Editor-in-Chief’s Top Picks From 2016: Part One

Each week, I record audio summaries for every article in JACC, as well as an issue summary. While this process has been incredibly time-consuming, I have become quite familiar with every paper that we publish. Thus, I personally select papers (both original investigations and review articles) from 15 distinct specialties each year for your review. In addition to my personal choices, I have included manuscripts that have been the most accessed or downloaded on our websites, as well as those selected by the JACC Editorial Board members. In order to present the full breadth of this important research in a consumable fashion, we will present these manuscripts in this issue of JACC.

Part One includes the sections: Basic & Translational Research, Cardiac Failure, Cardiomyopathies/Myocardial & Pericardial Diseases, Congenital Heart Disease, Coronary Disease & Interventions, and CVD Prevention & Health Promotion (1–74).

Part Two will include the sections: CV Medicine & Society, Hypertension, Imaging, Metabolic & Lipid Disorders, Rhythm Disorders, Valvular Heart Disease, and Vascular Medicine.

Basic & Translational Research

Aβ Amyloid Pathology Affects the Hearts of Patients With Alzheimer’s Disease: Mind the Heart

L. Troncone, et al.

Background

Individually, heart failure (HF) and Alzheimer’s disease (AD) are severe threats to population health, and their potential coexistence is an alarming prospect. In addition to sharing analogous epidemiological and genetic profiles, biochemical characteristics, and common triggers, the authors recently recognized common molecular and pathological features between the 2 conditions. Whereas cognitive impairment has been linked to HF through perfusion defects, angiopathy, and inflammation, whether patients with AD present with myocardial dysfunction, and if the 2 conditions bear a common pathogenesis as neglected siblings are unknown.

Objectives

Here, the authors investigated whether amyloid beta (Aβ) protein aggregates are present in the hearts of patients with a primary diagnosis of AD, affecting myocardial function.

Methods

The authors examined myocardial function in a retrospective cross-sectional study from a cohort of AD patients and age-matched controls. Imaging and proteomics approaches were used to identify and quantify Aβ deposits in AD heart and brain specimens compared with controls. Cell shortening and calcium transients were measured on isolated adult cardiomyocytes.

Results

Echocardiographic measurements of myocardial function suggest that patients with AD present with an anticipated diastolic dysfunction. As in the brain, Aβ₄₀ and Aβ₄₂ are present in the heart, and their expression is increased in AD.

Conclusions

Here, the authors provide the first report of the presence of compromised myocardial function and intramyocardial deposits of Aβ in AD patients. The findings depict a novel biological framework in which AD may be viewed either as a systemic disease or as a metastatic disorder leading to heart, and possibly multiorgan failure. AD and HF are both debilitating and life-threatening conditions, affecting enormous patient populations. Our findings underline a previously dismissed problem of a magnitude that will require new diagnostic approaches and treatments for brain and heart disease, and their combination (1).

AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy

R.H. Falk, et al.

The amyloidoses are a group of protein-folding disorders in which ≥1 organ is infiltrated by proteinaceous deposits known as amyloid. The deposits are derived from 1 of several amyloidogenic precursor proteins, and the prognosis of the disease is determined both by the organ(s) involved and the type of amyloid. Amyloid involvement of the heart (cardiac amyloidosis) carries the worst prognosis of any involved organ, and light-chain (AL) amyloidosis is the most serious form of the disease. The last decade has seen considerable progress in understanding the amyloidoses. In this review, current and novel approaches to the diagnosis and treatment of cardiac amyloidosis are discussed, with particular reference to AL amyloidosis in the heart (2).

Genetic and Pharmacological Inhibition of TREM-1 Limits the Development of Experimental Atherosclerosis

J. Joffre, et al.

Background

Innate immune responses activated through myeloid cells contribute to the initiation, progression, and complications of atherosclerosis in experimental models. However, the critical upstream pathways that link innate immune activation to foam cell formation are still poorly identified.

Objectives

This study sought to investigate the hypothesis that activation of the triggering receptor expressed on myeloid cells (TREM-1) plays a determinant role in macrophage atherogenic responses.

Methods

After genetically invalidating Trem-1 in chimeric Ldlr^−/− Trem-1^−/− mice and double knockout ApoE^−/− Trem-1^−/− mice, we pharmacologically inhibited Trem-1 using LR12 peptide.

Results

Ldlr^−/− mice reconstituted with bone marrow deficient for Trem-1 (Trem-1^−/−) showed a strong reduction of atherosclerotic plaque size in both the aortic sinus and the thoracoabdominal aorta, and were less inflammatory compared to plaques of Trem-1^+/+ chimeric mice. Genetic invalidation of Trem-1 led to alteration of monocyte recruitment into atherosclerotic lesions and inhibited toll-like receptor 4 (TLR 4)-initiated proinflammatory macrophage responses. We identified a critical role for Trem-1 in the upregulation of cluster of differentiation 36 (CD36), thereby promoting the formation of inflammatory foam cells. Genetic invalidation of Trem-1 in ApoE^−/−/Trem-1^−/− mice or pharmacological blockade of Trem-1 in ApoE^−/− mice using LR-12 peptide also significantly reduced the development of atherosclerosis throughout the vascular tree, and lessened plaque inflammation. TREM-1 was expressed in human atherosclerotic lesions, mainly in lipid-rich areas with significantly higher levels of expression in atheromatous than in fibrous plaques.

Conclusions

We identified TREM-1 as a major upstream proatherogenic receptor. We propose that TREM-1 activation orchestrates monocyte/macrophage proinflammatory responses and foam cell formation through coordinated and combined activation of CD36 and TLR4. Blockade of TREM-1 signaling may constitute an attractive novel and double-hit approach for the treatment of atherosclerosis (3).

Genetics and Genomics of Single-Gene Cardiovascular Diseases: Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders

A.J. Marian, et al.

This is the first of 2 review papers on genetics and genomics appearing as part of the series on “omics.” Genomics pertains to all components of an organism’s genes, whereas genetics involves analysis of a specific gene or genes in the context of heredity. The paper provides introductory comments, describes the basis of human genetic diversity, and addresses the phenotypic consequences of genetic variants. Rare variants with large effect sizes are responsible for single-gene disorders, whereas complex polygenic diseases are typically due to multiple genetic variants, each exerting a modest effect size. To illustrate the clinical implications of genetic variants with large effect sizes, 3 common forms of hereditary cardiomyopathies are discussed as prototypic examples of single-gene disorders, including their genetics, clinical manifestations, pathogenesis, and treatment. The genetic basis of complex traits is discussed in a separate paper (4).

Genetics: Implications for Prevention and Management of Coronary Artery Disease

T.L. Assimes, et al.

An exciting new era has dawned for the prevention and management of coronary artery disease (CAD) utilizing genetic risk variants. The recent identification of over 60 susceptibility loci for CAD confirms not only the importance of established risk factors, but also the existence of many novel causal pathways that are expected to improve our understanding of the genetic basis of CAD and facilitate the development of new therapeutic agents over time. Concurrently, Mendelian randomization studies have provided intriguing insights on the causal relationship between CAD-related traits, and highlight the potential benefits of long-term modifications of risk factors. Last, genetic risk scores of CAD may serve not only as prognostic, but also as predictive markers, and carry the potential to considerably improve the delivery of established prevention strategies. This review will summarize the evolution and discovery of genetic risk variants for CAD and their current and future clinical applications (5).

Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey)

M.S. Maurer, et al.

Background

Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.

Objectives

The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.

Methods

Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189).

Results

U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival.

Conclusions

In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745) (6).

Intratracheal Gene Delivery of SERCA2a Ameliorates Chronic Post-Capillary Pulmonary Hypertension: A Large Animal Model

J. Aguero, et al.

Background

Pulmonary hypertension (PH) is characterized by pulmonary arterial remodeling that results in increased pulmonary vascular resistance, right ventricular (RV) failure, and premature death. Down-regulation of sarcoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a) in the pulmonary vasculature leads to perturbations in calcium ion (Ca²⁺) homeostasis and transition of pulmonary artery smooth muscle cells to a proliferative phenotype.

Objectives

We assessed the feasibility of sustained pulmonary vascular SERCA2a gene expression using aerosolized delivery of adeno-associated virus type 1 (AAV1) in a large animal model of chronic PH and evaluated the efficacy of gene transfer regarding progression of pulmonary vascular and RV remodeling.

Methods

A model of chronic post-capillary PH was created in Yorkshire swine by partial pulmonary vein banding. Development of chronic PH was confirmed hemodynamically, and animals were randomized to intratracheal administration of aerosolized AAV1 carrying the human SERCA2a gene (n = 10, AAV1.SERCA2a group) or saline (n = 10). Therapeutic efficacy was evaluated 2 months after gene delivery.

Results

Transduction efficacy after intratracheal delivery of AAV1 was confirmed by β-galactosidase detection in the distal pulmonary vasculature. Treatment with aerosolized AAV1.SERCA2a prevented disease progression as evaluated by mean pulmonary artery pressure, vascular resistance, and limited vascular remodeling quantified by histology. Therapeutic efficacy was supported further by the preservation of RV ejection fraction (p = 0.014) and improvement of the RV end-diastolic pressure–volume relationship in PH pigs treated with aerosolized AAV1.SERCA2a.

Conclusions

Airway-based delivery of AAV vectors to the pulmonary arteries was feasible, efficient, and safe in a clinically relevant chronic PH model. Vascular SERCA2a overexpression resulted in beneficial effects on pulmonary arterial remodeling, with attendant improvements in pulmonary hemodynamics and RV performance, and might offer therapeutic benefit by modifying fundamental pathophysiology in pulmonary vascular diseases (7).

Leukocytes Link Local and Systemic Inflammation in Ischemic Cardiovascular Disease: An Expanded “Cardiovascular Continuum”

P. Libby, et al.

Physicians have traditionally viewed ischemic heart disease in a cardiocentric manner: plaques grow in arteries until they block blood flow, causing acute coronary and other ischemic syndromes. Recent research provides new insight into the integrative biology of inflammation as it contributes to ischemic cardiovascular disease. These results have revealed hitherto unsuspected inflammatory signaling networks at work in these disorders that link the brain, autonomic nervous system, bone marrow, and spleen to the atherosclerotic plaque and to the infarcting myocardium. A burgeoning clinical published data indicates that such inflammatory networks—far from a mere laboratory curiosity—operate in our patients and can influence aspects of ischemic cardiovascular disease that determine decisively clinical outcomes. These new findings enlarge the circle of the traditional “cardiovascular continuum” beyond the heart and vessels to include the nervous system, the spleen, and the bone marrow (8).

Long Noncoding RNAs: From Clinical Genetics to Therapeutic Targets?

R.A. Boon, et al.

Recent studies suggest that the majority of the human genome is transcribed, but only about 2% accounts for protein-coding exons. Long noncoding RNAs (lncRNAs) constitute a heterogenic class of RNAs that includes, for example, intergenic lncRNAs, antisense transcripts, and enhancer RNAs. Moreover, alternative splicing can lead to the formation of circular RNAs. In support of putative functions, GWAS for cardiovascular diseases have shown predictive single-nucleotide polymorphisms in lncRNAs, such as the 9p21 susceptibility locus that encodes the lncRNA antisense noncoding RNA in the INK4 locus (ANRIL). Many lncRNAs are regulated during disease. For example, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and myocardial infarction-associated transcript (MIAT) were shown to affect endothelial cell functions and diabetic retinopathy, whereas lincRNA-p21 controls neointima formation. In the heart, several lncRNAs were shown to act as microRNA sponges and to control ischemia-reperfusion injury or act as epigenetic regulators. In this review, the authors summarize the current understanding of lncRNA functions and their role as biomarkers in cardiovascular diseases (9).

MicroRNAs in Cardiovascular Disease

T. Barwari, et al.

Micro-ribonucleic acids (miRNAs) are in the spotlight as post-transcriptional regulators of gene expression. More than 1,000 miRNAs are encoded in the human genome. In this review, we provide an introduction to miRNA biology and research methodology, and highlight advances in cardiovascular research to date. This includes the potential of miRNAs as therapeutic targets in cardiac and vascular disease, and their use as novel biomarkers. Although some miRNA therapies are already undergoing clinical evaluation, we stress the importance of integrating current knowledge of miRNA biology into a systemic context. Discovery studies focus on miRNA effects within one specific organ, whereas the expression of most miRNAs is not restricted to a single tissue. Because most miRNA-based therapies act systemically, this may preclude widespread clinical use. The development of more targeted interventions will bolster well-informed clinical applications, increasing the chances of success and minimizing the risk of setbacks for miRNA-based therapeutics (10).

Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System

M. Grogan, et al.

Background

Wild-type transthyretin cardiac amyloidosis (ATTRwt) is increasingly recognized as an important cause of heart failure.

Objectives

The purpose of this study was to determine the natural history of ATTRwt and the predictors of survival.

Methods

We retrospectively reviewed patients diagnosed with ATTRwt at the Mayo Clinic through 2013 and recorded clinical data and survival data. Factors affecting overall survival (OS) were identified, and a prognostic staging system was developed.

Results

The median age of the 360 patients diagnosed before death was 75 years (range: 47 to 94 years), and 91% were male. Presenting signs and symptoms included dyspnea or heart failure in 67% and atrial arrhythmias in 62%. Median OS from diagnosis was 3.6 years and did not change over time. Multivariate predictors of mortality included age, ejection fraction, pericardial effusion, N-terminal pro–B-type natriuretic peptide, and troponin T. A staging system was developed that used thresholds of troponin T (0.05 ng/ml) and N-terminal pro–B-type natriuretic peptide (3,000 pg/ml). The respective 4-year OS estimates were 57%, 42%, and 18% for stage I (both values below cutoff), stage II (one above), and stage III (both above), respectively. Stage III patients were at an increased risk of mortality after adjustment for age and sex compared with stage I patients (hazard ratio: 3.6; p < 0.001).

Conclusions

The natural history of ATTRwt is poor. We report a novel cardiac biomarker staging system that enables risk stratification in an era of emerging treatment strategies (11).

Patient-Specific and Genome-Edited Induced Pluripotent Stem Cell–Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Brugada Syndrome

P. Liang, et al.

Background

Brugada syndrome (BrS), a disorder associated with characteristic electrocardiogram precordial ST-segment elevation, predisposes afflicted patients to ventricular fibrillation and sudden cardiac death. Despite marked achievements in outlining the organ level pathophysiology of the disorder, the understanding of human cellular phenotype has lagged due to a lack of adequate human cellular models of the disorder.

Objectives

The objective of this study was to examine single cell mechanism of Brugada syndrome using induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs).

Methods

This study recruited 2 patients with type 1 BrS carrying 2 different sodium voltage-gated channel alpha subunit 5 variants as well as 2 healthy control subjects. We generated iPSCs from their skin fibroblasts by using integration-free Sendai virus. We used directed differentiation to create purified populations of iPSC-CMs.

Results

BrS iPSC-CMs showed reductions in inward sodium current density and reduced maximal upstroke velocity of action potential compared with healthy control iPSC-CMs. Furthermore, BrS iPSC-CMs demonstrated increased burden of triggered activity, abnormal calcium (Ca²⁺) transients, and beating interval variation. Correction of the causative variant by genome editing was performed, and resultant iPSC-CMs showed resolution of triggered activity and abnormal Ca²⁺ transients. Gene expression profiling of iPSC-CMs showed clustering of BrS compared with control subjects. Furthermore, BrS iPSC-CM gene expression correlated with gene expression from BrS human cardiac tissue gene expression.

Conclusions

Patient-specific iPSC-CMs were able to recapitulate single-cell phenotype features of BrS, including blunted inward sodium current, increased triggered activity, and abnormal Ca²⁺ handling. This novel human cellular model creates future opportunities to further elucidate the cellular disease mechanism and identify novel therapeutic targets (12).

Proteomics Research in Cardiovascular Medicine and Biomarker Discovery

M.P.Y. Lam, et al.

Proteomics is a systems physiology discipline to address the large-scale characterization of protein species within a biological system, be it a cell, a tissue, a body biofluid, an organism, or a cohort population. Building on advances from chemical analytical platforms (e.g., mass spectrometry and other technologies), proteomics approaches have contributed powerful applications in cardiovascular biomedicine, most notably in: 1) the discovery of circulating protein biomarkers of heart diseases from plasma samples; and 2) the identification of disease mechanisms and potential therapeutic targets in cardiovascular tissues, in both preclinical models and translational studies. Contemporary proteomics investigations offer powerful means to simultaneously examine tens of thousands of proteins in various samples, and understand their molecular phenotypes in health and disease. This concise review introduces study design considerations, example applications and use cases, as well as interpretation and analysis of proteomics data in cardiovascular biomedicine (13).

The Emerging Role of Metabolomics in the Diagnosis and Prognosis of Cardiovascular Disease

J.R. Ussher, et al.

Perturbations in cardiac energy metabolism are major contributors to a number of cardiovascular pathologies. In addition, comorbidities associated with cardiovascular disease (CVD) can alter systemic and myocardial metabolism, often contributing to the worsening of cardiac function and health outcomes. State-of-the-art metabolomic technologies give us the ability to measure thousands of metabolites in biological fluids or biopsies, providing us with a metabolic fingerprint of individual patients. These metabolic profiles may serve as diagnostic and/or prognostic tools that have the potential to significantly alter the management of CVD. Herein, the authors review how metabolomics can assist in the interpretation of perturbed metabolic processes, and how this has improved our ability to understand the pathology of ischemic heart disease, atherosclerosis, and heart failure. Taken together, the integration of metabolomics with other “omics” platforms will allow us to gain insight into pathophysiological interactions of metabolites, proteins, genes, and disease states, while advancing personalized medicine (14).

Translation of Human-Induced Pluripotent Stem Cells: From Clinical Trial in a Dish to Precision Medicine

N. Sayed, et al.

The prospect of changing the plasticity of terminally differentiated cells toward pluripotency has completely altered the outlook for biomedical research. Human-induced pluripotent stem cells (iPSCs) provide a new source of therapeutic cells free from the ethical issues or immune barriers of human embryonic stem cells. iPSCs also confer considerable advantages over conventional methods of studying human diseases. Since its advent, iPSC technology has expanded with 3 major applications: disease modeling, regenerative therapy, and drug discovery. Here we discuss, in a comprehensive manner, the recent advances in iPSC technology in relation to basic, clinical, and population health (15).

Cardiac Failure

A Test in Context: Critical Evaluation of Natriuretic Peptide Testing in Heart Failure

Conclusions

In patients with severe systolic dysfunction following acute MI with an EF ≤35%, 57% had EF recovery to >35%. A model using clinical variables present at the time of MI can help predict EF recovery (23).

Cardiomyopathies/Myocardial & Pericardial Diseases

A Case-Control Study of Risk Markers and Mortality in Takotsubo Stress Cardiomyopathy

P. Tornvall, et al.

Background

Takotsubo stress cardiomyopathy (TSC) is a syndrome characterized by transient myocardial dysfunction with unknown etiology. Although recent studies have suggested that the syndrome is associated with comorbidity and has a dismal prognosis, there is a lack of comprehensive data describing the epidemiology and prognosis of TSC.

Objectives

This study compared risk markers and mortality in patients with TSC with that of individuals with or without coronary artery disease (CAD).

Methods

Patients with TSC and control subjects were identified from the Swedish Coronary Angiography and Angioplasty Register between 2009 and 2013 and linked with the Swedish national patient registry, cause of death registry, prescription drug registry, and education and income registries.

Results

Patients with TSC were characterized by a low cardiovascular risk factor profile but with increased chronic obstructive pulmonary disease, migraine, and affective disorders. The use of beta-blockers was less common but use of β₂-adrenergic agonist agents was more common in patients with TSC compared with either of the control groups. Being a patient with TSC was associated with a hazard ratio of 2.1 for death compared with the control subjects without CAD (95% confidence interval: 1.4 to 3.2). This was similar to the excess mortality risk seen among the CAD control subjects compared with control subjects without CAD (hazard ratio: 2.5; 95% confidence interval: 1.8 to 3.3). These associations remained significant after adjusting for CAD risk factors and risk markers for TSC.

Conclusions

The findings of increased risk associated with β₂-adrenergic agonist agents together with stress related to affective disorders emphasize the pathogenic role of sympathetic stimulation. The prognosis regarding mortality is worse than in control subjects without CAD and similar to patients with CAD emphasizing the urgent need for studies on optimal treatment of TSC (24).

Arrhythmogenic Right Ventricular Cardiomyopathy: Clinical Course and Predictors of Arrhythmic Risk

A. Mazzanti, et al.

Background

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death, but its progression over time and predictors of arrhythmias are still being defined.

Objectives

This study sought to describe the clinical course of ARVC and occurrence of life-threatening arrhythmic events (LAE) and cardiovascular mortality; identify risk factors associated with increased LAE risk; and define the response to therapy.

Methods

We determined the clinical course of 301 consecutive patients with ARVC using the Kaplan-Meier method adjusted to avoid the bias of delayed entry. Predictors of LAE over 5.8 years of follow-up were determined with Cox multivariable analysis. Treatment efficacy was assessed comparing LAE rates during matched time intervals.

Results

A first LAE occurred in 1.5 per 100 person-years between birth and age 20 years, in 4.0 per 100 person-years between ages 21 and 40 years, and in 2.4 per 100 person-years between ages 41 and 60 years. Cumulative probability of a first LAE at follow-up was 14% at 5 years, 23% at 10 years, and 30% at 15 years. Higher risk of LAE was predicted by atrial fibrillation (hazard ratio [HR]: 4.38; p = 0.002), syncope (HR: 3.36; p < 0.001), participation in strenuous exercise after the diagnosis (HR: 2.98; p = 0.028), hemodynamically tolerated sustained monomorphic ventricular tachycardia (HR: 2.19; p = 0.023), and male sex (HR: 2.49; p = 0.012). No difference was observed in the occurrence of LAE before and after treatment with amiodarone, beta-blockers, sotalol, or ablation. A total of 81 patients received an implantable cardioverter-defibrillator, 34 were successfully defibrillated.

Conclusions

The high risk of life-threatening arrhythmias in patients with ARVC spans from adolescence to advanced age, reaching its peak between ages 21 and 40 years. Atrial fibrillation, syncope, participation in strenuous exercise after the diagnosis of ARVC, hemodynamically tolerated sustained monomorphic ventricular tachycardia, and male sex predicted lethal arrhythmias at follow-up. The lack of efficacy of antiarrhythmic therapy and the life-saving role of the implantable cardioverter-defibrillator highlight the importance of risk stratification for patient management (25).

Complicated Pericarditis: Understanding Risk Factors and Pathophysiology to Inform Imaging and Treatment

P.C. Cremer, et al.

Most patients with acute pericarditis have a benign course and a good prognosis. However, a minority of patients develop complicated pericarditis, and the care of these patients is the focus of this review. Specifically, we address risk factors, multimodality imaging, pathophysiology, and novel treatments. The authors conclude that: 1) early high-dose corticosteroids, a lack of colchicine, and an elevated high-sensitivity C-reactive protein are associated with the development of complicated pericarditis; 2) in select cases, cardiovascular magnetic resonance imaging may aid in the assessment of pericardial inflammation and constriction; 3) given phenotypic similarities between recurrent idiopathic pericarditis and periodic fever syndromes, disorders of the inflammasome may contribute to relapsing attacks; and 4) therapies that target the inflammasome may lead to more durable remission and resolution. Finally, regarding future investigations, the authors discuss the potential of cardiovascular magnetic resonance to inform treatment duration and the need to compare steroid-sparing treatments to pericardiectomy (26).

Constrictive Pericarditis Versus Restrictive Cardiomyopathy?

M.J. Garcia, et al.

About one-half of the patients with congestive heart failure have preserved left ventricular ejection fraction (HFpEF). Although the etiology of HFpEF is most commonly related to long-standing hypertension and atherosclerosis, a significant number of suspected HFpEF patients have a restrictive cardiomyopathy or chronic pericardial disease. Recognizing these syndromes is important because early diagnosis may lead to instituting specific therapy that may prolong survival, improve quality of life, and/or recognize and treat an underlying systemic disorder. Advances in diagnostic imaging, biomarkers, and genetic testing today allow identification of the specific etiology in most cases. Novel pharmacological, immunologic, and surgical therapies are leading to improved quality of life and survival (27).

Differentiation of Constriction and Restriction: Complex Cardiovascular Hemodynamics

J.B. Geske, et al.

Differentiation of constrictive pericarditis (CP) from restrictive cardiomyopathy (RCM) is a complex and often challenging process. Because CP is a potentially curable cause of heart failure and therapeutic options for RCM are limited, distinction of these 2 conditions is critical. Although different in regard to etiology, prognosis, and treatment, CP and RCM share a common clinical presentation of predominantly right-sided heart failure, in the absence of significant left ventricular systolic dysfunction or valve disease, due to impaired ventricular diastolic filling. Fundamental to the diagnosis of either condition is a clear understanding of the underlying hemodynamic principles and pathophysiology. We present a contemporary review of the pathophysiology, hemodynamics, diagnostic assessment, and therapeutic approach to patients presenting with CP and RCM (28).

First Experience With Percutaneous Mitral Valve Plication as Primary Therapy for Symptomatic Obstructive Hypertrophic Cardiomyopathy

P. Sorajja, et al.

Background

Few therapeutic options exist for patients with severe heart failure due to obstructive hypertrophic cardiomyopathy (HCM) who are at unacceptable surgical risk. We hypothesized that percutaneous plication of the mitral valve could reduce left ventricular outflow tract (LVOT) obstruction and associated mitral regurgitation, thereby leading to amelioration of heart failure symptoms.

Objectives

This study sought to evaluate the potential effectiveness of percutaneous mitral valve plication as a therapy for patients with symptomatic, obstructive HCM.

Methods

Six patients (age 83 ± 8 years; 5 women), judged as not optimal candidates for septal myectomy, were referred for management of severe, drug-refractory heart failure symptoms due to obstructive HCM (New York Heart Association functional class III). Each underwent percutaneous mitral valve leaflet plication to reduce systolic anterior motion (SAM) and mitral regurgitation using the transcatheter mitral clip system.

Results

The procedure was completed in 5 patients with placement of a single clip at the A₂-P₂ segments of the mitral valve. One other patient experienced cardiac tamponade, leading to termination of the procedure. Among the 5 treated patients, percutaneous plication with the eliminated SAM and consequently decreased the intraoperative LVOT gradient (91 ± 44 mm Hg to 12 ± 6 mm Hg; p = 0.007), left atrial pressure (29 ± 11 mm Hg to 20 ± 8 mm Hg; p = 0.06), and mitral regurgitation grade (3.0 ± 0 vs. 0.8 ± 0.4; p = 0.0002) associated with improved cardiac output (in n = 4; 3.0 ± 0.6 l/min to 4.3 ± 1.2 l/min; p = 0.03). Over follow-up of 15 ± 4 months, symptom improvement to New York Heart Association functional class I or II occurred in all patients. Follow-up echocardiography after 15 ± 4 months demonstrated continued absence of SAM and significant reduction in mitral regurgitation, although high systolic LVOT velocities (i.e., >4 m/s) were evident in 3 of the 5 treated patients.

Conclusions

This is a report of percutaneous mitral valve plication as a primary therapy in the management of severely symptomatic, obstructive HCM patients. This initial experience suggests that percutaneous mitral valve plication may be effective for symptom relief in such patients via reduction of SAM and mitral regurgitation. The significance of persistent elevations of LVOT velocities in some patients requires further study (29).

Left Ventricular Noncompaction: A Distinct Genetic Cardiomyopathy?

Conclusions

This first systematic CMR study characterizing the cardiac phenotype in pheochromocytoma showed that cardiac involvement was frequent and, for some variables, persisted after curative surgery. These effects surpass those of hypertensive heart disease alone, supporting a direct role of catecholamine toxicity that may produce subtle but long-lasting myocardial alterations (33).

The Diagnosis and Evaluation of Dilated Cardiomyopathy

A.G. Japp, et al.

Dilated cardiomyopathy (DCM) is best understood as the final common response of myocardium to diverse genetic and environmental insults. A rigorous work-up can exclude alternative causes of left ventricular (LV) dilation and dysfunction, identify etiologies that may respond to specific treatments, and guide family screening. A significant proportion of DCM cases have an underlying genetic or inflammatory basis. Measurement of LV size and ejection fraction remain central to diagnosis, risk stratification, and treatment, but other aspects of cardiac remodeling inform prognosis and carry therapeutic implications. Assessment of myocardial fibrosis predicts both risk of sudden cardiac death and likelihood of LV functional recovery, and has significant potential to guide patient selection for cardioverter-defibrillator implantation. Detailed mitral valve assessment is likely to assume increasing importance with the emergence of percutaneous interventions for functional mitral regurgitation. Detection of pre-clinical DCM could substantially reduce morbidity and mortality by allowing early instigation of cardioprotective therapy (34).

The Quest for New Approaches in Myocarditis and Inflammatory Cardiomyopathy

S. Heymans, et al.

Myocarditis is a diverse group of heart-specific immune processes classified by clinical and histopathological manifestations. Up to 40% of dilated cardiomyopathy is associated with inflammation or viral infection. Recent experimental studies revealed complex regulatory roles for several microribonucleic acids and T-cell and macrophage subtypes. Although the prevalence of myocarditis remained stable between 1990 and 2013 at about 22 per 100,000 people, overall mortality from cardiomyopathy and myocarditis has decreased since 2005. The diagnostic and prognostic value of cardiac magnetic resonance has increased with new, higher-sensitivity sequences. Positron emission tomography has emerged as a useful tool for diagnosis of cardiac sarcoidosis. The sensitivity of endomyocardial biopsy may be increased, especially in suspected sarcoidosis, by the use of electrogram guidance to target regions of abnormal signal. Investigational treatments on the basis of mechanistic advances are entering clinical trials. Revised management recommendations regarding athletic participation after acute myocarditis have heightened the importance of early diagnosis (35).

Congenital Heart Disease

Aortic Valve Replacement and the Ross Operation in Children and Young Adults

M.T.A. Sharabiani, et al.

Background

There are several options available for aortic valve replacement (AVR), with few comparative reports in the literature. The optimal choice for AVR in each age group is not clear.

Objectives

The study sought to report and compare outcomes after AVR in the young using data from a national database.

Methods

AVR procedures were compared after advanced matching, both in pairs and in a 3-way manner, using a Bayesian dynamic survival model.

Results

A total of 1,501 patients who underwent AVR in the United Kingdom between 2000 and 2012 were included. Of these, 47.8% had a Ross procedure, 37.8% a mechanical AVR, 10.9% a bioprosthesis AVR, and 3.5% a homograft AVR, with Ross patients being significantly younger when compared to the other groups. Overall survival at 12 years was 94.6%. In children, the Ross procedure had a 12.7% higher event-free probability (death or any reintervention) at 10 years when compared to mechanical AVR (p = 0.05). We also compared all procedures except the homograft in a matched population of young adults, where the bioprosthesis had the lowest event-free probability of 78.8%, followed by comparable results in mechanical AVR and Ross, with 86.3% and 89.6%, respectively. Younger age was associated with mortality and pulmonary reintervention in the Ross group and with aortic reintervention in the mechanical AVR. Of all 3 options, only the patients undergoing the Ross procedure approached the survival of the general population.

Conclusions

AVR in the young achieves good results, with the Ross being overall better suited for this age group, especially in children. Although freedom from aortic valve reintervention is superior after the Ross procedure, the need for homograft reinterventions is an issue to take into account. All methods have advantages and limitations, with reinterventions being an issue in the long term for all, more crucially in smaller children (36).

Etiology of Sudden Death in Sports: Insights From a United Kingdom Regional Registry

A Test in Context: High-Sensitivity C-Reactive Protein

P.M. Ridker

The inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) adds prognostic information on cardiovascular risk comparable to blood pressure or cholesterol. Values <1, 1 to 3, and >3 mg/l indicate lower, average, or higher relative cardiovascular risk, respectively. Global risk algorithms that include hsCRP outperform those solely using Framingham covariates. Although diet, exercise, and smoking cessation are first steps for patients with a proinflammatory response, JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial data demonstrate that statins reduce by 47% the rate of first myocardial infarction, stroke, or confirmed cardiovascular death when given to patients with low-density lipoprotein-C levels of <130 mg/dl and hsCRP of >2 mg/l (hazard ratio: 0.53; 95% confidence interval: 0.40 to 0.69; p < 0.00001). In current U.S. guidelines, hsCRP carries a class IIb assessment and is most appropriate in primary prevention when clinical decisions to initiate statin therapy are uncertain. Ongoing multinational trials are pursuing whether reducing inflammation will decrease vascular event rates (41).

Beyond Coronary Calcification, Family History, and C-Reactive Protein: Cholesterol Efflux Capacity and Cardiovascular Risk Prediction

P. Mody, et al.

Background

Cholesterol efflux capacity (CEC), which is a key step in the reverse cholesterol transport pathway, is independently associated with atherosclerotic cardiovascular disease (ASCVD). However, whether it predicts ASCVD beyond validated novel risk markers is unknown.

Objectives

This study assessed if CEC improved ACSVD risk prediction beyond using coronary artery calcium (CAC), family history (FH), and high-sensitivity C-reactive protein (hs-CRP).

Methods

CEC, CAC, self-reported FH, and hs-CRP were assessed among participants without baseline ASCVD who were enrolled in the Dallas Heart Study (DHS). ASCVD was defined as a first nonfatal myocardial infarction (MI) or stroke, coronary revascularization, or cardiovascular death, assessed over a median 9.4 years. Risk prediction was assessed using various modeling techniques and improvements in the c-statistic, the integrated discrimination index (IDI), and the net reclassification index (NRI).

Results

The mean age of the population (N = 1,972) was 45 years, 52% had CAC (>0), 31% had FH, and 58% had elevated hs-CRP (≥2 mg/l). CEC greater than the median was associated with a 50% reduced incidence of ASCVD in those with CAC (5.4% vs. 10.5%; p = 0.003), FH (5.8% vs. 10%; p = 0.05), and elevated hs-CRP (3.8% vs. 7.9%; p = 0.004). CEC improved all metrics of discrimination and reclassification when added to CAC (c-statistic, p = 0.004; IDI, p = 0.02; NRI: 0.38; 95% confidence interval [CI]: 0.13 to 0.53), FH (c-statistic, p = 0.006; IDI, p = 0.008; NRI: 0.38; 95% CI: 0.13 to 0.55), or elevated hs-CRP (c-statistic p = 0.008; IDI p = 0.02; NRI: 0.36; 95% CI: 0.12 to 0.52).

Conclusions

CEC improves ASCVD risk prediction beyond using CAC, FH, and hs-CRP and warrants consideration as a novel ASCVD risk marker (42).

Cardiac Sarcoidosis

Heparin-Induced Thrombocytopenia: A Comprehensive Clinical Review

B.S. Salter, et al.

Heparin-induced thrombocytopenia is a profoundly dangerous, potentially lethal, immunologically mediated adverse drug reaction to unfractionated heparin or, less commonly, to low–molecular weight heparin. In this comprehensive review, the authors highlight heparin-induced thrombocytopenia’s risk factors, clinical presentation, pathophysiology, diagnostic principles, and treatment. The authors place special emphasis on the management of patients requiring procedures using cardiopulmonary bypass or interventions in the catheterization laboratory. Clinical vigilance of this disease process is important to ensure its recognition, diagnosis, and treatment. Misdiagnosis of the syndrome, as well as misunderstanding of the disease process, continues to contribute to its morbidity and mortality (48).

Impact of the Timing of Metoprolol Administration During STEMI on Infarct Size and Ventricular Function

J.M. García-Ruiz, et al.

Background

Pre-reperfusion administration of intravenous (IV) metoprolol reduces infarct size in ST-segment elevation myocardial infarction (STEMI).

Objectives

This study sought to determine how this cardioprotective effect is influenced by the timing of metoprolol therapy having either a long or short metoprolol bolus-to-reperfusion interval.

Methods

We performed a post hoc analysis of the METOCARD-CNIC (effect of METOprolol of CARDioproteCtioN during an acute myocardial InfarCtion) trial, which randomized anterior STEMI patients to IV metoprolol or control before mechanical reperfusion. Treated patients were divided into short- and long-interval groups, split by the median time from 15 mg metoprolol bolus to reperfusion. We also performed a controlled validation study in 51 pigs subjected to 45 min ischemia/reperfusion. Pigs were allocated to IV metoprolol with a long (−25 min) or short (−5 min) pre-perfusion interval, IV metoprolol post-reperfusion (+60 min), or IV vehicle. Cardiac magnetic resonance (CMR) was performed in the acute and chronic phases in both clinical and experimental settings.

Results

For 218 patients (105 receiving IV metoprolol), the median time from 15 mg metoprolol bolus to reperfusion was 53 min. Compared with patients in the short-interval group, those with longer metoprolol exposure had smaller infarcts (22.9 g vs. 28.1 g; p = 0.06) and higher left ventricular ejection fraction (LVEF) (48.3% vs. 43.9%; p = 0.019) on day 5 CMR. These differences occurred despite total ischemic time being significantly longer in the long-interval group (214 min vs. 160 min; p < 0.001). There was no between-group difference in the time from symptom onset to metoprolol bolus. In the animal study, the long-interval group (IV metoprolol 25 min before reperfusion) had the smallest infarcts (day 7 CMR) and highest long-term LVEF (day 45 CMR).

Conclusions

In anterior STEMI patients undergoing primary angioplasty, the sooner IV metoprolol is administered in the course of infarction, the smaller the infarct and the higher the LVEF. These hypothesis-generating clinical data are supported by a dedicated experimental large animal study (49).

Invasive FFR and Noninvasive CFR in the Evaluation of Ischemia: What Is the Future?

N.P. Johnson, et al.

This review provides an integrative and forward-looking perspective on the gamut of coronary physiology for the diagnosis and management of atherosclerosis. Because clinical events serve as the ultimate gold standard, the future of all diagnostic tests, including invasive fractional flow reserve and noninvasive coronary flow reserve, depends on their ability to improve patient outcomes. Given the prominent role of acute coronary syndromes and invasive procedures in cardiology, we practically consider 2 broad categories of patients with coronary disease: acute and stable. For patients with acute coronary disease, coronary physiology may potentially refine treatment of the culprit lesion. For both patients with stable and acute nonculprit disease, reducing hard endpoints with revascularization potentially occurs at the severe end of the focal physiological spectrum, an area under-represented in existing trials. Nonepicardial disease and diffuse atherosclerosis remain underexplored aspects of coronary physiology for testing of novel treatments (50).

Kawasaki Disease

J.W. Newburger, et al.

Kawasaki disease is an acute, self-limited vasculitis of unknown etiology that occurs predominantly in infants and children. If not treated early with high-dose intravenous immunoglobulin, 1 in 5 children develop coronary artery aneurysms; this risk is reduced 5-fold if intravenous immunoglobulin is administered within 10 days of fever onset. Coronary artery aneurysms evolve dynamically over time, usually reaching a peak dimension by 6 weeks after illness onset. Almost all the morbidity and mortality occur in patients with giant aneurysms. Risk of myocardial infarction from coronary artery thrombosis is greatest in the first 2 years after illness onset. However, stenosis and occlusion progress over years. Indeed, Kawasaki disease is no longer a rare cause of acute coronary syndrome presenting in young adults. Both coronary artery bypass surgery and percutaneous intervention have been used to treat Kawasaki disease patients who develop myocardial ischemia as a consequence of coronary artery aneurysms and stenosis (51).

Long-Term Mortality After Coronary Revascularization in Nondiabetic Patients With Multivessel Disease

M. Chang, et al.

Background

In diabetic patients with multivessel coronary artery disease (CAD), the survival difference between coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) favors CABG. However, there are few data on the mortality difference between the 2 strategies in nondiabetic patients.

Objectives

This study performed a patient-level meta-analysis to compare the effect of CABG versus PCI with drug-eluting stents on long-term mortality in 1,275 nondiabetic patients with multivessel CAD.

Methods

Individual patient data from the SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) and the BEST (Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease) trials were pooled. The primary outcome was death from any cause.

Results

The median follow-up time was 61 months (interquartile range: 50 months to 62 months). The risk of death from any cause was significantly lower in the CABG group than in the PCI group (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.43 to 0.98; p = 0.039). A similar finding was observed for the risk of death from cardiac causes. The superiority of CABG over PCI was consistent across the major clinical subgroups. Likewise, the rate of myocardial infarction was remarkably lower after CABG than after PCI (HR: 0.40; 95% CI: 0.24 to 0.65; p < 0.001). However, the rate of stroke was not different between the 2 groups (HR: 1.13; 95% CI: 0.59 to 2.17; p = 0.714). The need for repeat revascularization was significantly lower in the CABG group than in the PCI group (HR: 0.55; 95% CI: 0.40 to 0.75; p < 0.001).

Conclusions

CABG, as compared with PCI with drug-eluting stents, significantly reduced the long-term risk of mortality in nondiabetic patients with multivessel CAD (52).

Long-Term P2Y₁₂-Receptor Antagonists in Post-Myocardial Infarction Patients: Facing a New Trilemma?

D. Alexopoulos, et al.

Physicians considering prescription of P2Y₁₂-receptor antagonist for long-term (>1 year) protection of patients post-myocardial infarction face the trilemma of selecting between clopidogrel, prasugrel, or ticagrelor. Differential ischemic benefits derived from relevant trials may assist in tailoring treatment, although the different bleeding definitions applied make any meaningful comparison of each agent’s bleeding potential very difficult. Considering the available data and recognizing the significant limitation of observations obtained thus far from subgroup analyses, prasugrel appears to provide higher anti-ischemic protection than clopidogrel. Ticagrelor seems to be an attractive option for patients with renal dysfunction, peripheral arterial disease, or following a brief P2Y₁₂-receptor antagonist interruption, whereas clopidogrel may be advised in the presence of cost and availability issues. As head-to-head comparative trials between P2Y₁₂-receptor antagonists are lacking, selection of a specific agent by the clinician should be made on the basis of critical appraisal of available large clinical datasets (53).

Long-Term Post-Discharge Risks in Older Survivors of Myocardial Infarction With and Without Out-of-Hospital Cardiac Arrest

C.B. Fordyce, et al.

Background

Out-of-hospital cardiac arrest (OHCA) associated with acute myocardial infarction (MI) confers high in-hospital mortality; however, among those patients who survive, little is known regarding their post-discharge mortality and health care use rates.

Objectives

The purpose of this study was to determine 1-year survival and readmission rates after hospital discharge of older MI survivors with and without OHCA.

Methods

Using linked Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines and Medicare data, this study analyzed 54,860 patients with MI who were older than 65 years of age and who had been discharged alive from 545 U.S. hospitals between April 2011 and December 2012. Multivariable models examined the associations between MI-associated OHCA and 1-year post-discharge mortality or all-cause readmission rates. Patients discharged to hospice were excluded, given their known poor prognosis.

Results

Following hospital discharge, compared with older MI survivors without OHCA (n = 54,219), those with OHCA (n = 641, 1.2%) were more likely to be younger, male, and smokers, but less likely to have diabetes, heart failure, or prior revascularization. OHCA patients presented more often with ST-segment elevation myocardial infarction (63.2% vs. 29.6%) and cardiogenic shock (29.0% vs. 2.2%); however, among in-hospital MI survivors, OHCA was not associated with 1-year post-discharge mortality (unadjusted 13.8% vs. 15.8%, p = 0.17, adjusted hazard ratio [HR]: 0.89; 95% confidence interval [CI]: 0.68 to 1.15). In contrast, MI survivors with OHCA actually had lower unadjusted and adjusted risk of the composite outcome of 1-year mortality or all-cause readmission than patients without OHCA (44.0% vs. 50.0%, p = 0.03, adjusted HR: 0.84; 95% CI: 0.72 to 0.97).

Conclusions

Among older patients with MI who survived to hospital discharge and were not discharged to hospice, those presenting with OHCA did not have higher 1-year mortality or health care use rates compared with those MI survivors without OHCA. These findings show that the early risk of adverse events in patients with OHCA does not persist after hospital discharge, and they support efforts to improve initial survival rates of older patients with MI and OHCA (54).

Management of Patients With NSTE-ACS: A Comparison of the Recent AHA/ACC and ESC Guidelines

F. Rodriguez, et al.

Non–ST-segment elevation acute coronary syndromes (NSTE-ACS) are the leading cause of morbidity and mortality from cardiovascular disease worldwide. The American Heart Association/American College of Cardiology and the European Society of Cardiology periodically release practice guidelines to guide clinicians in the management of NSTE-ACS, most recently in in 2014 and 2015, respectively. The present review compares and contrasts the 2 guidelines, with a focus on the strength of recommendation and level of evidence in the approach to initial presentation and diagnosis of NSTE-ACS, risk assessment, treatments, and systems of care. Important differences include the use of a rapid rule-out protocol with high-sensitivity troponin assays, a preference for prasugrel/ticagrelor and fondaparinux for anticoagulation therapy, and a preference for radial arterial access in the European Society of Cardiology guidelines compared with the American Heart Association/American College of Cardiology guidelines. We also highlight the similarities and differences in the guidelines for special patient populations and suggest areas of further study (55).

Medical Therapy With Versus Without Revascularization in Stable Patients With Moderate and Severe Ischemia: The Case for Community Equipoise

The Risk Continuum of Atherosclerosis and its Implications for Defining CHD by Coronary Angiography

A. Arbab-Zadeh, et al.

Patients undergoing coronary angiography for suspected coronary heart disease who are found to have coronary atherosclerotic disease with <50% diameter stenosis may carry a risk of adverse cardiac events similar to that in patients with single-vessel obstructive disease. Yet clinical practice guidelines offer no direction for managing symptomatic patients with nonobstructive coronary atherosclerosis because current diagnostic criteria for coronary heart disease are not met. Accordingly, secondary preventive measures are not endorsed, and their role is not defined in this setting. Available data suggest that we are missing the opportunity to provide effective preventive measures in millions of patients with nonobstructive coronary heart disease. The emergence of noninvasive coronary angiography in patients with suspected coronary heart disease provides the opportunity to transition from a categorical perspective on the presence or absence of coronary heart disease to accepting the risk continuum from atherosclerosis and its implications for diagnosis and management (65).

Transatlantic Comparison of ST-Segment Elevation Myocardial Infarction Guidelines: Insights From the United States and Europe

K.R. Bainey, et al.

ST-segment elevation myocardial infarction (STEMI) remains a significant global public health concern. Practice guidelines in both the United States and Europe have been major contributors to providing evidence-based care. Rapid advances in contemporary therapies mandate regular and timely updates to guideline recommendations. In the fall of 2012, the European Society of Cardiology published their latest guidelines for the management of STEMI. In 2013 (∼3 months later), the American College of Cardiology Foundation and the American Heart Association jointly published their most recent STEMI guideline statements. In this review, we compare the transatlantic guidelines, highlighting differences in their recommendations and the interpretation of evidence addressing STEMI care (66).

CVD Prevention & Health Promotion

A Comprehensive Lifestyle Peer Group–Based Intervention on Cardiovascular Risk Factors: The Randomized Controlled Fifty-Fifty Program

E. Gómez-Pardo, et al.

Background

Cardiovascular diseases stem from modifiable risk factors. Peer support is a proven strategy for many chronic illnesses. Randomized trials assessing the efficacy of this strategy for global cardiovascular risk factor modification are lacking.

Objectives

This study assessed the hypothesis that a peer group strategy would help improve healthy behaviors in individuals with cardiovascular risk factors.

Methods

A total of 543 adults 25 to 50 years of age with at least 1 risk factor were recruited; risk factors included hypertension (20%), overweight (82%), smoking (31%), and physical inactivity (81%). Subjects were randomized 1:1 to a peer group–based intervention group (IG) or a self-management control group (CG) for 12 months. Peer-elected leaders moderated monthly meetings involving role-play, brainstorming, and activities to address emotions, diet, and exercise. The primary outcome was mean change in a composite score related to blood pressure, exercise, weight, alimentation, and tobacco (Fuster-BEWAT score, 0 to 15). Multilevel models with municipality as a cluster variable were applied to assess differences between groups.

Results

Participants’ mean age was 42 ± 6 years, 71% were female, and they had a mean baseline Fuster-BEWAT score of 8.42 ± 2.35. After 1 year, the mean scores were significantly higher in the IG (n = 277) than in the CG (n = 266) (IG mean score: 8.84; 95% confidence interval [CI]: 8.37 to 9.32; CG mean score: 8.17; 95% CI: 7.55 to 8.79; p = 0.02). The increase in the overall score was significantly larger in the IG compared with the CG (difference: 0.75; 95% CI: 0.32 to 1.18; p = 0.02). The mean improvement in the individual components was uniformly greater in the IG, with a significant difference for the tobacco component.

Conclusions

The peer group intervention had beneficial effects on cardiovascular risk factors, with significant improvements in the overall score and specifically on tobacco cessation. A follow-up assessment will be performed 1 year after the final assessment reported here to determine long-term sustainability of the improvements associated with peer group intervention. (Peer-Group-Based Intervention Program [Fifty-Fifty]; NCT02367963) (67).

Aspirin and Cancer

P. Patrignani, et al.

The place of aspirin in primary prevention remains controversial, with North American and European organizations issuing contradictory treatment guidelines. More recently, the U.S. Preventive Services Task Force recommended “initiating low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and colorectal cancer in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years.” This recommendation reflects increasing evidence for a chemopreventive effect of low-dose aspirin against colorectal (and other) cancer. The intent of this paper is to review the evidence supporting a chemopreventive effect of aspirin, discuss its potential mechanism(s) of action, and provide a conceptual framework for assessing current guidelines in the light of ongoing studies (68).

Assessing the Impact of Medication Adherence on Long-Term Cardiovascular Outcomes

S. Bansilal, et al.

Background

Although guideline-recommended therapies reduce major adverse cardiovascular events (MACE) in patients after myocardial infarction (MI) or those with atherosclerotic disease (ATH), adherence is poor.

Objectives

The goal of this study was to determine the association between medication adherence levels and long-term MACE in these patients.

Methods

We queried the claims database of a large health insurer for patients hospitalized for MI or with ATH. The primary outcome measure was a composite of all-cause death, MI, stroke, or coronary revascularization. Using proportion of days covered for statins and angiotensin-converting enzyme inhibitors, patients were stratified as fully adherent (≥80%), partially adherent (≥40% to ≤79%), or nonadherent (<40%). Per-patient annual direct medical (ADM) costs were estimated by using unit costs from 2 national files.

Results

Data were analyzed for 4,015 post-MI patients and 12,976 patients with ATH. In the post-MI cohort, the fully adherent group had a significantly lower rate of MACE than the nonadherent (18.9% vs. 26.3%; hazard ratio [HR]: 0.73; p = 0.0004) and partially adherent (18.9% vs. 24.7%; HR: 0.81; p = 0.02) groups at 2 years. The fully adherent group had reduced per-patient ADM costs for MI hospitalizations of $369 and $440 compared with the partially adherent and nonadherent groups, respectively. In the ATH cohort, the fully adherent group had a significantly lower rate of MACE than the nonadherent (8.42% vs. 17.17%; HR: 0.56; p < 0.0001) and the partially adherent (8.42% vs. 12.18%; HR: 0.76; p < 0.0001) groups at 2 years. The fully adherent group had reduced per-patient ADM costs for MI hospitalizations of $371 and $907 compared with the partially adherent and nonadherent groups.

Conclusions

Full adherence to guideline-recommended therapies was associated with a lower rate of MACE and cost savings, with a threshold effect at >80% adherence in the post-MI population; at least a 40% level of long-term adherence needs to be maintained to continue to accrue benefit. Novel approaches to improve adherence may significantly reduce cardiovascular events (69).

Association Between a Social-Business Eating Pattern and Early Asymptomatic Atherosclerosis

J.L. Peñalvo, et al.

Background

The importance of a healthy diet in relation to cardiovascular health promotion is widely recognized. Identifying specific dietary patterns related to early atherosclerosis would contribute greatly to inform effective primary prevention strategies.

Objectives

This study sought to quantify the association between specific dietary patterns and presence and extent of subclinical atherosclerosis in a population of asymptomatic middle-aged adults.

Methods

The PESA (Progression of Early Subclinical Atherosclerosis) study enrolled 4,082 asymptomatic participants 40 to 54 years of age (mean age 45.8 years; 63% male) to evaluate the presence of subclinical atherosclerosis in multiple vascular territories. A fundamental objective of this cohort study was to evaluate the life-style–related determinants, including diet, on atherosclerosis onset and development. We conducted a cross-sectional analysis of baseline data, including detailed information on dietary habits obtained as part of the overall life-style and risk factor assessment, as well as a complete vascular imaging study that was performed blinded to the clinical information.

Results

Most PESA participants follow a Mediterranean (40% of participants) or a Western (41%) dietary pattern. A new pattern, identified among 19% of participants, was labeled as a social-business eating pattern, characterized by a high consumption of red meat, pre-made foods, snacks, alcohol, and sugar-sweetened beverages and frequent eating-out behavior. Participants following this pattern presented a significantly worse cardiovascular risk profile and, after adjustment for risk factors, increased odds of presenting subclinical atherosclerosis (odds ratio: 1.31; 95% confidence interval: 1.06 to 1.63) compared with participants following a Mediterranean diet.

Conclusions

A new social-business eating pattern, characterized by high consumption of red and processed meat, alcohol, and sugar-sweetened beverages, and by frequent snacking and eating out as part of an overall unhealthy life-style, is associated with an increased prevalence, burden, and multisite presence of subclinical atherosclerosis. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318) (70).

Exercise at the Extremes: The Amount of Exercise to Reduce Cardiovascular Events

T.M.H. Eijsvogels, et al.

Habitual physical activity and regular exercise training improve cardiovascular health and longevity. A physically active lifestyle is, therefore, a key aspect of primary and secondary prevention strategies. An appropriate volume and intensity are essential to maximally benefit from exercise interventions. This document summarizes available evidence on the relationship between the exercise volume and risk reductions in cardiovascular morbidity and mortality. Furthermore, the risks and benefits of moderate- versus high-intensity exercise interventions are compared. Findings are presented for the general population and cardiac patients eligible for cardiac rehabilitation. Finally, the controversy of excessive volumes of exercise in the athletic population is discussed (71).

Family-Based Approaches to Cardiovascular Health Promotion

R. Vedanthan, et al.

Cardiovascular disease is the leading cause of mortality in the world, and the increasing burden is largely a consequence of modifiable behavioral risk factors that interact with genomics and the environment. Continuous cardiovascular health promotion and disease prevention throughout the lifespan is critical, and the family is a central entity in this process. In this review, we describe the potential rationale and mechanisms that contribute to the importance of family for cardiovascular health promotion, focusing on: 1) mutual interdependence of the family system; 2) shared environment; 3) parenting style; 4) caregiver perceptions; and 5) genomics. We conclude that family-based approaches that target both caregivers and children, encourage communication among the family unit, and address the structural and environmental conditions in which families live and operate are likely to be the most effective approach to promote cardiovascular health. We describe lessons learned, future implications, and applications to ongoing and planned studies (72).

Heavy Metals, Cardiovascular Disease, and the Unexpected Benefits of Chelation Therapy

G.A. Lamas, et al.

This review summarizes evidence from 2 lines of research previously thought to be unrelated: the unexpectedly positive results of TACT (Trial to Assess Chelation Therapy), and a body of epidemiological data showing that accumulation of biologically active metals, such as lead and cadmium, is an important risk factor for cardiovascular disease. Considering these 2 areas of work together may lead to the identification of new, modifiable risk factors for atherosclerotic cardiovascular disease. We examine the history of chelation up through the report of TACT. We then describe work connecting higher metal levels in the body with the future risk of cardiovascular disease. We conclude by presenting a brief overview of a newly planned National Institutes of Health trial, TACT2, in which we will attempt to replicate the findings of TACT and to establish that removal of toxic metal stores from the body is a plausible mechanistic explanation for the benefits of edetate disodium treatment (73).

Testosterone and Cardiovascular Disease

R.A. Kloner, et al.

Testosterone (T) is the principal male sex hormone. As men age, T levels typically fall. Symptoms of low T include decreased libido, vasomotor instability, and decreased bone mineral density. Other symptoms may include depression, fatigue, erectile dysfunction, and reduced muscle strength/mass. Epidemiology studies show that low levels of T are associated with more atherosclerosis, coronary artery disease, and cardiovascular events. However, treating hypogonadism in the aging male has resulted in discrepant results in regard to its effect on cardiovascular events. Emerging studies suggest that T may have a future role in treating heart failure, angina, and myocardial ischemia. A large, prospective, long-term study of T replacement, with a primary endpoint of a composite of adverse cardiovascular events including myocardial infarction, stroke, and/or cardiovascular death, is needed. The Food and Drug Administration recently put additional restrictions on T replacement therapy labeling and called for additional studies to determine its cardiac safety (74).

Footnotes

Listen to this manuscript's audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.

American College of Cardiology Foundation

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(2016) Translation of Human-Induced Pluripotent Stem Cells: From Clinical Trial in a Dish to Precision Medicine. J Am Coll Cardiol 67:2161–2176.
OpenUrl FREE Full Text
↵
1. Francis G.S.,
2. Felker G.M.,
3. Tang W.H.W.
(2016) A Test in Context: Critical Evaluation of Natriuretic Peptide Testing in Heart Failure. J Am Coll Cardiol 67:330–337.
OpenUrl FREE Full Text
↵
1. Shimada Y.J.,
2. Tsugawa Y.,
3. Brown D.F.M.,
4. Hasegawa K.
(2016) Bariatric Surgery and Emergency Department Visits and Hospitalizations for Heart Failure Exacerbation: Population-Based, Self-Controlled Series. J Am Coll Cardiol 67:895–903.
OpenUrl FREE Full Text
↵
1. Wever-Pinzon O.,
2. Drakos S.G.,
3. McKellar S.H.,
4. et al.
(2016) Cardiac Recovery During Long-Term Left Ventricular Assist Device Support. J Am Coll Cardiol 68:1540–1553.
OpenUrl FREE Full Text
↵
1. Kosmala W.,
2. Rojek A.,
3. Przewlocka-Kosmala M.,
4. Wright L.,
5. Mysiak A.,
6. Marwick T.H.
(2016) Effect of Aldosterone Antagonism on Exercise Tolerance in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol 68:1823–1834.
OpenUrl FREE Full Text
↵
1. Reddy Y.N.V.,
2. Melenovsky V.,
3. Redfield M.M.,
4. Nishimura R.A.,
5. Borlaug B.A.
(2016) High-Output Heart Failure: A 15-Year Experience. J Am Coll Cardiol 68:473–482.
OpenUrl FREE Full Text
↵
1. Desai A.S.,
2. Claggett B.L.,
3. Packer M.,
4. et al.,
5. for the PARADIGM-HF Investigators
(2016) Influence of Sacubitril/Valsartan (LCZ696) on 30-Day Readmission After Heart Failure Hospitalization. J Am Coll Cardiol 68:241–248.
OpenUrl FREE Full Text
↵
1. Opitz C.F.,
2. Hoeper M.M.,
3. Gibbs J.S.R.,
4. et al.
(2016) Pre-Capillary, Combined, and Post-Capillary Pulmonary Hypertension: A Pathophysiological Continuum. J Am Coll Cardiol 68:368–378.
OpenUrl FREE Full Text
↵
1. Brooks G.C.,
2. Lee B.K.,
3. Rao R.,
4. et al.,
5. on behalf of the PREDICTS Investigators
(2016) Predicting Persistent Left Ventricular Dysfunction Following Myocardial Infarction: The PREDICTS Study. J Am Coll Cardiol 67:1186–1196.
OpenUrl FREE Full Text
↵
1. Tornvall P.,
2. Collste O.,
3. Ehrenborg E.,
4. Järnbert-Petterson H.
(2016) A Case-Control Study of Risk Markers and Mortality in Takotsubo Stress Cardiomyopathy. J Am Coll Cardiol 67:1931–1936.
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1. Mazzanti A.,
2. Ng K.,
3. Faragli A.,
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(2016) Arrhythmogenic Right Ventricular Cardiomyopathy: Clinical Course and Predictors of Arrhythmic Risk. J Am Coll Cardiol 68:2540–2550.
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1. Cremer P.C.,
2. Kumar A.,
3. Kontzias A.,
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(2016) Complicated Pericarditis: Understanding Risk Factors and Pathophysiology to Inform Imaging and Treatment. J Am Coll Cardiol 68:2311–2328.
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1. Garcia M.J.
(2016) Constrictive Pericarditis Versus Restrictive Cardiomyopathy? J Am Coll Cardiol 67:2061–2076.
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1. Geske J.B.,
2. Anavekar N.S.,
3. Nishimura R.A.,
4. Oh J.K.,
5. Gersh B.J.
(2016) Differentiation of Constriction and Restriction: Complex Cardiovascular Hemodynamics. J Am Coll Cardiol 68:2329–2347.
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1. Sorajja P.,
2. Pedersen W.A.,
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4. et al.
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1. Arbustini E.,
2. Favalli V.,
3. Narula N.,
4. Serio A.,
5. Grasso M.
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1. Weir-McCall J.R.,
2. Yeap P.M.,
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(2016) Left Ventricular Noncompaction: Anatomical Phenotype or Distinct Cardiomyopathy? J Am Coll Cardiol 68:2157–2165.
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2. Pontone G.,
3. Bogaert J.,
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1. Ferreira V.M.,
2. Marcelino M.,
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1. Japp A.G.,
2. Gulati A.,
3. Cook S.A.,
4. Cowie M.R.,
5. Prasad S.K.
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2. Eriksson U.,
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1. Finocchiaro G.,
2. Papadakis M.,
3. Robertus J.-L.,
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(2016) Etiology of Sudden Death in Sports: Insights From a United Kingdom Regional Registry. J Am Coll Cardiol 67:2108–2115.
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1. Elkayam U.,
2. Goland S.,
3. Pieper P.G.,
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1. Egbe A.C.,
2. Connolly H.M.,
3. McLeod C.J.,
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1. Serruys P.W.,
2. Ormiston J.,
3. van Geuns R.-J.,
4. et al.
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1. Ridker P.M.
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3. Khera A.,
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1. Birnie D.H.,
2. Nery P.B.,
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1. Lee J.M.,
2. Jung J.-H.,
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1. Ottani F.,
2. Latini R.,
3. Staszewsky L.,
4. et al.,
5. on behalf of the CYCLE Investigators
(2016) Cyclosporine A in Reperfused Myocardial Infarction: The Multicenter, Controlled, Open-Label CYCLE Trial. J Am Coll Cardiol 67:365–374.
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↵
1. Roolvink V.,
2. Ibáñez B.,
3. Ottervanger J.P.,
4. et al.,
5. on behalf of the EARLY-BAMI Investigators
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1. Salter B.S.,
2. Weiner M.M.,
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4. et al.
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1. García-Ruiz J.M.,
2. Fernández-Jiménez R.,
3. García-Alvarez A.,
4. et al.
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1. Johnson N.P.,
2. Gould K.L.,
3. Di Carli M.F.,
4. Taqueti V.R.
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1. Newburger J.W.,
2. Takahashi M.,
3. Burns J.C.
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1. Chang M.,
2. Ahn J.-M.,
3. Lee C.W.,
4. et al.
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1. Alexopoulos D.,
2. Xanthopoulou I.,
3. Moulias A.,
4. Lekakis J.
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2. Wang T.Y.,
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1. Rodriguez F.,
2. Mahaffey K.W.
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1. Stone G.W.,
2. Hochman J.S.,
3. Williams D.O.,
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1. Mancini G.B.J.,
2. Farkouh M.E.,
3. Brooks M.M.,
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1. Shah R.U.,
2. de Lemos J.A.,
3. Wang T.Y.,
4. et al.
(2016) Post-Hospital Outcomes of Patients With Acute Myocardial Infarction With Cardiogenic Shock: Findings From the NCDR. J Am Coll Cardiol 67:739–747.
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1. Vaduganathan M.,
2. Bhatt D.L.,
3. Cryer B.L.,
4. et al.,
5. on behalf of the COGENT Investigators
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1. Gaudino M.,
2. Tondi P.,
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4. et al.
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1. Jensen L.O.,
2. Thayssen P.,
3. Christiansen E.H.,
4. et al.,
5. for the SORT OUT IV Investigators
(2016) Safety and Efficacy of Everolimus- Versus Sirolimus-Eluting Stents: 5-Year Results From SORT OUT IV. J Am Coll Cardiol 67:751–762.
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1. Sardella G.,
2. Lucisano L.,
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1. Maeremans J.,
2. Walsh S.,
3. Knaapen P.,
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1. Kobayashi Y.,
2. Nam C.-W.,
3. Tonino P.A.L.,
4. et al.,
5. on behalf of the FAME Study Investigators
(2016) The Prognostic Value of Residual Coronary Stenoses After Functionally Complete Revascularization. J Am Coll Cardiol 67:1701–1711.
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1. Arbab-Zadeh A.,
2. Fuster V.
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1. Bainey K.R.,
2. Armstrong P.W.
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1. Gómez-Pardo E.,
2. Fernández-Alvira J.M.,
3. Vilanova M.,
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1. Patrignani P.,
2. Patrono C.
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1. Bansilal S.,
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1. Peñalvo J.L.,
2. Fernández-Friera L.,
3. López-Melgar B.,
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1. Eijsvogels T.M.H.,
2. Molossi S.,
3. Lee D.-C.,
4. Emery M.S.,
5. Thompson P.D.
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2. Bansilal S.,
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1. Lamas G.A.,
2. Navas-Acien A.,
3. Mark D.B.,
4. Lee K.L.
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1. Kloner R.A.,
2. Carson C. III.,
3. Dobs A.,
4. Kopecky S.,
5. Mohler E.R. III.
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[1] ↵
Troncone L.,
Luciani M.,
Coggins M.,
et al.
(2016) Aβ Amyloid Pathology Affects the Hearts of Patients With Alzheimer’s Disease: Mind the Heart. J Am Coll Cardiol 68:2395–2407.
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[2] Troncone L.,

[3] Luciani M.,

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[5] et al.

[6] ↵
Falk R.H.,
Alexander K.M.,
Liao R.,
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(2016) AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy. J Am Coll Cardiol 68:1323–1341.
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[7] Falk R.H.,

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[11] ↵
Joffre J.,
Potteaux S.,
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(2016) Genetic and Pharmacological Inhibition of TREM-1 Limits the Development of Experimental Atherosclerosis. J Am Coll Cardiol 68:2776–2793.
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[12] Joffre J.,

[13] Potteaux S.,

[14] Zeboudj L.,

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[16] ↵
Marian A.J.,
van Rooij E.,
Roberts R.
(2016) Genetics and Genomics of Single-Gene Cardiovascular Diseases: Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders. J Am Coll Cardiol 68:2831–2849.
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[17] Marian A.J.,

[18] van Rooij E.,

[19] Roberts R.

[20] ↵
Assimes T.L.,
Roberts R.
(2016) Genetics: Implications for Prevention and Management of Coronary Artery Disease. J Am Coll Cardiol 68:2797–2818.
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[22] Roberts R.

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Maurer M.S.,
Hanna M.,
Grogan M.,
et al.,
on behalf of the THAOS Investigators
(2016) Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol 68:161–172.
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[24] Maurer M.S.,

[25] Hanna M.,

[26] Grogan M.,

[27] et al.,

[28] on behalf of the THAOS Investigators

[29] ↵
Aguero J.,
Ishikawa K.,
Hadri L.,
et al.
(2016) Intratracheal Gene Delivery of SERCA2a Ameliorates Chronic Post-Capillary Pulmonary Hypertension: A Large Animal Model. J Am Coll Cardiol 67:2032–2046.
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[30] Aguero J.,

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[34] ↵
Libby P.,
Nahrendorf M.,
Swirski F.K.
(2016) Leukocytes Link Local and Systemic Inflammation in Ischemic Cardiovascular Disease: An Expanded “Cardiovascular Continuum” J Am Coll Cardiol 67:1091–1103.
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[35] Libby P.,

[36] Nahrendorf M.,

[37] Swirski F.K.

[38] ↵
Boon R.A.,
Jaé N.,
Holdt L.,
Dimmeler S.
(2016) Long Noncoding RNAs: From Clinical Genetics to Therapeutic Targets? J Am Coll Cardiol 67:1214–1226.
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Barwari T.,
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Mayr M.
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[44] Barwari T.,

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[47] ↵
Grogan M.,
Scott C.G.,
Kyle R.A.,
et al.
(2016) Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System. J Am Coll Cardiol 68:1014–1020.
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[49] Scott C.G.,

[50] Kyle R.A.,

[51] et al.

[52] ↵
Liang P.,
Sallam K.,
Wu H.,
et al.
(2016) Patient-Specific and Genome-Edited Induced Pluripotent Stem Cell–Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Brugada Syndrome. J Am Coll Cardiol 68:2086–2096.
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[53] Liang P.,

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[56] et al.

[57] ↵
Lam M.P.Y.,
Ping P.,
Murphy E.
(2016) Proteomics Research in Cardiovascular Medicine and Biomarker Discovery. J Am Coll Cardiol 68:2819–2830.
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[58] Lam M.P.Y.,

[59] Ping P.,

[60] Murphy E.

[61] ↵
Ussher J.R.,
Elmariah S.,
Gerszten R.E.,
Dyck J.R.B.
(2016) The Emerging Role of Metabolomics in the Diagnosis and Prognosis of Cardiovascular Disease. J Am Coll Cardiol 68:2850–2870.
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[62] Ussher J.R.,

[63] Elmariah S.,

[64] Gerszten R.E.,

[65] Dyck J.R.B.

[66] ↵
Sayed N.,
Liu C.,
Wu J.C.
(2016) Translation of Human-Induced Pluripotent Stem Cells: From Clinical Trial in a Dish to Precision Medicine. J Am Coll Cardiol 67:2161–2176.
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[67] Sayed N.,

[68] Liu C.,

[69] Wu J.C.

[70] ↵
Francis G.S.,
Felker G.M.,
Tang W.H.W.
(2016) A Test in Context: Critical Evaluation of Natriuretic Peptide Testing in Heart Failure. J Am Coll Cardiol 67:330–337.
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[71] Francis G.S.,

[72] Felker G.M.,

[73] Tang W.H.W.

[74] ↵
Shimada Y.J.,
Tsugawa Y.,
Brown D.F.M.,
Hasegawa K.
(2016) Bariatric Surgery and Emergency Department Visits and Hospitalizations for Heart Failure Exacerbation: Population-Based, Self-Controlled Series. J Am Coll Cardiol 67:895–903.
OpenUrl FREE Full Text

[75] Shimada Y.J.,

[76] Tsugawa Y.,

[77] Brown D.F.M.,

[78] Hasegawa K.

[79] ↵
Wever-Pinzon O.,
Drakos S.G.,
McKellar S.H.,
et al.
(2016) Cardiac Recovery During Long-Term Left Ventricular Assist Device Support. J Am Coll Cardiol 68:1540–1553.
OpenUrl FREE Full Text

[80] Wever-Pinzon O.,

[81] Drakos S.G.,

[82] McKellar S.H.,

[83] et al.

[84] ↵
Kosmala W.,
Rojek A.,
Przewlocka-Kosmala M.,
Wright L.,
Mysiak A.,
Marwick T.H.
(2016) Effect of Aldosterone Antagonism on Exercise Tolerance in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol 68:1823–1834.
OpenUrl FREE Full Text

[85] Kosmala W.,

[86] Rojek A.,

[87] Przewlocka-Kosmala M.,

[88] Wright L.,

[89] Mysiak A.,

[90] Marwick T.H.

[91] ↵
Reddy Y.N.V.,
Melenovsky V.,
Redfield M.M.,
Nishimura R.A.,
Borlaug B.A.
(2016) High-Output Heart Failure: A 15-Year Experience. J Am Coll Cardiol 68:473–482.
OpenUrl FREE Full Text

[92] Reddy Y.N.V.,

[93] Melenovsky V.,

[94] Redfield M.M.,

[95] Nishimura R.A.,

[96] Borlaug B.A.

[97] ↵
Desai A.S.,
Claggett B.L.,
Packer M.,
et al.,
for the PARADIGM-HF Investigators
(2016) Influence of Sacubitril/Valsartan (LCZ696) on 30-Day Readmission After Heart Failure Hospitalization. J Am Coll Cardiol 68:241–248.
OpenUrl FREE Full Text

[98] Desai A.S.,

[99] Claggett B.L.,

[100] Packer M.,

[101] et al.,

[102] for the PARADIGM-HF Investigators

[103] ↵
Opitz C.F.,
Hoeper M.M.,
Gibbs J.S.R.,
et al.
(2016) Pre-Capillary, Combined, and Post-Capillary Pulmonary Hypertension: A Pathophysiological Continuum. J Am Coll Cardiol 68:368–378.
OpenUrl FREE Full Text

[104] Opitz C.F.,

[105] Hoeper M.M.,

[106] Gibbs J.S.R.,

[107] et al.

[108] ↵
Brooks G.C.,
Lee B.K.,
Rao R.,
et al.,
on behalf of the PREDICTS Investigators
(2016) Predicting Persistent Left Ventricular Dysfunction Following Myocardial Infarction: The PREDICTS Study. J Am Coll Cardiol 67:1186–1196.
OpenUrl FREE Full Text

[109] Brooks G.C.,

[110] Lee B.K.,

[111] Rao R.,

[112] et al.,

[113] on behalf of the PREDICTS Investigators

[114] ↵
Tornvall P.,
Collste O.,
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Author Information

Abstract

Basic & Translational Research

Aβ Amyloid Pathology Affects the Hearts of Patients With Alzheimer’s Disease: Mind the Heart

Background

Objectives

Methods

Results

Conclusions

AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy

Genetic and Pharmacological Inhibition of TREM-1 Limits the Development of Experimental Atherosclerosis

Background

Objectives

Methods

Results

Conclusions

Genetics and Genomics of Single-Gene Cardiovascular Diseases: Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders

Genetics: Implications for Prevention and Management of Coronary Artery Disease

Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey)

Background

Objectives

Methods

Results

Conclusions

Intratracheal Gene Delivery of SERCA2a Ameliorates Chronic Post-Capillary Pulmonary Hypertension: A Large Animal Model

Background

Objectives

Methods

Results

Conclusions

Leukocytes Link Local and Systemic Inflammation in Ischemic Cardiovascular Disease: An Expanded “Cardiovascular Continuum”

Long Noncoding RNAs: From Clinical Genetics to Therapeutic Targets?

MicroRNAs in Cardiovascular Disease

Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System

Background

Objectives

Methods

Results

Conclusions

Patient-Specific and Genome-Edited Induced Pluripotent Stem Cell–Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Brugada Syndrome

Background

Objectives

Methods

Results

Conclusions

Proteomics Research in Cardiovascular Medicine and Biomarker Discovery

The Emerging Role of Metabolomics in the Diagnosis and Prognosis of Cardiovascular Disease

Translation of Human-Induced Pluripotent Stem Cells: From Clinical Trial in a Dish to Precision Medicine

Cardiac Failure

A Test in Context: Critical Evaluation of Natriuretic Peptide Testing in Heart Failure

Bariatric Surgery and Emergency Department Visits and Hospitalizations for Heart Failure Exacerbation: Population-Based, Self-Controlled Series

Background

Objectives

Methods

Results

Conclusions

Cardiac Recovery During Long-Term Left Ventricular Assist Device Support

Background

Objectives

Methods

Results

Conclusions

Effect of Aldosterone Antagonism on Exercise Tolerance in Heart Failure With Preserved Ejection Fraction

Background

Objectives

Methods

Results

Conclusions

High-Output Heart Failure: A 15-Year Experience

Background

Objectives

Methods

Results

Conclusions

Influence of Sacubitril/Valsartan (LCZ696) on 30-Day Readmission After Heart Failure Hospitalization

Background

Objectives

Methods