Binding of FUNDC1 with Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum (ER) Membranes Maintains Mitochondrial Dynamics and Function in Hearts In Vivo Circulation (IF 19.309) Pub Date : 2017-09-23 Shengnan Wu, Qiulun Lu, Qilong Wang, Ye Ding, Zejun Ma, Xiaoxiang Mao, Kai Huang, Zhonglin Xie, Ming-Hui Zou
Background—FUN14 domain containing 1 (FUNDC1) is a highly conserved outer mitochondrial membrane protein. The aim of this study is to examine if FUNDC1 modulates the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondrial morphology, and function in cardiomyocytes and in intact hearts.Methods—The impacts of FUNDC1 on MAMs formation and cardiac functions were studied in mouse neonatal cardiomyocytes, in mice with cardiomyocyte-specific Fundc1 gene knockout (Fundc1f/Y/CreαMyHC+/−), and in the cardiac tissues of the patients with heart failure.Results—In mouse neonatal cardiomyocytes and intact hearts, FUNDC1 was localized in MAMs by binding to ER-resided inositol 1,4,5-trisphosphate type 2 receptor (IP3R2). Fundc1 ablation disrupted MAMs, reduced the levels of IP3R2 and Ca2+ in both mitochondria and cytosol whereas overexpression of Fundc1 increased the levels of IP3R2 and Ca2+ in both mitochondria and cytosol. Consistently, Fundc1 ablation increased Ca2+ levels in ER whereas Fundc1 overexpression lowered ER Ca2+ levels. Further, Fundc1 ablation in cardiomyocytes elongated mitochondria, and compromised mitochondrial functions. Mechanistically, we found that Fundc1 ablation-induced reduction of intracellular Ca2+ levels suppressed mitochondrial fission 1 protein (Fis1) expression and mitochondrial fission by reducing the binding of the cAMP response element binding protein (CREB) in the Fis1 promoter. Fundc1f/Y/CreαMyHC+/− mice but not their littermate control mice (Fundc1wt/Y/CreαMyHC+/−) exhibited cardiac dysfunction. The ligation of the left ventricle artery of Fundc1f/Y/CreαMyHC+/− mice caused more severe cardiac dysfunction than those in sham-treated Fundc1f/Y/CreαMyHC+/− mice. Finally, we found that the FUNDC1/MAMs/CREB/Fis1 signaling axis was significantly suppressed in the patients with heart failure.Conclusions—We conclude that FUNDC1 binds to IP3R2 to modulate ER Ca2+ release into mitochondria and cytosol and that a disruption of FUNDC1 and IP3R2 interaction lowers the levels of Ca2+ in mitochondria and cytosol, both of which instigate aberrant mitochondrial fission, mitochondrial dysfunction, cardiac dysfunction, and heart failure.
The J-curve in Patients Randomly Assigned to Different Systolic Blood Pressure Targets - an Experimental Approach to an Observational Paradigm Circulation (IF 19.309) Pub Date : 2017-09-22 Deborah N. Kalkman, Tom F. Brouwer, Jim T. Vehmeijer, Wouter R. Berger, Reinoud E. Knops, Robbert J. de Winter, Ron J. Peters, Bert-Jan H. van den Born
Background—Low systolic blood pressure (SBP) values are associated with an increased risk of cardiovascular events, giving rise to the so called J-curve phenomenon. We assessed the association between on-treatment SBP levels, cardiovascular events and all-cause mortality in patients randomized to different SBP targets.Methods—Data from two large randomized trials that randomly allocated hypertensive patients at high-risk for cardiovascular disease to intensive (SBP<120 mmHg) or conventional treatment (SBP<140 mmHg) were pooled and harmonized for outcomes and follow-up duration. Using natural cubic splines, the hazard ratio for all-cause mortality and cardiovascular events was plotted against the mean on-treatment systolic blood pressure per treatment group.Results—The pooled data consisted of 194,875 on-treatment SBP measurements in 13,946 (98.9%) patients. During a median follow-up of 3.3 years, cardiovascular events occurred in 1014 patients (7.3%) and 502 patients died (3.7%). For both blood pressure targets, an identical shape of the J-curve was present with a nadir for cardiovascular events and all-cause mortality just below the SBP target. Patients in the lowest SBP stratum were older, had a higher BMI, smoked more often and had a higher frequency of diabetes and cardiovascular events.Conclusions—Low on-treatment SBP levels are associated with increased cardiovascular events and all-cause mortality. This association is independent of the attained blood pressure level because the J-curve aligns with the SBP target. Our results suggest that the benefit or risk associated with intensive blood pressure lowering treatment can only be established via randomized clinical trials.Clinical Trial Registration—URL: https://clinicaltrials.gov Unique Identifiers: NCT01206062 and NCT00000620
Upregulation of HERV-K is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension Circulation (IF 19.309) Pub Date : 2017-09-21 Toshie Saito, Kazuya Miyagawa, Shih-Yu Chen, Rasa Tamosiuniene, Lingli Wang, Orr Sharp, Erik Samayoa, Daisuke Harada, Jan-Renier A. J. Moonen, Aiqin Cao, Pin-I Chen, Jan K. Hennigs, Mingxia Gu, Caiyun G. Li, Ryan D. Leib, Dan Li, Christopher M. Adams, Patricia A. del Rosario, Matthew A. Bill, Francois Haddad, Jose G. Montoya, William Robinson, Wendy J. Fantl, Garry P. Nolan, Roham T. Zamanian, Mark R. Nicolls, Charles Y. Chiu, Maria E. Ariza, Marlene Rabinovitch
Background—Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue and elevated cytokines have been related to PAH pathogenesis but without clear understanding of how these abnormalities are initiated, perpetuated and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies.Methods—Lung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry (LCMS), confirmed by ELISA, and localized by confocal microscopy. One PAH antigen linked to immunity and inflammation was pursued and a link to PAH pathophysiology was investigated by next generation sequencing, functional studies in cultured monocytes and endothelial cells (EC) and hemodynamic and lung studies in a rat.Results—SAM domain and HD1 domain-containing protein (SAMHD1), an innate immune factor that suppresses HIV replication was identified and confirmed as highly expressed in immune complexes from 16 hereditary and idiopathic PAH vs. 12 control lungs. Elevated SAMHD1 was localized to endothelial cells (EC), perivascular dendritic cells and macrophages and SAMHD1 antibodies were prevalent in tertiary lymphoid tissue. An unbiased screen using metagenomic sequencing related SAMHD1 to increased expression of human endogenous retrovirus K (HERV-K) in PAH vs. control lungs (n=4 each). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) mRNAs were elevated in PAH vs. control lungs (n=10) and proteins were localized to macrophages. HERV-K dUTPase induced SAMHD1 and pro-inflammatory cytokines (e.g., IL6, IL1β and TNFα) in circulating monocytes and pulmonary arterial (PA) EC, and activated B cells. Vulnerability of PAEC to apoptosis was increased by HERV-K dUTPase in an IL6 independent manner. Furthermore, three weekly injections of HERV-K dUTPase induced hemodynamic and vascular changes of pulmonary hypertension in rats (n=8), and elevated IL6.Conclusions—Our study reveals that upregulation of the endogenous retrovirus HERV-K could both initiate and sustain activation of the immune system and cause vascular changes associated with PAH.
Endoplasmic Reticulum Membrane Protein Complex Subunit 10 (EMC10) is a Bone Marrow-Derived Angiogenic Growth Factor Promoting Tissue Repair After Myocardial Infarction Circulation (IF 19.309) Pub Date : 2017-09-20 Marc R. Reboll, Mortimer Korf-Klingebiel, Stefanie Klede, Felix Polten, Eva Brinkmann, Ines Reimann, Hans-Joachim Schönfeld, Maria Bobadilla, Jan Faix, George Kensah, Ina Gruh, Michael Klintschar, Matthias Gaestel, Hans W. Niessen, Andreas Pich, Johann Bauersachs, Joseph A. Gogos, Yong Wang, Kai C. Wollert
Background—Clinical trials of bone marrow cell (BMC)-based therapies after acute myocardial infarction (MI) have produced mostly neutral results. Treatment with specific BMC-derived secreted proteins may provide an alternative biologic approach to improving tissue repair and heart function after MI. We recently performed a bioinformatic secretome analysis in BMCs from patients with acute MI and discovered a poorly characterized secreted protein, endoplasmic reticulum membrane protein complex subunit 10 (EMC10), showing activity in an angiogenic screen.Methods—We investigated the angiogenic potential of EMC10 and its mouse homolog (Emc10) in cultured endothelial cells and infarcted heart explants. We defined the cellular sources and function of Emc10 after MI using wild-type (WT), Emc10-deficient (knockout, KO), and Emc10 bone marrow-chimeric mice subjected to transient coronary artery ligation. Further, we explored the therapeutic potential of recombinant Emc10 delivered by osmotic minipumps after MI in heart failure-prone FVB/N mice.Results—Emc10 signaled through small GTPases, p21 activated kinase, and the p38 mitogen-activated protein kinase (MAPK)-MAPK-activated protein kinase 2 (MK2) pathway to promote actin polymerization and endothelial cell migration. Confirming the importance of these signaling events in the context of acute MI, Emc10 stimulated endothelial cell outgrowth from infarcted mouse heart explants via p38 MAPK-MK2. Emc10 protein abundance was increased in the infarcted region of the left ventricle and in the circulation of WT mice after MI. Emc10 expression was also increased in left ventricular (LV) tissue samples from patients with acute MI. Bone marrow-derived monocytes and macrophages were the predominant sources of Emc10 in the infarcted murine heart. Emc10 KO mice showed no cardiovascular phenotype at baseline. After MI, however, capillarization of the infarct border zone was impaired in KO mice, and the animals developed larger infarct scars and more pronounced LV remodeling compared to WT mice. Transplanting KO mice with WT BMCs rescued the angiogenic defect and ameliorated LV remodeling. Treating FVB/N mice with recombinant Emc10 enhanced infarct border zone capillarization and exerted a sustained beneficial effect on LV remodeling.Conclusions—We have identified Emc10 as a previously unknown angiogenic growth factor that is produced by bone marrow-derived monocytes and macrophages as part of an endogenous adaptive response that can be enhanced therapeutically to repair the heart after MI.
The Absence of an Ideal Observer Circulation (IF 19.309) Pub Date : 2017-09-19 Milton Packer
According to Richard Firth Green, a major change occurred in our conceptualization of the truth during the reign of Richard II of England in the late 14th century.1 Before then, “trouthe” was an ethical concept that resided within individuals; afterward, truth became an objective reality that existed outside ourselves.1,2 If so, who could be trusted with identifying the truth? Green proposed the “ideal observer”; ie, we can know that “x is better than y” if this judgment were made by an observer who was “fully informed and vividly imaginative, impartial, in a calm frame of mind and otherwise normal.”3 It is interesting to note that Green never claimed that any ideal observers actually existed. The ideal observer theory is appealing. We believe that investigators can describe an external reality that exists independently of their ethical compasses. We assume that stringent experimental conditions can reveal an unbiased truth. But does the scientific method always yield valid results? Before we answer, we should ask: when we execute a large-scale clinical trial, is there an ideal observer who is impartial, knowledgeable, rational and calm? A large clinical trial typically involves a leadership committee, a sponsor, numerous geographically dispersed investigators, and a group responsible for operational functions. The leadership committee helps to define the trial hypotheses and the methods by which they are tested; however, its members personally make no observations and may not know exactly how observations are made. The sponsor invests substantial sums of money, without assurance that the hypothesis is valid and …
Evaluating the Impact and Cost-Effectiveness of Statin Use Guidelines for Primary Prevention of Coronary Heart Disease and Stroke Circulation (IF 19.309) Pub Date : 2017-09-19 David J. Heller, Pamela G. Coxson, Joanne Penko, Mark J. Pletcher, Lee Goldman, Michelle C. Odden, Dhruv S. Kazi, Kirsten Bibbins-Domingo
Background: Statins are effective in the primary prevention of atherosclerotic cardiovascular disease. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline expands recommended statin use, but its cost-effectiveness has not been compared with other guidelines. Methods: We used the Cardiovascular Disease Policy Model to estimate the cost-effectiveness of the ACC/AHA guideline relative to current use, Adult Treatment Panel III guidelines, and universal statin use in all men 45 to 74 years of age and women 55 to 74 years of age over a 10-year horizon from 2016 to 2025. Sensitivity analyses varied costs, risks, and benefits. Main outcomes were incremental cost-effectiveness ratios and numbers needed to treat for 10 years per quality-adjusted life-year gained. Results: Each approach produces substantial benefits and net cost savings relative to the status quo. Full adherence to the Adult Treatment Panel III guideline would result in 8.8 million more statin users than the status quo, at a number needed to treat for 10 years per quality-adjusted life-year gained of 35. The ACC/AHA guideline would potentially result in up to 12.3 million more statin users than the Adult Treatment Panel III guideline, with a marginal number needed to treat for 10 years per quality-adjusted life-year gained of 68. Moderate-intensity statin use in all men 45 to 74 years of age and women 55 to 74 years of age would result in 28.9 million more statin users than the ACC/AHA guideline, with a marginal number needed to treat for 10 years per quality-adjusted life-year gained of 108. In all cases, benefits would be greater in men than women. Results vary moderately with different risk thresholds for instituting statins and statin toxicity estimates but depend greatly on the disutility caused by daily medication use (pill burden). Conclusions: At a population level, the ACC/AHA guideline for expanded statin use for primary prevention is projected to treat more people, to save more lives, and to cost less compared with Adult Treatment Panel III in both men and women. Whether individuals benefit from long-term statin use for primary prevention depends more on the disutility associated with pill burden than their degree of cardiovascular risk.
When to Start a Statin Is a Preference-Sensitive Decision Circulation (IF 19.309) Pub Date : 2017-09-19 Rodney A. Hayward
Article, see p 1087 In this issue of Circulation, Heller et al1 report results of a simulation model suggesting that the American Heart Association/American College of Cardiology (AHA/ACC) primary prevention lipid treatment guidelines treat many more people with a statin but also save many more lives compared with ATP III. These findings are consistent with previous reports,2,3 but their results further suggest that starting a statin at 40 years of age in everyone regardless of cardiovascular disease (CVD) risk would extend statin treatment to >28 million more Americans but would further and substantially improve the public’s health, but only if the disutility associated with pill burden is quite low. If starting a statin in all adults at 40 years of age would really save hundreds of thousands of quality-adjusted life years (QALYs), implementing such a policy would seem to be a public health priority. However, this perspective has several problems. Principally, taking a statin is an individual not a public health decision, such as interventions to improve air quality or a decision with externalities, such as treating contagious diseases. For an individual decision without externalities, an individual’s chance and magnitude of net benefit (absolute risk reduction minus absolute risk increase plus/minus uncertainties) is the only meaningful consideration.4 This may sound heretical, especially coming from a professor of public health, but the ethical and legal standards are clear. When counseling an individual patient about treatment, the most relevant question is almost always, “What is the magnitude of and uncertainty bounds for estimated net benefit for the considered treatment?” Heller et al1 present a relevant estimate in this regard. If their base-case estimates are correct, adoption of the treat at 40 years of age policy, compared with AHA/ACC guidelines, would average 1 additional QALY gained …
Stellarex Drug-Coated Balloon for Treatment of Femoropopliteal Disease Circulation (IF 19.309) Pub Date : 2017-09-19 Prakash Krishnan, Peter Faries, Khusrow Niazi, Ash Jain, Ravish Sachar, William B. Bachinsky, Joseph Cardenas, Martin Werner, Marianne Brodmann, J. A. Mustapha, Carlos Mena-Hurtado, Michael R. Jaff, Andrew H. Holden, Sean P. Lyden
Background: Drug-coated balloons (DCBs) are a predominant revascularization therapy for symptomatic femoropopliteal artery disease. Because of the differences in excipients, paclitaxel dose, and coating morphologies, varying clinical outcomes have been observed with different DCBs. We report the results of 2 studies investigating the pharmacokinetic and clinical outcomes of a new DCB to treat femoropopliteal disease. Methods: In the ILLUMENATE Pivotal Study (Prospective, Randomized, Single-Blind, U.S. Multi-Center Study to Evaluate Treatment of Obstructive Superficial Femoral Artery or Popliteal Lesions With A Novel Paclitaxel-Coated Percutaneous Angioplasty Balloon), 300 symptomatic patients (Rutherford class 2–4) were randomly assigned to DCB (n=200) or standard angioplasty (percutaneous transluminal angioplasty [PTA]) (n=100). The primary safety end point was freedom from device- and procedure-related death through 30 days, and freedom from target limb major amputation and clinically driven target lesion revascularization through 12 months. The primary effectiveness end point was primary patency through 12 months. In the ILLUMENATE PK study (Pharmacokinetic Study of the Stellarex Drug-Coated Angioplasty Balloon), paclitaxel plasma concentrations were measured after last DCB deployment and at prespecified times (at 1, 4, 24 hours and at 7 and 14 days postprocedure) until no longer detectable. Results: In the ILLUMENATE Pivotal Study, baseline characteristics were similar between groups: 50% had diabetes mellitus, 41% were women, mean lesion length was 8.3 cm, and 44% were severely calcified. The primary safety end point was met (92.1% for DCB versus 83.2% for PTA, P=0.025 for superiority) and the primary patency rate was significantly higher with DCB (76.3% for DCB versus 57.6% for PTA, P=0.003). Primary patency per Kaplan-Meier estimates at day 365 was 82.3% for DCB versus 70.9% for PTA (P=0.002). The rate of clinically driven target lesion revascularization was significantly lower in the DCB cohort (7.9% versus 16.8%, P=0.023). Improvements in ankle-brachial index, Rutherford class, and quality of life were comparable, but the PTA cohort required twice as many revascularizations. Pharmacokinetic outcomes showed that all patients had detectable paclitaxel levels after DCB deployment that declined within the first hour (54.4±116.9 ng/mL to 1.4±1.0 ng/mL). Conclusions: The data demonstrate superior safety and effectiveness of the Stellarex DCB in comparison with PTA, and plasma levels of paclitaxel fall to low levels within 1 hour. Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifiers: NCT01858428 and NCT01912937.
Long-Term Outcomes and Prognostic Factors of Complications in Takayasu Arteritis Circulation (IF 19.309) Pub Date : 2017-09-19 Cloé Comarmond, Lucie Biard, Marc Lambert, Arsène Mekinian, Yasmina Ferfar, Jean-Emmanuel Kahn, Ygal Benhamou, Laurent Chiche, Fabien Koskas, Philippe Cluzel, Eric Hachulla, Emmanuel Messas, Matthieu Resche-Rigon, Patrice Cacoub, Tristan Mirault, David Saadoun
Background: Because of the wide variation in the course of Takayasu arteritis (TA), predicting outcome is challenging. We assess long-term outcome and prognosis factors for vascular complications in patients with TA. Methods: A retrospective multicenter study of characteristics and outcomes of 318 patients with TA fulfilling American College of Rheumatology and Ishikawa criteria was analyzed. Factors associated with event-free survival, relapse-free survival, and incidences of vascular complications were assessed. Risk factors for vascular complications were identified in a multivariable model. Results: The median age at TA diagnosis was 36 [25–47] years, and 276 patients (86.8%) were women. After a median follow-up of 6.1 years, relapses were observed in 43%, vascular complications in 38%, and death in 5%. Progressive clinical course was observed in 45%, carotidodynia in 10%, and retinopathy in 4%. The 5- and 10-year event-free survival, relapse-free survival, and complication-free survival were 48.2% (42.2; 54.9) and 36.4% (30.3; 43.9), 58.6% (52.7; 65.1) and 47.7% (41.2; 55.1), and 69.9% (64.3; 76.0) and 53.7% (46.8; 61.7), respectively. Progressive disease course (P=0.018) and carotidynia (P=0.036) were independently associated with event-free survival. Male sex (P=0.048), elevated C-reactive protein (P=0.013), and carotidynia (P=0.003) were associated with relapse-free survival. Progressive disease course (P=0.017), thoracic aorta involvement (P=0.009), and retinopathy (P=0.002) were associated with complication-free survival. Conclusions: This nationwide study shows that 50% of patients with TA will relapse and experience a vascular complication ≤10 years from diagnosis. We identified specific characteristics that identified those at highest risk for subsequent vascular complications.
Multicellular Transcriptional Analysis of Mammalian Heart Regeneration Circulation (IF 19.309) Pub Date : 2017-09-19 Gregory A. Quaife-Ryan, Choon Boon Sim, Mark Ziemann, Antony Kaspi, Haloom Rafehi, Mirana Ramialison, Assam El-Osta, James E. Hudson, Enzo R. Porrello
Background: The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we assemble a transcriptomic framework of multiple cardiac cell populations during postnatal development and following injury, which enables comparative analyses of the regenerative (neonatal) versus nonregenerative (adult) state for the first time. Methods: Cardiomyocytes, fibroblasts, leukocytes, and endothelial cells from infarcted and noninfarcted neonatal (P1) and adult (P56) mouse hearts were isolated by enzymatic dissociation and fluorescence-activated cell sorting at day 3 following surgery. RNA sequencing was performed on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair, and regeneration. To complement our transcriptomic data, we also surveyed the epigenetic landscape of cardiomyocytes during postnatal maturation by performing deep sequencing of accessible chromatin regions by using the Assay for Transposase-Accessible Chromatin from purified mouse cardiomyocyte nuclei (P1, P14, and P56). Results: Profiling of cardiomyocyte and nonmyocyte transcriptional programs uncovered several injury-responsive genes across regenerative and nonregenerative time points. However, the majority of transcriptional changes in all cardiac cell types resulted from developmental maturation from neonatal stages to adulthood rather than activation of a distinct regeneration-specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state. In contrast, cardiomyocytes failed to reactivate the neonatal proliferative network following infarction, which was associated with loss of chromatin accessibility around cell cycle genes during postnatal maturation. Conclusions: This work provides a comprehensive framework and transcriptional resource of multiple cardiac cell populations during cardiac development, repair, and regeneration. Our findings define a regulatory program underpinning the neonatal regenerative state and identify alterations in the chromatin landscape that could limit reinduction of the regenerative program in adult cardiomyocytes.
Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis Circulation (IF 19.309) Pub Date : 2017-09-19 Anusha N. Seneviratne, Andreas Edsfeldt, Jennifer E. Cole, Christina Kassiteridi, Maarten Swart, Inhye Park, Patricia Green, Tariq Khoyratty, David Saliba, Michael E. Goddard, Stephen N. Sansom, Isabel Goncalves, Rob Krams, Irina A. Udalova, Claudia Monaco
Background: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis) promotes lesion growth and establishment of a necrotic core. The transcription factor interferon regulatory factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions. Methods: We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE-/-) mice and ApoE-/- mice with a genetic deletion of IRF5 (ApoE-/-Irf5-/-) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation. Results: Both lesion and necrotic core size were significantly reduced in ApoE-/-Irf5-/- mice compared with IRF5-competent ApoE-/- mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c+ macrophages was evident in ApoE-/-Irf5-/- mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c+ macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c- macrophages displayed a significant increase in expression of the efferocytosis-regulating integrin-β3 and its ligand milk fat globule-epidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ. Conclusions: IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c+ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.
Acute Coronary Syndromes Circulation (IF 19.309) Pub Date : 2017-09-19 Filippo Crea, Peter Libby
Well into the 21st century, we still triage acute myocardial infarction on the basis of the presence or absence of ST-segment elevation, a century-old technology. Meanwhile, we have learned a great deal about the pathophysiology and mechanisms of acute coronary syndromes (ACS) at the clinical, pathological, cellular, and molecular levels. Contemporary imaging studies have shed new light on the mechanisms of ACS. This review discusses these advances and their implications for clinical management of the ACS for the future. Plaque rupture has dominated our thinking about ACS pathophysiology for decades. However, current evidence suggests that a sole focus on plaque rupture vastly oversimplifies this complex collection of diseases and obscures other mechanisms that may mandate different management strategies. We propose segmenting coronary artery thrombosis caused by plaque rupture into cases with or without signs of concomitant inflammation. This distinction may have substantial therapeutic implications as direct anti-inflammatory interventions for atherosclerosis emerge. Coronary artery thrombosis caused by plaque erosion may be on the rise in an era of intense lipid lowering. Identification of patients with of ACS resulting from erosion may permit a less invasive approach to management than the current standard of care. We also now recognize ACS that occur without apparent epicardial coronary artery thrombus or stenosis. Such events may arise from spasm, microvascular disease, or other pathways. Emerging management strategies may likewise apply selectively to this category of ACS. We advocate this more mechanistic approach to the categorization of ACS to provide a framework for future tailoring, triage, and therapy for patients in a more personalized and precise manner.
Effects of the Selective Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin on Vascular Function and Central Hemodynamics in Patients With Type 2 Diabetes Mellitus Circulation (IF 19.309) Pub Date : 2017-09-19 Kristina Striepe, Agnes Jumar, Christian Ott, Marina V. Karg, Markus P. Schneider, Dennis Kannenkeril, Roland E. Schmieder
From a clinical perspective, type 2 diabetes mellitus might also be regarded as a vascular disease, characterized by increased arterial stiffness. Empagliflozin is a selective sodium-glucose cotransporter 2 inhibitor shown to improve glycemic control after short- and long-term treatment.1 In the EMPA-REG OUTCOME study (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), a prospective randomized double-blind study in patients with type 2 diabetes mellitus with established cardiovascular disease, treatment with empagliflozin reduced the primary combined cardiovascular end point (3P-MACE [3-point major adverse cardiovascular event]), as well as secondary end points of hospitalization because of heart failure, cardiovascular morbidity, total mortality, and renal end points.2 We tested the hypothesis that improvements of vascular function and stiffness are involved in the observed improved cardiovascular and renal outcomes with empagliflozin treatment. In this investigator-initiated prospective, double-blind, randomized, placebo-controlled, crossover, interventional single-center trial, 76 female and male patients (18–75 years of age) with diagnosed type 2 diabetes mellitus were randomized to either empagliflozin 25 mg orally once daily or placebo for 6 weeks, followed by the second 6-week treatment with the other compound (crossover). In 64 patients, any antidiabetic agent was withdrawn 4 weeks before the baseline examination. We analyzed the effects …
Letter by Donzelli Regarding Article, “Potential Deaths Averted and Serious Adverse Events Incurred From Adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) Intensive Blood Pressure Regimen in the United States: Projections From NHANES (National Health and Nutrition Examination Survey)” Circulation (IF 19.309) Pub Date : 2017-09-19 Alberto Donzelli
If SPRINT (Systolic Blood Pressure Intervention Trial) eligibility criteria were applied to the 1999 to 2006 NHANES (National Health and Nutrition Examination Survey), Bress and colleagues1 calculate that lowering systolic blood pressure (BP) to an intensive goal of <120 mm Hg (versus the standard goal of <140 mm Hg) could prevent ≈107 500 deaths per year, despite a higher incidence of treatment-related serious adverse events. A sensitivity analysis has tried to take into account the different methods of BP measurements in NHANES and SPRINT, finding reduced but still significant outcomes. The SPRINT methodology is not usually used in clinical practice. BP was measured at an office visit, in participants sitting quietly …
Letter by Koh Regarding Article, “Potential Deaths Averted and Serious Adverse Events Incurred From Adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) Intensive Blood Pressure Regimen in the United States: Projections From NHANES (National Health and Nutrition Examination Survey)” Circulation (IF 19.309) Pub Date : 2017-09-19 Kwang Kon Koh
Bress et al1 estimated the deaths prevented and excess serious adverse events incurred if the SPRINT (Systolic Blood Pressure Intervention Trial) intensive systolic blood pressure (SBP) treatment goal were implemented in all eligible US adults and observed that, if fully implemented in eligible US adults, intensive SBP treatment could prevent ≈107 500 deaths per year; however, a consequence of this treatment strategy could be an increase in serious adverse events. The best therapeutic target of SBP has been …
Response by Bress et al to Letters Regarding Article, “Potential Deaths Averted and Serious Adverse Events Incurred From Adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) Intensive Blood Pressure Regimen in the United States: Projections from NHANES (National Health and Nutrition Examination Survey)” Circulation (IF 19.309) Pub Date : 2017-09-19 Adam P. Bress, Holly Kramer, Richard S. Cooper
We thank Dr Koh for his comments and agree that clinical practice guidelines should evolve as new knowledge becomes available. For example, a recent network meta-analysis of 42 blood pressure–lowering trials including 144 220 patients found significantly lower risks of all-cause mortality among participants who achieved systolic blood pressure 120 to 124 mm Hg in comparison with all other achieved systolic blood pressure groups including 130 to 134, 140 to 144, 150 to 154, or 160 mm Hg or more.1 Specifically, randomized groups who achieved a mean systolic …
Contemporary Management of Cardiogenic Shock: A Scientific Statement From the American Heart Association Circulation (IF 19.309) Pub Date : 2017-01-01 Sean van Diepen, Jason N. Katz, Nancy M. Albert, Timothy D. Henry, Alice K. Jacobs, Navin K. Kapur, Ahmet Kilic, Venu Menon, E. Magnus Ohman, Nancy K. Sweitzer, Holger Thiele, Jeffrey B. Washam, Mauricio G. Cohen, On behalf of the American Heart Association Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; and Mission: Lifeline
Cardiogenic shock is a high-acuity, potentially complex, and hemodynamically diverse state of end-organ hypoperfusion that is frequently associated with multisystem organ failure. Despite improving survival in recent years, patient morbidity and mortality remain high, and there are few evidence-based therapeutic interventions known to clearly improve patient outcomes. This scientific statement on cardiogenic shock summarizes the epidemiology, pathophysiology, causes, and outcomes of cardiogenic shock; reviews contemporary best medical, surgical, mechanical circulatory support, and palliative care practices; advocates for the development of regionalized systems of care; and outlines future research priorities.
Inflammation and Atherosclerosis - The End of a Controversy Circulation (IF 19.309) Pub Date : 2017-09-15 Göran K. Hansson
Does inflammation matter in coronary artery disease? Is it a driving force in atherosclerosis, or merely an epiphenomenon? And is there space for novel therapies besides those targeting cholesterol? The CANTOS trial, which was presented at the European Society of Cardiology meeting in Barcelona a few weeks ago provides answers to these important questions. Indeed, the results of this trial open up a new avenue for cardiovascular prevention.
Clinical Profile and Consequences of Atrial Fibrillation in Hypertrophic Cardiomyopathy Circulation (IF 19.309) Pub Date : 2017-09-15 Ethan J. Rowin, Anais Hausvater, Mark S. Link, Patrick Abt, William Gionfriddo, Wendy Wang, Hassan Rastegar, N.A. Mark Estes, Martin S. Maron, Barry J. Maron
Background—Atrial fibrillation (AF), the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM), is capable of producing symptoms that impact quality of life and is associated with risk for embolic stroke. However, the influence of AF on clinical course and outcome in HCM remains incompletely resolved.Methods—Records were accessed of 1558 consecutive patients followed at the Tufts Medical Center Hypertrophic Cardiomyopathy Institute for 4.8 ± 3.4 years, from 2004 to 2014.Results—Of the 1558 HCM patients, 304 (20%) had episodes of AF, of which 226 (74%) were confined to symptomatic paroxysmal AF (PAF; average 5 ± 5; range 1 to > 20), while 78 (26%) developed permanent AF, preceded by 7 ± 6 PAF episodes. At last evaluation, 277 patients (91%) are alive at 62 ± 13 years of age, including 89% in NYHA class I or II. There was no difference in outcome measures for AF patients and age and gender matched HCM patients without AF. Four percent of AF patients died of HCM-related causes (n=11) with annual mortality 0.7 %; mortality directly attributable to AF (thromboembolism without prophylactic anticoagulation) was 0.1 %/year (n=2 patients). Patients were treated with antiarrhythmic drugs (most commonly amiodarone [n=103] or sotalol [n=78]), and with AF catheter ablation (n=49) or Maze procedure at surgical myectomy (n=72). Freedom from AF recurrence at 1 year was 44% for ablation patients and 75% with Maze (p<0.001). Embolic events were less common with anticoagulation prophylaxis (4/233; 2%) than without (9/66; 14%) (p<0.001).Conclusions—Transient symptomatic episodes of AF, although relatively uncommon in HCM, are unpredictable in frequency and timing, amenable to effective contemporary treatments, and infrequently progress to permanent AF. AF is not a major contributor to heart failure morbidity, nor a cause of arrhythmic sudden death, and when treated is associated with low-disease-related mortality, no different than for patients without AF. AF is an uncommon primary cause of death in HCM virtually limited to embolic stroke, supporting a low threshold for initiating anticoagulation therapy.
Preprints and Cardiovascular Science: Prescient or Premature? Circulation (IF 19.309) Pub Date : 2017-09-14 Brahmajee K. Nallamothu, Joseph A. Hill
Medical journals currently find themselves in the throes of 2 powerful trends: (1) a growing concern for the irreproducibility of scientific reports, and (2) a rising imperative to accelerate dissemination of new knowledge in the digital era. Without question, the individual merit of tackling each issue is readily apparent. Irreproducibility of scientific reports is surprisingly common and contributes to an overall loss of confidence in research by the public and other stakeholders. And who could argue with efforts to leverage new online technologies to distribute information as rapidly and widely as possible?
Empagliflozin and Clinical Outcomes in Patients with Type 2 Diabetes, Established Cardiovascular Disease and Chronic Kidney Disease Circulation (IF 19.309) Pub Date : 2017-09-13 Christoph Wanner, John M. Lachin, Silvio E. Inzucchi, David Fitchett, Michaela Mattheus, Jyothis T. George, Hans-Juergen Woerle, Uli C. Broedl, Maximilian von Eynatten, Bernard Zinman
Background—Empagliflozin, a sodium glucose cotransporter 2 inhibitor, reduced cardiovascular morbidity and mortality in patients with type 2 diabetes and established cardiovascular disease in the EMPA-REG OUTCOME® trial. Urinary glucose excretion with empagliflozin decreases with declining renal function, resulting in less potency for glucose lowering in patients with kidney disease. We investigated the effects of empagliflozin on clinical outcomes in patients with type 2 diabetes, established cardiovascular disease and chronic kidney disease.Methods—Patients with type 2 diabetes, established cardiovascular disease and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2 at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. We analyzed cardiovascular death, hospitalization for heart failure, all-cause hospitalization and all-cause mortality in patients with prevalent kidney disease (defined as eGFR <60 mL/min/1.73m2 and/or urine albumin-creatinine ratio [UACR] >300 mg/g) at baseline. Additional analyses were performed in subgroups by baseline eGFR (<45, 45 to <60, 60 to <90, ≥90 mL/min/1.73m2) and baseline UACR (>300, 30 to ≤300, <30 mg/g).Results—Of 7020 patients treated, 2250 patients had prevalent kidney disease at baseline, of whom 67% had a diagnosis of type 2 diabetes for >10 years, 58% were receiving insulin and 84% were taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers. In patients with prevalent kidney disease at baseline, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo (hazard ratio [HR] 0.71 [95% CI 0.52, 0.98]), the risk of all-cause mortality by 24% (HR 0.76 [95% CI 0.59, 0.99]), the risk of hospitalization for heart failure by 39% (HR 0.61 [95% CI 0.42, 0.87]) and the risk of all-cause hospitalization by 19% (HR 0.81 [95% CI 0.72, 0.92]). Effects of empagliflozin on these outcomes were consistent across categories of eGFR and of UACR at baseline and across the two doses studied. The adverse event profile of empagliflozin in patients with eGFR <60 mL/min/1.73m2 was consistent with the overall trial population.Conclusions—Empagliflozin improved clinical outcomes and reduced mortality in vulnerable patients with type 2 diabetes, established cardiovascular disease and chronic kidney disease.Clinical Trial Registration—URL: https://clinicaltrials.gov/. Unique identifier: NCT01131676.
Antiarrhythmic Drugs for Non-Shockable-Turned-Shockable Out-of-Hospital Cardiac Arrest: The Amiodarone, Lidocaine or Placebo Study (ALPS) Circulation (IF 19.309) Pub Date : 2017-09-13 Peter J. Kudenchuk, Brian G. Leroux, Mohamud Daya, Thomas Rea, Christian Vaillancourt, Laurie J. Morrison, Clifton W. Callaway, James Christenson, Joseph P. Ornato, James V. Dunford, Lynn Wittwer, Myron L. Weisfeldt, Tom P. Aufderheide, Gary M. Vilke, Ahamed H. Idris, Ian G. Stiell, M. Riccardo Colella, Tami Kayea, Debra A. Egan, Patrice Desvigne-Nickens, Pamela Gray, Randal Gray, Ron Straight, Paul Dorian
Background—Out-of-hospital cardiac arrest (OHCA) commonly presents with non-shockable rhythms (asystole and pulseless electrical activity (PEA)). Whether antiarrhythmic drugs are safe and effective when these evolve to shockable rhythms (ventricular fibrillation/pulseless ventricular tachycardia (VF/VT)) during resuscitation is not known.Methods—Adults with non-traumatic OHCA, vascular access and VF/VT anytime after ≥1 shock(s) were prospectively randomized, double-blind, to receive amiodarone, lidocaine or placebo by paramedics. Patients presenting with initial shock-refractory VF/VT were previously reported. The current study was a pre-specified analysis in a separate cohort who initially presented with non-shockable OHCA and were randomized upon subsequently developing shock-refractory VF/VT. The primary outcome was survival to hospital discharge; secondary outcomes included discharge functional status and adverse drug-related effects.Results—Of 37,889 patients with OHCA, 3,026 with initial VF/VT and 1,063 with initial non-shockable-turned-shockable rhythms were treatment-eligible, randomized and received their assigned drug. Baseline characteristics among non-shockable-turned-shockable patients were balanced across treatment arms except that placebo recipients included fewer men and were less likely to receive bystander-CPR. Active-drug recipients in this cohort required fewer shocks, supplemental doses of their assigned drug and ancillary antiarrhythmic drugs than placebo-recipients (p<0.05). In all, 16 (4.1%) amiodarone, 11 (3.1%) lidocaine and 6 (1.9%) placebo-treated patients survived to hospital discharge (p=0.24). There was no significant interaction of treatment assignment and discharge survival with the initiating OHCA rhythm (asystole, PEA, or VF/VT); survival in each of these categories was consistently higher with active-drugs, though the trends were not statistically significant. Adjusted absolute differences (95% confidence interval) in survival from non-shockable-turned-shockable arrhythmias with amiodarone vs placebo were 2.3% (-0.3, 4.8), p=0.08 and for lidocaine vs placebo 1.2% (-1.1, 3.6), p=0.30. Over one-half of these survivors were functionally independent or required minimal assistance. Drug-related adverse effects were infrequent.Conclusions—Outcome from non-shockable-turned-shockable OHCA is poor, but not invariably fatal. Though not statistically significant, point estimates for survival were greater after amiodarone or lidocaine than placebo, without increased risk of adverse effects or disability, and consistent with previously observed favorable trends from treatment of initial shock-refractory VF/VT with these drugs. Together the findings may signal a clinical benefit that invites further investigation.Clinical Trial Registration—URL: ClinicalTrials.gov Unique Identifier: NCT01401647
Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker Circulation (IF 19.309) Pub Date : 2017-09-13 Julianna Zadora, Manvendra Singh, Florian Herse, Lukasz Przybyl, Nadine Haase, Michaela Golic, Hong Wa Yung, Berthold Huppertz, Judith E. Cartwright, Guy S. Whitley, Guro M. Johnsen, Giovanni Levi, Annette Isbruch, Herbert Schulz, Friedrich C. Luft, Dominik N. Müller, Anne C. Staff, Laurence D. Hurst, Ralf Dechend, Zsuzsanna Izsvák
Background—Preeclampsia (PE) is a complex and common human-specific pregnancy syndrome associated with placental pathology. The human-specificity provides both intellectual and methodological challenges, lacking a robust model system. Given the role of imprinted genes in human placentation and the vulnerability of imprinted genes to loss of imprinting changes, there has been extensive speculation, but no robust evidence, that imprinted genes are involved in PE. Our study aims at investigating whether disturbed imprinting contributes to PE.Methods—We first aimed at confirming that PE is a disease of the placenta by generating and analysing genome-wide molecular data on well-characterized patient material. We performed high-throughput transcriptome analyses of multiple placenta samples from normal and PE patients. Next, we identified differentially expressed genes (DEGs) in PE placenta, and intersected them with the list of human imprinted genes. We employed bioinformatics/statistical analyses to confirm association between imprinting and PE, and to predict biological processes affected in PE. Validation included epigenetic and cellular assays. Regarding human-specificity, we established an in vitro invasion-differentiation trophoblast model. Our comparative phylogenetic analysis involved single-cell transcriptome data of human, macaque and mouse preimplantation embryogenesis.Results—We found disturbed placental imprinting in PE and revealed potential candidates, including GATA3 and DLX5, with poorly explored imprinted status and no prior association with PE. Due to loss of imprinting DLX5 was upregulated in 69% of PE placentas. Levels of DLX5 correlated with classical PE marker. DLX5 is expressed in human, but not in murine trophoblast. The DLX5high phenotype resulted in reduced proliferation, increased metabolism and ER stress-response activation in trophoblasts in vitro. The transcriptional profile of such cells mimics the transcriptome of PE placentas. Pan-mammalian comparative analysis identified DLX5 as a part of the human-specific regulatory network of trophoblast differentiation.Conclusions—Our analysis provides evidence of a true association between disturbed imprinting, gene expression and PE. Due to disturbed imprinting, the upregulated DLX5 affects trophoblast proliferation. Our in vitro model might fill a vital niche in PE research. Human-specific regulatory circuitry of DLX5 might help to explain certain aspects of PE.
Timing of Angiography and Outcomes in High-Risk Patients with Non-ST Segment Elevation Myocardial Infarction Managed Invasively: Insights from the TAO Trial Circulation (IF 19.309) Pub Date : 2017-09-11 Pierre Deharo, Gregory Ducrocq, Christoph Bode, Marc Cohen, Thomas Cuisset, Shamir Mehta, Charles V. Pollack, Stephen D. Wiviott, Yedid Elbez, Marc Sabatine, P. Gabriel Steg
Background—In patients with non ST-elevation myocardial infarction (NSTEMI) and Global Registry of Acute Coronary Events (GRACE) score >140, coronary angiography (CAG) is recommended by European and American guidelines within 24h. We sought to study the association of a "very early" (i.e. ≤12h), early (12-24h) and delayed (>24h) CAG in NSTEMI with GRACE score >140 with ischemic outcomes.Methods—The Treatment of Acute coronary syndrome with Otamixaban (TAO) trial randomized patients with NSTEMI and CAG scheduled within 72h to heparin plus eptifibatide versus otamixaban. In this post hoc analysis, patients with GRACE score > 140 were categorized into 3 groups according to timing of CAG from admission (<12h, ≥12h to <24h, ≥24h). The primary ischemic outcome was the composite of all-cause death and myocardial infarction (MI) within 180 days of randomization.Results—CAG was performed in 4,071 patients (<12h n=1648 (40.5%), 12-24h n=1420 (34.9%), ≥24h n=1003 (24.6%)). With CAG ≥24h as a reference, CAG from 12 to 24 hours was not associated with a lower risk of primary ischemic outcome at 180 days (odds ratio (OR) 0.96, 95% confidence interval (CI) 0.75-1.23), whereas CAG <12h was associated with a lower risk of death and MI (OR 0.71, 95% CI 0.55-0.91). Performing CAG <12h was also associated with a lower risk of death and MI (OR 0.76, 95%IC 0.61-0.94; p=0.01) compared to CAG performed 12-24h. No difference was observed regarding bleeding complications.Conclusions—In patients with high-risk NSTEMI, undergoing CAG within the initial 12 hours after admission (as opposed to later, either 12 to 24 h or ≥24 h) was associated with lower risk of ischemic outcomes at 180 days.
Mutation-Based Therapy for Duchenne Muscular Dystrophy Circulation (IF 19.309) Pub Date : 2017-09-12 Elizabeth M. McNally, Eugene J. Wyatt
Duchenne muscular dystrophy (DMD) arises from mutations in the dystrophin gene. The dystrophin gene is composed of 79 exons, and the majority of mutations in DMD are deletions, often spanning multiple exons.1 In 2016, the US Food and Drug Administration (FDA) granted accelerated approval for eteplirsen (Exondys51), an antisense oligonucleotide compound designed to block exon 51 of dystrophin to restore the reading frame in patients with DMD with specific mutations (Figure, A).2 This treatment is directed at ≈10% to 15% of patients with DMD (≈1500 treatment-eligible individuals). The approval of eteplirsen is game changing for the field of molecular gene correction. However, its approval was viewed as controversial because of the unconventional clinical trial data and limited efficacy. Eteplirsen (Exondys51)-mediated reading-frame correction of Duchenne muscular dystrophy (DMD) mutations. A, Top, Schematic of the dystrophin protein and its domains. ABD1 indicates actin binding domain; CR, cysteine rich domain; CT, C-terminal domain; and H, hinge regions. The spectrin-like repeats are numbered. The red bar indicates the approximate exon 51 targeting region. Middle, Schematic showing eteplirsen-mediated reading-frame correction of a DMD frameshift mutation. The normal dystrophin locus from exons 41 to 52 is shown, indicating the reading frame of each exon. Many patients with DMD have variable-sized deletions spanning exons 47 to 50, disrupting the reading frame (dashed blue line). Eteplirsen (red box) is an antisense oligonucleotide that binds to exon-splicing enhancer sequences in exon 51, causing its exclusion from mRNA. Because exon 51 is excluded, exons 46 (or 47, 48, and 49) joins to exon 52 (solid blue line) to restore an open reading frame. B, Antisense oligonucleotides have complementary sequences to those within an exon, in this case exon 51. Chemical modifications to the antisense oligonucleotides permit the double-stranded hybrid …
Physical Activity and Prognosis in the TOPCAT Trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) Circulation (IF 19.309) Pub Date : 2017-09-12 Sheila M. Hegde, Brian Claggett, Amil M. Shah, Eldrin F. Lewis, Inder Anand, Sanjiv J. Shah, Nancy K. Sweitzer, James C. Fang, Bertram Pitt, Marc A. Pfeffer, Scott D. Solomon
Background: Physical activity (PA) is inversely associated with adverse cardiovascular outcomes in healthy populations, but the impact of physical activity in patients with heart failure (HF) with preserved ejection fraction is less well characterized. Methods: The baseline self-reported PA of 1751 subjects enrolled in the Americas region of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) was categorized as poor, intermediate, or ideal PA with American Heart Association criteria. PA was related to the primary composite outcome (HF hospitalization, cardiovascular mortality, or aborted cardiac arrest), its components, and all-cause mortality with the use of multivariable Cox models. Results: The mean age at enrollment was 68.6±9.6 years. Few patients met American Heart Association criteria for ideal activity (11% ideal, 14% intermediate, 75% poor). Over a median follow-up of 2.4 years, the primary composite outcome occurred in 519 patients (397 HF hospitalizations, 222 cardiovascular deaths, and 6 aborted cardiac arrests). Compared with those with ideal baseline PA, poor and intermediate baseline PA was associated with a greater risk of the primary outcome (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.28–3.28; HR, 1.95; 95% CI, 1.15–3.33, respectively), HF hospitalization (HR, 1.93; 95% CI, 1.16–3.22; HR, 1.84; 95% CI, 1.02–3.31), cardiovascular mortality (HR, 4.36; 95% CI, 1.37–13.83; HR, 4.05; 95% CI, 1.17–14.04), and all-cause mortality (HR, 2.95; 95% CI, 1.44–6.02; HR, 2.05; 95% CI, 0.90–4.67) after multivariable adjustment for potential confounders. Conclusions: In patients with HF with preserved ejection fraction, both poor and intermediate self-reported PA were associated with higher risk of HF hospitalization and mortality. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00094302.
Physical Activity in Heart Failure With Preserved Ejection Fraction Circulation (IF 19.309) Pub Date : 2017-09-12 Ambarish Pandey, Jarett D. Berry
Article, see p 982 Physical inactivity and low fitness are important, modifiable risk factors for the development of heart failure (HF).1–4 Recent studies have demonstrated strong, dose-dependent inverse associations among physical activity, fitness, and risk of incident HF.5 Physical activity has been shown to have a stronger and more graded association with risk of HF with preserved ejection fraction (HFpEF) than HF with reduced ejection fraction.6 However, the prognostic role of physical activity among patients with established HFpEF is less well established. This finding is particularly relevant given the near-universal presence of exercise intolerance among patients with HFpEF. In this issue of Circulation, Hegde et al7 have addressed this knowledge gap by evaluating the association between physical activity levels and risk of adverse clinical outcomes among 1751 patients with HFpEF in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist). The authors observed several important findings. First, only 11% of the study participants engaged in guideline-recommended physical activity levels at baseline. Second, compared with individuals with ideal physical activity, those with poor and intermediate self-reported physical activity had a higher risk of HF hospitalization and mortality within …
Pericarditis as a Marker of Occult Cancer and a Prognostic Factor for Cancer Mortality Circulation (IF 19.309) Pub Date : 2017-09-12 Kirstine Kobberøe Søgaard, Dóra Körmendiné Farkas, Vera Ehrenstein, Krishnan Bhaskaran, Hans Erik Bøtker, Henrik Toft Sørensen
Background: Pericarditis may be a serious complication of malignancy. Its significance as a first symptom of occult cancer and as a prognostic factor for cancer survival is unknown. Methods: Using Danish medical databases, we conducted a nationwide cohort study of all patients with a first-time diagnosis of pericarditis during 1994 to 2013. We excluded patients with previous cancer and followed up the remaining patients for subsequent cancer diagnosis until November 30, 2013. We calculated risks and standardized incidence ratios of cancer for patients with pericarditis compared with the general population. We assessed whether pericarditis predicts cancer survival by the Kaplan-Meier method and Cox regression using a matched comparison cohort of cancer patients without pericarditis. Results: Among 13 759 patients with acute pericarditis, 1550 subsequently were diagnosed with cancer during follow-up. The overall cancer standardized incidence ratio was 1.5 (95% confidence interval [CI], 1.4–1.5), driven predominantly by increased rates of lung, kidney, and bladder cancer, lymphoma, leukemia, and unspecified metastatic cancer. The <3-month cancer risk among patients with pericarditis was 2.7%, and the standardized incidence ratio was 12.4 (95% CI, 11.2–13.7). The 3- to <12-month standardized incidence ratio of cancer was 1.5 (95% CI, 1.2–1.7), subsequently decreasing to 1.1 (95% CI, 1.0–1.2). Three-month survival after the cancer diagnosis was 80% and 86% among those with and without pericarditis, respectively, and the hazard ratio was 1.5 (95% CI, 1.3–1.8). One-year survival was 65% and 70%, respectively, corresponding to a 3- to <12-month hazard ratio of 1.3 (95% CI, 1.1–1.5). Conclusions: Pericarditis may be a marker of occult cancer and augurs increased mortality after a cancer diagnosis.
Optical Coherence Tomography Findings in Patients With Coronary Stent Thrombosis Circulation (IF 19.309) Pub Date : 2017-09-12 Tom Adriaenssens, Michael Joner, Thea C. Godschalk, Nikesh Malik, Fernando Alfonso, Erion Xhepa, Dries De Cock, Kenichi Komukai, Tomohisa Tada, Javier Cuesta, Vasile Sirbu, Laurent J. Feldman, Franz-Josef Neumann, Alison H. Goodall, Ton Heestermans, Ian Buysschaert, Ota Hlinomaz, Ann Belmans, Walter Desmet, Jurrien M. ten Berg, Anthony H. Gershlick, Steffen Massberg, Adnan Kastrati, Giulio Guagliumi, Robert A. Byrne
Background: Stent thrombosis (ST) is a serious complication following coronary stenting. Intravascular optical coherence tomography (OCT) may provide insights into mechanistic processes leading to ST. We performed a prospective, multicenter study to evaluate OCT findings in patients with ST. Methods: Consecutive patients presenting with ST were prospectively enrolled in a registry by using a centralized telephone registration system. After angiographic confirmation of ST, OCT imaging of the culprit vessel was performed with frequency domain OCT. Clinical data were collected according to a standardized protocol. OCT acquisitions were analyzed at a core laboratory. Dominant and contributing findings were adjudicated by an imaging adjudication committee. Results: Two hundred thirty-one patients presenting with ST underwent OCT imaging; 14 (6.1%) had image quality precluding further analysis. Of the remaining patients, 62 (28.6%) and 155 (71.4%) presented with early and late/very late ST, respectively. The underlying stent type was a new-generation drug-eluting stent in 50.3%. Mean reference vessel diameter was 2.9±0.6 mm and mean reference vessel area was 6.8±2.6 mm2. Stent underexpansion (stent expansion index <0.8) was observed in 44.4% of patients. The predicted average probability (95% confidence interval) that any frame had uncovered (or thrombus-covered) struts was 99.3% (96.1–99.9), 96.6% (92.4–98.5), 34.3% (15.0–60.7), and 9.6% (6.2–14.5) and malapposed struts was 21.8% (8.4–45.6), 8.5% (4.6–15.3), 6.7% (2.5–16.3), and 2.0% (1.2–3.3) for acute, subacute, late, and very late ST, respectively. The most common dominant finding adjudicated for acute ST was uncovered struts (66.7% of cases); for subacute ST, the most common dominant finding was uncovered struts (61.7%) and underexpansion (25.5%); for late ST, the most common dominant finding was uncovered struts (33.3%) and severe restenosis (19.1%); and for very late ST, the most common dominant finding was neoatherosclerosis (31.3%) and uncovered struts (20.2%). In patients presenting very late ST, uncovered stent struts were a common dominant finding in drug-eluting stents, and neoatherosclerosis was a common dominant finding in bare metal stents. Conclusions: In patients with ST, uncovered and malapposed struts were frequently observed with the incidence of both decreasing with longer time intervals between stent implantation and presentation. The most frequent dominant observation varied according to time intervals from index stenting: uncovered struts and underexpansion in acute/subacute ST and neoatherosclerosis and uncovered struts in late/very late ST.
A Cytokine-Like Protein Dickkopf-Related Protein 3 Is Atheroprotective Circulation (IF 19.309) Pub Date : 2017-09-12 Baoqi Yu, Stefan Kiechl, Dan Qi, Xiaocong Wang, Yanting Song, Siegfried Weger, Agnes Mayr, Alexandra Le Bras, Eirini Karamariti, Zhongyi Zhang, Ivan del Barco Barrantes, Christof Niehrs, Georg Schett, Yanhua Hu, Wen Wang, Johann Willeit, Aijuan Qu, Qingbo Xu
Background: Dickkopf-related protein 3 (DKK3) is a secreted protein that is involved in the regulation of cardiac remodeling and vascular smooth muscle cell differentiation, but little is known about its role in atherosclerosis. Methods: We tested the hypothesis that DKK3 is atheroprotective using both epidemiological and experimental approaches. Blood DKK3 levels were measured in the Bruneck Study in 2000 (n=684) and then in 2005 (n=574). DKK3-deficient mice were crossed with apolipoprotein E-/- mice to evaluate atherosclerosis development and vessel injury-induced neointimal formation. Endothelial cell migration and the underlying mechanisms were studied using in vitro cell culture models. Results: In the prospective population-based Bruneck Study, the level of plasma DKK3 was inversely related to carotid artery intima-media thickness and 5-year progression of carotid atherosclerosis independently from standard risk factors for atherosclerosis. Experimentally, we analyzed the area of atherosclerotic lesions, femoral artery injury-induced reendothelialization, and neointima formation in both DKK3-/-/apolipoprotein E-/- and DKK3+/+/apolipoprotein E-/- mice. It was demonstrated that DKK3 deficiency accelerated atherosclerosis and delayed reendothelialization with consequently exacerbated neointima formation. To explore the underlying mechanisms, we performed transwell and scratch migration assays using cultured human endothelial cells, which exhibited a significant induction in cell migration in response to DKK3 stimulation. This DKK3-induced migration activated ROR2 and DVL1, activated Rac1 GTPases, and upregulated JNK and c-jun phosphorylation in endothelial cells. Knockdown of the ROR2 receptor using specific siRNA or transfection of a dominant-negative form of Rac1 in endothelial cells markedly inhibited cell migration and downstream JNK and c-jun phosphorylation. Conclusions: This study provides the evidence for a role of DKK3 in the protection against atherosclerosis involving endothelial migration and repair, with great therapeutic potential implications against atherosclerosis.
Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling Circulation (IF 19.309) Pub Date : 2017-09-12 Mustapha Amyere, Nicole Revencu, Raphaël Helaers, Eleonore Pairet, Eulalia Baselga, Maria Cordisco, Wendy Chung, Josée Dubois, Jean-Philippe Lacour, Loreto Martorell, Juliette Mazereeuw-Hautier, Reed E. Pyeritz, David J. Amor, Annouk Bisdorff, Francine Blei, Hannah Bombei, Anne Dompmartin, David Brooks, Juliette Dupont, Maria Antonia González-Enseñat, Ilona Frieden, Marion Gérard, Malin Kvarnung, Andrea Kwan Hanson-Kahn, Louanne Hudgins, Christine Léauté-Labrèze, Catherine McCuaig, Denise Metry, Philippe Parent, Carle Paul, Florence Petit, Alice Phan, Isabelle Quere, Aicha Salhi, Anne Turner, Pierre Vabres, Asuncion Vicente, Orli Wargon, Shoji Watanabe, Lisa Weibel, Ashley Wilson, Marcia Willing, John B. Mulliken, Laurence M. Boon, Miikka Vikkula
Background: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. Methods: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. Results: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. Conclusions: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.
Conduction Disturbances After Transcatheter Aortic Valve Replacement Circulation (IF 19.309) Pub Date : 2017-09-12 Vincent Auffret, Rishi Puri, Marina Urena, Chekrallah Chamandi, Tania Rodriguez-Gabella, François Philippon, Josep Rodés-Cabau
Transcatheter aortic valve replacement (TAVR) has become a well-accepted option for treating patients with aortic stenosis at intermediate to high or prohibitive surgical risk. TAVR-related conduction disturbances, mainly new-onset left bundle-branch block and advanced atrioventricular block requiring permanent pacemaker implantation, remain the most common complication of this procedure. Furthermore, improvements in TAVR technology, akin to the increasing experience of operators/centers, have translated to a major reduction in periprocedural complications, yet the incidence of conduction disturbances has remained relatively high, with perhaps an increasing trend over time. Several factors have been associated with a heightened risk of conduction disturbances and permanent pacemaker implantation after TAVR, with prior right bundle-branch block and transcatheter valve type and implantation depth being the most commonly reported. New-onset left bundle-branch block and the need for permanent pacemaker implantation may have a significant detrimental association with patients’ prognosis. Consequently, strategies intended to reduce the risk and to improve the management of such complications are of paramount importance, particularly in an era when TAVR expansion toward treating lower-risk patients is considered inevitable. In this article, we review the available evidence on the incidence, predictive factors, and clinical association of conduction disturbances after TAVR and propose a strategy for the management of these complications.
Irregular Narrow Complex Tachycardia in a 29-Year-Old Woman Circulation (IF 19.309) Pub Date : 2017-09-12 Niyada Naksuk, J. William Schleifer, Abhishek J. Deshmukh, Malini Madhavan
A 29-year-old woman without known medical illness was evaluated for incessant palpitations. She presented to an emergency department multiple times, where various diagnoses were made, including junctional tachycardia, atrial tachycardia, and atrial fibrillation. Therapy with propafenone, metoprolol, and rivaroxaban was initiated, but her symptoms continued. Echocardiography did not show evidence of structural heart disease. The patient was then referred to our hospital for further treatment and potential ablation for atrial fibrillation. At her clinic visit, a 12- ECG revealed an irregular narrow complex tachycardia with group beating pattern (Figure 1). Figure 1. Twelve-lead electrocardiography shows narrow complex tachycardia with group beating pattern. What is the rhythm shown in Figure 1? Please turn the page to read the diagnosis. P waves arising from the sinus node are seen at a rate of 66 beats per minute. Each P wave is followed by 2 QRS complexes until the tachycardia terminates, followed by reinitiation of tachycardia with the same pattern. The double ventricular response to a single atrial activation, called 1 to 2 atrioventricular conduction …
Origin of Cardiac Troponin T Elevations in Chronic Kidney Disease Circulation (IF 19.309) Pub Date : 2017-09-12 Noreen van der Linden, Tom Cornelis, Dorien M. Kimenai, Lieke J.J. Klinkenberg, Judith M. Hilderink, Sarah Lück, Elisabeth J. R. Litjens, Frederique E.C.M. Peeters, Alexander S. Streng, Tobias Breidthardt, Luc J.C. van Loon, Otto Bekers, Jeroen P. Kooman, Pål O. Westermark, Christian Mueller, Steven J.R. Meex
Plasma concentrations of cardiac troponins, the preferred biomarkers for the diagnosis of acute myocardial infarction, are often persistently elevated in patients with chronic kidney disease (CKD). The origin of these elevations is unknown: Is it the heart, by increased release, or the kidneys, by decreased renal elimination? In clinical practice, this equivocal view on troponin elevations in patients with reduced glomerular clearance underlies countless clinical discussions among physicians and may delay rapid initiation of adequate treatment when these patients present with chest pain. In the present study, we aimed to discriminate between increased cardiac release and reduced renal elimination as the main process underlying this phenomenon. Specifically, we used the recently demonstrated rhythmic diurnal oscillation pattern of troponin T as a model to assess the contribution of impaired renal elimination to persistently elevated cardiac troponin levels in patients with CKD.1 The diurnal troponin T rhythm is characterized by gradually decreasing concentrations throughout daytime and rising concentrations during nighttime.1 If decreased renal clearance, and not increased production, is the key driver of elevated troponins in patients with CKD, the increased half-life and subsequent accumulation of cardiac troponin T will fade its diurnal rhythm. …
Letter by Ferrero et al Regarding Article, “Predictors of Death in Contemporary Adult Patients With Eisenmenger Syndrome: A Multicenter Study” Circulation (IF 19.309) Pub Date : 2017-09-12 Paolo Ferrero, Emilia D’Elia, Matteo Ciuffreda
We read with interest the article by Kempny et al,1 who developed a multivariate prognostic model to stratify the risk of death in patients with Eisemenger syndrome. This study represents a pivotal contribution to the clinical management of patients with congenital heart disease, whose underlying pathophysiology is usually too complex and heterogeneous to allow any standardization of prognosis estimation. From the methodological point of view, it should be recognized that every prognostic model is based on some fundamental constitutive feature that must be systematically appraised: determination cohort, selection of relevant variables, validation …
Response by Kempny et al to Letter Regarding Article, “Predictors of Death in Contemporary Adult Patients With Eisenmenger Syndrome: A Multicenter Study” Circulation (IF 19.309) Pub Date : 2017-09-12 Aleksander Kempny, Cristel Sørensen Hjortshøj, Wei Li, Annette Schophuus Jensen, Lars Søndergaard, Gerhard-Paul Diller, Konstantinos Dimopoulos, Stephen J. Wort, Michael A. Gatzoulis
We thank Ferrero et al for their interest in our recent publication in Circulation.1 We aimed in this study to assess mortality and management strategies in contemporary patients with Eisenmenger syndrome (ES). Although the incidence and prevalence of ES seem to decrease in developed countries, it remains worldwide a common complication of congenital heart disease.2,3 There has been considerable progress in the management of ES over the past 1 to 2 decades. Routine phlebotomies, for example, often resulting in iron deficiency, microcytosis, and inappropriately low hemoglobin levels, have been abandoned.4 There is increased awareness of the risks associated with even minor surgery and pregnancy; as a result, fewer patients with ES die of periprocedural …
Letter by Ciliberti and Capucci Regarding Article, “Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery Disease” Circulation (IF 19.309) Pub Date : 2017-09-12 Giuseppe Ciliberti, Alessandro Capucci
We have read “Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery Disease” by Lindahl and colleagues with great interest, and congratulate the authors for their accurate analysis of this large population of patients with myocardial infarction with nonobstructive coronary arteries (MINOCA).1 They retrospectively selected patients with MINOCA from the SWEDEHEART registry (the Swedish Web-system for Enhancement and Development of Evidence-based Care in Heart Disease Evaluated According to Recommended Therapies) thus obtaining a prevalence of 8.0%. For the first time, they clearly demonstrated an improvement in the prognosis of this population over …
Response by Lindahl et al to Letter Regarding Article, “Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery Disease” Circulation (IF 19.309) Pub Date : 2017-09-12 Bertil Lindahl, Tomasz Baron, David Erlinge, Nermin Hadziosmanovic, Anna Nordenskjöld, Anton Gard, Tomas Jernberg
We appreciate the valuable comments by Ciliberti et al in their letter to the editor on our article on medical therapy in patients with myocardial infarction with nonobstructive coronary arteries (MINOCA).1 Ciliberti et al raise several important issues on which we are happy to further comment. Our study population consisted of 9136 consecutive patients with acute myocardial infarction (AMI) and without any significant obstruction (≥50%) on coronary angiography reported to the nationwide quality registry, SWEDEHEART, during a 10-year period. We agree that there is a heterogeneity in this real-life population in terms of the underlying mechanisms for MINOCA. There is certainly a significant group of patients given the clinical diagnosis of MINOCA …
Correction to: When Lightning Strikes: Fulminant Myocarditis in the Realm of Inflammatory Cardiomyopathies Circulation (IF 19.309) Pub Date : 2017-09-12 Lippincott Williams & Wilkins
In the article by Cooper, “When Lightning Strikes Fulminant Myocarditis in the Realm of Inflammatory Cardiomyopathies,” which published …
Correction to: Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double-Blind, Crossover Trial of Air Purification Circulation (IF 19.309) Pub Date : 2017-09-12 Lippincott Williams & Wilkins
In the article by Li et al, “Particulate Matter Exposure and Stress Hormone Levels: A Randomized, …
LDL-Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men with Primary Elevations of LDL-Cholesterol Levels of 190 mg/dL or Above: Analyses from the WOSCOPS 5-year Randomised Trial and 20-year Observational Follow-Up Circulation (IF 19.309) Pub Date : 2017-09-06 Antonio J. Vallejo-Vaz, Michele Robertson, Alberico L. Catapano, Gerald F. Watts, John J. Kastelein, Chris J. Packard, Ian Ford, Kausik K. Ray
Background—Patients with primary elevations of LDL-C ≥190 mg/dL are at a higher risk of atherosclerotic cardiovascular disease as a result of long-term exposure to markedly elevated LDL-C levels. Therefore, initiation of statin therapy is recommended for these individuals. However, there is a lack of randomised trial evidence supporting these recommendations in primary prevention. In the present analysis we provide hitherto unpublished data on the cardiovascular effects of LDL-C lowering among a primary prevention population with LDL-C ≥190 mg/dL.Methods—We aimed to assess the benefits of LDL-C lowering on cardiovascular outcomes among individuals with primary elevations of LDL-C ≥190 mg/dL without pre-exiting vascular disease at baseline. We carried out post-hoc analyses from the West Of Scotland Coronary Prevention Study (WOSCOPS) randomised, placebo-controlled trial, and observational post-trial long-term follow-up, after excluding individuals with evidence of vascular disease at baseline. WOSCOPS enrolled 6595 men aged 45-64 years, who were randomised to pravastatin 40 mg/d or placebo. In the present analyses, 5529 participants without evidence of vascular disease were included, stratified by LDL-C levels into those with LDL-C <190 mg/dL (n=2969; mean LDL-C 178±6 mg/dL) and those with LDL-C ≥190 mg/dL (n=2560; mean LDL-C 206±12 mg/dL).The effect of pravastatin versus placebo on coronary heart disease (CHD) and major adverse cardiovascular events (MACE) were assessed over the 4.9-year randomised-controlled trial phase and on mortality outcomes over a total of 20-years of follow-up.Results—Among 5529 individuals without vascular disease, pravastatin reduced the risk of CHD by 27% (p=0.002) and MACE by 25% (p=0.004) consistently among those with and without LDL-C ≥190 mg/dL (p-interaction >0.9). Among individuals with LDL-C ≥190 mg/dL, pravastatin reduced the risk of CHD by 27% (p=0.033) and MACE by 25% (p=0.037) during the initial trial phase and the risk of CHD death, cardiovascular death and all-cause mortality by 28% (p=0.020), 25% (p=0.009) and 18% (p=0.004), respectively, over a total of 20-years of follow-up.Conclusions—The present analyses provide robust novel evidence for the short and long-term benefits of lowering LDL-C for the primary prevention of cardiovascular disease among individuals with primary elevations of LDL-C ≥190 mg/dL.
Potential Cardiovascular and Total Mortality Benefits of Air Pollution Control in Urban China Circulation (IF 19.309) Pub Date : 2017-09-07 Chen Huang, Andrew E. Moran, Pamela G. Coxson, Xueli Yang, Fangchao Liu, Jie Cao, Kai Chen, Miao Wang, Jiang He, Lee Goldman, Dong Zhao, Patrick L. Kinney, Dongfeng Gu
Background—Outdoor air pollution ranks fourth among preventable causes of China's burden of disease. We hypothesized that the magnitude of health gains from air quality improvement in urban China could compare with achieving recommended blood pressure or smoking control goals.Methods—The Cardiovascular Disease Policy Model-China projected coronary heart disease, stroke, and all-cause deaths in urban Chinese adults aged 35-84 years from 2017 to 2030 if recent air quality (particulate matter with aerodynamic diameter ≤ 2.5 μm, PM2.5) and traditional cardiovascular risk factor trends continue. We projected life years gained if urban China were to reach one of three air quality goals: Beijing Olympic Games level (mean PM2.5, 55 μg/m3), China Class II standard (35 μg/m3), or World Health Organization (WHO) standard (10 μg/m3). We compared projected air pollution reduction control benefits with potential benefits of reaching WHO hypertension and tobacco control goals.Results—Mean PM2.5 reduction to Beijing Olympic levels by 2030 would gain about 241,000 (95% uncertainty interval, 189,000-293,000) life-years annually. Achieving either the China Class II standard or WHO PM2.5 standard would yield greater health benefits [992,000 (95% uncertainty interval, 790,000-1,180,000) or 1,827,000 (95% uncertainty interval, 1,481,000-2,129,000) annual life years gained, respectively] than WHO-recommended goals of 25% improvement in systolic hypertension control and 30% reduction in smoking combined [928,000 (95% uncertainty interval, 830,000-1,033,000) life years].Conclusions—Air quality improvement at different scenarios could lead to graded health benefits ranging from 241,000 life-years gained to much greater benefits are equal to or greater than the combined benefits of 25% improvement in systolic hypertension control and 30% smoking reduction.
Modeling Major Adverse Outcomes of Pediatric and Adult Patients with Congenital Heart Disease Undergoing Cardiac Catheterization: Observations from the NCDR IMPACT Registry Circulation (IF 19.309) Pub Date : 2017-09-07 Natalie Jayaram, John A. Spertus, Kevin F. Kennedy, Robert Vincent, Gerard R. Martin, Jeptha P. Curtis, David G. Nykanen, Phillip M. Moore, Lisa Bergersen
Background—Risk-standardization for adverse events following congenital cardiac catheterization is needed to equitably compare patient outcomes among different hospitals as a foundation for quality improvement. The goal of this project was to develop a risk-standardization methodology to adjust for patient characteristics when comparing major adverse outcomes in the NCDR® IMPACTTM (Improving Pediatric and Adult Congenital Treatment) Registry.Methods—39,725 consecutive patients within IMPACT undergoing cardiac catheterization between January 2011 and March 2014 were identified. Given the heterogeneity of interventional procedures for congenital heart disease, new procedure-type risk categories were derived with empiric data and expert opinion, as were markers of hemodynamic vulnerability. A multivariable hierarchical logistic regression model to identify patient and procedural characteristics predictive of a major adverse event (MAE) or death following cardiac catheterization was derived in 70% of the cohort and validated in the remaining 30%.Results—The rate of MAE or death was 7.1% and 7.2% in the derivation and validation cohorts, respectively. Six procedure-type risk categories and six independent indicators of hemodynamic vulnerability were identified. The final risk adjustment model included procedure-type risk category, number of hemodynamic vulnerability indicators, renal insufficiency, single-ventricle physiology, and coagulation disorder. The model had good discrimination with a C-statistic of 0.76 and 0.75 in the derivation and validation cohorts, respectively. Model calibration in the validation cohort was excellent with a slope of 0.97 (standard error [SE] 0.04; p-value [for difference from 1]= 0.53) and an intercept of 0.007 (SE 0.12; p-value [for difference from 0]= 0.95).Conclusions—The creation of a validated risk-standardization model for adverse outcomes following congenital cardiac catheterization can support reporting of risk-adjusted outcomes in the IMPACT Registry as a foundation for quality improvement.
Age and Outcomes of Primary Prevention Implantable Cardioverter Defibrillators in Patients with Non-Ischemic Systolic Heart Failure Circulation (IF 19.309) Pub Date : 2017-09-06 Marie Bayer Elming, Jens C. Nielsen, Jens Haarbo, Lars Videbæk, Eva Korup, James Signorovitch, Line Lisbeth Olesen, Per Hildebrandt, Flemming H. Steffensen, Niels E. Bruun, Hans Eiskjær, Axel Brandes, Anna M. Thøgersen, Finn Gustafsson, Kenneth Egstrup, Regitze Videbæk, Christian Hassager, Jesper Hastrup Svendsen, Dan E. Høfsten, Christian Torp-Pedersen, Steen Pehrson, Lars Køber, Jens Jakob Thune
Background—The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators (ICD) in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) did not demonstrate an overall effect on all-cause mortality with ICD implantation. However, the pre-specified subgroup analysis suggested a possible age-dependent association between the ICD and mortality with survival benefit seen only in the youngest patients. The nature of this relationship between age and outcome of a primary prevention ICD in patients with non-ischemic systolic heart failure warrants further investigation.Methods—All 1116 patients from the DANISH study were included in this pre-specified subgroup analysis. We assessed the relationship between the ICD and mortality by age, and an optimal age cut-off was estimated non-parametrically using selection impact curves. Modes of death were divided into sudden cardiac death (SCD) and non-sudden death and compared between patients younger and older than this age cut-off, respectively, with the use of Chi2-analysis.Results—Median age of the study population was 63 years (range 21 - 84 years). There was a linearly decreasing relationship between the ICD and mortality with age, HR 1.03 (95% CI 1.003 - 1.06), p=0.03. An optimal age cut-off for ICD implantation was present at ≤70 years. There was an association between reduced all-cause mortality and the ICD in patients ≤70 years, HR 0.70 (0.51 - 0.96), p=0.03, but not in patients >70 years, HR 1.05 (0.68 - 1.62), p=0.84. For patients ≤70 years, SCD rate was 1.8 (1.3 - 2.5) and non-sudden death rate was 2.7 (2.1 - 3.5) events/100 patient years, whereas for patients older than 70 years SCD rate was 1.6 (0.8 - 3.2) and non-sudden death rate was 5.4 (3.7 - 7.8) events/100 patient years. This difference in modes of death between the two age groups was statistically significant (p=0.01).Conclusions—In patients with systolic heart failure not caused by ischemic heart disease, the association between the ICD and survival decreased linearly with increasing age. In this study population, an age cut-off for ICD implantation at ≤70 years yielded the highest survival for the population as a whole.
The Evolution of the Use of β-Blockers to Treat Heart Failure Circulation (IF 19.309) Pub Date : 2017-09-05 Finn Waagstein, John D. Rutherford
Finn Waagstein was born in Copenhagen in 1938. He graduated from Aarhus University Medical School in 1964. He received his cardiology training in the Sahlgrenska University Hospital at the University of Gothenburg, Sweden. He was appointed Associate Professor in 1980, and he assisted in establishing and directing the first Swedish heart transplant program. From 1990 he directed the heart failure and cardiomyopathy research programs. He is currently Professor of Cardiology and senior physician at Wallenberg Laboratory. In 2002, he was awarded the King Faisal International Prize for Medicine.
Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment–Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]) Circulation (IF 19.309) Pub Date : 2017-09-05 Sivabaskari Pasupathy, Rosanna Tavella, Suchi Grover, Betty Raman, Nathan E.K. Procter, Yang Timothy Du, Gnanadevan Mahadavan, Irene Stafford, Tamila Heresztyn, Andrew Holmes, Christopher Zeitz, Margaret Arstall, Joseph Selvanayagam, John D. Horowitz, John F. Beltrame
Background: Contemporary ST-segment–elevation myocardial infarction management involves primary percutaneous coronary intervention, with ongoing studies focusing on infarct size reduction using ancillary therapies. N-acetylcysteine (NAC) is an antioxidant with reactive oxygen species scavenging properties that also potentiates the effects of nitroglycerin and thus represents a potentially beneficial ancillary therapy in primary percutaneous coronary intervention. The NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction) examined the effects of NAC on infarct size in patients with ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention. Methods: This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous high-dose NAC (29 g over 2 days) with background low-dose nitroglycerin (7.2 mg over 2 days) on early cardiac magnetic resonance imaging–assessed infarct size. Secondary end points included cardiac magnetic resonance–determined myocardial salvage and creatine kinase kinetics. Results: Of 112 randomized patients with ST-segment–elevation myocardial infarction, 75 (37 in NAC group, 38 in placebo group) underwent early cardiac magnetic resonance imaging. Median duration of ischemia pretreatment was 2.4 hours. With background nitroglycerin infusion administered to all patients, those randomized to NAC exhibited an absolute 5.5% reduction in cardiac magnetic resonance–assessed infarct size relative to placebo (median, 11.0%; [interquartile range 4.1, 16.3] versus 16.5%; [interquartile range 10.7, 24.2]; P=0.02). Myocardial salvage was approximately doubled in the NAC group (60%; interquartile range, 37–79) compared with placebo (27%; interquartile range, 14–42; P<0.01) and median creatine kinase areas under the curve were 22 000 and 38 000 IU·h in the NAC and placebo groups, respectively (P=0.08). Conclusions: High-dose intravenous NAC administered with low-dose intravenous nitroglycerin is associated with reduced infarct size in patients with ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention. A larger study is required to assess the impact of this therapy on clinical cardiac outcomes. Clinical Trial Registration: Australian New Zealand Clinical Trials Registry. URL: http://www.anzctr.org.au/. Unique identifier: 12610000280000.
Combination Therapy to Target Reperfusion Injury After ST-Segment–Elevation Myocardial Infarction Circulation (IF 19.309) Pub Date : 2017-09-05 Derek J. Hausenloy, Derek M. Yellon
Article, see p 894 Timely reperfusion therapy by primary percutaneous coronary intervention (PPCI) combined with effective secondary preventive therapy has contributed to a decline in mortality rates after ST-segment–elevation myocardial infarction (STEMI) over the last few years. However, the incidence and severity of heart failure after STEMI are rising. Therefore, novel cardioprotective therapies are required to reduce myocardial infarct (MI) size and preserve left ventricular (LV) systolic function to prevent heart failure and improve clinical outcomes after PPCI.1,2 Over recent years, a large number of cardioprotective therapies, which have been demonstrated to be effective at reducing MI size in the laboratory setting, have been unable either to reduce MI size or to improve clinical outcomes after STEMI. The reasons for this are manifold and have been discussed extensively in the recent literature.1–3 In summary, the failure to translate cardioprotection for patient benefit has been attributed to several key factors: the inadequacy of the animal models used for testing novel cardioprotective therapies in the laboratory setting, a failure to demonstrate consistent and robust cardioprotection in experimental studies before proceeding to clinical studies, and poorly designed clinical cardioprotection studies.1–3 Another major reason for the failure to translate cardioprotection may have been the adoption of a single-targeted monotherapy approach, a strategy that may be inadequate to address the multifaceted components of myocardial reperfusion injury, including endothelial dysfunction, microvascular obstruction, oxidative stress, calcium overload, mitochondrial dysfunction, and inflammation.2,4 To address this issue, an emerging concept in the cardioprotection field has been to adopt …
Risk for Major Bleeding in Patients Receiving Ticagrelor Compared With Aspirin After Transient Ischemic Attack or Acute Ischemic Stroke in the SOCRATES Study (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) Circulation (IF 19.309) Pub Date : 2017-09-05 J. Donald Easton, Maria Aunes, Gregory W. Albers, Pierre Amarenco, Sara Bokelund-Singh, Hans Denison, Scott R. Evans, Peter Held, Marianne Jahreskog, Jenny Jonasson, Kazuo Minematsu, Carlos A. Molina, Yongjun Wang, K.S. Lawrence Wong, S. Claiborne Johnston, For the SOCRATES Steering Committee and Investigators
Background: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)–defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52–1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. Conclusions: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720.
Use of a Single Baseline Versus Multiyear 24-Hour Urine Collection for Estimation of Long-Term Sodium Intake and Associated Cardiovascular and Renal Risk Circulation (IF 19.309) Pub Date : 2017-09-05 Rik H.G. Olde Engberink, Thomas C. van den Hoek, Nicky D. van Noordenne, Bert-Jan H. van den Born, Hessel Peters-Sengers, Liffert Vogt
Background: A decrease in sodium intake has been shown to lower blood pressure, but data from cohort studies on the association with cardiovascular and renal outcomes are inconsistent. In these studies, sodium intake was often estimated with a single baseline measurement, which may be inaccurate considering day-to-day changes in sodium intake and sodium excretion. We compared the effects of single versus repetitive follow-up 24-hour urine samples on the relation between sodium intake and long-term cardiorenal outcomes. Methods: We selected adult subjects with an estimated glomerular filtration rate >60 mL/min/1.73m2, an outpatient 24-hour urine sample between 1998 and 1999, and at least 1 collection during a 17-year follow-up. Sodium intake was estimated with a single baseline collection and the average of samples collected during a 1-, 5-, and 15-year follow-up. We used Cox regression analysis and the landmark approach to investigate the relation between sodium intake and cardiovascular (cardiovascular events or mortality) and renal (end-stage renal disease: dialysis, transplantation, and/or >60% estimated glomerular filtration rate decline, or mortality) outcomes. Results: We included 574 subjects with 9776 twenty-four–hour urine samples. Average age was 47 years, and 46% were male. Median follow-up was 16.2 years. Average 24-hour sodium excretion, ranging from 3.8 to 3.9 g (165–170 mmol), was equal among all methods (P=0.88). However, relative to a single baseline measurement, 50% of the subjects had a >0.8-g (>34-mmol) difference in sodium intake with long-term estimations. As a result, 45%, 49%, and 50% of all subjects switched between tertiles of sodium intake when the 1-, 5-, or 15-year average was used, respectively. Consequently, hazard ratios for cardiorenal outcome changed up to 85% with the use of sodium intake estimations from short-term (1-year) and long-term (5-year) follow-up instead of baseline estimations. Conclusions: Relative to a single baseline 24-hour sodium measurement, the use of subsequent 24-hour urine samples resulted in different estimations of an individual’s sodium intake, whereas population averages remained similar. This finding had significant consequences for the association between sodium intake and long-term cardiovascular and renal outcomes.
Transcription Factor RUNX1 Regulates Platelet PCTP (Phosphatidylcholine Transfer Protein): Implications for Cardiovascular Events Circulation (IF 19.309) Pub Date : 2017-09-05 Guangfen Mao, Natthapol Songdej, Deepak Voora, Lawrence E. Goldfinger, Fabiola E. Del Carpio-Cano, Rachel A. Myers, A. Koneti Rao
Background: PCTP (phosphatidylcholine transfer protein) regulates the intermembrane transfer of phosphatidylcholine. Higher platelet PCTP expression is associated with increased platelet responses on activation of protease-activated receptor 4 thrombin receptors noted in black subjects compared with white subjects. Little is known about the regulation of platelet PCTP. Haplodeficiency of RUNX1, a major hematopoietic transcription factor, is associated with thrombocytopenia and impaired platelet responses on activation. Platelet expression profiling of a patient with a RUNX1 loss-of-function mutation revealed a 10-fold downregulation of the PCTP gene compared with healthy controls. Methods: We pursued the hypothesis that PCTP is regulated by RUNX1 and that PCTP expression is correlated with cardiovascular events. We studied RUNX1 binding to the PCTP promoter using DNA-protein binding studies and human erythroleukemia cells and promoter activity using luciferase reporter studies. We assessed the relationship between RUNX1 and PCTP in peripheral blood RNA and PCTP and death or myocardial infarction in 2 separate patient cohorts (587 total patients) with cardiovascular disease. Results: Platelet PCTP protein in the patient was reduced by ≈50%. DNA-protein binding studies showed RUNX1 binding to consensus sites in ≈1 kB of PCTP promoter. PCTP expression was increased with RUNX1 overexpression and reduced with RUNX1 knockdown in human erythroleukemia cells, indicating that PCTP is regulated by RUNX1. Studies in 2 cohorts of patients showed that RUNX1 expression in blood correlated with PCTP gene expression; PCTP expression was higher in black compared with white subjects and was associated with future death/myocardial infarction after adjustment for age, sex, and race (odds ratio, 2.05; 95% confidence interval 1.6–2.7; P<0.0001). RUNX1 expression is known to initiate at 2 alternative promoters, a distal P1 and a proximal P2 promoter. In patient cohorts, there were differential effects of RUNX1 isoforms on PCTP expression with a negative correlation in blood between RUNX1 expressed from the P1 promoter and PCTP expression. Conclusions: PCTP is a direct transcriptional target of RUNX1. PCTP expression is associated with death/myocardial infarction in patients with cardiovascular disease. RUNX1 regulation of PCTP may play a role in the pathogenesis of platelet-mediated cardiovascular events.
Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell–Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium Circulation (IF 19.309) Pub Date : 2017-09-05 Suresh K. Verma, Venkata N.S. Garikipati, Prasanna Krishnamurthy, Sarah M. Schumacher, Laurel A. Grisanti, Maria Cimini, Zhongjian Cheng, Mohsin Khan, Yujia Yue, Cindy Benedict, May M. Truongcao, Joseph E. Rabinowitz, David A. Goukassian, Douglas Tilley, Walter J. Koch, Raj Kishore
Background: Activated fibroblasts (myofibroblasts) play a critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear, warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast progenitor cells (BM-FPCs) in pressure overload–induced cardiac fibrosis. We have previously shown that interleukin-10 (IL10) suppresses pressure overload–induced cardiac fibrosis; however, the role of IL10 in inhibition of BM-FPC–mediated cardiac fibrosis is not known. We hypothesized that IL10 inhibits pressure overload–induced homing of BM-FPCs to the heart and their transdifferentiation to myofibroblasts and thus attenuates cardiac fibrosis. Methods: Pressure overload was induced in wild-type (WT) and IL10 knockout (IL10KO) mice by transverse aortic constriction. To determine the bone marrow origin, chimeric mice were created with enhanced green fluorescent protein WT mice marrow to the IL10KO mice. For mechanistic studies, FPCs were isolated from mouse bone marrow. Results: Pressure overload enhanced BM-FPC mobilization and homing in IL10KO mice compared with WT mice. Furthermore, WT bone marrow (from enhanced green fluorescent protein mice) transplantation in bone marrow–depleted IL10KO mice (IL10KO chimeric mice) reduced transverse aortic constriction–induced BM-FPC mobilization compared with IL10KO mice. Green fluorescent protein costaining with α-smooth muscle actin or collagen 1α in left ventricular tissue sections of IL10KO chimeric mice suggests that myofibroblasts were derived from bone marrow after transverse aortic constriction. Finally, WT bone marrow transplantation in IL10KO mice inhibited transverse aortic constriction–induced cardiac fibrosis and improved heart function. At the molecular level, IL10 treatment significantly inhibited transforming growth factor-β–induced transdifferentiation and fibrotic signaling in WT BM-FPCs in vitro. Furthermore, fibrosis-associated microRNA (miRNA) expression was highly upregulated in IL10KO-FPCs compared with WT-FPCs. Polymerase chain reaction–based selective miRNA analysis revealed that transforming growth factor-β–induced enhanced expression of fibrosis-associated miRNAs (miRNA-21, -145, and -208) was significantly inhibited by IL10. Restoration of miRNA-21 levels suppressed the IL10 effects on transforming growth factor-β–induced fibrotic signaling in BM-FPCs. Conclusions: Our findings suggest that IL10 inhibits BM-FPC homing and transdifferentiation to myofibroblasts in pressure-overloaded myocardium. Mechanistically, we show for the first time that IL10 suppresses Smad–miRNA-21–mediated activation of BM-FPCs and thus modulates cardiac fibrosis.
The Effects of Public Access Defibrillation on Survival After Out-of-Hospital Cardiac Arrest Circulation (IF 19.309) Pub Date : 2017-09-05 Josefine S. Bækgaard, Søren Viereck, Thea Palsgaard Møller, Annette Kjær Ersbøll, Freddy Lippert, Fredrik Folke
Background: Despite recent advances, the average survival after out-of-hospital cardiac arrest (OHCA) remains <10%. Early defibrillation by an automated external defibrillator is the most important intervention for patients with OHCA, showing survival proportions >50%. Accordingly, placement of automated external defibrillators in the community as part of a public access defibrillation program (PAD) is recommended by international guidelines. However, different strategies have been proposed on how exactly to increase and make use of publicly available automated external defibrillators. This systematic review aimed to evaluate the effect of PAD and the different PAD strategies on survival after OHCA. Methods: PubMed, Embase, and the Cochrane Library were systematically searched on August 31, 2015 for observational studies reporting survival to hospital discharge in OHCA patients where an automated external defibrillator had been used by nonemergency medical services. PAD was divided into 3 groups according to who applied the defibrillator: nondispatched lay first responders, professional first responders (firefighters/police) dispatched by the Emergency Medical Dispatch Center (EMDC), or lay first responders dispatched by the EMDC. Results: A total of 41 studies were included; 18 reported PAD by nondispatched lay first responders, 20 reported PAD by EMDC-dispatched professional first responders (firefighters/police), and 3 reported both. We identified no qualified studies reporting survival after PAD by EMDC-dispatched lay first responders. The overall survival to hospital discharge after OHCA treated with PAD showed a median survival of 40.0% (range, 9.1–83.3). Defibrillation by nondispatched lay first responders was associated with the highest survival with a median survival of 53.0% (range, 26.0–72.0), whereas defibrillation by EMDC-dispatched professional first responders (firefighters/police) was associated with a median survival of 28.6% (range, 9.0–76.0). A meta-analysis of the different survival outcomes could not be performed because of the large heterogeneity of the included studies. Conclusions: This systematic review showed a median overall survival of 40% for patients with OHCA treated by PAD. Defibrillation by nondispatched lay first responders was found to correlate with the highest impact on survival in comparison with EMDC-dispatched professional first responders. PAD by EMDC-dispatched lay first responders could be a promising strategy, but evidence is lacking.
Chronic Myocardial Infarction Circulation (IF 19.309) Pub Date : 2017-09-05 Diego Goldwasser, Marcelo V. Elizari, Antonio Bayés de Luna
This ECG was recorded during a routine checkup of a 77-year-old man who had a heart attack 8 months earlier. He was in the countryside when he felt constrictive chest pain lasting ≈2 hours but was not hospitalized until 20 hours later. A coronary angiogram was performed the following day. Based on ECG demonstrated in Figure 1, where is the culprit lesion? Where was the myocardial infarction (MI) located? Figure 1. The 12-lead ECG (see text for description). Please turn the page to read the diagnosis. This ECG shows sinus rhythm with left-axis deviation in the frontal plane (left anterior hemiblock) with notches in the S wave, a broad R>S in V1, and Rs with progressively decreased voltage until V6. In frontal plane leads, the voltage was low in all leads, and the T wave was flat in I leads and left …
Effect of Empagliflozin on the Metabolic Signature of Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease Circulation (IF 19.309) Pub Date : 2017-09-05 Ben A. Kappel, Michael Lehrke, Katharina Schütt, Anna Artati, Jerzy Adamski, Corinna Lebherz, Nikolaus Marx
In the recent EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), treatment with empagliflozin, a member of the group of antidiabetic sodium-glucose cotransporter 2 inhibitors, reduced cardiovascular mortality and hospitalization for heart failure in patients with type 2 diabetes mellitus and cardiovascular disease.1 In heart failure and type 2 diabetes mellitus, cardiac metabolic flexibility is impaired, and alteration in glucose or fatty acid (FA) metabolism and changes in the use of ketone bodies and branched chain amino acids (BCAAs) occur.2 Because sodium-glucose cotransporter 2 inhibitors lead to a mild increase in ketones, it has been hypothesized that empagliflozin may exhibit some of its beneficial effects through a shift in myocardial metabolism toward an energy-efficient use of ketone bodies, which may improve myocardial work efficiency and function.3,4 Still, these hypotheses are not proven yet, and data are lacking on the metabolic signature of sodium-glucose cotransporter 2 inhibitor-treated patients. Therefore, we performed an untargeted metabolomics approach in a group of empagliflozin-treated patients with type 2 diabetes mellitus and cardiovascular disease. In a prospective study (http://www.clinicaltrials.org; unique identifier: NCT03131232; ethics committee approved, and all patients gave informed consent), we enrolled 25 patients with type 2 diabetes mellitus and cardiovascular disease with a clinical indication for intensification of their glucose-lowering therapy and treated them with empagliflozin 10 mg/day. Serum was taken at baseline and after 1 month. Untargeted …
Letter by Jiang et al Regarding Article, “Fire Simulation and Cardiovascular Health in Firefighters” Circulation (IF 19.309) Pub Date : 2017-09-05 Xiao-Wei Jiang, Cheng-Zhi Yang, Shu-Bin Qiao
We read with great interest the wonderful research article presented by Hunter et al1 about myocardial infarction in firefighters. Their article presents an important clinical implication that firefighters during fire stimulation exposure could mitigate the risk of myocardial infarction through active cooling and effective rehydration. However, we think that the evidence …
Letter by Jin-Shan and Xue-Bin Regarding Article, “Fire Simulation and Cardiovascular Health in Firefighters” Circulation (IF 19.309) Pub Date : 2017-09-05 He Jin-Shan, Li Xue-Bin
We read with great interest the article by Hunter and colleagues1 on the pathogenic mechanism of cardiovascular injury in firefighters. Cardiovascular events are the main cause of deaths among firefighter and responsible for nearly 45% of on-duty fatalities each year in the United States. High temperatures, extreme physical exertion, and noxious air pollutants may contribute to the cardiovascular events. …
Response by Hunter and Mills to Letters Regarding Article, “Fire Simulation and Cardiovascular Health in Firefighters” Circulation (IF 19.309) Pub Date : 2017-09-05 Amanda L. Hunter, Nicholas L. Mills
We thank the correspondents for their interesting and thoughtful comments on our recent study,1 and we are pleased that they found our work to be clinically important and a useful contribution to the field. We agree with Drs Jin-Shan and Xue-Bin that fire suppression duties are usually preceded by an alarm response. The emotional stresses of firefighting are numerous and include being called into unforeseeable circumstances with unpredictable risks, time pressure, and the burden of being responsible for the lives of others. The combination of these stressors activates the adrenocortical axis, which is known to increase platelet numbers and to induce aggregation.2 We attempted to delineate the factors that pose the greatest threat to the cardiovascular health of firefighters; therefore, we examined the effects of exposure to high temperatures and physical …
Methodological Standards for Meta-Analyses and Qualitative Systematic Reviews of Cardiac Prevention and Treatment Studies: A Scientific Statement From the American Heart Association Circulation (IF 19.309) Pub Date : 2017-09-05 Goutham Rao, Francisco Lopez-Jimenez, Jack Boyd, Frank D’Amico, Nefertiti H. Durant, Mark A. Hlatky, George Howard, Katherine Kirley, Christopher Masi, Tiffany M. Powell-Wiley, Anthony E. Solomonides, Colin P. West, Jennifer Wessel
Meta-analyses are becoming increasingly popular, especially in the fields of cardiovascular disease prevention and treatment. They are often considered to be a reliable source of evidence for making healthcare decisions. Unfortunately, problems among meta-analyses such as the misapplication and misinterpretation of statistical methods and tests are long-standing and widespread. The purposes of this statement are to review key steps in the development of a meta-analysis and to provide recommendations that will be useful for carrying out meta-analyses and for readers and journal editors, who must interpret the findings and gauge methodological quality. To make the statement practical and accessible, detailed descriptions of statistical methods have been omitted. Based on a survey of cardiovascular meta-analyses, published literature on methodology, expert consultation, and consensus among the writing group, key recommendations are provided. Recommendations reinforce several current practices, including protocol registration; comprehensive search strategies; methods for data extraction and abstraction; methods for identifying, measuring, and dealing with heterogeneity; and statistical methods for pooling results. Other practices should be discontinued, including the use of levels of evidence and evidence hierarchies to gauge the value and impact of different study designs (including meta-analyses) and the use of structured tools to assess the quality of studies to be included in a meta-analysis. We also recommend choosing a pooling model for conventional meta-analyses (fixed effect or random effects) on the basis of clinical and methodological similarities among studies to be included, rather than the results of a test for statistical heterogeneity.
Correction to: Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association Circulation (IF 19.309) Pub Date : 2017-09-05 Lippincott Williams & Wilkins
In the article by Sacks et al, “Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association,” which published ahead of print June 15, 2017, and …
Correction to: Heart Disease and Stroke Statistics—2017 Update: A Report From the American Heart Association Circulation (IF 19.309) Pub Date : 2017-09-05 Lippincott Williams & Wilkins
In the article by Benjamin et al, “Heart Disease and Stroke Statistics—2017 Update: A Report From the American Heart Association,” which published online January 25, 2017, and appeared in …
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