Abstract

Origins of lifetime health around the time of conception: causes and consequences.

Fleming TP, Watkins AJ, Velazquez MA, Mathers JC, ... Gluckman PD, Godfrey KM
Parental environmental factors, including diet, body composition, metabolism, and stress, affect the health and chronic disease risk of people throughout their lives, as captured in the Developmental Origins of Health and Disease concept. Research across the epidemiological, clinical, and basic science fields has identified the period around conception as being crucial for the processes mediating parental influences on the health of the next generation. During this time, from the maturation of gametes through to early embryonic development, parental lifestyle can adversely influence long-term risks of offspring cardiovascular, metabolic, immune, and neurological morbidities, often termed developmental programming. We review periconceptional induction of disease risk from four broad exposures: maternal overnutrition and obesity; maternal undernutrition; related paternal factors; and the use of assisted reproductive treatment. Studies in both humans and animal models have demonstrated the underlying biological mechanisms, including epigenetic, cellular, physiological, and metabolic processes. We also present a meta-analysis of mouse paternal and maternal protein undernutrition that suggests distinct parental periconceptional contributions to postnatal outcomes. We propose that the evidence for periconceptional effects on lifetime health is now so compelling that it calls for new guidance on parental preparation for pregnancy, beginning before conception, to protect the health of offspring.

Lancet: 15 Apr 2018; epub ahead of print
Fleming TP, Watkins AJ, Velazquez MA, Mathers JC, ... Gluckman PD, Godfrey KM
Lancet: 15 Apr 2018; epub ahead of print | PMID: 29673874
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Abstract

Antithrombotic Therapy in Peripheral Artery Disease: Generating and Translating Evidence Into Practice.

Jones WS, Patel MR
Atherosclerotic cardiovascular (CV) disease remains a major health concern affecting more than 200 million adults worldwide, and lower extremity peripheral artery disease (PAD) is associated with significant morbidity and mortality. Treatment strategies to reduce the burden of major adverse CV events and limb events have mainly involved the use of antiplatelet and statin medications. Unlike other types of atherosclerotic CV disease, the evidence base is not well developed for therapies in patients with PAD. Recently, studies from subgroups of patients with PAD and a large clinical trial of PAD patients have been published, signaling a burgeoning interest in studying this higher risk population. This review outlines the inherent CV risks of patients with PAD, risk reduction strategies, emerging clinical trial data, and opportunities for the CV community to generate evidence in real-world settings and translate evidence into practice as new therapies become available.

J Am Coll Cardiol: 22 Jan 2018; 71:352-362
Jones WS, Patel MR
J Am Coll Cardiol: 22 Jan 2018; 71:352-362 | PMID: 29348028
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Abstract

Implications of Underlying Mechanisms for the Recognition and Management of Diabetic Cardiomyopathy.

Marwick TH, Ritchie R, Shaw JE, Kaye D
Heart failure is a complex clinical syndrome, the incidence and prevalence of which is increased in diabetes mellitus, pre-diabetes, and obesity. Although this may arise from underlying coronary artery disease, it often occurs in the absence of significant major epicardial coronary disease, and most commonly manifests as heart failure with preserved ejection fraction. Despite epidemiological evidence linking diabetes to heart failure incidence and outcome, the presence of a distinct primary \"diabetic\" cardiomyopathy has been difficult to prove, because the link between diabetes and heart failure is confounded by hypertension, microvascular dysfunction, and autonomic neuropathy. Nonetheless, several mechanistic associations at systemic, cardiac, and cellular/molecular levels explain different aspects of myocardial dysfunction, including impaired cardiac relaxation, compliance, and contractility. This review seeks to describe recent advances and limitations pertinent to integrating molecular mechanisms, clinical screening, and potential therapeutic avenues for this condition.

J Am Coll Cardiol: 22 Jan 2018; 71:339-351
Marwick TH, Ritchie R, Shaw JE, Kaye D
J Am Coll Cardiol: 22 Jan 2018; 71:339-351 | PMID: 29348027
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Abstract

Hypertension and Atrial Fibrillation: Doubts and Certainties From Basic and Clinical Studies.

Verdecchia P, Angeli F, Reboldi G
Hypertension and atrial fibrillation (AF) are 2 important public health priorities. Their prevalence is increasing worldwide, and the 2 conditions often coexist in the same patient. Hypertension and AF are strikingly related to an excess risk of cardiovascular disease and death. Hypertension ultimately increases the risk of AF, and because of its high prevalence in the population, it accounts for more cases of AF than other risk factors. Among patients with established AF, hypertension is present in about 60% to 80% of individuals. Despite the well-known association between hypertension and AF, several pathogenetic mechanisms underlying the higher risk of AF in hypertensive patients are still incompletely known. From an epidemiological standpoint, it is unclear whether the increasing risk of AF with blood pressure (BP) is linear or threshold. It is uncertain whether an intensive control of BP or the use of specific antihypertensive drugs, such as those inhibiting the renin-angiotensin-aldosterone system, reduces the risk of subsequent AF in hypertensive patients in sinus rhythm. Finally, in spite of the observational evidence suggesting a progressive relation between BP levels and the risk of thromboembolism and bleeding in patients with hypertension and AF, the extent to which BP should be lowered in these patients, including those who undergo catheter ablation, remains uncertain. This article summarizes the main basic mechanisms through which hypertension is believed to promote AF. It also explores epidemiological data supporting an evolutionary pathway from hypertension to AF, including the emerging evidence favoring an intensive BP control or the use of drugs, which inhibit the renin-angiotensin-aldosterone system to reduce the risk of AF. Finally, it examines the impact of non-vitamin K antagonist oral anticoagulants compared with warfarin in relation to hypertension.

Circ Res: 18 Jan 2018; 122:352-368
Verdecchia P, Angeli F, Reboldi G
Circ Res: 18 Jan 2018; 122:352-368 | PMID: 29348255
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Abstract

Translational Research in Cardiovascular Repair: A Call for a Paradigm Shift.

Chamuleau SAJ, van der Naald M, Climent AM, Kraaijeveld AO, ... Bolli R,
The international consortium TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes) has recently addressed key priorities in the field of cell-based therapy for cardiac repair, identifying the efficacy of translational research as one of the main challenges to ultimately improve the quality of life of patients with ischemic disease. Much of the controversy and confusion surrounding cardiac regenerative therapy stems from insufficient rigor in the conduct of preclinical studies, and there is an increasing recognition of a number of problems that undermine its quality that may contribute to translational failure. Here, we introduce well defined stages for preclinical research, and put forth proposals that should promote more rigorous preclinical work, in an effort to improve its quality and translatability. To augment the utility of preclinical research and its translation, it is necessary to (1) improve the quality of preclinical research, (2) promote collaborative efforts, and (3) enhance the sharing of knowledge and protocols. In particular, confirmatory (stage III) preclinical studies should be considered as a preamble to clinical studies and therefore must adhere to their standards of quality (including internal validity, standardization of protocols, and multicenter design). To increase transparency and minimize bias, these studies should be prospectively registered in an independent, open database. Ultimately, these recommendations should be implemented in the daily routine of investigators and in the policies of institutions, journals, and funding agencies.

Circ Res: 18 Jan 2018; 122:310-318
Chamuleau SAJ, van der Naald M, Climent AM, Kraaijeveld AO, ... Bolli R,
Circ Res: 18 Jan 2018; 122:310-318 | PMID: 29348252
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Abstract

Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling.

Dell\'Italia LJ, Collawn JF, Ferrario CM
Chymase is the most efficient Ang II (angiotensin II)-forming enzyme in the human body and has been implicated in a wide variety of human diseases that also implicate its many other protease actions. Largely thought to be the product of mast cells, the identification of other cellular sources including cardiac fibroblasts and vascular endothelial cells demonstrates a more widely dispersed production and distribution system in various tissues. Furthermore, newly emerging evidence for its intracellular presence in cardiomyocytes and smooth muscle cells opens an entirely new compartment of chymase-mediated actions that were previously thought to be limited to the extracellular space. This review illustrates how these multiple chymase-mediated mechanisms of action can explain the residual risk in clinical trials of cardiovascular disease using conventional renin-angiotensin system blockade.

Circ Res: 18 Jan 2018; 122:319-336
Dell'Italia LJ, Collawn JF, Ferrario CM
Circ Res: 18 Jan 2018; 122:319-336 | PMID: 29348253
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Abstract

NHLBI Working Group Recommendations to Reduce Lipoprotein(a)-Mediated Risk of Cardiovascular Disease and Aortic Stenosis.

Tsimikas S, Fazio S, Ferdinand KC, Ginsberg HN, ... Olive M, Liu L
Pathophysiological, epidemiological, and genetic studies provide strong evidence that lipoprotein(a) [Lp(a)] is a causal mediator of cardiovascular disease (CVD) and calcific aortic valve disease (CAVD). Specific therapies to address Lp(a)-mediated CVD and CAVD are in clinical development. Due to knowledge gaps, the National Heart, Lung, and Blood Institute organized a working group that identified challenges in fully understanding the role of Lp(a) in CVD/CAVD. These included the lack of research funding, inadequate experimental models, lack of globally standardized Lp(a) assays, and inadequate understanding of the mechanisms underlying current drug therapies on Lp(a) levels. Specific recommendations were provided to facilitate basic, mechanistic, preclinical, and clinical research on Lp(a); foster collaborative research and resource sharing; leverage expertise of different groups and centers with complementary skills; and use existing National Heart, Lung, and Blood Institute resources. Concerted efforts to understand Lp(a) pathophysiology, together with diagnostic and therapeutic advances, are required to reduce Lp(a)-mediated risk of CVD and CAVD.

J Am Coll Cardiol: 15 Jan 2018; 71:177-192
Tsimikas S, Fazio S, Ferdinand KC, Ginsberg HN, ... Olive M, Liu L
J Am Coll Cardiol: 15 Jan 2018; 71:177-192 | PMID: 29325642
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Abstract

Role of Invasive Functional Assessment in Surgical Revascularization of Coronary Artery Disease.

Baibhav B, Gedela M, Moulton M, Pavlides G, ... Siddique A, Chatzizisis YS
In patients with stable coronary artery disease, percutaneous coronary intervention is associated with improved outcomes if the lesion is deemed significant by invasive functional assessment using fractional flow reserve. Recent studies have shown that a revascularization strategy using instantaneous wave-free ratio is noninferior to fractional flow reserve in patients with intermediate-grade stenoses. The decision to perform coronary artery bypass grafting surgery is usually based on anatomic assessment of stenosis severity by coronary angiography. The data on the role of invasive functional assessment in guiding surgical revascularization are limited. In this review, we discuss the diagnostic and prognostic significance of invasive functional assessment in patients considered for coronary artery bypass grafting. In addition, we critically discuss ongoing and future clinical trials on the role of invasive functional assessment in surgical revascularization.

Circulation: 16 Apr 2018; 137:1731-1739
Baibhav B, Gedela M, Moulton M, Pavlides G, ... Siddique A, Chatzizisis YS
Circulation: 16 Apr 2018; 137:1731-1739 | PMID: 29661951
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Abstract

Cardiovascular Magnetic Resonance in Acute ST-Segment-Elevation Myocardial Infarction: Recent Advances, Controversies, and Future Directions.

Bulluck H, Dharmakumar R, Arai AE, Berry C, Hausenloy DJ
Although mortality after ST-segment elevation myocardial infarction (MI) is on the decline, the number of patients developing heart failure as a result of MI is on the rise. Apart from timely reperfusion by primary percutaneous coronary intervention, there is currently no established therapy for reducing MI size. Thus, new cardioprotective therapies are required to improve clinical outcomes after ST-segment-elevation MI. Cardiovascular magnetic resonance has emerged as an important imaging modality for assessing the efficacy of novel therapies for reducing MI size and preventing subsequent adverse left ventricular remodeling. The recent availability of multiparametric mapping cardiovascular magnetic resonance imaging has provided new insights into the pathophysiology underlying myocardial edema, microvascular obstruction, intramyocardial hemorrhage, and changes in the remote myocardial interstitial space after ST-segment-elevation MI. In this article, we provide an overview of the recent advances in cardiovascular magnetic resonance imaging in reperfused patients with ST-segment-elevation MI, discuss the controversies surrounding its use, and explore future applications of cardiovascular magnetic resonance in this setting.

Circulation: 30 Apr 2018; 137:1949-1964
Bulluck H, Dharmakumar R, Arai AE, Berry C, Hausenloy DJ
Circulation: 30 Apr 2018; 137:1949-1964 | PMID: 29712696
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Abstract

Atrial Fibrillation Burden: Moving Beyond Atrial Fibrillation as a Binary Entity: A Scientific Statement From the American Heart Association.

Chen LY, Chung MK, Allen LA, Ezekowitz M, ... Turakhia MP,
Our understanding of the risk factors and complications of atrial fibrillation (AF) is based mostly on studies that have evaluated AF in a binary fashion (present or absent) and have not investigated AF burden. This scientific statement discusses the published literature and knowledge gaps related to methods of defining and measuring AF burden, the relationship of AF burden to cardiovascular and neurological outcomes, and the effect of lifestyle and risk factor modification on AF burden. Many studies examine outcomes by AF burden classified by AF type (paroxysmal versus nonparoxysmal); however, quantitatively, AF burden can be defined by longest duration, number of AF episodes during a monitoring period, and the proportion of time an individual is in AF during a monitoring period (expressed as a percentage). Current guidelines make identical recommendations for anticoagulation regardless of AF pattern or burden; however, a review of recent evidence suggests that higher AF burden is associated with higher risk of stroke. It is unclear whether the risk increases continuously or whether a threshold exists; if a threshold exists, it has not been defined. Higher burden of AF is also associated with higher prevalence and incidence of heart failure and higher risk of mortality, but not necessarily lower quality of life. A structured and comprehensive risk factor management program targeting risk factors, weight loss, and maintenance of a healthy weight appears to be effective in reducing AF burden. Despite this growing understanding of AF burden, research is needed into validation of definitions and measures of AF burden, determination of the threshold of AF burden that results in an increased risk of stroke that warrants anticoagulation, and discovery of the mechanisms underlying the weak temporal correlations of AF and stroke. Moreover, developments in monitoring technologies will likely change the landscape of long-term AF monitoring and could allow better definition of the significance of changes in AF burden over time.

Circulation: 15 Apr 2018; epub ahead of print
Chen LY, Chung MK, Allen LA, Ezekowitz M, ... Turakhia MP,
Circulation: 15 Apr 2018; epub ahead of print | PMID: 29661944
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Abstract

Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Artery Disease.

Stone GW, Sabik JF, Serruys PW, Simonton CA, ... Kappetein AP, EXCEL Trial Investigators
Background Patients with obstructive left main coronary artery disease are usually treated with coronary-artery bypass grafting (CABG). Randomized trials have suggested that drug-eluting stents may be an acceptable alternative to CABG in selected patients with left main coronary disease. Methods We randomly assigned 1905 eligible patients with left main coronary artery disease of low or intermediate anatomical complexity to undergo either percutaneous coronary intervention (PCI) with fluoropolymer-based cobalt-chromium everolimus-eluting stents (PCI group, 948 patients) or CABG (CABG group, 957 patients). Anatomic complexity was assessed at the sites and defined by a Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score of 32 or lower (the SYNTAX score reflects a comprehensive angiographic assessment of the coronary vasculature, with 0 as the lowest score and higher scores [no upper limit] indicating more complex coronary anatomy). The primary end point was the rate of a composite of death from any cause, stroke, or myocardial infarction at 3 years, and the trial was powered for noninferiority testing of the primary end point (noninferiority margin, 4.2 percentage points). Major secondary end points included the rate of a composite of death from any cause, stroke, or myocardial infarction at 30 days and the rate of a composite of death, stroke, myocardial infarction, or ischemia-driven revascularization at 3 years. Event rates were based on Kaplan-Meier estimates in time-to-first-event analyses. Results At 3 years, a primary end-point event had occurred in 15.4% of the patients in the PCI group and in 14.7% of the patients in the CABG group (difference, 0.7 percentage points; upper 97.5% confidence limit, 4.0 percentage points; P=0.02 for noninferiority; hazard ratio, 1.00; 95% confidence interval, 0.79 to 1.26; P=0.98 for superiority). The secondary end-point event of death, stroke, or myocardial infarction at 30 days occurred in 4.9% of the patients in the PCI group and in 7.9% in the CABG group (P<0.001 for noninferiority, P=0.008 for superiority). The secondary end-point event of death, stroke, myocardial infarction, or ischemia-driven revascularization at 3 years occurred in 23.1% of the patients in the PCI group and in 19.1% in the CABG group (P=0.01 for noninferiority, P=0.10 for superiority). Conclusions In patients with left main coronary artery disease and low or intermediate SYNTAX scores by site assessment, PCI with everolimus-eluting stents was noninferior to CABG with respect to the rate of the composite end point of death, stroke, or myocardial infarction at 3 years. (Funded by Abbott Vascular; EXCEL ClinicalTrials.gov number, NCT01205776 .).

N Engl J Med: 30 Oct 2016; epub ahead of print
Stone GW, Sabik JF, Serruys PW, Simonton CA, ... Kappetein AP, EXCEL Trial Investigators
N Engl J Med: 30 Oct 2016; epub ahead of print | PMID: 27797291
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Abstract

COSCA (Core Outcome Set for Cardiac Arrest) in Adults: An Advisory Statement From the International Liaison Committee on Resuscitation.

Haywood K, Whitehead L, Nadkarni VM, Achana F, ... Perkins GD,
Cardiac arrest effectiveness trials have traditionally reported outcomes that focus on survival. A lack of consistency in outcome reporting between trials limits the opportunities to pool results for meta-analysis. The COSCA initiative (Core Outcome Set for Cardiac Arrest), a partnership between patients, their partners, clinicians, research scientists, and the International Liaison Committee on Resuscitation, sought to develop a consensus core outcome set for cardiac arrest for effectiveness trials. Core outcome sets are primarily intended for large, randomized clinical effectiveness trials (sometimes referred to as or ) rather than for pilot or efficacy studies. A systematic review of the literature combined with qualitative interviews among cardiac arrest survivors was used to generate a list of potential outcome domains. This list was prioritized through a Delphi process, which involved clinicians, patients, and their relatives/partners. An international advisory panel narrowed these down to 3 core domains by debate that led to consensus. The writing group refined recommendations for when these outcomes should be measured and further characterized relevant measurement tools. Consensus emerged that a core outcome set for reporting on effectiveness studies of cardiac arrest (COSCA) in adults should include survival, neurological function, and health-related quality of life. This should be reported as survival status and modified Rankin scale score at hospital discharge, at 30 days, or both. Health-related quality of life should be measured with ≥1 tools from Health Utilities Index version 3, Short-Form 36-Item Health Survey, and EuroQol 5D-5L at 90 days and at periodic intervals up to 1 year after cardiac arrest, if resources allow.

Circulation: 25 Apr 2018; epub ahead of print
Haywood K, Whitehead L, Nadkarni VM, Achana F, ... Perkins GD,
Circulation: 25 Apr 2018; epub ahead of print | PMID: 29700122
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Abstract

Domain Management Approach to Heart Failure in the Geriatric Patient: Present and Future.

Gorodeski EZ, Goyal P, Hummel SL, Krishnaswami A, ... Alexander KP,
Heart failure (HF) is a quintessential geriatric cardiovascular condition, with more than 50% of hospitalizations occurring in adults age 75 years or older. In older patients, HF is closely linked to processes inherent to aging, which include cellular and structural changes to the myocardium, vasculature, and skeletal muscle. In addition, HF cannot be considered in isolation of physical functioning, or without the social, psychological, and behavioral dimensions of illness. The role of frailty, depression, cognitive impairment, nutrition, and goals of care are each uniquely relevant to the implementation and success of medical therapy. In this paper, we discuss a model of caring for older adults with HF through a 4-domain framework that can address the unique multidimensional needs and vulnerabilities of this population. We believe that clinicians who embrace this approach can improve health outcomes for older adults with HF.

J Am Coll Cardiol: 30 Apr 2018; 71:1921-1936
Gorodeski EZ, Goyal P, Hummel SL, Krishnaswami A, ... Alexander KP,
J Am Coll Cardiol: 30 Apr 2018; 71:1921-1936 | PMID: 29699619
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Abstract

Medical Nutrition Education, Training, and Competencies to Advance Guideline-Based Diet Counseling by Physicians: A Science Advisory From the American Heart Association.

Aspry KE, Van Horn L, Carson JAS, Wylie-Rosett J, ... Kris-Etherton P,
Growing scientific evidence of the benefits of heart-healthy dietary patterns and of the massive public health and economic burdens attributed to obesity and poor diet quality have triggered national calls to increase diet counseling in outpatients with atherosclerotic cardiovascular disease or risk factors. However, despite evidence that physicians are willing to undertake this task and are viewed as credible sources of diet information, they engage patients in diet counseling at less than desirable rates and cite insufficient knowledge and training as barriers. These data align with evidence of large and persistent gaps in medical nutrition education and training in the United States. Now, major reforms in undergraduate and graduate medical education designed to incorporate advances in the science of learning and to better prepare physicians for 21st century healthcare delivery are providing a new impetus and novel ways to expand medical nutrition education and training. This science advisory reviews gaps in undergraduate and graduate medical education in nutrition in the United States, summarizes reforms that support and facilitate more robust nutrition education and training, and outlines new opportunities for accomplishing this goal via multidimensional curricula, pedagogies, technologies, and competency-based assessments. Real-world examples of efforts to improve undergraduate and graduate medical education in nutrition by integrating formal learning with practical, experiential, inquiry-driven, interprofessional, and population health management activities are provided. The authors conclude that enhancing physician education and training in nutrition, as well as increasing collaborative nutrition care delivery by 21st century health systems, will reduce the health and economic burdens from atherosclerotic cardiovascular disease to a degree not previously realized.

Circulation: 29 Apr 2018; epub ahead of print
Aspry KE, Van Horn L, Carson JAS, Wylie-Rosett J, ... Kris-Etherton P,
Circulation: 29 Apr 2018; epub ahead of print | PMID: 29712711
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Abstract

Cerebrovascular Events After Cardiovascular Procedures: Risk Factors, Recognition, and Prevention Strategies.

Devgun JK, Gul S, Mohananey D, Jones BM, ... Tuzcu EM, Kapadia SR
Stroke has long been a devastating complication of any cardiovascular procedure that unfavorably affects survival and quality of life. Over time, strategies have been developed to substantially reduce the incidence of stroke after traditional cardiovascular procedures such as coronary artery bypass grafting, isolated valve surgery, and carotid endarterectomy. Subsequently, with the advent of minimally invasive technologies including percutaneous coronary intervention, carotid artery stenting, and transcatheter valve therapies, operators were faced with a new host of procedural risk factors, and efforts again turned toward identifying novel ways to reduce the risk of stroke. Fortunately, by understanding the procedural factors unique to these new techniques and applying many of the lessons learned from prior experiences, we are seeing significant improvements in the safety of these new technologies. In this review, the authors: 1) carefully analyze data from different cardiac procedural experiences ranging from traditional open heart surgery to percutaneous coronary intervention and transcatheter valve therapies; 2) explore the unique risk factors for stroke in each of these areas; and 3) describe how these risks can be mitigated with improved patient selection, adjuvant pharmacotherapy, procedural improvements, and novel technological advancements.

J Am Coll Cardiol: 30 Apr 2018; 71:1910-1920
Devgun JK, Gul S, Mohananey D, Jones BM, ... Tuzcu EM, Kapadia SR
J Am Coll Cardiol: 30 Apr 2018; 71:1910-1920 | PMID: 29699618
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Abstract

Evaluation and Management of Right-Sided Heart Failure: A Scientific Statement From the American Heart Association.

Konstam MA, Kiernan MS, Bernstein D, Bozkurt B, ... Ward C,
The diverse causes of right-sided heart failure (RHF) include, among others, primary cardiomyopathies with right ventricular (RV) involvement, RV ischemia and infarction, volume loading caused by cardiac lesions associated with congenital heart disease and valvular pathologies, and pressure loading resulting from pulmonic stenosis or pulmonary hypertension from a variety of causes, including left-sided heart disease. Progressive RV dysfunction in these disease states is associated with increased morbidity and mortality. The purpose of this scientific statement is to provide guidance on the assessment and management of RHF.

Circulation: 11 Apr 2018; epub ahead of print
Konstam MA, Kiernan MS, Bernstein D, Bozkurt B, ... Ward C,
Circulation: 11 Apr 2018; epub ahead of print | PMID: 29650544
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Abstract

Cardiopulmonary Resuscitation in Infants and Children With Cardiac Disease: A Scientific Statement From the American Heart Association.

Marino BS, Tabbutt S, MacLaren G, Hazinski MF, ... Laussen PC,
Cardiac arrest occurs at a higher rate in children with heart disease than in healthy children. Pediatric basic life support and advanced life support guidelines focus on delivering high-quality resuscitation in children with normal hearts. The complexity and variability in pediatric heart disease pose unique challenges during resuscitation. A writing group appointed by the American Heart Association reviewed the literature addressing resuscitation in children with heart disease. MEDLINE and Google Scholar databases were searched from 1966 to 2015, cross-referencing pediatric heart disease with pertinent resuscitation search terms. The American College of Cardiology/American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. The recommendations in this statement concur with the critical components of the 2015 American Heart Association pediatric basic life support and pediatric advanced life support guidelines and are meant to serve as a resuscitation supplement. This statement is meant for caregivers of children with heart disease in the prehospital and in-hospital settings. Understanding the anatomy and physiology of the high-risk pediatric cardiac population will promote early recognition and treatment of decompensation to prevent cardiac arrest, increase survival from cardiac arrest by providing high-quality resuscitations, and improve outcomes with postresuscitation care.

Circulation: 22 Apr 2018; epub ahead of print
Marino BS, Tabbutt S, MacLaren G, Hazinski MF, ... Laussen PC,
Circulation: 22 Apr 2018; epub ahead of print | PMID: 29685887
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Abstract

The Alchemist\'s Nightmare: Might Mesenchymal Stem Cells That Are Recruited to Repair the Injured Heart Be Transformed Into Fibroblasts Rather Than Cardiomyocytes?

Packer M
The injection of mesenchymal stem cells into the injured myocardium to induce cardiac regeneration has yielded disappointing results, conceivably because cells with cardioreparative potential must be supplied for long periods of time to produce a salutary effect. Accordingly, investigators have devised ways of directing such cells to the heart on an ongoing basis: by enhancing the action of endogenous peptides that function as cardiac homing signals (eg, stromal cell-derived factor-1). Stromal cell-derived factor-1 is released during acute cardiac injury and heart failure, but it has a short half-life because of degradation by dipeptidyl peptidase-4. Inhibition of dipeptidyl peptidase-4 potentiates the actions of stromal cell-derived factor-1 and, theoretically, could enhance cardiac recovery. However, in large-scale trials in patients with type 2 diabetes mellitus, dipeptidyl peptidase-4 inhibitors have not reduced the risk of atherosclerotic ischemic events, and they have unexpectedly increased the risk of heart failure, most probably heart failure with a preserved ejection fraction. Such an outcome might be explained if the channeling of mesenchymal stem cells to the heart by the actions of stromal cell-derived factor-1 (especially from nearby adipose tissue) were followed by the transformation of these cells into fibroblasts rather than cardiomyocytes. This concern has been supported by experimental studies; the resulting fibrosis would be expected to exacerbate the pathophysiological derangements that lead to heart failure with a preserved ejection fraction. Given the widespread use of dipeptidyl peptidase-4 inhibitors, the possibility that these drugs potentiate the cardiac homing of mesenchymal stem cells that cause myocardial fibrosis (rather than repair) warrants further study.

Circulation: 07 May 2018; 137:2068-2073
Packer M
Circulation: 07 May 2018; 137:2068-2073 | PMID: 29735591
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Abstract

Myeloid cell contributions to cardiovascular health and disease.

Nahrendorf M
Recent advances in cell tracing and sequencing technologies have expanded our knowledge on leukocyte behavior. As a consequence, inflammatory cells, such as monocyte-derived macrophages, and their actions and products are increasingly being considered as potential drug targets for treatment of atherosclerosis, myocardial infarction and heart failure. Particularly promising developments are the identification of harmful arterial and cardiac macrophage subsets, the cells\' altered, sometimes even clonal production in hematopoietic organs, and epigenetically entrained memories of myeloid progenitors and macrophages in the setting of cardiovascular disease. Given the roles of monocytes and macrophages in host defense, intricately understanding the involved cellular subsets, sources and functions is essential for the design of precision therapeutics that preserve protective innate immunity. Here I review how new clinical and preclinical data, often linking the cardiovascular, immune and other organ systems, propel conceptual advances to a point where cardiovascular immunotherapy appears within reach.

Nat Med: 03 Jun 2018; epub ahead of print
Nahrendorf M
Nat Med: 03 Jun 2018; epub ahead of print | PMID: 29867229
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Abstract

Precision Profiling of the Cardiovascular Post-Translationally Modified Proteome: Where There Is a Will, There Is a Way.

Fert-Bober J, Murray CI, Parker SJ, Van Eyk JE
There is an exponential increase in biological complexity as initial gene transcripts are spliced, translated into amino acid sequence, and post-translationally modified. Each protein can exist as multiple chemical or sequence-specific proteoforms, and each has the potential to be a critical mediator of a physiological or pathophysiological signaling cascade. Here, we provide an overview of how different proteoforms come about in biological systems and how they are most commonly measured using mass spectrometry-based proteomics and bioinformatics. Our goal is to present this information at a level accessible to every scientist interested in mass spectrometry and its application to proteome profiling. We will specifically discuss recent data linking various protein post-translational modifications to cardiovascular disease and conclude with a discussion for enablement and democratization of proteomics across the cardiovascular and scientific community. The aim is to inform and inspire the readership to explore a larger breadth of proteoform, particularity post-translational modifications, related to their particular areas of expertise in cardiovascular physiology.

Circ Res: 26 Apr 2018; 122:1221-1237
Fert-Bober J, Murray CI, Parker SJ, Van Eyk JE
Circ Res: 26 Apr 2018; 122:1221-1237 | PMID: 29700069
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Abstract

Coronary Artery Disease in Patients ≥80 Years of Age.

Madhavan MV, Gersh BJ, Alexander KP, Granger CB, Stone GW
Coronary artery disease (CAD) is a major cause of morbidity and mortality in patients ≥80 years of age. Nonetheless, older patients have typically been under-represented in cardiovascular clinical trials. Understanding the pathophysiology, epidemiology, and optimal means of diagnosis and treatment of CAD in older adults is crucial to improving outcomes in this high-risk population. A patient-centered approach, taking into account health status, functional ability and frailty, cognitive skills, and patient preferences is essential when caring for older adults with CAD. The present systematic review focuses on the current knowledge base, gaps in understanding, and directions for future investigation pertaining to CAD in patients ≥80 years of age.

J Am Coll Cardiol: 07 May 2018; 71:2015-2040
Madhavan MV, Gersh BJ, Alexander KP, Granger CB, Stone GW
J Am Coll Cardiol: 07 May 2018; 71:2015-2040 | PMID: 29724356
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Abstract

Cardiovascular Metabolomics.

McGarrah RW, Crown SB, Zhang GF, Shah SH, Newgard CB
Disturbances in cardiac metabolism underlie most cardiovascular diseases. Metabolomics, one of the newer omics technologies, has emerged as a powerful tool for defining changes in both global and cardiac-specific metabolism that occur across a spectrum of cardiovascular disease states. Findings from metabolomics studies have contributed to better understanding of the metabolic changes that occur in heart failure and ischemic heart disease and have identified new cardiovascular disease biomarkers. As technologies advance, the metabolomics field continues to evolve rapidly. In this review, we will discuss the current state of metabolomics technologies, including consideration of various metabolomics platforms and elements of study design; the emerging utility of stable isotopes for metabolic flux studies; and the use of metabolomics to better understand specific cardiovascular diseases, with an emphasis on recent advances in the field.

Circ Res: 26 Apr 2018; 122:1238-1258
McGarrah RW, Crown SB, Zhang GF, Shah SH, Newgard CB
Circ Res: 26 Apr 2018; 122:1238-1258 | PMID: 29700070
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Abstract

Taking Systems Medicine to Heart.

Trachana K, Bargaje R, Glusman G, Price ND, Huang S, Hood LE
Systems medicine is a holistic approach to deciphering the complexity of human physiology in health and disease. In essence, a living body is constituted of networks of dynamically interacting units (molecules, cells, organs, etc) that underlie its collective functions. Declining resilience because of aging and other chronic environmental exposures drives the system to transition from a health state to a disease state; these transitions, triggered by acute perturbations or chronic disturbance, manifest as qualitative shifts in the interactions and dynamics of the disease-perturbed networks. Understanding health-to-disease transitions poses a high-dimensional nonlinear reconstruction problem that requires deep understanding of biology and innovation in study design, technology, and data analysis. With a focus on the principles of systems medicine, this Review discusses approaches for deciphering this biological complexity from a novel perspective, namely, understanding how disease-perturbed networks function; their study provides insights into fundamental disease mechanisms. The immediate goals for systems medicine are to identify early transitions to cardiovascular (and other chronic) diseases and to accelerate the translation of new preventive, diagnostic, or therapeutic targets into clinical practice, a critical step in the development of personalized, predictive, preventive, and participatory (P4) medicine.

Circ Res: 26 Apr 2018; 122:1276-1289
Trachana K, Bargaje R, Glusman G, Price ND, Huang S, Hood LE
Circ Res: 26 Apr 2018; 122:1276-1289 | PMID: 29700072
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Abstract

Defining the Human Envirome: An Omics Approach for Assessing the Environmental Risk of Cardiovascular Disease.

Riggs DW, Yeager RA, Bhatnagar A
Both genetic and environmental factors contribute to the development of cardiovascular disease, but in comparison with genetics, environmental factors have received less attention. Evaluation of environmental determinants of cardiovascular disease is limited by the lack of comprehensive omics approaches for integrating multiple environmental exposures. Hence, to understand the effects of the environment as a whole (envirome), it is important to delineate specific domains of the environment and to assess how, individually and collectively; these domains affect cardiovascular health. In this review, we present a hierarchical model of the envirome; defined by 3 consecutively nested domains, consisting of natural, social, and personal environments. Extensive evidence suggests that features of the natural environment such as sunlight, altitude, diurnal rhythms, vegetation, and biodiversity affect cardiovascular health. However, the effects of the natural environment are moderated by the social environment comprised of built environments, agricultural and industrial activities, pollutants and contaminants, as well as culture, economic activities, and social networks that affect health by influencing access to healthcare, social cohesion, and socioeconomic status. From resources available within society, individuals create personal environments, characterized by private income, wealth and education, and populated by behavioral and lifestyle choices relating to nutrition, physical activity, sleep, the use of recreational drugs, and smoking. An understanding of the interactions between different domains of the envirome and their integrated effects on cardiovascular health could lead to the development of new prevention strategies and deeper insights into etiologic processes that contribute to cardiovascular disease risk and susceptibility.

Circ Res: 26 Apr 2018; 122:1259-1275
Riggs DW, Yeager RA, Bhatnagar A
Circ Res: 26 Apr 2018; 122:1259-1275 | PMID: 29700071
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Abstract

Emerging Role of Precision Medicine in Cardiovascular Disease.

Leopold JA, Loscalzo J
Precision medicine is an integrative approach to cardiovascular disease prevention and treatment that considers an individual\'s genetics, lifestyle, and exposures as determinants of their cardiovascular health and disease phenotypes. This focus overcomes the limitations of reductionism in medicine, which presumes that all patients with the same signs of disease share a common pathophenotype and, therefore, should be treated similarly. Precision medicine incorporates standard clinical and health record data with advanced panomics (ie, transcriptomics, epigenomics, proteomics, metabolomics, and microbiomics) for deep phenotyping. These phenotypic data can then be analyzed within the framework of molecular interaction (interactome) networks to uncover previously unrecognized disease phenotypes and relationships between diseases, and to select pharmacotherapeutics or identify potential protein-drug or drug-drug interactions. In this review, we discuss the current spectrum of cardiovascular health and disease, population averages and the response of extreme phenotypes to interventions, and population-based versus high-risk treatment strategies as a pretext to understanding a precision medicine approach to cardiovascular disease prevention and therapeutic interventions. We also consider the search for resilience and Mendelian disease genes and argue against the theory of a single causal gene/gene product as a mediator of the cardiovascular disease phenotype, as well as an Erlichian magic bullet to solve cardiovascular disease. Finally, we detail the importance of deep phenotyping and interactome networks and the use of this information for rational polypharmacy. These topics highlight the urgent need for precise phenotyping to advance precision medicine as a strategy to improve cardiovascular health and prevent disease.

Circ Res: 26 Apr 2018; 122:1302-1315
Leopold JA, Loscalzo J
Circ Res: 26 Apr 2018; 122:1302-1315 | PMID: 29700074
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Abstract

Biomedical Informatics on the Cloud: A Treasure Hunt for Advancing Cardiovascular Medicine.

Ping P, Hermjakob H, Polson JS, Benos PV, Wang W
In the digital age of cardiovascular medicine, the rate of biomedical discovery can be greatly accelerated by the guidance and resources required to unearth potential collections of knowledge. A unified computational platform leverages metadata to not only provide direction but also empower researchers to mine a wealth of biomedical information and forge novel mechanistic insights. This review takes the opportunity to present an overview of the cloud-based computational environment, including the functional roles of metadata, the architecture schema of indexing and search, and the practical scenarios of machine learning-supported molecular signature extraction. By introducing several established resources and state-of-the-art workflows, we share with our readers a broadly defined informatics framework to phenotype cardiovascular health and disease.

Circ Res: 26 Apr 2018; 122:1290-1301
Ping P, Hermjakob H, Polson JS, Benos PV, Wang W
Circ Res: 26 Apr 2018; 122:1290-1301 | PMID: 29700073
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Abstract

Arrhythmias in Patients ≥80 Years of Age: Pathophysiology, Management, and Outcomes.

Curtis AB, Karki R, Hattoum A, Sharma UC
Advances in medical care have led to an increase in the number of octogenarians and even older patients, forming an important and unique patient subgroup. It is clear that advancing age is an independent risk factor for the development of most arrhythmias, causing substantial morbidity and mortality. Patients ≥80 years of age have significant structural and electrical remodeling of cardiac tissue; accrue competing comorbidities; react differently to drug therapy; and may experience falls, frailty, and cognitive impairment, presenting significant therapeutic challenges. Unfortunately, very old patients are under-represented in clinical trials, leading to critical gaps in evidence to guide effective and safe treatment of arrhythmias. In this state-of-the-art review, we examine the pathophysiology of aging and arrhythmias and then present the available evidence on age-specific management of the most common arrhythmias, including drugs, catheter ablation, and cardiac implantable electronic devices.

J Am Coll Cardiol: 07 May 2018; 71:2041-2057
Curtis AB, Karki R, Hattoum A, Sharma UC
J Am Coll Cardiol: 07 May 2018; 71:2041-2057 | PMID: 29724357
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Abstract

Valvular Heart Disease in Patients ≥80 Years of Age.

Kodali SK, Velagapudi P, Hahn RT, Abbott D, Leon MB
In the United States, the octogenarian population is projected to triple by 2050. With this aging population, the prevalence of valvular heart disease (VHD) is on the rise. The etiology, approach to treatment, and expected outcomes of VHD are different in the elderly compared with younger patients. Both stenotic and regurgitant lesions are associated with unfavorable outcomes if left untreated. Surgical mortality remains high due to multiple co-morbidities, and long-term survival benefit is dependent on many variables including valvular pathology. Quality of life is an important consideration in treatment decisions in this age group. Increasingly, octogenarian patients are receiving transcatheter therapies, with transcatheter aortic valve replacement having the greatest momentum. Numerous transcatheter devices for management of other valve lesions are currently in early clinical trials. This review will describe the epidemiology, etiology, diagnosis, and therapeutic options for VHD in the oldest old, with a focus on transcatheter technologies.

J Am Coll Cardiol: 07 May 2018; 71:2058-2072
Kodali SK, Velagapudi P, Hahn RT, Abbott D, Leon MB
J Am Coll Cardiol: 07 May 2018; 71:2058-2072 | PMID: 29724358
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Abstract

Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications.

England BR, Thiele GM, Anderson DR, Mikuls TR
Rheumatoid arthritis is a systemic autoimmune disease characterized by excess morbidity and mortality from cardiovascular disease. Mechanisms linking rheumatoid arthritis and cardiovascular disease include shared inflammatory mediators, post-translational modifications of peptides/proteins and subsequent immune responses, alterations in the composition and function of lipoproteins, increased oxidative stress, and endothelial dysfunction. Despite a growing understanding of these mechanisms and their complex interplay with conventional cardiovascular risk factors, optimal approaches of risk stratification, prevention, and treatment in the context of rheumatoid arthritis remain unknown. A multifaceted approach to reduce the burden posed by cardiovascular disease requires optimal management of traditional risk factors in addition to those intrinsic to rheumatoid arthritis such as increased disease activity. Treatments for rheumatoid arthritis seem to exert differential effects on cardiovascular risk as well as the mechanisms linking these conditions. More research is needed to establish whether preferential rheumatoid arthritis therapies exist in terms of prevention of cardiovascular disease. Ultimately, understanding the unique mechanisms for cardiovascular disease in rheumatoid arthritis will aid in risk stratification and the identification of novel targets for meaningful reduction of cardiovascular risk in this patient population.

BMJ: 22 Apr 2018; 361:k1036
England BR, Thiele GM, Anderson DR, Mikuls TR
BMJ: 22 Apr 2018; 361:k1036 | PMID: 29685876
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Abstract

Socioeconomic Status and Cardiovascular Outcomes: Challenges and Interventions.

Schultz WM, Kelli HM, Lisko JC, Varghese T, ... Mensah GA, Sperling LS
Socioeconomic status (SES) has a measurable and significant effect on cardiovascular health. Biological, behavioral, and psychosocial risk factors prevalent in disadvantaged individuals accentuate the link between SES and cardiovascular disease (CVD). Four measures have been consistently associated with CVD in high-income countries: income level, educational attainment, employment status, and neighborhood socioeconomic factors. In addition, disparities based on sex have been shown in several studies. Interventions targeting patients with low SES have predominantly focused on modification of traditional CVD risk factors. Promising approaches are emerging that can be implemented on an individual, community, or population basis to reduce disparities in outcomes. Structured physical activity has demonstrated effectiveness in low-SES populations, and geomapping may be used to identify targets for large-scale programs. Task shifting, the redistribution of healthcare management from physician to nonphysician providers in an effort to improve access to health care, may have a role in select areas. Integration of SES into the traditional CVD risk prediction models may allow improved management of individuals with high risk, but cultural and regional differences in SES make generalized implementation challenging. Future research is required to better understand the underlying mechanisms of CVD risk that affect individuals of low SES and to determine effective interventions for patients with high risk. We review the current state of knowledge on the impact of SES on the incidence, treatment, and outcomes of CVD in high-income societies and suggest future research directions aimed at the elimination of these adverse factors, and the integration of measures of SES into the customization of cardiovascular treatment.

Circulation: 14 May 2018; 137:2166-2178
Schultz WM, Kelli HM, Lisko JC, Varghese T, ... Mensah GA, Sperling LS
Circulation: 14 May 2018; 137:2166-2178 | PMID: 29760227
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Abstract

Resuscitation Education Science: Educational Strategies to Improve Outcomes From Cardiac Arrest: A Scientific Statement From the American Heart Association.

Cheng A, Nadkarni VM, Mancini MB, Hunt EA, ... Bhanji F,
The formula for survival in resuscitation describes educational efficiency and local implementation as key determinants in survival after cardiac arrest. Current educational offerings in the form of standardized online and face-to-face courses are falling short, with providers demonstrating a decay of skills over time. This translates to suboptimal clinical care and poor survival outcomes from cardiac arrest. In many institutions, guidelines taught in courses are not thoughtfully implemented in the clinical environment. A current synthesis of the evidence supporting best educational and knowledge translation strategies in resuscitation is lacking. In this American Heart Association scientific statement, we provide a review of the literature describing key elements of educational efficiency and local implementation, including mastery learning and deliberate practice, spaced practice, contextual learning, feedback and debriefing, assessment, innovative educational strategies, faculty development, and knowledge translation and implementation. For each topic, we provide suggestions for improving provider performance that may ultimately optimize patient outcomes from cardiac arrest.

Circulation: 20 Jun 2018; epub ahead of print
Cheng A, Nadkarni VM, Mancini MB, Hunt EA, ... Bhanji F,
Circulation: 20 Jun 2018; epub ahead of print | PMID: 29930020
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Abstract

Public-Access Defibrillation and Out-of-Hospital Cardiac Arrest in Japan.

Kitamura T, Kiyohara K, Sakai T, Matsuyama T, ... Kawamura T, Iwami T
Background Early defibrillation plays a key role in improving survival in patients with out-of-hospital cardiac arrests due to ventricular fibrillation (ventricular-fibrillation cardiac arrests), and the use of publicly accessible automated external defibrillators (AEDs) can help to reduce the time to defibrillation for such patients. However, the effect of dissemination of public-access AEDs for ventricular-fibrillation cardiac arrest at the population level has not been extensively investigated. Methods From a nationwide, prospective, population-based registry of patients with out-of-hospital cardiac arrest in Japan, we identified patients from 2005 through 2013 with bystander-witnessed ventricular-fibrillation arrests of presumed cardiac origin in whom resuscitation was attempted. The primary outcome measure was survival at 1 month with a favorable neurologic outcome (Cerebral Performance Category of 1 or 2, on a scale from 1 [good cerebral performance] to 5 [death or brain death]). The number of patients in whom survival with a favorable neurologic outcome was attributable to public-access defibrillation was estimated. Results Of 43,762 patients with bystander-witnessed ventricular-fibrillation arrests of cardiac origin, 4499 (10.3%) received public-access defibrillation. The percentage of patients receiving public-access defibrillation increased from 1.1% in 2005 to 16.5% in 2013 (P<0.001 for trend). The percentage of patients who were alive at 1 month with a favorable neurologic outcome was significantly higher with public-access defibrillation than without public-access defibrillation (38.5% vs. 18.2%; adjusted odds ratio after propensity-score matching, 1.99; 95% confidence interval, 1.80 to 2.19). The estimated number of survivors in whom survival with a favorable neurologic outcome was attributed to public-access defibrillation increased from 6 in 2005 to 201 in 2013 (P<0.001 for trend). Conclusions In Japan, increased use of public-access defibrillation by bystanders was associated with an increase in the number of survivors with a favorable neurologic outcome after out-of-hospital ventricular-fibrillation cardiac arrest.

N Engl J Med: 25 Oct 2016; 375:1649-1659
Kitamura T, Kiyohara K, Sakai T, Matsuyama T, ... Kawamura T, Iwami T
N Engl J Med: 25 Oct 2016; 375:1649-1659 | PMID: 27783922
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Abstract

Leptin-Aldosterone-Neprilysin Axis: Identification of Its Distinctive Role in the Pathogenesis of the Three Phenotypes of Heart Failure in People With Obesity.

Packer M
Obesity (especially visceral adiposity) can be associated with 3 different phenotypes of heart failure: heart failure with a reduced ejection fraction, heart failure with a preserved ejection fraction, and high-output heart failure. All 3 phenotypes are characterized by an excessive secretion of aldosterone and sodium retention. In addition, obesity is accompanied by increased signaling through the leptin receptor, which can promote activation of both the sympathetic nervous system and the renin-angiotensin system and can directly stimulate the secretion of aldosterone. The deleterious interaction of leptin and aldosterone is potentiated by the simultaneous action of adiposity and the renal sympathetic nerves to cause overactivity of neprilysin; the loss of the counterbalancing effects of natriuretic peptides is exacerbated by an additional effect of both obesity and heart failure to interfere with adiponectin signaling. This intricate neurohormonal interplay leads to plasma volume expansion as well as to adverse ventricular remodeling and cardiac fibrosis. Furthermore, the activity of aldosterone and neprilysin is not only enhanced by obesity, but these mechanisms can also promote adipogenesis and adipocyte dysfunction, thereby enhancing the positive feedback loop. Last, in elderly obese women, changes in quantity and biology of epicardial adipose tissue further enhances the release of leptin and other proinflammatory adipokines, thereby leading to cardiac and systemic inflammation, end-organ fibrosis, and multiple comorbidities. Regardless of the phenotypic expression, activation of the leptin-aldosterone-neprilysin axis appears to contribute importantly to the evolution and progression of heart failure in people with obesity. Efforts to interfere with the detrimental interactions of this distinctive neurohormonal ecosystem with existing or novel therapeutic agents are likely to yield unique clinical benefits.

Circulation: 09 Apr 2018; 137:1614-1631
Packer M
Circulation: 09 Apr 2018; 137:1614-1631 | PMID: 29632154
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Abstract

Child-Parent Familial Hypercholesterolemia Screening in Primary Care.

Wald DS, Bestwick JP, Morris JK, Whyte K, Jenkins L, Wald NJ
Background Child-parent screening for familial hypercholesterolemia has been proposed to identify persons at high risk for inherited premature cardiovascular disease. We assessed the efficacy and feasibility of such screening in primary care practice. Methods We obtained capillary blood samples to measure cholesterol levels and to test for familial hypercholesterolemia mutations in 10,095 children 1 to 2 years of age during routine immunization visits. Children were considered to have positive screening results for familial hypercholesterolemia if their cholesterol level was elevated and they had either a familial hypercholesterolemia mutation or a repeat elevated cholesterol level 3 months later. A parent of each child with a positive screening result for familial hypercholesterolemia was considered to have a positive screening result for familial hypercholesterolemia if he or she had the same mutation as the child or, if no mutations were identified, had the higher cholesterol level of the two parents. Results The use of a prespecified cholesterol cutoff value of 1.53 multiples of the median (MoM, corresponding to a percentile of 99.2) identified 28 children who had positive screening results for familial hypercholesterolemia (0.3% of the 10,095 children; 95% confidence interval [CI], 0.2 to 0.4), including 20 with a familial hypercholesterolemia mutation and 8 with a repeat cholesterol level of at least 1.53 MoM. A total of 17 children who had a cholesterol level of less than 1.53 MoM also had a familial hypercholesterolemia mutation. The overall mutation prevalence was 1 in 273 children (37 in 10,095; 95% CI, 1 in 198 to 1 in 388). The use of an initial cholesterol cutoff value of 1.35 MoM (95th percentile) plus a mutation, or two cholesterol values of at least 1.50 MoM (99th percentile), identified 40 children who had positive screening results for familial hypercholesterolemia (0.4% of the 10,095 children, including 32 children who had a familial hypercholesterolemia mutation and 8 who did not have the mutation) and 40 parents who had positive screening results for familial hypercholesterolemia. Conclusions Child-parent screening was feasible in primary care practices at routine child immunization visits. For every 1000 children screened, 8 persons (4 children and 4 parents) were identified as having positive screening results for familial hypercholesterolemia and were consequently at high risk for cardiovascular disease. (Funded by the Medical Research Council.).

N Engl J Med: 25 Oct 2016; 375:1628-1637
Wald DS, Bestwick JP, Morris JK, Whyte K, Jenkins L, Wald NJ
N Engl J Med: 25 Oct 2016; 375:1628-1637 | PMID: 27783906
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Abstract

Thyroid Hormones and Cardiovascular Function and Diseases.

Razvi S, Jabbar A, Pingitore A, Danzi S, ... Zaman A, Iervasi G
Thyroid hormone (TH) receptors are present in the myocardium and vascular tissue, and minor alterations in TH concentration can affect cardiovascular (CV) physiology. The potential mechanisms that link CV disease with thyroid dysfunction are endothelial dysfunction, changes in blood pressure, myocardial systolic and diastolic dysfunction, and dyslipidemia. In addition, cardiac disease itself may lead to alterations in TH concentrations (notably, low triiodothyronine syndrome) that are associated with higher morbidity and mortality. Experimental data and small clinical trials have suggested a beneficial role of TH in ameliorating CV disease. The aim of this review is to provide clinicians dealing with CV conditions with an overview of the current knowledge of TH perturbations in CV disease.

J Am Coll Cardiol: 23 Apr 2018; 71:1781-1796
Razvi S, Jabbar A, Pingitore A, Danzi S, ... Zaman A, Iervasi G
J Am Coll Cardiol: 23 Apr 2018; 71:1781-1796 | PMID: 29673469
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Abstract

Standardized End Point Definitions for Coronary Intervention Trials: The Academic Research Consortium-2 Consensus Document.

Garcia-Garcia HM, McFadden EP, Farb A, Mehran R, ... Serruys PW,
The Academic Research Consortium (ARC)-2 initiative revisited the clinical and angiographic end point definitions in coronary device trials, proposed in 2007, to make them more suitable for use in clinical trials that include increasingly complex lesion and patient populations and incorporate novel devices such as bioresorbable vascular scaffolds. In addition, recommendations for the incorporation of patient-related outcomes in clinical trials are proposed. Academic Research Consortium-2 is a collaborative effort between academic research organizations in the United States and Europe, device manufacturers, and European, US, and Asian regulatory bodies. Several in-person meetings were held to discuss the changes that have occurred in the device landscape and in clinical trials and regulatory pathways in the last decade. The consensus-based end point definitions in this document are endorsed by the stakeholders of this document and strongly advocated for clinical trial purposes. This Academic Research Consortium-2 document provides further standardization of end point definitions for coronary device trials, incorporating advances in technology and knowledge. Their use will aid interpretation of trial outcomes and comparison among studies, thus facilitating the evaluation of the safety and effectiveness of these devices.

Circulation: 11 Jun 2018; 137:2635-2650
Garcia-Garcia HM, McFadden EP, Farb A, Mehran R, ... Serruys PW,
Circulation: 11 Jun 2018; 137:2635-2650 | PMID: 29891620
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Abstract

Hypertension Across a Woman\'s Life Cycle.

Wenger NK, Arnold A, Bairey Merz CN, Cooper-DeHoff RM, ... Walsh MN, Pepine CJ
Hypertension accounts for 1 in 5 deaths among American women, posing a greater burden for women than men, and is among their most important risk factors for death and development of cardiovascular and other diseases. Hypertension affects women in all phases of life, with specific characteristics relating to risk factors and management for primary prevention of hypertension in teenage and young adult women; hypertension in pregnancy; hypertension during use of oral contraceptives and assisted reproductive technologies, lactation, menopause, or hormone replacement; hypertension in elderly women; and issues of race and ethnicity. All are detailed in this review, as is information relative to women in clinical trials of hypertension and medication issues. The overarching message is that effective treatment and control of hypertension improves cardiovascular outcomes. But many knowledge gaps persist, including the contribution of hypertensive disorders of pregnancy to cardiovascular disease risk, the role of hormone replacement, blood pressure targets for elderly women, and so on.

J Am Coll Cardiol: 23 Apr 2018; 71:1797-1813
Wenger NK, Arnold A, Bairey Merz CN, Cooper-DeHoff RM, ... Walsh MN, Pepine CJ
J Am Coll Cardiol: 23 Apr 2018; 71:1797-1813 | PMID: 29673470
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Abstract

Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy.


Background In patients with established cardiovascular disease, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein (LDL) cholesterol levels with statin therapy. It is unclear whether extended-release niacin added to simvastatin to raise low levels of high-density lipoprotein (HDL) cholesterol is superior to simvastatin alone in reducing such residual risk. Methods We randomly assigned eligible patients to receive extended-release niacin, 1500 to 2000 mg per day, or matching placebo. All patients received simvastatin, 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed, to maintain an LDL cholesterol level of 40 to 80 mg per deciliter (1.03 to 2.07 mmol per liter). The primary end point was the first event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. Results A total of 3414 patients were randomly assigned to receive niacin (1718) or placebo (1696). The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy. At 2 years, niacin therapy had significantly increased the median HDL cholesterol level from 35 mg per deciliter (0.91 mmol per liter) to 42 mg per deciliter (1.08 mmol per liter), lowered the triglyceride level from 164 mg per deciliter (1.85 mmol per liter) to 122 mg per deciliter (1.38 mmol per liter), and lowered the LDL cholesterol level from 74 mg per deciliter (1.91 mmol per liter) to 62 mg per deciliter (1.60 mmol per liter). The primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio, 1.02; 95% confidence interval, 0.87 to 1.21; P=0.79 by the log-rank test). Conclusions Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter (1.81 mmol per liter), there was no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; AIM-HIGH ClinicalTrials.gov number, NCT00120289 .).

N Engl J Med: 16 Nov 2011; epub ahead of print
N Engl J Med: 16 Nov 2011; epub ahead of print | PMID: 22085343
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Abstract

Projected Costs of Informal Caregiving for Cardiovascular Disease: 2015 to 2035: A Policy Statement From the American Heart Association.

Dunbar SB, Khavjou OA, Bakas T, Hunt G, ... Roger VL, Whitsel LP
In a recent report, the American Heart Association estimated that medical costs and productivity losses of cardiovascular disease (CVD) are expected to grow from $555 billion in 2015 to $1.1 trillion in 2035. Although the burden is significant, the estimate does not include the costs of family, informal, or unpaid caregiving provided to patients with CVD. In this analysis, we estimated projections of costs of informal caregiving attributable to CVD for 2015 to 2035.

Circulation: 08 Apr 2018; epub ahead of print
Dunbar SB, Khavjou OA, Bakas T, Hunt G, ... Roger VL, Whitsel LP
Circulation: 08 Apr 2018; epub ahead of print | PMID: 29632217
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Abstract

Five-Year Outcomes after Off-Pump or On-Pump Coronary-Artery Bypass Grafting.

Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, ... Yusuf S, CORONARY Investigators
Background We previously reported that there was no significant difference at 30 days or at 1 year in the rate of the composite outcome of death, stroke, myocardial infarction, or renal failure between patients who underwent coronary-artery bypass grafting (CABG) performed with a beating-heart technique (off-pump) and those who underwent CABG performed with cardiopulmonary bypass (on-pump). We now report the results at 5 years (the end of the trial). Methods A total of 4752 patients (from 19 countries) who had coronary artery disease were randomly assigned to undergo off-pump or on-pump CABG. For this report, we analyzed a composite outcome of death, stroke, myocardial infarction, renal failure, or repeat coronary revascularization (either CABG or percutaneous coronary intervention). The mean follow-up period was 4.8 years. Results There were no significant differences between the off-pump group and the on-pump group in the rate of the composite outcome (23.1% and 23.6%, respectively; hazard ratio with off-pump CABG, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72) or in the rates of the components of the outcome, including repeat coronary revascularization, which was performed in 2.8% of the patients in the off-pump group and in 2.3% of the patients in the on-pump group (hazard ratio, 1.21; 95% CI, 0.85 to 1.73; P=0.29). The secondary outcome for the overall period of the trial - the mean cost in U.S. dollars per patient - also did not differ significantly between the off-pump group and the on-pump group ($15,107 and $14,992, respectively; between-group difference, $115; 95% CI, -$697 to $927). There were no significant between-group differences in quality-of-life measures. Conclusions In our trial, the rate of the composite outcome of death, stroke, myocardial infarction, renal failure, or repeat revascularization at 5 years of follow-up was similar among patients who underwent off-pump CABG and those who underwent on-pump CABG. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294 .).

N Engl J Med: 23 Oct 2016; epub ahead of print
Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, ... Yusuf S, CORONARY Investigators
N Engl J Med: 23 Oct 2016; epub ahead of print | PMID: 27771985
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Abstract

Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery.

Myles PS, Smith JA, Forbes A, Silbert B, ... Wallace S, ATACAS Investigators of the ANZCA Clinical Trials Network
Background Tranexamic acid reduces the risk of bleeding among patients undergoing cardiac surgery, but it is unclear whether this leads to improved outcomes. Furthermore, there are concerns that tranexamic acid may have prothrombotic and proconvulsant effects. Methods In a trial with a 2-by-2 factorial design, we randomly assigned patients who were scheduled to undergo coronary-artery surgery and were at risk for perioperative complications to receive aspirin or placebo and tranexamic acid or placebo. The results of the tranexamic acid comparison are reported here. The primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery. Results Of the 4662 patients who were enrolled and provided consent, 4631 underwent surgery and had available outcomes data; 2311 were assigned to the tranexamic acid group and 2320 to the placebo group. A primary outcome event occurred in 386 patients (16.7%) in the tranexamic acid group and in 420 patients (18.1%) in the placebo group (relative risk, 0.92; 95% confidence interval, 0.81 to 1.05; P=0.22). The total number of units of blood products that were transfused during hospitalization was 4331 in the tranexamic acid group and 7994 in the placebo group (P<0.001). Major hemorrhage or cardiac tamponade leading to reoperation occurred in 1.4% of the patients in the tranexamic acid group and in 2.8% of the patients in the placebo group (P=0.001), and seizures occurred in 0.7% and 0.1%, respectively (P=0.002 by Fisher\'s exact test). Conclusions Among patients undergoing coronary-artery surgery, tranexamic acid was associated with a lower risk of bleeding than was placebo, without a higher risk of death or thrombotic complications within 30 days after surgery. Tranexamic acid was associated with a higher risk of postoperative seizures. (Funded by the Australian National Health and Medical Research Council and others; ATACAS Australia New Zealand Clinical Trials Registry number, ACTRN12605000557639 .).

N Engl J Med: 23 Oct 2016; epub ahead of print
Myles PS, Smith JA, Forbes A, Silbert B, ... Wallace S, ATACAS Investigators of the ANZCA Clinical Trials Network
N Engl J Med: 23 Oct 2016; epub ahead of print | PMID: 27774838
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Abstract

Risk Stratification of Genetic, Dilated Cardiomyopathies Associated With Neuromuscular Disorders: Role of Cardiac Imaging.

van der Bijl P, Delgado V, Bootsma M, Bax JJ
The etiology of dilated cardiomyopathy (DCM) can be grouped as either genetic or nongenetic. More than 50 pathogenic genes have been described, with sarcomeric and lamin A/C mutations being the most common. Mutation carriers for genetic DCM are often asymptomatic until cardiac disease manifests with heart failure, arrhythmias, or sudden cardiac death. Preventive strategies are promising but can only be applied and tested adequately if genetic DCM can be diagnosed at an early stage. Early diagnosis of mutation carriers that may develop overt DCM requires advanced imaging techniques that can detect subtle structural and functional abnormalities. Advanced echocardiographic techniques such as tissue Doppler imaging and speckle tracking strain analysis permit early detection of functional abnormalities, whereas cardiovascular magnetic resonance techniques provide information on tissue characterization and myocardial energetics that may be altered at an early stage. Furthermore, nuclear imaging techniques provide information on cellular function (metabolism, perfusion). Once the diagnosis of overt DCM has been established, various imaging parameters such as echocardiography-based myocardial mechanics and cardiovascular magnetic resonance-based tissue characterization have shown incremental benefit to left ventricular ejection fraction in risk stratification. Further research is required to understand how imaging techniques may help to choose management strategies that could delay progression when instituted early in the course of the disease. The present article reviews the role of imaging in the risk stratification of genetic DCM in general, with specific emphasis on DCM associated with neuromuscular disorders.

Circulation: 04 Jun 2018; 137:2514-2527
van der Bijl P, Delgado V, Bootsma M, Bax JJ
Circulation: 04 Jun 2018; 137:2514-2527 | PMID: 29866775
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Abstract

Drug-Eluting or Bare-Metal Stents for Coronary Artery Disease.

Bønaa KH, Mannsverk J, Wiseth R, Aaberge L, ... Nordrehaug JE, NORSTENT Investigators
Background Limited data are available on the long-term effects of contemporary drug-eluting stents versus contemporary bare-metal stents on rates of death, myocardial infarction, repeat revascularization, and stent thrombosis and on quality of life. Methods We randomly assigned 9013 patients who had stable or unstable coronary artery disease to undergo percutaneous coronary intervention (PCI) with the implantation of either contemporary drug-eluting stents or bare-metal stents. In the group receiving drug-eluting stents, 96% of the patients received either everolimus- or zotarolimus-eluting stents. The primary outcome was a composite of death from any cause and nonfatal spontaneous myocardial infarction after a median of 5 years of follow-up. Secondary outcomes included repeat revascularization, stent thrombosis, and quality of life. Results At 6 years, the rates of the primary outcome were 16.6% in the group receiving drug-eluting stents and 17.1% in the group receiving bare-metal stents (hazard ratio, 0.98; 95% confidence interval [CI], 0.88 to 1.09; P=0.66). There were no significant between-group differences in the components of the primary outcome. The 6-year rates of any repeat revascularization were 16.5% in the group receiving drug-eluting stents and 19.8% in the group receiving bare-metal stents (hazard ratio, 0.76; 95% CI, 0.69 to 0.85; P<0.001); the rates of definite stent thrombosis were 0.8% and 1.2%, respectively (P=0.0498). Quality-of-life measures did not differ significantly between the two groups. Conclusions In patients undergoing PCI, there were no significant differences between those receiving drug-eluting stents and those receiving bare-metal stents in the composite outcome of death from any cause and nonfatal spontaneous myocardial infarction. Rates of repeat revascularization were lower in the group receiving drug-eluting stents. (Funded by the Norwegian Research Council and others; NORSTENT ClinicalTrials.gov number, NCT00811772 .).

N Engl J Med: 29 Aug 2016; epub ahead of print
Bønaa KH, Mannsverk J, Wiseth R, Aaberge L, ... Nordrehaug JE, NORSTENT Investigators
N Engl J Med: 29 Aug 2016; epub ahead of print | PMID: 27572953
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Abstract

Investing in non-communicable diseases: an estimation of the return on investment for prevention and treatment services.

Bertram MY, Sweeny K, Lauer JA, Chisholm D, ... George K, Deane S
The global burden of non-communicable diseases (NCDs) is growing, and there is an urgent need to estimate the costs and benefits of an investment strategy to prevent and control NCDs. Results from an investment-case analysis can provide important new evidence to inform decision making by governments and donors. We propose a methodology for calculating the economic benefits of investing in NCDs during the Sustainable Development Goals (SDGs) era, and we applied this methodology to cardiovascular disease prevention in 20 countries with the highest NCD burden. For a limited set of prevention interventions, we estimated that US$120 billion must be invested in these countries between 2015 and 2030. This investment represents an additional $1·50 per capita per year and would avert 15 million deaths, 8 million incidents of ischaemic heart disease, and 13 million incidents of stroke in the 20 countries. Benefit-cost ratios varied between interventions and country-income levels, with an average ratio of 5·6 for economic returns but a ratio of 10·9 if social returns are included. Investing in cardiovascular disease prevention is integral to achieving SDG target 3.4 (reducing premature mortality from NCDs by a third) and to progress towards SDG target 3.8 (the realisation of universal health coverage). Many countries have implemented cost-effective interventions at low levels, so the potential to achieve these targets and strengthen national income by scaling up these interventions is enormous.

Lancet: 04 Apr 2018; epub ahead of print
Bertram MY, Sweeny K, Lauer JA, Chisholm D, ... George K, Deane S
Lancet: 04 Apr 2018; epub ahead of print | PMID: 29627159
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Abstract

Multimorbidity in Older Adults With Cardiovascular Disease.

Forman DE, Maurer MS, Boyd C, Brindis R, ... Zieman S, Rich MW
Multimorbidity occurs in adults of all ages, but the number and complexity of comorbid conditions commonly increase with advancing age such that cardiovascular disease (CVD) in older adults typically occurs in a context of multimorbidity. Current clinical practice and research mainly target single disease-specific care that does not embrace the complexities imposed by concurrent conditions. In this paper, emerging concepts regarding CVD in combination with multimorbidity are reviewed, including recommendations for incorporating multimorbidity into clinical decision making, critical knowledge gaps, and research priorities to optimize care of complex older patients.

J Am Coll Cardiol: 14 May 2018; 71:2149-2161
Forman DE, Maurer MS, Boyd C, Brindis R, ... Zieman S, Rich MW
J Am Coll Cardiol: 14 May 2018; 71:2149-2161 | PMID: 29747836
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Abstract

Cardiovascular Diseases in India Compared With the United States.

Prabhakaran D, Singh K, Roth GA, Banerjee A, Pagidipati NJ, Huffman MD
This review describes trends in the burden of cardiovascular diseases (CVDs) and risk factors in India compared with the United States; provides potential explanations for these differences; and describes strategies to improve cardiovascular health behaviors, systems, and policies in India. The prevalence of CVD in India has risen over the past 2 decades due to population growth, aging, and a stable age-adjusted CVD mortality rate. Over the same time period, the United States has experienced an overall decline in age-adjusted CVD mortality, although the trend has begun to plateau. These improvements in CVD mortality in the United States are largely due to favorable population-level risk factor trends, specifically with regard to tobacco use, cholesterol, and blood pressure, although improvements in secondary prevention and acute care have also contributed. To realize similar gains in reducing premature death and disability from CVD, India needs to implement population-level policies while strengthening and integrating its local, regional, and national health systems. Achieving universal health coverage that includes financial risk protection should remain a goal to help all Indians realize their right to health.

J Am Coll Cardiol: 02 Jul 2018; 72:79-95
Prabhakaran D, Singh K, Roth GA, Banerjee A, Pagidipati NJ, Huffman MD
J Am Coll Cardiol: 02 Jul 2018; 72:79-95 | PMID: 29957235
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Abstract

Mobile Health Advances in Physical Activity, Fitness, and Atrial Fibrillation: Moving Hearts.

McConnell MV, Turakhia MP, Harrington RA, King AC, Ashley EA
The growing recognition that \"health\" takes place outside of the hospital and clinic, plus recent advances in mobile and wearable devices, have propelled the field of mobile health (mHealth). Cardiovascular disease and prevention are major opportunities for mHealth, as mobile devices can monitor key physiological signals (e.g., physical activity, heart rate and rhythm) for promoting healthy behaviors, detecting disease, and aid in ongoing care. In this review, the authors provide an update on cardiovascular mHealth by highlighting recent progress and challenges with mobile and wearable devices for assessing and promoting physical activity and fitness, and for monitoring heart rate and rhythm for the detection and management of atrial fibrillation.

J Am Coll Cardiol: 11 Jun 2018; 71:2691-2701
McConnell MV, Turakhia MP, Harrington RA, King AC, Ashley EA
J Am Coll Cardiol: 11 Jun 2018; 71:2691-2701 | PMID: 29880130
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Abstract

The Long-Term Effect of Premier Pay for Performance on Patient Outcomes.

Jha AK, Joynt KE, Orav EJ, Epstein AM
Background Pay for performance has become a central strategy in the drive to improve health care. We assessed the long-term effect of the Medicare Premier Hospital Quality Incentive Demonstration (HQID) on patient outcomes. Methods We used Medicare data to compare outcomes between the 252 hospitals participating in the Premier HQID and 3363 control hospitals participating in public reporting alone. We examined 30-day mortality among more than 6 million patients who had acute myocardial infarction, congestive heart failure, or pneumonia or who underwent coronary-artery bypass grafting (CABG) between 2003 and 2009. Results At baseline, the composite 30-day mortality was similar for Premier and non-Premier hospitals (12.33% and 12.40%, respectively; difference, -0.07 percentage points; 95% confidence interval [CI], -0.40 to 0.26). The rates of decline in mortality per quarter at the two types of hospitals were also similar (0.04% and 0.04%, respectively; difference, -0.01 percentage points; 95% CI, -0.02 to 0.01), and mortality remained similar after 6 years under the pay-for-performance system (11.82% for Premier hospitals and 11.74% for non-Premier hospitals; difference, 0.08 percentage points; 95% CI, -0.30 to 0.46). We found that the effects of pay for performance on mortality did not differ significantly among conditions for which outcomes were explicitly linked to incentives (acute myocardial infarction and CABG) and among conditions not linked to incentives (congestive heart failure and pneumonia) (P=0.36 for interaction). Among hospitals that were poor performers at baseline, mortality was similar in the two groups of hospitals at the start of the study (15.12% and 14.73%; difference, 0.39 percentage points; 95% CI, -0.36 to 1.15), with similar rates of improvement per quarter (0.10% and 0.07%; difference, -0.03 percentage points; 95% CI, -0.08 to 0.02) and similar mortality rates at the end of the study (13.37% and 13.21%; difference, 0.15 percentage points; 95% CI, -0.70 to 1.01). Conclusions We found no evidence that the largest hospital-based pay-for-performance program led to a decrease in 30-day mortality. Expectations of improved outcomes for programs modeled after Premier HQID should therefore remain modest.

N Engl J Med: 28 Mar 2012; epub ahead of print
Jha AK, Joynt KE, Orav EJ, Epstein AM
N Engl J Med: 28 Mar 2012; epub ahead of print | PMID: 22455751
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Abstract

Cardiovascular Outcomes Reported in Hemodialysis Trials.

O\'Lone E, Viecelli AK, Craig JC, Tong A, ... Webster AC, Wheeler DC
Patients on long-term hemodialysis are at very high risk for cardiovascular disease but are usually excluded from clinical trials conducted in the general population or in at-risk populations. There are no universally agreed cardiovascular outcomes for trials conducted specifically in the hemodialysis population. In this review, we highlight that trials reporting cardiovascular outcomes in hemodialysis patients are usually of short duration (median 3 to 6 months) and are small (59% of trials have <100 participants). Overall, the cardiovascular outcomes are very heterogeneous and may not reflect outcomes that are meaningful to patients and clinicians in supporting decision making, as they are often surrogates of uncertain clinical importance. Composite outcomes used in different trials rarely share the same components. In a field in which a single trial is often insufficiently powered to fully assess the clinical and economic impact of interventions, differences in outcome reporting across trials make the task of meta-analysis and interpretation of all the available evidence challenging. Core outcome sets are now being established across many specialties in health care to prevent these problems. Through the global Standardized Outcomes in Nephrology-Hemodialysis initiative, cardiovascular disease was identified as a critically important core domain to be reported in all trials in hemodialysis. Informed by the current state of reporting of cardiovascular outcomes, a core outcome measure for cardiovascular disease is currently being established with involvement of patients, caregivers, and health professionals. Consistent reporting of cardiovascular outcomes that are critically important to hemodialysis patients and clinicians will strengthen the evidence base to inform care in this very high-risk population.

J Am Coll Cardiol: 18 Jun 2018; 71:2802-2810
O'Lone E, Viecelli AK, Craig JC, Tong A, ... Webster AC, Wheeler DC
J Am Coll Cardiol: 18 Jun 2018; 71:2802-2810 | PMID: 29903353
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Abstract

Artificial Intelligence in Cardiology.

Johnson KW, Torres Soto J, Glicksberg BS, Shameer K, ... Ashley E, Dudley JT
Artificial intelligence and machine learning are poised to influence nearly every aspect of the human condition, and cardiology is not an exception to this trend. This paper provides a guide for clinicians on relevant aspects of artificial intelligence and machine learning, reviews selected applications of these methods in cardiology to date, and identifies how cardiovascular medicine could incorporate artificial intelligence in the future. In particular, the paper first reviews predictive modeling concepts relevant to cardiology such as feature selection and frequent pitfalls such as improper dichotomization. Second, it discusses common algorithms used in supervised learning and reviews selected applications in cardiology and related disciplines. Third, it describes the advent of deep learning and related methods collectively called unsupervised learning, provides contextual examples both in general medicine and in cardiovascular medicine, and then explains how these methods could be applied to enable precision cardiology and improve patient outcomes.

J Am Coll Cardiol: 11 Jun 2018; 71:2668-2679
Johnson KW, Torres Soto J, Glicksberg BS, Shameer K, ... Ashley E, Dudley JT
J Am Coll Cardiol: 11 Jun 2018; 71:2668-2679 | PMID: 29880128
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Abstract

Cardiovascular Effects of New Oral Glucose-Lowering Agents: DPP-4 and SGLT-2 Inhibitors.

Scheen AJ
Cardiovascular disease (CVD) is a major challenge in the management of type 2 diabetes mellitus. Glucose-lowering agents that reduce the risk of major cardiovascular events would be considered a major advance, as recently reported with liraglutide and semaglutide, 2 glucagon-like peptide-1 receptor agonists, and with empagliflozin and canagliflozin, 2 SGLT-2 (sodium-glucose cotransporter type 2) inhibitors, but not with DPP-4 (dipeptidyl peptidase-4) inhibitors. The present review is devoted to CV effects of new oral glucose-lowering agents. DPP-4 inhibitors (gliptins) showed some positive cardiac and vascular effects in preliminary studies, and initial data from phase 2 to 3 clinical trials suggested a reduction in major cardiovascular events. However, subsequent CV outcome trials with alogliptin, saxagliptin, and sitagliptin showed noninferiority but failed to demonstrate any superiority compared with placebo in patients with type 2 diabetes mellitus and high CV risk. An unexpected higher risk of hospitalization for heart failure was reported with saxagliptin. SGLT-2 inhibitors (gliflozins) promote glucosuria, thus reducing glucose toxicity and body weight, and enhance natriuresis, thus lowering blood pressure. Two CV outcome trials in type 2 diabetes mellitus patients mainly in secondary prevention showed remarkable positive results. Empagliflozin in EMPA-REG-OUTCOME (EMPAgliflozin Cardiovascular OUTCOME Events in Type 2 Diabetes Mellitus Patients) reduced major cardiovascular events, CV mortality, all-cause mortality, and hospitalization for heart failure. In CANVAS (Canagliflozin Cardiovascular Assessment Study), the reduction in CV mortality with canagliflozin failed to reach statistical significance despite a similar reduction in major cardiovascular events. The underlying protective mechanisms of SGLT-2 inhibitors remain unknown and both hemodynamic and metabolic explanations have been proposed. CVD-REAL studies (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors; with the limitation of an observational approach) suggested that these favorable results may be considered as a class effect shared by all SGLT-2 inhibitors (including dapagliflozin) and be extrapolated to a larger population of patients with type 2 diabetes mellitus in primary prevention. Ongoing CV outcome trials with other DPP-4 (linagliptin) and SGLT-2 (dapagliflozin, ertugliflozin) inhibitors should provide additional information about CV effects of both pharmacological classes.

Circ Res: 10 May 2018; 122:1439-1459
Scheen AJ
Circ Res: 10 May 2018; 122:1439-1459 | PMID: 29748368
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Abstract

The Role of Nutraceuticals in Statin Intolerant Patients.

Banach M, Patti AM, Giglio RV, Cicero AFG, ... Rizzo M,
Statins are the most common drugs administered for patients with cardiovascular disease. However, due to statin-associated muscle symptoms, adherence to statin therapy is challenging in clinical practice. Certain nutraceuticals, such as red yeast rice, bergamot, berberine, artichoke, soluble fiber, and plant sterols and stanols alone or in combination with each other, as well as with ezetimibe, might be considered as an alternative or add-on therapy to statins, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. These nutraceuticals could exert significant lipid-lowering activity and might present multiple non-lipid-lowering actions, including improvement of endothelial dysfunction and arterial stiffness, as well as anti-inflammatory and antioxidative properties. The aim of this expert opinion paper is to provide the first attempt at recommendation on the management of statin intolerance through the use of nutraceuticals with particular attention on those with effective low-density lipoprotein cholesterol reduction.

J Am Coll Cardiol: 02 Jul 2018; 72:96-118
Banach M, Patti AM, Giglio RV, Cicero AFG, ... Rizzo M,
J Am Coll Cardiol: 02 Jul 2018; 72:96-118 | PMID: 29957236
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Abstract

Health Literacy and Cardiovascular Disease: Fundamental Relevance to Primary and Secondary Prevention: A Scientific Statement From the American Heart Association.

Magnani JW, Mujahid MS, Aronow HD, Cené CW, ... Willey JZ,
Health literacy is the degree to which individuals are able to access and process basic health information and services and thereby participate in health-related decisions. Limited health literacy is highly prevalent in the United States and is strongly associated with patient morbidity, mortality, healthcare use, and costs. The objectives of this American Heart Association scientific statement are (1) to summarize the relevance of health literacy to cardiovascular health; (2) to present the adverse associations of health literacy with cardiovascular risk factors, conditions, and treatments; (3) to suggest strategies that address barriers imposed by limited health literacy on the management and prevention of cardiovascular disease; (4) to demonstrate the contributions of health literacy to health disparities, given its association with social determinants of health; and (5) to propose future directions for how health literacy can be integrated into the American Heart Association\'s mandate to advance cardiovascular treatment and research, thereby improving patient care and public health. Inadequate health literacy is a barrier to the American Heart Association meeting its 2020 Impact Goals, and this statement articulates the rationale to anticipate and address the adverse cardiovascular effects associated with health literacy.

Circulation: 03 Jun 2018; epub ahead of print
Magnani JW, Mujahid MS, Aronow HD, Cené CW, ... Willey JZ,
Circulation: 03 Jun 2018; epub ahead of print | PMID: 29866648
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Abstract

Calcium Signaling and Reactive Oxygen Species in Mitochondria.

Bertero E, Maack C
In heart failure, alterations of Na and Ca handling, energetic deficit, and oxidative stress in cardiac myocytes are important pathophysiological hallmarks. Mitochondria are central to these processes because they are the main source for ATP, but also reactive oxygen species (ROS), and their function is critically controlled by Ca During physiological variations of workload, mitochondrial Ca uptake is required to match energy supply to demand but also to keep the antioxidative capacity in a reduced state to prevent excessive emission of ROS. Mitochondria take up Ca via the mitochondrial Ca uniporter, which exists in a multiprotein complex whose molecular components were identified only recently. In heart failure, deterioration of cytosolic Ca and Na handling hampers mitochondrial Ca uptake and the ensuing Krebs cycle-induced regeneration of the reduced forms of NADH (nicotinamide adenine dinucleotide) and NADPH (nicotinamide adenine dinucleotide phosphate), giving rise to energetic deficit and oxidative stress. ROS emission from mitochondria can trigger further ROS release from neighboring mitochondria termed ROS-induced ROS release, and cross talk between different ROS sources provides a spatially confined cellular network of redox signaling. Although low levels of ROS may serve physiological roles, higher levels interfere with excitation-contraction coupling, induce maladaptive cardiac remodeling through redox-sensitive kinases, and cell death through mitochondrial permeability transition. Targeting the dysregulated interplay between excitation-contraction coupling and mitochondrial energetics may ameliorate the progression of heart failure.

Circ Res: 10 May 2018; 122:1460-1478
Bertero E, Maack C
Circ Res: 10 May 2018; 122:1460-1478 | PMID: 29748369
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Abstract

PCSK9: From Basic Science Discoveries to Clinical Trials.

Shapiro MD, Tavori H, Fazio S
Unknown 15 years ago, PCSK9 (proprotein convertase subtilisin/kexin type 9) is now common parlance among scientists and clinicians interested in prevention and treatment of atherosclerotic cardiovascular disease. What makes this story so special is not its recent discovery nor the fact that it uncovered previously unknown biology but rather that these important scientific insights have been translated into an effective medical therapy in record time. Indeed, the translation of this discovery to novel therapeutic serves as one of the best examples of how genetic insights can be leveraged into intelligent target drug discovery. The PCSK9 saga is unfolding quickly but is far from complete. Here, we review major scientific understandings as they relate to the role of PCSK9 in lipoprotein metabolism and atherosclerotic cardiovascular disease and the impact that therapies designed to inhibit its action are having in the clinical setting.

Circ Res: 10 May 2018; 122:1420-1438
Shapiro MD, Tavori H, Fazio S
Circ Res: 10 May 2018; 122:1420-1438 | PMID: 29748367
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Abstract

Outcomes of PCI at Hospitals with or without On-Site Cardiac Surgery.

Aversano T, Lemmon CC, Liu L, the Atlantic CPORT Investigators
Background Performance of percutaneous coronary intervention (PCI) is usually restricted to hospitals with cardiac surgery on site. We conducted a noninferiority trial to compare the outcomes of PCI performed at hospitals without and those with on-site cardiac surgery. Methods We randomly assigned participants to undergo PCI at a hospital with or without on-site cardiac surgery. Patients requiring primary PCI were excluded. The trial had two primary end points: 6-week mortality and 9-month incidence of major adverse cardiac events (the composite of death, Q-wave myocardial infarction, or target-vessel revascularization). Noninferiority margins for the risk difference were 0.4 percentage points for mortality at 6 weeks and 1.8 percentage points for major adverse cardiac events at 9 months. Results A total of 18,867 patients were randomly assigned in a 3:1 ratio to undergo PCI at a hospital without on-site cardiac surgery (14,149 patients) or with on-site cardiac surgery (4718 patients). The 6-week mortality rate was 0.9% at hospitals without on-site surgery versus 1.0% at those with on-site surgery (difference, -0.04 percentage points; 95% confidence interval [CI], -0.31 to 0.23; P=0.004 for noninferiority). The 9-month rates of major adverse cardiac events were 12.1% and 11.2% at hospitals without and those with on-site surgery, respectively (difference, 0.92 percentage points; 95% CI, 0.04 to 1.80; P=0.05 for noninferiority). The rate of target-vessel revascularization was higher in hospitals without on-site surgery (6.5% vs. 5.4%, P=0.01). Conclusions We found that PCI performed at hospitals without on-site cardiac surgery was noninferior to PCI performed at hospitals with on-site cardiac surgery with respect to mortality at 6 weeks and major adverse cardiac events at 9 months. (Funded by the Cardiovascular Patient Outcomes Research Team [C-PORT] participating sites; ClinicalTrials.gov number, NCT00549796 .).

N Engl J Med: 25 Mar 2012; epub ahead of print
Aversano T, Lemmon CC, Liu L, the Atlantic CPORT Investigators
N Engl J Med: 25 Mar 2012; epub ahead of print | PMID: 22443460
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Abstract

Anemia and Iron Deficiency in Heart Failure: Current Concepts and Emerging Therapies.

Anand IS, Gupta P
Anemia and iron deficiency are important and common comorbidities that often coexist in patients with heart failure. Both conditions, together or independently, are associated with poor clinical status and worse outcomes. Whether anemia and iron deficiency are just markers of heart failure severity or whether they mediate heart failure progression and outcomes and therefore should be treated is not entirely clear. Treatment of anemia in patients with heart failure with erythropoiesis-stimulating agents has been evaluated intensively during the past several years. Unfortunately, these agents did not improve outcomes but were associated with a higher risk of adverse events. Iron deficiency in patients with heart failure can be absolute, when total body iron is decreased, or functional, when total body iron is normal or increased but is inadequate to meet the needs of target tissues because of sequestration in the storage pool. Whereas iron replacement is appropriate in patients with anemia resulting from absolute iron deficiency, it has been unclear whether and how absolute or functional iron deficiency should be treated in nonanemic patients with heart failure. Recently, small studies found that administration of intravenous iron in patients with heart failure and absolute or functional iron deficiency with or without anemia improves symptoms and exercise capacity, but long-term outcomes and safety data are not yet available. In this review, we discuss the causes and pathogenesis of and treatment options for anemia and iron deficiency in patients with heart failure.

Circulation: 02 Jul 2018; 138:80-98
Anand IS, Gupta P
Circulation: 02 Jul 2018; 138:80-98 | PMID: 29967232
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Abstract

Off-Pump or On-Pump Coronary-Artery Bypass Grafting at 30 Days.

Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, ... Yusuf S, the CORONARY Investigators
Background The relative benefits and risks of performing coronary-artery bypass grafting (CABG) with a beating-heart technique (off-pump CABG), as compared with cardiopulmonary bypass (on-pump CABG), are not clearly established. Methods At 79 centers in 19 countries, we randomly assigned 4752 patients in whom CABG was planned to undergo the procedure off-pump or on-pump. The first coprimary outcome was a composite of death, nonfatal stroke, nonfatal myocardial infarction, or new renal failure requiring dialysis at 30 days after randomization. Results There was no significant difference in the rate of the primary composite outcome between off-pump and on-pump CABG (9.8% vs. 10.3%; hazard ratio for the off-pump group, 0.95; 95% confidence interval [CI], 0.79 to 1.14; P=0.59) or in any of its individual components. The use of off-pump CABG, as compared with on-pump CABG, significantly reduced the rates of blood-product transfusion (50.7% vs. 63.3%; relative risk, 0.80; 95% CI, 0.75 to 0.85; P<0.001), reoperation for perioperative bleeding (1.4% vs. 2.4%; relative risk, 0.61; 95% CI, 0.40 to 0.93; P=0.02), acute kidney injury (28.0% vs. 32.1%; relative risk, 0.87; 95% CI, 0.80 to 0.96; P=0.01), and respiratory complications (5.9% vs. 7.5%; relative risk, 0.79; 95% CI, 0.63 to 0.98; P=0.03) but increased the rate of early repeat revascularizations (0.7% vs. 0.2%; hazard ratio, 4.01; 95% CI, 1.34 to 12.0; P=0.01). Conclusions There was no significant difference between off-pump and on-pump CABG with respect to the 30-day rate of death, myocardial infarction, stroke, or renal failure requiring dialysis. The use of off-pump CABG resulted in reduced rates of transfusion, reoperation for perioperative bleeding, respiratory complications, and acute kidney injury but also resulted in an increased risk of early revascularization. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294 .).

N Engl J Med: 26 Mar 2012; epub ahead of print
Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, ... Yusuf S, the CORONARY Investigators
N Engl J Med: 26 Mar 2012; epub ahead of print | PMID: 22449296
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Abstract

CT Angiography for Safe Discharge of Patients with Possible Acute Coronary Syndromes.

Litt HI, Gatsonis C, Snyder B, Singh H, ... Pacella CB, Hollander JE
Background Admission rates among patients presenting to emergency departments with possible acute coronary syndromes are high, although for most of these patients, the symptoms are ultimately found not to have a cardiac cause. Coronary computed tomographic angiography (CCTA) has a very high negative predictive value for the detection of coronary disease, but its usefulness in determining whether discharge of patients from the emergency department is safe is not well established. Methods We randomly assigned low-to-intermediate-risk patients presenting with possible acute coronary syndromes, in a 2:1 ratio, to undergo CCTA or to receive traditional care. Patients were enrolled at five centers in the United States. Patients older than 30 years of age with a Thrombolysis in Myocardial Infarction risk score of 0 to 2 and signs or symptoms warranting admission or testing were eligible. The primary outcome was safety, assessed in the subgroup of patients with a negative CCTA examination, with safety defined as the absence of myocardial infarction and cardiac death during the first 30 days after presentation. Results We enrolled 1370 subjects: 908 in the CCTA group and 462 in the group receiving traditional care. The baseline characteristics were similar in the two groups. Of 640 patients with a negative CCTA examination, none died or had a myocardial infarction within 30 days (0%; 95% confidence interval [CI], 0 to 0.57). As compared with patients receiving traditional care, patients in the CCTA group had a higher rate of discharge from the emergency department (49.6% vs. 22.7%; difference, 26.8 percentage points; 95% CI, 21.4 to 32.2), a shorter length of stay (median, 18.0 hours vs. 24.8 hours; P<0.001), and a higher rate of detection of coronary disease (9.0% vs. 3.5%; difference, 5.6 percentage points; 95% CI, 0 to 11.2). There was one serious adverse event in each group. Conclusions A CCTA-based strategy for low-to-intermediate-risk patients presenting with a possible acute coronary syndrome appears to allow the safe, expedited discharge from the emergency department of many patients who would otherwise be admitted. (Funded by the Commonwealth of Pennsylvania Department of Health and the American College of Radiology Imaging Network Foundation; ClinicalTrials.gov number, NCT00933400 .).

N Engl J Med: 26 Mar 2012; epub ahead of print
Litt HI, Gatsonis C, Snyder B, Singh H, ... Pacella CB, Hollander JE
N Engl J Med: 26 Mar 2012; epub ahead of print | PMID: 22449295
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Abstract

Supplemental Vitamins and Minerals for CVD Prevention and Treatment.

Jenkins DJA, Spence JD, Giovannucci EL, Kim YI, ... Pichika SC, Sievenpiper JL
The authors identified individual randomized controlled trials from previous meta-analyses and additional searches, and then performed meta-analyses on cardiovascular disease outcomes and all-cause mortality. The authors assessed publications from 2012, both before and including the U.S. Preventive Service Task Force review. Their systematic reviews and meta-analyses showed generally moderate- or low-quality evidence for preventive benefits (folic acid for total cardiovascular disease, folic acid and B-vitamins for stroke), no effect (multivitamins, vitamins C, D, β-carotene, calcium, and selenium), or increased risk (antioxidant mixtures and niacin [with a statin] for all-cause mortality). Conclusive evidence for the benefit of any supplement across all dietary backgrounds (including deficiency and sufficiency) was not demonstrated; therefore, any benefits seen must be balanced against possible risks.

J Am Coll Cardiol: 04 Jun 2018; 71:2570-2584
Jenkins DJA, Spence JD, Giovannucci EL, Kim YI, ... Pichika SC, Sievenpiper JL
J Am Coll Cardiol: 04 Jun 2018; 71:2570-2584 | PMID: 29852980
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Abstract

Acute rheumatic fever.

Karthikeyan G, Guilherme L
Acute rheumatic fever is caused by an autoimmune response to throat infection with Streptococcus pyogenes. Cardiac involvement during acute rheumatic fever can result in rheumatic heart disease, which can cause heart failure and premature mortality. Poverty and household overcrowding are associated with an increased prevalence of acute rheumatic fever and rheumatic heart disease, both of which remain a public health problem in many low-income countries. Control efforts are hampered by the scarcity of accurate data on disease burden, and effective approaches to diagnosis, prevention, and treatment. The diagnosis of acute rheumatic fever is entirely clinical, without any laboratory gold standard, and no treatments have been shown to reduce progression to rheumatic heart disease. Prevention mainly relies on the prompt recognition and treatment of streptococcal pharyngitis, and avoidance of recurrent infection using long-term antibiotics. But evidence for the effectiveness of either approach is not strong. High-quality research is urgently needed to guide efforts to reduce acute rheumatic fever incidence and prevent progression to rheumatic heart disease.

Lancet: 13 Jul 2018; 392:161-174
Karthikeyan G, Guilherme L
Lancet: 13 Jul 2018; 392:161-174 | PMID: 30025809
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Abstract

Comparative Effectiveness of Revascularization Strategies.

Weintraub WS, Grau-Sepulveda MV, Weiss JM, O\'Brien SM, ... Dangas GD, Edwards FH
Background Questions persist concerning the comparative effectiveness of percutaneous coronary intervention (PCI) and coronary-artery bypass grafting (CABG). The American College of Cardiology Foundation (ACCF) and the Society of Thoracic Surgeons (STS) collaborated to compare the rates of long-term survival after PCI and CABG. Methods We linked the ACCF National Cardiovascular Data Registry and the STS Adult Cardiac Surgery Database to claims data from the Centers for Medicare and Medicaid Services for the years 2004 through 2008. Outcomes were compared with the use of propensity scores and inverse-probability-weighting adjustment to reduce treatment-selection bias. Results Among patients 65 years of age or older who had two-vessel or three-vessel coronary artery disease without acute myocardial infarction, 86,244 underwent CABG and 103,549 underwent PCI. The median follow-up period was 2.67 years. At 1 year, there was no significant difference in adjusted mortality between the groups (6.24% in the CABG group as compared with 6.55% in the PCI group; risk ratio, 0.95; 95% confidence interval [CI], 0.90 to 1.00). At 4 years, there was lower mortality with CABG than with PCI (16.4% vs. 20.8%; risk ratio, 0.79; 95% CI, 0.76 to 0.82). Similar results were noted in multiple subgroups and with the use of several different analytic methods. Residual confounding was assessed by means of a sensitivity analysis. Conclusions In this observational study, we found that, among older patients with multivessel coronary disease that did not require emergency treatment, there was a long-term survival advantage among patients who underwent CABG as compared with patients who underwent PCI. (Funded by the National Heart, Lung, and Blood Institute.).

N Engl J Med: 27 Mar 2012; epub ahead of print
Weintraub WS, Grau-Sepulveda MV, Weiss JM, O'Brien SM, ... Dangas GD, Edwards FH
N Engl J Med: 27 Mar 2012; epub ahead of print | PMID: 22452338
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Abstract

Cardiovascular Disease and Homelessness.

Baggett TP, Liauw SS, Hwang SW
Cardiovascular disease (CVD) is a major cause of death among homeless adults, at rates that exceed those in nonhomeless individuals. A complex set of factors contributes to this disparity. In addition to a high prevalence of cigarette smoking and suboptimal control of traditional CVD risk factors such as hypertension and diabetes, a heavy burden of nontraditional psychosocial risk factors like chronic stress, depression, heavy alcohol use, and cocaine use may confer additional risk for adverse CVD outcomes beyond that predicted by conventional risk estimation methods. Poor health care access and logistical challenges to cardiac testing may lead to delays in presentation and diagnosis. The management of established CVD may be further challenged by barriers to medication adherence, communication, and timely follow-up. The authors present practical, patient-centered strategies for addressing these challenges, emphasizing the importance of multidisciplinary collaboration and partnership with homeless-tailored clinical programs to improve CVD outcomes in this population.

J Am Coll Cardiol: 04 Jun 2018; 71:2585-2597
Baggett TP, Liauw SS, Hwang SW
J Am Coll Cardiol: 04 Jun 2018; 71:2585-2597 | PMID: 29852981
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Abstract

Vorapaxar in the Secondary Prevention of Atherothrombotic Events.

Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, ... Murphy SA, the TRA 2P–TIMI 50 Steering Committee and Investigators
Background Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. Methods We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. Results At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). Conclusions Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474 .).

N Engl J Med: 25 Mar 2012; epub ahead of print
Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, ... Murphy SA, the TRA 2P–TIMI 50 Steering Committee and Investigators
N Engl J Med: 25 Mar 2012; epub ahead of print | PMID: 22443427
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Abstract

Transcatheter Aortic-Valve Replacement for Inoperable Severe Aortic Stenosis.

Makkar RR, Fontana GP, Jilaihawi H, Kapadia S, ... Leon MB, the PARTNER Trial Investigators
Background Transcatheter aortic-valve replacement (TAVR) is the recommended therapy for patients with severe aortic stenosis who are not suitable candidates for surgery. The outcomes beyond 1 year in such patients are not known. Methods We randomly assigned patients to transfemoral TAVR or to standard therapy (which often included balloon aortic valvuloplasty). Data on 2-year outcomes were analyzed. Results A total of 358 patients underwent randomization at 21 centers. The rates of death at 2 years were 43.3% in the TAVR group and 68.0% in the standard-therapy group (P<0.001), and the corresponding rates of cardiac death were 31.0% and 62.4% (P<0.001). The survival advantage associated with TAVR that was seen at 1 year remained significant among patients who survived beyond the first year (hazard ratio, 0.58; 95% confidence interval [CI], 0.36 to 0.92; P=0.02 with the use of the log-rank test). The rate of stroke was higher after TAVR than with standard therapy (13.8% vs. 5.5%, P=0.01), owing, in the first 30 days, to the occurrence of more ischemic events in the TAVR group (6.7% vs. 1.7%, P=0.02) and, beyond 30 days, to the occurrence of more hemorrhagic strokes in the TAVR group (2.2% vs. 0.6%, P=0.16). At 2 years, the rate of rehospitalization was 35.0% in the TAVR group and 72.5% in the standard-therapy group (P<0.001). TAVR, as compared with standard therapy, was also associated with improved functional status (P<0.001). The data suggest that the mortality benefit after TAVR may be limited to patients who do not have extensive coexisting conditions. Echocardiographic analysis showed a sustained increase in aortic-valve area and a decrease in aortic-valve gradient, with no worsening of paravalvular aortic regurgitation. Conclusions Among appropriately selected patients with severe aortic stenosis who were not suitable candidates for surgery, TAVR reduced the rates of death and hospitalization, with a decrease in symptoms and an improvement in valve hemodynamics that were sustained at 2 years of follow-up. The presence of extensive coexisting conditions may attenuate the survival benefit of TAVR. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894 .).

N Engl J Med: 25 Mar 2012; epub ahead of print
Makkar RR, Fontana GP, Jilaihawi H, Kapadia S, ... Leon MB, the PARTNER Trial Investigators
N Engl J Med: 25 Mar 2012; epub ahead of print | PMID: 22443478
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Abstract

Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes.

Schauer PR, Kashyap SR, Wolski K, Brethauer SA, ... Nissen SE, Bhatt DL
Background Observational studies have shown improvement in patients with type 2 diabetes mellitus after bariatric surgery. Methods In this randomized, nonblinded, single-center trial, we evaluated the efficacy of intensive medical therapy alone versus medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy in 150 obese patients with uncontrolled type 2 diabetes. The mean (±SD) age of the patients was 49±8 years, and 66% were women. The average glycated hemoglobin level was 9.2±1.5%. The primary end point was the proportion of patients with a glycated hemoglobin level of 6.0% or less 12 months after treatment. Results Of the 150 patients, 93% completed 12 months of follow-up. The proportion of patients with the primary end point was 12% (5 of 41 patients) in the medical-therapy group versus 42% (21 of 50 patients) in the gastric-bypass group (P=0.002) and 37% (18 of 49 patients) in the sleeve-gastrectomy group (P=0.008). Glycemic control improved in all three groups, with a mean glycated hemoglobin level of 7.5±1.8% in the medical-therapy group, 6.4±0.9% in the gastric-bypass group (P<0.001), and 6.6±1.0% in the sleeve-gastrectomy group (P=0.003). Weight loss was greater in the gastric-bypass group and sleeve-gastrectomy group (-29.4±9.0 kg and -25.1±8.5 kg, respectively) than in the medical-therapy group (-5.4±8.0 kg) (P<0.001 for both comparisons). The use of drugs to lower glucose, lipid, and blood-pressure levels decreased significantly after both surgical procedures but increased in patients receiving medical therapy only. The index for homeostasis model assessment of insulin resistance (HOMA-IR) improved significantly after bariatric surgery. Four patients underwent reoperation. There were no deaths or life-threatening complications. Conclusions In obese patients with uncontrolled type 2 diabetes, 12 months of medical therapy plus bariatric surgery achieved glycemic control in significantly more patients than medical therapy alone. Further study will be necessary to assess the durability of these results. (Funded by Ethicon Endo-Surgery and others; ClinicalTrials.gov number, NCT00432809 .).

N Engl J Med: 26 Mar 2012; epub ahead of print
Schauer PR, Kashyap SR, Wolski K, Brethauer SA, ... Nissen SE, Bhatt DL
N Engl J Med: 26 Mar 2012; epub ahead of print | PMID: 22449319
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Abstract

Sex Differences in Cardiovascular Pathophysiology: Why Women Are Overrepresented in Heart Failure With Preserved Ejection Fraction.

Beale AL, Meyer P, Marwick TH, Lam CSP, Kaye DM
Consistent epidemiological data demonstrate that patients with heart failure with preserved ejection fraction (HFpEF) are more likely to be women than men. Exploring mechanisms behind this sex difference in heart failure epidemiology may enrich the understanding of underlying HFpEF pathophysiology and phenotypes, with the ultimate goal of identifying therapeutic approaches for the broader HFpEF population. In this review we evaluate the influence of sex on the key domains of cardiac structure and function, the systemic and pulmonary circulation, as well as extracardiac factors and comorbidities that may explain the predisposition of women to HFpEF. We highlight the potential role of factors exclusive to or more prevalent in women such as pregnancy, preeclampsia, and iron deficiency. Finally, we discuss existing controversies and gaps in knowledge, as well as the clinical importance of known sex differences in the context of the potential need for sex-specific diagnostic criteria, improved risk stratification models, and targeted therapies.

Circulation: 09 Jul 2018; 138:198-205
Beale AL, Meyer P, Marwick TH, Lam CSP, Kaye DM
Circulation: 09 Jul 2018; 138:198-205 | PMID: 29986961
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Abstract

Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis.

Gordon AC, Perkins GD, Singer M, McAuley DF, ... Liu KD, Ashby D
Background Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis. Methods We conducted a double-blind, randomized clinical trial to investigate whether levosimendan reduces the severity of organ dysfunction in adults with sepsis. Patients were randomly assigned to receive a blinded infusion of levosimendan (at a dose of 0.05 to 0.2 μg per kilogram of body weight per minute) for 24 hours or placebo in addition to standard care. The primary outcome was the mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; maximum score, 20). Secondary outcomes included 28-day mortality, time to weaning from mechanical ventilation, and adverse events. Results The trial recruited 516 patients; 259 were assigned to receive levosimendan and 257 to receive placebo. There was no significant difference in the mean (±SD) SOFA score between the levosimendan group and the placebo group (6.68±3.96 vs. 6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], -0.07 to 1.29; P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference, 3.6 percentage points; 95% CI, -4.5 to 11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolute difference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04). Conclusions The addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality. Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia. (Funded by the NIHR Efficacy and Mechanism Evaluation Programme and others; LeoPARDS Current Controlled Trials number, ISRCTN12776039 .).

N Engl J Med: 04 Oct 2016; epub ahead of print
Gordon AC, Perkins GD, Singer M, McAuley DF, ... Liu KD, Ashby D
N Engl J Med: 04 Oct 2016; epub ahead of print | PMID: 27705084
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Abstract

Use of Intracardiac Echocardiography in Interventional Cardiology: Working With the Anatomy Rather Than Fighting It.

Enriquez A, Saenz LC, Rosso R, Silvestry FE, ... Marchlinski FE, Garcia F
The indications for catheter-based structural and electrophysiological procedures have recently expanded to more complex scenarios, in which an accurate definition of the variable individual cardiac anatomy is key to obtain optimal results. Intracardiac echocardiography (ICE) is a unique imaging modality able to provide high-resolution real-time visualization of cardiac structures, continuous monitoring of catheter location within the heart, and early recognition of procedural complications, such as pericardial effusion or thrombus formation. Additional benefits are excellent patient tolerance, reduction of fluoroscopy time, and lack of need for general anesthesia or a second operator. For these reasons, ICE has largely replaced transesophageal echocardiography as ideal imaging modality for guiding certain procedures, such as atrial septal defect closure and catheter ablation of cardiac arrhythmias, and has an emerging role in others, including mitral valvuloplasty, transcatheter aortic valve replacement, and left atrial appendage closure. In electrophysiology procedures, ICE allows integration of real-time images with electroanatomic maps; it has a role in assessment of arrhythmogenic substrate, and it is particularly useful for mapping structures that are not visualized by fluoroscopy, such as the interatrial or interventricular septum, papillary muscles, and intracavitary muscular ridges. Most recently, a three-dimensional (3D) volumetric ICE system has also been developed, with potential for greater anatomic information and a promising role in structural interventions. In this state-of-the-art review, we provide guidance on how to conduct a comprehensive ICE survey and summarize the main applications of ICE in a variety of structural and electrophysiology procedures.

Circulation: 21 May 2018; 137:2278-2294
Enriquez A, Saenz LC, Rosso R, Silvestry FE, ... Marchlinski FE, Garcia F
Circulation: 21 May 2018; 137:2278-2294 | PMID: 29784681
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Abstract

Seafood Long-Chain n-3 Polyunsaturated Fatty Acids and Cardiovascular Disease: A Science Advisory From the American Heart Association.

Rimm EB, Appel LJ, Chiuve SE, Djoussé L, ... Lichtenstein AH,
Since the 2002 American Heart Association scientific statement \"Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease,\" evidence from observational and experimental studies and from randomized controlled trials continues to emerge to further substantiate the beneficial effects of seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease. A recent American Heart Association science advisory addressed the specific effect of n-3 polyunsaturated fatty acid supplementation on clinical cardiovascular events. This American Heart Association science advisory extends that review and offers further support to include n-3 polyunsaturated fatty acids from seafood consumption. Several potential mechanisms have been investigated, including antiarrhythmic, anti-inflammatory, hematologic, and endothelial, although for most, longer-term dietary trials of seafood are warranted to substantiate the benefit of seafood as a replacement for other important sources of macronutrients. The present science advisory reviews this evidence and makes a suggestion in the context of the and in consideration of other constituents of seafood and the impact on sustainability. We conclude that 1 to 2 seafood meals per week be included to reduce the risk of congestive heart failure, coronary heart disease, ischemic stroke, and sudden cardiac death, especially when seafood replaces the intake of less healthy foods.

Circulation: 16 May 2018; epub ahead of print
Rimm EB, Appel LJ, Chiuve SE, Djoussé L, ... Lichtenstein AH,
Circulation: 16 May 2018; epub ahead of print | PMID: 29773586
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Abstract

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

Marso SP, Bain SC, Consoli A, Eliaschewitz FG, ... Vilsbøll T, SUSTAIN-6 Investigators
Background Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. Methods We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. Results At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal. Conclusions In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).

N Engl J Med: 15 Sep 2016; epub ahead of print
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, ... Vilsbøll T, SUSTAIN-6 Investigators
N Engl J Med: 15 Sep 2016; epub ahead of print | PMID: 27633186
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Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop.

Goldberg IJ, Reue K, Abumrad NA, Bickel PE, ... Walther TC, Chen J
Lipid droplets (LDs) are distinct and dynamic organelles that affect the health of cells and organs. Much progress has been made in understanding how these structures are formed, how they interact with other cellular organelles, how they are used for storage of triacylglycerol in adipose tissue, and how they regulate lipolysis. Our understanding of the biology of LDs in the heart and vascular tissue is relatively primitive in comparison with LDs in adipose tissue and liver. The National Heart, Lung, and Blood Institute convened a working group to discuss how LDs affect cardiovascular diseases. The goal of the working group was to examine the current state of knowledge on the cell biology of LDs, including current methods to study them in cells and organs and reflect on how LDs influence the development and progression of cardiovascular diseases. This review summarizes the working group discussion and recommendations on research areas ripe for future investigation that will likely improve our understanding of atherosclerosis and heart function.

Circulation: 16 Jul 2018; 138:305-315
Goldberg IJ, Reue K, Abumrad NA, Bickel PE, ... Walther TC, Chen J
Circulation: 16 Jul 2018; 138:305-315 | PMID: 30012703
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Abstract

Transcatheter Tricuspid Valve Interventions: Landscape, Challenges, and Future Directions.

Asmarats L, Puri R, Latib A, Navia JL, Rodés-Cabau J
Tricuspid regurgitation is a common finding in patients with left-sided valvular or myocardial disease, often being a marker for late-stage chronic heart failure with a grim prognosis. However, isolated tricuspid valve surgery remains infrequent and is associated with the highest mortality among all valve procedures. Hence, a largely unmet clinical need exists for less invasive therapeutic options in these patients. In recent times, multiple percutaneous therapies have been developed for treating severe tricuspid regurgitation, including tricuspid valve repair and, more recently replacement, opening an entirely new venue for managing tricuspid regurgitation. The aim of this review is to provide an updated overview and a clinical perspective on novel transcatheter tricuspid valve therapies, highlighting potential challenges and future directions.

J Am Coll Cardiol: 25 Jun 2018; 71:2935-2956
Asmarats L, Puri R, Latib A, Navia JL, Rodés-Cabau J
J Am Coll Cardiol: 25 Jun 2018; 71:2935-2956 | PMID: 29929618
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Abstract

Dronedarone in High-Risk Permanent Atrial Fibrillation.

Connolly SJ, Camm AJ, Halperin JL, Joyner C, ... Hohnloser SH, the PALLAS Investigators
Background Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular anti-arrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in high-risk permanent atrial fibrillation. Methods We assigned patients who were at least 65 years of age with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The first coprimary outcome was stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second coprimary outcome was unplanned hospitalization for a cardiovascular cause or death. Results After the enrollment of 3236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P=0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P=0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P=0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P=0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P=0.02). Conclusions Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients. (Funded by Sanofi-Aventis; PALLAS ClinicalTrials.gov number, NCT01151137 .).

N Engl J Med: 15 Nov 2011; epub ahead of print
Connolly SJ, Camm AJ, Halperin JL, Joyner C, ... Hohnloser SH, the PALLAS Investigators
N Engl J Med: 15 Nov 2011; epub ahead of print | PMID: 22082198
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Abstract

Irbesartan in patients with atrial fibrillation.

ACTIVE I Investigators, Yusuf S, Healey JS, Pogue J, ... Pfeffer MA, Connolly SJ
Background The risk of cardiovascular events among patients with atrial fibrillation is high. We evaluated whether irbesartan, an angiotensin-receptor blocker, would reduce this risk. Methods We randomly assigned patients with a history of risk factors for stroke and a systolic blood pressure of at least 110 mm Hg to receive either irbesartan at a target dose of 300 mg once daily or double-blind placebo. These patients were already enrolled in one of two trials (of clopidogrel plus aspirin versus aspirin alone or versus oral anticoagulants). The first coprimary outcome was stroke, myocardial infarction, or death from vascular causes; the second was this composite outcome plus hospitalization for heart failure. Results A total of 9016 patients were enrolled and followed for a mean of 4.1 years. The mean reduction in systolic blood pressure was 2.9 mm Hg greater in the irbesartan group than in the placebo group, and the mean reduction in diastolic blood pressure was 1.9 mm Hg greater. The first coprimary outcome occurred at a rate of 5.4% per 100 person-years in both groups (hazard ratio with irbesartan, 0.99; 95% confidence interval [CI], 0.91 to 1.08; P=0.85). The second coprimary outcome occurred at a rate of 7.3% per 100 person-years among patients receiving irbesartan and 7.7% per 100 person-years among patients receiving placebo (hazard ratio, 0.94; 95% CI, 0.87 to 1.02; P=0.12). The rates of first hospitalization for heart failure (a prespecified secondary outcome) were 2.7% per 100 person-years among patients receiving irbesartan and 3.2% per 100 person-years among patients receiving placebo (hazard ratio, 0.86; 95% CI, 0.76 to 0.98). Among patients who were in sinus rhythm at baseline, there was no benefit of irbesartan in preventing hospitalization for atrial fibrillation or atrial fibrillation recorded on 12-lead electrocardiography, nor was there a benefit in a subgroup that underwent transtelephonic monitoring. More patients in the irbesartan group than in the placebo group had symptomatic hypotension (127 vs. 64) and renal dysfunction (43 vs. 24). Conclusions Irbesartan did not reduce cardiovascular events in patients with atrial fibrillation. (Funded by Bristol-Myers Squibb and Sanofi-Aventis; ClinicalTrials.gov number, NCT00249795 .).

N Engl J Med: 10 Mar 2011; 364:928-38
ACTIVE I Investigators, Yusuf S, Healey JS, Pogue J, ... Pfeffer MA, Connolly SJ
N Engl J Med: 10 Mar 2011; 364:928-38 | PMID: 21388310
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Abstract

Cardiac Arrest during Long-Distance Running Races.

Kim JH, Malhotra R, Chiampas G, d\'Hemecourt P, ... Baggish AL, the Race Associated Cardiac Arrest Event Registry (RACER) Study Group
Background Approximately 2 million people participate in long-distance running races in the United States annually. Reports of race-related cardiac arrests have generated concern about the safety of this activity. Methods We assessed the incidence and outcomes of cardiac arrest associated with marathon and half-marathon races in the United States from January 1, 2000, to May 31, 2010. We determined the clinical characteristics of the arrests by interviewing survivors and the next of kin of nonsurvivors, reviewing medical records, and analyzing postmortem data. Results Of 10.9 million runners, 59 (mean [?SD] age, 42?13 years; 51 men) had cardiac arrest (incidence rate, 0.54 per 100,000 participants; 95% confidence interval [CI], 0.41 to 0.70). Cardiovascular disease accounted for the majority of cardiac arrests. The incidence rate was significantly higher during marathons (1.01 per 100,000; 95% CI, 0.72 to 1.38) than during half-marathons (0.27; 95% CI, 0.17 to 0.43) and among men (0.90 per 100,000; 95% CI, 0.67 to 1.18) than among women (0.16; 95% CI, 0.07 to 0.31). Male marathon runners, the highest-risk group, had an increased incidence of cardiac arrest during the latter half of the study decade (2000?2004, 0.71 per 100,000 [95% CI, 0.31 to 1.40]; 2005?2010, 2.03 per 100,000 [95% CI, 1.33 to 2.98]; P=0.01). Of the 59 cases of cardiac arrest, 42 (71%) were fatal (incidence, 0.39 per 100,000; 95% CI, 0.28 to 0.52). Among the 31 cases with complete clinical data, initiation of bystander-administered cardiopulmonary resuscitation and an underlying diagnosis other than hypertrophic cardiomyopathy were the strongest predictors of survival. Conclusions Marathons and half-marathons are associated with a low overall risk of cardiac arrest and sudden death. Cardiac arrest, most commonly attributable to hypertrophic cardiomyopathy or atherosclerotic coronary disease, occurs primarily among male marathon participants; the incidence rate in this group increased during the past decade.

N Engl J Med: 12 Jan 2012; 366:130-140
Kim JH, Malhotra R, Chiampas G, d'Hemecourt P, ... Baggish AL, the Race Associated Cardiac Arrest Event Registry (RACER) Study Group
N Engl J Med: 12 Jan 2012; 366:130-140 | PMID: 22236223
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Abstract

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.

Connolly SJ, Milling TJ, Eikelboom JW, Gibson CM, ... Crowther M, ANNEXA-4 Investigators
Background Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers. Methods In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication. Results The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up. Conclusions On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

N Engl J Med: 29 Aug 2016; epub ahead of print
Connolly SJ, Milling TJ, Eikelboom JW, Gibson CM, ... Crowther M, ANNEXA-4 Investigators
N Engl J Med: 29 Aug 2016; epub ahead of print | PMID: 27573206
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Abstract

Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure.

Køber L, Thune JJ, Nielsen JC, Haarbo J, ... Pehrson S, DANISH Investigators
Background The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT). Methods In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death. Results After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29). Conclusions In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).

N Engl J Med: 28 Aug 2016; epub ahead of print
Køber L, Thune JJ, Nielsen JC, Haarbo J, ... Pehrson S, DANISH Investigators
N Engl J Med: 28 Aug 2016; epub ahead of print | PMID: 27571011
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Abstract

Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome.

Pfeffer MA, Claggett B, Diaz R, Dickstein K, ... Tardif JC, ELIXA Investigators
Background Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes, particularly those with concomitant cardiovascular diseases, than in most other populations. We assessed the effects of lixisenatide, a glucagon-like peptide 1-receptor agonist, on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary event. Methods We randomly assigned patients with type 2 diabetes who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo in addition to locally determined standards of care. The trial was designed with adequate statistical power to assess whether lixisenatide was noninferior as well as superior to placebo, as defined by an upper boundary of the 95% confidence interval for the hazard ratio of less than 1.3 and 1.0, respectively, for the primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina. Results The 6068 patients who underwent randomization were followed for a median of 25 months. A primary end-point event occurred in 406 patients (13.4%) in the lixisenatide group and in 399 (13.2%) in the placebo group (hazard ratio, 1.02; 95% confidence interval [CI], 0.89 to 1.17), which showed the noninferiority of lixisenatide to placebo (P<0.001) but did not show superiority (P=0.81). There were no significant between-group differences in the rate of hospitalization for heart failure (hazard ratio in the lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions than was placebo. Conclusions In patients with type 2 diabetes and a recent acute coronary syndrome, the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events. (Funded by Sanofi; ELIXA ClinicalTrials.gov number, NCT01147250 .).

N Engl J Med: 01 Dec 2015; 373:2247-2257
Pfeffer MA, Claggett B, Diaz R, Dickstein K, ... Tardif JC, ELIXA Investigators
N Engl J Med: 01 Dec 2015; 373:2247-2257 | PMID: 26630143
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Abstract

Long-term effects of intensive glucose lowering on cardiovascular outcomes.


Background Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events. Methods We randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial. Results Before the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P=0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups. Conclusions As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620 .).

N Engl J Med: 03 Mar 2011; 364:818-28
N Engl J Med: 03 Mar 2011; 364:818-28 | PMID: 21366473
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Abstract

Comparison of Shunt Types in the Norwood Procedure for Single-Ventricle Lesions.

Ohye RG, Sleeper LA, Mahony L, Newburger JW, ... Gaynor JW, the Pediatric Heart Network Investigators
Background: The Norwood procedure with a modified Blalock-Taussig (MBT) shunt, the first palliative stage for single-ventricle lesions with systemic outflow obstruction, is associated with high mortality. The right ventricle-pulmonary artery (RVPA) shunt may improve coronary flow but requires a ventriculotomy. We compared the two shunts in infants with hypoplastic heart syndrome or related anomalies. Methods: Infants undergoing the Norwood procedure were randomly assigned to the MBT shunt (275 infants) or the RVPA shunt (274 infants) at 15 North American centers. The primary outcome was death or cardiac transplantation 12 months after randomization. Secondary outcomes included unintended cardiovascular interventions and right ventricular size and function at 14 months and transplantation-free survival until the last subject reached 14 months of age. Results: Transplantation-free survival 12 months after randomization was higher with the RVPA shunt than with the MBT shunt (74% vs. 64%, P=0.01). However, the RVPA shunt group had more unintended interventions (P=0.003) and complications (P=0.002). Right ventricular size and function at the age of 14 months and the rate of nonfatal serious adverse events at the age of 12 months were similar in the two groups. Data collected over a mean (+/-SD) follow-up period of 32+/-11 months showed a nonsignificant difference in transplantation-free survival between the two groups (P=0.06). On nonproportional-hazards analysis, the size of the treatment effect differed before and after 12 months (P=0.02). Conclusions: In children undergoing the Norwood procedure, transplantation-free survival at 12 months was better with the RVPA shunt than with the MBT shunt. After 12 months, available data showed no significant difference in transplantation-free survival between the two groups. (ClinicalTrials.gov number, NCT00115934.) Copyright 2010 Massachusetts Medical Society.

N Engl J Med: 27 May 2010; 362:1980-1992
Ohye RG, Sleeper LA, Mahony L, Newburger JW, ... Gaynor JW, the Pediatric Heart Network Investigators
N Engl J Med: 27 May 2010; 362:1980-1992 | PMID: 20505177
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Abstract

Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms.

Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, ... Pitt B, the EMPHASIS-HF Study Group
Background Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms. Methods In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. Results The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001). Conclusions Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.).

N Engl J Med: 15 Nov 2010; epub ahead of print
Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, ... Pitt B, the EMPHASIS-HF Study Group
N Engl J Med: 15 Nov 2010; epub ahead of print | PMID: 21073363
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Abstract

Energetics of Blood Flow in Cardiovascular Disease: Concept and Clinical Implications of Adverse Energetics in Patients With a Fontan Circulation.

Rijnberg FM, Hazekamp MG, Wentzel JJ, de Koning PJH, ... Blom NA, Roest AAW
Visualization and quantification of the adverse effects of distorted blood flow are important emerging fields in cardiology. Abnormal blood flow patterns can be seen in various cardiovascular diseases and are associated with increased energy loss. These adverse energetics can be measured and quantified using 3-dimensional blood flow data, derived from computational fluid dynamics and 4-dimensional flow magnetic resonance imaging, and provide new, promising hemodynamic markers. In patients with palliated single-ventricular heart defects, the Fontan circulation passively directs systemic venous return to the pulmonary circulation in the absence of a functional subpulmonary ventricle. Therefore, the Fontan circulation is highly dependent on favorable flow and energetics, and minimal energy loss is of great importance. A focus on reducing energy loss led to the introduction of the total cavopulmonary connection (TCPC) as an alternative to the classical Fontan connection. Subsequently, many studies have investigated energy loss in the TCPC, and energy-saving geometric factors have been implemented in clinical care. Great advances have been made in computational fluid dynamics modeling and can now be done in 3-dimensional patient-specific models with increasingly accurate boundary conditions. Furthermore, the implementation of 4-dimensional flow magnetic resonance imaging is promising and can be of complementary value to these models. Recently, correlations between energy loss in the TCPC and cardiac parameters and exercise intolerance have been reported. Furthermore, efficiency of blood flow through the TCPC is highly variable, and inefficient blood flow is of clinical importance by reducing cardiac output and increasing central venous pressure, thereby increasing the risk of experiencing the well-known Fontan complications. Energy loss in the TCPC will be an important new hemodynamic parameter in addition to other well-known risk factors such as pulmonary vascular resistance and can possibly be improved by patient-specific surgical design. This article describes the theoretical background of mechanical energy of blood flow in the cardiovascular system and the methods of calculating energy loss, and it gives an overview of geometric factors associated with energy efficiency in the TCPC and its implications on clinical outcome. Furthermore, the role of 4-dimensional flow magnetic resonance imaging and areas of future research are discussed.

Circulation: 28 May 2018; 137:2393-2407
Rijnberg FM, Hazekamp MG, Wentzel JJ, de Koning PJH, ... Blom NA, Roest AAW
Circulation: 28 May 2018; 137:2393-2407 | PMID: 29844073
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Abstract

Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Disease.

Bangalore S, Guo Y, Samadashvili Z, Blecker S, Xu J, Hannan EL
Background Results of trials and registry studies have shown lower long-term mortality after coronary-artery bypass grafting (CABG) than after percutaneous coronary intervention (PCI) among patients with multivessel disease. These previous analyses did not evaluate PCI with second-generation drug-eluting stents. Methods In an observational registry study, we compared the outcomes in patients with multivessel disease who underwent CABG with the outcomes in those who underwent PCI with the use of everolimus-eluting stents. The primary outcome was all-cause mortality. Secondary outcomes were the rates of myocardial infarction, stroke, and repeat revascularization. Propensity-score matching was used to assemble a cohort of patients with similar baseline characteristics. Results Among 34,819 eligible patients, 9223 patients who underwent PCI with everolimus-eluting stents and 9223 who underwent CABG had similar propensity scores and were included in the analyses. At a mean follow-up of 2.9 years, PCI with everolimus-eluting stents, as compared with CABG, was associated with a similar risk of death (3.1% per year and 2.9% per year, respectively; hazard ratio, 1.04; 95% confidence interval [CI], 0.93 to 1.17; P=0.50), higher risks of myocardial infarction (1.9% per year vs. 1.1% per year; hazard ratio, 1.51; 95% CI, 1.29 to 1.77; P<0.001) and repeat revascularization (7.2% per year vs. 3.1% per year; hazard ratio, 2.35; 95% CI, 2.14 to 2.58; P<0.001), and a lower risk of stroke (0.7% per year vs. 1.0% per year; hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). The higher risk of myocardial infarction with PCI than with CABG was not significant among patients with complete revascularization but was significant among those with incomplete revascularization (P=0.02 for interaction). Conclusions In a contemporary clinical-practice registry study, the risk of death associated with PCI with everolimus-eluting stents was similar to that associated with CABG. PCI was associated with a higher risk of myocardial infarction (among patients with incomplete revascularization) and repeat revascularization but a lower risk of stroke. (Funded by Abbott Vascular.).

N Engl J Med: 15 Mar 2015; epub ahead of print
Bangalore S, Guo Y, Samadashvili Z, Blecker S, Xu J, Hannan EL
N Engl J Med: 15 Mar 2015; epub ahead of print | PMID: 25775087
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Abstract

One-Year Risk of Stroke after Transient Ischemic Attack or Minor Stroke.

Amarenco P, Lavallée PC, Labreuche J, Albers GW, ... Wong LK, TIAregistry.org Investigators
Background Previous studies conducted between 1997 and 2003 estimated that the risk of stroke or an acute coronary syndrome was 12 to 20% during the first 3 months after a transient ischemic attack (TIA) or minor stroke. The TIAregistry.org project was designed to describe the contemporary profile, etiologic factors, and outcomes in patients with a TIA or minor ischemic stroke who receive care in health systems that now offer urgent evaluation by stroke specialists. Methods We recruited patients who had had a TIA or minor stroke within the previous 7 days. Sites were selected if they had systems dedicated to urgent evaluation of patients with TIA. We estimated the 1-year risk of stroke and of the composite outcome of stroke, an acute coronary syndrome, or death from cardiovascular causes. We also examined the association of the ABCD(2) score for the risk of stroke (range, 0 [lowest risk] to 7 [highest risk]), findings on brain imaging, and cause of TIA or minor stroke with the risk of recurrent stroke over a period of 1 year. Results From 2009 through 2011, we enrolled 4789 patients at 61 sites in 21 countries. A total of 78.4% of the patients were evaluated by stroke specialists within 24 hours after symptom onset. A total of 33.4% of the patients had an acute brain infarction, 23.2% had at least one extracranial or intracranial stenosis of 50% or more, and 10.4% had atrial fibrillation. The Kaplan-Meier estimate of the 1-year event rate of the composite cardiovascular outcome was 6.2% (95% confidence interval, 5.5 to 7.0). Kaplan-Meier estimates of the stroke rate at days 2, 7, 30, 90, and 365 were 1.5%, 2.1%, 2.8%, 3.7%, and 5.1%, respectively. In multivariable analyses, multiple infarctions on brain imaging, large-artery atherosclerosis, and an ABCD(2) score of 6 or 7 were each associated with more than a doubling of the risk of stroke. Conclusions We observed a lower risk of cardiovascular events after TIA than previously reported. The ABCD(2) score, findings on brain imaging, and status with respect to large-artery atherosclerosis helped stratify the risk of recurrent stroke within 1 year after a TIA or minor stroke. (Funded by Sanofi and Bristol-Myers Squibb.).

N Engl J Med: 19 Apr 2016; 374:1533-1542
Amarenco P, Lavallée PC, Labreuche J, Albers GW, ... Wong LK, TIAregistry.org Investigators
N Engl J Med: 19 Apr 2016; 374:1533-1542 | PMID: 27096581
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Abstract

Randomized Trial of Primary PCI with or without Routine Manual Thrombectomy.

Jolly SS, Cairns JA, Yusuf S, Meeks B, ... Džavík V, TOTAL Investigators
Background During primary percutaneous coronary intervention (PCI), manual thrombectomy may reduce distal embolization and thus improve microvascular perfusion. Small trials have suggested that thrombectomy improves surrogate and clinical outcomes, but a larger trial has reported conflicting results. Methods We randomly assigned 10,732 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI to a strategy of routine upfront manual thrombectomy versus PCI alone. The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association (NYHA) class IV heart failure within 180 days. The key safety outcome was stroke within 30 days. Results The primary outcome occurred in 347 of 5033 patients (6.9%) in the thrombectomy group versus 351 of 5030 patients (7.0%) in the PCI-alone group (hazard ratio in the thrombectomy group, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P=0.86). The rates of cardiovascular death (3.1% with thrombectomy vs. 3.5% with PCI alone; hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P=0.34) and the primary outcome plus stent thrombosis or target-vessel revascularization (9.9% vs. 9.8%; hazard ratio, 1.00; 95% CI, 0.89 to 1.14; P=0.95) were also similar. Stroke within 30 days occurred in 33 patients (0.7%) in the thrombectomy group versus 16 patients (0.3%) in the PCI-alone group (hazard ratio, 2.06; 95% CI, 1.13 to 3.75; P=0.02). Conclusions In patients with STEMI who were undergoing primary PCI, routine manual thrombectomy, as compared with PCI alone, did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days but was associated with an increased rate of stroke within 30 days. (Funded by Medtronic and the Canadian Institutes of Health Research; TOTAL ClinicalTrials.gov number, NCT01149044 .).

N Engl J Med: 15 Mar 2015; epub ahead of print
Jolly SS, Cairns JA, Yusuf S, Meeks B, ... Džavík V, TOTAL Investigators
N Engl J Med: 15 Mar 2015; epub ahead of print | PMID: 25775387
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Abstract

Coronary-Artery Bypass Surgery in Patients with Left Ventricular Dysfunction.

Velazquez EJ, Lee KL, Deja MA, Jain A, ... Rouleau JL, the STICH Investigators
Background The role of coronary-artery bypass grafting (CABG) in the treatment of patients with coronary artery disease and heart failure has not been clearly established. Methods Between July 2002 and May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to medical therapy alone (602 patients) or medical therapy plus CABG (610 patients). The primary outcome was the rate of death from any cause. Major secondary outcomes included the rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. Results The primary outcome occurred in 244 patients (41%) in the medical-therapy group and 218 (36%) in the CABG group (hazard ratio with CABG, 0.86; 95% confidence interval [CI], 0.72 to 1.04; P=0.12). A total of 201 patients (33%) in the medical-therapy group and 168 (28%) in the CABG group died from an adjudicated cardiovascular cause (hazard ratio with CABG, 0.81; 95% CI, 0.66 to 1.00; P=0.05). Death from any cause or hospitalization for cardiovascular causes occurred in 411 patients (68%) in the medical-therapy group and 351 (58%) in the CABG group (hazard ratio with CABG, 0.74; 95% CI, 0.64 to 0.85; P<0.001). By the end of the follow-up period (median, 56 months), 100 patients in the medical-therapy group (17%) underwent CABG, and 555 patients in the CABG group (91%) underwent CABG. Conclusions In this randomized trial, there was no significant difference between medical therapy alone and medical therapy plus CABG with respect to the primary end point of death from any cause. Patients assigned to CABG, as compared with those assigned to medical therapy alone, had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; STICH ClinicalTrials.gov number, NCT00023595 .).

N Engl J Med: 05 Apr 2011; epub ahead of print
Velazquez EJ, Lee KL, Deja MA, Jain A, ... Rouleau JL, the STICH Investigators
N Engl J Med: 05 Apr 2011; epub ahead of print | PMID: 21463150
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Abstract

Effect of home testing of international normalized ratio on clinical events.

Matchar DB, Jacobson A, Dolor R, Edson R, ... Lavori P, THINRS Executive Committee and Site Investigators
Background: Warfarin anticoagulation reduces thromboembolic complications in patients with atrial fibrillation or mechanical heart valves, but effective management is complex, and the international normalized ratio (INR) is often outside the target range. As compared with venous plasma testing, point-of-care INR measuring devices allow greater testing frequency and patient involvement and may improve clinical outcomes. Methods: We randomly assigned 2922 patients who were taking warfarin because of mechanical heart valves or atrial fibrillation and who were competent in the use of point-of-care INR devices to either weekly self-testing at home or monthly high-quality testing in a clinic. The primary end point was the time to a first major event (stroke, major bleeding episode, or death). Results: The patients were followed for 2.0 to 4.75 years, for a total of 8730 patient-years of follow-up. The time to the first primary event was not significantly longer in the self-testing group than in the clinic-testing group (hazard ratio, 0.88; 95% confidence interval, 0.75 to 1.04; P=0.14). The two groups had similar rates of clinical outcomes except that the self-testing group reported more minor bleeding episodes. Over the entire follow-up period, the self-testing group had a small but significant improvement in the percentage of time during which the INR was within the target range (absolute difference between groups, 3.8 percentage points; P<0.001). At 2 years of follow-up, the self-testing group also had a small but significant improvement in patient satisfaction with anticoagulation therapy (P=0.002) and quality of life (P<0.001). Conclusions: As compared with monthly high-quality clinic testing, weekly self-testing did not delay the time to a first stroke, major bleeding episode, or death to the extent suggested by prior studies. These results do not support the superiority of self-testing over clinic testing in reducing the risk of stroke, major bleeding episode, and death among patients taking warfarin therapy. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT00032591.).

N Engl J Med: 21 Oct 2010; 363:1608-20
Matchar DB, Jacobson A, Dolor R, Edson R, ... Lavori P, THINRS Executive Committee and Site Investigators
N Engl J Med: 21 Oct 2010; 363:1608-20 | PMID: 20961244
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Abstract

CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea.

McEvoy RD, Antic NA, Heeley E, Luo Y, ... Anderson CS, SAVE Investigators and Coordinators
Background Obstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain. Methods After a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood. Results Most of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood. Conclusions Therapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT00738179 ; Australian New Zealand Clinical Trials Registry number, ACTRN12608000409370 .).

N Engl J Med: 28 Aug 2016; epub ahead of print
McEvoy RD, Antic NA, Heeley E, Luo Y, ... Anderson CS, SAVE Investigators and Coordinators
N Engl J Med: 28 Aug 2016; epub ahead of print | PMID: 27571048
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Abstract

Trial of Everolimus-Eluting Stents or Bypass Surgery for Coronary Disease.

Park SJ, Ahn JM, Kim YH, Park DW, ... Ong TK, BEST Trial Investigators
Background Most trials comparing percutaneous coronary intervention (PCI) with coronary-artery bypass grafting (CABG) have not made use of second-generation drug-eluting stents. Methods We conducted a randomized noninferiority trial at 27 centers in East Asia. We planned to randomly assign 1776 patients with multivessel coronary artery disease to PCI with everolimus-eluting stents or to CABG. The primary end point was a composite of death, myocardial infarction, or target-vessel revascularization at 2 years after randomization. Event rates during longer-term follow-up were also compared between groups. Results After the enrollment of 880 patients (438 patients randomly assigned to the PCI group and 442 randomly assigned to the CABG group), the study was terminated early owing to slow enrollment. At 2 years, the primary end point had occurred in 11.0% of the patients in the PCI group and in 7.9% of those in the CABG group (absolute risk difference, 3.1 percentage points; 95% confidence interval [CI], -0.8 to 6.9; P=0.32 for noninferiority). At longer-term follow-up (median, 4.6 years), the primary end point had occurred in 15.3% of the patients in the PCI group and in 10.6% of those in the CABG group (hazard ratio, 1.47; 95% CI, 1.01 to 2.13; P=0.04). No significant differences were seen between the two groups in the occurrence of a composite safety end point of death, myocardial infarction, or stroke. However, the rates of any repeat revascularization and spontaneous myocardial infarction were significantly higher after PCI than after CABG. Conclusions Among patients with multivessel coronary artery disease, the rate of major adverse cardiovascular events was higher among those who had undergone PCI with the use of everolimus-eluting stents than among those who had undergone CABG. (Funded by CardioVascular Research Foundation and others; BEST ClinicalTrials.gov number, NCT00997828 .).

N Engl J Med: 15 Mar 2015; epub ahead of print
Park SJ, Ahn JM, Kim YH, Park DW, ... Ong TK, BEST Trial Investigators
N Engl J Med: 15 Mar 2015; epub ahead of print | PMID: 25774645
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This program is still in alpha version.