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  • Cystatin C- Versus Creatinine-Based Assessment of Renal Function and Prediction of Early Outcomes Among Patients With a Left Ventricular Assist Device
    Circ. Heart Fail. (IF 6.526) Pub Date : 2020-01-21
    Alberto Pinsino; Giulio M. Mondellini; Eugene A. Royzman; Katherine L. Hoffman; Debra D’Angelo; Melissa Mabasa; Antonia Gaudig; Amelia M. Zuver; Amirali Masoumi; A. Reshad Garan; Sumit Mohan; Syed A. Husain; Katherine Toma; Robert T. Faillace; Jon T. Giles; Koji Takeda; Hiroo Takayama; Yoshifumi Naka; Veli K. Topkara; Ryan T. Demmer; Jai Radhakrishnan; Paolo C. Colombo; Melana Yuzefpolskaya

    Background:Estimated glomerular filtration rate (eGFR) based on serum creatinine (sCr) improves early after left ventricular assist device (LVAD) implantation but subsequently declines. Although sCr is a commonly accepted clinical standard, cystatin C (CysC) has shown superiority in assessment of renal function in disease states characterized by muscle wasting. Among patients with an LVAD, we aimed to (1) longitudinally compare CysC-eGFR and sCr-eGFR, (2) assess their predictive value for early postoperative outcomes, and (3) investigate mechanisms which might explain potential discrepancies.Methods:A prospective cohort (n=116) with CysC and sCr concurrently measured at serial time points, and a retrospective cohort (n=91) with chest computed tomography performed within 40 days post-LVAD were studied. In the prospective cohort, the primary end point was a composite of in-hospital mortality, renal replacement therapy, or severe right ventricular failure. In the retrospective cohort, muscle mass was estimated using pectoralis muscle area indexed to body surface area (pectoralis muscle index).Results:In the prospective cohort, sCr-eGFR significantly improved early post-LVAD and subsequently declined, whereas CysC-eGFR remained stable. CysC-eGFR but not sCr-eGFR predicted the primary end point: odds ratio per 5 mL/(min·1.73 m2) decrease 1.16 (1.02–1.31) versus 0.99 (0.94–1.05). In retrospective cohort, for every 5 days post-LVAD, a 6% decrease in pectoralis muscle index was observed (95% CI, 2%–9%, P=0.003). After adjusting for time on LVAD, for every 1 cm2/m2 decrease in pectoralis muscle index, there was a 4% decrease in 30-day post-LVAD sCr (95% CI, 1%–6%, P=0.004).Conclusions:Initial improvement in sCr-eGFR is likely due to muscle wasting following LVAD surgery. CysC may improve assessment of renal function and prediction of early postoperative outcomes in patients with an LVAD.

    更新日期:2020-01-22
  • Low- Versus Moderate-Sodium Diet in Patients With Recent Hospitalization for Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2020-01-21
    Andreas Kalogeropoulos; Lampros Papadimitriou; Vasiliki V. Georgiopoulou; Sandra B. Dunbar; Hal Skopicki; Javed Butler

    Background:We conducted a pilot study to assess feasibility, on-study retention, trends in natriuretic peptide levels, quality of life, and safety of a 12-week feeding trial with 1500- versus 3000-mg daily sodium meals in high-risk patients with heart failure.Methods:Of 196 patients with recent (≤2 weeks) hospitalization for heart failure, ejection fraction ≤40%, on optimal medical therapy, functionally independent, and able to communicate, 83 (47%) consented to participate. Of these, 27 (age, 62±11 years; 22 men; 20 white; ejection fraction, 26±8%) had 24-hour urine sodium ≥3000 mg and agreed to randomly receive either 1500-mg (N=12) or 3000-mg (N=15) sodium meals.Results:On-study retention at 12 weeks was 77% (82% versus 73%; P=0.53); 6 patients (2 in 1500-mg, 4 in 3000-mg arm) withdrew before study completion. Food satisfaction questionnaires indicated that both diets were well tolerated. Quality of life improved in the 1500-mg arm at 12 weeks but did not change in the 3000-mg arm. Average compliance with meals was 52% (based on urinary sodium) and was not significantly different between arms (42% versus 60%; P=0.25). Study meals reduced 24-hour urinary sodium by 137±21 mmol (1500-mg arm) and 82±16 mmol (3000-mg arm), both P<0.001; between-arms difference was 55 mmol (95% CI, 3–107; P=0.037). NT-proBNP (N-terminal pro-B-type natriuretic peptide) was not affected. Hospitalizations and low blood pressure events did not differ significantly between arms. Serum creatinine decreased more (by 0.17 mg/dL [95% CI, 0.06–0.28]; P=0.003) in the 1500-mg arm. Creatinine increases >0.5 mg/dL over baseline only occurred in 1 patient in the 3000-mg arm.Conclusions:Even with prepared meals, investigating optimal dietary sodium in heart failure comes with challenges, including need for extensive screening, reluctance to participate, and compliance issues. Because both diets reduced urinary sodium without adverse safety or quality of life signals, a larger trial, with modifications to improve participation and compliance, would be ethical and feasible.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT02467296

    更新日期:2020-01-22
  • Percutaneous Mechanical Unloading Simultaneously With Reperfusion Induces Increased Myocardial Salvage in Experimental Acute Myocardial Infarction
    Circ. Heart Fail. (IF 6.526) Pub Date : 2020-01-21
    Byungsoo Ko; Stavros G. Drakos; Homam Ibrahim; Tae Soo Kang; Aspasia Thodou; Michael Bonios; Iosif Taleb; Frederick GP. Welt

    Background:Despite advances in reperfusion times, patients presenting with acute myocardial infarction carry an unacceptably high rate of mortality and morbidity. Mechanical unloading of the left ventricle (LV) has been suggested to reduce infarct size after acute myocardial infarction. Although prior studies have investigated LV unloading during ischemia with a delay in reperfusion, little is known about the optimal timing for LV unloading in the setting of acute myocardial infarction.Methods:Studies were conducted in 17 adult Yorkshire swine weighing 67±5 kg. A coronary balloon was inflated in the mid left anterior descending for 60 minutes to induce a myocardial infarction. The coronary balloon was then deflated for 120 minutes (reperfusion). The animals were stratified into 3 groups: group 1 (control, reperfusion with no LV unloading, n=5), group 2 (LV unloading during ischemia with delayed reperfusion, n=6), and group 3 (simultaneous LV unloading and reperfusion, n=6). Staining the hearts with Evans blue and 2,3,5-triphenyltetrazolium chloride was used to identify the area at risk and the infarct area respectively. Infarct percent size was defined as the area of infarcted myocardium divided by the area at risk.Results:Of the 3 groups, group 3 demonstrated significantly smaller infarct percent size compared with controls (54.7±20.3% versus 22.2±13.4%; P=0.03). Comparison between group 1 and group 2 did not reveal significant difference (54.7±20.3% versus 43.3±24.6%; P=0.19).Conclusions:In our large animal experimental model, simultaneous reperfusion and mechanical LV unloading yielded the smallest infarct size compared with no LV unloading or LV unloading with delayed reperfusion. In the context of prior studies showing benefit to unloading before reperfusion, these findings raise questions about how this strategy may be translated to humans.

    更新日期:2020-01-22
  • Empagliflozin Blunts Worsening Cardiac Dysfunction Associated With Reduced NLRP3 (Nucleotide-Binding Domain-Like Receptor Protein 3) Inflammasome Activation in Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2020-01-20
    Nikole J. Byrne; Nobutoshi Matsumura; Zaid H. Maayah; Mourad Ferdaoussi; Shingo Takahara; Ahmed M. Darwesh; Jody L. Levasseur; James Won Suk Jahng; Dyonne Vos; Nirmal Parajuli; Ayman O.S. El-Kadi; Branko Braam; Martin E. Young; Subodh Verma; Peter E. Light; Gary Sweeney; John M. Seubert; Jason R.B. Dyck

    Background:Although empagliflozin was shown to profoundly reduce cardiovascular events in diabetic patients and blunt the decline in cardiac function in nondiabetic mice with established heart failure (HF), the mechanism of action remains unknown.Methods and Results:We treated 2 rodent models of HF with 10 mg/kg per day empagliflozin and measured activation of the NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome in the heart. We show for the first time that beneficial effects of empagliflozin in HF with reduced ejection fraction (HF with reduced ejection fraction [HFrEF]; n=30–34) occur in the absence of changes in circulating ketone bodies, cardiac ketone oxidation, or increased cardiac ATP production. Of note, empagliflozin attenuated activation of the NLRP3 inflammasome and expression of associated markers of sterile inflammation in hearts from mice with HFrEF, implicating reduced cardiac inflammation as a mechanism of empagliflozin that contributes to sustained function in HFrEF in the absence of diabetes mellitus. In addition, we validate that the beneficial cardiac effects of empagliflozin in HF with preserved ejection fraction (HFpEF; n=9–10) are similarly associated with reduced activation of the NLRP3 inflammasome. Lastly, the ability of empagliflozin to reduce inflammation was completely blunted by a calcium (Ca2+) ionophore, suggesting that empagliflozin exerts its benefit upon restoring optimal cytoplasmic Ca2+ levels in the heart.Conclusions:These data provide evidence that the beneficial cardiac effects of empagliflozin are associated with reduced cardiac inflammation via blunting activation of the NLRP3 inflammasome in a Ca2+-dependent manner and hence may be beneficial in treating HF even in the absence of diabetes mellitus.

    更新日期:2020-01-21
  • Long Noncoding RNA Ahit Protects Against Cardiac Hypertrophy Through SUZ12 (Suppressor of Zeste 12 Protein Homolog)-Mediated Downregulation of MEF2A (Myocyte Enhancer Factor 2A)
    Circ. Heart Fail. (IF 6.526) Pub Date : 2020-01-20
    Junyi Yu; Yang Yang; Zaicheng Xu; Cong Lan; Caiyu Chen; Chuanwei Li; Zhi Chen; Cheng Yu; Xuewei Xia; Qiao Liao; Pedro A. Jose; Chunyu Zeng; Gengze Wu

    Background:Long noncoding RNA (lncRNA) can regulate various physiological and pathological processes through multiple molecular mechanisms in cis and in trans. However, the role of lncRNAs in cardiac hypertrophy is yet to be fully elucidated.Methods:A mouse lncRNA microarray was used to identify differentially expressed lncRNAs in the mouse hearts following transverse aortic constriction–induced pressure overload comparing to the sham-operated samples. The direct impact of one lncRNA, Ahit, on cardiomyocyte hypertrophy was characterized in neonatal rat cardiomyocytes in response to phenylephrine by targeted knockdown and overexpression. The in vivo function of Ahit was analyzed in mouse hearts by using cardiac-specific adeno-associated virus, serotype 9–short hairpin RNA to knockdown Ahit in combination with transverse aortic constriction. Using catRAPID program, an interaction between Ahit and SUZ12 (suppressor of zeste 12 protein homolog) was predicted and validated by RNA immunoprecipitation and immunoblotting following RNA pull-down. Chromatin immunoprecipitation was performed to determine SUZ12 or H3K27me3 occupancy on the MEF2A (myocyte enhancer factor 2A) promoter. Finally, the expression of human Ahit (leukemia-associated noncoding IGF1R activator RNA 1 [LUNAR1]) in the serum samples from patients of hypertrophic cardiomyopathy was tested by quantitative real-time polymerase chain reaction.Results:A previously unannotated lncRNA, antihypertrophic interrelated transcript (Ahit), was identified to be upregulated in the mouse hearts after transverse aortic constriction. Inhibition of Ahit induced cardiac hypertrophy, both in vitro and in vivo, associated with increased expression of MEF2A, a critical transcriptional factor involved in cardiac hypertrophy. In contrast, overexpression of Ahit significantly attenuated stress-induced cardiac hypertrophy in vitro. Furthermore, Ahit was significantly upregulated in serum samples of patients diagnosed with hypertensive heart disease versus nonhypertrophic hearts (1.46±0.17 fold, P=0.0325). Mechanistically, Ahit directly bound and recruited SUZ12, a core PRC2 (polycomb repressive complex 2) protein, to the promoter of MEF2A, triggering its trimethylation on H3 lysine 27 (H3K27me3) residues and mediating the downregulation of MEF2A, thereby preventing cardiac hypertrophy.Conclusions:Ahit is a lncRNA with a significant role in cardiac hypertrophy regulation through epigenomic modulation. Ahit is a potential therapeutic target of cardiac hypertrophy.

    更新日期:2020-01-21
  • Mechanistic Effects of Spironolactone on Cardiovascular and Renal Biomarkers in Heart Failure With Preserved Ejection Fraction
    Circ. Heart Fail. (IF 6.526) Pub Date : 2020-01-20
    Peder L. Myhre; Muthiah Vaduganathan; Eileen O’Meara; Brian L. Claggett; Simon de Denus; Petr Jarolim; Inder S. Anand; Bertram Pitt; Jean L. Rouleau; Scott D. Solomon; Marc A. Pfeffer; Akshay S. Desai

    Background:Spironolactone has been demonstrated to reduce heart failure (HF) hospitalization in patients with HF with preserved ejection fraction in the Americas region of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). We assessed effects of 12 months of treatment with spironolactone on biomarkers reflecting myocardial stress, myocardial injury, renal function, and systemic inflammation.Methods:This TOPCAT biorepository substudy evaluated 247 patients (14% of the total 1767 patients in the Americas region) with symptomatic HF, ejection fraction ≥45%, and elevated natriuretic peptides or a prior HF hospitalization. Paired blood samples at baseline and after 12 months of treatment with spironolactone or placebo were available in 204 patients.Results:At baseline, the median (interquartile range) concentration of BNP (B-type natriuretic peptide) was 124 (69–197) ng/L, NT-proBNP (N-terminal-pro-B-type natriuretic peptide) 624 (307–1312) ng/L, hs-cTnI (high sensitivity cardiac troponin I) 6.3 (3.4–13.0) ng/L, hs-CRP (high sensitivity C-reactive protein) 2.8 (1.3–6.1) mg/L, uric acid 7.2 (5.8–8.7) mg/dL, and urine protein-creatinine ratio 0.11 (0.08–0.20) mg/mg. Compared with placebo-assigned participants at 12 months, those randomized to spironolactone experienced greater reductions from baseline in levels of NT-proBNP (P=0.017) and BNP (P=0.002); these differences persisted after adjustment for demographics, comorbidities, estimated glomerular filtration rate, and enrollment strata. No between-group differences in changes in hs-cTnI, CRP, uric acid, or urine protein-creatinine ratio were observed.Conclusions:This TOPCAT biorepository substudy suggests potential effects on markers of cardiac wall stress or filling pressures during 12 months of treatment with spironolactone in patients with chronic HF with preserved ejection fraction.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00094302.

    更新日期:2020-01-21
  • β1-Adrenoreceptor Autoantibodies in Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2020-01-20
    Hans-Dirk Düngen; Aleksandar Dordevic; Stephan B. Felix; Burkert Pieske; Adriaan A. Voors; John J.V. McMurray; Javed Butler

    Antibodies that activate the β1-AR (β1-adrenoreceptor) can induce heart failure in animal models. These antibodies are often found in patients with heart failure secondary to varying etiologies. Their binding to the β1 receptor leads to prolonged receptor activation with subsequent induction of cellular dysfunction, apoptosis, and arrhythmias. β-blocker therapy while highly effective for heart failure, may not be sufficient treatment for patients who have β1 receptor autoantibodies. Removal of these autoantibodies by immunoadsorption has been shown to improve heart failure in small studies. However, immunoadsorption is costly, time consuming, and carries potential risks. An alternative to immunoadsorption is neutralization of autoantibodies through the intravenous application of small soluble molecules, such as peptides or aptamers, which specifically target and neutralize β1-AR autoantibodies. Peptides may induce immunogenicity. Animal as well as early phase human studies with aptamers have not shown safety concerns to date and have demonstrated effectiveness in reducing autoantibody levels. Novel aptamers have the potential advantage of having a wide spectrum of action, neutralizing a variety of known circulating G-protein coupled receptor autoantibodies. These aptamers, therefore, have the potential to be novel therapeutic option for patients with heart failure who have positive for β1-AR autoantibodies. However, clinical outcomes trials are needed to assess the clinical utility of this novel approach to treat heart failure.

    更新日期:2020-01-21
  • Differential microRNA-21 and microRNA-221 Upregulation in the Biventricular Failing Heart Reveals Distinct Stress Responses of Right Versus Left Ventricular Fibroblasts
    Circ. Heart Fail. (IF 6.526) Pub Date : 2020-01-09
    Jeffery C. Powers; Abdelkarim Sabri; Dalia Al-Bataineh; Dhruv Chotalia; Xinji Guo; Florence Tsipenyuk; Remus Berretta; Pavithra Kavitha; Heramba Gopi; Steven R. Houser; Mohsin Khan; Emily J. Tsai; Fabio A. Recchia

    Background:The failing right ventricle (RV) does not respond like the left ventricle (LV) to guideline-directed medical therapy of heart failure, perhaps due to interventricular differences in their molecular pathophysiology.Methods:Using the canine tachypacing–induced biventricular heart failure (HF) model, we tested the hypothesis that interventricular differences in microRNAs (miRs) expression distinguish failing RV from failing LV.Results:Severe RV dysfunction was indicated by elevated end-diastolic pressure (11.3±2.5 versus 5.7±2.0 mm Hg; P<0.0001) and diminished fractional area change (24.9±7.1 versus 48.0±3.6%; P<0.0001) relative to prepacing baselines. Microarray analysis of ventricular tissue revealed that miR-21 and miR-221, 2 activators of profibrotic and proliferative processes, increased the most, at 4- and 2-fold, respectively, in RV-HF versus RV-Control. Neither miR-21 or miR-221 was statistically significantly different in LV-HF versus LV-Control. These changes were accompanied by more extensive fibrosis in RV-HF than LV-HF. To test whether miR-21 and miR-221 upregulation is specific to RV cellular response to mechanical and hormonal stimuli associated with HF, we subjected fibroblasts and cardiomyocytes isolated from normal canine RV and LV to cyclic overstretch and aldosterone. These 2 stressors markedly upregulated miR-21 and miR-221 in RV fibroblasts but not in LV fibroblasts nor cardiomyocytes of either ventricle. Furthermore, miR-21/221 knockdown significantly attenuated RV but not LV fibroblast proliferation.Conclusions:We identified a novel, biological difference between RV and LV fibroblasts that might underlie distinctions in pathological remodeling of the RV in biventricular HF.

    更新日期:2020-01-10
  • Effect of Blood Flow Restricted Resistance Exercise and Remote Ischemic Conditioning on Functional Capacity and Myocellular Adaptations in Patients With Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-12-13
    Thomas Groennebaek; Peter Sieljacks; Roni Nielsen; Kasper Pryds; Nichlas R. Jespersen; Jakob Wang; Caroline R. Carlsen; Michael R. Schmidt; Frank V. de Paoli; Benjamin F. Miller; Kristian Vissing; Hans Erik Bøtker

    Background:Patients with congestive heart failure (CHF) have impaired functional capacity and inferior quality of life. The clinical manifestations are associated with structural and functional impairments in skeletal muscle, emphasizing a need for feasible rehabilitation strategies beyond optimal anticongestive medical treatment. We investigated whether low-load blood flow restricted resistance exercise (BFRRE) or remote ischemic conditioning (RIC) could improve functional capacity and quality of life in patients with CHF and stimulate skeletal muscle myofibrillar and mitochondrial adaptations.Methods:We randomized 36 patients with CHF to BFRRE, RIC, or nontreatment control. BFRRE and RIC were performed 3× per week for 6 weeks. Before and after intervention, muscle biopsies, tests of functional capacity, and quality of life assessments were performed. Deuterium oxide was administered throughout the intervention to measure cumulative RNA and subfraction protein synthesis. Changes in muscle fiber morphology and mitochondrial respiratory function were also assessed.Results:BFRRE improved 6-minute walk test by 39.0 m (CI, 7.0–71.1, P=0.019) compared with control. BFRRE increased maximum isometric strength by 29.7 Nm (CI, 10.8–48.6, P=0.003) compared with control. BFRRE improved quality of life by 5.4 points (CI, −0.04 to 10.9; P=0.052) compared with control. BFRRE increased mitochondrial function by 19.1 pmol/s per milligram (CI, 7.3–30.8; P=0.002) compared with control. RIC did not produce similar changes.Conclusions:Our results demonstrate that BFRRE, but not RIC, improves functional capacity, quality of life, and muscle mitochondrial function. Our findings have clinical implications for rehabilitation of patients with CHF and provide new insights on the myopathy accompanying CHF.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT03380663.

    更新日期:2019-12-13
  • Collaborative Regulation of LRG1 by TGF-β1 and PPAR-β/δ Modulates Chronic Pressure Overload–Induced Cardiac Fibrosis
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-12-13
    Chenghao Liu; Seok Ting Lim; Melissa Hui Yen Teo; Michelle Si Ying Tan; Madhura Dattatraya Kulkarni; Beiying Qiu; Amy Li; Sean Lal; Cristobal G. dos Remedios; Nguan Soon Tan; Walter Wahli; Michael Alan Ferenczi; Weihua Song; Wanjin Hong; Xiaomeng Wang

    Background:Despite its established significance in fibrotic cardiac remodeling, clinical benefits of global inhibition of TGF (transforming growth factor)-β1 signaling remain controversial. LRG1 (leucine-rich-α2 glycoprotein 1) is known to regulate endothelial TGFβ signaling. This study evaluated the role of LRG1 in cardiac fibrosis and its transcriptional regulatory network in cardiac fibroblasts.Methods:Pressure overload–induced heart failure was established by transverse aortic constriction. Western blot, quantitative reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to evaluate the expression level and pattern of interested targets or pathology during fibrotic cardiac remodeling. Cardiac function was assessed by pressure-volume loop analysis.Results:LRG1 expression was significantly suppressed in left ventricle of mice with transverse aortic constriction–induced fibrotic cardiac remodeling (mean difference, −0.00085 [95% CI, −0.0013 to −0.00043]; P=0.005) and of patients with end-stage ischemic-dilated cardiomyopathy (mean difference, 0.13 [95% CI, 0.012–0.25]; P=0.032). More profound cardiac fibrosis (mean difference, −0.014% [95% CI, −0.029% to −0.00012%]; P=0.048 for interstitial fibrosis; mean difference, −1.3 [95% CI, −2.5 to −0.2]; P=0.016 for perivascular fibrosis), worse cardiac dysfunction (mean difference, −2.5 ms [95% CI, −4.5 to −0.4 ms]; P=0.016 for Tau-g; mean difference, 13% [95% CI, 2%–24%]; P=0.016 for ejection fraction), and hyperactive TGFβ signaling in transverse aortic constriction–operated Lrg1-deficient mice (mean difference, −0.27 [95% CI, −0.47 to −0.07]; P<0.001), which could be reversed by cardiac-specific Lrg1 delivery mediated by adeno-associated virus 9. Mechanistically, LRG1 inhibits cardiac fibroblast activation by competing with TGFβ1 for receptor binding, while PPAR (peroxisome proliferator-activated receptor)-β/δ and TGFβ1 collaboratively regulate LRG1 expression via SMRT (silencing mediator for retinoid and thyroid hormone receptor). We further demonstrated functional interactions between LRG1 and PPARβ/δ in cardiac fibroblast activation.Conclusions:Our results established a highly complex molecular network involving LRG1, TGFβ1, PPARβ/δ, and SMRT in regulating cardiac fibroblast activation and cardiac fibrosis. Targeting LRG1 or PPARβ/δ represents a promising strategy to control pathological cardiac remodeling in response to chronic pressure overload.

    更新日期:2019-12-13
  • Extracorporeal Membrane Oxygenation Use in Acute Myocardial Infarction in the United States, 2000 to 2014
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-12-12
    Saraschandra Vallabhajosyula; Abhiram Prasad; Malcolm R. Bell; Gurpreet S. Sandhu; Mackram F. Eleid; Shannon M. Dunlay; Gregory J. Schears; John M. Stulak; Mandeep Singh; Bernard J. Gersh; Allan S. Jaffe; David R. Holmes Jr; Charanjit S. Rihal; Gregory W. Barsness

    Background:Extracorporeal membrane oxygenation (ECMO) is increasingly used in acute myocardial infarction (AMI); however, there are limited large-scale national data.Methods:Using the National Inpatient Sample database from 2000 to 2014, a retrospective cohort of AMI utilizing ECMO was identified. Use of percutaneous coronary intervention, intra-aortic balloon pump, and percutaneous left ventricular assist device (LVAD) was also identified in this population. Outcomes of interest included temporal trends in utilization of ECMO alone and with concomitant procedures (percutaneous coronary intervention, intra-aortic balloon pump, and percutaneous LVAD), in-hospital mortality, and resource utilization.Results:In ≈9 million AMI admissions, ECMO was used in 2962 (<0.01%) and implanted a median of 1 day after admission. ECMO was used in 0.5% and 0.3% AMI admissions complicated by cardiogenic shock and cardiac arrest, respectively. ECMO was used more commonly in admissions that were younger, nonwhite, and with less comorbidity. ECMO use was 11× higher in 2014 as compared with 2000 (odds ratio, 11.37 [95% CI, 7.20–17.97]). Same-day percutaneous coronary intervention was performed in 23.1%; intra-aortic balloon pump/percutaneous LVAD was used in 57.9%, of which 30.3% were placed concomitantly. In-hospital mortality with ECMO was 59.2% overall but decreased from 100% (2000) to 45.1% (2014). Durable LVAD and cardiac transplantation were performed in 11.7% as an exit strategy. Of the hospital survivors, 40.8% were discharged to skilled nursing facilities. Older age, male sex, nonwhite race, and lower socioeconomic status were independently associated with higher in-hospital mortality with ECMO use.Conclusions:In AMI admissions, a steady increase was noted in the utilization of ECMO alone and with concomitant procedures (percutaneous coronary intervention, intra-aortic balloon pump, and percutaneous LVAD). In-hospital mortality remained high in AMI admissions treated with ECMO.

    更新日期:2019-12-13
  • Baseline Characteristics of the VANISH Cohort
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-12-09
    Anna Axelsson Raja, Ling Shi, Sharlene M. Day, Mark Russell, Kenneth Zahka, Harry Lever, Steven D. Colan, Renee Margossian, E. Kevin Hall, Jason Becker, John Lynn Jefferies, Amit R. Patel, Lubna Choudhury, Anne M. Murphy, Charles Canter, Richard Bach, Matthew Taylor, Luisa Mestroni, Matthew T. Wheeler, Lee Benson, Anjali T. Owens, Joseph Rossano, Kimberly Y. Lin, Elfriede Pahl, Alexandre C. Pereira, Henning Bundgaard, Gregory D. Lewis, Jose D. Vargas, Allison L. Cirino, John J.V. McMurray, Calum A. MacRae, Scott D. Solomon, E. John Orav, Eugene Braunwald, Carolyn Y. Ho

    Background:The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers.Methods:Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy.Results:In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and Z score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age, MYH7 variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19–133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required.Conclusions:The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and MYH7 variants, suggesting both phenotype and genotype contribute to disease manifestations.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.

    更新日期:2019-12-09
  • Sex-Related Differences in Heart Failure With Preserved Ejection Fraction
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-12-09
    Pooja Dewan, Rasmus Rørth, Valeria Raparelli, Ross T. Campbell, Li Shen, Pardeep S. Jhund, Mark C. Petrie, Inder S. Anand, Peter E. Carson, Akshay S. Desai, Christopher B. Granger, Lars Køber, Michel Komajda, Robert S. McKelvie, Eileen O’Meara, Marc A. Pfeffer, Bertram Pitt, Scott D. Solomon, Karl Swedberg, Michael R. Zile, John J.V. McMurray

    Background:To describe characteristics and outcomes in women and men with heart failure with preserved ejection fraction.Methods:Baseline characteristics (including biomarkers and quality of life) and outcomes (primary outcome: composite of first heart failure hospitalization or cardiovascular death) were compared in 4458 women and 4010 men enrolled in CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) (EF≥45%), I-Preserve (Irbesartan in heart failure with Preserved ejection fraction), and TOPCAT-Americas (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial).Results:Women were older and more often obese and hypertensive but less likely to have coronary artery disease or atrial fibrillation. Women had more symptoms and signs of congestion and worse quality of life. Despite this, the risk of the primary outcome was lower in women (hazard ratio, 0.80 [95% CI, 0.73–0.88]), as was the risk of cardiovascular death (hazard ratio, 0.70 [95% CI, 0.62–0.80]), but there was no difference in the rate for first hospitalization for heart failure (hazard ratio, 0.92 [95% CI, 0.82–1.02]). The lower risk of cardiovascular death in women, compared with men, was in part explained by a substantially lower risk of sudden death (hazard ratio, 0.53 [0.43–0.65]; P<0.001). E/A ratio was lower in women (1.1 versus 1.2).Conclusions:There are significant differences between women and men with heart failure with preserved ejection fraction. Despite worse symptoms, more congestion, and lower quality of life, women had similar rates of hospitalization and better survival than men. Their risk of sudden death was half that of men.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00853658, NCT01035255.

    更新日期:2019-12-09
  • Validation of Cardiovascular Magnetic Resonance–Derived Equation for Predicted Left Ventricular Mass Using the UK Biobank Imaging Cohort
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-12-06
    Kenneth Fung, Caitlin Cheshire, Jackie A. Cooper, Pedro Catarino, Stefan K. Piechnik, Stefan Neubauer, Sai Bhagra, Stephen Pettit, Steffen E. Petersen

    Background:Current guidance from International Society for Heart and Lung Transplantation recommends using body weight for donor-recipient size matching for heart transplantation. However, recent studies have shown that predicted heart mass, using body weight, height, age, and sex, may represent a better method of size matching. We aim to validate a cardiovascular magnetic resonance (CMR)–derived equation for predicted left ventricular mass (LVM) in a cohort of normal individuals in the United Kingdom.Methods:This observational study was conducted in 5065 middle-aged (44–77 years old) UK Biobank participants who underwent CMR imaging in 2014 to 2015. Individuals with cancer diagnosis in the previous 12 months or history of cardiovascular disease were excluded. Predicted LVM was calculated based on participants’ sex, height, and weight recorded at the time of imaging. Correlation analyses were performed between the predicted LVM and the LVM obtained from manual contouring of CMR cine images. The analysis included 3398 participants (age 61.5±7.5 years, 47.8% males).RESULTS:Predicted LVM was considerably higher than CMR-derived LVM (mean±SD of 138.8±28.9 g versus 86.3±20.9 g). However, there was a strong correlation between the 2 measurements (Spearman correlation coefficient 0.802, P<0.0001).Conclusions:Predicted LVM calculated using a CMR-derived equation that incorporates height, weight, and sex has a strong correlation with CMR LVM in large cohort of normal individuals in the United Kingdom. Our findings suggest that predicted heart mass equations may be a valid tool for donor-recipient size matching for heart transplantation in the United Kingdom.

    更新日期:2019-12-06
  • Impact of Autonomic Regulation Therapy in Patients with Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-11-14
    Marvin A. Konstam, James E. Udelson, Javed Butler, Helmut U. Klein, John D. Parker, John R. Teerlink, Patricia M. Wedge, Benjamin R. Saville, Jeffrey L. Ardell, Imad Libbus, Lorenzo A. DiCarlo

    Background:The ANTHEM-HFrEF (Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction) pivotal study is an adaptive, open-label, randomized, controlled study evaluating whether autonomic regulation therapy will benefit patients with advanced HFrEF. While early-phase studies have supported potential use of vagus nerve stimulation to deliver autonomic regulation therapy for HFrEF, results of larger clinical trials have been inconsistent. The ANTHEM-HFrEF study uses a novel design, with adaptive sample size selection, evaluating effects on morbidity and mortality as well as symptoms and function.Methods:The ANTHEM-HFrEF study will randomize patients (2:1) to autonomic regulation therapy plus guideline-directed medical therapy, or guideline-directed medical therapy alone. The morbidity and mortality trial utilizes a conventional frequentist approach for analysis of the primary outcome end point—reduction in the composite of cardiovascular death or first HF hospitalization—and a Bayesian adaptive approach toward sample size selection. Embedded within the ANTHEM-HFrEF study is a second trial evaluating improvement in symptoms and function. Symptom/function success will require meeting 2 risk-related conditions (trend for reduced cardiovascular death/HF hospitalization and sufficient freedom from device-related serious adverse events) and 3 efficacy end point components (changes in left ventricular EF, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire overall score).Conclusions:Vagus nerve stimulation remains a promising, yet unproven treatment in HFrEF. A successful ANTHEM-HFrEF pivotal study would provide an important advance in HFrEF treatment and offer a model for expediting evaluation of new therapies.Clinical Trial Registration:URL: http://www.clinicaltrials.gov. Unique identifier: NCT03425422.

    更新日期:2019-11-14
  • Optimal Strategy and Timing of Left Ventricular Venting During Veno-Arterial Extracorporeal Life Support for Adults in Cardiogenic Shock
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-11-13
    Abdulrahman A. Al-Fares, Varinder K. Randhawa, Marina Englesakis, Michael A. McDonald, A. Dave Nagpal, Jerry D. Estep, Edward G. Soltesz, Eddy Fan

    Background:Veno-arterial extracorporeal life support (VA-ECLS) is widely used to treat refractory cardiogenic shock. However, increased left ventricular (LV) afterload in VA-ECLS can worsen pulmonary congestion and compromise myocardial recovery. Our objectives were to explore the efficacy, safety, and optimal timing of adjunctive LV venting strategies.Methods:A systematic search was performed on Medline, EMBASE, PubMed, CDSR, CCRCT, CINAHL, ClinicalTrials.Gov, and WHO ICTRP from inception until January 2019 for all relevant studies, including LV venting. Data were analyzed for mortality and weaning from VA-ECLS on the basis of timing of LV venting, along with adverse complications.Results:A total of 7995 patients were included from 62 observational studies, wherein 3458 patients had LV venting during VA-ECLS. LV venting significantly improved weaning from VA-ECLS (odds ratio, 0.62 [95% CI, 0.47–0.83]; P=0.001) and reduced short-term (30 day; risk ratio [RR], 0.86 [95% CI, 0.77–0.96]; P=0.008) but not in-hospital (RR, 0.92 [95% CI, 0.83–1.01] P=0.09) or long-term (6 months; RR, 0.96 [95% CI, 0.90–1.03]; P=0.27) mortality. Early (<12 hours; RR, 0.86 [95% CI, 0.75–0.99]; P=0.03) but not late (≥12 hours; RR, 0.99 [95% CI, 0.71–1.38]; P=0.93) LV venting significantly reduced short-term mortality. Patients with LV venting spent more time on VA-ECLS (3.6 versus 2.8 days, P<0.001), and mechanical ventilation (7.1 versus 4.6 days, P=0.013). With the exception of hemolysis (RR, 2.18 [95% CI, 1.58–3.01]; P<0.00001), overall adverse events did not differ.Conclusions:LV venting, especially if done early (<12 hours), appears to be associated with an increased success of weaning and reduced short-term mortality. Future studies are required to delineate the importance of any or early LV venting adjuncts on mortality and morbidity outcomes.

    更新日期:2019-11-13
  • Long-Term Survival After Heart Transplantation at Centers Stratified by Short-Term Performance
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-11-13
    Tajinder P. Singh, Mandeep R. Mehra, Kimberlee Gauvreau

    Background:Center differences in short-term survival after heart transplant (HT) are known. We sought to compare long-term graft survival (freedom from death or retransplantation) at currently active United States HT centers stratified by performance for short-term survival.Methods:We used the Organ Procurement and Transplant Network database to identify subjects ≥18 years old who received primary HT during 2000 to 2014 at US centers active during 2013 and 2014. Follow-up was available until March 2016. Center case-mix was assessed by computing expected 90-day mortality and short-term performance by 90-day standardized mortality ratio (SMR; observed/expected mortality). Centers were stratified by case-mix as transplanting low-, intermediate-, and high-risk patients and by short-term performance as SMR quintiles. Center-level differences in long-term graft survival were assessed by risk-adjusted, mixed-effects Weibull survival models with center as a random effect.Results:We analyzed 25 467 HT recipients at 96 centers. Those receiving HT at centers with superior (lower) 90-day SMR had longer graft survival (P for trend <0.001). Survival difference among SMR groups remained significant in 90-day conditional survivors (P for trend <0.001). There was significant center-level variation in risk-adjusted graft survival censored at 5 years (P<0.001) and with all follow-up (P<0.001). Adjusting for 90-day SMR was associated with 62% reduction in center variation in 5-year graft survival and 56% reduction in center variation in overall graft survival.Conclusions:HT recipients at centers with superior short-term outcomes have longer graft survival on long-term follow-up. Allocating resources to improve patient care processes and transplant expertise at high-SMR centers may improve short-term and overall survival after HT.

    更新日期:2019-11-13
  • Characteristics and Healthcare Utilization Among Veterans Treated for Heart Failure With Reduced Ejection Fraction Who Switched to Sacubitril/Valsartan
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-11-13
    April F. Mohanty, Emily B. Levitan, John A. Dodson, Orly Vardeny, Jordan B. King, Joanne LaFleur, Tao He, Olga V. Patterson, Patrick R. Alba, Patricia A. Russo, Michelle E. Choi, Adam P. Bress

    Background:US guidelines recommend that patients with heart failure with reduced ejection fraction (HFrEF), who tolerate an ACEI (angiotensin-converting enzyme inhibitor) or ARB (angiotensin II receptor blocker), be switched to sacubitril/valsartan to reduce morbidity and mortality. We compared characteristics and healthcare utilization between Veterans with HFrEF who were switched to sacubitril/valsartan versus maintained on an ACEI or ARB.Methods:retrospective cohort study of treated HFrEF (July 2015–June 2017) using Veterans Affairs data. The index date was the first fill for sacubitril/valsartan and if none, for an ACEI or ARB. Treated HFrEF was defined by (1) left ventricular ejection fraction ≤40%, (2) ≥1 in/outpatient HF encounter, and (3) ≥1 ACEI or ARB fill, all within 1-year preindex. Poisson regression models were used to compare baseline characteristics and 1:1 propensity score-matched adjusted 4-month follow-up healthcare utilization between sacubitril/valsartan switchers and ACEI or ARB maintainers.Results:Switchers (1612; 4.2%) were less likely than maintainers (37 065; 95.8%) to have a history of myocardial infarction or hypertension, and more likely to be black, have a lower left ventricular ejection fraction, and higher preindex healthcare utilization. Switchers were less likely to experience follow-up all-cause hospitalizations (11.2% versus 14.0%; risk ratio 0.80 [95% CI, 0.65–0.98], P value 0.035).Conclusions:Few Veterans with treated HFrEF were switched to sacubitril/valsartan within the first 2 years of Food and Drug Administration approval. Sacubitril/valsartan use was associated with a lower risk for all-cause hospitalizations at 4 months follow-up. Reasons for lack of guideline-recommended sacubitril/valsartan initiation warrant investigation and may reveal opportunities for HFrEF care optimization.

    更新日期:2019-11-13
  • Early Treatment of Coxsackievirus B3–Infected Animals With Soluble Coxsackievirus-Adenovirus Receptor Inhibits Development of Chronic Coxsackievirus B3 Cardiomyopathy
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-11-13
    Sandra Pinkert, Babette Dieringer, Robert Klopfleisch, Konstantinos Savvatis, Sophie Van Linthout, Markian Pryshliak, Carsten Tschöpe, Karin Klingel, Jens Kurreck, Antje Beling, Henry Fechner

    Background:Coxsackie-B-viruses (CVB) are frequent causes of acute myocarditis and dilated cardiomyopathy, but an effective antiviral therapy is still not available. Previously, we and others have demonstrated that treatment with an engineered sCAR-Fc (soluble coxsackievirus-adenovirus receptor fused to the carboxyl-terminus of human IgG) efficiently neutralizes CVB3 and inhibits the development of cardiac dysfunction in mice with acute CVB3-induced myocarditis. In this study, we analyzed the potential of sCAR-Fc for treatment of chronic CVB3-induced myocarditis in an outbred NMRI mouse model.Methods:NMRI mice were infected with the CVB3 strain 31-1-93 and treated with a sCAR-Fc expressing adeno-associated virus 9 vector 1, 3, and 7 days after CVB3 infection. Chronic myocarditis was analyzed on day 28 after infection.Results:Initial investigations showed that NMRI mice develop pronounced chronic myocarditis between day 18 and day 28 after infection with the CVB3 strain 31-1-93. Chronic cardiac infection was characterized by inflammation and fibrosis as well as persistence of viral genomes in the heart tissue and by cardiac dysfunction. Treatment of NMRI mice resulted in a distinct reduction of cardiac inflammation and fibrosis and almost complete elimination of virus RNA from the heart by day 28 after infection. Moreover, hemodynamic measurement revealed improved cardiac contractility and diastolic relaxation in treated mice compared with mice treated with a control vector (mean±SD; maximal pressure, 81.9±9.2 versus 69.4±8.6 mm Hg, P=0.02; left ventricular ejection fraction, 68.9±8.5 versus 54.2±11.5%, P=0.02; dP/dtmax, 7275.2±1674 versus 4432.6±1107 mm Hg/s, P=0.004; dP/dtmin, −4046.9±776 versus −3146.3±642 mm Hg/s, P=0.046). The therapeutic potential of sCAR-Fc is limited, however, since postponed start of sCAR-Fc treatment either 3 or 7 days after infection could not attenuate myocardial injury.Conclusions:Early therapeutic employment of sCAR-Fc, initiated at the beginning of the primary viremia, inhibits the development of chronic CVB3-induced myocarditis and improves the cardiac function to a level equivalent to that of uninfected animals.

    更新日期:2019-11-13
  • Journey Through Advanced Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-11-05
    Jane E. Wilcox

    Persistence and determination alone are omnipotent. The slogan Press On! has solved and always will solve the problems of the human race. —Calvin Coolidge In 2001, at the age of 55, my father was diagnosed with acute heart failure (HF) due to nonischemic cardiomyopathy. A college student at the time, I remember his doctors telling us that his prognosis was extremely poor, maybe 3 years at best given his ejection fraction was only 10%. Over the next year, his left ventricular ejection fraction improved to 35%, along with his functional status. Despite his improvement into what we now would call HF with recovered or improved ejection fraction, every passing year, my family and I thought he was nearing the end. From our perspective, because he had been diagnosed with HF, it was hard to imagine any other outcome besides the inevitable, premature death. My dad ultimately lived for many years with class II-III HF symptoms. While many of us in the medical field view this as a success, living with persistent class III HF is hardly a win for patients, who are still unable to enjoy many activities of daily living that make up their quintessential self. Like many of the patients I now care for as an advanced HF physician, he was no longer able to work, was frustrated by his inability to maintain his home and property, and faced the financial pressures that accompany long-term disability. Sixteen years later, the balance shifted, and my dad was now having more bad days than good. While visiting me in Chicago, he almost collapsed after climbing a flight of stairs. As I reflect now on the events preceding this (progressive functional limitations, worsening renal function, the "hail Mary" cardiac resynchronization therapy), it became clear that he had been suffering from stage D HF for some time. However, in the midst of things, it was just the new normal. This new normal included his first ever hospitalization in the spring of 2017, at the age of 72. Subsequently, he again began to feel much worse. He called me and said, “Well…what should I do?” As I sat on the other end of the phone, I was overcome with emotion. As an HF specialist, I knew deep down his window for advanced therapies was closing. But as a daughter, I was scared and also angry. Why weren't his doctors addressing a ventricular assist device (VAD) with him? What if I nudged him into VAD placement and something went terribly wrong? So, I did what any daughter would do; I rallied the troops and called a friend, who is also a cardiac surgeon. As we met in his office, he shook my dad’s hand, looked him square in the eyes, and he said two very simple yet utterly important things. He acknowledged his symptoms with “Well…you’re pretty sick,” immediately followed by “we’re going to take care of you.” I could hear my dad exhale a sigh of relief. I wasn’t far behind. We listened to the risks and benefits of VAD surgery versus the alternatives of living at home with inotropes. In that moment, the value of shared decision-making when facing end-of-life options was tangible. My dad wanted to live, was willing to be connected to batteries, and understood the associated risks (eg, stroke, infection, and bleeding)…a “small price to pay to see my grandkids.” A few days later, I sat in the waiting area and shared a few nods with other family members, a half smile of “I know what you’re going through, I hope it turns out okay.” My dad was now being wheeled away to the operating room for VAD surgery. Holding back tears, I squeezed his hand and confidently told him that he was "going to crush it," and we would see him afterward. My family and I waited the 6 (felt like 60) hours together. As per usual, my mom was a rock throughout, holding steady. On one rare occasion, she broke down and cried from the enormity of it all. The past 6 months had “felt like we were flailing” she said, “but at least now we have a plan.” I felt privileged that I had knowledge that probably very few other caregivers/family members have. I also felt extreme anxiety; I worried most about a future devastating stroke or infection. I anticipated the fear and anxiety, normal emotions for any high-stakes event. But embarrassment also crept in and honestly caught me a bit off guard. I consider myself an empathetic doctor who values building a rapport with patients and families. However, as I waited, I mentally reviewed my script for advanced HF patients. I realized that I rarely opened the conversation with recognition of how awful this disease is and how difficult this must be to endure. In that moment, I promised to actively listen and to acknowledge the weight of the HF journey. At the time of my father’s diagnosis, 1-year survival with advanced HF was 25% with optimal medical therapy1; it now approaches 90% with durable mechanical support.2 However, the numbers don’t tell the whole story. I admire those experts in our field working to inform quality of life after durable mechanical support—an immensely important issue. My father, not unlike other patients, wanted to live better, not just longer. Managing expectations is key, and mechanical support is not for everyone. However, everyone with advanced HF should be informed of his or her prognosis, made aware of options for life-prolonging therapies, and referred for such in a timely manner. Like many other family members affected by HF, awareness and advocacy are part of my life’s mission. As of Father’s Day 2019, my dad is now in his third year of living with his VAD. As my 6-year old son says, “Grandpa has batteries, but he feels better.” I guess you could call it a success story. My mom is back at work, and they have adjusted to life on a device. They go out with friends, go on walks, (yes) boat rides, and spend time with their grandchildren. VAD self-care has become second nature. As a family, we take things day by day and have a renewed sense of gratitude for time spent together. Admittedly, it is difficult to hold both hope for the future and end-of-life planning in your hands concurrently—an emotional paradox. My dad has been hospitalized for right ventricular failure and volume overload, and we know he will likely experience more complications. We also know that he will die with this device, and we are planning for this. But until the balance shifts again in his HF journey, he is focused on living with his device. What we do as an advanced HF community is truly remarkable. We provide hope for patients and families, but we also create new challenges. I am simultaneously amazed at how far our field has come in the last 20 years and also dissatisfied with our risk assessment abilities and lack of personalized therapies for HF. My hope is that this discontent will continue to fuel the fervor of current and future investigators to reduce the burden of HF, improve the risk profile of our durable assist devices, and alleviate suffering. My father’s journey with advanced HF over the past 20 years tells me that with both hope and persistence, we can. I thank Simon Maltais, MD, PhD, Department of Cardiac Surgery, Centre Hospitalié de l’Université de Montréal. Dr Wilcox reports consulting honoraria from Abbott and Medtronic. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. For Disclosures, see page 2.

    更新日期:2019-11-11
  • Treatment of Pulmonary Hypertension With Angiotensin II Receptor Blocker and Neprilysin Inhibitor Sacubitril/Valsartan
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-11-11
    Richard T. Clements, Alexander Vang, Ana Fernandez-Nicolas, Nouaying R. Kue, Thomas J. Mancini, Alan R. Morrison, Krishna Mallem, Danielle J. McCullough, Gaurav Choudhary

    Background:Angiotensin II has been implicated in maladaptive right ventricular (RV) hypertrophy and fibrosis associated with pulmonary hypertension (PH). Natriuretic peptides decrease RV afterload by promoting pulmonary vasodilation and inhibiting vascular remodeling but are degraded by neprilysin. We hypothesized that angiotensin receptor blocker and neprilysin inhibitor, sacubitril/valsartan (Sac/Val, LCZ696), will attenuate PH and improve RV function by targeting both pulmonary vascular and RV remodeling.Methods:PH was induced in rats using the SU5416/hypoxia model (Su/Hx), followed by 6-week treatment with placebo, Sac/Val, or Val alone. There were 4 groups: CON—normoxic animals with placebo (n=18); PH−Su/Hx rats+placebo (n=34); PH+Sac/Val (N=24); and PH+Val (n=16).Results:In animals with PH, treatment with Sac/Val but not Val resulted in significant reduction in RV pressure (mm Hg: PH: 62±4, PH+Sac/Val: 46±5), hypertrophy (RV/LV+S: PH: 0.74±0.06, PH+Sac/Val: 0.46±0.06), collagen content (µg/50 µg protein: PH: 8.2±0.3, PH+Sac/Val: 6.4±0.4), pressures and improvement in RVs (mm/s: PH: 31.2±1.8, PH+Sac/Val: 43.1±3.6) compared with placebo. This was associated with reduced pulmonary vascular wall thickness, increased lung levels of ANP (atrial natriuretic peptide), BNP (brain-type natriuretic peptide), and cGMP, and decreased plasma endothelin-1 compared with PH alone. Also, PH+Sac/Val animals had altered expression of PKC isozymes in RV tissue compared with PH alone.Conclusions:Sac/Val reduces pulmonary pressures, vascular remodeling, as well as RV hypertrophy in a rat model of PH and may be appropriate for treatment of pulmonary hypertension and RV dysfunction.

    更新日期:2019-11-11
  • Clinical Implications of Respiratory Failure in Patients Receiving Durable Left Ventricular Assist Devices for End-Stage Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-11-11
    P. Elliott Miller, Cesar Caraballo, Neal G. Ravindra, Catherine Mezzacappa, Megan McCullough, Jadry Gruen, Andrew Levin, Samuel Reinhardt, Ayyaz Ali, Nihar R. Desai, Tariq Ahmad

    Background:The impact of respiratory failure on patients undergoing left ventricular assist device (LVAD) implantation is not well understood, especially since these patients were excluded from landmark clinical trials. We sought to evaluate the associations between immediate preimplant and postimplant respiratory failure on outcomes in advanced heart failure patients undergoing LVAD implantation.Methods and Results:We included all patients in the Interagency Registry for Mechanically Assisted Circulatory Support who were implanted with continuous-flow LVADs from 2008 to 2016. Of the 16 362 patients who underwent continuous-flow LVAD placement, 906 (5.5%) required preimplant intubation within 48 hours before implantation, and 1001 (6.1%) patients developed respiratory failure within 1 week after implantation. A higher proportion of patients requiring preimplant intubation were Interagency Registry for Mechanically Assisted Circulatory Support profile 1, required mechanical circulatory support, and presented with cardiac arrest or myocardial infarction (P<0.001, all). At 1 year, 54.3% of patients intubated preimplant were alive without transplant, 20.1% had been transplanted, and 24.2% died before transplant. Patients requiring preimplant intubation had higher rates of postimplant complications, including bleeding, stroke, and right ventricular assist device implantation (P<0.01 for all). Among Interagency Registry for Mechanically Assisted Circulatory Support profile 1 patients, preimplant intubation incurred additional risk of death at 1 year compared with Interagency Registry for Mechanically Assisted Circulatory Support profile 1 patients not intubated (hazard ratio, 1.37 [95% CI, 1.13–1.65]; P=0.001). After multivariable analysis, both preimplant intubation (hazard ratio, 1.20 [95% CI, 1.03–1.41]; P=0.021) and respiratory failure within 1 week (hazard ratio, 2.54 [95% CI, 2.26–2.85]; P<0.001) were associated with higher all-cause 1-year mortality.Conclusions:Respiratory failure both before and after LVAD implantation identifies an advanced heart failure population with significantly worse 1-year mortality. This data might be helpful in counseling patients and their families about expectations about life with an LVAD.

    更新日期:2019-11-11
  • Sphingosine-1-Phosphate Receptor Modulator, FTY720, Improves Diastolic Dysfunction and Partially Reverses Atrial Remodeling in a Tm-E180G Mouse Model Linked to Hypertrophic Cardiomyopathy
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-11-05
    David M. Ryba, Chad M. Warren, Chehade N. Karam, Robert T. Davis 3rd, Shamim A.K. Chowdhury, Manuel G. Alvarez, Maximilian McCann, Chong Wee Liew, David F. Wieczorek, Peter Varga, R. John Solaro, Beata M. Wolska

    Background:Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disorder, primarily involving mutations in sarcomeric proteins. HCM patients present with hypertrophy, diastolic dysfunction, and fibrosis, but there is no specific treatment. The sphingosine-1-phosphate receptor modulator, FTY720/fingolimod, is approved for treatment of multiple sclerosis. We hypothesize that modulation of the sphingosine-1-phosphate receptor by FTY720 would be of therapeutic benefit in sarcomere-linked HCM.Methods:We treated mice with an HCM-linked mutation in tropomyosin (Tm-E180G) and nontransgenic littermates with FTY720 or vehicle for 6 weeks. Compared with vehicle-treated, FTY720-treated Tm-E180G mice had a significant reduction in left atrial size (1.99±0.19 [n=7] versus 2.70±0.44 [n=6] mm; P<0.001) and improvement in diastolic function (E/A ratio: 2.69±0.38 [n=7] versus 5.34±1.19 [n=6]; P=0.004) as assessed by echocardiography.Results:Pressure-volume relations revealed significant improvements in the end-diastolic pressure volume relationship, relaxation kinetics, preload recruitable stroke work, and ejection fraction. Detergent-extracted fiber bundles revealed a significant decrease in myofilament Ca2+-responsiveness (pCa50=6.15±0.11 [n=13] versus 6.24±0.06 [n=14]; P=0.041). We attributed these improvements to a downregulation of S-glutathionylation of cardiac myosin binding protein-C in FTY720-treated Tm-E180G mice and reduction in oxidative stress by downregulation of NADPH oxidases with no changes in fibrosis.Conclusions:This is the first demonstration that modulation of S1PR results in decreased myofilament-Ca2+-responsiveness and improved diastolic function in HCM. We associated these changes with decreased oxidative modification of myofilament proteins via downregulation of NOX2. Our data support the hypothesis that modification of sphingolipid signaling may be a novel therapeutic approach in HCM.

    更新日期:2019-11-11
  • Clinical Practice Patterns in Temporary Mechanical Circulatory Support for Shock in the Critical Care Cardiology Trials Network (CCCTN) Registry
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-11-11
    David D. Berg, Christopher F. Barnett, Benjamin B. Kenigsberg, Alexander Papolos, Carlos L. Alviar, Vivian M. Baird-Zars, Gregory W. Barsness, Erin A. Bohula, Joseph Brennan, James A. Burke, Anthony P. Carnicelli, Sunit-Preet Chaudhry, Paul C. Cremer, Lori B. Daniels, Andrew P. DeFilippis, Daniel A. Gerber, Christopher B. Granger, Steven Hollenberg, James M. Horowitz, James D. Gladden, Jason N. Katz, Ellen C. Keeley, Norma Keller, Michael C. Kontos, Patrick R. Lawler, Venu Menon, Thomas S. Metkus, P. Elliott Miller, Jose Nativi-Nicolau, L. Kristin Newby, Jeong-Gun Park, Nicholas Phreaner, Robert O. Roswell, Steven P. Schulman, Shashank S. Sinha, R. Jeffrey Snell, Michael A. Solomon, Jeffrey J. Teuteberg, Wayne Tymchak, Sean van Diepen, David A. Morrow

    Background:Temporary mechanical circulatory support (MCS) devices provide hemodynamic assistance for shock refractory to pharmacological treatment. Most registries have focused on single devices or specific etiologies of shock, limiting data regarding overall practice patterns with temporary MCS in cardiac intensive care units.Methods:The CCCTN (Critical Care Cardiology Trials Network) is a multicenter network of tertiary CICUs in North America. Between September 2017 and September 2018, each center (n=16) contributed a 2-month snapshot of consecutive medical CICU admissions.Results:Of the 270 admissions using temporary MCS, 33% had acute myocardial infarction-related cardiogenic shock (CS), 31% had CS not related to acute myocardial infarction, 11% had mixed shock, and 22% had an indication other than shock. Among all 585 admissions with CS or mixed shock, 34% used temporary MCS during the CICU stay with substantial variation between centers (range: 17%–50%). The most common temporary MCS devices were intraaortic balloon pumps (72%), Impella (17%), and veno-arterial extracorporeal membrane oxygenation (11%), although intraaortic balloon pump use also varied between centers (range: 40%–100%). Patients managed with intraaortic balloon pump versus other forms of MCS (advanced MCS) had lower Sequential Organ Failure Assessment scores and less severe metabolic derangements. Illness severity was similar at high- versus low-MCS utilizing centers and at centers with more advanced MCS use.Conclusions:There is wide variation in the use of temporary MCS among patients with shock in tertiary CICUs. While hospital-level variation in temporary MCS device selection is not explained by differences in illness severity, patient-level variation appears to be related, at least in part, to illness severity.

    更新日期:2019-11-11
  • Identification of Racial Inequities in Access to Specialized Inpatient Heart Failure Care at an Academic Medical Center
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-10-29
    Lauren A. Eberly, Aaron Richterman, Anne G. Beckett, Bram Wispelwey, Regan H. Marsh, Emily C. Cleveland Manchanda, Cindy Y. Chang, Robert J. Glynn, Katherine C. Brooks, Robert Boxer, Rose Kakoza, Jennifer Goldsmith, Joseph Loscalzo, Michelle Morse, Eldrin F. Lewis, Samantha Abel, Ayrenne Adams, Joseph Anaya, Erik H Andrews, Benjamin Atkinson, Viswatej Avutu, Alexandra Bachorik, Omar Badri, Mariel Bailey, Katie Baird, Salina Bakshi, Denis Balaban, Kenneth Barshop, Emily Baumrin, Omar Bayomy, Julia Beamesderfer, Nora Becker, David D. Berg,, Adam N. , Berman, Steven M. Blum, Alexander P. Boardman, Kaeleen Boden, Robert A Bonacci, Sarah Brown, Kirsti Campbell, Siobhan Case, Emily Cetrone, Alexandra Charrow, David Chiang, Devin Clark, Aaron J. Cohen, Alissa Cooper, Tomas Cordova, C. Nicholas Cuneo, Alsina Alejandro de Feria, Karen Deffenbacher, Ersilia M. DeFilippis, Geneva DeGregorio, Aaron J. Deutsch, Bradford Diephuis, Sanjay Divakaran, Peter Dorschner, Nicholas Downing, Caitlin Drescher, Kristin M. D’Silva, Peter Dunbar, David Duong, Sarah Earp, Christine Eckhardt, Scott A. Elman, Ross England, Kay Everett, Natalie Fedotova, Tamara Feingold-Link, Mark Ferreira, Herrick Fisher, Patricia Foo, Michael Foote, Idalid Franco, Thomas Gilliland, Jacqueline Greb, Katherine Greco, Sungat Grewal, Benjamin Grin, Matthew E. Growdon, Brendan Guercio, Cynthia K. Hahn, Brian Hasselfeld, Erika J Haydu, Zachary Hermes, Gordon Hildick-Smith, Zachary Holcomb, Kathryn Holroyd, Laura Horton, George Huang, Stanley Jablonski, Douglas Jacobs, Nina Jain, Sohan Japa, Richard Joseph, Mariya Kalashnikova, Neil Kalwani, Daniel Kang, Abraar Karan, Joel T Katz, Daniel Kellner, Khameer Kidia, June-Ho Kim, Scott M Knowles, Laura Kolbe, Idil Kore, Yiannis Koullias, Ifedayo Kuye, Joshua Lang, Matthew Lawlor, Melissa G. Lechner, Ken Lee, Scott Lee, Zachary Lee, Neha Limaye, Stephanie Lin-Beckford, Marla Lipsyc, Jessica Little, Julia Loewenthal, Ranjani Logaraj, Diana M Lopez, Daniel Loriaux, Yi Lu, Kevin Ma, Nareh Marukian, Wilfredo Matias, Jared R. Mayers, Ian McConnell, Michael McLaughlin, Christina Meade, Catherine Meador, Anish Mehta, Elizabeth Messenger, Constantinos Michaelidis, Jacob Mirsky, Emilie Mitten, Alisa Mueller, Jyotsna Mullur, Amir Munir, Emily Murphy, Ellen Nagami, Abirami Natarajan, Michelle Nsahlai, Chijioke Nze, Noreen Okwara, Peter Olds, Rafael Paez, Michael Pardo, Siddharth Patel, Alec Petersen, Laura Phelan, Erica Pimenta, Daniel Pipilas, Molly Plovanich, Denise Pong, Brian W. Powers, Anita Rao, Haiyan Ramirez Batlle, Mattheus Ramsis, Anna Reichardt, Sheridan Reiger, Michelle Rengarajan, Stephanie Rico, Benjamin N. Rome, Rachael Rosales, Lisa Rotenstein, Alexis Roy, Sarah Royston, Hallie Rozansky, Meghan Rudder, Christine E. Ryan, Sanjay Salgado, Pablo Sanchez,, Jennifer Schulte, Aswin Sekar, Nicholas Semenkovich, Evan Shannon, Neil Shaw, Andrew Ben Shorten, William Shrauner, Lauren Sinnenberg, James W. Smithy, Gregory Snyder, Anirudh Sreekrishnan, Hans Stabenau, Eleni Stavrou, Andrew Stergachis, Robert Stern, Alexander Stone, Shervin Tabrizi, Sam Tanyos, Cristina Thomas, Haley Thun, Kristine Torres-Lockhart, An Tran, Carolyn Treasure, Frederick D. Tsai, Stephen Tsaur, Evan Tschirhart, Justin Tuwatananurak, Ramkumar V. Venkateswaran, Anastasia Vishnevetsky, Lindsay Wahl, April Wall, Frances Wallace, Elisa Walsh, Priscilla Wang, Heather B. Ward, Lindsay N. Warner, Lachelle D. Weeks, Kipp Weiskopf, Jordan Wengrod, Jessica N. Williams, Marisa Winkler, Jeffrey L. Wong, Devin Worster, Aileen Wright, Caroline Wunsch, Jamila S. Wynter, Chase Yarbrough, Wai-Ying Yau, Daniel Yazdi, Jennifer Yeh, Maria A. Yialamas, Nicholas Yozamp, Marina Zambrotta, Rebecca Zon

    Background:Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race. This study examined the relationship between race and admission service, and its effect on 30-day readmission and mortalityMethods:We performed a retrospective cohort study from September 2008 to November 2017 at a single large urban academic referral center of all patients self-referred to the emergency department and admitted to either the cardiology or general medicine service with a principal diagnosis of HF, who self-identified as white, black, or Latinx. We used multivariable generalized estimating equation models to assess the relationship between race and admission to the cardiology service. We used Cox regression to assess the association between race, admission service, and 30-day readmission and mortality.Results:Among 1967 unique patients (66.7% white, 23.6% black, and 9.7% Latinx), black and Latinx patients had lower rates of admission to the cardiology service than white patients (adjusted rate ratio, 0.91; 95% CI, 0.84–0.98, for black; adjusted rate ratio, 0.83; 95% CI, 0.72–0.97 for Latinx). Female sex and age >75 years were also independently associated with lower rates of admission to the cardiology service. Admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race.Conclusions:Black and Latinx patients were less likely to be admitted to cardiology for HF care. This inequity may, in part, drive racial inequities in HF outcomes.

    更新日期:2019-10-29
  • High-Output Heart Failure From Growth of Vascular Malformations in Multiple Gestation Pregnancy
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-10-29
    Pratyaksh K. Srivastava, Nina Vyas, Jesse Jones, Thalia C. Wong, Kerry Holliman, Adam J. Small, Rashmi R. Rao, Erin P. Dowling, J. Paul Finn, Gary R. Duckwiler, Leigh C. Reardon, Jamil A. Aboulhosn, Simon B. Ascher, Marcia Hogeling, Gentian Lluri, Eric H. Yang

    A 29-year-old woman (gravida 2, para 1) at 26 weeks of gestation with monochorionic diamniotic twins presented with 6 weeks of dyspnea, orthopnea, palpitations, lower extremity edema, and enlargement of a facial birthmark (Figure 1). She had a history of heart failure as a newborn secondary to cerebral arteriovenous malformation (AVM), which was resected at 10 weeks of age with no further heart failure symptoms. She had previously carried a singleton pregnancy to term without complications. Family history was significant for cutaneous capillary malformations (CMs) in her mother, sister, and brother. Figure 1. Superficial appearance of left cheek vascular malformation. Vascular malformation shown (A) before pregnancy, (B) on initial presentation (26 wks, 1d), (C) before embolization (29wks, 3d), (D) 4 d after delivery, and (E) 2wks after delivery. She presented with a temperature of 37°C, a heart rate of 131 beats per minute, a blood pressure of 129/84 mm Hg, a respiratory rate of 22 breaths per minute, and an oxygen saturation of 98% on room air. Exam demonstrated a pulsatile 12×7.5 cm left-sided facial mass (Figure 1), a 4×2 cm pulsatile left-sided scalp mass, a jugular venous pressure of 10 cm of water, a II/VI systolic murmur at the left sternal border, and 2+ bilateral lower extremity pitting edema. Laboratories revealed a hemoglobin of 8.6 g/dL, cardiac troponin I of <0.04 ng/mL, B-type natriuretic peptide of 93 pg/mL, and a thyroid stimulating hormone of 0.55 mcIU/mL. ECG demonstrated sinus tachycardia at 132 beats per minute. Transthoracic echocardiogram revealed an ejection fraction of 65% to 70%, biatrial enlargement, and a calculated noninvasive cardiac output (CO) of 16.5 L/min (normal CO for twin gestation, 7–8 L/min).1 Magnetic resonance angiography with ferumoxytol revealed a CO of 14 L/min, and high-flow vascular lesions of the left cheek, left skull vertex, and right lower lateral neck (Figure 2). Figure 2. Magnetic resonance angiography time resolved series at 27 wk gestation demonstrating left check (green arrow), left scalp (red arrow), and right shoulder (pink arrow) high-flow vascular malformations. The 3 frames show progressive evolution of enhancement from arterial to late venous phases. The patient was diagnosed with high-output heart failure and was initially managed for 3 weeks with intravenous and oral diuretics in the inpatient and outpatient settings. Despite diuresis, she developed progressive heart failure and subsequently underwent embolization of her cheek and skull vertex vascular malformations with N-butyl cyanoacrylate glue and polyvinyl alcohol particles, resulting in ≈50% flow reduction by angiography (Figure 3). The patient symptomatically improved postoperatively. Transthoracic echocardiogram after the procedure demonstrated a calculated noninvasive CO of 11.9 L/min. On postembolization day 5, she developed thrombocytopenia and acute kidney injury. Given the concern for preeclampsia, she underwent cesarean section at 30 weeks and 1 day with resolution of heart failure symptoms. Twins A and B were born with birthweights of 1300 and 1700 g, respectively. Twin A was born with hypospadias and a small ventricular septal defect. Transesophageal echocardiography immediately after delivery demonstrated a calculated noninvasive CO of 9.3 L/min. The patient was discharged on oral diuretics. Her facial engorgement fully resolved 2 weeks postpartum (Figure 1). At time of writing, the twins are 23 weeks old and doing well. Figure 3. Angiography of the vascular malformation and surrounding blood vessels.A, Before embolization: left external carotid artery angiogram demonstrates a hypervascular blush overlying the left parietal scalp primarily supplied by a hypertrophied branch of the superficial temporal artery. B, After embolization: left external carotid artery angiogram shows decreased opacification of the vascular malformation nidus. The hypertrophied superficial temporal artery branch has been occluded. Here, we describe a case of high-output heart failure secondary to enlarging vascular malformations in the setting of multiple gestation pregnancy. CMs manifest as red patches on the head and neck and are found in 0.3% of newborns.2 More rarely, CMs associate with high-flow AVMs in an autosomal dominant disorder called CM-AVM syndrome.3 The patient’s presentation, lesion appearance, and family history of cutaneous CMs (mother, sister, and brother) point to a clinical diagnosis of CM-AVM syndrome. This disorder frequently associates with loss-of-function mutations in RASA1 and EPHB4 and has high penetrance and variable expressivity.4–6 The patient is still considering genetic testing. AVMs are hormone sensitive and increase their size and flow in response to hormonal changes. As a result, they may enlarge during adolescence or pregnancy.3,7,8 The cardiovascular changes associated with pregnancy increase the risk for heart failure in those with vascular malformations. In the first trimester, women experience a drop in peripheral vascular resistance due to systemic vasodilation.1 Heart rate and stroke volume rise, resulting in an increase in CO. This rise can approach 145% of normal in singleton pregnancies and can reach 7 to 8 L/min in twin gestations.1,9 The increased estrogen and progesterone from the patient’s multiple gestation pregnancy likely significantly contributed to the increased size and flow of her existing CM-AVMs. Vascular malformations in pregnancy are typically managed with a conservative watch and wait strategy. Given the patient’s clinical deterioration, embolization of the AVMs was performed. To our knowledge, this represents the first report of CM-AVM embolization during pregnancy. Despite significant postoperative reduction in arteriovenous shunting and mild symptomatic improvement, the patient developed signs of superimposed preeclampsia, ultimately requiring preterm delivery. The regression of her AVMs postpartum confirmed their hormonal sensitivity. Acute decompensated high-output heart failure in pregnancy due to congenital vascular malformations is rare and can pose significant management challenges. Endovascular embolization may have a role in the management of such conditions following the failure of conservative medical therapies. The postoperative development of preeclampsia necessitating urgent delivery in this report, however, highlights the complexities inherent in such cases. Dr Hogeling is a Principal Investigator on a study sponsored by Celgene. The other authors report no conflicts. *Drs Srivastava and Vyas contributed equally to this work. For Disclosures, see page 3.

    更新日期:2019-10-29
  • Insights Into Myocardial Oxygen Consumption, Energetics, and Efficiency Under Left Ventricular Assist Device Support Using Noninvasive Pressure-Volume Loops
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-10-15
    Pankaj Jain, Sajad Shehab, Kavitha Muthiah, Desiree Robson, Marcus Granegger, Stavros G. Drakos, Paul Jansz, Peter S. Macdonald, Christopher S. Hayward

    Background:Assessment of left ventricular (LV) recovery under continuous-flow LV assist device therapy is hampered by concomitant pump support. We describe derivation of noninvasive pressure-volume loops in continuous-flow LV assist device patients and demonstrate an application in the assessment of recovery.Methods and Results:Using pump controller parameters and noninvasive arterial pressure waveforms, central aortic pressure, outflow conduit pressure gradient, and instantaneous LV pressure were calculated. Instantaneous LV volumes were calculated from echocardiographic LV end-diastolic volume accounting for the integral of pump flow with respect to time and aortic ejection volume derived from the pump speed waveform. Pressure-volume loops were derived during pump speed adjustment and following bolus intravenous milrinone to assess changes in loading conditions and contractility, respectively. Fourteen patients were studied. Baseline noninvasive LV end-diastolic pressure correlated with invasive pulmonary arterial wedge pressure (r2=0.57, root mean square error 5.0 mm Hg, P=0.003). Measured noninvasively, milrinone significantly increased LV ejection fraction (40.3±13.6% versus 36.8±14.2%, P<0.0001), maximum dP/dt (623±126 versus 555±122 mm Hg/s, P=0.006), and end-systolic elastance (1.03±0.57 versus 0.89±0.38 mm Hg/mL, P=0.008), consistent with its expected inotropic effect. Milrinone reduced myocardial oxygen consumption (0.15±0.06 versus 0.16±0.07 mL/beat, P=0.003) and improved myocardial efficiency (43.7±14.0% versus 41.2±15.5%, P=0.001). Reduced pump speed caused increased LV end-diastolic volume (190±80 versus 165±71 mL, P<0.0001) and LV end-diastolic pressure (14.3±10.2 versus 9.9±9.3 mm Hg, P=0.024), consistent with a predictable increase in preload. There was increased myocardial oxygen consumption (0.16±0.07 versus 0.14±0.06 mL O2/beat, P<0.0001) despite unchanged stroke work (P=0.24), reflecting decreased myocardial efficiency (39.2±12.7% versus 45.2±17.0%, P=0.003).Conclusions:Pressure-volume loops are able to be derived noninvasively in patients with the HeartWare HVAD and can detect induced changes in load and contractility.

    更新日期:2019-10-16
  • Myocardial Energetics in Heart Failure With Preserved Ejection Fraction
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-10-15
    Omar F. AbouEzzeddine, Bradley J. Kemp, Barry A. Borlaug, Brian P. Mullan, Atta Behfar, Sorin V. Pislaru, Marat Fudim, Margaret M. Redfield, Panithaya Chareonthaitawee

    Background:The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O2 consumption [MVO2]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O2 extraction. Lastly, we assessed whether coupling of MVO2 to EW (mechanical efficiency) was impaired in HFpEF.Methods and Results:In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11C-acetate positron emission tomography assessing MVO2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO2, and MBF. With dobutamine, LV EW, MVO2, and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls.Conclusions:In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O2 supply relative to demand, and is associated with reserve dysfunction.

    更新日期:2019-10-16
  • Mechanisms of the Multitasking Endothelial Protein NRG-1 as a Compensatory Factor During Chronic Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-10-14
    Gilles W. De Keulenaer, Eline Feyen, Lindsey Dugaucquier, Hadis Shakeri, Anastasia Shchendrygina, Yury N. Belenkov, Marijke Brink, Zarha Vermeulen, Vincent F. M. Segers

    Heart failure is a complex syndrome whose phenotypic presentation and disease progression depends on a complex network of adaptive and maladaptive responses. One of these responses is the endothelial release of NRG (neuregulin)-1—a paracrine growth factor activating ErbB2 (erythroblastic leukemia viral oncogene homolog B2), ErbB3, and ErbB4 receptor tyrosine kinases on various targets cells. NRG-1 features a multitasking profile tuning regenerative, inflammatory, fibrotic, and metabolic processes. Here, we review the activities of NRG-1 on different cell types and organs and their implication for heart failure progression and its comorbidities. Although, in general, effects of NRG-1 in heart failure are compensatory and beneficial, translation into therapies remains unaccomplished both because of the complexity of the underlying pathways and because of the challenges in the development of therapeutics (proteins, peptides, small molecules, and RNA-based therapies) for tyrosine kinase receptors. Here, we give an overview of the complexity to be faced and how it may be tackled.

    更新日期:2019-10-14
  • Shared Decision-Making About End-of-Life Care Scenarios Compared Among Implantable Cardioverter Defibrillator Patients
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-10-11
    Jessica Harman Thompson, Ingela Thylén, Debra K. Moser

    Background:Authors of expert guidelines and consensus statements recommend that decisions at the end-of-life (EOL) be discussed before and after implantation of an implantable cardioverter defibrillator (ICD) and include promotion of shared decision-making. The purpose of this study was to describe experiences, attitudes, and knowledge about the ICD at EOL in ICD recipients and to compare experiences, attitudes, and knowledge in ICD recipients with and without heart failure (HF). We further sought to determine factors associated with having discussions about EOL.Methods and Results:Using a national registry in Sweden of all ICD recipients (n=5355) in 2012, an EOL questionnaire, along with other ICD-related measures, was completed by 2403 ICD recipients. Of the participants, 1275 (n=53%) had HF. Their responses in the knowledge, experience, and attitude domains were almost identical to those without HF. Forty percent of patients with and without HF did not want to discuss their illness trajectory or deactivation of their ICD ever. In logistic regression analyses, we found that having had an ICD shock (OR, 2.05; CI, 1.64–2.56), having high levels of anxiety (OR, 1.41; CI, 1.04–1.92), and having high levels of ICD concerns (OR, 1.53; CI, 1.22–1.92) were the only significant predictors of having discussions with providers about EOL scenarios (P<0.001 for full model).Conclusions:HF was not a predictor of having an EOL conversation. Further research is needed to determine if attitudes related to not wanting to discuss EOL interfere with good quality of life and of death, or if shared decision-making should be encouraged in these individuals.

    更新日期:2019-10-12
  • Survival Outcomes After Heart Transplantation
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-10-10
    Yasbanoo Moayedi, Chun Po S. Fan, Wida S. Cherikh, Joseph Stehlik, Jeffrey J. Teuteberg, Heather J. Ross, Kiran K. Khush

    Background:Currently, women represent <25% of heart transplant recipients. Reasons for this female underrepresentation have been attributed to selection and referral bias and potentially poorer outcomes in female recipients. The aim of this study was to compare long-term posttransplant survival between men and women, when matched for recipient and donor characteristics.Methods and Results:Using the International Society for Heart and Lung Transplantation Registry, we performed descriptive analyses and estimated overall freedom from posttransplant death stratified by sex using Kaplan-Meier survival methods. Male and female recipients were matched according to the Index for Mortality Prediction After Cardiac Transplantation and Donor Risk Index score using 1:1 propensity score matching. The study cohort comprised 34 198 heart transplant recipients (76.3% men, 23.7% women) between 2004 and 2014. Compared with men, women were more likely younger (51 [39–59] versus 55 [46–61] years; P<0.001) and had a different distribution of heart failure etiology (P<0.001). In general, the prevalence of comorbidities was lower in women than in men. Women were less likely to have diabetes mellitus (19.1% versus 26.2%; P<0.001), hypertension (40.7% versus 47.9%; P<0.001), peripheral vascular disease (2.4% versus 3.3%; P=0.002), tobacco use (36.5% versus 52.3%; P<0.001), and prior cardiovascular surgery (38.6% versus 50.7%; P<0.001). Women were more likely to have a history of malignancy (10.5% versus 5.3%; P<0.001), require intravenous inotropes (41.4% versus 37.2%; P<0.001), and were less likely supported by an intra-aortic balloon pump (3.3% versus 3.8%; P=0.03) or durable ventricular assist device (22% versus 31.5%; P<0.001). Transplanted male recipients had a higher Index for Mortality Prediction After Cardiac Transplantation score (5 [2–7] versus 4 [1–6]; P<0.001). When male and female heart transplant recipients were matched for recipient and donor characteristics, there was no significant survival difference (P=0.57).Conclusions:Overall survival does not differ between men and women after cardiac transplantation. Women who survive to heart transplantation appear to have lower risk features than male recipients but receive hearts from higher risk donors.

    更新日期:2019-10-12
  • Sex-Based Differences in Left Ventricular Assist Device Utilization
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-09-13
    Aditya A. Joshi, Joseph B. Lerman, Aparna P. Sajja, Garima Dahiya, Avantee V. Gokhale, Amit K. Dey, Andreas Kyvernitakis, M. Scott Halbreiner, Stephen Bailey, Craig M. Alpert, Indu G. Poornima, Srinivas Murali, Raymond L. Benza, Manreet Kanwar, Amresh Raina

    Background:Women comprise approximately one-third of the advanced heart failure population but may receive fewer advanced heart failure therapies including left ventricular assist devices (LVADs). During the early pulsatile-flow device era, women had higher post-LVAD mortality and increased complications. However, knowledge about these differences in the continuous-flow device era is limited. Therefore, we sought to explore temporal trends in LVAD utilization and post-LVAD mortality by sex.Methods and Results:Patients with LVAD implantation from 2004 to 2016 were identified using the Nationwide Inpatient Sample. Trends in LVAD utilization and post-LVAD inpatient mortality were compared by sex and device era. Although LVADs are being increasingly utilized for patients with advanced systolic heart failure, women continue to represent a smaller proportion of LVAD recipients—25.8% in 2004 to 21.9% in 2016 (P for trend, 0.91). Women had increased inpatient mortality after LVAD implantation compared with men in the pulsatile-flow era (46.9% versus 31.1%, P<0.0001) but not in the continuous-flow era (13.3% versus 12.1%, P=0.27; P for interaction=0.0002). Inpatient mortality decreased for both sexes over time after LVAD, with a sharp fall in 2008 to 2009. Female sex was independently associated with increased post-LVAD inpatient mortality beyond adjustment for demographics and risk factors during the pulsatile-flow era (odds ratio, 2.13; 95% CI, 1.45–3.10; P<0.0001) but not during the continuous-flow era (1.18; 0.93–1.48; P=0.16).Conclusions:Although utilization of LVAD therapy increased over time for both sexes, LVAD implantation remains stably lower in women, which may suggest a potential underutilization of this potentially life-saving therapy. Prospective studies are needed to confirm these findings.

    更新日期:2019-09-14
  • Dynamic Changes in the Molecular Signature of Adverse Left Ventricular Remodeling in Patients With Compensated and Decompensated Chronic Primary Mitral Regurgitation
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-09-12
    Keir McCutcheon, Caroline Dickens, Jos van Pelt, Therese Dix-Peek, Sacha Grinter, Lindsay McCutcheon, Atulkumar Patel, Martin Hale, Nqoba Tsabedze, Ahmed Vachiat, Don Zachariah, Raquel Duarte, Stefan Janssens, Pravin Manga

    Background:There is no proven medical therapy that attenuates adverse left ventricular remodeling in patients with chronic primary mitral regurgitation (CPMR). Identification of molecular pathways important in the progression of left ventricular remodeling in patients with CPMR may lead to development of new therapeutic strategies.Methods and Results:We performed baseline echocardiographic, cardiac catheterization, and serum NT-pro-BNP analysis in patients with severe CPMR awaiting mitral valve surgery and stratified the study population into compensated or decompensated CPMR. We obtained left ventricular endomyocardial biopsies (n=12) for mRNA expression analysis, and compared baseline transcript levels of 109 genes important in volume-overload left ventricular remodeling with levels in normal hearts (n=5) and between patients with compensated (n=6) versus decompensated (n=6) CPMR. Patients were then randomized to treatment with and without carvedilol and followed until the time of surgery (mean follow-up 8.3 months) when repeat endomyocardial biopsies were obtained to correlate transcriptional dynamics with indices of adverse remodeling. CPMR was associated with increased NPPA expression levels (21.6-fold, P=0.004), decreased transcripts of genes important in cell survival, and enrichment of extracellular matrix genes. Decompensated CPMR was associated with downregulation of SERCA2 (0.77-fold, P=0.009) and mitochondrial gene expression levels and upregulation of genes related to inflammation, the extracellular matrix, and apoptosis, which were refractory to carvedilol therapy.Conclusions:Transition to decompensated CPMR is associated with calcium dysregulation, increased expression of inflammatory, extracellular matrix and apoptotic genes, and downregulation of genes important in bioenergetics. These changes are not attenuated by carvedilol therapy and highlight the need for development of specific combinatorial therapies, targeting myocardial inflammation and apoptosis, together with urgent surgical or percutaneous valve interventions.

    更新日期:2019-09-14
  • Prevalence of American Heart Association Heart Failure Stages in Black and White Young and Middle-Aged Adults
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-09-11
    Samuel S. Gidding, Donald Lloyd-Jones, Joao Lima, Bharat Ambale-Venkatesh, Sanjiv J. Shah, Ravi Shah, Cora E. Lewis, David R. Jacobs Jr, Norrina B. Allen

    Background:Staging criteria for heart failure (HF) range from stage 0 (without risk) to being at risk (stage A) to presence of cardiac structural/functional abnormalities (stage B) to symptomatic/end stage (stages C/D). There are limited data on the prevalence of these stages in early adulthood and predictors of HF stage and symptoms in middle age.Methods and Results:The CARDIA study (Coronary Artery Risk Development in Young Adults)—a cohort of generally healthy black and white men and women—collected phenotypic, echocardiographic, and outcomes data at the year 5 and year 30 examinations when participants were 22 to 37 and 47 to 62 years of age. Prevalence of HF stages was calculated and relationship of year 5 stage to year 30 classification and outcomes was assessed. At year 5, 2189 participants had complete data. Prevalence of HF stage A/B increased from 24% to 76% in black men, from 13% to 64% in white men, from 34% to 81% in black women, and from 13% to 56% in white women. Blacks were more likely to be in any stage or with morbidity at both time points because of higher risk factor prevalence. Of 33 participants with HF or HF deaths by year 30, 21 (64%) had been in stage A or B at year 5. Only 6 participants at year 5 in stage A (at risk) improved risk status at year 30.Conclusions:Risk for HF increased in participants from 1990 (age 22–37 years) to 2015 (age 47–62 years). Symptomatic HF or death from HF is associated with HF stage at 22 to 37 years of age. Blacks are disproportionately affected.

    更新日期:2019-09-11
  • Duration of Heart Failure and Effect of Defibrillator Implantation in Patients With Nonischemic Systolic Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-09-10
    Marie Bayer Elming, Anna M. Thøgersen, Lars Videbæk, Niels E. Bruun, Hans Eiskjær, Jens Haarbo, Kenneth Egstrup, Finn Gustafsson, Jesper Hastrup Svendsen, Dan E. Høfsten, Steen Pehrson, Jens C. Nielsen, Lars Køber, Jens Jakob Thune

    Background:Patients with nonischemic systolic heart failure (HF) have increased risk of sudden cardiac death (SCD) and death from progressive pump failure. Whether the risk of SCD changes over time is unknown. We seek here to investigate the relation between duration of HF, mode of death, and effect of implantable cardioverter-defibrillator implantation.Methods and Results:We examined the risk of all-cause death and SCD according to the duration of HF among patients with nonischemic systolic HF enrolled in the DANISH (Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality). In all, 1116 patients were included. Patients were divided according to quartiles of HF duration (≤8, 9≤18, 19≤65, and ≥66 months). Patients with the longest duration of HF were older, more often men, had more comorbidity, and more often received a cardiac resynchronization therapy device. Doubling of HF duration was an independent predictor of both all-cause mortality (hazard ratio [HR], 1.27; 95% CI, 1.17–1.38; P<0.0001), and SCD (HR, 1.29; 95% CI, 1.11–1.50; P=0.0007). The proportion of deaths caused by SCD was not different between HF quartiles (P=0.91), and the effect of implantable cardioverter-defibrillator implantation on all-cause mortality was not modified by the duration of HF (P=0.59).Conclusions:Duration of HF predicted both all-cause mortality and risk of SCD independently of other risk indicators. However, the proportion of death caused by SCD did not change with longer duration of HF, and the effect of implantable cardioverter-defibrillator was not modified by the duration of HF.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00542945.

    更新日期:2019-09-10
  • Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-09-04
    Mathew S. Maurer, Sabahat Bokhari, Thibaud Damy, Sharmila Dorbala, Brian M. Drachman, Marianna Fontana, Martha Grogan, Arnt V. Kristen, Isabelle Lousada, Jose Nativi-Nicolau, Candida Cristina Quarta, Claudio Rapezzi, Frederick L. Ruberg, Ronald Witteles, Giampaolo Merlini

    Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in various tissues and organs. ATTR amyloidosis is debilitating and associated with poor life expectancy, especially in those with cardiac dysfunction, but a variety of treatment options have recently become available. Considered a rare disease, ATTR amyloidosis may be more prevalent than thought, particularly in older persons. Diagnosis is often delayed because of a lack of disease awareness and the heterogeneity of symptoms at presentation. Given the recent availability of effective treatments, early recognition and diagnosis are especially critical because treatment is likely more effective earlier in the disease course. The Amyloidosis Research Consortium recently convened a group of experts in ATTR amyloidosis who, through an iterative process, agreed on best practices for suspicion, diagnosis, and characterization of disease. This review describes these consensus recommendations for ATTR associated with cardiomyopathy as a resource to aid cardiologists and others in the recognition and diagnosis of ATTR associated with cardiomyopathy. Included in this review is an overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping.

    更新日期:2019-09-04
  • Effect of Continuous-Flow Left Ventricular Assist Device Support on Coronary Artery Endothelial Function in Ischemic and Nonischemic Cardiomyopathy
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-08-19
    J. David Symons, Lance Deeter, Nicholas Deeter, Trevor Bonn, Jae Min Cho, Peter Ferrin, Lauren McCreath, Nikolaos A. Diakos, Iosif Taleb, Rami Alharethi, Stephen McKellar, Omar Wever-Pinzon, Sutip Navankasattusas, Craig H. Selzman, James C. Fang, Stavros G. Drakos

    Background:The coronary vasculature encounters a reduction in pulsatility after implementing durable continuous-flow left ventricular assist device (CF-LVAD) circulatory support. Evidence exists that appropriate pulsatility is required to maintain endothelial cell homeostasis. We hypothesized that coronary artery endothelial function would be impaired after CF-LVAD intervention.Methods and Results:Coronary arteries from patients with end-stage heart failure caused by ischemic cardiomyopathy (ICM; n=16) or non-ICM (n=22) cardiomyopathy were isolated from the left ventricular apical core, which was removed for the CF-LVAD implantation. In 11 of these patients, paired coronary arteries were obtained from an adjacent region of myocardium after the CF-LVAD intervention (n=6 ICM, 5 non-ICM). Vascular function was assessed ex vivo using isometric tension procedures in these patients and in 7 nonfailing donor controls. Maximal endothelium-dependent vasorelaxation to BK (bradykinin; 10−6–10−10 M) was blunted (P<0.05) in arteries from patients with ICM compared with non-ICM and donor controls, whereas responses to sodium nitroprusside (10−4–10−9 M) were similar among the groups. Contrary to our hypothesis, vasorelaxation responses to BK and sodium nitroprusside were similar before and 219±37 days after CF-LVAD support. Of these patients, an exploratory subgroup analysis revealed that BK-induced coronary artery vasorelaxation was greater (P<0.05) after (87±6%) versus before (54±14%) CF-LVAD intervention in ICM patients, whereas sodium nitroprusside–evoked responses were similar.Conclusions:Coronary artery endothelial function is not impaired by durable CF-LVAD support and in ICM patients appears to be improved. Investigating coronary endothelial function using in vivo approaches in a larger patient population is warranted.

    更新日期:2019-08-19
  • Pulmonary Arterial Elastance and INTERMACS-Defined Right Heart Failure Following Left Ventricular Assist Device
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-08-12
    Rahatullah Muslem, Chin S. Ong, Brett Tomashitis, Jessica Schultz, Bhavadharini Ramu, Michael L. Craig, Adrian B. Van Bakel, Nisha A. Gilotra, Kavita Sharma, Steven Hsu, Glenn J. Whitman, Peter J. Leary, Rebecca Cogswell, Lucian Lozonschi, Brian A. Houston, Felix Zijlstra, Kadir Caliskan, Ad J.J.C. Bogers, Ryan J. Tedford

    Background:Acute right heart failure (RHF) after left ventricular assist device implantation remains a major source of morbidity and mortality, yet the definition of RHF and the preimplant variables that predict RHF remain controversial. This study evaluated the ability of (1) INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) RHF classification to predict post-left ventricular assist device survival and (2) preoperative characteristics and hemodynamic parameters to predict severe and severe acute RHF.Methods and Results:An international, multicenter study at 4 large academic centers was conducted between 2008 and 2016. All subjects with hemodynamics measured by right heart catheterization within 30 days before left ventricular assist device implantation were included. RHF was defined using the INTERMACS definition for RHF. In total, 375 subjects were included (mean age, 57.4±13.2 years, 54% bridge-to-transplant). Mild RHF was most common (34%), followed by moderate RHF (16%), severe RHF (13%), and severe acute RHF (9%). Estimated on-device survival rates at 2 years were 72%, 71%, and 55% in the patients with none, mild-to-moderate, and severe-to-severe acute RHF, respectively (P=0.004). In addition, the independent hazard ratio for mortality was only increased in the patients with severe-to-severe acute RHF (hazard ratio, 3.95; 95% CI, 2.16–7.23; P<0.001). INTERMACS-defined RHF was superior to postimplant inotrope duration alone in the prediction of all-cause mortality. In multivariable analysis, older age, lower INTERMACS classes, and higher pulmonary arterial elastance (ratio of systolic pulmonary artery pressure to stroke volume) before left ventricular assist device, were identified as significant predictors of severe-to-severe acute RHF. Stratifying patients by ratio of systolic pulmonary artery pressure to stroke volume and right atrial pressure significantly improved the discrimination between patients at risk for severe-to-severe acute RHF.Conclusions:The INTERMACS RHF classification correctly identifies patients at risk for mortality, though this risk is only increased in patients with severe-to-severe acute RHF. Several predictors for RHF were identified, of which ratio of systolic pulmonary artery pressure to stroke volume was the strongest hemodynamic predictor. Coupling ratio of systolic pulmonary artery pressure to stroke volume with right atrial pressure may be most helpful in identifying patients at risk for severe-to-severe acute RHF.

    更新日期:2019-08-12
  • Adenosine Kinase Inhibition Augments Conducted Vasodilation and Prevents Left Ventricle Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-08-01
    Alec Davila, Yanna Tian, Istvan Czikora, Jie Li, Huabo Su, Yuqing Huo, Vijay Patel, Vincent Robinson, Gaston Kapuku, Neal Weintraub, Zsolt Bagi

    Background:Heart failure with preserved ejection fraction (HFpEF) is often manifested as impaired cardiovascular reserve. We sought to determine if conducted vasodilation, which coordinates microvascular resistance longitudinally to match tissue metabolic demand, becomes compromised in HFpEF. We hypothesized that the metabolic vasodilator adenosine facilitates and that inhibition of ADK (adenosine kinase) augments conducted vasodilation for a more efficient myocardial perfusion and improved left ventricle (LV) diastolic function in HFpEF.Methods and Results:We assessed conducted vasodilation in obese ZSF1 rats that develop LV diastolic dysfunction and is used to model human HFpEF. Additionally, conducted vasodilation was measured in arterioles isolated from the right atrial appendages of patients with HFpEF. We found a markedly reduced conducted vasodilation both in obese ZSF1 rats and in patients with HFpEF. Impaired conducted vasodilation was accompanied by increased vascular ADK expression. Isolated rat and human arterioles incubated with adenosine (10 nmol/L) or ADK inhibitor ABT-702 (0.1 µmol/L) both displayed augmented conducted vasodilation. Treatment of obese ZSF1 rats with ABT-702 (1.5 mg/kg, IP for 8 weeks) prevented LV diastolic dysfunction, and in a crossover design augmented conducted vasodilation and improved LV diastolic function. ABT-702 treated obese ZSF1 rats exhibited reduced expression of myocardial carbonic anhydrase 9 and collagen, surrogate markers of myocardial hypoxia.Conclusions:Upregulation of vascular ADK mitigates adenosine-facilitated conducted vasodilation in obese ZSF1 rats and in patients with HFpEF. We propose that pharmacological inhibition of ADK could be beneficial for therapeutic augmentation of conducted vasodilation, thereby improving tissue perfusion and LV diastolic function in HFpEF.

    更新日期:2019-08-01
  • Effect of Baseline Left Ventricular Ejection Fraction on 2-Year Outcomes After Transcatheter Aortic Valve Replacement
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-08-01
    Ariel Furer, Shmuel Chen, Bjorn Redfors, Sammy Elmariah, Philippe Pibarot, Howard C. Herrmann, Rebecca T. Hahn, Susheel Kodali, Vinod H. Thourani, Pamela S. Douglas, Maria C. Alu, William F. Fearon, Jonathan Passeri, S. Chris Malaisrie, Aaron Crowley, Thomas McAndrew, Philippe Genereux, Ori Ben-Yehuda, Martin B. Leon, Daniel Burkhoff

    Background:Impaired left ventricular function is associated with worse prognosis among patients with aortic stenosis treated medically or with surgical aortic valve replacement. It is unclear whether reduced left ventricular ejection fraction (LVEF) is an independent predictor of adverse outcomes after transcatheter aortic valve replacement.Methods and Results:Patients who underwent transcatheter aortic valve replacement in the PARTNER 2 trials (Placement of Aortic Transcatheter Valves) and registries were stratified according to presence of reduced LVEF (<50%) at baseline, and 2-year risk of cardiovascular mortality was compared using Kaplan–Meier methods and multivariable Cox proportional hazards regression. Of 2991 patients, 839 (28%) had reduced LVEF. These patients were younger, more often males, and were more likely to have comorbidities, such as coronary disease, diabetes mellitus, and renal insufficiency. Compared with patients with normal LVEF, patients with low LVEF had higher crude rates of 2-year cardiovascular mortality (19.8% versus 12.0%, P<0.0001) and all-cause mortality (27.4% versus 19.2%, P<0.0001). Mean aortic valve gradient was not associated with clinical outcomes other than heart failure hospitalizations (hazard ratio [HR], 0.99; CI, 0.99–1.00; P=0.03). After multivariable adjustment, patients with reduced versus normal LVEF had significantly higher adjusted risk of cardiovascular death (adjusted HR, 1.42, 95% CI, 1.11–1.81; P=0.005), but not all-cause death (adjusted HR, 1.20; 95% CI, 0.99–1.47; P=0.07). When LVEF was treated as continuous variable, it was associated with increased 2-year risk of both cardiovascular mortality (adjusted HR per 10% decrease in LVEF, 1.16; 95% CI, 1.07–1.27; P=0.0006) and all-cause mortality (adjusted HR, 1.09; 95% CI, 1.01–1.16; P=0.02).Conclusions:In this patient-level pooled analysis of PARTNER 2 patients who underwent transcatheter aortic valve replacement, baseline LVEF was an independent predictor of 2-year cardiovascular mortality.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01314313, NCT02184442, NCT03222128, and NCT02184441.

    更新日期:2019-08-01
  • Internal Jugular Vein as Alternative Access for Implantation of a Wireless Pulmonary Artery Pressure Sensor
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-08-01
    Jacob Abraham, Patrick McCann, Lian Wang, Amanda Schnell Heringer, Jeff Paulsen, Jay Chappell, Joshua Remick, Daniel Westerdahl, Rebecca Lewis, Katherine Callis, Kateri J. Spinelli, Liviu Klein

    Background:A wireless pulmonary artery pressure sensor (CardioMEMS) is approved for implantation via the femoral vein. The internal jugular vein (IJ) is an attractive alternative access route commonly used in pulmonary artery catheterization.Methods and Results:Retrospective chart review was performed for all sensor implants from 10 providers at 4 centers from September 2016 to June 2018. To compare procedural outcomes and discharge efficiency between groups, multivariate analyses incorporating potential confounders were performed. Seventy-three (28%) patients had femoral access, and 189 (72%) had IJ access; demographics were similar between the groups. Complications, including one case of hematoma and 4 cases of mild hemoptysis, and 30-day mortality (2%–3%) did not differ between groups. Provider preference for IJ access substantially increased over time, with IJ accounting for 90% of cases in 2018. After risk-adjustment, IJ cases had 20% (5%–33%) shorter fluoroscopy time (P=0.01) and 24% (7%–38%) lower contrast volume (P=0.008). Compared with outpatient femoral cases, outpatient IJ cases had 62% (52%–69%) faster needle-to-door time and were 34 times (6–235) more likely to have same-day discharge (P<0.001 for both).Conclusions:IJ access for CardioMEMS implant is a safe alternative associated with superior procedural and discharge outcomes. Implanters at 4 high-volume centers adopted IJ access as the preferred implant approach.

    更新日期:2019-08-01
  • TACIT (High Sensitivity Troponin T Rules Out Acute Cardiac Insufficiency Trial)
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-07-01
    Peter S. Pang, Gregory J. Fermann, Benton R. Hunter, Phillip D. Levy, Kathleen A. Lane, Xiaochun Li, Mette Cole, Sean P. Collins

    Background:Identifying low-risk acute heart failure patients safe for discharge from the emergency department is a major unmet need.Methods AND RESULTS:A prospective, observational, multicenter pilot study targeting lower risk acute heart failure patients to determine whether hsTnT (high-sensitivity troponin T) identifies emergency department acute heart failure patients at low risk for rehospitalization and mortality. hsTnT was drawn at baseline and 3 hours. Phone follow-up occurred at 30 and 90 days. The primary end point composite of all-cause mortality, rehospitalization, and emergency department visits at 90 days (changed from 30 days because of lack of mortality events), analyzed using logistic regression. Secondary end points: 30- and 90-day all-cause mortality. hsTnT values less than the 99th percentile were defined as low hsTnT. Out of 527 enrolled patients, 499 comprised the initial analysis set. Of these, 332 had both 0- and 3-hour hsTnT drawn, of whom 319 completed 30 day follow-up. The average age was 62, 60% male, and 57% black. Median hsTnT was 26.4 ng/L (interquartile range, 15.1–44.3). There were 99 (21%) 30-day composite events, 13 (2.7%) deaths at 30 days, and 25 deaths (8.2%) at 90 days. Serial hsTnT values below the 99th percentile were not associated with a lower risk for the 90-day primary composite end point (odds ratio, 0.79; 95% CI, 0.42–1.50; P=0.4736). However, no deaths occurred in the low hsTnT group at 30 days with 1 death at 90 days.Conclusions:hsTnT did not identify patients at low risk for the primary outcome of rehospitalization, emergency department visits, and mortality at 90 days.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT02592135.

    更新日期:2019-07-10
  • Arterial Remodeling and Dysfunction in the ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-07-01
    Sara Leite, Rui J. Cerqueira, Jaime Ibarrola, Dulce Fontoura, Amaya Fernández-Celis, Faiez Zannad, Inês Falcão-Pires, Walter J. Paulus, Adelino F. Leite-Moreira, Patrick Rossignol, Natalia López-Andrés, André P. Lourenço

    Background:The interplay between the stiffened heart and vessels has long been viewed as a core mechanism in heart failure with preserved ejection fraction, but the incremental vascular molecular remodeling mechanisms from systemic arterial hypertension to heart failure with preserved ejection fraction remain poorly investigated. Our aim was to characterize central arterial remodeling and dysfunction in ZSF1 obese rats and to compare it with hypertensive ZSF1 lean and healthy Wistar-Kyoto controls.Methods and Results:Twenty-week-old male ZSF1 obese (n=9), lean (n=9), and Wistar-Kyoto rats (n=9) underwent left ventricular pressure-volume loop evaluation and synchronous acquisition of ascending aortic flow and pressure. Aortic rings underwent functional evaluation, histology, and molecular biology studies. Although mean arterial pressure, characteristic aortic impedance, and reactivity to phenylephrine were similarly increased in hypertensive ZSF1 lean and obese, only ZSF1 obese showed impaired relaxation and upward-shifted end-diastolic pressure-volume relationships despite preserved systolic function indexes, denoting heart failure with preserved ejection fraction. ZSF1 obese phenotype further showed decreased aortic compliance, increased wave reflection, and impaired direct NO donor and endothelial-mediated vasodilation which were accompanied on structural and molecular grounds by aortic media thickening, higher collagen content and collagen/elastin ratio, increased fibronectin and α-5 integrin protein expression and upregulated TGF (transforming growth factor)-β and CTGF (connective tissue growth factor) levels.Conclusions:Functional, molecular, and structural disturbances of central vessels and their potentially underlying pathways were newly characterized in experimental heart failure with preserved ejection fraction rendering the ZSF1 obese rat model suitable for preclinical testing.

    更新日期:2019-07-01
  • Utility of the Cardiovascular Physical Examination and Impact of Spironolactone in Heart Failure With Preserved Ejection Fraction
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-07-01
    Senthil Selvaraj, Brian Claggett, Sanjiv J. Shah, Inder S. Anand, Jean L. Rouleau, Akshay S. Desai, Eldrin F. Lewis, Muthiah Vaduganathan, Stephen Y. Wang, Bertram Pitt, Nancy K. Sweitzer, Marc A. Pfeffer, Scott D. Solomon

    Background:The prognostic value of physical examination, its relation to quality of life, and influence of therapy in heart failure with preserved ejection fraction is not well known.Methods and Results:We studied participants from the Americas with available physical examination (jugular venous distention, rales, and edema) at baseline in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). The association of the number of signs of congestion with the primary outcome (cardiovascular death or heart failure hospitalization), its individual components, and all-cause mortality was assessed using time-updated, multivariable-adjusted Cox regression analyses. We evaluated whether spironolactone improved congestion at 4 months and whether improvement in congestion was related to quality of life as assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores and to outcomes. Among 1644 participants, 22%, 54%, 20%, and 4% had 0, 1, 2, and 3 signs of congestion, respectively, at baseline. After multivariable adjustment, each additional increase in sign of congestion was associated with a 30% to 60% increased risk of each outcome (P<0.001). Spironolactone reduced the total number of signs of congestion by −0.10 (P=0.005) signs, jugular venous distention (odds ratio, 0.60; P=0.01), and edema (odds ratio, 0.74; P=0.006) at 4 months compared with placebo. Each reduction in sign of congestion was independently associated with a 4.0 (95% CI, 2.4–5.6) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score. When assessed simultaneously, time-updated, but not baseline congestion, predicted outcomes.Conclusions:In heart failure with preserved ejection fraction, the physical exam provides independent prognostic value for adverse outcomes. Spironolactone improved congestion compared with placebo. Reducing congestion was independently associated with improved quality of life and outcomes and is a modifiable risk factor.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00094302.

    更新日期:2019-06-21
  • Psychosocial Evaluation of Candidates for Heart Transplant and Ventricular Assist Devices: Beyond the Current Consensus
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-07-01
    Quan M. Bui, Larry A. Allen, Lisa LeMond, Michela Brambatti, Eric Adler

    Advanced heart failure therapies, including heart transplantation and durable mechanical circulatory support, are available to a limited number of patients because of the scarcity of donors, expense, and large burden of care. The importance of psychological and social determinants of health, including cognitive status, health literacy, psychopathology, social support, medical adherence, and substance abuse, are emphasized in advanced heart failure and further amplified in the context of mechanical circulatory support and heart transplantation. The psychosocial assessment of advanced heart failure therapy candidates remains largely subjective, requiring a multidisciplinary evaluation, which may include psychiatrists, social workers, case managers, financial coordinators, pharmacists, and clinicians. Objective tools—including the Stanford Integrated Psychosocial Assessment for Transplantation, Psychosocial Assessment of Candidates for Transplantation, and Transplant Evaluation Rating Scale—were developed and validated in limited populations to help standardize the evaluation process. Small, retrospective studies have inconsistently shown that these tools may predict clinical outcomes in the transplant population, with higher-risk scores associated with readmissions, rejection episodes, and infections. However, it has been more difficult to show that these tools can predict mortality, and their applicability to the mechanical circulatory support population is less studied. The International Society for Heart and Lung Transplantation released a consensus statement in 2018 to promote consistency of psychosocial evaluation across advanced heart failure programs, but it lacks specific recommendations given the current state of evidence. This state-of-the-art review expands on the current consensus by critically reviewing current studies supporting available objective assessment tools, proposing a psychosocial evaluation framework that uses a multidisciplinary approach and offering future directions for research.

    更新日期:2019-06-19
  • Preimplant Phosphodiesterase-5 Inhibitor Use Is Associated With Higher Rates of Severe Early Right Heart Failure After Left Ventricular Assist Device Implantation
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-06-01
    Gaurav Gulati, E. Wilson Grandin, Kevin Kennedy, Fausto Cabezas, David D. DeNofrio, Robb Kociol, J. Eduardo Rame, Francis D. Pagani, James K. Kirklin, Robert L. Kormos, Jeffrey Teuteberg, Michael Kiernan

    BackgroundEarly right heart failure (RHF) occurs commonly in left ventricular assist device (LVAD) recipients, and increased right ventricular (RV) afterload may contribute. Selective pulmonary vasodilators, like phosphodiesterase-5 inhibitors (PDE5i), are used off-label to reduce RV afterload before LVAD implantation, but the association between preoperative PDE5i use and early RHF after LVAD is unknown.Methods and ResultsWe analyzed adult patients from the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support) who received a continuous flow LVAD after 2012. Patients on PDE5i were propensity-matched 1:1 to controls. The primary outcome was the incidence of severe early RHF, defined as the composite of death from RHF within 30 days, need for RV assist device support within 30 days, or use of inotropes beyond 14 days. Of 11 544 continuous flow LVAD recipients, 1199 (10.4%) received preoperative PDE5i. Compared to controls, patients on PDE5i had higher pulmonary artery systolic pressure (53.4 mm Hg versus 49.5 mm Hg) and pulmonary vascular resistance (2.6 WU versus 2.3 WU; P<0.001 for both). Before propensity matching, the incidence of severe early RHF was higher among patients on PDE5i than in controls (29.4% versus 23.1%; unadjusted odds ratio (OR), 1.32; 95% CI, 1.17–1.50). This association persisted after propensity matching (PDE5i, 28.9% versus control 23.7%; OR, 1.31; 95% CI, 1.09–1.57), driven by a higher incidence of prolonged inotropic support. Similar results were observed across a wide range of subgroups stratified by markers of pulmonary vascular disease and RV dysfunction.ConclusionsPatients treated with preoperative PDE5i had markers of increased RV afterload and HF severity compared to unmatched controls. Even after propensity matching, patients receiving preimplant PDE5i therapy had higher rates of post-LVAD RHF.

    更新日期:2019-06-11
  • Phosphodiesterase-5 Inhibitor Therapy and Post–Left Ventricular Assist Device Outcomes
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-06-01
    Brian A. Houston

    See Article by Gulati et al We demand rigidly defined areas of doubt and uncertainty! —Douglas Adams, The Hitchhiker’s Guide to the Galaxy In Douglas Adams’ The Hitchhiker’s Guide to the Galaxy, a group of “hyperintelligent pan-dimensional beings” create an omniscient computer (dubbed Deep Thought) as the ultimate arbiter of truth.1 The creation of this computer greatly discomfits a pair of philosophers, Vroomfondel and Majikthise, who worry that it will put them “straight out of a job.” As the pair’s vexation grows, Vroomfondel makes his demand to Deep Thought for “rigidly defined areas of doubt and uncertainty” (with the obvious and ridiculous corollary demand for rigidly defined areas of certainty). As physicians, we often feel the same discomfiture—particularly when a study calls into question a concept we had previously assigned as certain or a clinical practice ingrained by biological plausibility. In their important study about the association of preimplant PDE5i (phosphodiesterase-5 inhibitor) use with post-left ventricular assist device (LVAD) outcomes, Gulati et al2 have further advanced the boundary of doubt and uncertainty surrounding the use of these medications in patients undergoing LVAD implantation and indeed in any patient with underlying left heart disease (LHD).2 In this issue of Circulation: Heart Failure, Gulati et al retrospectively queried the Interagency Registry for Mechanically Assisted Circulatory Support registry to investigate the association of pre-LVAD PDE5i use and post-LVAD severe early right heart failure (RHF). The primary outcome was defined largely per the current Interagency Registry for Mechanically Assisted Circulatory Support definition: death from RHF or multiorgan system failure within 30 days, need for right ventricular assist device within 30 days, or use of inotropes beyond 14 days.3 The authors excluded patients who received durable right ventricular assist devices during the index procedure from the primary outcome, as it was thought this likely represented a preventive instead of reactive operative strategy. Given the retrospective and nonrandomized nature of the study, selection bias was addressed via a robust propensity matching system using 22 variables in the assigned propensity score to model the likelihood of receiving PDE5i therapy. Importantly, the authors also took pains to perform quality control on the registry-reported hemodynamic data by ensuring pulmonary arterial wedge pressure did not exceed pulmonary arterial diastolic pressure, carefully selecting between right atrial and central venous pressures based on plausibility, and not accepting pulmonary arterial wedge pressures <1 mm Hg. Ultimately, the study compared 1177 propensity-matched PDE5i and control patients. Even with the extensive propensity matching model, severe early RHF remained more common in the PDE5i group versus controls (odds ratio, 1.31; 95% CI, 1.09–1.57). Interestingly, this was driven solely by prolonged inotrope duration, with no significant difference in right ventricular assist device use or death from RHF. Furthermore, although total hospital length of stay was 3 days longer in the PDE5i group, at 6 months the groups had similar survival, quality of life scores, and 6-minute walk distance. The authors astutely investigated the association of PDE5i use and major bleeding events, finding a significantly higher incidence of major bleeding within the first 7 postoperative days in the PDE5i group (hazards ratio, 1.52; 95% CI, 1.15–2.0). The incautious interpretation of the study is that preoperative PDE5i use increases the risk for post-LVAD severe early RHF. However, several aspects of the study counsel caution in reaching this conclusion. First, despite extensive propensity matching endeavors, it is possible that residual selection bias exists in this retrospective study—it may still be that patients receiving preoperative PDE5i therapy were sicker in unknown unknown ways than the matched control cohort. Notably, of the 22 variables used in the propensity scoring system, pulmonary arterial wedge pressure was missing in 30% of cases. The authors report that pulmonary vascular resistance was higher in the PDE5i group (2.6 versus 2.3 WU, P<0.001), but the high proportion of missing pulmonary arterial wedge pressure values may lead us to underestimate the true difference in pulmonary vascular load between the groups. Second, it is noteworthy that though the authors report a higher incidence of severe early RHF in the PDE5i group, this was driven entirely by prolonged inotrope use. The PDE5i group did not suffer higher early mortality, need for early right ventricular assist device implantation, or even higher morbidity or mortality at 6 months. Many prior studies have found an association between severe early RHF and mortality,4–6 and so its absence here is conspicuous and leads us to question exactly what specific outcome we are capturing—true hemodynamic failure of the right heart system, covariation of preoperative PDE5i use and postoperative provider decision making regarding inotrope use, or association of PDE5i use with a postoperative event necessitating prolonged inotrope use but not representing causative hemodynamic failure of the right heart? The finding of a higher risk of early postoperative bleeding in the PDE5i group points a tentative finger at the latter explanation. However, we must note that the propensity scoring system did not account for important bleeding risk factors, such as platelet count and international normalized ratio. It is possible that the noted bleeding risk was itself confounded by unaccounted for selection bias. Despite these caveats, this study adds an important voice to others which together push the use of PDE5i therapy in patients with pulmonary hypertension due to LHD into an increasingly “rigidly defined area of doubt and uncertainty.” It is notable that, of the patients meeting the inclusion criteria in this study, 10.4% were on preoperative PDE5i therapy—a striking proportion in a patient population selected for the most severe degree of LV failure and ostensibly in whom preoperative right ventricular embarrassment is selectively avoided. Prior studies have indicated that the majority of real-world PDE5i use is in patients without WHO Group 1 precapillary pulmonary arterial hypertension.7,8 In one study of veterans treated with PDE5i, over half did not even have a verifiable right heart catheterization.7 We might be forgiven to a degree for this prescribing pattern; we know that patients with pulmonary hypertension due to LHD do worse, and as clinicians we are desperate for helpful therapies in this scenario. The afterload sensitive nature of the right ventricle,9 the ability of PDE5i therapy to reduce pulmonary vascular load,10 and early small studies with promising surrogate end points11 all present an enticing, biologically plausible argument for their use in these patients. However, together with the recently published SIOVAC study (Sildenafil for Improving Outcomes After Valvular Correction) showing worse outcomes with PDE5i therapy in patients with persistent pulmonary hypertension after valvular intervention,12 the current study weakens the arguments of biological plausibility for the utility of these agents in patients with LHD. Importantly, this study begs the important next question of the role of PDE5i therapy initiated as a treatment for RHF after LVAD implantation. Other important areas of doubt and uncertainty urgently requiring answer include whether any patient phenotype with pulmonary hypertension due to LHD benefits from PDE5i therapy and whether other pulmonary arterial hypertension–specific therapy may be more effective for these patients. The currently enrolling SOPRANO study may shed light on the utility of endothelin receptor antagonist therapy post-LVAD,13 although doubtless questions will remain. In the current study, Gulati et al are to be congratulated not for providing an answer to these questions but for more rigidly defining the area of doubt and uncertainty. In doing so, they have provided what Lewandowsky et al14 describe as uncertainty as actionable knowledge. The call to action as presented by this study is increasingly pressing—if pulmonary arterial hypertension–specific therapy is indeed shown to increase the risk of harm to our patients with LVAD or LHD, guidelines and practice patterns should expeditiously abandon the arguments of biological plausibility and surrogate end points just as they did with antiarrhythmic agents for premature ventricular contractions and inotropic medications for LV failure. Ultimately, the philosophers in The Hitchhiker’s Guide are placated when Deep Thought assures them that it will take 7.5 million years to reach "the answer to the Ultimate Question of Life, the Universe, and Everything," giving them plenty of time to ply their trade. Hopefully, we will not have to wait that long to answer these important questions regarding pulmonary arterial hypertension–specific therapy in patients with LVAD or LHD. 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 Kenneth B. Margulies, MD.

    更新日期:2019-06-11
  • Epidemiology of Cardiac Amyloidosis–Associated Heart Failure Hospitalizations Among Fee-for-Service Medicare Beneficiaries in the United States
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-06-01
    Lauren G. Gilstrap, Francesca Dominici, Yun Wang, M. Samir El-Sady, Amitoj Singh, Marcelo F. Di Carli, Rodney H. Falk, Sharmila Dorbala

    BackgroundCardiac amyloidosis is a substantially underdiagnosed disease, and contemporary estimates of the epidemiology of amyloidosis are lacking. This study aims to determine the incidence and prevalence of cardiac amyloidosis among Medicare beneficiaries from 2000 to 2012.Methods and ResultsMedicare beneficiaries were counted in the prevalence cohort in each year they had (1) ≥1 principal or secondary International Classification of Diseases, Ninth Revision code for amyloidosis and (2) ≥1 principal or secondary International Classification of Diseases, Ninth Revision code for heart failure or cardiomyopathy within 2 years after the systemic amyloidosis code. A beneficiary was counted in the incidence cohort only during the first year in which they met criteria. Primary outcomes included the prevalence and incidence of hospitalizations for cardiac amyloidosis. There were 4746 incident cases of cardiac amyloidosis in 2012 and 15 737 prevalent cases in 2012. There was also a significant increase in the prevalence rate (8 to 17 per 100 000 person-years) and incidence rate (18 to 55 per 100 000 person-years) from 2000 to 2012, most notable after 2006. Incidence and prevalence increased substantially more among men, the elderly, and in blacks.ConclusionsThe incidence and prevalence rates of cardiac amyloidosis are higher than previously thought. The incidence and prevalence rates of cardiac amyloidosis among hospitalized patients have increased since 2000, particularly among specific patient subgroups and after 2006, suggesting improved amyloidosis awareness and higher diagnostic rates with noninvasive imaging. In light of these trends, cardiac amyloidosis should be considered during the initial work up of patients ≥65 years old hospitalized with heart failure.

    更新日期:2019-06-07
  • Renal Effects of Intensive Volume Removal in Heart Failure Patients With Preexisting Worsening Renal Function
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-06-01
    Veena S. Rao, Tariq Ahmad, Meredith A. Brisco-Bacik, Joseph V. Bonventre, F. Perry Wilson, Edward D. Siew, G. Michael Felker, Kevin K. Anstrom, Devin D. Mahoney, Bradley A. Bart, W.H. Wilson Tang, Eric J. Velazquez, Jeffrey M. Testani

    BackgroundThe relationship between intensive volume removal in acute decompensated heart failure patients with preexisting worsening renal function (WRF) and renal tubular injury, postdischarge renal function, and clinical outcomes is unknown.Methods and ResultsWe used data from the multicenter CARRESS-HF trial (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) that randomized patients with acute decompensated heart failure and preexisting WRF to intensive volume removal with stepped pharmacological therapy or fixed rate ultrafiltration. Patients in the urinary renal tubular injury biomarker substudy (NAG [N-acetyl-b-D-glucosaminidase], KIM-1 [kidney injury molecule-1], and NGAL [neutrophil gelatinase-associated lipocalin]) were evaluated (N=105). The severity of prerandomization WRF was unrelated to baseline renal tubular injury biomarkers (r=0.14; P=0.17). During randomized intensive volume removal, creatinine further worsened in 53% of patients. Despite a small to moderate magnitude increase in creatinine in most of these patients, postrandomization WRF was strongly associated with worsening in renal tubular injury biomarkers (odds ratio, 12.6; P=0.004). This observation did not differ by mode of volume removal (stepped pharmacological therapy versus ultrafiltration, Pinteraction=0.46). Increase in renal tubular injury biomarkers was associated with a higher incidence of hemoconcentration (odds ratio, 3.1; P=0.015), and paradoxically, better recovery of creatinine at 60 days (P=0.01).ConclusionsIn acute decompensated heart failure patients with preexisting WRF, intensive volume removal resulted in a further worsening of creatinine approximately half of the time, a finding associated with a rise in tubular injury biomarkers. However, decongestion and renal function recovery at 60 days were superior in patients with increased tubular injury markers. These data suggest that the benefits of decongestion may outweigh any modest or transient increases in serum creatinine or tubular injury markers that occur during intensive volume removal.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00608491.

    更新日期:2019-06-05
  • Empagliflozin Improves Kidney Outcomes in Patients With or Without Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-06-01
    Javed Butler, Faiez Zannad, David Fitchett, Bernard Zinman, Audrey Koitka-Weber, Maximilian von Eynatten, Isabella Zwiener, Jyothis George, Martina Brueckmann, Alfred K. Cheung, Christoph Wanner

    BackgroundIn EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) empagliflozin significantly reduced the risk of cardiovascular and kidney outcomes in patients with type 2 diabetes mellitus and established cardiovascular disease. Post hoc, we evaluated empagliflozin on kidney outcomes in patients with or without heart failure (HF).Methods and ResultsIndividuals were randomized to empagliflozin 10 mg, 25 mg, or placebo. Prespecified analyses by baseline HF status included risk of incident or worsening nephropathy and estimated glomerular filtration rate slope analyses. Cox proportional hazards models assessed consistency of treatment effect across subgroups. Safety evaluations included kidney-related adverse events. At baseline, 244 (10.5%) and 462 (9.9%) patients had HF in the placebo and empagliflozin groups, respectively. Overall, the incidence of kidney outcome events was numerically higher in patients with than without HF. In the HF group, empagliflozin reduced risk of incident or worsening nephropathy or cardiovascular death by 43% (hazard ratio, 0.57 [95% CI, 0.42–0.77]) and progression to macroalbuminuria by 50% (hazard ratio, 0.50 [0.33–0.75]). After an initial transient decrease, estimated glomerular filtration rate stabilized over time with empagliflozin but gradually declined with placebo. Kidney effects in patients with HF were consistent with those in the overall study population (all P values for interaction >0.05). Across groups, the incidence rate of kidney-related adverse events/100 patient-years was higher in patients with than without HF; however, overall rates were comparable between groups.ConclusionsThese findings from EMPA-REG OUTCOME support the hypothesis that empagliflozin could reduce the risk of clinically relevant kidney events and may slow progression of chronic kidney disease in individuals with type 2 diabetes mellitus regardless of HF status.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676.

    更新日期:2019-06-05
  • Development and Initial Validation of the PROMIS®-Plus-HF Profile Measure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-06-01
    Faraz S. Ahmad, Michael A. Kallen, Karen E. Schifferdecker, Kathleen L. Carluzzo, Susan E. Yount, Jill M. Gelow, Peter A. McCullough, Stephen E. Kimmel, Elliot S. Fisher, David Cella

    BackgroundBringing together generic and heart failure (HF)–specific items in a publicly available, patient-reported outcome measure may facilitate routine health status assessment for improving clinical care and shared decision-making, assessing quality of care, evaluating new interventions, and comparing groups with different conditions.Methods and ResultsWe performed a mixed-methods study to develop and validate the PROMIS®-Plus-HF (Patient-Reported Outcomes Measurement Information System®-Plus-Heart Failure) profile measure—a HF-specific instrument based on the generic PROMIS. We conducted 8 focus groups with 61 patients with HF and phone interviews with 10 HF clinicians. The measure was developed via an iterative process of reviewing existing PROMIS items and developing and testing new HF items. In a 600-patient sample, we estimated reliability (internal consistency; test-retest, with n=100 participants). We conducted validity analyses using Pearson r and Spearman ρ correlations with Kansas City Cardiomyopathy Questionnaire subscores. In a longitudinal sample, we performed responsiveness testing (paired t tests) with 75 patients with HF receiving interventions with expected health status improvement. The PROMIS-Plus-HF measure comprises 86 items (64 existing; 22 new) across 18 domains. Internal consistency reliability (Cronbach α) coefficients ranged from 0.52 to 0.96, with α≥0.70 in 12 of 17 domains. Test-retest intraclass correlation coefficients were ≥0.90. Correlations with Kansas City Cardiomyopathy Questionnaire subscores supported expected convergent (r/ρ>0.60) and divergent validity (r/ρ<0.30). In the longitudinal sample, 10 of 18 domains had improved (P<0.05) scores from baseline to follow-up.ConclusionsThe PROMIS-Plus-HF profile measure—a complete assessment of physical, mental, and social health—exhibited good psychometric characteristics and may facilitate patient-centered care and research. Subsets of domains and items can be used depending on the clinical or research purpose.

    更新日期:2019-06-05
  • Cognitive Domains and Postdischarge Outcomes in Hospitalized Patients With Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-06-01
    Quan L. Huynh, Kazuaki Negishi, Carmine G. De Pasquale, James L. Hare, Dominic Leung, Tony Stanton, Thomas H. Marwick

    BackgroundCognitive impairment is a prevalent, independent marker of readmission in heart failure (HF), but the screening is time-consuming. This study sought (1) to identify HF patients at low risk of cognitive impairment (obviating screening) and (2) to simplify a predictive model of HF outcomes by only using cognitive domains that are most predictive.Methods and ResultsThe Montreal Cognitive Assessment was performed in 1152 Australian patients with HF who were followed for 12 months. One-third (376/1152) of the patients were enrolled into an HF disease management plan to reduce early readmission. Postdischarge outcomes in HF included 30- and 90-day readmission or death and days alive and out of hospital within 12 months of discharge. Cognitive impairment—present in 54% of patients—independently predicted HF outcomes. Normal cognition could be predicted with common clinical and sociodemographic factors with good discrimination (C statistic=0.74 [0.69–0.78]). The visuospatial/executive and orientation domains were most predictive of HF postdischarge outcomes. Using either Montreal Cognitive Assessment score or these 2 domains provided similar incremental values (P=0.0004 and P=0.0008, respectively) in predicting HF outcomes (both C statistic=0.76) and could similarly identify a group of high-risk patients who benefited most from an HF disease management plan.ConclusionsCognitive function independently predicts HF outcomes and may also contribute to how a patient responds to intervention. The time and resources spent on cognitive assessment for risk-stratification in HF may be minimized by (1) identifying patients with low risk of cognitive impairment and (2) simplifying the screening instrument to include only the domains that are most predictive of postdischarge outcomes in HF.

    更新日期:2019-05-31
  • Understanding Contemporary Use of Thiazolidinediones
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-06-01
    Suzanne V. Arnold, Silvio E. Inzucchi, Justin B. Echouffo-Tcheugui, Fengming Tang, Carolyn S.P. Lam, Laurence S. Sperling, Mikhail Kosiborod

    BackgroundThiazolidinediones (rosiglitazone, pioglitazone) are oral insulin-sensitizing medications used in type 2 diabetes mellitus that reduce glucose with minimal risk of hypoglycemia and potential benefits on atherosclerosis. However, thiazolidinediones can cause fluid retention thereby increasing the risk of heart failure—a common complication of type 2 diabetes mellitus.Methods and ResultsData were analyzed from the Diabetes Collaborative Registry, a US outpatient registry of patients with type 2 diabetes mellitus that currently encompasses 203 cardiology, endocrinology, and primary care practices and 3074 providers. Among 424 061 US adults enrolled in Diabetes Collaborative Registry who had type 2 diabetes mellitus and were taking ≥1 glucose-lowering medication, 35 018 patients (8.3%) were on a thiazolidinedione, which has remained stable over time. Patients on thiazolidinediones tended to be old (mean age, 69.2±10.7 years), 61.9% had coronary disease, and 17.2% had class 3 obesity. In total, 40.3% of patients on a thiazolidinedione had either a clinical diagnosis of heart failure (23.7%), had an ejection fraction of <40% (7.7%), or were on a loop diuretic (29.9%).ConclusionsAlthough thiazolidinediones lost significant market share after 2007 when concerns arose regarding their safety, thiazolidinediones are still commonly used. At least a quarter, and up to two-fifths, of patients currently treated with thiazolidinediones have some evidence of heart failure and therefore should not be candidates for this therapy. Accordingly, heart failure concerns with thiazolidinediones may be under-recognized.

    更新日期:2019-05-27
  • What Number Are We?
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-05-01
    David A. Baran, Hannah Copeland, Jack Copeland

    BackgroundIn 2007, the United Network for Organ Sharing changed the way centers were notified of possible organ donors. In the new system, a donor sequence number (DSN) was provided signifying the position of a recipient on the list for a particular donor. Whether high DSN donors have equivalent outcomes is unknown.Methods and ResultsThe United Network for Organ Sharing database was queried between May 2007 and March 2014. DSNs were divided into cohorts of 5 (sequence 1–5, 6–10, and so forth). Survival was analyzed by Kaplan-Meier method. In this dataset, 12 363 adult de novo heart transplants were performed, and the median DSN was 3 with 58.3% of donors allocated locally. The distance from donor to transplant hospital was ≤500 miles in 93.8% of cases. With increasing DSN group, recipients were older, with longer ischemic time, and higher distance (P <0.001 for all comparisons). As well, with increasing DSN, donors were increasingly older, female sex, mismatched gender (female donor with a male recipient), lower ejection fraction, hypertensive, and had a history of smoking, alcohol, or cocaine use. For the whole cohort, the 1-year and 5-year survivals were 89.7% and 74.8%, respectively. Survival based on various cut points of DSN was investigated; there was no difference regardless of DSN.ConclusionsMost donors since 2007 were allocated within a close geographic range. DSN functions as a crowdsourced rank with most donors being selected within low numbers. Given the similar survival of donors at higher DSN, this represents an opportunity to increase transplant volumes.

    更新日期:2019-05-20
  • Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-05-01
    João Pedro Ferreira, Job Verdonschot, Timothy Collier, Ping Wang, Anne Pizard, Christian Bär, Jens Björkman, Alessandro Boccanelli, Javed Butler, Andrew Clark, John G. Cleland, Christian Delles, Javier Diez, Nicolas Girerd, Arantxa González, Mark Hazebroek, Anne-Cécile Huby, Wouter Jukema, Roberto Latini, Joost Leenders, Daniel Levy, Alexandre Mebazaa, Harald Mischak, Florence Pinet, Patrick Rossignol, Naveed Sattar, Peter Sever, Jan A. Staessen, Thomas Thum, Nicolas Vodovar, Zhen-Yu Zhang, Stephane Heymans, Faiez Zannad

    BackgroundIdentifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies.Methods and ResultsTo identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as the first hospitalization for HF, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20 000 individuals). Controls were matched on cohort, follow-up time, age, and sex. Two independent sample sets (a discovery set with 286 cases and 591 controls and a replication set with 276 cases and 280 controls) were used to discover and replicate the findings. Two hundred fifty-two circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase. These 38 proteins pointed to 4 main network clusters underlying incident HF: (1) inflammation and apoptosis, indicated by the expression of the TNF (tumor necrosis factor)-family members; (2) extracellular matrix remodeling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function, and vascular homeostasis; (3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin-angiotensin-aldosterone system; and (4) metabolism, associated with cholesterol and atherosclerosis.ConclusionsClusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodeling, blood pressure control, and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT02556450.

    更新日期:2019-05-20
  • Rationale and Design of the VITALITY-HFpEF Trial
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-05-01
    Javed Butler, Carolyn S.P. Lam, Kevin J. Anstrom, Justin Ezekowitz, Adrian F. Hernandez, Christopher M. O’Connor, Burkert Pieske, Piotr Ponikowski, Sanjiv J. Shah, Scott D. Solomon, Adriaan A. Voors, Yi Wu, Francine Carvalho, Luke Bamber, Robert O. Blaustein, Lothar Roessig, Paul W. Armstrong

    BackgroundThe VITALITY-HFpEF trial (Evaluate the Efficacy and Safety of the Oral sGC Stimulator Vericiguat to Improve Physical Functioning in Daily Living Activities of Patients With Heart Failure and Preserved Ejection Fraction) is designed to determine the efficacy and safety of a novel oral soluble guanylate cyclase stimulator, vericiguat, on quality of life and exercise tolerance in heart failure patients with preserved ejection fraction (HFpEF). Impaired physical functioning reduces the quality of life in patients with HFpEF. The primary goal of HF treatment along with improving survival is to improve function, reduce symptoms, and maximize quality of life. Abnormal cyclic guanosine monophosphate signaling may contribute to physical limitations in patients with HFpEF via central and peripheral mechanisms. Exploratory post hoc analyses from a prior trial showed that vericiguat can improve patient-relevant domains of the Kansas City Cardiomyopathy Questionnaire, especially the physical limitation score.Methods and ResultsVITALITY-HFpEF is a placebo-controlled, double-blind, multi-center, phase IIb trial of ≈735 patients, ≥45 years with HFpEF and ejection fraction ≥45% who will be randomized 1:1:1 to placebo, 10 mg, or 15 mg vericiguat. The primary end point is change in Kansas City Cardiomyopathy Questionnaire physical limitation score from baseline to week 24 and change in 6-minute walk test from baseline to week 24 is the secondary end point.ConclusionsVITALITY-HFpEF is the first trial designed to assess the efficacy of vericiguat in patients with HFpEF using the Kansas City Cardiomyopathy Questionnaire physical limitation score as a novel primary end point. This study will also extend the prior dosing experience with vericiguat in HF by studying the safety and efficacy of a 15 mg dose.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT03547583.

    更新日期:2019-05-17
  • Proenkephalin, an Opioid System Surrogate, as a Novel Comprehensive Renal Marker in Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-05-01
    Johanna E. Emmens, Jozine M. ter Maaten, Kevin Damman, Dirk J. van Veldhuisen, Rudolf A. de Boer, Joachim Struck, Andreas Bergmann, Iziah E. Sama, Koen W. Streng, Stefan D. Anker, Kenneth Dickstein, Chim C. Lang, Marco Metra, Nilesh J. Samani, Leong L. Ng, Adriaan A. Voors

    Background:PENK (proenkephalin) is a stable surrogate for enkephalins, endogenous opioid peptides, which exert cardiodepressive effects and improve renal function. PENK has been associated with heart failure (HF) severity and renal dysfunction. We therefore hypothesized that PENK could be associated with deterioration of kidney function and could have a role as a novel renal marker in HF.Methods and Results:In 2180 patients with HF of a large multicenter cohort (BIOSTAT-CHF [A Systems Biology Study to Tailored Treatment in Chronic Heart Failure]), the relationship between PENK and clinical variables, plasma and urinary biomarkers, and clinical end points was established. Data were validated in a separate cohort of 1703 patients with HF. PENK was elevated (>80 pmol/L, 99th percentile) in 1245 (57%) patients. Higher PENK was associated with more advanced HF and glomerular and tubular dysfunction. The strongest independent predictor of PENK was estimated glomerular filtration rate. Others were plasma NGAL (neutrophil gelatinase–associated lipocalin) and NT-proBNP (N-terminal pro-B-type natriuretic peptide; all P<0.001). Using correlation heatmaps and hierarchical cluster analyses, PENK clustered with estimated glomerular filtration rate, creatinine, NGAL, galectin-3, and urea. Higher PENK was independently associated with increased risk of deterioration of kidney function between baseline and 9 months (odds ratio, 1.29 [1.02–1.65] per PENK doubling; P=0.038; defined as >25% decrease in estimated glomerular filtration rate) and mortality (hazard ratio, 1.23 [1.07–1.43] per doubling; P=0.004). Analyses in the validation cohort yielded comparable findings.Conclusions:Higher PENK levels are associated with more severe HF, with glomerular and tubular renal dysfunction, with incidence of a deterioration of kidney function, and with mortality. These findings suggest that the opioid system might be involved in deteriorating kidney function in HF.

    更新日期:2019-05-16
  • Root Cause of Heart Failure
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-05-01
    Kartik Telukuntla, Pavan Bhat, Andrew Higgins, Grant Reed, Amar Krishnaswamy, Venu Menon

    Acute aortic insufficiency (AI) is an established class I indication for surgical aortic valve replacement.1 In contrast to chronic AI where the left ventricle (LV) has time to compensate and adapt to the demands of the additional regurgitant volume, acute severe AI results in a precipitous rise in left ventricular end-diastolic pressure (LVEDP) that in turn results in pulmonary edema and hemodynamic instability. The sudden drop in aortic diastolic blood pressure accompanied by the previously mentioned rise in LVEDP can markedly reduce coronary perfusion pressure (diastolic blood pressure LVEDP) and mimic LV dysfunction due to an acute coronary syndrome. We present a case of a patient with homograft failure resulting in acute severe AI that is illustrative of these physiological principles. Due to high surgical risk from his hemodynamic compromise, depressed ejection fraction, and prior homograft operation, the patient underwent a successful emergent transcatheter aortic valve implantation with subsequent rapid improvement of hemodynamics and normalization of LV function. A 65-year-old male with history of hypertension, gout, seizure disorder, and bicuspid aortic stenosis who underwent a cadaveric homograft in 1995 presented to his local emergency department with acute-onset dyspnea. From a cardiopulmonary standpoint, he had been asymptomatic since his remote homograft surgery. He had been appropriately monitored with serial echocardiograms, which previously showed only mild AI. Social and family histories were noncontributory. His physical exam was notable for tachycardia, significant hypoxia requiring 5 liters oxygen by nasal cannula, and a short diastolic murmur heard at the left lower sternal border with expiration. With the exception of rales at the lung bases, the remainder of his physical exam was unremarkable. His initial ECG showed sinus tachycardia with a heart rate of 119 beats per minute and ST depressions in the lateral leads (V5 through V6). He was transferred to our institution for further evaluation and management. Results of his basic metabolic panel and complete blood count were normal. His initial cardiac biomarkers were elevated (fourth generation troponin T 0.267 ng/mL). His echocardiogram demonstrated a dilated LV with reduced ejection fraction (28%) with an apical wall motion abnormality (Movie IA in the Data Supplement). Although the AI was relatively unremarkable on color Doppler (a consequence of rapid equalization of pressures), holodiastolic flow reversal was noted in the descending thoracic aorta confirming severe aortic regurgitation (Figure 1). While in the cardiac intensive care unit, a Swan-Ganz catheter was placed, and the patient was initiated on sodium nitroprusside with the goal of decreasing systemic arterial impedance which can result in a decreased LVEDP and increased systemic diastolic blood pressure.2 Coronary angiography showed no significant epicardial coronary artery disease (Movie II in the Data Supplement). Figure 1. Select images illustrating echo findings in acute aortic regurgitation.A, Apical 3 chamber view with color flow underestimating severe aortic insufficiency. B, M-mode through the mitral valve in the parasternal long-axis view showing premature closure of the mitral valve. C, Continuous wave Doppler across aortic valve with a pressure half-time of 74 ms suggestive of severe aortic insufficiency. D, Pulse wave Doppler in the descending aorta showing holodiastolic flow reversal. Due to the depressed ejection fraction, overt heart failure, and his history of prior sternotomy in the setting of a prior homograft with marked calcification of the aorta, he was deemed high risk for emergent surgical intervention. The patient successfully underwent transfemoral approach transcatheter aortic valve implantation with a 29 mm Edwards Sapien S3 Valve. Hemodynamic pressure measurements immediately postdeployment of valve revealed a marked decline in LVEDP, rise in aortic diastolic pressures, and recovery of aortic dicrotic notch (Figure 2). Similar improvements were evident both clinically and echocardiographically with an immediate reduction in oxygen requirement, improvement in heart rate and mild recovery of left ventricular function (Movie IB in the Data Supplement). Echocardiography performed 2 weeks after the procedure showed a significant recovery in LV function and trivial AI (Movie IC in the Data Supplement). Figure 2. Select hemodynamic tracings obtain in the catheterization laboratory.A, Pre-transcatheter aortic valve implantation (TAVI) hemodynamics: simultaneous hemodynamic tracings of the left ventricle (LV) and aorta on 200 mm Hg scale showing near equalization of LV end-diastolic pressure (LVEDP) and aortic diastolic pressure which lead to decreased coronary perfusion. B, Pre-TAVI: simultaneous hemodynamic tracings of the LV (40 mm Hg scale) and aorta (200 mm Hg scale) show loss of the aortic dicrotic notch which represents closure of the aortic valve. C, Post-TAVI: simultaneous hemodynamic tracings of the LV and aorta on 200 mm Hg scale showing significant reduction in LVEDP after transcatheter aortic valve implantation. D, Post-TAVI: simultaneous hemodynamic tracings of the LV (40 mm Hg scale) and aorta (200 mm Hg scale) show recovery of the aortic dicrotic notch. The impact of a sudden loss of coronary perfusion pressure on LV function is highlighted by this case. The apical wall motion abnormality noted resembles that often seen with a stress-induced cardiomyopathy, but is likely a manifestation of this phenomenon. Previous studies have shown that severe AI can lead to a reduction in coronary blood flow potentiating myocardial ischemia due to increased LVEDP with a concomitant fall in aortic diastolic pressure.3 The immediate normalization of LVEDP and rise in aortic diastolic pressure with correction of the regurgitation illustrates the dramatic effect of acute AI on the unprepared LV. The subsequent echocardiogram showing significant improvement of systolic function further supports this observation. This clinical vignette highlights several salient features of acute AI. Recognition of the cause of acute heart failure is pivotal to implementing an appropriate therapeutic intervention. Support for publication was provided by the Ralph C. Wilson Jr. Fellow Leadership Education endowment. None. The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCHEARTFAILURE.119.005896.

    更新日期:2019-05-16
  • Sacubitril/Valsartan Decreases Cardiac Fibrosis in Left Ventricle Pressure Overload by Restoring PKG Signaling in Cardiac Fibroblasts
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-04-10
    Ryan M. Burke, Janet K. Lighthouse, Deanne M. Mickelsen, Eric M. Small

    BackgroundHeart failure (HF) is invariably accompanied by development of cardiac fibrosis, a form of scarring that increases muscular tissue rigidity and decreases cardiac contractility. Cardiac fibrosis arises from a pathological attempt to repair tissue damaged during maladaptive remodeling. Treatment options to block or reverse fibrosis have proven elusive. Neprilysin is an endopeptidase that degrades vasoactive peptides, including atrial natriuretic peptide. Thus, neprilysin inhibition reduces hypertension, ultimately limiting maladaptive cardiac remodeling. LCZ696, which consists of an angiotensin receptor blocker (valsartan [VAL]) and a neprilysin inhibitor (sacubitril [SAC]), was shown to be well tolerated and significantly reduced the risk of death and hospitalization in HF patients with reduced ejection fraction. We hypothesized that SAC/VAL directly inhibits fibroblast activation and development of pathological fibrosis.Methods and ResultsWe used a mouse model of left ventricle pressure overload coupled to in vitro studies in primary mouse and human cardiac fibroblasts (CFs) to study the impact of SAC/VAL on CF activation and cardiac fibrosis. SAC/VAL significantly ameliorated pressure overload–induced cardiac fibrosis by blocking CF activation and proliferation, leading to functional improvement. Mechanistically, the beneficial impact of SAC/VAL at least partially stemmed from restoration of PKG (protein kinase G) signaling in HF patient-derived CF, which inhibited Rho activation associated with myofibroblast transition.ConclusionsThis study reveals that SAC/VAL acts directly on CF to prevent maladaptive cardiac fibrosis and dysfunction during pressure overload–induced hypertrophy and suggests that SAC/VAL should be evaluated as a direct antifibrotic therapeutic for conditions such as HF with preserved ejection fraction.

    更新日期:2019-04-10
  • Hearts Donated After Circulatory Death and Reconditioned Using Normothermic Regional Perfusion Can Be Successfully Transplanted Following an Extended Period of Static Storage
    Circ. Heart Fail. (IF 6.526) Pub Date : 2019-04-08
    Roberto V. P. Ribeiro, Juglans S. Alvarez, Frank Yu, Emanuela Paradiso, Mitchell B. Adamson, Giulia Maria Ruggeri, Naoto Fukunaga, Ved Bissoondath, Cyril Serrick, Massimiliano Meineri, Heather Ross, Vivek Rao, Mitesh V. Badiwala

    Background:There has been an increased interest in donation after circulatory death (DCD) to expand donor pool for cardiac transplantation. Normothermic regional perfusion (NRP) allows in situ assessment of DCD hearts, allowing only acceptable organs to be procured. We sought to determine if extended cold storage was possible for DCD hearts following NRP and to compare hearts stored using standard cold storage with a novel cardioprotective solution designed for room temperature storage.Methods and Results:Donor pigs underwent hypoxic cardiac arrest (DCD) followed by 15 minutes of warm ischemia and resuscitation on NRP. They were then randomly assigned to static storage with histidine-tryptophan-ketoglutarate (HTK) at 4°C (HTK group, n=5) or SOM-TRN-001 at 21°C (SOM group, n=5). Conventional beating-heart donations were used as controls (n=4). Fourteen transplants were successfully performed. HTK hearts showed initial dysfunction following reperfusion; however, they demonstrated significant recovery up to 3 hours post-transplant. No significant differences were seen between HTK and control hearts post-transplantation (cardiac index: control 49.5±6% and HTK 48.5±5% of baseline). SOM improved myocardial preservation; hearts showed stable contractility after transplantation (cardiac index: 113.0±43% of NRP function) and improved diastolic function compared with HTK. Preservation in SOM also significantly reduced proinflammatory cytokine production and release following transplantation and partially prevented endothelial dysfunction.Conclusions:DCD hearts stored using a standard preservation solution demonstrated comparable post-transplantation myocardial function to standard controls. Thus, short periods of cold storage following successful NRP and documented adequate function is an acceptable strategy for DCD hearts. Preservation in SOM at room temperature is feasible and can improve cardiac recovery by minimizing endothelial dysfunction and tissue injury.

    更新日期:2019-04-08
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