Journal of the American College of Cardiology
Editor-in-Chief’s Top Picks From 2016: Part One
Author + information
- Published online February 20, 2017.
Author Information
- Valentin Fuster, MD, PhD
Abstract
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
G.S. Francis, et al.
Circulating natriuretic peptide measurements have been used extensively over the past 15 years to diagnose and monitor patients with heart failure. We are still learning how complex the dynamics of natriuretic peptides can be in the interpretation of test results in individual patients. Although natriuretic peptide measurements are widely used in practice, there are questions regarding why these peptides may not necessarily track with blood volume or invasive hemodynamic measurements in individual patients. Interpretation of natriuretic peptide measurements will depend on many factors, including special patient populations, obesity, renal function, the state of congestion or decongestion, and whether patients are receiving specific therapies. Natriuretic peptide measurements have clearly revolutionized clinical care for patients with heart failure, but further research should provide insights to help use these measurements to individualize patient care beyond the current guidelines (16).
Bariatric Surgery and Emergency Department Visits and Hospitalizations for Heart Failure Exacerbation: Population-Based, Self-Controlled Series
Y.J. Shimada, et al.
Background
The United States is battling obesity and heart failure (HF) epidemics. Although studies have suggested relationships between obesity and HF morbidity, little is known regarding the effects of substantial weight reduction in obese patients with HF.
Objectives
This study investigated whether bariatric surgery is associated with a decreased rate of HF exacerbation.
Methods
We performed a self-controlled case series study of obese patients with HF who underwent bariatric surgery, using the population-based emergency department (ED) and inpatient sample in California, Florida, and Nebraska. Primary outcome was ED visit or hospitalization for HF exacerbation from 2005 to 2011. We used conditional logistic regression to compare the outcome event rate during sequential 12-month periods, using pre-surgery months 13 to 24 as the reference period.
Results
We identified 524 patients with HF who underwent bariatric surgery. During the reference period, 16.2% of patients had an ED visit or hospitalization for HF exacerbation. The rate remained unchanged in the subsequent 12-month pre-surgery period (15.3%; p = 0.67). In the first 12-month period after bariatric surgery, we observed a nonsignificantly reduced rate (12.0%; p = 0.052). However, the rate was significantly lower in the subsequent 13 to 24 months after bariatric surgery (9.9%; adjusted odds ratio: 0.57; p = 0.003). By contrast, there was no significant reduction in the rate of HF exacerbation among obese patients who underwent nonbariatric surgery (i.e., cholecystectomy, hysterectomy).
Conclusions
Our findings indicate that bariatric surgery is associated with a decline in the rate of HF exacerbation requiring ED evaluation or hospitalization among obese patients with HF (17).
Cardiac Recovery During Long-Term Left Ventricular Assist Device Support
O. Wever-Pinzon, et al.
Background
The number of centers with left ventricular assist device (LVAD) research programs focused on cardiac recovery is very small. Therefore, this phenomenon has been reported in real-world multi-center registries as a rare event.
Objectives
This study evaluated the incidence of cardiac recovery with an a priori LVAD implantation strategy of bridge-to-recovery (BTR) and constructed a recovery predictive model.
Methods
The study included LVAD recipients registered in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). Cardiac recovery was evaluated in BTR and non-BTR patients. A weighted score was derived and externally validated in patients of the Utah Cardiac Recovery (UCAR) program.
Results
Of 15,138 INTERMACS patients, cardiac recovery occurred in 192 (1.3%). The incidence of recovery was 11.2% (n = 14) in BTR compared with 1.2% (n = 178) in non-BTR patients (p < 0.0001). Independent predictors of recovery included: age <50 years, non-ischemic cardiomyopathy, time from cardiac diagnosis <2 years, absence of ICD, creatinine ≤1.2 mg/dl, and LVEDD <6.5 cm (c-index: 0.85; p < 0.0001). A weighted score termed I-CARS, effectively stratified patients based on their probability of recovery. I-CARS was validated in the UCAR cohort (n = 190) with good performance (AUC: 0.94; 95% CI: 0.91 to 0.98). One-year survival after LVAD explantation, available in INTERMACS for 21 (11%) patients, was 86%.
Conclusions
The incidence of cardiac recovery is higher in patients implanted with an a priori BTR strategy. We developed a simple tool to help identify patients in whom recovery is feasible. In BTR patients with favorable characteristics, I-CARS suggests a 24% probability of successful LVAD explantation. Large-scale studies to better address post-explantation outcomes are warranted (18).
Effect of Aldosterone Antagonism on Exercise Tolerance in Heart Failure With Preserved Ejection Fraction
W. Kosmala, et al.
Background
Impaired functional capacity is a hallmark of patients with heart failure with preserved ejection fraction (HFpEF). Despite the association of HFpEF with reduced myocardial compliance attributed to fibrosis, spironolactone has not been shown to alter outcomes—perhaps reflecting the heterogeneity of underlying pathological mechanisms.
Objectives
The authors sought to identify improvement in exercise capacity with spironolactone in the subset of patients with HFpEF with exercise-induced increase in ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e′) reflecting elevation of left ventricular (LV) filling pressure.
Methods
In this randomized, blinded, parallel-group, placebo-controlled trial, 150 subjects (age 67 ± 9 years) with exertional dyspnea (New York Heart Association functional class II to III, left ventricular ejection fraction >50%, diastolic dysfunction, and exertional E/e′ >13), excluding those with ischemic heart disease, were recruited in a tertiary cardiology center. Patients were randomized to 6 months of oral spironolactone 25 mg/day or matching placebo. Primary outcomes were improvements in peak oxygen uptake (VO2) and exertional E/e′ ratio, and secondary outcomes were improvements in exercise blood pressure response and global LV longitudinal strain.
Results
At follow-up, 131 patients completed therapy—64 taking spironolactone and 67 placebo. At baseline, subjects had substantial exercise limitation (peak VO2 64 ± 17% predicted). The spironolactone group showed improvement in exercise capacity (increment in peak VO2 [2.9 ml/min/kg (95% confidence interval [CI]: 1.9 to 3.9 ml/min/kg) vs. 0.3 ml/min/kg (95% CI: −0.5 to 1.1 ml/min/kg); p < 0.001], anaerobic threshold [2.0 ml/min/kg (95% CI: 0.9 to 3.2 ml/min/kg) vs. −0.9 ml/min/kg (95% CI: −3.4 to 1.6 ml/min/kg); p = 0.03], and O2 uptake efficiency [0.19 (95% CI: 0.06 to 0.31) vs. −0.07 (95% CI: −0.17 to 0.04); p = 0.002]), with reduction in exercise-induced increase in E/e′ (−3.0 [95% CI: −3.9 to −2.0] vs. 0.5 [95% CI: −0.6 to 1.6]; p < 0.001). There was a significant interaction of spironolactone and change in E/e′ on VO2 (p = 0.039).
Conclusions
In patients with HFpEF and abnormal diastolic response to exertion, improvement in exercise E/e′ mediates the beneficial effect of spironolactone on exercise capacity. Identification of exercise-induced increase in LV filling pressure in patients with HFpEF may define a subgroup with warranting trial of spironolactone (19).
High-Output Heart Failure: A 15-Year Experience
Y.N.V. Reddy, et al.
Background
High-output heart failure (HF) is an unusual cause of cardiac failure that has not been well-characterized.
Objectives
This study sought to characterize the etiologies, pathophysiology, clinical and hemodynamic characteristics, and outcomes of high-output HF in the modern era.
Methods
We performed a retrospective analysis of all consecutive patients referred to the Mayo Clinic catheterization laboratory for hemodynamic assessment between 2000 and 2014. Subjects with definite HF, as defined by the Framingham criteria, were compared to controls of similar age and sex.
Results
The most common etiologies of high-output HF (n = 120) were obesity (31%), liver disease (23%), arteriovenous shunts (23%), lung disease (16%), and myeloproliferative disorders (8%). Compared with controls (n = 24), subjects with high-output HF displayed eccentric left ventricular remodeling, greater natriuretic peptide activation, higher filling pressures, pulmonary hypertension, and increased cardiac output, despite similar ejection fraction. Elevated cardiac output in high-output HF patients was related to both lower arterial afterload (decreased systemic vascular resistance) and higher metabolic rate. Mortality was increased in high-output HF as compared with controls (hazard ratio: 3.4; 95% confidence interval: 1.6 to 7.6). Hemodynamics and outcomes were poorest amongst patients with the lowest systemic vascular resistance.
Conclusions
High-output HF is an important cause of clinical HF in the modern era that is related to excessive vasodilation, and most frequently caused by obesity, arteriovenous shunts, and liver disease. Given the high mortality and increasing prevalence of these comorbidities in Western countries, high-output HF must be considered in the differential diagnosis of patients presenting with dyspnea, congestion, and a normal ejection fraction (20).
Influence of Sacubitril/Valsartan (LCZ696) on 30-Day Readmission After Heart Failure Hospitalization
A.S. Desai, et al.
Background
Patients with heart failure (HF) are at high risk for hospital readmission in the first 30 days following HF hospitalization.
Objectives
This study sought to determine if treatment with sacubitril/valsartan (LCZ696) reduces rates of hospital readmission at 30-days following HF hospitalization compared with enalapril.
Methods
We assessed the risk of 30-day readmission for any cause following investigator-reported hospitalizations for HF in the PARADIGM-HF trial, which randomized 8,399 participants with HF and reduced ejection fraction to treatment with LCZ696 or enalapril.
Results
Accounting for multiple hospitalizations per patient, there were 2,383 investigator-reported HF hospitalizations, of which 1,076 (45.2%) occurred in subjects assigned to LCZ696 and 1,307 (54.8%) occurred in subjects assigned to enalapril. Rates of readmission for any cause at 30 days were 17.8% in LCZ696-assigned subjects and 21.0% in enalapril-assigned subjects (odds ratio: 0.74; 95% confidence interval: 0.56 to 0.97; p = 0.031). Rates of readmission for HF at 30-days were also lower in subjects assigned to LCZ696 (9.7% vs. 13.4%; odds ratio: 0.62; 95% confidence interval: 0.45 to 0.87; p = 0.006). The reduction in both all-cause and HF readmissions with LCZ696 was maintained when the time window from discharge was extended to 60 days and in sensitivity analyses restricted to adjudicated HF hospitalizations.
Conclusions
Compared with enalapril, treatment with LCZ696 reduces 30-day readmissions for any cause following discharge from HF hospitalization (21).
Pre-Capillary, Combined, and Post-Capillary Pulmonary Hypertension: A Pathophysiological Continuum
C.F. Opitz, et al.
Background
Pulmonary hypertension (PH) is hemodynamically classified as pre-capillary (as seen in idiopathic pulmonary arterial hypertension [IPAH]) or post-capillary (as seen in heart failure with preserved ejection fraction [HFpEF]). Overlaps between these conditions exist. Some patients present with risk factors for left heart disease but pre-capillary PH, whereas patients with HFpEF may have combined pre- and post-capillary PH.
Objectives
This study sought to further characterize similarities and differences among patient populations with either PH-HFpEF or IPAH.
Methods
We used registry data to analyze clinical characteristics, hemodynamics, and treatment responses in patients with typical IPAH (<3 risk factors for left heart disease; n = 421), atypical IPAH (≥3 risk factors for left heart disease; n = 139), and PH-HFpEF (n = 226) receiving PH-targeted therapy.
Results
Compared with typical IPAH, patients with atypical IPAH and PH-HFpEF were older, had a higher body mass index, had more comorbidities, and had a lower 6-min walking distance, whereas mean pulmonary artery pressure (46.9 ± 13.3 mm Hg vs. 43.9 ± 10.7 mm Hg vs. 45.7 ± 9.4 mm Hg, respectively) and cardiac index (2.3 ± 0.8 l/min/m2 vs. 2.2 ± 0.8 l/min/m2 vs. 2.2 ± 0.7 l/min/m2, respectively) were comparable among groups. After initiation of targeted PH therapies, all groups showed improvement in exercise capacity, functional class, and natriuretic peptides from baseline to 12 months, but treatment effects were less pronounced in patients with PH-HFpEF than typical IPAH; with atypical IPAH in between. Survival rates at 1, 3, and 5 years were almost identical for the 3 groups.
Conclusions
Patients with atypical IPAH share features of both typical IPAH and PH-HFpEF, suggesting that there may be a continuum between these conditions (22).
Predicting Persistent Left Ventricular Dysfunction Following Myocardial Infarction: The PREDICTS Study
G.C. Brooks, et al.
Background
Persistent severe left ventricular (LV) systolic dysfunction after myocardial infarction (MI) is associated with increased mortality and is a class I indication for implantation of a cardioverter-defibrillator.
Objectives
This study developed models and assessed independent predictors of LV recovery to >35% and ≥50% after 90-day follow-up in patients presenting with acute MI and severe LV dysfunction.
Methods
Our multicenter prospective observational study enrolled participants with ejection fraction (EF) of ≤35% at the time of MI (n = 231). Predictors for EF recovery to >35% and ≥50% were identified after multivariate modeling and validated in a separate cohort (n = 236).
Results
In the PREDICTS (PREDiction of ICd Treatment Study) study, 43% of patients had persistent EF ≤35%, 31% had an EF of 36% to 49%, and 26% had an EF ≥50%. The model that best predicted recovery of EF to >35% included EF at presentation, length of stay, prior MI, lateral wall motion abnormality at presentation, and peak troponin. The model that best predicted recovery of EF to ≥50% included EF at presentation, peak troponin, prior MI, and presentation with ventricular fibrillation or cardiac arrest. After predictors were transformed into point scores, the lowest point scores predicted a 9% and 4% probability of EF recovery to >35% and ≥50%, respectively, whereas profiles with the highest point scores predicted an 87% and 49% probability of EF recovery to >35% and ≥50%, respectively.
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?
E. Arbustini, et al.
Left ventricular noncompaction (LVNC) describes a ventricular wall anatomy characterized by prominent left ventricular (LV) trabeculae, a thin compacted layer, and deep intertrabecular recesses. Individual variability is extreme, and trabeculae represent a sort of individual “cardioprinting.” By itself, the diagnosis of LVNC does not coincide with that of a “cardiomyopathy” because it can be observed in healthy subjects with normal LV size and function, and it can be acquired and is reversible. Rarely, LVNC is intrinsically part of a cardiomyopathy; the paradigmatic examples are infantile tafazzinopathies. When associated with LV dilation and dysfunction, hypertrophy, or congenital heart disease, the genetic cause may overlap. The prevalence of LVNC in healthy athletes, its possible reversibility, and increasing diagnosis in healthy subjects suggests cautious use of the term LVNC cardiomyopathy, which describes the morphology but not the functional profile of the cardiomyopathy (30).
Left Ventricular Noncompaction: Anatomical Phenotype or Distinct Cardiomyopathy?
J.R. Weir-McCall, et al.
Background
There is considerable overlap between left ventricular noncompaction (LVNC) and other cardiomyopathies. LVNC has been reported in up to 40% of the general population, raising questions about whether it is a distinct pathological entity, a remodeling epiphenomenon, or merely an anatomical phenotype.
Objectives
The authors determined the prevalence and predictors of LVNC in a healthy population using 4 cardiac magnetic resonance imaging diagnostic criteria.
Methods
Volunteers >40 years of age (N = 1,651) with no history of cardiovascular disease (CVD), a 10-year risk of CVD < 20%, and a B-type natriuretic peptide level greater than their gender-specific median underwent magnetic resonance imaging scan as part of the TASCFORCE (Tayside Screening for Cardiac Events) study. LVNC ratios were measured on the horizontal and vertical long axis cine sequences. All individuals with a noncompaction ratio of ≥2 underwent short axis systolic and diastolic LVNC ratio measurements, and quantification of noncompacted and compacted myocardial mass ratios. Those who met all 4 criteria were considered to have LVNC.
Results
Of 1,480 participants analyzed, 219 (14.8%) met ≥1 diagnostic criterion for LVNC, 117 (7.9%) met 2 criteria, 63 (4.3%) met 3 criteria, and 19 (1.3%) met all 4 diagnostic criteria. There was no difference in demographic or allometric measures between those with and without LVNC. Long axis noncompaction ratios were the least specific, with current diagnostic criteria positive in 219 (14.8%), whereas the noncompacted to compacted myocardial mass ratio was the most specific, only being met in 61 (4.4%).
Conclusions
A significant proportion of an asymptomatic population free from CVD satisfy all currently used cardiac magnetic resonance imaging diagnostic criteria for LVNC, suggesting that those criteria have poor specificity for LVNC, or that LVNC is an anatomical phenotype rather than a distinct cardiomyopathy (31).
Long-Term Prognostic Value of Cardiac Magnetic Resonance in Left Ventricle Noncompaction: A Prospective Multicenter Study
D. Andreini, et al.
Background
Cardiac magnetic resonance (CMR) is useful for the diagnosis of left ventricular noncompaction (LVNC). However, there are limited data regarding its prognostic value.
Objectives
The goal of this study was to evaluate the prognostic relevance of CMR findings in patients with LVNC.
Methods
A total of 113 patients with an echocardiographic diagnosis of LVNC underwent CMR at 5 referral centers. CMR diagnostic criterion of LVNC (noncompacted/compacted ratio >2.3 in end-diastole) was confirmed in all patients. We performed left ventricular (LV) and right ventricular quantitative analysis and late gadolinium enhancement (LGE) assessments and analyzed the following LVNC diagnostic criteria: left ventricular noncompacted myocardial mass (LV-ncMM) >20% and >25%, total LV-ncMM index >15 g/m2, noncompacted/compacted ratio ≥3:1 ≥1 of segments 1 to 3 and 7 to 16 or ≥2:1 in at least 1 of segments 4 to 6 of the American Heart Association model. Outcome was a composite of thromboembolic events, heart failure hospitalizations, ventricular arrhythmias, and cardiac death.
Results
At a mean follow-up of 48 ± 24 months, cardiac events (CEs) occurred in 36 patients (16 heart failure hospitalizations, 10 ventricular arrhythmias, 5 cardiac deaths, and 5 thromboembolic events). LV dilation, impaired LV ejection fraction, and LV-ncMM >20% was significantly more frequent in patients with CEs. LV fibrosis was detected by using LGE in 11 cases. CMR predictors of CEs were LV dilation and LGE. LGE was associated with improved prediction of CEs, compared with clinical data and CMR functional parameters in all 3 models. No CEs occurred in patients without dilated cardiomyopathy and/or LGE.
Conclusions
In patients with LVNC evaluated by using CMR, the degree of LV trabeculation seems to have no prognostic impact over and above LV dilation, LV systolic dysfunction, and presence of LGE (32).
Pheochromocytoma Is Characterized by Catecholamine-Mediated Myocarditis, Focal and Diffuse Myocardial Fibrosis, and Myocardial Dysfunction
V.M. Ferreira, et al.
Background
Pheochromocytoma is associated with catecholamine-induced cardiac toxicity, but the extent and nature of cardiac involvement in clinical cohorts is not well-characterized.
Objectives
This study characterized the cardiac phenotype in patients with pheochromocytoma using cardiac magnetic resonance (CMR).
Methods
A total of 125 subjects were studied, including patients with newly diagnosed pheochromocytoma (n = 29), patients with previously surgically cured pheochromocytoma (n = 31), healthy control subjects (n = 51), and hypertensive control subjects (HTN) (n = 14), using CMR (1.5-T) cine, strain imaging by myocardial tagging, late gadolinium enhancement, and native T1 mapping (Shortened Modified Look-Locker Inversion recovery [ShMOLLI]).
Results
Patients who were newly diagnosed with pheochromocytoma, compared with healthy and HTN control subjects, had impaired left ventricular (LV) ejection fraction (<56% in 38% of patients), peak systolic circumferential strain (p < 0.05), and diastolic strain rate (p < 0.05). They had higher myocardial T1 (974 ± 25 ms, as compared with 954 ± 16 ms in healthy and 958 ± 23 ms in HTN subjects; p < 0.05), areas of myocarditis (median 22% LV with T1 >990 ms, as compared with 1% in healthy and 2% in HTN subjects; p < 0.05), and focal fibrosis (59% had nonischemic late gadolinium enhancement, as compared with 14% in HTN subjects). Post-operatively, impaired LV ejection fraction typically normalized, but systolic and diastolic strain impairment persisted. Focal fibrosis (median 5% LV) and T1 abnormalities (median 12% LV) remained, the latter of which may suggest some diffuse fibrosis. Previously cured patients demonstrated abnormal diastolic strain rate (p < 0.001), myocardial T1 (median 12% LV), and small areas of focal fibrosis (median 1% LV). LV mass index was increased in HTN compared with healthy control subjects (p < 0.05), but not in the 2 pheochromocytoma groups.
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
G. Finocchiaro, et al.
Background
Accurate knowledge of causes of sudden cardiac death (SCD) in athletes and its precipitating factors is necessary to establish preventative strategies.
Objectives
This study investigated causes of SCD and their association with intensive physical activity in a large cohort of athletes.
Methods
Between 1994 and 2014, 357 consecutive cases of athletes who died suddenly (mean 29 ± 11 years of age, 92% males, 76% Caucasian, 69% competitive) were referred to our cardiac pathology center. All subjects underwent detailed post-mortem evaluation, including histological analysis by an expert cardiac pathologist. Clinical information was obtained from referring coroners.
Results
Sudden arrhythmic death syndrome (SADS) was the most prevalent cause of death (n = 149 [42%]). Myocardial disease was detected in 40% of cases, including idiopathic left ventricular hypertrophy (LVH) and/or fibrosis (n = 59, 16%); arrhythmogenic right ventricular cardiomyopathy (ARVC) (13%); and hypertrophic cardiomyopathy (HCM) (6%). Coronary artery anomalies occurred in 5% of cases. SADS and coronary artery anomalies affected predominantly young athletes (≤ 35 years of age), whereas myocardial disease was more common in older individuals. SCD during intense exertion occurred in 61% of cases; ARVC and left ventricular fibrosis most strongly predicted SCD during exertion.
Conclusions
Conditions predisposing to SCD in sports demonstrate a significant age predilection. The strong association of ARVC and left ventricular fibrosis with exercise-induced SCD reinforces the need for early detection and abstinence from intense exercise. However, almost 40% of athletes die at rest, highlighting the need for complementary preventive strategies (37).
High-Risk Cardiac Disease in Pregnancy: Part I
U. Elkayam, et al.
The incidence of pregnancy in women with cardiovascular disease is rising, primarily due to the increased number of women with congenital heart disease reaching childbearing age and the changing demographics associated with advancing maternal age. Although most cardiac conditions are well tolerated during pregnancy and women can deliver safely with favorable outcomes, there are some cardiac conditions that have significant maternal and fetal morbidity and mortality. The purpose of this paper is to review the available published reports and provide recommendations on the management of women with high-risk cardiovascular conditions during pregnancy (38).
Thrombotic and Embolic Complications Associated With Atrial Arrhythmia After Fontan Operation: Role of Prophylactic Therapy
A.C. Egbe, et al.
Background
There are limited data about the risk of thrombotic and embolic complication (TEC) in adults with atrial arrhythmia after Fontan operation.
Objectives
This study sought to determine the risk of TEC in this population and the role of anticoagulation therapy in TEC prevention.
Methods
This was a retrospective review of adults with atrial arrhythmia after Fontan operation who were evaluated at the Mayo Clinic between 1994 to 2014. TEC was classified into 2 groups: systemic TEC, defined as intracardiac thrombus, ischemic stroke, or systemic arterial embolus; and nonsystemic TEC, defined as Fontan conduit/right atrial thrombus or pulmonary embolus. Patients were divided into 3 groups: anticoagulation, antiplatelet, and no therapy cohorts.
Results
We followed 278 patients, mean age 31 ± 9 years, for 88 ± 14 months (1,464 patient-years). Patient groups included antiplatelet (n = 181), anticoagulation (n = 91), and no therapy (n = 6). There were 97 TEC in 81 patients (29%); 32 were systemic, yielding an event rate of 2.1 systemic TEC per 100 patient-years, and 65 were nonsystemic TEC, yielding an event rate of 4.4 nonsystemic TEC per 100 patient-years. Prevalence of TEC was 18% and 55% at 5 and 10 years, respectively. Atriopulmonary connection was a risk factor for TEC (hazard ratio: 2.31; 95% confidence interval: 1.61 to 4.64), and TEC were associated with higher risk of death and hospitalization (p < 0.0001). Anticoagulation was protective against TEC and resulted in a reduction of TEC risk by 2.5 TEC per 100 patient-years. Anticoagulation was also associated with lower risk of death and hospitalization (p = 0.02). Bleeding complications occurred in 21 (7%) patients and were similar in all groups.
Conclusions
Anticoagulation was associated with lower TEC rate and lower risk of death and hospitalization, without a significant increase in bleeding risk. Perhaps anticoagulation should be the preferred preventive strategy (39).
Coronary Disease & Interventions
A Polylactide Bioresorbable Scaffold Eluting Everolimus for Treatment of Coronary Stenosis: 5-Year Follow-Up
P.W. Serruys, et al.
Background
Long-term benefits of coronary stenosis treatment with an everolimus-eluting bioresorbable scaffold are unknown.
Objectives
This study sought to evaluate clinical and imaging outcomes 5 years after bioresorbable scaffold implantation.
Methods
In the ABSORB multicenter, single-arm trial, 45 (B1) and 56 patients (B2) underwent coronary angiography, intravascular ultrasound (IVUS), and optical coherence tomography (OCT) at different times. At 5 years, 53 patients without target lesion revascularization underwent final imaging.
Results
Between 6 months/1 year and 5 years, angiographic luminal late loss remained unchanged (B1: 0.14 ± 19 mm vs. 0.13 ± 0.33 mm; p = 0.7953; B2: 0.23 ± 0.28 mm vs. 0.18 ± 0.32 mm; p = 0.5685). When patients with a target lesion revascularization were included, luminal late loss was 0.15 ± 0.20 mm versus 0.15 ± 0.24 mm (p = 0.8275) for B1 and 0.30 ± 0.37 mm versus 0.32 ± 0.48 mm (p = 0.8204) for B2. At 5 years, in-scaffold and -segment binary restenosis was 7.8% (5 of 64) and 12.5% (8 of 64). On IVUS, the minimum lumen area of B1 decreased from 5.23 ± 0.97 mm2 at 6 months to 4.89 ± 1.81 mm2 at 5 years (p = 0.04), but remained unchanged in B2 (4.95 ± 0.91 mm2 at 1 year to 4.84 ± 1.28 mm2 at 5 years; p = 0.5). At 5 years, struts were no longer discernable by OCT and IVUS. On OCT, the minimum lumen area in B1 decreased from 4.51 ± 1.28 mm2 at 6 months to 3.65 ± 1.39 mm2 at 5 years (p = 0.01), but remained unchanged in B2, 4.35 ± 1.09 mm2 at 1 year and 4.12 ± 1.38 mm2 at 5 years (p = 0.24). Overall, the 5-year major adverse cardiac event rate was 11.0%, without any scaffold thrombosis.
Conclusions
At 5 years, bioresorbable scaffold implantation in a simple stenotic lesion resulted in stable lumen dimensions and low restenosis and major adverse cardiac event rates. (ABSORB Clinical Investigation, Cohort B [ABSORB B]; NCT00856856) (40).
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
D.H. Birnie, et al.
Clinically manifest cardiac involvement occurs in perhaps 5% of patients with sarcoidosis. The 3 principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure. An estimated 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic cardiac involvement (clinically silent disease). In 2014, the first international guideline for the diagnosis and management of CS was published. In 7 patients with clinically manifest CS, the extent of left ventricular dysfunction seems to be the most important predictor of prognosis. There is controversy in published reports as to the outcome of patients with clinically silent CS. Despite a paucity of data, immunosuppression therapy (primarily with corticosteroids) has been advocated for the treatment of clinically manifest CS. Device therapy, primarily with implantable cardioverter-defibrillators, is often recommended for patients with clinically manifest disease (43).
Causes of Death Following PCI Versus CABG in Complex CAD: 5-Year Follow-Up of SYNTAX
M. Milojevic, et al.
Background
There are no data available on specific causes of death from randomized trials that have compared coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI).
Objectives
The purpose of this study was to investigate specific causes of death, and its predictors, after revascularization for complex coronary disease in patients.
Methods
An independent Clinical Events Committee consisting of expert physicians who were blinded to the study treatment subclassified causes of death as cardiovascular (cardiac and vascular), noncardiovascular, or undetermined according to the trial protocol. Cardiac deaths were classified as sudden cardiac, related to myocardial infarction (MI), and other cardiac deaths.
Results
In the randomized cohort, there were 97 deaths after CABG and 123 deaths after PCI during a 5-year follow-up. After CABG, 49.4% of deaths were cardiovascular, with the greatest cause being heart failure, arrhythmia, or other causes (24.6%), whereas after PCI, the majority of deaths were cardiovascular (67.5%) and as a result of MI (29.3%). The cumulative incidence rates of all-cause death were not significantly different between CABG and PCI (11.4% vs. 13.9%, respectively; p = 0.10), whereas there were significant differences in terms of cardiovascular (5.8% vs. 9.6%, respectively; p = 0.008) and cardiac death (5.3% vs. 9.0%, respectively; p = 0.003), which were caused primarily by a reduction in MI-related death with CABG compared with PCI (0.4% vs. 4.1%, respectively; p <0.0001). Treatment with PCI versus CABG was an independent predictor of cardiac death (hazard ratio: 1.55; 95% confidence interval: 1.09 to 2.33; p = 0.045). The difference in MI-related death was seen largely in patients with diabetes, 3-vessel disease, or high SYNTAX (TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries) trial scores.
Conclusions
During a 5-year follow-up, CABG in comparison with PCI was associated with a significantly reduced rate of MI-related death, which was the leading cause of death after PCI. Treatments following PCI should target reducing post-revascularization spontaneous MI. Furthermore, secondary preventive medication remains essential in reducing events post-revascularization. (TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX]; NCT00114972) (44).
Coronary Flow Reserve and Microcirculatory Resistance in Patients With Intermediate Coronary Stenosis
J.M. Lee, et al.
Background
The prognostic impact of microvascular status in patients with high fractional flow reserve (FFR) is not clear.
Objectives
The goal of this study was to investigate the implications of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) in patients who underwent FFR measurement.
Methods
Patients with high FFR (>0.80) were grouped according to CFR (≤2) and IMR (≥23 U) levels: group A, high CFR with low IMR; group B, high CFR with high IMR; group C, low CFR with low IMR; and group D, low CFR with high IMR. Patient-oriented composite outcome (POCO) of any death, myocardial infarction, and revascularization was assessed. The median follow-up was 658 days (interquartile range: 503.8 to 1,139.3 days).
Results
A total of 313 patients (663 vessels) were assessed with FFR, CFR, and IMR. Correlation (r = 0.201; p < 0.001) and categorical agreement (kappa value = 0.178; p < 0.001) between FFR and CFR were modest. Low CFR was associated with higher POCO than high CFR (p = 0.034). There were no significant differences in clinical and angiographic characteristics among groups. Patients with high IMR with low CFR had the highest POCO (p = 0.002). Overt microvascular disease (p = 0.008), multivessel disease (p = 0.033), and diabetes mellitus (p = 0.033) were independent predictors of POCO. Inclusion of a physiological index significantly improved the discriminant function of a predictive model (relative integrated discrimination improvement 0.467 [p = 0.037]; category-free net reclassification index 0.648 [p = 0.007]).
Conclusions
CFR and IMR improved the risk stratification of patients with high FFR. Low CFR with high IMR was associated with poor prognosis. (Clinical, Physiological and Prognostic Implication of Microvascular Status; NCT02186093) (45).
Cyclosporine A in Reperfused Myocardial Infarction: The Multicenter, Controlled, Open-Label CYCLE Trial
F. Ottani, et al.
Background
Whether cyclosporine A (CsA) has beneficial effects in reperfused myocardial infarction (MI) is debated.
Objectives
This study investigated whether CsA improved ST-segment resolution in a randomized, multicenter phase II study.
Methods
The authors randomly assigned 410 patients from 31 cardiac care units, age 63 ± 12 years, with large ST-segment elevation MI within 6 h of symptom onset, Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 to 1 in the infarct-related artery, and committed to primary percutaneous coronary intervention, to 2.5 mg/kg intravenous CsA (n = 207) or control (n = 203) groups. The primary endpoint was incidence of ≥70% ST-segment resolution 60 min after TIMI flow grade 3. Secondary endpoints included high-sensitivity cardiac troponin T (hs-cTnT) on day 4, left ventricular (LV) remodeling, and clinical events at 6-month follow-up.
Results
Time from symptom onset to first antegrade flow was 180 ± 67 min; a median of 5 electrocardiography leads showed ST-segment deviation (quartile [Q]1 to Q3: 4 to 6); 49.8% of MIs were anterior. ST-segment resolution ≥70% was found in 52.0% of CsA patients and 49.0% of controls (p = 0.55). Median hs-cTnT on day 4 was 2,160 (Q1 to Q3: 1,087 to 3,274) ng/l in CsA and 2,068 (1,117 to 3,690) ng/l in controls (p = 0.85). The 2 groups did not differ in LV ejection fraction on day 4 and at 6 months. Infarct site did not influence CsA efficacy. There were no acute allergic reactions or nonsignificant excesses of 6-month mortality (5.7% CsA vs. 3.2% controls, p = 0.17) or cardiogenic shock (2.4% CsA vs. 1.5% controls, p = 0.33).
Conclusions
In the CYCLE (CYCLosporinE A in Reperfused Acute Myocardial Infarction) trial, a single intravenous CsA bolus just before primary percutaneous coronary intervention had no effect on ST-segment resolution or hs-cTnT, and did not improve clinical outcomes or LV remodeling up to 6 months. (CYCLosporinE A in Reperfused Acute Myocardial Infarction [CYCLE]; NCT01650662; EudraCT number 2011-002876-18) (46).
Early Intravenous Beta-Blockers in Patients With ST-Segment Elevation Myocardial Infarction Before Primary Percutaneous Coronary Intervention
V. Roolvink, et al.
Background
The impact of intravenous (IV) beta-blockers before primary percutaneous coronary intervention (PPCI) on infarct size and clinical outcomes is not well established.
Objectives
This study sought to conduct the first double-blind, placebo-controlled international multicenter study testing the effect of early IV beta-blockers before PPCI in a general ST-segment elevation myocardial infarction (STEMI) population.
Methods
STEMI patients presenting <12 h from symptom onset in Killip class I to II without atrioventricular block were randomized 1:1 to IV metoprolol (2 × 5-mg bolus) or matched placebo before PPCI. Primary endpoint was myocardial infarct size as assessed by cardiac magnetic resonance imaging (CMR) at 30 days. Secondary endpoints were enzymatic infarct size and incidence of ventricular arrhythmias. Safety endpoints included symptomatic bradycardia, symptomatic hypotension, and cardiogenic shock.
Results
A total of 683 patients (mean age 62 ± 12 years; 75% male) were randomized to metoprolol (n = 336) or placebo (n = 346). CMR was performed in 342 patients (54.8%). Infarct size (percent of left ventricle [LV]) by CMR did not differ between the metoprolol (15.3 ± 11.0%) and placebo groups (14.9 ± 11.5%; p = 0.616). Peak and area under the creatine kinase curve did not differ between both groups. LV ejection fraction by CMR was 51.0 ± 10.9% in the metoprolol group and 51.6 ± 10.8% in the placebo group (p = 0.68). The incidence of malignant arrhythmias was 3.6% in the metoprolol group versus 6.9% in placebo (p = 0.050). The incidence of adverse events was not different between groups.
Conclusions
In a nonrestricted STEMI population, early intravenous metoprolol before PPCI was not associated with a reduction in infarct size. Metoprolol reduced the incidence of malignant arrhythmias in the acute phase and was not associated with an increase in adverse events. (Early-Beta blocker Administration before reperfusion primary PCI in patients with ST-elevation Myocardial Infarction [EARLY-BAMI]; EudraCT no: 2010-023394-19) (47).
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
G.W. Stone, et al.
All patients with stable ischemic heart disease (SIHD) should be managed with guideline-directed medical therapy (GDMT), which reduces progression of atherosclerosis and prevents coronary thrombosis. Revascularization is also indicated in patients with SIHD and progressive or refractory symptoms, despite medical management. Whether a strategy of routine revascularization (with percutaneous coronary intervention or coronary artery bypass graft surgery as appropriate) plus GDMT reduces rates of death or myocardial infarction, or improves quality of life compared to an initial approach of GDMT alone in patients with substantial ischemia is uncertain. Opinions run strongly on both sides, and evidence may be used to support either approach. Careful review of the data demonstrates the limitations of our current knowledge, resulting in a state of community equipoise. The ongoing ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) is being performed to determine the optimal approach to managing patients with SIHD, moderate-to-severe ischemia, and symptoms that can be controlled medically. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522) (56).
Medical Treatment and Revascularization Options in Patients With Type 2 Diabetes and Coronary Disease
G.B.J. Mancini, et al.
Background
There are scant outcomes data in patients with type 2 diabetes and stable coronary artery disease (CAD) stratified by detailed angiographic burden of CAD or left ventricular ejection fraction (LVEF).
Objectives
This study determined the effect of optimal medical therapy (OMT), with or without percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), on long-term outcomes with respect to LVEF and number of diseased vessels, including proximal left anterior descending artery involvement.
Methods
A patient-level pooled analysis was undertaken in 3 federally-funded trials. The primary endpoint was the composite of death, myocardial infarction (MI), or stroke, adjusted for trial and randomization strategy.
Results
Among 5,034 subjects, 15% had LVEF <50%, 77% had multivessel CAD, and 28% had proximal left anterior descending artery involvement. During a median 4.5-year follow-up, CABG + OMT was superior to PCI + OMT for the primary endpoint (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.59 to 0.85; p = 0.0002), death (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.024), and MI (HR: 0.50; 95% CI: 0.38 to 0.67; p = 0.0001), but not stroke (HR: 1.54; 95% CI: 0.96 to 2.48; p = 0.074). CABG + OMT was also superior to OMT alone for prevention of the primary endpoint (HR: 0.79; 95% CI: 0.64 to 0.97; p = 0.022) and MI (HR: 0.55; 95% CI: 0.41 to 0.74; p = 0.0001), and was superior to PCI + OMT for the primary endpoint in patients with 3-vessel CAD (HR: 0.72; 95% CI: 0.58 to 0.89; p = 0.002) and normal LVEF (HR: 0.71; 95% CI: 0.58 to 0.87; p = 0.0012). There were no significant differences in OMT versus PCI + OMT.
Conclusions
CABG + OMT reduced the primary endpoint during long-term follow-up in patients with type 2 diabetes and stable CAD, supporting this as the preferred management strategy (57).
Post-Hospital Outcomes of Patients With Acute Myocardial Infarction With Cardiogenic Shock: Findings From the NCDR
R.U. Shah, et al.
Background
Many patients with acute myocardial infarction (AMI) and cardiogenic shock survive hospitalization; little is known about their subsequent prognosis.
Objectives
This study sought to evaluate the associations between cardiogenic shock and post-discharge mortality and all-cause hospitalization among hospital survivors.
Methods
We included patients ≥65 years of age with AMI from the ACTION Registry–GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With The Guidelines) who survived hospitalization and linked these patients with Medicare claims data. We used proportional hazards models to test the association between cardiogenic shock and outcomes, adjusting for patient and hospital characteristics. Hazard ratios (HRs) are reported for early (1 to 60 days) and late (61 to 365 days) post-discharge time periods.
Results
Among 112,668 AMI survivors, 5% had cardiogenic shock during hospitalization. The rate of death was significantly higher among patients with cardiogenic shock at 60 days (9.6% vs. 5.5%) and 1 year (22.4% vs. 16.7%). After accounting for baseline characteristics, the risk of death remained higher for cardiogenic shock patients in the first 60 days after discharge (adjusted HR: 1.62; 95% confidence interval [CI]: 1.46 to 1.80), but was similar to nonshock patients thereafter (adjusted HR: 1.08 for days 61 to 365; 95% CI: 1.00 to 1.18). The rate of all-cause hospitalization or death was significantly higher among shock patients at 60 days (33.9% vs. 24.9%) and 1 year (59.1% vs. 52.3%). After adjustment, the risk of this outcome was also clustered in the first 60 days (adjusted HR: 1.28; 95% CI: 1.21 to 1.35) and was similar thereafter (adjusted HR: 0.95 for days 61 to 365; 95% CI: 0.89 to 1.01).
Conclusions
Hospital survivors of AMI who had cardiogenic shock have a higher risk of death and/or hospitalization during the first year after discharge. The risk is time-dependent and is clustered in the early post-discharge period, after which the prognosis is similar in patients with and without cardiogenic shock (58).
Proton-Pump Inhibitors Reduce Gastrointestinal Events Regardless of Aspirin Dose in Patients Requiring Dual Antiplatelet Therapy
M. Vaduganathan, et al.
Background
The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) showed that proton-pump inhibitors (PPIs) safely reduced rates of gastrointestinal (GI) events in patients requiring dual antiplatelet therapy (DAPT). However, utilization of appropriate prophylactic PPI therapy remains suboptimal, especially with low-dose aspirin.
Objectives
The authors investigated the safety and efficacy of PPI therapy in patients receiving DAPT in low- and high-dose aspirin subsets.
Methods
Randomized patients with available aspirin dosing information in COGENT (N = 3,752) were divided into “low-dose” (≤100 mg) and “high-dose” (>100 mg) aspirin groups. The primary GI and cardiovascular endpoints were composite upper GI events and major adverse cardiac events, respectively. All events were adjudicated by independent, blinded gastroenterologists and cardiologists.
Results
Median duration of follow-up was 110 days. Low-dose aspirin users (n = 2,480; 66.1%) were more likely to be older, female, and have higher rates of peripheral artery disease, prior stroke, and hypertension, whereas high-dose aspirin users (n = 1,272; 33.9%) had higher rates of hyperlipidemia, smoking, a history of percutaneous coronary intervention, and were more than twice as likely to be enrolled from sites within the United States (80.4% vs. 39.8%). High-dose aspirin was associated with similar 180-day Kaplan-Meier estimates of adjudicated composite GI events (1.7% vs. 2.1%; adjusted hazard ratio: 0.88; 95% confidence interval: 0.46 to 1.66) and major adverse cardiac events (4.8% vs. 5.5%; adjusted hazard ratio: 0.73; 95% confidence interval: 0.48 to 1.11) compared with low-dose aspirin. Randomization to PPI therapy reduced 180-day Kaplan-Meier estimates of the primary GI endpoint in low-dose (1.2% vs. 3.1%) and high-dose aspirin subsets (0.9% vs. 2.6%; p for interaction = 0.80), and did not adversely affect the primary cardiovascular endpoint in either group.
Conclusions
Gastroprotection with PPI therapy should be utilized in appropriately selected patients with coronary artery disease requiring DAPT, even if the patients are on low-dose aspirin. (Clopidogrel and the Optimization of Gastrointestinal Events Trial [COGENT]; NCT00557921) (59).
Radial Artery as a Coronary Artery Bypass Conduit: 20-Year Results
M. Gaudino, et al.
Background
There is a lack of evidence for the choice of the second conduit in coronary surgery. The radial artery (RA) is a possible option, but few data on very-long-term outcomes exist.
Objectives
This study describes 20-year results of RA grafts used for coronary artery bypass grafting and the effects of RA removal on forearm circulation.
Methods
We report the results of the prospective 20-year follow-up of the first 100 consecutive patients who received the RA as a coronary bypass conduit at our institution.
Results
Follow-up was 100% complete. There were 64 deaths, 23 (35.9%) from cardiovascular causes. Kaplan-Meier 20-year survival was 31%. Of the 36 survivors, 33 (91.6%) underwent RA graft control at a mean of 19.0 ± 2.5 years after surgery. The RA was found to be patent in 24 cases (84.8% patency). In the overall population, probability of graft failure at 20 years was 19.0 ± 0.2% for the left internal thoracic artery (ITA), 25.0 ± 0.2% for the RA, and 55.0 ± 0.2% for the saphenous vein (p = 0.002 for RA vs. saphenous vein, 0.11 for RA vs. ITA, and p < 0.001 for ITA vs. saphenous vein). Target vessel stenosis >90%, but not location of distal anastomosis, significantly influenced long-term RA graft patency. No patients reported hand or forearm symptoms. The ulnar artery diameter was increased in the operated arm (2.44 ± 0.43 mm vs. 2.01 ± 0.47 mm; p < 0.05) and correlated with the peak systolic velocity of the second palmar digital artery (Pearson coefficient: 0.621; p < 0.05).
Conclusions
The 20-year patency rate of RA grafts is good, and not inferior to the ITA, especially when the conduit is used to graft a vessel with >90% stenosis. RA harvesting does not lead to hand or forearm symptoms, even at a very-long-term follow-up (60).
Safety and Efficacy of Everolimus- Versus Sirolimus-Eluting Stents: 5-Year Results From SORT OUT IV
L.O. Jensen, et al.
Background
Long-term safety and efficacy for everolimus-eluting stents (EES) versus those of sirolimus-eluting stents (SES) are unknown.
Objectives
This study compared 5-year outcomes for EES with those for SES from the SORT OUT IV (Scandinavian Organization for Randomized Trials with Clinical Outcome) trial.
Methods
Five-year follow-up was completed for 2,771 patients (99.9%). Primary endpoint was a composite of major adverse cardiac events (MACE), including cardiac death, myocardial infarction (MI), target vessel revascularization (TVR), and definite stent thrombosis.
Results
At 5-years, MACE occurred in 14.0% and 17.4% in the EES and SES groups, respectively (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.66 to 0.97; p = 0.02). The MACE rate did not differ significantly within the first year (HR: 0.96, 95% CI: 0.71 to 1.19; p = 0.79), but from years 1 through 5, the MACE rate was lower with EES (HR: 0.71, 95% CI: 0.55 to 0.90; p = 0.006; p interaction = 0.12). Definite stent thrombosis was lower with EES (0.4%) than with SES (2.0%; HR: 0.18, 95% CI: 0.07 to 0.46), with a lower risk of very late definite stent thrombosis in the EES group (0.2% vs. 1.4%, respectively; HR: 0.16, 95% CI: 0.05 to 0.53). When censoring the patients at the time of stent thrombosis, we found no significant differences between the 2 stent groups for MACE rates (HR: 0.89, 95% CI: 0.73 to 1.08; p = 0.23), target lesion revascularization (HR: 0.90, 95% CI: 0.64 to 1.27; p = 0.55), and MI (HR: 0.93, 95% CI: 0.64 to 1.36; p = 0.72).
Conclusions
At 5-year follow-up, MACE rate was significantly lower with EES- than with SES-treated patients, due largely due to a lower risk of very late definite stent thrombosis. (Randomized Clinical Comparison of the Xience V and the Cypher Coronary Stents in Non-selected Patients With Coronary Heart Disease [SORT OUT IV]; NCT00552877) (61).
Single-Staged Compared With Multi-Staged PCI in Multivessel NSTEMI Patients: The SMILE Trial
G. Sardella, et al.
Background
A lack of clarity exists about the role of complete coronary revascularization in patients presenting with non–ST-segment elevation myocardial infarction.
Objectives
The aim of our study was to compare long-term outcomes in terms of major adverse cardiovascular and cerebrovascular events of 2 different complete coronary revascularization strategies in patients with non–ST-segment elevation myocardial infarction and multivessel coronary artery disease: 1-stage percutaneous coronary intervention (1S-PCI) during the index procedure versus multistage percutaneous coronary intervention (MS-PCI) complete coronary revascularization during the index hospitalization.
Methods
In the SMILE (Impact of Different Treatment in Multivessel Non ST Elevation Myocardial Infarction Patients: One Stage Versus Multistaged Percutaneous Coronary Intervention) trial, 584 patients were randomly assigned in a 1:1 manner to 1S-PCI or MS-PCI. The primary study endpoint was the incidence of major adverse cardiovascular and cerebrovascular events, which were defined as cardiac death, death, reinfarction, rehospitalization for unstable angina, repeat coronary revascularization (target vessel revascularization), and stroke at 1 year.
Results
The occurrence of the primary endpoint was significantly lower in the 1-stage group (1S-PCI: n = 36 [13.63%] vs. MS-PCI: n = 61 [23.19%]; hazard ratio [HR]: 0.549 [95% confidence interval (CI): 0.363 to 0.828]; p = 0.004). The 1-year rate of target vessel revascularization was significantly higher in the MS-PCI group (1S-PCI: n = 22 [8.33%] vs. MS-PCI: n = 40 [15.20%]; HR: 0.522 [95% CI: 0.310 to 0.878]; p = 0.01; p log-rank = 0.013). When the analyses were limited to cardiac death (1S-PCI: n = 9 [3.41%] vs. MS-PCI: n = 14 [5.32%]; HR: 0.624 [95% CI: 0.270 to 1.441]; p = 0.27) and myocardial infarction (1S-PCI: n = 7 [2.65%] vs. MS-PCI: n = 10 [3.80%]; HR: 0.678 [95% CI: 0.156 to 2.657]; p = 0.46), no significant differences were observed between groups.
Conclusions
In multivessel non–ST-segment elevation myocardial infarction patients, complete 1-stage coronary revascularization is superior to multistage PCI in terms of major adverse cardiovascular and cerebrovascular events. (Impact of Different Treatment in Multivessel Non ST Elevation Myocardial Infarction [NSTEMI] Patients: One Stage Versus Multistaged Percutaneous Coronary Intervention [PCI] [SMILE]: NCT01478984) (62).
The Hybrid Algorithm for Treating Chronic Total Occlusions in Europe: The RECHARGE Registry
J. Maeremans, et al.
Background
The hybrid algorithm for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) was developed to improve procedural outcomes. Large, prospective studies validating the algorithm in a broad multicenter setting with operators of different experience levels are lacking.
Objectives
The RECHARGE (REgistry of Crossboss and Hybrid procedures in FrAnce, the NetheRlands, BelGium and UnitEd Kingdom) registry aims to report achievable results using the hybrid algorithm.
Methods
Between January 2014 and October 2015, consecutive patients undergoing hybrid CTO-PCI were prospectively enrolled in 17 centers. Procedural techniques, outcomes, and in-hospital complications were analyzed.
Results
A total of 1,253 CTO-PCIs were performed in 1,177 patients, of which 86% were men. Mean age was 66 ± 11 years. The average Japanese CTO score was 2.0 ± 1.0, and was higher in the failure group (2.6 ± 0.6 vs. 1.9 ± 1.0; p < 0.001). Overall procedure success was 86% and major in-hospital complications occurred in 2.6%. Antegrade wire escalation was the preferred primary strategy in 77%, followed by retrograde (17%) and antegrade dissection re-entry strategies (7%). Primary strategies were successful in 60%. Consecutive strategies were applied in 34% and were successful in 74%. Antegrade dissection re-entry and retrograde strategies were the most common bailout strategies and were successful in 67% and 62%, respectively. Median procedure and fluoroscopy time were 90 (interquartile range [IQR]: 60 to 120) min and 35 (IQR: 21 to 55) min, contrast volume was 250 (IQR: 180 to 340) ml, and radiation doses (air kerma and dose area product) were 1.6 (IQR: 1.0 to 2.7) Gy and 98 (IQR: 57 to 168) Gy·cm2, respectively.
Conclusions
High procedure and patient success rates, combined with a low event rate and improved procedural characteristics, support further use of the hybrid algorithm for a broad community of appropriately trained CTO operators (63).
The Prognostic Value of Residual Coronary Stenoses After Functionally Complete Revascularization
Y. Kobayashi, et al.
Background
The residual SYNTAX score (RSS) and SYNTAX revascularization index (SRI) quantitatively assess angiographic completeness of revascularization for patients with multivessel coronary artery disease. Whether residual angiographic disease remains of prognostic importance after “functionally” complete revascularization with fractional flow reserve (FFR) guidance is unknown.
Objectives
This study sought to investigate the prognostic value of the RSS and SRI after FFR-guided functionally complete revascularization.
Methods
From the FFR-guided percutaneous coronary intervention (PCI) cohort of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) trial, the RSS and SRI were calculated in 427 patients after functionally complete revascularization. The RSS was defined as the SYNTAX score (SS) recalculated after PCI. The SRI was calculated as: 100 × (1 − RSS/baseline SS) (%). We compared differences in 1- and 2-year outcomes among patients with RSS of 0, >0 to 4, >4 to 8, and >8, and with SRI of 100%, 50% to <100%, and 0 to <50%.
Results
The mean baseline SS, RSS, and SRI were 14.4 ± 7.2, 6.5 ± 5.8, and 55.1 ± 32.5%, respectively. Major adverse cardiac events (MACE) at 1 year occurred in 53 patients (12.4%). Patients with MACE had higher SS than those without (18.0 [interquartile range (IQR): 11.0 to 21.0] vs. 12.0 [IQR: 9.0 to 18.0], p = 0.001), but had similar RSS and SRI after PCI (RSS: 6.0 [IQR: 3.0 to 10.0] vs. 5.0 [IQR: 2.0 to 9.5], p = 0.51 and SRI: 60.0% [IQR: 40.9% to 78.9%] vs. 58.8% [IQR: 26.7% to 81.8%], p = 0.24, respectively). Kaplan-Meier analysis showed similar 1-year incidence of MACE with RSS/SRI stratifications (log-rank p = 0.55 and p = 0.54, respectively). Results were similar with 2-year outcome data analysis.
Conclusions
After functionally complete revascularization with FFR guidance, residual angiographic lesions that are not functionally significant do not reflect residual ischemia or predict a worse outcome, supporting functionally complete, rather than angiographically complete, revascularization. (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation [FAME]; NCT00267774) (64).
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).
- American College of Cardiology Foundation
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