baseline, but exacerbates HF in mice subjected to aortic banding,9 suggesting that this metabolic pathway plays a compensatory role in the pressure-overloaded heart. Finally, ketone bodies may have beneficial effects not directly related to energy metabolism, such as anti-inflammatory properties related to inhibition of inflammasome activation.10 FA utilization for ATP production is achieved predominantly via the β-oxidative pathway, which is accomplished inside mitochondria by the cleavage of 2 carbons at a time from the fatty acyl chain (Figure). FA import into mitochondria is mediated by the carnitine shuttle, which entails the conjugation of a fatty acyl chain with a carnitine moiety, which is again replaced by CoA once the acyl-carnitine intermediate reaches the mitochondrial matrix (Figure). Of note, although increases in plasma fatty acyl-carnitines are commonly observed in HF patients, they represent a poor or even misleading indirect indicator of inefficient β-oxidation. In fact, lipid metabolism depends on the tight balance between FA synthesis (de novo lipogenesis from dietary carbohydrate metabolism), uptake, and oxidation of lipid intermediates (dietary lipids). A low-fat carbohydrate-enriched diet contributes up to 27-fold more to de novo lipogenesis than a low carbohydrate diet during prolonged fasting.11,12 Considering that over the past decades, the western world has adopted a high-carbohydrate diet consumption (eg, sugar-sweetened beverages),13 the large increases in plasma fatty acyl-carnitines can also be factored in by greater liver FA synthesis. The latter, which is not generally taken into account, can potentially explain the confounding reports of diminished,14 unchanged,15 or even increased myocardial FA oxidation in HF with reduced ejection fraction populations.16 Figure. Ketone and fatty acid metabolism. Ketone bodies produced from acetyl-CoA in the liver are released into circulation and transported into cardiomyocyte`s cytosol via the MCTs (monocarboxylate transporters). Mitochondrial passive diffusion allows ketone bodies to access the mitochondrial matrix, to be metabolized to acetyl-CoA and oxidized in the Krebs cycle. Fatty acids are carried in the blood bound to either albumin or lipoproteins. In addition to passive diffusion, sarcolemmal fatty acid translocase (FAT/CD36), FABPpm (fatty acid-binding protein), and FATP (fatty acid transport protein) traffic fatty acids across the plasma membrane to the cytosol. In the cytosol, fatty acids are activated to fatty acyl-CoA. They enter the mitochondrial outer membrane via CPT1 (carnitine O-palmitoyltransferase 1, which resides within the membrane) and are subsequently linked to carnitine (carnitine exchanges with CoA). Fatty acyl-carnitine enters the inner mitochondrial membrane via a translocase (T). Inside the inner mitochondrial membrane (mitochondrial matrix), fatty acyl-carnitine is again exchanged back to fatty acyl-CoA via CPT2 (which resides attached to the interior of the inner mitochondrial membrane). In the mitochondrial matrix, fatty acyl-CoA is degraded via the β-oxidation pathway that cleaves 2 carbons at a time from the acyl chain, forming an acetyl-CoA molecule. Furthermore, β-oxidation produces reduced nicotinamide and flavin adenine dinucleotide (NADH and FADH2), electron donors for the respiratory chain. Finally, acetyl-CoA enters the Krebs cycle to provide more NADH and FADH2. In the liver, acetyl-CoA can additionally be used to produce ketone bodies. Ketone bodies uptake increases in both patients with end-stage HF with reduced ejection fraction (HFrEF) and aortic stenosis, whereas fatty acid uptake increases solely in patients with aortic stenosis (left), but not with HFrEF (right). Interestingly, the study by Voros et al4 observes net increases of FA concentration gradients (and thereby, myocardial uptake) solely in the AS population (Figure). An increase in cardiac afterload, such as observed in patients with AS or hypertension, increases the energetic demand of the heart. It can be assumed that the increased FA and ketone body utilization is an adaptive process to match the elevated energetics requirements of the heart. Furthermore, it may be speculated that despite the maintained elevated ketone body utilization, a decrease in FA utilization may contribute to the transition of compensated hypertrophy towards failure. In conclusion, Voros et al4 need to be commended for providing novel and important insights into metabolic remodeling in the hypertrophied and failing human heart. The emerging concept that ketone bodies represent a thrifty substrate8 compensating for compromised glucose and FA oxidation is intriguing and might eventually translate into novel therapeutic approaches for HF patients. For instance, nutritional ketosis shifts metabolism away from glucose utilization and increases FA oxidation during exercise in skeletal muscle, thereby improving endurance performance.17 Furthermore, increased metabolic efficiency of myocardial ketone body oxidation might partly account for the beneficial effects associated with SGLT2 (sodium/glucose cotransporter 2) inhibitors, a new class of antidiabetic agents which substantially reduced the risk for HF hospitalization and mortality in diabetic patients at high cardiovascular risk.18,19 In fact, SGLT2 inhibition induces glycosuria, removing a substantial amount of glucose from the body and consequently reducing the insulin/glucagon ratio.20 This metabolic milieu stimulates ketogenesis in the liver, and thereby, the energetically starved heart is provided with a more oxygen-efficient fuel. Overall, this novel avenue of research might spark new enthusiasm towards targeting metabolic remodeling in the failing heart. Dr Maack is supported by the Deutsche Forschungsgemeinschaft (Ma 2528/7-1, SFB-894 and TRR-219), Corona Foundation, and the Federal Ministry of Education and Science (Bundesministerium für Bildung und Forschung). Dr Maack received speaker honoraria from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Berlin Chemie, Daiichi Sankyo, Pfizer, Servier, and Novartis and is an advisor to Servier. The other authors report no conflicts. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
National Burden of Heart Failure Events in the United States, 2006 to 2014 Circ. Heart Fail. (IF 5.684) Pub Date : 2018-12-11 Sandra L. Jackson, Xin Tong, Raymond J. King, Fleetwood Loustalot, Yuling Hong, Matthew D. Ritchey
Background:Heart failure (HF)—a serious and costly condition—is increasingly prevalent. We estimated the US burden including emergency department (ED) visits, inpatient hospitalizations and associated costs, and mortality.Methods and Results:We analyzed 2006 to 2014 data from the Healthcare Cost and Utilization Project Nationwide Emergency Department Sample, the Healthcare Cost and Utilization Project National (nationwide) Inpatient Sample, and the National Vital Statistics System. International Classification of Disease codes identified HF and comorbidities. Burden was estimated separately for ED visits, hospitalizations, and mortality. In addition, criteria were applied to identify total unique acute events. Rates of primary HF (primary diagnosis or underlying cause of death) and comorbid HF (comorbid diagnosis or contributing cause of death) were calculated, age standardized to the 2010 US population. In 2014, there were an estimated 1 068 412 ED visits, 978 135 hospitalizations, and 83 705 deaths with primary HF. There were 4 071 546 ED visits, 3 370 856 hospitalizations, and 230 963 deaths with comorbid HF. Between 2006 and 2014, the total unique acute event rate for primary HF declined from 536 to 449 per 100 000 (relative percent change of –16%; P for trend, <0.001) but increased for comorbid HF from 1467 to 1689 per 100 000 (relative percentage change, 15%; P for trend, <0.001). HF-related mortality decreased significantly from 2006 to 2009 but did not change meaningfully after 2009. For hospitalizations with primary HF, the estimated mean cost was $11 552 in 2014, totaling an estimated $11 billion.Conclusions:Given substantial healthcare and mortality burden of HF, rising healthcare costs, and the aging US population, continued improvements in HF prevention, management, and surveillance are important.
Correction to: Surgical Thoracic Society Risk Score and EuroSCORE-2 Appropriately Assess 30-Day Postoperative Mortality in the STICH Trial and a Contemporary Cohort of Patients With Left Ventricular Dysfunction Undergoing Surgical Revascularization Circ. Heart Fail. (IF 5.684) Pub Date : 2018-12-11
In the article by Bouabdallaoui et al, “Surgical Thoracic Society Risk Score and EuroSCORE-2 Appropriately Assess 30-Day Postoperative Mortality in the STICH Trial and a Contemporary Cohort of Patients With Left Ventricular Dysfunction Undergoing Surgical Revascularization,” which appeared in the November 2018 issue of the journal (Circ Heart Fail. 2018;11:e005531), corrections were needed. In several places in the article, including the title, “Surgical Thoracic Society” was used instead of “Society of Thoracic Surgeons.” The title should read “Society of Thoracic Surgeons Risk Score and EuroSCORE-2 Appropriately Assess 30-Day Postoperative Mortality in the STICH Trial and a Contemporary Cohort of Patients With Left Ventricular Dysfunction Undergoing Surgical Revascularization.” The publisher regrets this error. These corrections have been made to the current version of the article, which is available at https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.118.005531.
Current Use of Hearts From Hepatitis C Viremic Donors Circ. Heart Fail. (IF 5.684) Pub Date : 2018-12-04 Yasbanoo Moayedi, Chun Po S. Fan, Aliya F. Gulamhusein, Cedric Manlhiot, Heather J. Ross, Jeffrey J. Teuteberg, Kiran K. Khush
Background:Strategies to improve donor heart utilization are required in the setting of limited donor availability. One innovative strategy is to consider the use of hepatitis C viremic (HCV) nucleic acid amplification test positive donors in hepatitis C-negative recipients, given the availability of highly effective direct acting antiviral agents. We utilized United Network for Organ Sharing data to evaluate the geographic distribution, clinical characteristics, and post-transplant outcomes of HCV+ donor hearts.Methods and Results:The United Network for Organ Sharing registry was queried for all HCV+ recovered donors and those considered for heart donation classified by sex, age group, United Network for Organ Sharing region, and cause of death from January 1, 2014, to December 31, 2017. Propensity score matching (3:1) was applied to the recipients based on the index for mortality prediction after cardiac transplantation score and donor risk index. A total of 1306 HCV+ donors were recovered from 2014 to 2017 of whom 1078 (82.5%) were 18 to 49 and predominantly from the Appalachia region (United Network for Organ Sharing regions 2, 3, and 11). A total of 64 (5%) HCV+ donor hearts were transplanted in this interval. The match-adjusted risk difference in survival was estimated to be 0.87% (P=0.83) at 12 months.Conclusions:To meet the demands of heart transplantation, we must consider additional strategies to expand the donor pool. From 2014 to 2017, despite availability of highly effective direct acting antiviral therapy, only 5% of HCV+ donor hearts were accepted for transplantation. National efforts may be required to capitalize on this resource while we continue to carefully monitor the safety of this novel approach.
Expanding the Donor Pool With Use of Hepatitis C Infected Hearts Circ. Heart Fail. (IF 5.684) Pub Date : 2018-12-04 Michael M. Givertz, Ann E. Woolley, Lindsey R. Baden
See Article by Moayedi et al Listen to the mustn’ts, child. Listen to the don’ts. Listen to the shouldn’ts, the impossibles, the won’ts. Listen to the never haves, then listen close to me... Anything can happen, child. Anything can be. —Shel Silverstein, American author and songwriter (1930–1999) More than 25 years ago, experts in the field of cardiac transplantation met in Bethesda, MD, to discuss challenges to the field, including the static level of organ procurement and growing waitlist times.1 In addition to creating objective criteria for transplant listing (and delisting) and thereby limiting the waitlist size, much discussion focused on expanding the donor pool. Around the same time, increasing numbers of adults in the general population were becoming infected with hepatitis C virus (HCV) through blood transfusions and increased-risk behaviors.2 The question as to whether organs from these donors could be used safely was hotly debated in national forums, as well as at local selection committee meetings. Early surveys found that 69% to 74% of programs accepted HCV-positive donor organs but restricted these to status 1, high-risk, or HCV-positive recipients.3,4 A similar proportion of programs listed candidates that were HCV positive. Since that time, much has been learned about the outcomes of heart transplant recipients receiving organs from increased-risk donors. In early reports of heart transplantation using HCV-positive donors,5–9 many important clinical observations were made: (1) the transmission rate of HCV as documented by RNA testing was high, ≈80%, and occurred within weeks of transplant; (2) acute transaminitis followed by the development of chronic liver disease, including fibrosing cholestatic hepatitis and cirrhosis, occurred and appeared more aggressive than in the general population; (3) factors associated with the development of chronic liver disease included high donor viral load, high-dose steroids, and the use of mycophenolate mofetil; and (4) as suggested by earlier surveys, centers were targeting HCV-positive donors to patients at risk of imminent death or in the case of UCLA to alternate list recipients. In 2001, the American Heart Association released a consensus report on maximizing donor organs stating that HCV-positive donors may be appropriate in selected higher-risk recipients.10 With growing use of HCV-positive donors, investigators sought to explore longer-term clinical outcomes in transplant recipients. In a study from the Cleveland Clinic, Haji et al11 first reported the association between HCV viremia and development of cardiac allograft vasculopathy (CAV). The risk for any CAV was increased 3-fold and for advanced CAV up to 9-fold, with risk increasing further with allosensitization. In retrospect, this proinflammatory effect was not surprising given earlier data showing that renal transplant patients with chronic HCV infection were at increased risk of death from coronary artery disease12 and that HCV infection in the general population was associated with the development of carotid atherosclerosis.13 Moving beyond single-center studies, Gasink et al14 analyzed Scientific Registry of Transplant Recipients data from 1994 to 2003 on nearly 11 000 heart transplant recipients to examine the association between donor HCV positivity and survival. Recipients of HCV-positive donor hearts (≈2% of the cohort) had increased mortality at 1, 5, and 10 years and were more likely to die of liver disease (13.7% versus 0.4%) and CAV (8.8% versus 3.6%). After propensity matching, the overall hazard ratio associated with receipt of an HCV-positive donor heart was 2.1, and these findings were independent of recipient age or HCV status. These results were replicated using United Network of Organ Sharing (UNOS) data from 1991 to 2014 on >24 000 heart transplants; an analysis that also demonstrated increased 30-day mortality (6% versus 4.4%, odds ratio 1.54).15 Despite major limitations with these analyses, including lack of information on donor HCV RNA status in addition to lack of safe and effective treatment of HCV, these data as a whole led to a moratorium on the use of HCV-positive donors in all recipients. In 2014, HCV treatment was revolutionized with the development of potent direct-acting antivirals, which are well tolerated and highly effective with clinical trials showing >95% cure rate, defined as an HCV sustained virologic response at 12 weeks.16 Although direct-acting antivirals have been studied primarily in immunocompetent hosts, their direct viral effects suggest that they should be equally effective in immunocompromised patients following solid organ transplantation. Goldberg et al17 tested this hypothesis in a small series of renal transplant recipients receiving HCV-infected kidneys and demonstrated sustained virologic response at 12 weeks in all patients. Subsequently, case reports18,19 and a small single-center series20 have described early experiences with use of HCV nucleic acid testing (NAT) positive (ie, viremic) donor hearts in HCV naïve recipients. Treatment has been well tolerated with minimal side effects and no significant drug-drug interactions. Notably, these transplants were not performed as part of a clinical trial, but rather as compassionate use in urgent, high-risk candidates using multistep consent of patients and families. Mean waiting time for transplant decreased from 256 days to 11 days after consent. Given these data and the growing number of increased-risk donors in the face of an opioid epidemic,21 we are left to consider the future, unfulfilled promise of transplantation. Are most/all transplant centers ready to increase access to organs from donors infected with HCV? Can this be done safely? If so, which donors should be accepted and which recipients transplanted? What is the potential impact on transplant volume and outcomes? In this issue of Circulation: Heart Failure, Moayedi et al22 sought to answer some of these questions by querying the UNOS registry from 2014 to 2017. While the number of HCV viremic (NAT positive) donors increased markedly over time from 12 in 2014 to 503 in 2017 for a total of 1306, only 68 hearts (5.2%) were recovered for transplant. Compared with accepted organs, discarded hearts had lower ejection fraction, more hypertension and greater prevalence of other cardiac abnormalities. Remarkably, the reason for discard was unknown in 40%. Highlighting the variability in clinical practice, 48% of all HCV positive recovered organs came from UNOS region 11 (KY, NC, SC, TN, VA) with recipients of HCV-infected organs being older, heavier, and having longer ischemic times. In cohorts matched on donor and recipient risk factors, investigators could find no difference in 1-year survival. Recognizing the limitations of UNOS data, they still conclude by calling for action to expand the donor pool to meet the demands of heart transplantation. While the patient-centric response to this clarion call would be to move forward expeditiously with heart transplantation from HCV-positive donors, several important issues and unanswered questions need to be addressed (Table). First, the tolerability, safety, and efficacy of direct-acting antivirals in this transplant population need to be systematically studied. With time, the development of drug resistance may occur. Consideration must also be given to renal dysfunction, common in heart transplant recipients, as this complicates HCV treatment and the potential for drug-drug interactions. Optimal timing and duration of HCV therapy also require study. To this end, we recently reported preliminary data on successful direct-acting antiviral preemptive treatment with a shortened, 4-week course in recipients of HCV NAT positive thoracic organs, in an effort to block establishment of viral infection in the recipients.23 Finally, the cost-effectiveness of this approach will need to be demonstrated. Whether payers will cover this additional transplant cost remains unknown, although Centers for Medicare & Medicaid Services coverage of chronic HCV treatment offers hope. Table. Issues and Unanswered Questions About Use of HCV-Infected Donor Hearts CAV indicates cardiac allograft vasculopathy; CPR, cardiopulmonary resuscitation; DAA, direct-acting antiviral; HBV, hepatitis B virus; HCV, hepatitis C virus; IRB, institutional review board; and NAT, nucleic acid testing. Looking beyond HCV treatment, clinical outcomes of transplant recipients will need to be followed prospectively with particular attention to the incidence of cardiac allograft rejection (early), CAV (later), and malignancy. Interestingly in the small series reported by the Vanderbilt group, 5 of 9 HCV-infected patients had grade 2R rejection during short-term follow-up.20 Whether HCV viremia alters the immune system or the effectiveness of immunosuppressant drugs during the early post-transplant period requires further study. These challenges need to be balanced by the mortality of remaining on the waitlist. The growing population of HCV-positive donors has already begun to change the landscape of solid organ transplantation in the United States.21 From a heart allocation standpoint, the impact of accepting HCV-positive donors would shorten waiting times by expanding the donor pool. Notably, these donors may have unknown downtimes and concomitant cocaine use that could impact outcomes, as well as other potential latent infections, although registry data suggest otherwise.24 For now, if clinicians remain uncertain about using HCV viremic donor hearts, the use of organs from HCV antibody positive/NAT negative donors should be considered. While there have been cases of HCV transmission from NAT negative organ donors, the risk seems low and similar to that of HCV transmission from HCV negative increased-risk donors.25 Patel et al26 recently reported outcomes on 14 patients who underwent heart transplantation with NAT negative donors who all remained HCV RNA negative at a median follow-up of 256 days. Using UNOS data from 2016, these authors also highlighted missed opportunities for United States transplants; among 220 HCV antibody positive/NAT negative donors, only 7 hearts (3.2%) were accepted. They estimate conservatively that acceptance of such organs could increase the number of heart transplants by close to 100 annually. Finally, a retrospective analysis of registry data suggests that acceptance of an increased-risk donor offer is associated with significant and clinically meaningful survival benefit, representing an opportunity to decrease waitlist mortality.27 It is time to stop listening to the shouldn’ts and the don’ts, and fulfill the true promise of organ transplantation. We owe it to our patients. None. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Correction to: Prognostic Value of Albuminuria and Influence of Spironolactone in Heart Failure With Preserved Ejection Fraction: The TOPCAT Trial Circ. Heart Fail. (IF 5.684) Pub Date : 2018-12-04
In the article by Selvaraj et al, “Prognostic Value of Albuminuria and Influence of Spironolactone in Heart Failure With Preserved Ejection Fraction: The TOPCAT Trial,” which appeared in the November 2018 issue of the journal (Circ Heart Fail. 2018;11:e005288), a correction was needed. In Table 3, in the row containing data for eGFR (Absent), the confidence interval is incorrect: “0.72 (0.52, 1.54), P=0.05” should read “0.72 (0.52, 1.00), P=0.05”. The authors regret this error. These corrections have been made to the current version of the article, which is available at https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.118.005288.
Physical Function, Frailty, Cognition, Depression, and Quality of Life in Hospitalized Adults ≥60 Years With Acute Decompensated Heart Failure With Preserved Versus Reduced Ejection Fraction Circ. Heart Fail. (IF 5.684) Pub Date : 2018-11-16 Haider J. Warraich, Dalane W. Kitzman, David J. Whellan, Pamela W. Duncan, Robert J. Mentz, Amy M. Pastva, M. Benjamin Nelson, Bharathi Upadhya, Gordon R. Reeves
Background:Older hospitalized acute decompensated heart failure (HF) patients have persistently poor outcomes and delayed recovery regardless of ejection fraction (EF). We hypothesized that impairments in physical function, frailty, cognition, mood, and quality of life (QoL) potentially contributing to poor clinical outcomes would be similarly severe in acute decompensated HF patients ≥60 years of age with preserved versus reduced EF (HFpEF and HFrEF).Methods and Results:In 202 consecutive older (≥60 years) hospitalized acute decompensated HF patients in a multicenter trial, we prospectively performed at baseline: short physical performance battery, 6-minute walk distance, frailty assessment, Geriatric Depression Scale, Montreal Cognitive Assessment, and QoL assessments. Older acute decompensated HFpEF (EF ≥45%, n=96) and HFrEF (EF <45%, n=106) patients had similar impairments in all physical function measures (short physical performance battery [5.9±0.3 versus 6.2±0.2]; 6-minute walk distance [184±10 versus 186±9 m]; and gait speed [0.60±0.02 versus 0.61±0.02 m/s]) and rates of frailty (55% versus 52%; P=0.70) and cognitive impairment (77% versus 81%; P=0.56) when adjusted for differences in sex, body mass index, and comorbidities. However, depression and QoL were consistently worse in HFpEF versus HFrEF. Depression was usually unrecognized clinically with 38% having Geriatric Depression Scale ≥5 and no documented history of depression.Conclusions:Patients ≥60 years hospitalized with acute decompensated HF patients have broad, marked impairments in physical function and high rates of frailty and impaired cognition: these impairments are similar in HFpEF versus HFrEF. Further, depression was common and QoL was reduced, and both were worse in HFpEF than HFrEF. Depression was usually unrecognized clinically. These findings suggest opportunities for novel interventions to improve these important patient-centered outcomes.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT02196038.
Lessons From the First 202 REHAB-HF Participants Circ. Heart Fail. (IF 5.684) Pub Date : 2018-11-16 Kelsey M. Flint, Daniel E. Forman
See Article by Warraich et al Over 70% of Medicare beneficiaries who are hospitalized for heart failure (HF) die or are rehospitalized by 1 year after discharge.1 Most suffer progressive functional decline, dependency, and poor quality of life over time. Although such grim outcomes are commonly attributed to cardiac disease, noncardiovascular complexities are also detrimental.2 Older adults hospitalized for HF are particularly vulnerable to the adverse effects from muscle atrophy,3 disability, confusion, comorbidities, and other intricacies which undermine potential for recovery and survival. Whereas physical activity is recommended as part of the guidelines for recovery in patients hospitalized for HF,4 the majority of older HF patients remain sedentary, often challenged by their noncardiovascular conditions. REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) is a ground-breaking HF exercise trial5 that is designed to fill the gaps left by the HF-ACTION trial (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training).6 The primary focus of the REHAB-HF trial is the utility of exercise therapy after acute hospitalization among older adults. In their report of a subset of REHAB-HF enrollees, Warraich et al7 extend the value of REHAB-HF by delineating important characteristics of this population that constitute critical impediments to exercise interventions. HF-ACTION is widely promulgated as an endorsement of exercise therapy for HF, yet it is commonly criticized for inherent limitations.8 End points included reduced all-cause mortality and hospitalization and improved quality of life with aerobic exercise in a diverse population already receiving optimal medical therapy.6,9,10 Still, statistically significant benefits of the exercise intervention for mortality and rehospitalization were only detected after adjustment for baseline characteristics predictive of these clinical outcomes (cardiopulmonary exercise test duration, left ventricular ejection fraction, depression, atrial fibrillation).8 Such statistical tweaking is regarded by many as a limitation, but more fundamentally, HF-ACTION enrolled only patients with EF ≤35% and excluded patients hospitalized in the past 6 weeks. Such restrictions overlook the potential utility of exercise in the many HF patients with preserved EF (which is particularly prevalent in older adults), and during the critical posthospitalization period when functional decline and rehospitalization are most likely to occur.11 An even more prominent criticism of HF-ACTION was the remarkably poor adherence it achieved with its exercise intervention despite considerable prompting and support. Patients attended on average only 1.8 of the prescribed 3 sessions/week. With the benefit of hindsight, it is notable that HF-ACTION failed to consider common noncardiovascular impediments to adherence such as multimorbidity, frailty, and cognitive impairment. Furthermore, the absence of strength, balance, or mobility training in HF-ACTION may have further exacerbated poor adherence, by omitting critical aspects of conditioning that address the idiosyncratic needs in this population (ie, they were too weak for the purely aerobic HF-ACTION intervention); this ultimately may have reduced the potential to successfully execute the protocol. The REHAB-HF trial is addressing these shortcomings with a physical therapy, site-based intervention designed to improve the strength, balance, endurance, and mobility of older adults hospitalized for HF, regardless of ejection fraction.5 The REHAB-HF trial is enrolling patients ≥60 years old who are hospitalized for HF and are expected to be discharged home. The intervention begins during hospitalization and continues after discharge 3 days per week for 12 weeks. The baseline characteristics of the first 202 (out of 360) patients enrolled in the REHAB-HF trial are reported in this issue of Circulation: Heart Failure. The report highlights the large number of comorbid illnesses and high prevalence of depression, cognitive impairment, debilitating HF symptoms, and physical frailty. Although the REHAB-HF intervention focuses primarily on exercise therapy to improve physical deficits, this report expands the value of the trial by recognizing the diverse dimensions that impact exercise feasibility and sustainability.12 Such perspectives can not only be used to shape exercise prescription, but to ultimately inform exercise and wellness strategies that can be further studied as part of multifaceted cardiac rehabilitation programs. Comorbid conditions are associated with reduced exercise adherence among patients with HF.12 REHAB-HF participants have an average of ≥5 comorbid illnesses. Comorbid illnesses that limit mobility—such as arthritis or neurological conditions—may prevent patients from participating in exercise or rehabilitation. Furthermore, comorbid illnesses compete for patients’ time, attention, financial, and social resources. For example, patients with diabetes mellitus must check their blood sugar, adhere to a low carbohydrate diet, go to appointments for diabetes mellitus control, and (in some cases) take medications to control blood sugar. All of these activities may cause patients to place less absolute importance on HF and, therefore, detract from participation in an exercise training program. Depression is a key comorbid illness in HF. Depression is associated with reduced adherence to exercise training,12 although exercise is one of the few successful interventions among patients with depression and HF.2,13 In REHAB-HF, depression is particularly prominent in patients with HF with preserved ejection fraction and is clinically under-recognized (ie, depression was not mentioned in the patient’s chart, but the patient screened positive on the Geriatric Depression Scale, which was administered as part of the study). Depression may be clinically under-recognized in HF because it is difficult to treat. Antidepressants are often less effective for depression in HF patients, and cognitive behavioral therapy, one of the few efficacious interventions in this population,14 is not routinely available in most cardiology clinics. These challenges may lead to untreated depression reducing adherence in the REHAB-HF intervention arm. Cognitive impairment was present in a remarkable 78% of REHAB-HF participants. Cognitive impairment represents a challenge to HF self-care2; however, mild cognitive impairment (ie, objective memory loss but able to function in day-to-day life) in and of itself is not a barrier to exercise. Some data suggest that exercise improves cognitive performance.15 However, patients with cognitive impairment will require greater caregiver support for transportation and remembering to perform home exercises. HF-specific health status, as measured by the Kansas City Cardiomyopathy Questionnaire, is very poor among REHAB-HF participants. Poor Kansas City Cardiomyopathy Questionnaire scores reflect the highly symptomatic nature of these patients. Unfortunately, bothersome HF symptoms are associated with reduced adherence to exercise training.12 Therefore, ensuring excellent medical management of HF to minimize these symptoms may be important to exercise adherence. Physical frailty, as measured by the Fried criteria,16 was also highly prevalent among REHAB-HF participants (53%). Physical frailty is considered present if ≥3 Fried criteria are met: unintentional weight loss, exhaustion, slow gait speed, weak handgrip strength, or low physical activity.16 The effect of physical frailty on exercise adherence is not known in the HF population; however, the slow gait speed, weak handgrip strength, and low physical activity components of the Fried criteria would likely respond to exercise and to the REHAB-HF intervention in particular. The exhaustion and unintentional weight loss components of the Fried criteria may hinder exercise adherence. Final results of the REHAB-HF trial may shed more light on the interaction between physical frailty and adherence to exercise training. The REHAB-HF investigators are commended for designing an exercise intervention spanning the intersecting fields of geriatric cardiology, HF hospitalization, and exercise science. The high burden of comorbid illness and high prevalence of depression, cognitive impairment, debilitating HF symptoms, and physical frailty have wide-reaching implications, both for exercise therapy but also for geriatric HF care in general. Although we wait for the REHAB-HF trial to finish enrollment and follow-up, it seems prudent for clinicians caring for older adults with HF to promote physical activity and to consider strategies to overcome common noncardiovascular impediments in this vulnerable patient population. Whereas REHAB-HF is a clinical trial designed to specifically study the benefits of exercise training as a rigorous therapeutic intervention, multifaceted cardiac rehabilitation programs tailored to this population are still needed. Cardiac rehabilitation has complementary potential to emphasize critical aspects of adherence that are especially challenging amid geriatric impediments. A recent position paper defined 4 domains of geriatric HF care; physical function was only 1 of them.2 For patients to succeed in a rigorous exercise rehabilitation program like REHAB-HF, clinicians will need to address barriers in the other 3 domains (Medical, Mind and Emotion, and Social Environment). For example, careful, patient-centered deprescribing may decrease bothersome symptoms from polypharmacy that may deplete energy, blunt cognition, and exacerbate other impediments to daily activity. Alerting caregivers to a patient’s cognitive impairment, and thus need for greater supervision of day-to-day self-care activities, may help patients remain out of the hospital and provide them with the extra support needed to participate regularly in an exercise or rehabilitation program. Identification of financial or transportation problems may prompt clinicians to harness community resources to help patients and potentially suggest home- over site-based programs. The baseline characteristics of the first 202 REHAB-HF participants describe a vulnerable population with multiple comorbid illnesses and highly prevalent depression, cognitive impairment, bothersome HF symptoms, and physical frailty. These initial data not only describe the challenges faced by the REHAB-HF investigators in ensuring adherence to the REHAB-HF intervention, but they also represent a call to action for HF clinicians and investigators alike. Although we await the final trial results of REHAB-HF, we should focus on leveraging the detailed characterization of the REHAB-HF participants to improve the clinical care of, and development of novel interventions for, older adults hospitalized for HF. None. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Association Between Regional Adipose Tissue Distribution and Risk of Heart Failure Among Blacks Circ. Heart Fail. (IF 5.684) Pub Date : 2018-11-10 Ambarish Pandey, Nitin Kondamudi, Kershaw V. Patel, Colby Ayers, Shawn Simek, Michael E. Hall, Solomon K. Musani, Chad Blackshear, Robert J. Mentz, Hassan Khan, James G. Terry, Adolfo Correa, Javed Butler, Ian J. Neeland, Jarett D. Berry
Background:Obesity is highly prevalent among blacks and is associated with a greater risk of heart failure (HF). However, the contribution of regional adiposity depots such as visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue toward risk of HF in blacks is unknown.Methods and Results:We included 2602 participants (mean age: 59 years, 35% men) from the Jackson Heart Study without prevalent HF who underwent computed tomography quantification of VAT and subcutaneous adipose tissue during the second visit (2005–2009). The associations between different adiposity measures and HF were evaluated using adjusted Cox models. There were 122 incident HF events over a median follow-up of 7.1 years. Higher amounts of VAT were associated with greater risk of HF in age- and sex-adjusted analyses (hazard ratio [95% CI] per 1-SD higher VAT: 1.29 [1.09–1.52]). This association was attenuated and not significant after additional adjustment for traditional HF risk factors and body mass index. Overall obesity, represented by body mass index, was associated with higher risk of HF independent of risk factors and VAT (hazard ratio [95% CI] per 1-kg/m2 higher body mass index: 1.06 [1.02–1.11]). Subcutaneous adipose tissue was not associated with risk of HF in adjusted analyses.Conclusions:In a community-dwelling black population, higher amounts of overall and visceral adiposity are associated with higher risk of HF. The association between VAT and HF risk in blacks may reflect differences in traditional HF risk factor burden. Future studies are needed to confirm this observation and clarify the independent role of different measures of adiposity on HF outcomes.
Surgical Thoracic Society Risk Score and EuroSCORE-2 Appropriately Assess 30-Day Postoperative Mortality in the STICH Trial and a Contemporary Cohort of Patients With Left Ventricular Dysfunction Undergoing Surgical Revascularization Circ. Heart Fail. (IF 5.684) Pub Date : 2018-11-16 Nadia Bouabdallaoui, Susanna R. Stevens, Torsten Doenst, Mark C. Petrie, Nawwar Al-Attar, Imtiaz S. Ali, Andrew P. Ambrosy, Anna K. Barton, Raymond Cartier, Alexander Cherniavsky, Pierre Demondion, Patrice Desvigne-Nickens, Robert R. Favaloro, Sinisa Gradinac, Petra Heinisch, Anil Jain, Marek Jasinski, Jerome Jouan, Renato A.K. Kalil, Lorenzo Menicanti, Robert E. Michler, Vivek Rao, Peter K. Smith, Marian Zembala, Eric J. Velazquez, Hussein R. Al-Khalidi, Jean L. Rouleau, for the STICH Trial Investigators
Background:The STICH trial (Surgical Treatment for Ischemic Heart Failure) demonstrated a survival benefit of coronary artery bypass grafting in patients with ischemic cardiomyopathy and left ventricular dysfunction. The Surgical Thoracic Society (STS) risk score and the EuroSCORE-2 (ES2) are used for risk assessment in cardiac surgery, with little information available about their accuracy in patients with left ventricular dysfunction. We assessed the ability of the STS score and ES2 to evaluate 30-day postoperative mortality risk in STICH and a contemporary cohort (CC) of patients with a left ventricle ejection fraction ≤35% undergoing coronary artery bypass grafting outside of a trial setting.Methods and Results:The STS and ES2 scores were calculated for 814 STICH patients and 1246 consecutive patients in a CC. There were marked variations in 30-day postoperative mortality risk from 1 patient to another. The STS scores consistently calculated lower risk scores than ES2 (1.5 versus 2.9 for the CC and 0.9 versus 2.4 for the STICH cohort), and underestimated postoperative mortality risk. The STS and ES2 scores had moderately good C statistics: CC (0.727, 95% CI: 0.650–0.803 for STS, and 0.707, 95% CI: 0.620–0.795 for ES2); STICH (0.744, 95% CI: 0.677–0.812, for STS and 0.736, 95% CI: 0.665–0.808 for ES2). Despite the CC patients having higher STS and ES2 scores than STICH patients, mortality (3.5%) was lower than that of STICH (4.8%), suggesting a possible decrease in postoperative mortality over the past decade.Conclusions:The 30-day postoperative mortality risk of coronary artery bypass grafting in patients with left ventricular dysfunction varies markedly. Both the STS and ES2 score are effective in evaluating risk, although the STS score tend to underestimate risk.CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00023595.
Novel Model to Predict Gastrointestinal Bleeding During Left Ventricular Assist Device Support Circ. Heart Fail. (IF 5.684) Pub Date : 2018-11-16 Michael Yaoyao Yin, Shane Ruckel, Abdallah G. Kfoury, Stephen H. McKellar, Iosef Taleb, Edward M. Gilbert, Jose Nativi-Nicolau, Josef Stehlik, Bruce B. Reid, Antigone Koliopoulou, Gregory J. Stoddard, James C. Fang, Stavros G. Drakos, Craig H. Selzman, Omar Wever-Pinzon
Background:Gastrointestinal bleeding (GIB) is a leading cause of morbidity during continuous-flow left ventricular assist device (CF-LVAD) support. GIB risk assessment could have important implications for candidate selection, informed consent, and postimplant therapeutic strategies. The aim of the study is to derive and validate a predictive model of GIB in CF-LVAD patients.Methods and Results:CF-LVAD recipients at the Utah Transplantation Affiliated Hospitals program between 2004 and 2017 were included. GIB associated with a decrease in hemoglobin ≥2 g/dL was the primary end point. A weighted score comprising preimplant variables independently associated with GIB was derived and internally validated. A total of 351 patients (median age, 59 years; 82% male) were included. After a median of 196 days, GIB occurred in 120 (34%) patients. Independent predictors of GIB included age >54 years, history of previous bleeding, coronary artery disease, chronic kidney disease, severe right ventricular dysfunction, mean pulmonary artery pressure <18 mm Hg, and fasting glucose >107 mg/dL. A weighted score termed Utah bleeding risk score, effectively stratified patients based on their probability of GIB: low (0–1 points) 4.8%, intermediate (2–4) 39.8%, and high risk (5–9) 83.8%. Discrimination was good in the development sample (c-index: 0.83) and after internal bootstrap validation (c-index: 0.74).Conclusions:The novel Utah bleeding risk score is a simple tool that can provide personalized GIB risk estimates in CF-LVAD patients. This scoring system may assist clinicians and investigators in designing tailored risk-based strategies aimed at reducing the burden posed by GIB in the individual CF-LVAD patient and healthcare systems.
Cardiac Troponin I and Risk of Cardiac Events in Patients With Heart Failure and Preserved Ejection Fraction Circ. Heart Fail. (IF 5.684) Pub Date : 2018-11-16 Peder L. Myhre, Eileen O’Meara, Brian L. Claggett, Simon de Denus, Petr Jarolim, Inder S. Anand, Iris E. Beldhuis, Jerome L. Fleg, Eldrin Lewis, Bertram Pitt, Jean L. Rouleau, Scott D. Solomon, Marc A. Pfeffer, Akshay S. Desai
Background:Levels of cTn (cardiac troponin) are frequently elevated in patients with heart failure (HF) and reduced ejection fraction (EF) and correlate with the risk for mortality. However, factors associated with high cTn concentrations and the association with cardiovascular events in patients with HF and preserved EF are unclear.Methods and Results:Of 1767 subjects with symptomatic HF with preserved EF from the Americas part of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial), 236 underwent baseline measurements of high-sensitivity (hs) cTnI using the Abbott Architect STAT assay. Baseline factors correlated with hs-cTnI levels were assessed in stepwise linear regression models and the association between hs-cTnI and adjudicated study outcomes was examined in Cox models. The median hs-cTnI concentration at baseline was 6.3 ng/L (interquartile range, 3.4–12.9 ng/L) with levels detectable in 99.2% of patients. Higher hs-cTnI concentrations were associated with male sex, black race, lower estimated glomerular filtration rate and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. After multivariable adjustment, higher concentrations of hs-cTnI were associated with greater risk for the composite of cardiovascular death or HF hospitalization (69 events during mean follow-up 2.6±1.5 years): hazard ratio 1.42 (95% CI, 1.20–1.69), P<0.001 per doubling of hs-cTnI. Compared with those in the lowest quartile of hs-cTnI, patients in the highest quartile demonstrated a nearly 5-fold higher risk of cardiovascular death and HF hospitalization (hazard ratio 4.85 [1.99–11.83], P=0.001). There was no interaction between hs-cTnI and spironolactone treatment with regard to the primary composite end point (interaction P=0.94).Conclusions:In ambulatory patients with HF with preserved EF, levels of hs-cTnI are higher in male patients with black race, lower estimated glomerular filtration rate, and higher NT-proBNP. As in those with HF and reduced EF, higher hs-cTnI levels are independently associated with risk for cardiovascular death and HF hospitalization.CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00094302.
Prognostic Value of Albuminuria and Influence of Spironolactone in Heart Failure With Preserved Ejection Fraction Circ. Heart Fail. (IF 5.684) Pub Date : 2018-11-11 Senthil Selvaraj, Brian Claggett, Sanjiv J. Shah, Inder Anand, Jean L. Rouleau, Eileen O’Meara, Akshay S. Desai, Eldrin F. Lewis, Bertram Pitt, Nancy K. Sweitzer, James C. Fang, Marc A. Pfeffer, Scott D. Solomon
Background:Albuminuria predicts adverse events in heart failure with preserved ejection fraction. No therapies to date have reduced albuminuria in heart failure with preserved ejection fraction.Methods and Results:We analyzed 1175 participants from the Americas from the TOPCAT study (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) with urinary albumin:creatinine ratio (UACR) measurements at baseline. We examined the association of UACR with the primary outcome (cardiovascular death, aborted cardiac arrest, or heart failure hospitalization) and its individual components, all-cause mortality, and several safety end points using multivariable-adjusted Cox regression. We evaluated whether spironolactone reduced albuminuria at the 1-year visit in a subpopulation (N=744). Thirty-five percent had microalbuminuria, 13% had macroalbuminuria, and 80% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Increasing UACR was associated with male sex, higher systolic blood pressure, diabetes mellitus, and renal dysfunction. Macroalbuminuria (hazard ratio, 1.67; 95% CI, 1.22–2.28) and microalbuminuria (hazard ratio, 1.47; 95% CI, 1.15–1.86) were independently associated with the TOPCAT primary end point (compared with normoalbuminuria). Adjusting for placebo response, spironolactone reduced albuminuria by 39% in all participants at the 1-year visit compared with baseline (geometric mean ratio, 0.61; 95% CI, 0.49–0.77) and by 76% (geometric mean ratio, 0.24; 95% CI, 0.10–0.56) among those with macroalbuminuria. Reducing UACR by 50% was independently associated with a reduction in heart failure hospitalization (hazard ratio, 0.90; P=0.017) and all-cause mortality (hazard ratio, 0.91; P=0.019). The change in UACR was significantly associated with change in systolic blood pressure (P=0.001).Conclusions:In TOPCAT, albuminuria was independently associated with worse cardiovascular outcomes. Spironolactone significantly reduced albuminuria compared with placebo. Reducing albuminuria was independently associated with improved outcomes.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00094302.
Correction to: Omega-3 Therapy Is Associated With Reduced Gastrointestinal Bleeding in Patients With Continuous-Flow Left Ventricular Assist Device Circ. Heart Fail. (IF 5.684) Pub Date : 2018-11-08
In the article by Imamura et al, “Omega-3 Therapy Is Associated With Reduced Gastrointestinal Bleeding in Patients With Continuous-Flow Left Ventricular Assist Device,” which appeared in the October 2018 issue of the journal (Circ Heart Fail.2018;11:e005082), a correction was needed. In the Methods and Results section of the abstract, “4 mg/d of omega-3 therapy” should read “4 g/d of omega-3 therapy”. The authors regret this error. This correction has been made to the current version of the article, which is available at https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.118.005082
Clinical Phenotype and Genotype Associations With Improvement in Left Ventricular Function in Dilated Cardiomyopathy Circ. Heart Fail. (IF 5.684) Pub Date : 2018-11-07 Job A.J. Verdonschot, Mark R. Hazebroek, Ping Wang, Sandra Sanders-van Wijk, Jort J. Merken, Yvonne A. Adriaansen, Arthur van den Wijngaard, Ingrid P.C. Krapels, Hans-Peter Brunner-La Rocca, Han G. Brunner, Stephane R.B. Heymans
Background:Improvement of left ventricular function (also called left ventricular reverse remodeling [LVRR]) is an important treatment goal in patients with dilated cardiomyopathy (DCM) and hypokinetic non-DCM (HNDC) and is prognostically favorable. We tested whether genetic DCM mutations impact LVRR independent from clinical parameters.Methods and Results:Patients with DCM and hypokinetic non-DCM (n=346; mean left ventricular ejection fraction, 30%) underwent genotyping for 47 DCM-associated genes in addition to extensive phenotyping. LVRR was defined as improvement of left ventricular ejection fraction >50% or ≥10% absolute increase, with cardiac dimensions (left ventricular end diastolic diameter) ≤33 mm/m2 or ≥10% relative decrease. LVRR occurred in 180 (52%) patients after a median follow-up of 12-month optimal medical treatment. Low baseline left ventricular ejection fraction, a hypokinetic non-DCM phenotype, high systolic blood pressure, absence of a family history of DCM, female sex, absence of atrioventricular block, and treatment with β-blockers were all independent positive clinical predictors of LVRR. With the exception of TTN, genetic mutations were strongly associated with a lower rate of LVRR (odds ratio, 0.19 [0.09–0.42]; P<0.0001). TTN and LMNA were independently associated with LVRR (odds ratio, 2.49 [1.09–6.20]; P=0.038 and 0.11 [0.01–0.99]; P=0.049, respectively). Adding mutation status significantly improved discrimination (C statistics) and reclassification (integrated discrimination improvement/net reclassification index) of the clinical model predicting LVRR. Furthermore, the risk for heart failure hospitalization and cardiovascular death is lower in the LVRR patients on the long term (hazard ratio, 0.47 [0.24–0.91]; P=0.009 and 0.18 [0.04–0.82]; P=0.007, respectively), and LVRR is an independent predictor for event-free survival.Conclusions:The genetic substrate is associated with the clinical course and long-term prognosis of patients with DCM/hypokinetic non-DCM.
Linking Clinical Parameters and Genotype in Dilated Cardiomyopathy Circ. Heart Fail. (IF 5.684) Pub Date : 2018-11-07 Jared M. Churko
See Article by Verdonschot et al Establishing an accurate diagnosis, assessing prognosis, and managing treatment are fundamental to patient care. Clinical parameters, such as left ventricular (LV) ejection fraction and LV end-diastolic diameter, are critical to initially establish a diagnosis of dilated cardiomyopathy (DCM) and hypokinetic non-DCM. These clinical parameters are also used to monitor disease progression and treatment response. However, use of sequencing/genotyping technologies within the clinic is becoming more common in the era of personalized medicine. Efforts to sequence patients and classify the impact of mutations in cardiomyopathy-associated genes are helping to identify key diagnostic subgroups. In this issue of Circulation: Heart Failure, Verdonschot et al1 studied the association between DCM and hypokinetic non-DCM patients’ genotype with improvement in reverse remodeling of the LV in response to medical therapy. The study defined reverse remodeling of the LV as an increase in LV ejection fraction and a decrease in LV end-diastolic diameter for ≈1 year of follow-up. Patients were genotyped using a custom panel of 47 genes associated with cardiomyopathy. Over 52% of the 346 patients studied had reverse remodeling of the LV after 12 months of treatment. Pathogenic gene mutations were found in 22% of patients (n=78). The most prevalent genes involved in these patients were titin (TTN, 9.5%) followed by lamin A/C (LMNA; 2.6%). The findings of Verdonschot et al1 confirm and enhance the published literature,2–6 indicating that disease caused by mutations in LMNA are associated with a particularly severe form of DCM, with high arrhythmic burden, progression to end-stage heart failure, and here, lower likelihood of LV recovery. In contrast, disease caused by truncation mutations in titin (TTNtv) is associated with more mild disease that seems more responsive to unloading therapy,7–9 and thus more likely to favorably remodel and recover with standard medical therapy for heart failure. Furthermore, because of the large size of titin and the presence of multiple isoforms, the location of variants within the gene also plays a role in determining DCM disease burden. TTNtv localized towards the N terminus, affecting certain TTN isoforms (N2B and N2BA), and within exons commonly removed during splicing have been associated with a more mild or no pathology,10 whereas variants located in commonly expressed exons (and thus, translated into the final protein product) are predicted to be pathogenic.9 These findings underscore that genotype can influence the clinical decision-making process and that differentiating clinically relevant subgroups of DCM, guided by genetic cause, may play an important role in diagnosis, prognosis, and management. From an academic perspective, gaining greater understanding in gene- and variant-specific mechanisms will undoubtedly lead to advances in our understanding of how protein-protein domain perturbations,11 changes in mRNA splicing,12 and protein functional changes13 contribute to in disease pathogenesis. This information will be critical to identify molecular mechanisms leading to DCM and to design targeted drug therapies to treat distinct genetic subclasses of DCM pathology. The genetic basis of DCM/hypokinetic non-DCM also has important clinical implications. Receipt of genetic results is a reminder to think about the patient’s family in addition to the individual presenting for care in clinic.14 If there is no clear explanation for why cardiomyopathy developed, a detailed family history should be obtained, and first-degree relatives should be screened to evaluate for familial disease.15 Although the genetic cause of DCM is diverse and incompletely resolved and the yield of clinical genetic testing is currently relatively modest (a genetic cause can be detected ≈20% of the time),15,16 identifying a pathogenic mutation in a patient provides unique and valuable information to guide management of the patient and their family. At-risk relatives can be definitively identified and followed appropriately. Relatives not at risk can be reassured. Affected individuals can be given more precise prognostic forecasts, and more aggressive therapy can be steered towards those predicted to have more aggressive disease, based on genetic substrate. The work of Verdonschot et al1 highlight that adding genetic information, in addition to clinical parameters, may better predict reverse remodeling of the LV than clinical parameters alone. Linking the degree of disease burden to variants (and properly defining variants of unknown significance) is still necessary. Efforts in linking disease burden to variants will ultimately lead to improvements in patient care and in our understanding of cardiomyopathies. None. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Use of Oral Anticoagulation in Eligible Patients Discharged With Heart Failure and Atrial Fibrillation Circ. Heart Fail. (IF 5.684) Pub Date : 2018-10-12 Nancy Luo, Haolin Xu, Hani Jneid, Gregg C. Fonarow, Renato D. Lopes, Jonathan P. Piccini, Anne B. Curtis, Andrea M. Russo, William R. Lewis, Roland A. Matsouaka, Christopher B. Granger, Robert J. Mentz, Sana M. Al-Khatib
Background:Stroke prophylaxis in patients with atrial fibrillation (AF) and heart failure (HF) in the era of direct oral anticoagulants is not well characterized. Using data from American Heart Association Get With The Guidelines–AFIB, we sought to evaluate oral anticoagulation (OAC) use at discharge among AF patients with concomitant HF.Methods and Results:AF patients with a diagnosis of HF hospitalized from January 2013 to March 2017 were included. We compared patient characteristics and use of OAC at discharge among patients with reduced (redundant ejection fraction [EF], EF≤40%), borderline (40%
The American Heart Association Heart Failure Summit, Bethesda, April 12, 2017 Circ. Heart Fail. (IF 5.684) Pub Date : 2018-10-12 Pamela N. Peterson, Larry A. Allen, Paul A. Heidenreich, Nancy M. Albert, Ileana L. Piña, on behalf of the American Heart Association
The American Heart Association convened a meeting to summarize the changing landscape of heart failure (HF), anticipate upcoming challenges and opportunities to achieve coordinated identification and treatment, and to recommend areas in need of focused efforts. The conference involved representatives from clinical care organizations, governmental agencies, researchers, patient advocacy groups, and public and private healthcare partners, demonstrating the breadth of stakeholders interested in improving care and outcomes for patients with HF. The main purposes of this meeting were to foster dialog and brainstorm actions to close gaps in identifying people with or at risk for HF and reduce HF-related morbidity, mortality, and hospitalizations. This report highlights the key topics covered during the meeting, including (1) identification of patients with or at risk for HF, (2) tracking patients once diagnosed, (3) application of population health approaches to HF, (4) improved strategies for reducing HF hospitalization (not just rehospitalization), and (5) promoting HF self-management.
IGFBP7 (Insulin-Like Growth Factor–Binding Protein-7) and Neprilysin Inhibition in Patients With Heart Failure Circ. Heart Fail. (IF 5.684) Pub Date : 2018-10-11 James L. Januzzi, Jr, Milton Packer, Brian Claggett, Jiankang Liu, Amil M. Shah, Michael R. Zile, Burkert Pieske, Adriaan Voors, Parul U. Gandhi, Margaret F. Prescott, Victor Shi, Martin P. Lefkowitz, John J.V. McMurray, Scott D. Solomon
Background:Increased activity of IGFBP7 (insulin-like growth factor–binding protein-7) is associated with cellular senescence, tissue aging, and obesity. IGFBP7 may be related to heart failure with preserved ejection fraction, a disease of elderly obese people.Methods and Results:In a subset of patients with heart failure with preserved ejection fraction (N=228) randomized to receive sacubitril/valsartan versus valsartan, IGFBP7 concentrations were measured at baseline, 12 weeks, and 36 weeks. Patient characteristics and echocardiographic measures including left atrial (LA) size and volume, ratio of early mitral inflow velocity/annular diastolic velocity, and ratio of early diastole/peak late diastolic velocity were assessed as a function of IGFBP7 concentration. Effect of sacubitril/valsartan on IGFBP7 concentrations was analyzed. With increasing baseline IGFBP7 quartiles, LA size and LA volume index (LAVi) were higher (both P<0.001); modest association between IGFBP7 and higher early mitral inflow velocity/annular diastolic velocity (P=0.03) and early diastole/peak late diastolic velocity ratio (P=0.04) was also seen. IGFBP7 concentrations were higher in those with LAVi ≥34 mL/m2 compared with lower LAVi at all time points (all P<0.01). IGFBP7 independently predicted LAVi at baseline even in the presence of NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentrations; highest LAVi was seen in those with elevation in both biomarkers. Treatment with sacubitril/valsartan resulted in lower IGFBP7 concentrations over 36 weeks compared with valsartan (adjusted treatment effect, −7%; P<0.001).Conclusions:Among patients with heart failure with preserved ejection fraction, concentrations of the cellular senescence biomarker IGFBP7 were associated with abnormalities in diastolic filling and LA dilation. Treatment with sacubitril/valsartan resulted in lower IGFBP7 concentrations compared with valsartan.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00887588.
Ufm1-Specific Ligase Ufl1 Regulates Endoplasmic Reticulum Homeostasis and Protects Against Heart Failure Circ. Heart Fail. (IF 5.684) Pub Date : 2018-10-11 Jie Li, Guihua Yue, Wenxia Ma, Aizhen Zhang, Jianqiu Zou, Yafei Cai, Xiaoli Tang, Jun Wang, Jinbao Liu, Honglin Li, Huabo Su
Background:Defects in protein homeostasis are sufficient to provoke cardiac remodeling and dysfunction. Although posttranslational modifications by ubiquitin and ubiquitin-like proteins are emerging as an important regulatory mechanism of protein function, the role of Ufm1 (ubiquitin-fold modifier 1)—a novel ubiquitin-like protein—has not been explored in either the normal or stressed heart.Methods and Results:Western blotting revealed that Ufl1 (Ufm1-specific E3 ligase 1)—an enzyme essential for Ufm1 modification—was increased in hypertrophic mouse hearts but reduced in the failing hearts of patients with dilated cardiomyopathy. To determine the functional role of Ufl1 in the heart, we generated a cardiac-specific knockout mouse and showed that Ufl1-deficient mice developed age-dependent cardiomyopathy and heart failure, as indicated by elevated cardiac fetal gene expression, increased fibrosis, and impaired cardiac contractility. When challenged with pressure overload, Ufl1-deficient hearts exhibited remarkably greater hypertrophy, exacerbated fibrosis, and worsened cardiac contractility compared with control counterparts. Transcriptome analysis identified that genes associated with the endoplasmic reticulum (ER) function were dysregulated in Ufl1-deficient hearts. Biochemical analysis revealed that excessive ER stress preceded and deteriorated along with the development of cardiomyopathy in Ufl1-deficient hearts. Mechanistically, Ufl1 depletion impaired (PKR-like ER-resident kinase) signaling and aggravated cardiomyocyte cell death after ER stress. Administration of the chemical ER chaperone tauroursodeoxycholic acid to Ufl1-deficient mice alleviated ER stress and attenuated pressure overload-induced cardiac dysfunction.Conclusions:Our results advance a novel concept that the Ufm1 system is essential for cardiac homeostasis through regulation of ER function and that upregulation of myocardial Ufl1 could be protective against heart failure.
Putting the Stress on UFM1 (Ubiquitin-Fold Modifier 1) Circ. Heart Fail. (IF 5.684) Pub Date : 2018-10-11 James D. Sutherland, Rosa Barrio
See Article by J. Li et al Defects in protein homeostasis (also known as proteostasis) are intrinsically linked to age-related decline of cardiac function and likely contribute to cardiomyopathies. Protein-folding chaperones and protein quality control systems work overtime in the high stress cardiac environment, responding to wear and tear. Tight regulation of the pathway components is often controlled by posttranslational modifications. In addition to compact posttranslational modifications such as phosphorylation, bulkier posttranslational modifications involve Ub (ubiquitin) and other small UbL (Ub-like) proteins, which are covalently conjugated to target proteins. These modifications can affect stability, localization, and function of the target protein. Ufm1 (ubiquitin-fold modifier 1) is a less-studied UbL, but modification by Ufm1 (ufmylation1) is emerging as an important mediator of the endoplasmic reticulum (ER) stress response, which is activated in cardiomyocytes during heart failure. Focusing on Ufl1 (Ufm1-ligase 1), one of the enzymes that mediate ufmylation, the report from Li et al2 provide strong evidence that Ufl1 has a cardioprotective role and points to the ufmylation pathway as a potential target for pharmacological intervention for some cardiomyopathies. Ub and UbLs share a common biology in the way they are added to targets and recycled in the cell, but each class tends to have specialized roles.3 They are varied in their individual protein sequences, with Ub/UbLs sharing a common structural fold as revealed by crystallographic as revealed by protein crystallographic studies. After synthesis as a pro-protein, Ub/UbLs are cleaved at the C terminus by a protease, a prerequisite for entering the conjugation cycle. The cleaved Ub/UbL is engaged by an activation enzyme (generically termed E1 or enzyme 1). Via this Ub-E1 intermediate, the Ub/UbL is then passed to a conjugating enzyme (E2 or enzyme 2). In some cases, the E2 can engage directly with target proteins, and the Ub/UbL is conjugated by its C terminus to the targets, usually to a lysine. In most cases, however, the Ub-E2 intermediate engages with a ligating enzyme (or E3 ligase; enzyme 3). The structure of the E3 may vary greatly, from being a single protein to a multiprotein complex, but in general, the E3 serves to enhance delivery of the mature Ub/UbL to a lysine on specific target proteins. Certain conserved protein domains are characteristic of E3 ligases (eg, RING [really interesting new gene] or HECT [homologous to the E6-AP carboxyl terminus] domains), and by this measure, it is estimated that >600 E3 Ub/UbL ligases are encoded by the human genome. Other E3 ligases have been described that lack these domains but may function as scaffolding adaptors to bridge the E2-Ub/UbL and targets (Ufl1, featured in Li et al,2 is one example). Ub/UbL posttranslational modifications vastly increase the complexity of the human proteome and require exquisite regulation to allow cells to cycle, survive, and respond to signals and stress. Correct regulation of proteostasis underlies both healthy and diseased/damaged heart function. This complex task balances protein synthesis, folding, and degradation, with the latter relying on multiple systems (autophagy, calpains, proteasomes4,5). Specifically, contributions to cardiac proteostasis by the Ub-proteasome system have been extensively reviewed.6,7 Cardiac roles for modifications by other UbLs (NEDD8 [neural precursor cell expressed, developmentally down-regulated 8], SUMO [small ubiquitin modifier]) have also been described.8,9 Many of the studies defining cardiac roles for Ub/UbL modifications rely on either classical or conditional knockout mice, with the latter allowing heart-specific deletion of the genes encoding the UbL or its associated pathway enzymes. These precise genetic studies allow molecular, histological, and physiological analysis of the heart in experimental animals. When coupled with surgical methods to induce heart stress or with drug administration or both, such studies can reveal promising targets and therapies for future clinical trials. Ufmylation was discovered by chance in a search for proteins implicated in autophagy,10 and like ubiquitylation, it occurs through a multienzyme cascade (Figure). The E1-activating enzyme Uba5 (ubiquitin like modifier activating enzyme 5) was identified first, and further biochemical and proteomic analysis revealed Ufm1 as the novel UbL that is activated by Uba5. The same study also discovered the dedicated E2 enzyme, Ufc1 (UFM1 conjugating enzyme 1), responsible for conjugation of Ufm1 to target proteins. Later studies uncovered Ufl1, a Ufm1 E3 ligase, as an interactor of both Ufm1 and the E2 Ufc1.11 The search for proteases that were capable of processing pro-Ufm1 and that could remove and recycle Ufm1 from target proteins yielded 2 related proteins, Ufsp1 and Ufsp2 (UFM1 specific peptidase 1 and 2).12 All of these proteins show close association to the ER, and functional studies (including the present report) point to specialized roles for ufmylation in regulating ER-related stress. The ER is a major site of protein quality control, housing the synthesis machinery for proteins destined to be secreted or membrane-trafficked within the cell, as well as chaperones to assist protein folding and 3 separate systems (PERK [protein kinase R-like ER kinase], ATF6 [activating transcription factor 6], IRE1 [inositol-requiring enzyme 1]) that mediate the unfolded protein response. Several ufmylated target proteins have been identified, although these are few in number compared with those modified by Ub or SUMO. One ufmylated target, Ufbp1 (also known as Ddrgk1 [DDRGK domain containing 1]), warrants particular mention since it is required for efficient ufmylation of other targets and may act as a cofactor for the Ufl1 E3 ligase. Loss-of-function classical knockouts in mice (Uba5, Ufl1, or Ufbp1) have revealed an essential role for ufmylation in erythroid development and lead to embryonic lethality.1 Tissue-specific knockouts can be used to reveal roles later in development, exemplified by Li et al.2 This approach has uncovered a novel role for Ufl1 in mouse cardiac health. Figure. Features of the ufmylation cycle, a key pathway for endoplasmic reticulum (ER)-based stress response in cardiac development and disease. UFM1 (ubiquitin-fold modifier 1) is conjugated to substrates through a multienzyme cascade. After proteolytic maturation, UFM1 is passed via 3 enzymes (activating E1, conjugating E2, and ligating E3) as it attaches to substrates. Specific proteases remove and recycle Ufm1. Li et al2 demonstrate that Ufl1 (Ufm1-ligase 1), a Ufm1 E3 ligase, is cardioprotective in both physiological and pathological conditions. How ufmylation influences substrates, whether E3 ligases are obligatory, whether additional E3 ligases exist, and how the Ufbp2 cofactor affects E3 activity are still open questions for future investigation. Even so, the ufmylation pathway may offer unique drug targets for cardiac and other diseases that feature ER stress response as cause or consequence of the pathology. ATP indicates adenosine tri-phosphate; Ufbp1, UFM1-specific binding protein 1; and Ufc1, UFM1 conjugating enzyme 1. Their study begins with the observation that, although ufmylation of major target proteins in the heart seems to increase over time (from 1-day to 1-year old), levels of Ufl1 E3 ligase seem to decrease. This may seem counterintuitive, but possible explanations may lie in altered levels or activities of other ufmylation mediators (Uba5, Ufc1, Ufbp1, Ufsp1/2). Upon surgically induced cardiac hypertrophy in mice, levels of both ufmylation and Ufl1 increased. Levels of Ufl1 decreased during induced ischemia/reperfusion, likely because of cardiomyocyte death. Samples from patients with dilated cardiomyopathy also showed reduced Ufl1 levels, all leading to the hypothesis that ufmylation might be a key player in cardiac stress response. To address this, the authors used a conditional mouse mutant to remove Ufl1 from the cardiomyocyte population, to see how this affected both normal heart development, as well as response to heart stress and injury. While Ufl1 levels were significantly reduced in whole heart extracts from knockouts, detectable Ufl1 and ufmylation still remained, suggesting that genetic removal was not complete, or that noncardiomyocyte cells contribute to residual activity. Alternatively, as seen with SUMOylation, perhaps ufmylation of some targets does not require an E3 ligase, or perhaps another uncharacterized Ufm1 E3 ligase acts redundantly to Ufl1 (Figure). Still, reduction of Ufl1 was sufficient to induce cardiac remodeling and progressive functional deterioration as measured by echography, histology, and changes in gene expression. Using induced cardiac hypertrophy, Ufl1CKO mice were unable to make compensatory changes and developed heart failure, with increased fibrosis and decreased contractility, suggesting that Ufl1 has a cardioprotective role. Turning to molecular mechanisms, comparative analysis of transcriptomes from control and Ufl1CKO mice pointed to ER dysfunction when Ufl1 was reduced. Indeed, as reported previously for cells and other organ systems, loss of Ufl1 and ufmylation in the heart leads to increased ER stress, evident as an increase in stress response chaperones and changes in ER ultrastructure. Induced cardiac hypertrophy also induced stress chaperones, but the same treatment in Ufl1CKO mice led to even higher levels. Using primary cardiomyocytes from rat and drugs to induce ER stress, the authors show that at least 1 of 3 unfolded protein response pathways (PERK) was affected by Ufl1 reduction. Using a previously reported strategy,13 administration of tauroursodeoxycholic acid, a chemical chaperone known to alleviate ER stress, was able to reduce the cardiac enlargement and ER stress-induced cell death seen in Ufl1CKO mice with surgically induced cardiac hypertrophy. Overall, the results convincingly show that Ufl1 and ER stress regulation are tightly connected and that ufmylation may be a druggable cardioprotective pathway. Although tauroursodeoxycholic acid is being testing in clinical trials, including some focused on cardiac issues (eg, https://www.clinicaltrials.gov. Unique identifier: NCT01855360), a treatment more focused on Ufl1 and the ufmylation pathway may yield less secondary effects. Given the current push to exploit E3 ligases and deubiquitinases as druggable targets,14,15 the ufmylation pathway will certainly be explored and new drug candidates will likely emerge in the upcoming years. Li et al2 suggests that activation of ufmylation would be beneficial in the case of some cardiomyopathies and perhaps age-related decline of cardiac health. A better understanding of how Ufl1 interacts with targets for ufmylation and how Ufsp1 (the potential Ufl1 cofactor; Figure) contributes to the E3 activity of Ufl1 may lead to new ideas on how to find or design activating compounds. Activators of Uba5 and Ufc1 could also lead to overall increases of ufmylation. Conversely, a search for inhibitors of Ufm1 proteases may identify a compound capable of enriching for ufmylated proteins. A recent report shows that the loss of Ufsp2 in cells leads to a dramatic increase in ufmylated targets,16 suggesting that inhibitors may yield the desired effect. Since heart failure is a leading cause of morbidity and mortality, especially among middle-aged and older adults, this important study reveals ufmylation as a promising pathway to explore for therapeutic benefits in cardiomyopathies and likely other ER stress-based illnesses. Drs Sutherland and Barrio are funded by BFU2017-84653-P (MINECO/FEDER, EU), the Severo Ochoa Excellence Program (SEV-2016- 0644), the UbiCODE program (765445, EU) and PROTEOSTASIS (COST BM1307, EU). Additional support was provided by the Department of Industry, Tourism, and Trade of the Government of the Autonomous Community of the Basque Country (Elkartek Research Programs) and by the Innovation Technology Department of the Bizkaia County. None. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. https://www.ahajournals.org/journal/circheartfailure
Rare Case of Pericardial Angiosarcoma Circ. Heart Fail. (IF 5.684) Pub Date : 2018-10-08 Yuman Li, Bin Wang, Li Zhang, Yali Yang, Jing Wang, Qing Lv, Mingxing Xie
Primary angiosarcoma of the pericardium is exceptionally rare, and diagnosis remains challenging because of the variability of its clinical presentation. Here, we report a case of a 26-year-old woman with pericardial angiosarcoma who presented with recurrent hemorrhagic pericardial effusion diagnosed at histopathologic examination. A 26-year-old female patient had a 4-month history of dyspnea, chest pain, cough, palpitation, and fatigue. Echocardiography revealed pericardial effusion. However, no obvious mass was identified either in the pericardium or in the heart. Pericardiocentesis and drainage were performed 3×, draining 700 mL of hemorrhagic pericardial effusion. The patient’s symptoms improved after percutaneous drainage of bloody pericardial fluid. The effusion cultures for bacteria, acid-fast bacilli, and viruses were always negative. Repeated cytological examination of the pericardial effusion did not show malignant cells. Her dyspnea and cough recurred after 2 months. Echocardiography showed thickened pericardium and mild pericardial effusion. The patient was empirically treated for tuberculous pericarditis, considering the unexplained hemorrhagic pericardial effusion and the high incidence of tuberculous pericarditis in China. After 1 month, she did not respond to antituberculous therapy, and her clinical condition rapidly deteriorated. Therefore, she was referred to our institution for further examination. On physical examination, her pulse rate, respiration rate, and blood pressure were 127 beats per minute, 22 per minute, and 117/65 mm Hg, respectively. Kussmaul sign and paradoxical pulse were present. No cardiac murmur or pericardial rub was detected. Chest radiograph showed marked cardiomegaly (Figure [A]). Transthoracic echocardiography revealed a huge mass in the pericardium surrounding and compressing the ventricles, atria, ascending aorta, and pulmonary trunk (Figure [B] and [C]; Movies I through III in the Data Supplement). Her echocardiography demonstrated septal bounce and dilation and diminished collapse of the inferior vena cava. Color Doppler flow imaging showed mild tricuspid regurgitation (Figure [D]; Movie IV in the Data Supplement). Pulsed-wave Doppler echocardiography demonstrated that peak mitral E inflow decreased (>25%) after inspiration (Figure [E]). High enhancement of contrast agent in the pericardial mass was noted after contrast echocardiography (Figure [F]; Movie V in the Data Supplement). Chest computed tomography showed that the entire heart was encased by the pericardial mass. Cardiac magnetic resonance imaging revealed that the large mass within the pericardium surrounded and severely compressed the entire heart and great vessels. On T1- and T2-weighted cardiac magnetic resonance images, the pericardial mass appeared heterogeneous and hyperintense relative to the myocardium (Figure [G], [H], and [I]). After intravenous contrast with gadopentetate dimeglumine, enhancement was observed as multiple lines in the tumor radiating from the epicardium to pericardium (a sunray appearance; Figure [J]). Positron emission tomography revealed a neoplastic mass in the pericardium (Figure [K]). Distant metastases were found only in the lymph node of the right cardiophrenic angle and the left musculus obliquus externus abdominis (Figure [L]). Figure. Multimodal imaging and pathological findings.A, Chest radiograph showing marked cardiomegaly. B and C, Transthoracic echocardiography showing a large pericardial mass surrounding and compressing ventricles and atria. D, Color Doppler flow imaging indicates mild tricuspid regurgitation. E, Pulsed-wave Doppler echocardiography demonstrates that peak mitral E inflow decreased (>25%) after inspiration. F, Contrast echocardiography showing high enhancement of contrast agent in the pericardial mass. G, The pericardial mass appears heterogeneous and hyperintense relative to the myocardium on T1-weighted cardiac magnetic resonance (CMR) images. H and I, The pericardial mass is heterogeneous and hyperintense on T2-weighted CMR images. J, Enhanced CMR imaging reveals multiple lines in pericardial tumor, radiating from the epicardium to pericardium (sunray appearance). K and L, Positron emission tomography reveals a neoplastic mass in the pericardium and distant metastases. Ao indicates aorta; Ee, E velocity during expiration; Ei, E velocity during inspiration; LA, left atrium; LV, left ventricle; M, mass; RA, right atrium; and RV, right ventricle. Open biopsy was performed for a definitive diagnosis. Histopathologic examination showed a malignant tumor. Immunohistochemical staining indicated that these cells were positive for CD (cluster of differentiation) 31, CD34, ETS-related gene, and Ki67. Hence, the overall findings were consistent with pericardial angiosarcoma. The patient refused chemotherapy and radiotherapy, considering the distant metastases of pericardial angiosarcoma and poor prognosis, and she died after 2 months. Primary cardiac tumors are rare entities (0.0017%–0.003% of routine autopsy studies, 25% malignant).1 Cardiac angiosarcomas, although rare, are the most common primary malignant cardiac tumors (31% of all malignancies).2 They tend to be found in patients aged 20 to 50 years and are more common in men.3 Most cases are more often found in the right atrium, making pericardial angiosarcoma extremely rare. Pericardial angiosarcomas respond poorly to chemotherapy. Prognosis is poor, with mean survival time of 6 to 11 months.4 Making an accurate diagnosis remains challenging because its clinical presentation is variable, and available noninvasive imaging modalities lack specificity. Echocardiography, although frequently performed, plays a limited role in the evaluation of primary pericardial angiosarcoma. Echocardiography frequently demonstrates pericardial effusion but may not show a mass because it depends on good acoustic window. Pericardiocentesis commonly yields hemorrhagic fluid that does not contain malignant cells, as seen in our case. Computed tomography demonstrates the location, size and extent of the tumor, and its invasion of vital structures. Cardiac magnetic resonance imaging is a more powerful tool for characterizing the lesion. Cardiac magnetic resonance imaging may also demonstrate constrictive physiology with diffuse thickening of the pericardium. Positron emission tomography may be a useful tool because it may demonstrate distant or locoregional metastatic disease. Detecting this malignant tumor in the early stage may be challenging, despite the application of various advanced imaging modalities. We describe a case of a patient with pericardial angiosarcoma who presented with recurrent hemorrhagic pericardial effusion that rapidly progressed in a short period. Our case indicates that unexplained hemorrhagic pericardial effusion should prompt the clinician to seek for a malignant etiology, even when malignant cells are not found on fluid cytology. This work was supported by the National Natural Science Foundation of China (No. 81401432 and 81727805). None. https://www.ahajournals.org/journal/circheartfailure The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCHEARTFAILURE.118.005342.
Omega-3 Therapy Is Associated With Reduced Gastrointestinal Bleeding in Patients With Continuous-Flow Left Ventricular Assist Device Circ. Heart Fail. (IF 5.684) Pub Date : 2018-10-04 Teruhiko Imamura, Ann Nguyen, Daniel Rodgers, Gene Kim, Jayant Raikhelkar, Nitasha Sarswat, Sara Kalantari, Bryan Smith, Ben Chung, Nikhil Narang, Colleen Juricek, Daniel Burkhoff, Tae Song, Takeyoshi Ota, Valluvan Jeevanandam, Gabriel Sayer, Nir Uriel
BackgroundGastrointestinal bleeding (GIB) is a common complication seen in patients supported with left ventricular assist devices (LVADs) and is related to increased inflammation and angiogenesis. Omega-3 is an unsaturated fatty acid that possesses anti-inflammatory and antiangiogenic properties. This study aims to assess the prophylactic efficacy of treatment with omega-3 on the incidence of GIB in LVAD patients.Methods and ResultsAmong consecutive 166 LVAD patients enrolled in this analysis, 30 patients (49 years old and 26 male) received 4 mg/d of omega-3 therapy for 310±87 days and 136 patients in the control group (58 years old and 98 male) were observed for 302±102 days. One-year GIB-free rate was significantly higher in the omega-3 group as compared with the control group (97% versus 73%; P=0.02). Omega-3 therapy was associated with the occurrence of GIB in both the univariate (hazard ratio, 0.12; 95% CI, 0.02–0.91; P=0.040) and multivariate Cox proportional hazard ratio analyses (hazard ratio, 0.13; 95% CI, 0.02–0.98; P=0.047). The frequency of GIB was significantly lower in the omega-3 group (0.08±0.42 versus 0.37±0.93 events/y; P=0.01), accompanied by significantly lower blood product transfusion and shorter days in the hospital. The frequency of GIB remained lower among the omega-3 group after matching for patient background characteristics (96% versus 73%, P=0.028).ConclusionsLVAD patients treated with omega-3 had a significant increase in freedom from GIB. A randomized controlled study is warranted to evaluate the use of omega-3 in LVAD patients.
Venoarterial Extracorporeal Membrane Oxygenation in the New Heart Allocation Scheme Circ. Heart Fail. (IF 5.684) Pub Date : 2018-09-18 Muddassir Mehmood
The United Network for Organ Sharing will implement changes to the adult heart allocation system this fall. Adults supported by Venoarterial extracorporeal membrane oxygenation (VA ECMO) will be eligible for the highest status listing during the first 7 days, and for status 2, from the seventh through 14th day of support, renewable thereafter.1 The new policy strives to reduce wait-list mortality by prioritizing heart allocation to the most critically ill. Many have raised concerns about the status of ECMO in the new allocation scheme with regards to its impact on organ allocation. But there is an elephant in the room. Is VA ECMO ready for prime time as the standard of care for managing profound cardiogenic shock in the United States? Since the first ECMO intervention in 1972, the extracorporeal life support family of therapies has evolved. In 1989, therapeutic advances in extracorporeal life support contributed to the formation of a scientific platform, the Extracorporeal Life Support Organization. In the year 2017, 379 centers provided ECMO therapy worldwide, a number that has steadily increased from 83 in 1990.2 The ECMO financial market is anticipated to reach USD 305.3 million by 2021 from USD 247.2 million in 2016.3 However, despite the advances, ECMO therapy faces several challenges. The management of patients on ECMO remains complex and resource intense. As a result, the use of ECMO remains restricted to specialized centers with center-specific utilization protocols. Ironically, to date, there is not a single blood pump with Food and Drug Administration approval for providing >6 hours of circulatory support, in a VA ECMO configuration, for patients with cardiogenic shock from left ventricular or combined right and left ventricular failure. The paradigm shift in heart allocation policy should serve as a call to action to transform advances in extracorporeal life support therapy to standards of care for managing profound cardiogenic shock and refractory cardiac arrest. To accomplish this, a multifaceted approach is suggested as follows: (1) at the healthcare delivery level, a system based approach should integrate ECMO into existing networks of ST-segment–elevation myocardial infarction care. Hub and spoke models for advanced heart failure care must be clearly delineated such that community cardiology centers establish efficient channels of communication and transfer mechanisms to advanced heart failure centers for patients on or in need for ECMO support. (2) At the scientific level, working knowledge of extracorporeal life support therapies should be integrated into resident and fellow training curricula across multiple specialties. Key scientific societies need to collaboratively update recommendations for VA ECMO therapy and monitor utilization via a single registry. The American Heart Association needs to work toward taking the Mission: Lifeline to the next level by incorporating ECMO assisted cardiopulmonary resuscitation for refractory cardiac arrest. (3) At the regulatory level, the Food and Drug Administration needs to ensure that the process of applying for ECMO product labeling is conducive to inviting competition from the industry to help curtail cost and deal with future supply shortages. (4) At the industry level, manufacturers need to gear up for innovations to make ECMO safer for longer-term support, resource efficient, portable, and cost effective. I think the status of ECMO in the new United Network for Organ Sharing scheme is well intended. Given the severity of illness of patients requiring ECMO support, its impact on heart allocation may be less than generally perceived. More importantly, we need to get our act together to make VA ECMO an accessible standard of care across the United States. In my opinion, the implications of the latter will be far greater. None. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. https://www.ahajournals.org/journal/circheartfailure
Skeletal Muscle Abnormalities and Iron Deficiency in Chronic Heart Failure Circ. Heart Fail. (IF 5.684) Pub Date : 2018-09-18 Vojtech Melenovsky, Katerina Hlavata, Petr Sedivy, Monika Dezortova, Barry A. . Borlaug, Jiri Petrak, Josef Kautzner, Milan Hajek
Background:Heart failure (HF) is often associated with iron deficiency (ID). Skeletal muscle abnormalities are common in HF, but the potential role of ID in this phenomenon is unclear. In addition to hemopoiesis, iron is essential for muscle bioenergetics. We examined whether energetic abnormalities in skeletal muscle in HF are affected by ID and if they are responsive to intravenous iron.Methods and Results:Forty-four chronic HF subjects and 25 similar healthy volunteers underwent 31P magnetic resonance spectroscopy of calf muscle at rest and during exercise (plantar flexions). Results were compared between HF subjects with or without ID. In 13 ID-HF subjects, examinations were repeated 1 month after intravenous ferric carboxymaltose administration (1000 mg). As compared with controls, HF subjects displayed lower resting high-energy phosphate content, lower exercise pH, and slower postexercise PCr recovery. Compared with non-ID HF, ID-HF subjects had lower muscle strength, larger PCr depletion, and more profound intracellular acidosis with exercise, consistent with an earlier metabolic shift to anaerobic glycolysis. The exercise-induced PCr drop strongly correlated with pH change in HF group (r=−0.71, P<0.001) but not in controls (r=0.13, P=0.61, interaction: P<0.0001). Short-term iron administration corrected the iron deficit but had no effect on muscle bioenergetics assessed 1 month later.Conclusions:HF patients display skeletal muscle myopathy that is more severe in those with iron deficiency. The presence of ID is associated with greater acidosis with exercise, which may explain early muscle fatigue. Further study is warranted to identify the strategy to restore iron content in skeletal muscle.
Venoarterial Extracorporeal Membrane Oxygenation for Cardiogenic Shock and Cardiac Arrest Circ. Heart Fail. (IF 5.684) Pub Date : 2018-09-18 Prashant Rao, Zain Khalpey, Richard Smith, Daniel Burkhoff, Robb D. Kociol
Venoarterial extracorporeal membrane oxygenation (VA-ECMO)—also referred to as extracorporeal life support—is a form of temporary mechanical circulatory support and simultaneous extracorporeal gas exchange. The initiation of VA-ECMO has emerged as a salvage intervention in patients with cardiogenic shock, even cardiac arrest refractory to standard therapies. Analogous to veno-venous ECMO for acute respiratory failure, VA-ECMO provides circulatory support and allows time for other treatments to promote recovery or may be a bridge to a more durable mechanical solution in the setting of acute or acute on chronic cardiopulmonary failure. In this review, we provide a brief overview of VA-ECMO, the attendant physiological considerations of peripheral VA-ECMO, and its complications, namely that of left ventricular distention, bleeding, heightened systemic inflammatory response syndrome, thrombosis and thromboembolism, and extremity ischemia or necrosis.
Patient, Provider, and Practice Characteristics Associated With Sacubitril/Valsartan Use in the United States Circ. Heart Fail. (IF 5.684) Pub Date : 2018-09-15 Adam D. DeVore, C. Larry Hill, Laine Thomas, Puza P. Sharma, Nancy M. Albert, Javed Butler, J. Herbert Patterson, John A. Spertus, Fredonia B. Williams, Carol I. Duffy, Kevin McCague, Adrian F. Hernandez, Gregg C. Fonarow
BackgroundCurrent guidelines recommend sacubitril/valsartan for patients with heart failure with reduced ejection fraction, but the rate of adoption in the United States has been slow.Methods and ResultsUsing data from CHAMP-HF (Change the Management of Patients With Heart Failure), we described current sacubitril/valsartan use and identified patient, provider, and practice characteristics associated with its use. We considered patients to be on sacubitril/valsartan if they were prescribed it before enrollment or initiated on it at the baseline visit. We excluded patients with a contraindication to sacubitril/valsartan and practices with <10 patients enrolled. Of 4216 patients from 121 sites, 616 (15%) were prescribed sacubitril/valsartan, 2506 (59%) an angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), and 1094 (26%) neither. Patients prescribed sacubitril/valsartan were younger (63 years versus 66 years ACE inhibitor/ARB versus 69 years neither, P<0.001), less likely to have chronic kidney disease (15% versus 17% ACE inhibitor/ARB versus 30% neither, P<0.001), more likely to have cardiac resynchronization therapy (12% versus 7% ACE inhibitor/ARB versus 7% neither, P<0.001), and had lower ejection fraction (27% versus 30% ACE inhibitor/ARB versus 30% neither, P<0.001). Larger practices, based on number of cardiologists and advanced practice providers, were associated with the highest sacubitril/valsartan use. After multivariable adjustment, the number of advanced practice providers was associated with sacubitril/valsartan use (adjusted odds ratio,1.08; 95% CI, 1.03–1.14).ConclusionsDespite current guideline recommendations, adoption of sacubitril/valsartan remains low. Provider and practice characteristics associated with sacubitril/valsartan use were related to general practice size and were not associated with practice characteristics specific for heart failure. Further research is needed to identify strategies for effective quality improvement interventions in chronic heart failure with reduced ejection fraction.
Clinical and In Vitro Evidence That Left Ventricular Assist Device–Induced von Willebrand Factor Degradation Alters Angiogenesis Circ. Heart Fail. (IF 5.684) Pub Date : 2018-09-14 Carlo R. Bartoli, David M. Zhang, Samson Hennessy-Strahs, Jooeun Kang, David J. Restle, Christian Bermudez, Pavan Atluri, Michael A. Acker
BackgroundGastrointestinal bleeding from angiodysplasia is a major problem in continuous-flow left ventricular assist device (LVAD) patients. LVAD shear stress causes pathologic degradation of VWF (von Willebrand factor). A mechanistic relationship between VWF degradation and angiodysplasia has not been explored. We tested 2 novel hypotheses: (1) clinical hypothesis: VWF fragments are elevated in LVAD patients that develop angiodysplasia and (2) in vitro hypothesis: VWF fragments generated during LVAD support alter angiogenesis, which may contribute to angiodysplasia.Methods and ResultsClinical study: Paired blood samples were collected from continuous-flow LVAD patients (n=35). VWF was quantified with immunoblotting. In vitro experiments: (1) To investigate whether LVAD support alters angiogenesis, human endothelial cells were cultured with LVAD patient plasma (n=11). To investigate mechanism, endothelial cells were cultured with VWF fragments produced by exposing human VWF and ADAMTS-13 (VWF protease) to LVAD-like shear stress (175 dyne/cm2, n=8). Clinical study results: in all patients (n=35, mean support 666±430 days), LVAD support degraded high-molecular-weight VWF multimers (P<0.0001) into low-molecular-weight VWF multimers (P<0.0001) and VWF fragments (P<0.0001). In patients with gastrointestinal bleeding from angiodysplasia (n=7), VWF fragments were elevated (P=0.02) versus nonbleeders. In contrast, in patients with gastrointestinal bleeding without angiodysplasia, VWF fragments were not elevated versus nonbleeders (P=0.96). In vitro experiments results: LVAD patient plasma caused abnormal angiogenesis with reduced tubule length (P=0.04) and migration (P=0.05). Similarly, endothelial cells grown with VWF degradation fragments exhibited reduced tubule length (P<0.001) and migration (P=0.01).ConclusionsLVAD patients who bled from angiodysplasia had higher levels of VWF fragments than nonbleeders and gastrointestinal bleeders without angiodysplasia. VWF fragments caused abnormal angiogenesis in vitro. These findings suggest that VWF fragments may be a mechanistic link between LVAD support, abnormal angiogenesis, angiodysplasia, and gastrointestinal bleeding.
Bleeding and Angiogenesis During Continuous-Flow Left Ventricular Assist Device Support Circ. Heart Fail. (IF 5.684) Pub Date : 2018-09-14 Omar Saeed, Snehal R. Patel, Ulrich P. Jorde
See Article by Bartoli et al This is your last chance. After this, there is no turning back. You take the blue pill—the story ends, you wake up in your bed and believe whatever you want to believe. You take the red pill—you stay in Wonderland and I show you how deep the rabbit-hole goes. —Morpheus in The Matrix1 The advent of continuous flow left ventricular assist devices (CF LVADs) for end-stage heart failure has led to marked improvements in survival, device miniaturization and durability, yet serious adverse hematologic events limit this therapy. Although changes in CF LVAD design have led to a reduction in device thrombosis, gastrointestinal bleeding (GIB) remains a major source of morbidity occurring in ≈30% of patients.2,3 The exact pathophysiology of GIB during CF LVAD remains unclear, but it has become apparent that 2 major factors contribute toward excessive bleeding: (1) a hematologic disturbance, specifically an acquired von Willebrand factor (VWF) syndrome (avWs) and (2) angiodysplasia formation in the gastrointestinal tract. VWF is a glycoprotein synthesized in endothelial cells (ECs) and megakaryocytes that undergoes post-translational modification to form ultralarge or high-molecular-weight multimers (HMWMs).4 These HMWMs are stored in the Weibel Palade bodies of ECs and platelets and released in response to hemorrhage. On release, HMWMs serve as bridges crosslinking exposed collagen and platelets to form a platelet plug at the site of injury within a blood vessel.4 HMWMs are cleaved by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) into smaller multimers at its A2 domain. Although VWF multimers of all sizes contribute to coagulation, the larger the multimer, the greater the hemostatic potential. Increased shear stress, as produced by CF LVADs, elongates the multimers and causes changes in the conformation of the A2 domain making it more susceptible to cleavage by ADAMTS13.5 Thus, shear forces generated during passage of blood elements through a CF LVAD accelerate degradation of HMWMs via increased proteolysis and to create avWs. Although various subtypes of von Willebrand disease were known to be associated with angiodysplasia, novel in vitro studies by Starke et al6 further demonstrated VWF as a negative regulator of angiogenesis. In their investigation, inhibition of VWF expression in human umbilical vein ECs by siRNA led to an increase in VEGF (vascular endothelial growth factor)-dependent cell proliferation, migration, and tubule formation.6 It was suggested that VWF inhibits angiogenesis through the following 2 spatially separate mechanisms: (1) extracellular binding of VWF to integrin αvβ3 reduced VEGF-2–dependent proliferation of ECs and (2) defective Weibel Palade body formation from loss of VWF led to ineffective intracellular storage and unregulated release of Ang-2 (angiopoietin-2), thereby creating angiodysplasia.6,7 Further investigation into dysregulated angiogenesis has shed some light toward a possible pathogenesis of angiodysplasia during CF LVAD support. Tabit et al reported higher levels of thrombin induced Ang-2 in patients with a CF LVAD. Moreover, antibody blockade of Ang-2 resulted in a reduction of tubule formation by human umbilical vein ECs after exposure to serum from CF LVAD patients.8 Additionally, retrospective studies have associated angiotensin-converting enzyme inhibitors/angiotensin receptor blockers9 and digoxin10—medications that can reduce Ang-2 levels—with reduced angiodysplasia-related GIB during CF LVAD support. In this issue of Circulation: Heart Failure, Bartoli et al11 further relate avWs to clinical bleeding and propose a potentially unifying mechanism that associates VWF multimer loss and fragment formation to the development of angiodysplasia during CF LVAD support. The authors confirm previous findings12 and show a reduction in HMWMs with an increase in low-molecular-weight multimers, irrespective of clinical bleeding events. More interestingly, they note greater levels of VWF 450-kDA fragments in 7 (20%) patients who experienced an angiodysplasia-related GIB in comparison with nonbleeders (P=0.02).11 To further investigate the relation between VWF multimers and angiodysplasia, they assess tubule length and migration of human umbilical vein ECs plated on matrigels with (1) exposure of fragment-rich whole blood from CF LVAD patients and (2) addition of 450-kDA VWF fragments isolated from a shear stress mock loop. In both experiments, there is reduction in tubule length and migration as compared with pre-CF LVAD controls. Overall, the authors conclude that CF LVAD-related shear stress creates VWF fragments, which in turn are associated with angiodysplasia and ultimately lead to the clinical manifestation of mucosal bleeding. The investigators are to be commended for exploring a multifaceted and prevalent device-related adverse event in a prospective method on both clinical and mechanistic levels. An enigmatic clinical inquiry into device-related GIB has been why bleeding does not occur in all patients exposed to a CF LVAD since all patients develop avWs. In this study, Bartoli et al offer some granularity by proposing for the first time specific phenotypes of CF LVAD-related avWs, defined by a ratio of VWF multimers to fragments. With precise phenotypic identification, there could be potential for identifying at-risk individuals and developing targeted therapy, which would be a major step toward addressing the current Achilles heel of CF LVADs; yet, caution must be exercised, and findings must be framed within the scope of the present methodology aimed only at associating VWF profile with angiodysplasia. Although it is interesting that patients with elevated VWF fragments shortly after LVAD implantation were noted to develop angiodysplasia-related bleeding, and in an in vitro experiment, isolated VWF fragments reduced tubule formation, the authors rightly mention that such results may not implicate in vivo causality. In the ex vivo experiment, with exposure of fragment-rich whole blood from CF LVAD patients to human umbilical vein ECs, there is reduced tubule formation, but it is uncertain whether there are other antiangiogenic mediators that may impede normal microvessel development. More pressing is the uncertainty in reconciling the matrix, that is, the role of decreased in vitro tubule formation related to VWF fragments and increased tubule formation with loss of VWF/elevated Ang-2, as shown in previous studies,6,8 toward angiodysplasia formation. In other words, whether VWF fragment associated reduction in tubule formation and migration is indeed equivalent to in vivo CF LVAD-related angiodysplasia bleeding remains to be further established. As with any intriguing findings, there tend to be more questions than answers. A few queries at the forefront are as follows: (1) Why do only a subset of CF LVAD patients form VWF fragments? (2) How do VWF fragments prevent normal microvessel formation? (3) What is the role of pulsatility in determining the VWF profile, as recent animal model studies suggest preservation of HMWMs under pulsatile conditions?13 (4) Is there device-specific VWF fragment formation? and (5) How can this VWF fragment-related hypothesis be integrated with the recent observation that small bowel mucosal angiodysplasia may precede CF LVAD implantation?14 Moreover, if VWF profile is related to GIB, since differing VWF breakdown patterns are reported among various CF LVADs,15 there should be differences in the prevalence of GIB between such devices; but this was not reported in the 2-year outcomes of the MOMENTUM trial (The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3).2 Though likely not the sole culprit toward angiodysplasia-related GIB, perhaps knowledge of VWF fragment formation may eventually inform therapeutic use of downstream antiangiogenic mediators and tailored anticoagulation therapies to modify disease burden. Bartoli et al11 have made another important contribution to exploration of the von Willebrand matrix, but the mechanistic underpinnings of GIB in CF LVAD are yet to be fully elucidated. For now, we shall take the red pill with a few video capsules and remain in wonderland. Dr Jorde is a nonpaid consultant to Abbott. The other authors report no conflicts. https://www.ahajournals.org/journal/circheartfailure The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Heart Transplant Recipients Circ. Heart Fail. (IF 5.684) Pub Date : 2018-09-07 Satish Arora, Arne K. Andreassen, Kristjan Karason, Finn Gustafsson, Hans Eiskjær, Hans Erik Bøtker, Göran Rådegran, Einar Gude, Dan Ioanes, Dag Solbu, Göran Dellgren, Thor Ueland, Pål Aukrust, Lars Gullestad, on behalf of the SCHEDULE (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) Investigators
BackgroundCardiac allograft vasculopathy (CAV) limits survival after heart transplantation, and the effect of different immunosuppressive regimens on CAV is not fully understood. The randomized SCHEDULE trial (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) evaluated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine elimination can reduce CAV development.Methods and ResultsThe SCHEDULE trial was a multicenter Scandinavian trial, where 115 de novo heart transplantation recipients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Seventy-six (66%) patients had matched intravascular ultrasound examinations at baseline and 12 and 36 months. Intravascular ultrasound analysis evaluated maximal intimal thickness, percent atheroma volume, and total atheroma volume. Qualitative plaque analysis using virtual histology assessed fibrous, fibrofatty, and calcified tissue as well as necrotic core. Serum inflammatory markers were measured in parallel. The everolimus group (n=37) demonstrated significantly reduced CAV progression as compared with the cyclosporine group (n=39) at 36 months (Δ maximal intimal thickness, 0.09±0.05 versus 0.15±0.16 mm [P=0.03]; Δ percent atheroma volume, 5.3±2.8% versus 7.6±5.9% [P=0.03]; and Δ total atheroma volume, 33.9±71.2 versus 54.2±96.0 mm3 [P=0.34], respectively]. At 36 months the number of everolimus patients with rejection graded ≥2R was 15 (41%) as compared with 5 (13%) in the cyclosporine group (P=0.01). Everolimus did not affect CAV morphology or immune marker activity during the follow-up period.ConclusionsThe SCHEDULE trial demonstrates that everolimus initiation and early cyclosporine elimination significantly reduces CAV progression at 12 months, and this beneficial effect is clearly sustained at 36 months.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01266148.
Phosphodiesterase-5 Is Elevated in Failing Single Ventricle Myocardium and Affects Cardiomyocyte Remodeling In Vitro Circ. Heart Fail. (IF 5.684) Pub Date : 2018-08-29 Anastacia M. Garcia, Stephanie J. Nakano, Anis Karimpour-Fard, Karin Nunley, Penny Blain-Nelson, Natalie M. Stafford, Brian L. Stauffer, Carmen C. Sucharov, Shelley D. Miyamoto
BackgroundSingle ventricle (SV) congenital heart disease is fatal without intervention, and eventual heart failure is a major cause of morbidity and mortality. Although there are no proven medical therapies for the treatment or prevention of heart failure in the SV heart disease population, phosphodiesterase-5 inhibitors (PDE5i), such as sildenafil, are increasingly used. Although the pulmonary vasculature is the primary target of PDE5i therapy in patients with SV heart disease, the effects of PDE5i on the SV heart disease myocardium remain largely unknown. We sought to determine PDE5 expression and activity in the single right ventricle of SV heart disease patients relative to nonfailing controls and to determine whether PDE5 impacts cardiomyocyte remodeling using a novel serum-based in vitro model.Methods and ResultsPDE5 expression (n=9 nonfailing; n=7 SV heart disease), activity (n=8 nonfailing; n=9 SV heart disease), and localization (n=3 SV heart disease) were determined in explanted human right ventricle myocardium. PDE5 is expressed in SV heart disease cardiomyocytes, and PDE5 protein expression and activity are increased in SV heart disease right ventricle compared with nonfailing right ventricle. Isolated neonatal rat ventricular myocytes were treated for 72 hours with nonfailing or SV heart disease patient serum±sildenafil. Reverse transcription quantitative polymerase chain reaction (n=5 nonfailing; n=12 SV heart disease) and RNA sequencing (n=3 nonfailing; n=3 SV heart disease) were performed on serum-treated neonatal rat ventricular myocytes and demonstrated that treatment with SV heart disease sera results in pathological gene expression changes that are attenuated with PDE5i.ConclusionsPDE5 is increased in failing SV heart disease myocardium, and pathological gene expression changes in SV heart disease serum-treated neonatal rat ventricular myocytes are abrogated by PDE5i. These results suggest that PDE5 represents an intriguing myocardial therapeutic target in this population.
Incident Atrial Fibrillation Is Associated With MYH7 Sarcomeric Gene Variation in Hypertrophic Cardiomyopathy Circ. Heart Fail. (IF 5.684) Pub Date : 2018-09-12 Seung-Pyo Lee, Euan A. Ashley, Julian Homburger, Colleen Caleshu, Eric M. Green, Daniel Jacoby, Steven D. Colan, Edmundo Arteaga-Fernández, Sharlene M. Day, Francesca Girolami, Iacopo Olivotto, Michelle Michels, Carolyn Y. Ho, Marco V. Perez, on behalf of the SHaRe Investigators
BackgroundAlthough atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM) patients, the relationship between genetic variation and AF has been poorly defined. Characterizing genetic subtypes of HCM and their associations with AF may help to improve personalized medical care. We aimed to investigate the link between sarcomeric gene variation and incident AF in HCM patients.Methods and ResultsPatients from the multinational Sarcomeric Human Cardiomyopathy Registry were followed for incident AF. Those with likely pathogenic or pathogenic variants in sarcomeric genes were included. The AF incidence was ascertained by review of medical records and electrocardiograms at each investigative site. One thousand forty adult HCM patients, without baseline AF and with likely pathogenic or pathogenic variation in either MYH7 (n=296), MYBPC3 (n=659), or thin filament genes (n=85), were included. Compared with patients with variation in other sarcomeric genes, those with MYH7 variants were younger on first clinical encounter at the Sarcomeric Human Cardiomyopathy Registry site and more likely to be probands than the MYBPC3 variants. During an average follow-up of 7.2 years, 198 incident AF events occurred. Patients with likely pathogenic or pathogenic mutations in MYH7 had the highest incidence of AF after adjusting for age, sex, proband status, left atrial size, maximal wall thickness, and peak pressure gradient (hazard ratio, 1.7; 95% CI, 1.1–2.6; P=0.009).ConclusionsDuring a mean follow-up of 7.2 years, new-onset AF developed in 19% of HCM patients with sarcomeric mutations. Compared with other sarcomeric genes, patients with likely pathogenic or pathogenic variation in MYH7 had a higher rate of incident AF independent of clinical and echocardiographic factors.
Validity of Performance and Outcome Measures for Heart Failure Circ. Heart Fail. (IF 5.684) Pub Date : 2018-09-12 Jay Patel, Alex Sandhu, Justin Parizo, Yasbanoo Moayedi, Gregg C. . Fonarow, Paul A. . Heidenreich
BackgroundNumerous quality metrics for heart failure (HF) care now exist based on process and outcome. What remains unclear, however, is if the correct quality metrics are being emphasized. To determine the validity of certain measures, we compared correlations between measures and reliability over time. Measures assessed include guideline-recommended β-blocker (BB), any BB, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker, mineralocorticoid receptor antagonist, and hydralazine/isosorbide dinitrate (in blacks) use among candidates, 30-day mortality, 1-year mortality, and 30-day readmission.Methods and ResultsThis was an observational cohort analysis using chart review and electronic resources for 55 735 patients from 102 Veterans Affairs medical centers hospitalized with HF from 2008 to 2013. Assessments of convergent validity and reliability were performed. Significant correlations were found between in-hospital rates of ACE inhibitor use and the following measures: BB use, 30-day mortality, and 1-year mortality. Guideline-recommended BB use was also significantly correlated with mineralocorticoid receptor antagonists, 30-day mortality, and 1-year mortality. There was no correlation between 30-day readmission rates and any therapy or mortality. Measure reliability over time was seen for guideline-recommended BBs (r=0.57), mineralocorticoid receptor antagonists (r=0.50), 30-day mortality (r=0.29), and 1-year mortality (r=0.31). ACE inhibitor and readmission rates were not reliable measures over time.ConclusionsBB use, ACE inhibitor use, mortality, and mineralocorticoid receptor antagonist use are valid measures of HF quality. Thirty-day readmission rate did not seem to be a valid measure of HF quality of care. If the goal is to identify high-quality HF care, the emphasis on decreasing readmission rates might be better directed towards improving usage of the recommended therapies.
Left Atrial Contracture or Failure to Dilate Circ. Heart Fail. (IF 5.684) Pub Date : 2018-08-31 Masaru Obokata, Yogesh N.V. Reddy, Jeong Hoon Yang, Brandon M. Wiley, Barry A. Borlaug
Catheter ablation is a well-established treatment for atrial fibrillation. A subset of patients developed dyspnea secondary to loss of left atrial (LA) compliance after ablation, which is referred as the stiff LA syndrome.1 Stiff LA syndrome has traditionally been associated with profound eccentric LA remodeling. We report the case of a patient with this clinical syndrome who developed giant V waves during exercise but had a strikingly small LA. A 76-year-old man who had been a competitive cyclist was referred for invasive hemodynamic exercise testing for evaluation of dyspnea, which had become progressively more severe during the past 3 years. Medical history was notable for chronic systemic hypertension and atrial fibrillation, which had been treated with 3 ablation procedures in the preceding 2 decades. ECG revealed normal sinus rhythm, and transthoracic echocardiography demonstrated normal left ventricular ejection fraction (57%), LA volume of 34 mL (indexed LA volume, 16 mL/m2; Figure), impaired LA reservoir function (LA ejection fraction, 27%), a structurally normal mitral valve with mild regurgitation, normal right ventricular systolic function, and an estimated right ventricular systolic pressure of 36 mm Hg. There was no evidence of pulmonary vein stenosis or pulmonary embolism on computed tomography. Figure. Pulmonary capillary wedge pressure tracings and echocardiograms at rest and during peak exercise.A, Baseline 4-chamber echocardiogram showing a small left atrium. B, Pulmonary capillary wedge pressure waveforms at rest and (C) during peak exercise. D, Simultaneously obtained sonogram of the lung parenchyma shows development of B lines indicative of interstitial pulmonary congestion. E, Simultaneous echocardiography revealed only mild mitral regurgitation. LV indicates left ventricle. *Peak of the V wave. Cardiac catheterization revealed mildly elevated right atrial pressure (8 mm Hg) and normal mean pulmonary artery pressure (19 mm Hg) at rest. Pulmonary artery wedge pressure was normal (14 mm Hg at mid C wave) with a prominent V wave (34 mm Hg; Figure). The patient exercised to exhaustion on a supine cycle ergometer achieving a peak workload of 120 W (peak Vo2, 15.7 mL/min per kg). Right atrial pressure (17 mm Hg) and mean pulmonary arterial pressure (43 mm Hg) increased during exercise. Pulmonary capillary wedge pressure increased to 38 mm Hg, with an increase in the V-wave amplitude to 72 mm Hg (Figure). The patient complained of severe dyspnea, and simultaneous echocardiographic imaging revealed development of sonographic lung B lines (12 lines over 4 left chest sites; Figure) but only mild mitral regurgitation with minimal change in LA volume from rest to peak exercise (31–32 mL). Based on the findings, the diagnosis of the stiff LA syndrome was made. The stiff LA syndrome is an important complication that may develop years after surgical or catheter ablation.1 Ablation can prevent LA enlargement because of scarring, but in this case, the LA was exceedingly small, particularly in view of a long-standing history of atrial fibrillation. This suggests that the prior ablation procedures might have caused LA contracture. The normal LA dilates during exercise to augment reservoir function and receive greater venous return from pulmonary veins, protecting the lung capillaries from barotrauma. When the LA volume shrinks, as in this case, this ability to function as a compliance chamber that stores blood during ventricular systole is exhausted, leading to pulmonary venous hypertension with profound increase in the height of the V wave, even in the absence of mitral regurgitation. LA dilation clearly promotes LA dysfunction, increased filling pressures, and worsening pulmonary hypertension and is an important treatment target.2 However, this case illustrates that some degree of LA dilation may also serve as an important compensatory mechanism to protect the lung capillaries from the hydrostatic trauma induced by LA hypertension. With LA contracture, atrial and thus pulmonary venous pressure increases dramatically as the atrium fills to the steeper portion of its compliance curve, leading to the development of so-called giant V waves even in the absence of mitral regurgitation (Figure). The subsequent increase in pulmonary capillary pressure then favors fluid filtration out of the vascular space and into the lung parenchyma, leading to the development of interstitial edema (B lines; Figure [D]) and the perception of dyspnea.3 Treatment remains unknown. Creation of an interatrial septostomy may be helpful to mitigate the pressure rise, as has been performed in patients with heart failure, as well as stiff LA syndrome.4,5 However, it is unknown whether the septal defect created through these approaches (8 mm) would be sufficient to allow normalization of LA pressure in a case such as this. Prevention may be the most effective treatment. Atrial ablations may reduce LA volume because of myocyte injury, fibrosis, and scar formation. Further study is required to devise less traumatic ablative procedures and to determine whether antifibrotic drugs, such as mineralocorticoid antagonists, may prevent or even reverse LA fibrosis.6 In summary, although LA reverse remodeling is a generally a favorable indicator that is associated with lower risk for atrial fibrillation recurrence and better outcomes, the current data suggest that LA volume contraction or failure to dilate could also contribute to pulmonary venous hypertension and symptomatic heart failure in some patients. Further study is needed to better understand the complex role of the LA in patients with cardiovascular disease. Dr Borlaug has received research funding from the National Heart, Lung, and Blood Institute (RO1 HL128526, R01 HL126638, U01 HL125205, and U10 HL110262). Dr Obokata is supported by a research fellowship from the Uehara Memorial Foundation, Japan. None. https://www.ahajournals.org/journal/circheartfailure
Temporal Trends in Contemporary Use of Ventricular Assist Devices by Race and Ethnicity Circ. Heart Fail. (IF 5.684) Pub Date : 2018-08-01 Khadijah Breathett, Larry A. Allen, Laura Helmkamp, Kathryn Colborn, Stacie L. Daugherty, Irene V. Blair, Jacqueline Jones, Prateeti Khazanie, Sula Mazimba, Marylyn McEwen, Jeff Stone, Elizabeth Calhoun, Nancy K. Sweitzer, Pamela N. Peterson
Background The proportion of racial/ethnic minorities receiving ventricular assist devices (VADs) has previously been less than expected. It is unclear if trends have changed since the broadening of access to insurance in 2014 and the rapid adoption of VAD technology. Methods and Results Using the Interagency Registry of Mechanically Assisted Circulatory Support, we analyzed time trends by race/ethnicity for 10 795 patients (white, 67.4%; African-American, 24.8%; Hispanic, 6.3%; Asian, 1.5%) who had a VAD implanted between 2012 and 2015. Linear models were fit to the annual census-adjusted rate of VAD implantation for each racial/ethnic group, stratified by sex and age group. From 2012 to 2015, African-Americans had an increase in the census-adjusted annual rate of VAD implantation per 100 000 (0.26 [95% confidence interval, 0.17–0.34]) while other ethnic groups exhibited no significant changes (white: 0.06 [−0.03 to 0.14]; Hispanic: 0.04 [−0.05 to 0.12]; Asian: 0.04 [−0.04 to 0.13]). Stratified by sex, rates increased in both African-American men and women (P<0.05), but the change in rate was highest among African-American men (men 0.37 [0.28–0.46]; women 0.16 [0.07–0.25]; interaction with sex P=0.004). Stratified by age group, rates increased in African-Americans aged 40 to 69 years and Asians aged 50 to 59 years (P<0.05). The observed differential change in VAD implantation rate by age group was significant among African-Americans (interaction with age, P<0.01) and Asians (interaction with age, P=0.02). Conclusions From 2012 to 2015, VAD implantation rates increased among African-Americans but not other racial/ethnic groups. The greatest increase in rate was observed among middle-aged African-American men, suggesting a decline in racial disparities. Further investigation is warranted to reduce disparities among women and older racial/ethnic minorities.
Left Ventricular Mass Change After Anthracycline Chemotherapy Circ. Heart Fail. (IF 5.684) Pub Date : 2018-07-01 Jennifer H. Jordan, Sharon M. Castellino, Giselle C. Meléndez, Heidi D. Klepin, Leslie R. Ellis, Zanetta Lamar, Sujethra Vasu, Dalane W. Kitzman, William O. Ntim, Peter H. Brubaker, Nathaniel Reichek, Ralph B. D’Agostino, W. Gregory Hundley
Background: Myocardial atrophy and left ventricular (LV) mass reductions are associated with fatigue and exercise intolerance. The relationships between the receipt of anthracycline-based chemotherapy (Anth-bC) and changes in LV mass and heart failure (HF) symptomatology are unknown, as is their relationship to LV ejection fraction (LVEF), a widely used measurement performed in surveillance strategies designed to avert symptomatic HF associated with cancer treatment. Methods and Results: We performed blinded, serial assessments of body weight, LVEF and mass, LV-arterial coupling, aortic stiffness, and Minnesota Living with Heart Failure Questionnaire measures before and 6 months after initiating Anth-bC (n=61) and non–Anth-bC (n=15), and in 24 cancer-free controls using paired t and χ2 tests and multivariable linear models. Participants averaged 51±12 years, and 70% were women. Cancer diagnoses included breast cancer (53%), hematologic malignancy (42%), and soft tissue sarcoma (5%). We observed a 5% decline in both LVEF (P<0.0001) and LV mass (P=0.03) in the setting of increased aortic stiffness and disrupted ventricular-arterial coupling in those receiving Anth-bC but not other groups (P=0.11–0.92). A worsening of the Minnesota Living with Heart Failure Questionnaire score in Anth-bC recipients was associated with myocardial mass declines (r=−0.27; P<0.01) but not with LVEF declines (r=0.11; P=0.45). Moreover, this finding was independent of LVEF changes and body weight. Conclusions: Early after Anth-bC, LV mass reductions associate with worsening HF symptomatology independent of LVEF. These data suggest an alternative mechanism whereby anthracyclines may contribute to HF symptomatology and raise the possibility that surveillance strategies during Anth-bC should also assess LV mass.
Anthracycline Cardiomyopathy Circ. Heart Fail. (IF 5.684) Pub Date : 2018-07-01 Amanda J. Favreau-Lessard, Douglas B. Sawyer, Sanjeev A. Francis
See Article by Jordan et al Anthracycline-based chemotherapy regimens remain in wide use for treatment of many malignancies, despite the rapid growth and development of targeted pathway inhibitors and immunotherapies (both of which can be associated with a variety of cardiovascular toxicities). Discovered in the late 1960s and commonly used as a chemotherapeutic in the early 1970s, anthracycline cardiotoxicity was quickly recognized as a serious complication1,2 and served as the canonical example of chemotherapy-associated cardiomyopathy, spurring the development of the field of cardio-oncology. The observation that left ventricular (LV) mass and growth potential are reduced after exposure to anthracycline chemotherapy was first observed in survivors of childhood cancer and the term Grinch Syndrome was coined by Lipshultz et al3 to describe the potential evolution of reduced LV mass after anthracycline therapy to a restrictive cardiomyopathy in some patients. In adults, a reduction in LV mass has been observed several years after anthracycline-based chemotherapy and is associated with increased cardiac events.4 In this issue of Circulation: Heart Failure , Jordan et al5 provide further details to our understanding of how anthracycline chemotherapy alters cardiac structure and function, using serial cardiac magnetic resonance imaging in a cohort of …
Data-Driven Approach to Identify Subgroups of Heart Failure With Reduced Ejection Fraction Patients With Different Prognoses and Aldosterone Antagonist Response Patterns Circ. Heart Fail. (IF 5.684) Pub Date : 2018-07-01 João Pedro Ferreira, Kevin Duarte, John J.V. McMurray, Bertram Pitt, Dirk J. van Veldhuisen, John Vincent, Tariq Ahmad, Jasper Tromp, Patrick Rossignol, Faiez Zannad
Background: Patients with heart failure with reduced ejection fraction have a poor prognosis. The identification of subgroups with different outcomes and treatment response patterns may help to tailor strategies to each individual patient. We present an exploratory study of patients enrolled in the EMPHASIS-HF trial (Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms) using latent class analysis with validation using the EPHESUS trial (Eplerenone, a Selective Aldosterone Blocker, in Patients With Left Ventricular Dysfunction After Myocardial Infarction) to identify subgroups of patients with different prognosis and response to eplerenone therapy. Methods and Results: Latent class analysis identifies mutually exclusive groups of individuals maximizing within-group similarities and between-group differences. In the EMPHASIS-HF trial, 2279 heart failure with reduced ejection fraction patients were randomized to eplerenone or placebo and were characterized according to 18 clinical features. Subgroup definitions were applied to 6472 patients enrolled in the EPHESUS trial to validate observations. Event-free survival and effect of eplerenone on the composite of cardiovascular death and heart failure hospitalization were determined for each subgroup. Four subgroups were identified with significant differences in event-free survival (P=0.002). The subgroup C had the worst event-free survival in both studies and was characterized by older age, lower body mass index, worse renal function, higher baseline potassium levels, high prevalence of anemia, diabetes mellitus, previous revascularization and higher rates of eplerenone discontinuation, and hyperkalemia during follow-up. Two subgroups (B and C) showed a poorer response to eplerenone in both studies and these groups shared common features such as lower body mass index and high prevalence of anemia. Clinical profiles, prognosis, and treatment response patterns of the 4 subgroups applied in EPHESUS trial presented similarities to those observed in EMPHASIS. Conclusions: Using a data-driven approach, we identified heart failure with reduced ejection fraction subgroups with significantly different prognoses and potentially different responses to eplerenone. However, these data should be regarded as hypothesis-generating and prospective validation is warranted, to assess the potential clinical implications of these subgroups. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00232180.
Embracing the Long Road to Precision Medicine Circ. Heart Fail. (IF 5.684) Pub Date : 2018-07-01 Julio A. Chirinos, David E. Lanfear
See Article by Ferreira et al In classic cardiovascular phase III trials, individuals satisfying a well-defined set of inclusion and exclusion criteria are randomly assigned to receive one of 2 or more treatments in a nonadaptive parallel-arm design. If the trial is positive, for example in favor of treatment A (a new treatment) over treatment B (standard of care), it is concluded that the new treatment benefits such a patient population. A more concrete hypothetical trial may demonstrate that treatment A significantly reduces the composite end point of death or heart failure–related hospitalizations by 20% relative to treatment B. A subjective interpretation that may follow such trial results is that a patient that meets trial criteria will experience a benefit from the treatment (ie, a reduction in adverse outcomes). This interpretation is flawed. In reality, some individuals benefit, some individuals are harmed, and some individuals experience neither benefit nor harm, but the number of individuals who benefit exceeds the number of those who are harmed, such that the net rate of the end point is ≈20% lower in a group of patients receiving treatment A relative to treatment B (for the purposes of our discussion, we will ignore the confidence interval). Explicitly acknowledging this difference in interpretations has increasingly important implications in the era of precision medicine. Implantable cardioverter defibrillator (ICD) trials can further illustrate these concepts. Consider the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial),1 which demonstrated that among patients with heart failure with reduced ejection fraction (HFrEF), New York Heart Association class II or III symptoms, and a left ventricular ejection fraction ≤35%, ICD therapy decreased the risk of death by 23%. Patients who meet indications for ICDs based on well-designed phase III trials may experience infection, bleeding, or mechanical complications as a direct consequence of …
HeartLogic Multisensor Algorithm Identifies Patients During Periods of Significantly Increased Risk of Heart Failure Events Circ. Heart Fail. (IF 5.684) Pub Date : 2018-07-01 Roy S. Gardner, Jagmeet P. Singh, Branislav Stancak, Devi G. Nair, Michael Cao, Christopher Schulze, Pramodsingh H. Thakur, Qi An, Scott Wehrenberg, Eric F. Hammill, Yi Zhang, John P. Boehmer
Background: Care of heart failure (HF) patients results in a high burden on healthcare resources, and estimating prognosis is becoming increasingly important to triage resources wisely. Natriuretic peptides are recommended prognosticators in chronic HF. Our objective was to evaluate whether a multisensor HF index and alert algorithm (HeartLogic) replaces or augments current HF risk stratification. Methods and Results: MultiSENSE (Multisensor Chronic Evaluation in Ambulatory Heart Failure Patients) enrolled 900 patients with cardiac resynchronization therapy defibrillators enabled for collection of heart sounds, respiration, thoracic impedance, heart rate, and activity data. The HeartLogic algorithm automatically calculated a daily HF index and identified periods IN or OUT of an active alert state relative to a configurable threshold. Patients experienced 192 independently adjudicated HF events (average rate, 0.20/patient-year [pt-yr]) during 1 year of follow-up. HF event rates while IN alert was 10-fold higher than OUT of alert (0.80 versus 0.08 events/pt-yr). Combined with NT-proBNP (N-terminal pro-B-type natriuretic peptide) at enrollment (relative to 1000 pg/mL threshold, event rate was 0.42 [HIGH] versus 0.07 [LOW] events/pt-yr), substratification found the lowest risk group (LOW NT-proBNP and OUT of alert) experienced 0.02 events/pt-yr, whereas the highest risk group (HIGH NT-proBNP and IN alert) was associated with a 50-fold increased risk of an HF event (1.00 events/pt-yr) relative to the lowest risk group. Conclusions: Dynamic assessment using implantable device sensors within HeartLogic by itself or in conjunction with NT-proBNP measurements can identify time-intervals when patients are at significantly increased risk of worsening HF and potentially better triage resources to this vulnerable patient population. Clinical Trial Registration: https://www.clinicaltrials.gov. Unique identifier: NCT01128166.
The Luck of Having a Cardiac Implantable Electronic Device Circ. Heart Fail. (IF 5.684) Pub Date : 2018-07-01 Maria Rosa Costanzo
See Article by Gardner et al > Shallow men believe in luck or in circumstance. > > Strong men believe in cause and effect. > > —Ralph Waldo Emerson The principle aims of the post hoc analysis by Gardner et al1 were to use data from the MultiSENSE study (Multisensor Chronic Evaluation in Ambulatory Heart Failure Patients) to further stratify the 1-year risk of heart failure events (HFE) based on different thresholds of the HeartLogic alert algorithm, compare their prognostic power to that of different NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and assess whether the combination of algorithm and biomarker values stratified the risk of an HFE better than each measure alone.2 To develop the HeartLogic alert algorithm, data collected from multiple device sensors were used in combination with clinical baseline and HFE data. Initial analyses evaluated the performance of each sensor parameter to predict an HFE. Heart sounds (S1 and S3), thoracic impedance, respiration, heart rate, and activity emerged as variables detectable by device sensors that are predictive of an HFE. Changes in these features from each patient’s baseline were aggregated and weighted based on an individual’s daily risk for worsening HF. The HeartLogic index value is updated daily, and an alert is issued when the index crosses the nominal threshold of 16. In the MultiSENSE study, this alert index predicted the occurrence of HFE with a 70% sensitivity and a median of 34-day warning.2 The findings of the analysis by Gardner et al1 are undoubtedly impressive. Among 900 patients (average event rate: 0.20/patient-year), 145 HFE occurred over 1 year in 88 patients with evaluable HeartLogic alert algorithm. The risk of a HFE during periods in alert status was 10-fold that occurring during periods out of alert status (0.80 versus 0.08/patient-year).2 Substratification showed that, compared with the lowest risk …
Baseline Characteristics of Patients With Heart Failure and Preserved Ejection Fraction in the PARAGON-HF Trial Circ. Heart Fail. (IF 5.684) Pub Date : 2018-07-01 Scott D. Solomon, Adel R. Rizkala, Martin P. Lefkowitz, Victor C. Shi, JianJian Gong, Nagesh Anavekar, Stefan D. Anker, Juan L. Arango, Jose L. Arenas, Dan Atar, Turia Ben-Gal, Sergey A. Boytsov, Chen-Huan Chen, Vijay K. Chopra, John Cleland, Josep Comin-Colet, Hans-Dirk Duengen, Luis E. Echeverría Correa, Gerasimos Filippatos, Andreas J. Flammer, Michel Galinier, Armando Godoy, Eva Goncalvesova, Stefan Janssens, Tzvetana Katova, Lars Køber, Małgorzata Lelonek, Gerard Linssen, Lars H. Lund, Eileen O’Meara, Béla Merkely, Davor Milicic, Byung-Hee Oh, Sergio V. Perrone, Naresh Ranjith, Yoshihiko Saito, Jose F. Saraiva, Sanjiv Shah, Petar M. Seferovic, Michele Senni, Antonio S. Sibulo, David Sim, Nancy K. Sweitzer, Jyrki Taurio, Dragos Vinereanu, Bojan Vrtovec, Jiří Widimský, Mehmet B. Yilmaz, Jingmin Zhou, Robert Zweiker, Inder S. Anand, Junbo Ge, Carolyn S.P. Lam, Aldo P. Maggioni, Felipe Martinez, Milton Packer, Marc A. Pfeffer, Burkert Pieske, Margaret M. Redfield, Jean L. Rouleau, Dirk J. Van Veldhuisen, Faiez Zannad, Michael R. Zile, John J.V. McMurray
Background: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. Methods and Results: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), β-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464–1610), and structural heart disease. Conclusions: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.
Dermal Interstitial Alterations in Patients With Heart Failure and Reduced Ejection Fraction Circ. Heart Fail. (IF 5.684) Pub Date : 2018-07-01 Petra Nijst, Mikhail Olinevich, Petra Hilkens, Pieter Martens, Matthias Dupont, W.H. Wilson Tang, Ivo Lambrichts, Jean-Paul Noben, Wilfried Mullens
Background: Large networks of interstitial glycosaminoglycans help to regulate water and electrolyte homeostasis. The relation between dermal interstitial alterations and occurrence of edema in heart failure patients with reduced ejection fraction (HFrEF) is unknown. We hypothesize that in HFrEF patients (1) interstitial glycosaminoglycan density is increased, (2) changes in the interstitial glycosaminoglycan network are associated with interstitial fluid accumulation, and (3) there is a link between the interstitial glycosaminoglycan network and the renin-angiotensin-aldosterone system. Methods and Results: Two punch biopsies of the skin were obtained in healthy subjects (n=18) and HFrEF patients (n=29). Alcian blue staining and immunostaining for the angiotensin II type 1 receptor was performed. After obtaining tissue water content, total interstitial glycosaminoglycan (uronic acid) and sulfated glycosaminoglycan were quantified. A venous blood sample, clinical examination, and echocardiography were obtained. A significantly higher interstitial glycosaminoglycan content was observed in HFrEF patients compared with healthy subjects (uronic acid: 13.0±4.2 versus 9.6±1.6 μg/mg; P=0.002; sulfated glycosaminoglycan: 14.1 [11.7; 18.1] versus 10.0 [9.1; 10.8] μg/mg; P<0.001). Uronic acid and sulfated glycosaminoglycan density were strongly associated with tissue water content and peripheral edema (uronic acid: ρ=0.66; P<0.0001 and sulfated glycosaminoglycan: τ=0.58; P<0.0001). Expression of the angiotensin II type 1 receptor was found on dermal cells, although use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker was associated with significantly lower levels of interstitial glycosaminoglycans in HFrEF patients. Conclusions: Interstitial glycosaminoglycan concentration is significantly increased in HFrEF patients compared with healthy subjects and correlated with tissue water content and clinical signs of volume overload. A better appreciation of the interstitial compartment might improve management of volume overload in HF.
Regulation of Fluid Volume From the Outside Circ. Heart Fail. (IF 5.684) Pub Date : 2018-07-01 Helge Wiig
See Article by Nijst et al Few will argue against the central role of salt in fluid volume and blood pressure homeostasis—a role that has passed the test of time through classical studies linking blood pressure and Na+ balance,1 also placing the kidney in the very center of extracellular fluid volume and blood pressure homeostasis.2 This fact notwithstanding, a role for other tissues like the interstitium, mostly in skin, has more recently been suggested in an increasing number of studies.3 Indeed, already Guyton et al4 proposed that strongly negatively charged mucopolysaccharides (now named glycosaminoglycans [GAGs]) could attract and thereby generate a higher density of cations, notably Na+, and that “tissue fluids, pressures, and gel” could influence overall regulation of circulation.5 There are 2 major types of GAGs, hyaluronan having 1 charge and sulfated GAGs having ≤3 charges per disaccharide unit.6 At physiological pH, GAGs have a net negative charge, thus attracting counterions. Although there existed data showing Na+ accumulation in skin, thus challenging the commonly accepted sodium homeostasis principle,7 this challenge was brought to a new level by Titze et al who introduced a new paradigm with regard to salt handling in the body. In studies from humans, rats, and mice, they showed that Na+ can be buffered in the body in kidney-independent reservoirs. This occurs without commensurate water retention, thereby making the Na+ osmotically inactive by association with negatively charged GAGs and thereby invisible to the kidney. In a series of studies, they demonstrated that the skin acts as kidney-independent regulator of the release and storage of Na+, for example,8 making the interstitium and its extracellular matrix and gel phase an additional player in Na+ homeostasis. Without questioning the undisputed role of …
Sarcomeric Auto-Oscillations in Single Myofibrils From the Heart of Patients With Dilated Cardiomyopathy Circ. Heart Fail. (IF 5.684) Pub Date : 2018-07-01 Tatsuya Kagemoto, Kotaro Oyama, Mitsunori Yamane, Seiichi Tsukamoto, Fuyu Kobirumaki-Shimozawa, Amy Li, Cristobal Dos Remedios, Norio Fukuda, Shin’ichi Ishiwata
Background: Left ventricular wall motion is depressed in patients with dilated cardiomyopathy (DCM). However, whether or not the depressed left ventricular wall motion is caused by impairment of sarcomere dynamics remains to be fully clarified. Methods and Results: We analyzed the mechanical properties of single sarcomere dynamics during sarcomeric auto-oscillations (calcium spontaneous oscillatory contractions [Ca-SPOC]) that occurred at partial activation under the isometric condition in myofibrils from donor hearts and from patients with severe DCM (New York Heart Association classification III-IV). Ca-SPOC reproducibly occurred in the presence of 1 μmol/L free Ca2+ in both nonfailing and DCM myofibrils, and sarcomeres exhibited a saw-tooth waveform along single myofibrils composed of quick lengthening and slow shortening. The period of Ca-SPOC was longer in DCM myofibrils than in nonfailing myofibrils, in association with prolonged shortening time. Lengthening time was similar in both groups. Then, we performed Tn (troponin) exchange in myofibrils with a DCM-causing homozygous mutation (K36Q) in cTnI (cardiac TnI). On exchange with the Tn complex from healthy porcine ventricles, period, shortening time, and shortening velocity in cTnI-K36Q myofibrils became similar to those in Tn-reconstituted nonfailing myofibrils. Protein kinase A abbreviated period in both Tn-reconstituted nonfailing and cTnI-K36Q myofibrils, demonstrating acceleration of cross-bridge kinetics. Conclusions: Sarcomere dynamics was found to be depressed under loaded conditions in DCM myofibrils because of impairment of thick-thin filament sliding. Thus, microscopic analysis of Ca-SPOC in human cardiac myofibrils is beneficial to systematically unveil the kinetic properties of single sarcomeres in various types of heart disease.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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