Journal: Circulation

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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

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

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

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

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

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

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

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

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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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

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

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

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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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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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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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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Atherosclerotic Cardiovascular Disease in South Asians in the United States: Epidemiology, Risk Factors, and Treatments: A Scientific Statement From the American Heart Association.

Volgman AS, Palaniappan LS, Aggarwal NT, Gupta M, ... Watson KE,
South Asians (from Bangladesh, Bhutan, India, the Maldives, Nepal, Pakistan, and Sri Lanka) make up one quarter of the world\'s population and are one of the fastest-growing ethnic groups in the United States. Although native South Asians share genetic and cultural risk factors with South Asians abroad, South Asians in the United States can differ in socioeconomic status, education, healthcare behaviors, attitudes, and health insurance, which can affect their risk and the treatment and outcomes of atherosclerotic cardiovascular disease (ASCVD). South Asians have higher proportional mortality rates from ASCVD compared with other Asian groups and non-Hispanic whites, in contrast to the finding that Asian Americans (Asian Indian, Chinese, Filipino, Japanese, Korean, and Vietnamese) aggregated as a group are at lower risk of ASCVD, largely because of the lower risk observed in East Asian populations. Literature relevant to South Asian populations regarding demographics and risk factors, health behaviors, and interventions, including physical activity, diet, medications, and community strategies, is summarized. The evidence to date is that the biology of ASCVD is complex but is no different in South Asians than in any other racial/ethnic group. A majority of the risk in South Asians can be explained by the increased prevalence of known risk factors, especially those related to insulin resistance, and no unique risk factors in this population have been found. This scientific statement focuses on how ASCVD risk factors affect the South Asian population in order to make recommendations for clinical strategies to reduce disease and for directions for future research to reduce ASCVD in this population.

Circulation: 23 May 2018; epub ahead of print
Volgman AS, Palaniappan LS, Aggarwal NT, Gupta M, ... Watson KE,
Circulation: 23 May 2018; epub ahead of print | PMID: 29794080
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Recommended Dietary Pattern to Achieve Adherence to the American Heart Association/American College of Cardiology (AHA/ACC) Guidelines: A Scientific Statement From the American Heart Association.

Van Horn L, Carson JA, Appel LJ, Burke LE, ... Wylie-Rosett J, Kris-Etherton P
In 2013, the American Heart Association and American College of Cardiology published the "Guideline on Lifestyle Management to Reduce Cardiovascular Risk," which was based on a systematic review originally initiated by the National Heart, Lung, and Blood Institute. The guideline supports the American Heart Association\'s 2020 Strategic Impact Goals for cardiovascular health promotion and disease reduction by providing more specific details for adopting evidence-based diet and lifestyle behaviors to achieve those goals. In addition, the 2015-2020 Dietary Guidelines for Americans issued updated evidence relevant to reducing cardiovascular risk and provided additional recommendations for adopting healthy diet and lifestyle approaches. This scientific statement, intended for healthcare providers, summarizes relevant scientific and translational evidence and offers practical tips, tools, and dietary approaches to help patients/clients adapt these guidelines according to their sociocultural, economic, and taste preferences.

Circulation: 27 Oct 2016; epub ahead of print
Van Horn L, Carson JA, Appel LJ, Burke LE, ... Wylie-Rosett J, Kris-Etherton P
Circulation: 27 Oct 2016; epub ahead of print | PMID: 27789558
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Abstract

Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, ... Vanden Hoek TL, Kronick SL
The goal of immediate post-cardiac arrest care is to optimize systemic perfusion, restore metabolic homeostasis, and support organ system function to increase the likelihood of intact neurological survival. The post-cardiac arrest period is often marked by hemodynamic instability as well as metabolic abnormalities. Support and treatment of acute myocardial dysfunction and acute myocardial ischemia can increase the probability of survival. Interventions to reduce secondary brain injury, such as therapeutic hypothermia, can improve survival and neurological recovery. Every organ system is at risk during this period, and patients are at risk of developing multiorgan dysfunction. The comprehensive treatment of diverse problems after cardiac arrest involves multidisciplinary aspects of critical care, cardiology, and neurology. For this reason, it is important to admit patients to appropriate critical-care units with a prospective plan of care to anticipate, monitor, and treat each of these diverse problems. It is also important to appreciate the relative strengths and weaknesses of different tools for estimating the prognosis of patients after cardiac arrest.

Circulation: 19 Oct 2010; 122:S768-86
Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, ... Vanden Hoek TL, Kronick SL
Circulation: 19 Oct 2010; 122:S768-86 | PMID: 20956225
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Abstract

Part 10: acute coronary syndromes: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

O\'Connor RE, Brady W, Brooks SC, Diercks D, ... Travers AH, Yannopoulos D
There has been tremendous progress in reducing disability and death from ACS. But many patients still die before reaching the hospital because patients and family members fail to recognize the signs of ACS and fail to activate the EMS system. Once the patient with ACS contacts the healthcare system, providers must focus on support of cardiorespiratory function, rapid transport, and early classification of the patient based on ECG characteristics. Patients with STEMI require prompt reperfusion; the shorter the interval from symptom onset to reperfusion, the greater the benefit. In the STEMI population, mechanical reperfusion with percutaenous coronary intervention improves survival and decreases major cardiovascular events compared to fibrinolysis. Patients with UA/NSTEMI (non-STEMI ACS) or nonspecific or normal ECGs require risk stratification and appropriate monitoring and therapy. Healthcare providers can improve survival rates and myocardial function of patients with ACS by providing skilled, efficient, and coordinated out-of-hospital and in-hospital care.

Circulation: 19 Oct 2010; 122:S787-817
O'Connor RE, Brady W, Brooks SC, Diercks D, ... Travers AH, Yannopoulos D
Circulation: 19 Oct 2010; 122:S787-817 | PMID: 20956226
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Abstract

Cardiovascular and Metabolic Heterogeneity of Obesity: Clinical Challenges and Implications for Management.

Neeland IJ, Poirier P, Després JP
The prevalence of obesity has increased globally over the last 2 decades. Although the body mass index has been a convenient and simple index of obesity at the population level, studies have shown that obesity defined by body mass index alone is a remarkably heterogeneous condition with varying cardiovascular and metabolic manifestations across individuals. Adipose tissue is an exquisitely active metabolic organ engaged in cross-talk between various systems; perturbation of adipose tissue results in a pathological response to positive caloric balance in susceptible individuals that directly and indirectly contributes to cardiovascular and metabolic disease. Inadequate subcutaneous adipose tissue expansion in the face of dietary triglycerides leads to visceral and ectopic fat deposition, inflammatory/adipokine dysregulation, and insulin resistance. Conversely, preferential fat storage in the lower body depot may act as a metabolic buffer and protect other tissues from lipotoxicity caused by lipid overflow and ectopic fat. Translational, epidemiological, and clinical studies over the past 30 years have clearly demonstrated a strong link between visceral and ectopic fat and the development of a clinical syndrome characterized by atherogenic dyslipidemia, hyperinsulinemia/glucose intolerance, hypertension, atherosclerosis, and adverse cardiac remodeling/heart failure. This relationship is even more nuanced when clinical entities such as metabolically healthy obesity phenotype and the obesity paradox are considered. Although it is clear that the accumulation of visceral/ectopic fat is a major contributor to cardiovascular and metabolic risk above and beyond the body mass index, implementation of fat distribution assessment into clinical practice remains a challenge. Anthropometric indexes of obesity are easily implemented, but newer imaging-based methods offer improved sensitivity and specificity for measuring specific depots. Lifestyle, pharmacological, and surgical interventions allow a multidisciplinary approach to overweight/obesity that may improve outcomes and align with a public health message to combat the growing epidemic of obesity worldwide and to build healthier lives free of cardiovascular diseases.

Circulation: 26 Mar 2018; 137:1391-1406
Neeland IJ, Poirier P, Després JP
Circulation: 26 Mar 2018; 137:1391-1406 | PMID: 29581366
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Abstract

Lnc-ing NOTCH1 to Idiopathic Calcific Aortic Valve Disease.

Merryman WD, Clark CR
Calcific aortic valve disease (CAVD) is an age-related disorder that causes significant cardiovascular morbidity and mortality, and is directly responsible for ~15,000 patient deaths per year in the USA. Currently, the molecular mechanism by which CAVD initiates is unknown, making discovery of a non-surgical strategy challenging (reviewed in (1)). Garg et al. made a seminal discovery in 2005 when they showed NOTCH1 mutations led to heritable CAVD.(2) Since then, the heart valve research community has sought a causal mechanism that could connect NOTCH1 dysfunction to idiopathic CAVD. That causal link has been elusive until the recent and impressive work by Hadjj et al., in this issue of Circulation, demonstrated that the promoter region of the long non-coding (lnc) RNA H19 is hypomethylated in patients with CAVD.(3) This hypomethylation, in turn, increases H19 expression in the valve interstitial cells (VICs) where it prevents NOTCH1 transcription by seemingly blocking or outcompeting p53\'s recruitment to the NOTCH1 promoter. Thus, H19 appears to be the missing link (or lncRNA, if you will) connecting NOTCH1 to idiopathic CAVD.

Circulation: 27 Oct 2016; epub ahead of print
Merryman WD, Clark CR
Circulation: 27 Oct 2016; epub ahead of print | PMID: 27789554
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Abstract

The Dogged Search for Cryptic Effects of Ticagrelor: Wishful Thinking or Real Benefits Beyond P2Y12 Inhibition?

Gurbel PA, Jeong YH, Tantry U
Greater protection against ischemic event occurrences has been associated with lower levels of platelet reactivity to adenosine diphosphate in patients with high risk coronary artery disease (1-3). The latter observations serve as the basis of the "platelet hypothesis"- i.e. greater inhibition of P2Y12 =less thrombotic event occurrence (4). Ticagrelor, a cyclo-pentyl-triazolo-pyrimidine, is indisputably a more potent P2Y12 inhibitor than clopidogrel (5) and when administered to patients with acute coronary syndrome (ACS) in the PLATelet inhibition and patient Outcomes (PLATO) trial resulted in a reduction not only in myocardial infarction (MI) but also, vascular death as compared to clopidogrel (6). The observed reduction in vascular death has provided a strong impetus to search for mechanisms of benefit beyond greater P2Y12 inhibition which are not shared by other P2Y12 inhibitors - the "non-P2Y12 - mediated" hypothesis of ticagrelor. The latter hypothesis is largely based on the property of ticagrelor to inhibit adenosine reuptake, thereby, increasing systemic and tissue adenosine levels (7). Most of the subsequent beneficial effects proceed downstream for this pivotal step, as adenosine has been proposed as an important molecule that attenuates ischemia-reperfusion injury.

Circulation: 27 Oct 2016; epub ahead of print
Gurbel PA, Jeong YH, Tantry U
Circulation: 27 Oct 2016; epub ahead of print | PMID: 27789557
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Abstract

Surgical Management of Infective Endocarditis Complicated by Embolic Stroke: Practical Recommendations for Clinicians.

Yanagawa B, Pettersson GB, Habib G, Ruel M, ... Latter DA, Verma S
There has been an overall improvement in surgical mortality for patients with infective endocarditis (IE), presumably because of improved diagnosis and management, centered around a more aggressive early surgical approach. Surgery is currently performed in approximately half of all cases of IE. Improved survival in surgery-treated patients is correlated with a reduction in heart failure and the prevention of embolic sequelae. It is reported that between 20% and 40% of patients with IE present with stroke or other neurological conditions. It is for these IE patients that the timing of surgical intervention remains a point of considerable discussion and debate. Despite evidence of improved survival in IE patients with earlier surgical treatment, a significant proportion of patients with IE and preexisting neurological complications either undergo delayed surgery or do not have surgery at all, even when surgery is indicated and guideline endorsed. Physicians and surgeons are caught in a common conundrum where the urgency of the heart operation must be balanced against the real or perceived risks of neurological exacerbation. Recent data suggest that the risk of neurological exacerbation may be lower than previously believed. Current guidelines reflect a shift toward early surgery for such patients, but there continue to be important areas of clinical equipoise. Individualized clinical assessment is of major importance for decision making, and, as such, we emphasize the need for the functioning of an endocarditis team, including cardiac surgeons, cardiologists, infectious diseases specialists, neurologists, neurosurgeons, and interventional neuroradiologists. Here, we present 2 illustrative cases, critically review contemporary data, and offer conceptual and practical suggestions for clinicians to address this important, common, and often fatal cardiac condition.

Circulation: 24 Oct 2016; 134:1280-1292
Yanagawa B, Pettersson GB, Habib G, Ruel M, ... Latter DA, Verma S
Circulation: 24 Oct 2016; 134:1280-1292 | PMID: 27777297
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Abstract

Management of Systemic Right Ventricular Failure in Patients With Congenitally Corrected Transposition of the Great Arteries.

Filippov AA, Del Nido PJ, Vasilyev NV
In recent decades, significant progress has been made in the diagnosis and management of congenitally corrected transposition of the great arteries (ccTGA). Nevertheless, gradual dysfunction and failure of the right ventricle (RV) in the systemic circulation remain the main contributors to mortality and disability for patients with ccTGA, especially after adolescence. Anatomic repair of ccTGA effectively resolves the problem of failure of the systemic RV and has good early and midterm results. However, this strategy is applicable primarily in infants and children up to their teens and has associated risks and limitations, and new challenges can arise in the late postoperative period. Patients with ccTGA manifesting progressive systemic RV dysfunction beyond adolescence represent the major challenge. Several palliative options such as cardiac resynchronization therapy, tricuspid valve repair or replacement, pulmonary artery banding, and implantation of an assist device into the systemic RV can be used to improve functional status and to delay the progression of ventricular dysfunction in patients who are not suitable for anatomic correction of ccTGA. For adult patients with severe systemic RV failure, heart transplantation currently remains the only long-term lifesaving procedure, although donor organ availability remains one of the most limiting factors in this type of therapy. This review focuses on current surgical and medical strategies and interventional options for the prevention and management of systemic RV failure in adults and children with ccTGA.

Circulation: 24 Oct 2016; 134:1293-1302
Filippov AA, Del Nido PJ, Vasilyev NV
Circulation: 24 Oct 2016; 134:1293-1302 | PMID: 27777298
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Abstract

Current Therapy for Hypoplastic Left Heart Syndrome and Related Single Ventricle Lesions.

Ohye RG, Schranz D, D\'Udekem Y
Universally fatal only 4 decades ago, the progress in the 3-stage palliation of hypoplastic left heart syndrome and related single right ventricular lesions has drastically improved the outlook for these patients. Although the stage II operation (hemi-Fontan or bidirectional Glenn) and stage III Fontan procedure have evolved into relatively low-risk operations, the stage I Norwood procedure remains one of the highest-risk and costliest common operations performed in congenital heart surgery. Yet, despite this fact, experienced centers now report hospital survivals of >90% for the Norwood procedure. This traditional 3-stage surgical palliation has seen several innovations in the past decade aimed at improving outcomes, particularly for the Norwood procedure. One significant change is a renewed interest in the right ventricle-to-pulmonary artery shunt as the source of pulmonary blood flow, rather than the modified Blalock-Taussig shunt for the Norwood. The multi-institutional Single Ventricle Reconstruction trial randomly assigned 555 patients to one or the other shunt, and these subjects continue to be followed closely as they now approach 10 years postrandomization. In addition to modifications to the Norwood procedure, the hybrid procedure, a combined catheter-based and surgical approach, avoids the Norwood procedure in the newborn period entirely. The initial hybrid procedure is then followed by a comprehensive stage II, which combines components of both the Norwood and the traditional stage II, and later completion of the Fontan. Proponents of this approach hope to improve not only short-term survival, but also potentially longer-term outcomes, such as neurodevelopment, as well. Regardless of the approach, traditional surgical staged palliation or the hybrid procedure, survivals have vastly improved, and large numbers of these patients are surviving not only through their Fontan in early childhood, but also into adolescence and young adulthood. As this population grows, it becomes increasingly important to understand the longer-term outcomes of these Fontan patients, not only in terms of survival, but also in terms of the burden of disease, neurodevelopmental outcomes, psychosocial development, and quality of life.

Circulation: 24 Oct 2016; 134:1265-1279
Ohye RG, Schranz D, D'Udekem Y
Circulation: 24 Oct 2016; 134:1265-1279 | PMID: 27777296
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Abstract

Ruling In Myocardial Injury and Ruling Out Myocardial Infarction With the European Society of Cardiology (ESC) 1-Hour Algorithm.

Jaffe AS, White HD
High sensitivity cardiac troponin (hscTn) assays are used everywhere except in the United States.(1) One potential advantage of these assays is the ability to triage patients with possible ischemia more rapidly and, there is an understandable desire to find easy, facile algorithms to do this. This was the approach taken with hscTn in the evaluation of patients with possible acute myocardial infarction (AMI) using an algorithm developed by the Advantageous Predictors of Acute Coronary Syndromes Evaluation (APACE) trial.(2) Intrinsic to it is the concept that both ruling-out and ruling-in AMI rapidly (within one hour) is based on initially low concentrations (<2 ng/L for hscTnI Abbott and < 5 ng/L hscTnT Roche) or small changes over the first hour (<2 ng/L hscTnI and <3 ng/L hscTnT) for ruling out and the use of larger changes (6 ng/L hscTnI and 5 ng/L hscTnT) and fixed cut off concentrations for ruling in (see Figure 1 of the article by Pickering et al in this issue of Circulation).(3) Unfortunately, the validation of this algorithm has often left a good deal to be desired. Despite that fact, it was incorporated into the European Society of Cardiology (ESC) guidelines.(4).

Circulation: 17 Oct 2016; epub ahead of print
Jaffe AS, White HD
Circulation: 17 Oct 2016; epub ahead of print | PMID: 27754880
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Abstract

Risk Assessment of Recurrence in Patients With Unprovoked Deep Vein Thrombosis or Pulmonary Embolism. The Vienna Prediction Model.

Eichinger S, Heinze G, Jandeck LM, Kyrle PA
Background: -Predicting the risk of recurrent venous thromboembolism (VTE) in an individual patient is often not feasible. We aimed to develop a simple risk assessment model that improves prediction of the recurrence risk. Methods and results-In a prospective cohort study, 929 patients with a first unprovoked VTE were followed up for a median of 43.3 months after discontinuation of anticoagulation. We excluded patients with a strong thrombophilic defect such as a natural inhibitor deficiency, the lupus anticoagulant, and homozygous or combined defects. A total of 176 patients (18.9%) had recurrent VTE. Preselected clinical and laboratory variables (age, sex, location of VTE, body mass index, factor V Leiden, prothrombin G20210A mutation, D-dimer, and in vitro thrombin generation) were analyzed in a Cox proportional hazards model, and those variables that were significantly associated with recurrence were used to compute risk scores. Male sex (hazard ratio versus female sex 1.90, 95% confidence interval 1.31 to 2.75), proximal deep vein thrombosis (hazard ratio versus distal 2.08, 95% confidence interval 1.16 to 3.74), pulmonary embolism (hazard ratio versus distal thrombosis 2.60, 95% confidence interval 1.49 to 4.53), and elevated levels of D-dimer (hazard ratio per doubling 1.27, 95% confidence interval 1.08 to 1.51) were related to a higher recurrence risk. Using these variables, we developed a nomogram that can be used to calculate risk scores and to estimate the cumulative probability of recurrence in an individual patient. The model was cross validated, and patients were assigned to different risk categories based on their risk score. Recurrence rates corresponded well with the different risk categories. Conclusions-By use of a simple scoring system, the assessment of the recurrence risk in patients with a first unprovoked VTE and without strong thrombophilic defects can be improved.

Circulation: 30 Mar 2010; epub ahead of print
Eichinger S, Heinze G, Jandeck LM, Kyrle PA
Circulation: 30 Mar 2010; epub ahead of print | PMID: 20351233
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Abstract

Potential and Caveats of Lipidomics for Cardiovascular Disease.

Pechlaner R, Kiechl S, Mayr M
Since the seminal publications from the Framingham study in the mid-sixties,(1) the measurement of lipid levels, mainly of total cholesterol, total triglycerides, and LDL and HDL cholesterol, is routine clinical practice for cardiovascular disease (CVD) and lipid-lowering therapy. A more detailed assessment of the lipid composition, that is, the molecular species that constitute the lipid classes is not widely used, mainly due to the caveats of assessing the lipidome. The human lipidome is estimated to include thousands of molecular lipid species with functional diversity. The molecular lipid species within a lipid classes share a modular composition with fatty acids being attached to a common backbone. While a characteristic head group within the backbone defines the lipid class, the diversity of molecular lipid species derives from the conjugated fatty acids.(2) The conjugated fatty acids can differ in their carbon chain length, the number, position, and configuration (cis or trans) of their double bonds, and in the position and type (acyl, alkyl, or vinyl) of linkage to the backbone.

Circulation: 18 Oct 2016; epub ahead of print
Pechlaner R, Kiechl S, Mayr M
Circulation: 18 Oct 2016; epub ahead of print | PMID: 27756782
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Abstract

Puma Deletion Delays Cardiac Dysfunction in Murine Heart Failure Models Through Attenuation of Apoptosis.

Mandl A, Pham LH, Toth K, Zambetti G, Erhardt P
Background- Puma (p53-upregulated modulator of apoptosis) is a proapoptotic Bcl-2 family protein that serves as a general sensor in response to pathological apoptotic stimuli. In previous work, we demonstrated that puma ablation protects the heart from reperfusion injury in a Langendorff setting. Consistent with this, downregulation of Puma in isolated cardiac myocytes prevented apoptosis induced by different proapoptotic agents. Here, we extended our research to investigate the role of Puma, a downstream mediator of p53, in the development of heart failure using Puma(-/-) mice. Methods and results- Mice underwent transverse aortic constriction, and the characteristics of cardiac remodeling were analyzed by echocardiography, histology, and gene expression at multiple time points after surgery. Four weeks after the operation, puma deletion attenuated pressure overload-induced apoptosis and fibrosis; however, it did not affect hypertrophy and angiogenesis and maintained functional performance (fractional shortening, 39% versus 25.2% in Puma(-/-) versus WT mice, respectively). Even at 12 weeks after transverse aortic constriction, Puma(-/-) mice displayed only slightly reduced contractility. In addition, transverse aortic constriction induced puma expression in a partially p53-dependent manner. To corroborate these findings, we studied another heart failure model in which heart-specific mdm4 deletion leads to p53 activation and dilated cardiomyopathy. In these mice, Puma was upregulated and its deletion rescued the cardiomyopathy phenotype. Conclusions- Our data indicate that Puma might be a critical component of the apoptotic signaling pathways that contribute to ventricular remodeling and heart failure. Therefore, Puma inactivation may serve as a preferential target to prevent heart failure induced by cellular stress.

Circulation: 14 Jun 2011; epub ahead of print
Mandl A, Pham LH, Toth K, Zambetti G, Erhardt P
Circulation: 14 Jun 2011; epub ahead of print | PMID: 21670227
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Abstract

Long-Term Results of Catheter Ablation in Paroxysmal Atrial Fibrillation: Lessons From a 5-Year Follow-Up.

Ouyang F, Tilz R, Chun J, Schmidt B, ... Fuernkranz A, Kuck KH
Background- Paroxysmal atrial fibrillation (AF) naturally progresses toward chronic AF at an estimated rate of 15% to 30% over a 1- to 3-year period. Pulmonary vein (PV) isolation is increasingly performed for the treatment of drug-refractory paroxysmal AF. The long-term data on clinical outcome after circumferential PV isolation are limited. Methods and results- From 2003 to late 2004, 161 patients (121 men; age, 59.8±9.7 years) with symptomatic paroxysmal AF and normal left ventricular function underwent circumferential PV isolation guided by 3-dimensional mapping and double Lasso technique. Right-sided and left-sided continuous circular lesions encircling the ipsilateral PVs were placed with irrigated radiofrequency energy. The procedure end point was the absence of all PV spikes for at least 30 minutes after PV isolation verified by 2 Lasso catheters placed within the ipsilateral PVs. Sinus rhythm was present in 75 patients (46.6%) after the initial procedure during a median follow-up period of 4.8 years (0.33 to 5.5 years). A second procedure was performed in 66 and a third procedure in 12 patients. Recovered PV isolation conduction was observed in 62 of 66 patients (94.0%) during the second and in 8 of 12 patients (66.7%) during the third procedure. After a median of 1 (1 to 3) procedure, stable sinus rhythm was achieved in 128 of 161 patients (79.5%), whereas clinical improvement occurred in an additional 21 of 161 patients (13.0%) during a median follow-up of 4.6 years (0.33 to 5.5 years). Four patients in stable sinus rhythm died during follow-up. Progression toward chronic AF was observed in 4 patients (2.4%); however, only 2 patients reported symptoms. Conclusion- In patients with paroxysmal AF and normal left ventricular function, circumferential PV isolation results in stable sinus rhythm in the majority of patients, and low incidence of chronic AF was observed after ablation during up to 5 years of follow-up.

Circulation: 24 Nov 2010; epub ahead of print
Ouyang F, Tilz R, Chun J, Schmidt B, ... Fuernkranz A, Kuck KH
Circulation: 24 Nov 2010; epub ahead of print | PMID: 21098450
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Abstract

Cardiac Index Is Associated With Brain Aging. The Framingham Heart Study.

Jefferson AL, Himali JJ, Beiser AS, Au R, ... Wolf PA, Manning WJ
Background: -Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Methods and results-Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, or dementia (age, 61+/-9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI-assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent cardiovascular disease were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post hoc comparisons revealed that participants in the bottom cardiac index tertile (values <2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values >2.92). Conclusions-Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.

Circulation: 03 Aug 2010; epub ahead of print
Jefferson AL, Himali JJ, Beiser AS, Au R, ... Wolf PA, Manning WJ
Circulation: 03 Aug 2010; epub ahead of print | PMID: 20679552
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Abstract

Heart Rate Response During Exercise and Pregnancy Outcome in Women With Congenital Heart Disease.

Lui GK, Silversides CK, Khairy P, Fernandes SM, ... Gersony DR, for the Alliance for Adult Research in Congenital Cardiology (AARCC)
Background- Cardiopulmonary exercise testing is often used to evaluate exercise capacity in adults with congenital heart disease including women who are considering pregnancy. The relationship between cardiopulmonary exercise testing parameters and pregnancy outcome has not been defined. Methods and results- We conducted a multicenter retrospective observational study of women with congenital heart disease who had undergone cardiopulmonary exercise testing within 2 years of pregnancy or during the first trimester. Cardiopulmonary exercise testing variables included peak oxygen consumption and measures of chronotropic response: peak heart rate, percentage of maximum age predicted heart rate, heart rate reserve (peak heart rate-resting heart rate), and chronotropic index [(peak heart rate-resting heart rate)/(220-age-resting heart rate)]. We identified 89 pregnancies in 83 women. There were 4 spontaneous abortions and 1 termination. One or more adverse cardiac events occurred in 18%; congestive heart failure in 14%, and sustained arrhythmia in 7%. Peak heart rate (odds ratio [OR] 0.71; 95% confidence interval [CI] [0.53, 0.94]; P=0.02), percentage of maximum age predicted heart rate (OR 0.93; 95% CI [0.88, 0.98]; P=0.01), and chronotropic index (OR 0.65; 95% CI [0.47, 0.90]; P=0.01) were associated with a cardiac event. Neonatal events occurred in 20%. Peak heart rate (OR 0.75; 95% CI [0.58, 0.98]; P=0.04), percentage of maximum age predicted heart rate (OR 0.94; 95% CI [0.89, 0.99]; P=0.02), heart rate reserve (OR 0.8; 95% CI [0.64, 0.99]; P=0.04), and chronotropic index (OR 0.73; 95% CI [0.54, 0.98]; P=0.04) correlated with a neonatal event. Peak oxygen consumption was not associated with an adverse pregnancy outcome. Conclusions- Abnormal chronotropic response correlates with adverse pregnancy outcomes in women with congenital heart disease and should be considered in refining risk stratification schemes.

Circulation: 11 Jan 2011; epub ahead of print
Lui GK, Silversides CK, Khairy P, Fernandes SM, ... Gersony DR, for the Alliance for Adult Research in Congenital Cardiology (AARCC)
Circulation: 11 Jan 2011; epub ahead of print | PMID: 21220738
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Abstract

Protein Kinase D2 Controls Cardiac Valve Formation in Zebrafish by Regulating Histone Deacetylase 5 Activity.

Just S, Berger IM, Meder B, Backs J, ... Katus HA, Rottbauer W
Background- The molecular mechanisms that guide heart valve formation are not well understood. However, elucidation of the genetic basis of congenital heart disease is one of the prerequisites for the development of tissue-engineered heart valves. Methods and results- We isolated here a mutation in zebrafish, bungee (bng(jh177)), which selectively perturbs valve formation in the embryonic heart by abrogating endocardial Notch signaling in cardiac cushions. We found by positional cloning that the bng phenotype is caused by a missense mutation (Y849N) in zebrafish protein kinase D2 (pkd2). The bng mutation selectively impairs PKD2 kinase activity and hence Histone deacetylase 5 phosphorylation, nuclear export, and inactivation. As a result, the expression of Histone deacetylase 5 target genes Krüppel-like factor 2a and 4a, transcription factors known to be pivotal for heart valve formation and to act upstream of Notch signaling, is severely downregulated in bungee (bng) mutant embryos. Accordingly, the expression of Notch target genes, such as Hey1, Hey2, and HeyL, is severely decreased in bng mutant embryos. Remarkably, downregulation of Histone deacetylase 5 activity in homozygous bng mutant embryos can rescue the mutant phenotype and reconstitutes notch1b expression in atrioventricular endocardial cells. Conclusions- We demonstrate for the first time that proper heart valve formation critically depends on Protein kinase D2-Histone deacetylase 5-Krüppel-like factor signaling.

Circulation: 06 Jul 2011; epub ahead of print
Just S, Berger IM, Meder B, Backs J, ... Katus HA, Rottbauer W
Circulation: 06 Jul 2011; epub ahead of print | PMID: 21730303
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Abstract

Primary Results From the SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial: A Randomized Trial Comparing Empirical, Echocardiography-Guided, and Algorithmic Atrioventricular Delay Programming in Cardiac Resynchronization Therapy.

Ellenbogen KA, Gold MR, Meyer TE, Lozano IF, ... Rapkin J, Stein KM
Background- One variable that may influence cardiac resynchronization therapy response is the programmed atrioventricular (AV) delay. The SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial prospectively randomized patients to a fixed empirical AV delay (120 milliseconds), echocardiographically optimized AV delay, or AV delay optimized with SmartDelay, an electrogram-based algorithm. Methods and results- A total of 1014 patients (68% men; mean age, 66±11 years; mean left ventricular ejection fraction, 25±7%) who met enrollment criteria received a cardiac resynchronization therapy defibrillator, and 980 patients were randomized in a 1:1:1 ratio. All patients were programmed (DDD-60 or DDDR-60) and evaluated after implantation and 3 and 6 months later. The primary end point was left ventricular end-systolic volume. Secondary end points included New York Heart Association class, quality-of-life score, 6-minute walk distance, left ventricular end-diastolic volume, and left ventricular ejection fraction. The medians (quartiles 1 and 3) for change in left ventricular end-systolic volume at 6 months for the SmartDelay, echocardiography, and fixed arms were -21 mL (-45 and 6 mL), -19 mL (-45 and 6 mL), and -15 mL (-41 and 6 mL), respectively. No difference in improvement in left ventricular end-systolic volume at 6 months was observed between the SmartDelay and echocardiography arms (P=0.52) or the SmartDelay and fixed arms (P=0.66). Secondary end points, including structural (left ventricular end-diastolic volume and left ventricular ejection fraction) and functional (6-minute walk, quality of life, and New York Heart Association classification) measures, were not significantly different between arms. Conclusions- Neither SmartDelay nor echocardiography was superior to a fixed AV delay of 120 milliseconds. The routine use of AV optimization techniques assessed in this trial is not warranted. However, these data do not exclude possible utility in selected patients who do not respond to cardiac resynchronization therapy. Clinical trial registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00677014.

Circulation: 24 Nov 2010; epub ahead of print
Ellenbogen KA, Gold MR, Meyer TE, Lozano IF, ... Rapkin J, Stein KM
Circulation: 24 Nov 2010; epub ahead of print | PMID: 21098426
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Abstract

CD69 Limits the Severity of Cardiomyopathy After Autoimmune Myocarditis.

Cruz-Adalia A, Jiménez-Borreguero LJ, Ramírez-Huesca M, Chico-Calero I, ... Sánchez-Madrid F, Martín P
Background: -Experimental autoimmune myocarditis (EAM), a mouse model of post-infectious cardiomyopathy, reflects mechanisms of inflammatory cardiomyopathy in humans. EAM is characterized by an infiltration of inflammatory cells into the myocardium that can be followed by myocyte fibrosis, edema, and necrosis, leading to ventricular wall dysfunction and heart failure. Different data indicate that CD69 exerts an important immunoregulatory effect in vivo. However, the possible role of CD69 in autoimmune myocarditis has not been studied. Methods and results-We have explored the role of the leukocyte regulatory molecule CD69 in the inflammation that leads to cardiac dysfunction after myocardial injury in EAM. We have found that after induction of EAM, the draining lymph nodes from CD69-deficient mice developed an exacerbated Th17 inflammatory response, resulting in increases in the numbers of infiltrating leukocytes in the myocardium. In the chronic phase of EAM, transthoracic echocardiography revealed a significantly reduced left ventricular fractional shortening and a decreased ejection fraction in CD69-deficient mice, indicative of an impaired cardiac contractility. This condition was accompanied by a greater extent of myocardial fibrosis, an elevated number of sinus pauses on ECG, and an enhanced ratio of heart weight to body weight in CD69(-/-) mice. Moreover, both bone marrow transplantation and adoptive transfer of Th17 cells isolated from immunized CD69(-/-) mice with EAM into naive wild-type recipients reproduced the severity of the disease, demonstrating that CD69 exerts its function within the lymphocyte compartment. Conclusion-Our findings indicate that CD69 negatively regulates heart-specific Th17 responses, cardiac inflammation, and heart failure progression in EAM.

Circulation: 21 Sep 2010; epub ahead of print
Cruz-Adalia A, Jiménez-Borreguero LJ, Ramírez-Huesca M, Chico-Calero I, ... Sánchez-Madrid F, Martín P
Circulation: 21 Sep 2010; epub ahead of print | PMID: 20855659
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Abstract

Frequency and Predictors of Stent Thrombosis After Percutaneous Coronary Intervention in Acute Myocardial Infarction.

Dangas GD, Caixeta A, Mehran R, Parise H, ... Stone GW, for the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial Investigators
Background- Concerns persist regarding the risk of stent thrombosis in the setting of primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Methods and results- The Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial included 3602 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention who were randomized to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) (n=1802) versus bivalirudin monotherapy (n=1800). Stents were implanted in 3202 patients, including 2261 who received drug-eluting stents and 861 who received only bare metal stents. Definite or probable stent thrombosis within 2 years occurred in 137 patients (4.4%), including 28 acute events (0.9%), 49 subacute events (1.6%), 32 late events (1.0%), and 33 very late events (1.1%). The 2-year cumulative rates of stent thrombosis were 4.4% with both drug-eluting stents and bare metal stents (P=0.98) and 4.3% versus 4.6% in patients randomized to bivalirudin monotherapy versus heparin plus a GPI, respectively (P=0.73). Acute stent thrombosis occurred more frequently in patients assigned to bivalirudin compared with heparin plus a GPI (1.4% versus 0.3%; P<0.001), whereas stent thrombosis after 24 hours occurred less frequently in patients with bivalirudin compared with heparin plus a GPI (2.8% versus 4.4%; P=0.02). Prerandomization heparin and a 600-mg clopidogrel loading dose were independent predictors of reduced acute and subacute stent thrombosis, respectively. Conclusions- Stent thrombosis is not uncommon within the first 2 years after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction, and occurs with similar frequency in patients receiving drug-eluting stents versus bare metal stents and bivalirudin alone versus heparin plus a GPI. Optimizing adjunct pharmacology including early antithrombin therapy preloading with a potent antiplatelet therapy may further reduce stent thrombosis in ST-segment elevation myocardial infarction. Clinical Trial registration:- http://www.clinicaltrials.gov. Unique identifier: NCT00433966.

Circulation: 12 Apr 2011; epub ahead of print
Dangas GD, Caixeta A, Mehran R, Parise H, ... Stone GW, for the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial Investigators
Circulation: 12 Apr 2011; epub ahead of print | PMID: 21482968
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Abstract

Transmural Heterogeneity and Remodeling of Ventricular Excitation-Contraction Coupling in Human Heart Failure.

Lou Q, Fedorov VV, Glukhov AV, Moazami N, Fast VG, Efimov IR
Background- Excitation-contraction (EC) coupling is altered in end-stage heart failure. However, spatial heterogeneity of this remodeling has not been established at the tissue level in failing human heart. The objective of this article was to study functional remodeling of excitation-contraction coupling and calcium handling in failing and nonfailing human hearts. Methods and results- We simultaneously optically mapped action potentials and calcium transients in coronary perfused left ventricular wedge preparations from nonfailing (n=6) and failing (n=5) human hearts. Our major findings are the following. First, calcium transient duration minus action potential duration was longer at subendocardium in failing compared with nonfailing hearts during bradycardia (40 bpm). Second, the transmural gradient of calcium transient duration was significantly smaller in failing hearts compared with nonfailing hearts at fast pacing rates (100 bpm). Third, calcium transient in failing hearts had a flattened plateau at the midmyocardium and exhibited a 2-component slow rise at the subendocardium in 3 failing hearts. Fourth, calcium transient relaxation was slower at the subendocardium than at the subepicardium in both groups. Protein expression of sarcoplasmic reticulum Ca(2+)-ATPase 2a was lower at the subendocardium than the subepicardium in both nonfailing and failing hearts. Sarcoplasmic reticulum Ca(2+)-ATPase 2a protein expression at subendocardium was lower in hearts with ischemic cardiomyopathy compared with those with nonischemic cardiomyopathy. Conclusions- For the first time, we present direct experimental evidence of transmural heterogeneity of excitation-contraction coupling and calcium handling in human hearts. End-stage heart failure is associated with the heterogeneous remodeling of excitation-contraction coupling and calcium handling.

Circulation: 19 Apr 2011; epub ahead of print
Lou Q, Fedorov VV, Glukhov AV, Moazami N, Fast VG, Efimov IR
Circulation: 19 Apr 2011; epub ahead of print | PMID: 21502574
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Abstract

Mobile Thrombus on Device Leads in Patients Undergoing Ablation: Identification, Incidence, Location, and Association With Increased Pulmonary Artery Systolic Pressure.

Supple GE, Ren JF, Zado ES, Marchlinski FE
Background- Mobile thrombi, not routinely recognized on transthoracic echocardiography, are frequently identified on cardiovascular implantable electronic device leads with intracardiac echocardiography (ICE) during ablation procedures. Their incidence, characteristics, and consequences have not yet been defined. Methods and results- We used ICE to examine leads for thrombi and to measure the pulmonary artery systolic pressure in patients with a cardiovascular implantable electronic device presenting for ablation. Patient clinical characteristics, device type, and lead characteristics were correlated with presence of thrombi. Most patients had congestive heart failure (84%), with an average left ventricular ejection fraction of 40%. Thrombi were seen with ICE in 26 of 86 patients (30%) but were seen on transthoracic echocardiography in only 1 of the 26 patients. Thrombi on ICE were mobile, averaged 18±5.9 mm long by 4.4±2.3 mm wide, and were more commonly identified in the right atrium (n=25) than in the right ventricle (n=5). Thrombi were associated with higher pulmonary artery systolic pressure: 39±9 mm Hg with thrombi versus 33±7 mm Hg without thrombi (odds ratio, 1.11; 95% confidence interval, 1.03 to 1.20; P=0.01). No other characteristic assessed was associated with a significant difference in the presence of lead thrombi. Conclusions- Mobile thrombi on cardiovascular implantable electronic device leads are present in 30% of patients undergoing ablation and are readily identified with ICE despite being underrecognized with transthoracic echocardiography. Further study is warranted to determine whether lead thrombi are a clinically relevant source of pulmonary emboli in some patients with cardiovascular implantable electronic devices.

Circulation: 26 Jul 2011; epub ahead of print
Supple GE, Ren JF, Zado ES, Marchlinski FE
Circulation: 26 Jul 2011; epub ahead of print | PMID: 21788588
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Abstract

MicroRNA-24 Regulates Vascularity After Myocardial Infarction.

Fiedler J, Jazbutyte V, Kirchmaier BC, Gupta SK, ... Bauersachs J, Thum T
Background- Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood. Methods and results- Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Respective downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2-associated death promoter) and Sirtuin1 were identified by transcriptome, protein arrays, and chromatin immunoprecipitation analyses. Overexpression of miR-24 or silencing of its targets significantly impaired angiogenesis in zebrafish embryos. Blocking of endothelial miR-24 limited myocardial infarct size of mice via prevention of endothelial apoptosis and enhancement of vascularity, which led to preserved cardiac function and survival. Conclusions- Our findings indicate that miR-24 acts as a critical regulator of endothelial cell apoptosis and angiogenesis and is suitable for therapeutic intervention in the setting of ischemic heart disease.

Circulation: 26 Jul 2011; epub ahead of print
Fiedler J, Jazbutyte V, Kirchmaier BC, Gupta SK, ... Bauersachs J, Thum T
Circulation: 26 Jul 2011; epub ahead of print | PMID: 21788589
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Abstract

Cardiomyopathy in Friedreich\'s Ataxia: Exemplifying the Challenges Faced by the Cardiologists in the Management of Rare Diseases.

Jensen MK, Bundgaard H
Friedreich\'s ataxia (FA) is an autosomal recessively inherited neurodegenerative disease that most often presents in childhood or in young adults. A substantial proportion of the patients with FA also develops a cardiomyopathy that mainly presents as left ventricular hypertrophy (FA-CM). The mean life expectancy is significantly reduced to approximately 40 years, and approximately 60% of patients with FA die from cardiac causes(1,2). The prevalence of FA is 0.1-4.7:100.000 and estimated 9.000 Americans are affected(3). The potential ability to reduce the disease progression or even reverse the FA-CM by antioxidants underscores the importance of early identification of the disease and the development of clinically identifiable markers of cardiac involvement. In the current issue of Circulation the MICONOS study group investigated such markers(4). (SELECT FULL TEXT TO CONTINUE).

Circulation: 29 Feb 2012; epub ahead of print
Jensen MK, Bundgaard H
Circulation: 29 Feb 2012; epub ahead of print | PMID: 22379113
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Abstract

Factor XIIa Inhibitor Recombinant Human Albumin Infestin-4 Abolishes Occlusive Arterial Thrombus Formation Without Affecting Bleeding.

Hagedorn I, Schmidbauer S, Pleines I, Kleinschnitz C, ... Dickneite G, Nieswandt B
Background: -Blood coagulation is a tightly regulated process of sequentially activated serine proteases culminating in fibrin formation, which is critical for limiting posttraumatic blood loss but also may contribute to acute thrombotic diseases, most notably myocardial infarction and stroke. Recent studies with factor XII-deficient mice revealed that the factor XII-induced intrinsic coagulation pathway is essential for pathological thrombus formation but dispensable for hemostasis. Consequently, these findings led to the hypothesis that factor XII could be a promising pharmacological target for safe antithrombotic therapy. Methods and results-The complementary DNA of the previously described factor XIIa inhibitor Infestin-4, cloned from the midgut of Triatoma infestans, was fused to recombinant human albumin (rHA) and analyzed in vitro. The resulting protein rHA-Infestin-4 specifically inhibits factor XIIa and causes prolonged activated partial thromboplastin time in human, mouse, and rat plasma. To assess its inhibitory potency in vivo, mice and rats were injected with rHA-Infestin-4 and challenged in pathological thrombus formation models. In addition, bleeding assays were performed. rHA-Infestin-4 completely abolished occlusive arterial thrombus formation in mice and rats while leaving hemostasis fully intact. Furthermore, rHA-Infestin-4 was highly protective in a murine model of ischemic stroke. Conclusion-These results identify rHA-Infestin-4 as a promising agent to achieve powerful protection from ischemic cardiovascular and cerebrovascular events without affecting hemostasis.

Circulation: 23 Mar 2010; epub ahead of print
Hagedorn I, Schmidbauer S, Pleines I, Kleinschnitz C, ... Dickneite G, Nieswandt B
Circulation: 23 Mar 2010; epub ahead of print | PMID: 20308613
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Abstract

Testing of Low-Risk Patients Presenting to the Emergency Department With Chest Pain. A Scientific Statement From the American Heart Association.

Amsterdam EA, Kirk JD, Bluemke DA, Diercks D, ... Council on Cardiovascular Nursing, and Interdisciplinary Council on Quality of Care and Outcomes Research
Abstract-The management of low-risk patients presenting to emergency departments is a common and challenging clinical problem entailing 8 million emergency department visits annually. Although a majority of these patients do not have a life-threatening condition, the clinician must distinguish between those who require urgent treatment of a serious problem and those with more benign entities who do not require admission. Inadvertent discharge of patients with acute coronary syndrome from the emergency department is associated with increased mortality and liability, whereas inappropriate admission of patients without serious disease is neither indicated nor cost-effective. Clinical judgment and basic clinical tools (history, physical examination, and electrocardiogram) remain primary in meeting this challenge and affording early identification of low-risk patients with chest pain. Additionally, established and newer diagnostic methods have extended clinicians\' diagnostic capacity in this setting. Low-risk patients presenting with chest pain are increasingly managed in chest pain units in which accelerated diagnostic protocols are performed, comprising serial electrocardiograms and cardiac injury markers to exclude acute coronary syndrome. Patients with negative findings usually complete the accelerated diagnostic protocol with a confirmatory test to exclude ischemia. This is typically an exercise treadmill test or a cardiac imaging study if the exercise treadmill test is not applicable. Rest myocardial perfusion imaging has assumed an important role in this setting. Computed tomography coronary angiography has also shown promise in this setting. A negative accelerated diagnostic protocol evaluation allows discharge, whereas patients with positive findings are admitted. This approach has been found to be safe, accurate, and cost-effective in low-risk patients presenting with chest pain.

Circulation: 27 Jul 2010; epub ahead of print
Amsterdam EA, Kirk JD, Bluemke DA, Diercks D, ... Council on Cardiovascular Nursing, and Interdisciplinary Council on Quality of Care and Outcomes Research
Circulation: 27 Jul 2010; epub ahead of print | PMID: 20660809
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Abstract

Signature microRNA Expression Profile of Essential Hypertension and Its Novel Link to Human Cytomegalovirus Infection.

Li S, Zhu J, Zhang W, Chen Y, ... Yang X, Cai J
Background- Essential hypertension has been recognized as a disease resulting from a combination of environmental and genetic factors. Recent studies demonstrated that microRNAs (miRNAs) are involved in cardiac hypertrophy and heart failure. However, little is known about the roles of miRNAs in essential hypertension. Methods and results- Using microarray-based miRNA expression profiling, we compared the miRNA expressions in plasma samples from 13 hypertensive patients and 5 healthy control subjects. Twenty-seven miRNAs were found to be differentially expressed. The expressions of selected miRNAs (miR-296-5p, let-7e, and a human cytomegalovirus [HCMV]-encoded miRNA, hcmv-miR-UL112) were validated independently in plasma samples from 24 hypertensive patients and 22 control subjects. The absolute expression levels of hcmv-miR-UL112, miR-296-5p, and let-7e were further determined in 127 patients and 67 control subjects (fold changes are 2.5, 0.5, and 1.7 respectively; all P<0.0001). Additionally, we demonstrated that interferon regulatory factor 1 is a direct target of hcmv-miR-UL112. Increased HCMV seropositivity and quantitative titers were found in the hypertension group compared with the control group (52.7% versus 30.9%, P=0.0005; 1870 versus 54 copies per 1 mL plasma, P<0.0001). Seropositivity, log-transformed copies of HCMV, and hcmv-miR-UL112 were independently associated with an increased risk of hypertension (odds ratio, 2.48; 95% confidence interval, 1.48 to 4.15; P=0.0005; odds ratio, 1.97; 95% confidence interval, 1.58 to 2.46; P<0.0001; and odds ratio, 2.55; 95% confidence interval, 1.98 to 3.27; P<0.0001, respectively). Conclusions- We report for the first time a circulating miRNA profile for hypertensive patients and demonstrate a novel link between HCMV infection and essential hypertension. These findings may reveal important insights into the pathogenesis of essential hypertension. Clinical trial registration- URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00420784.

Circulation: 21 Jun 2011; epub ahead of print
Li S, Zhu J, Zhang W, Chen Y, ... Yang X, Cai J
Circulation: 21 Jun 2011; epub ahead of print | PMID: 21690488
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Abstract

Conduction Remodeling in Human End-Stage Non-Ischemic Left Ventricular Cardiomyopathy.

Glukhov AV, Fedorov VV, Kalish PW, Ravikumar VK, ... Moazami N, Efimov IR
Background: Several arrhythmogenic mechanisms have been inferred from animal heart failure (HF) models. However, the translation of these hypotheses is difficult due to lack of functional human data. We aimed to investigate the electrophysiological substrate for arrhythmia in human end-stage non-ischemic cardiomyopathy. Methods and results: We optically mapped the coronary-perfused left ventricular wedge preparations from human hearts with end-stage non-ischemic cardiomyopathy (HF, n=10) and non-failing hearts (NF, n=10). Molecular remodeling was studied with immunostaining, Western blotting, and histological analyses. HF produced heterogeneous prolongation of action potential duration (APD) resulting in the decrease of transmural APD dispersion (64±12 ms vs 129±15 ms in NF, P<0.005). In the failing hearts, transmural activation was significantly slowed from the endocardium (39±3 cm/s versus 49±2 cm/s in NF, P=0.008) to the epicardium (28±3 cm/s versus 40±2 cm/s in NF, P=0.008). Conduction slowing was likely due to Cx43 downregulation, decreased colocalization of Cx43 with N-cadherin (40±2% versus 52±5% in NF, P=0.02), and an altered distribution of phosphorylated Cx43 isoforms by the upregulation of the dephosphorylated Cx43 in both the subendocardium and subepicardium layers. Failing hearts further demonstrated spatially discordant conduction velocity alternans which resulted in nonuniform propagation discontinuities and wavebreaks conditioned by strands of increased interstitial fibrosis (fibrous tissue content in HF 16.4±7.7 versus 9.9±1.4% in NF, P=0.02). Conclusions: Conduction disorder resulting from the anisotropic downregulation of Cx43 expression, the reduction of Cx43 phosphorylation, and increased fibrosis is likely to be a critical component of arrhythmogenic substrate in patients with non-ischemic cardiomyopathy.

Circulation: 12 Mar 2012; epub ahead of print
Glukhov AV, Fedorov VV, Kalish PW, Ravikumar VK, ... Moazami N, Efimov IR
Circulation: 12 Mar 2012; epub ahead of print | PMID: 22412072
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Abstract

Black Lives Do Matter.

Churchwell KB
In this issue of Circulation, Mehta and colleagues(1) provide additional information on the state of cardiovascular care for the African-American population in the United States and once again, the results remain mixed in our ability to optimize care for all. Their data remains consistent with findings from Bridges, et al.,(2) from 2000 in identifying race as an adverse factor for mortality for CABG and from Konety, et al.,(3) from 2005 who found the differences in morbidity and mortality outcomes worsened significantly over a 365 day period between blacks and whites in the dataset. With advancements in care both medically and operatively for multi-vessel coronary disease over the past 30 years, there has been a steady improvement in the operative outcomes for all patients undergoing coronary bypass surgery, but there continues to be a persistent disparity in morbidity and mortality between blacks and whites across cardiovascular centers in this country with a direct relationship to these differences based upon our definitions of race. Despite a cardiovascular care network that is extensive with modern resources available throughout our systems of care, we are still searching for answers to these differences; solutions that are a mixture of medical and societal ills that we need to understand, accept and correct.

Circulation: 24 Nov 2015; epub ahead of print
Churchwell KB
Circulation: 24 Nov 2015; epub ahead of print | PMID: 26603033
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Abstract

Downregulation of Kv7.4 Channel Activity in Primary and Secondary Hypertension.

Jepps TA, Chadha PS, Davis AJ, Harhun MI, ... Hansen RS, Greenwood IA
Background- Voltage-gated potassium (K(+)) channels encoded by KCNQ genes (Kv7 channels) have been identified in various rodent and human blood vessels as key regulators of vascular tone; however, nothing is known about the functional impact of these channels in vascular disease. We ascertained the effect of 3 structurally different activators of Kv7.2 through Kv7.5 channels (BMS-204352, S-1, and retigabine) on blood vessels from normotensive and hypertensive animals. Methods and results- Precontracted thoracic aorta and mesenteric artery segments from normotensive rats were relaxed by all 3 Kv7 activators, with potencies of BMS-204352=S-1>retigabine. We also tested these agents in the coronary circulation using the Langendorff heart preparation. BMS-204352 and S-1 dose dependently increased coronary perfusion at concentrations between 0.1 and 10 μmol/L, whereas retigabine was effective at 1 to 10 μmol/L. In addition, S-1 increased K(+) currents in isolated mesenteric artery myocytes. The ability of these agents to relax precontracted vessels, increase coronary flow, or augment K(+) currents was impaired considerably in tissues isolated from spontaneously hypertensive rats (SHRs). Of the 5 KCNQ genes, only the expression of KCNQ4 was reduced (≈3.7 fold) in SHRs aorta. Kv7.4 protein levels were ≈50% lower in aortas and mesenteric arteries from spontaneously hypertensive rats compared with normotensive vessels. A similar attenuated response to S-1 and decreased Kv7.4 were observed in mesenteric arteries from mice made hypertensive by angiotensin II infusion compared with normotensive controls. Conclusions- In 2 different rat and mouse models of hypertension, the functional impact of Kv7 channels was dramatically downregulated.

Circulation: 12 Jul 2011; epub ahead of print
Jepps TA, Chadha PS, Davis AJ, Harhun MI, ... Hansen RS, Greenwood IA
Circulation: 12 Jul 2011; epub ahead of print | PMID: 21747056
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Abstract

Pulmonary and Systemic Vascular Dysfunction in Young Offspring of Mothers With Preeclampsia.

Jayet PY, Rimoldi SF, Stuber T, Salmòn CS, ... Scherrer U, Sartori C
Background: -Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. Methods and results-We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean+/-SD, 32.1+/-5.6 versus 25.3+/-4.7 mm Hg; P<0.001) and flow-mediated dilation was 30% smaller (6.3+/-1.2% versus 8.3+/-1.4%; P<0.0001) in offspring of mothers with preeclampsia than in control subjects. A strong inverse relationship existed between flow-mediated dilation and pulmonary artery pressure (r=-0.61, P<0.001). The vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function. Augmented oxidative stress may represent an underlying mechanism because thiobarbituric acid-reactive substances plasma concentration was increased in offspring of mothers with preeclampsia. Conclusions-Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life.

Circulation: 20 Jul 2010; epub ahead of print
Jayet PY, Rimoldi SF, Stuber T, Salmòn CS, ... Scherrer U, Sartori C
Circulation: 20 Jul 2010; epub ahead of print | PMID: 20644018
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Abstract

Relationships Between Race, Bleeding, and Mortality in Coronary Reperfusion.

Giugliano RP
There are several examples of therapies that have differential effects in specific racially or ethnically distinct subgroups of the US population. For example, persons of African heritage generally have a poorer blood pressure response to angiotensin-converting enzyme inhibitors and beta-blockers compared to Caucasians, but derive greater benefit in the prevention of heart failure from the combination of isosorbide dinitrate and hydralazine. Indeed, this latter finding led to the first drug approved to treat a disease in patients identified by race. The explanations for racial and ethnic differences in response may be related to genetic factors that determine drug exposure (i.e., differences in absorption, distribution, metabolism, elimination), intrinsic factors (e.g., age, gender, weight, renal and/or hepatic function), extrinsic influences (e.g., diet, concomitant medications and non-traditional therapies, environmental exposure, cultural factors), or a combination therein. (SELECT FULL TEXT TO CONTINUE).

Circulation: 14 Mar 2012; epub ahead of print
Giugliano RP
Circulation: 14 Mar 2012; epub ahead of print | PMID: 22419698
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Evaluating the Performance of the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) Bleeding Score in a Contemporary Spanish Cohort of Patients With Non-ST-Segment Elevation Acute Myocardial Infarction.

Abu-Assi E, Gracía-Acuña JM, Ferreira-González I, Peña-Gil C, Gayoso-Diz P, González-Juanatey JR
Background: -The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) model provides a risk score that predicts the likelihood of major bleeding in patients hospitalized for non-ST-elevation acute myocardial infarction. The aim of the present work was to evaluate the performance of this model in a contemporary cohort of patients hospitalized for non-ST-elevation acute myocardial infarction in Spain. Methods and results-The study subjects were 782 consecutive patients admitted to our center between February 2004 and June 2009 with non-ST-elevation acute myocardial infarction. For each patient, we calculated the CRUSADE risk score and evaluated its discrimination and calibration by the C statistic and the Hosmer-Lemeshow goodness-of-fit test, respectively. The performance of the CRUSADE risk score was evaluated for the patient population as a whole and for groups of patients treated with or without >/=2 antithrombotic medications and who underwent cardiac catheterization or not. The median CRUSADE score was 30 points (range, 18 to 45). A total of 657 patients (84%) were treated with >/=2 antithrombotic, of whom 609 (92.7%) underwent cardiac catheterization. The overall incidence of major bleeding was 9.5%. This incidence increased with the risk category: very low, 1.5%; low, 4.3%; moderate, 7.8%; high, 11.8%; and very high, 28.9% (P<0.001). For the patients as a whole, for the groups treated with or without >/=2 antithrombotics, and for the subgroup treated with >/=2 antithrombotics who did or did not undergo cardiac catheterization, the CRUSADE score showed adequate calibration and excellent discriminatory capacity (Hosmer-Lemeshow P>0.3 and C values of 0.82, 0.80, 0.70, and 0.80, respectively). However, it showed little capacity to discriminate bleeding risk in patients treated with >/=2 antithrombotics who did not undergo cardiac catheterization (C=0.56). Conclusions-The CRUSADE risk score was generally validated and found to be useful in a Spanish cohort of patients treated with or without >/=2 antithrombotics and in those treated with or without >/=2 antithrombotics who underwent cardiac catheterization. More studies are needed to clarify the validity of the CRUSADE score in the subgroup treated with >/=2 antithrombotics who do not undergo cardiac catheterization.

Circulation: 25 May 2010; epub ahead of print
Abu-Assi E, Gracía-Acuña JM, Ferreira-González I, Peña-Gil C, Gayoso-Diz P, González-Juanatey JR
Circulation: 25 May 2010; epub ahead of print | PMID: 20497978
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Abstract

Dispatcher-Assisted Cardiopulmonary Resuscitation. Risks for Patients Not in Cardiac Arrest.

White L, Rogers J, Bloomingdale M, Fahrenbruch C, ... Eisenberg M, Rea T
Background: -Dispatcher-assisted cardiopulmonary resuscitation (CPR) instructions can increase bystander CPR and thereby increase the rate of survival from cardiac arrest. The risk of bystander CPR for patients not in arrest is uncertain and has implications for how assertive dispatch is in instructing CPR. We determined the frequency of dispatcher-assisted CPR for patients not in arrest and the frequency and severity of injury related to chest compressions. Methods and results-The investigation was a prospective cohort study of adult patients not in cardiac arrest for whom dispatchers provided CPR instructions in King County, Washington, between June 1, 2004, and January 31, 2007. The study focused on those who received chest compressions. Information was collected through review of the audio and written dispatch report, written emergency medical services report, hospital record, and telephone survey. Of the 1700 patients for whom dispatcher CPR instructions were initiated, 55% (938 of 1700) were in arrest, 45% (762 of 1700) were not in arrest, and 18% (313 of 1700) were not in arrest and received bystander chest compressions. Of the 247 not in arrest who received chest compressions and had complete outcome ascertainment, 12% (29 of 247) experienced discomfort, and 2% (6 of 247) sustained injuries likely or possibly caused by bystander CPR. Only 2% (5 of 247) suffered a fracture, and no patients suffered visceral organ injury. Conclusions-In this prospective study, the frequency of serious injury related to dispatcher-assisted bystander CPR among nonarrest patients was low. When coupled with the established benefits of bystander CPR among those with arrest, these results support an assertive program of dispatcher-assisted CPR.

Circulation: 22 Dec 2009; epub ahead of print
White L, Rogers J, Bloomingdale M, Fahrenbruch C, ... Eisenberg M, Rea T
Circulation: 22 Dec 2009; epub ahead of print | PMID: 20026780
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Abstract

Rhesus Macaques Develop Metabolic Syndrome With Reversible Vascular Dysfunction Responsive to Pioglitazone.

Zhang X, Zhang R, Raab S, Zheng W, ... Cheng H, Huang PL
Background- The metabolic syndrome (MetS) is a constellation of clinical features that include central obesity, hypertension, atherogenic dyslipidemia, and insulin resistance. However, the concept remains controversial; it has been debated whether MetS represents nothing more than simultaneous co-occurrence of individual risk factors or whether there are common shared pathophysiological mechanisms that link the individual components. Methods and results- To investigate the emergence of metabolic and cardiovascular components during the development of MetS, we identified MetS-predisposed animals (n=35) in a large population of rhesus macaques (Macaca mulatta, 12.7±2.9 years old, n=408), acclimated them to standardized conditions, and monitored the progression of individual component features over 18 months. In 18 MetS animals with recently developed fasting hyperinsulinemia, central obesity, hypertension, and atherogenic dyslipidemia, we found that individual metabolic and cardiovascular components track together during the transition from pre-MetS to onset of MetS; MetS was associated with a 60% impairment of flow-mediated dilation, establishing the mechanistic link with vascular dysfunction. Pioglitazone treatment (3 mg/kg body weight/d for 6 weeks), a peroxisome proliferator-activated receptor γ agonist, reversibly improved atherogenic dyslipidemia and insulin resistance and fully restored flow-mediated dilation with persistent benefits. Conclusions- Coemergence of metabolic and cardiovascular components during MetS progression and complete normalization of vascular dysfunction with peroxisome proliferator-activated receptor γ agonists suggest shared underlying mechanisms rather than separate processes, arguing for the benefit of early intervention of MetS components. Predictive nonhuman primate (NHP) models of MetS should be highly valuable in mechanistic and translational studies on the pathogenesis of MetS in relation to cardiovascular disease and diabetes mellitus.

Circulation: 21 Jun 2011; epub ahead of print
Zhang X, Zhang R, Raab S, Zheng W, ... Cheng H, Huang PL
Circulation: 21 Jun 2011; epub ahead of print | PMID: 21690491
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Abstract

Role of Pyruvate Dehydrogenase Inhibition in the Development of Hypertrophy in the Hyperthyroid Rat Heart: A Combined Magnetic Resonance Imaging and Hyperpolarized Magnetic Resonance Spectroscopy Study.

Atherton HJ, Dodd MS, Heather LC, Schroeder MA, ... Clarke K, Tyler DJ
Background- Hyperthyroidism increases heart rate, contractility, cardiac output, and metabolic rate. It is also accompanied by alterations in the regulation of cardiac substrate use. Specifically, hyperthyroidism increases the ex vivo activity of pyruvate dehydrogenase kinase, thereby inhibiting glucose oxidation via pyruvate dehydrogenase. Cardiac hypertrophy is another effect of hyperthyroidism, with an increase in the abundance of mitochondria. Although the hypertrophy is initially beneficial, it can eventually lead to heart failure. The aim of this study was to use hyperpolarized magnetic resonance spectroscopy to investigate the rate and regulation of in vivo pyruvate dehydrogenase flux in the hyperthyroid heart and to establish whether modulation of flux through pyruvate dehydrogenase would alter cardiac hypertrophy. Methods and results- Hyperthyroidism was induced in 18 male Wistar rats with 7 daily intraperitoneal injections of freshly prepared triiodothyronine (0.2 mg · kg(-1) · d(-1)). In vivo pyruvate dehydrogenase flux, assessed with hyperpolarized magnetic resonance spectroscopy, was reduced by 59% in hyperthyroid animals (0.0022±0.0002 versus 0.0055±0.0005 second(-1); P=0.0003), and this reduction was completely reversed by both short- and long-term delivery of dichloroacetic acid, a pyruvate dehydrogenase kinase inhibitor. Hyperpolarized [2-(13)C]pyruvate was also used to evaluate Krebs cycle metabolism and demonstrated a unique marker of anaplerosis, the level of which was significantly increased in the hyperthyroid heart. Cine magnetic resonance imaging showed that long-term dichloroacetic acid treatment significantly reduced the hypertrophy observed in hyperthyroid animals (100±20 versus 200±30 mg; P=0.04) despite no change in the increase observed in cardiac output. Conclusions- This work has demonstrated that inhibition of glucose oxidation in the hyperthyroid heart in vivo is mediated by pyruvate dehydrogenase kinase. Relieving this inhibition can increase the metabolic flexibility of the hyperthyroid heart and reduce the level of hypertrophy that develops while maintaining the increased cardiac output required to meet the higher systemic metabolic demand.

Circulation: 24 May 2011; epub ahead of print
Atherton HJ, Dodd MS, Heather LC, Schroeder MA, ... Clarke K, Tyler DJ
Circulation: 24 May 2011; epub ahead of print | PMID: 21606392
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Abstract

The Heart in Friedreich Ataxia: Definition of Cardiomyopathy, Disease Severity, and Correlation with Neurological Symptoms.

Weidemann F, Rummey C, Bijnens B, Störk S, ... Schulz JB, Meier T
Background: This cross sectional study provides a practical approach for the clinical assessment of Friedreich ataxia (FA) cardiomyopathy (FA-CM). Methods and results: A comprehensive cardiac assessment, including standard echocardiography, color Doppler myocardial imaging (CDMI), cardiac magnetic resonance imaging (cMRI), electrocardiography (ECG) and exercise stress testing was performed in 205 FA patients. To assess myocardial hypertrophy in FA-CM, the end-diastolic interventricular septal wall thickness (IVSTd) was found to be the best echocardiographic parameter when compared to cMRI-determined left ventricular mass. Using this parameter, four groups of FA-CM could be defined. Patients with normal values for IVSTd (31.7%) classified as "no FA-CM". Patients with an IVSTd exceeding the predicted normal IVSTd were classified as "mild FA-CM" (40%) if IVSTd exceeds the normal value by < 18% or as "intermediate FA-CM" (16.1%) if IVSTd exceeds by ≥18%. Patients with ejection fraction (EF) <50% were classified as "severe FA-CM" (12.2%). Besides increased myocardial mass, severe FA-CM was further characterized by dilatation of the left ventricle, reduced systolic strain-rate of the posterior wall, and ECG abnormalities. Regional myocardial function correlated negatively with FA-CM groups. Younger patients had a tendency for a more advanced FA-CM. Importantly, no clear correlation was found between FA-CM groups and neurological function. Conclusions: We provide and describe a readily applicable clinical grouping of the cardiomyopathy associated with FA based on echocardiographic IVSTd and EF data. As no distinct interrelations between FA-CM and neurological status could be determined, regular follow-up of potential cardiac involvement in FA patients is essential in clinical practice. CLINICAL TRIAL REGISTRATION INFORMATION: Clinicaltrials.gov; ID: NCT00905268.

Circulation: 29 Feb 2012; epub ahead of print
Weidemann F, Rummey C, Bijnens B, Störk S, ... Schulz JB, Meier T
Circulation: 29 Feb 2012; epub ahead of print | PMID: 22379112
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Abstract

Activation of CD4+ T-Lymphocytes Improves Wound Healing and Survival after Experimental Myocardial Infarction in Mice.

Hofmann U, Beyersdorf N, Weirather J, Podolskaya A, ... Kerkau T, Frantz S
Background: The role of the adaptive immunity, especially CD4(+) T-helper cells, has not yet been systematically investigated in wound healing and remodelling after myocardial infarction (MI). Therefore, we studied, whether CD4(+) T-cells become activated and influence wound healing after experimental MI in mice. Methods and results: When comparing sham vs. MI in wild-type (WT) mice, T-cell receptor dependent activation of both conventional Foxp3(-) and regulatory Foxp3(+) CD4(+) T-cells could be demonstrated in heart-draining lymph nodes within the first week after MI. Concomitantly, we found infiltration of CD4(+) T-cells in infarcted myocardium. To study the role of CD4(+) T-cells in wound healing and remodelling, CD4(+) T-cell deficient mice (CD4 KO, MHCII(Δ/Δ)) and T-cell receptor-transgenic OT-II mice recognizing an irrelevant ovalbumin-derived peptide were studied. Serial echocardiography up to day 56 after MI revealed increased left ventricular dilation in CD4 KO when compared to WT mice. Within the infarcted myocardium, CD4 KO mice displayed higher total numbers of leukocytes and of pro-inflammatory monocytes (18.3 ± 3.0 WT vs. 75.7 ± 17.0 CD4 KO, p<0.05). MHCII(Δ/Δ) and OT-II mice displayed significantly higher mortality (21% WT vs. 48% OT-II, p<0.05 and WT 22% vs. 52% MHCII(Δ/Δ), p<0.05) and myocardial rupture rates than WT mice. Collagen matrix formation in the infarct zone was severely disturbed in CD4 KO and MHCII(Δ/Δ) as well as OT-II mice. Conclusions: The study provides first evidence that CD4(+) T-cells become activated after myocardial infarction, presumably driven by recognition of cardiac autoantigens, and facilitate wound healing of the myocardium.

Circulation: 04 Mar 2012; epub ahead of print
Hofmann U, Beyersdorf N, Weirather J, Podolskaya A, ... Kerkau T, Frantz S
Circulation: 04 Mar 2012; epub ahead of print | PMID: 22388323
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Abstract

Aspirin for Primary Cardiovascular Risk Prevention and Beyond in Diabetes Mellitus.

Capodanno D, Angiolillo DJ
Daily administration of low-dose of aspirin has proven to be beneficial in preventing recurrent cardiovascular events. However, the role of aspirin for primary prevention in patients with no overt cardiovascular disease is more controversial. In fact, in lower risk patients, the modest benefit in reducing serious vascular events can be offset by the increased risk of bleeding, including intracranial and gastrointestinal hemorrhage. Diabetes mellitus (DM) has been associated with a substantially increased risk of both first and recurrent atherothrombotic events, which makes aspirin therapy of potential value in these subjects. Moving from general aspects of aspirin pharmacology and specific issues in DM, this article reviews the literature on the topic of aspirin for primary prevention in general, and in subjects with DM in particular, to end up with arguments pro and con, and a practical risk-based algorithm for aspirin initiation in daily practice.

Circulation: 11 Oct 2016; epub ahead of print
Capodanno D, Angiolillo DJ
Circulation: 11 Oct 2016; epub ahead of print | PMID: 27729421
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Abstract

Mineralocorticoid Accelerates Transition to Heart Failure With Preserved Ejection Fraction Via "Nongenomic Effects"

Mohammed SF, Ohtani T, Korinek J, Lam CS, ... Burnett JC, Redfield MM
Background: -Mechanisms promoting the transition from hypertensive heart disease to heart failure with preserved ejection fraction are poorly understood. When inappropriate for salt status, mineralocorticoid (deoxycorticosterone acetate) excess causes hypertrophy, fibrosis, and diastolic dysfunction. Because cardiac mineralocorticoid receptors are protected from mineralocorticoid binding by the absence of 11-beta hydroxysteroid dehydrogenase, salt-mineralocorticoid-induced inflammation is postulated to cause oxidative stress and to mediate cardiac effects. Although previous studies have focused on salt/nephrectomy in accelerating mineralocorticoid-induced cardiac effects, we hypothesized that hypertensive heart disease is associated with oxidative stress and sensitizes the heart to mineralocorticoid, accelerating hypertrophy, fibrosis, and diastolic dysfunction. Methods and results-Cardiac structure and function, oxidative stress, and mineralocorticoid receptor-dependent gene transcription were measured in sham-operated and transverse aortic constriction (studied 2 weeks later) mice without and with deoxycorticosterone acetate administration, all in the setting of normal-salt diet. Compared with sham mice, sham plus deoxycorticosterone acetate mice had mild hypertrophy without fibrosis or diastolic dysfunction. Transverse aortic constriction mice displayed compensated hypertensive heart disease with hypertrophy, increased oxidative stress (osteopontin and NOX4 gene expression), and normal systolic function, filling pressures, and diastolic stiffness. Compared with transverse aortic constriction mice, transverse aortic constriction plus deoxycorticosterone acetate mice had similar left ventricular systolic pressure and fractional shortening but more hypertrophy, fibrosis, and diastolic dysfunction with increased lung weights, consistent with heart failure with preserved ejection fraction. There was progressive activation of markers of oxidative stress across the groups but no evidence of classic mineralocorticoid receptor-dependent gene transcription. Conclusions-Pressure-overload hypertrophy sensitizes the heart to mineralocorticoid excess, which promotes the transition to heart failure with preserved ejection fraction independently of classic mineralocorticoid receptor-dependent gene transcription.

Circulation: 13 Jul 2010; epub ahead of print
Mohammed SF, Ohtani T, Korinek J, Lam CS, ... Burnett JC, Redfield MM
Circulation: 13 Jul 2010; epub ahead of print | PMID: 20625113
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Abstract

Antenatal Sildenafil Treatment Attenuates Pulmonary Hypertension in Experimental Congenital Diaphragmatic Hernia.

Luong C, Rey-Perra J, Vadivel A, Gilmour G, ... Archer SL, Thébaud B
Background- Lung hypoplasia and persistent pulmonary hypertension of the newborn limit survival in congenital diaphragmatic hernia (CDH). Unlike other diseases resulting in persistent pulmonary hypertension of the newborn, infants with CDH are refractory to inhaled nitric oxide (NO). Nitric oxide mediates pulmonary vasodilatation at birth in part via cyclic GMP production. Phosphodiesterase type 5 (PDE5) limits the effects of NO by inactivation of cyclic GMP. Because of the limited success in postnatal management of CDH, we hypothesized that antenatal PDE5 inhibition would attenuate pulmonary artery remodeling in experimental nitrofen-induced CDH. Methods and results- Nitrofen administered at embryonic day 9.5 to pregnant rats resulted in a 60% incidence of CDH in the offspring and recapitulated features seen in human CDH, including structural abnormalities (lung hypoplasia, decreased pulmonary vascular density, pulmonary artery remodeling, right ventricular hypertrophy), and functional abnormalities (decreased pulmonary artery relaxation in response to the NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide). Antenatal sildenafil administered to the pregnant rat from embryonic day 11.5 to embryonic day 20.5 crossed the placenta, increased fetal lung cyclic GMP and decreased active PDE5 expression. Antenatal sildenafil improved lung structure, increased pulmonary vessel density, reduced right ventricular hypertrophy, and improved postnatal NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide-induced pulmonary artery relaxation. This was associated with increased lung endothelial NO synthase and vascular endothelial growth factor protein expression. Antenatal sildenafil had no adverse effect on retinal structure/function and brain development. Conclusions- Antenatal sildenafil improves pathological features of persistent pulmonary hypertension of the newborn in experimental CDH and does not alter the development of other PDE5-expressing organs. Given the high mortality/morbidity of CDH, the potential benefit of prenatal PDE5 inhibition in improving the outcome for infants with CDH warrants further studies.

Circulation: 03 May 2011; epub ahead of print
Luong C, Rey-Perra J, Vadivel A, Gilmour G, ... Archer SL, Thébaud B
Circulation: 03 May 2011; epub ahead of print | PMID: 21537000
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Abstract

Mortality Resulting From Congenital Heart Disease Among Children and Adults in the United States, 1999 to 2006.

Gilboa SM, Salemi JL, Nembhard WN, Fixler DE, Correa A
Background- Previous reports suggest that mortality resulting from congenital heart disease (CHD) among infants and young children has been decreasing. There is little population-based information on CHD mortality trends and patterns among older children and adults. Methods and results- We used data from death certificates filed in the United States from 1999 to 2006 to calculate annual CHD mortality by age at death, race-ethnicity, and sex. To calculate mortality rates for individuals ≥1 year of age, population counts from the US Census were used in the denominator; for infant mortality, live birth counts were used. From 1999 to 2006, there were 41 494 CHD-related deaths and 27 960 deaths resulting from CHD (age-standardized mortality rates, 1.78 and 1.20 per 100 000, respectively). During this period, mortality resulting from CHD declined 24.1% overall. Mortality resulting from CHD significantly declined among all race-ethnicities studied. However, disparities persisted; overall and among infants, mortality resulting from CHD was consistently higher among non-Hispanic blacks compared with non-Hispanic whites. Infant mortality accounted for 48.1% of all mortality resulting from CHD; among those who survived the first year of life, 76.1% of deaths occurred during adulthood (≥18 years of age). Conclusions- CHD mortality continued to decline among both children and adults; however, differences between race-ethnicities persisted. A large proportion of CHD-related mortality occurred during infancy, although significant CHD mortality occurred during adulthood, indicating the need for adult CHD specialty management.

Circulation: 24 Nov 2010; epub ahead of print
Gilboa SM, Salemi JL, Nembhard WN, Fixler DE, Correa A
Circulation: 24 Nov 2010; epub ahead of print | PMID: 21098447
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Very Late Stent Thrombosis and Late Target Lesion Revascularization after Sirolimus-Eluting Stent Implantation: Five-year Outcome of the j-Cypher Registry.

Kimura T, Morimoto T, Nakagawa Y, Kawai K, ... Nobuyoshi M, Mitsudo K
Background: There is a scarcity of long-term data from large-scale drug-eluting stent registries with enough sample size to evaluate low-frequency events such as stent thrombosis (ST). Methods and results: Five-year outcomes were evaluated in 12812 consecutive patients undergoing sirolimus-eluting stents (SES) implantation in the j-Cypher registry. Cumulative incidence of definite ST was low (30-day: 0.3%, 1-year: 0.6%, and 5-year: 1.6%). However, late and very late ST continued to occur without attenuation up to 5 years after SES implantation (0.26%/year). Cumulative incidence of target lesion revascularization (TLR) within the first year was low (7.3%). However, late TLR beyond 1 year also continued to occur without attenuation up to 5 years (2.2%/year). Independent risk factors of ST were completely different according to the timing of ST onset, suggesting presence of different pathophysiologic mechanisms of ST according to the timing of ST onset; acute coronary syndrome and target of proximal left anterior descending coronary artery for early ST, side-branch stenting, diabetes mellitus, and end-stage renal disease with or without hemodialysis for late ST, and current smoking and total stent length >28mm for very late ST. Independent risk factors of late TLR beyond 1 year were generally similar to those risk factors identified for early TLR. Conclusions: Late adverse events such as very late ST and late TLR are the continuous hazard lasting at least up to 5 years after implantation of the first generation drug-eluting stents (SES), which should be the targets in developing improved coronary stents.

Circulation: 28 Dec 2011; epub ahead of print
Kimura T, Morimoto T, Nakagawa Y, Kawai K, ... Nobuyoshi M, Mitsudo K
Circulation: 28 Dec 2011; epub ahead of print | PMID: 22203694
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Abstract

Paracrine Regulation of Cardiac miRNAs by Bone Marrow Mononuclear Cell Therapy in Myocardial Infarction.

Iekushi K, Seeger F, Assmus B, Zeiher AM, Dimmeler S
Background: Cell therapy with bone marrow-derived mononuclear cells (BMC) can improve recovery of cardiac function after ischemia, however, the molecular mechanisms are not yet fully understood. MicroRNAs (miRNAs) are key regulators of gene expression and modulate the pathophysiology of cardiovascular diseases. Methods and results: We demonstrated that intramyocardial delivery of BMC in infarcted mice regulates the expression of cardiac miRNAs and significantly down-regulates the pro-apoptotic miR-34a. In vitro studies confirmed that the supernatant of BMC inhibited the expression of H(2)O(2)-induced miR-34a and cardiomyocytes apoptosis. These effects were blocked by neutralizing antibodies directed against insulin growth factor-1 (IGF-1). Indeed, IGF-1 significantly inhibited H(2)O(2)-induced miR-34a expression, and miR-34a overexpression abolished the anti-apoptotic effect of IGF-1. Likewise, inhibition of IGF-1 signaling in vivo abolished the BMC-mediated inhibition of miR-34 expression and the protective effect on cardiac function and increased apoptosis and cardiac fibrosis. IGF-1 specifically blocked the expression of the precursor and the mature miR-34a, but did not interfere with the transcription of the primary miR-34a demonstrating that IGF-1 blocks the processing of miR-34a. Conclusions: Together, our data demonstrate that the paracrine regulation of cardiac miRNAs by transplanted BMC contributes to the protective effects of cell therapy. BMC release IGF-1, which inhibits the processing of miR-34a, thereby blocking cardiomyocyte apoptosis.

Circulation: 08 Mar 2012; epub ahead of print
Iekushi K, Seeger F, Assmus B, Zeiher AM, Dimmeler S
Circulation: 08 Mar 2012; epub ahead of print | PMID: 22403243
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Abstract

Cost-Effectiveness of Statin Therapy for Primary Prevention in a Low-Cost Statin Era.

Lazar LD, Pletcher MJ, Coxson PG, Bibbins-Domingo K, Goldman L
Background- With wide availability of low-cost generics, primary prevention with statins has become less expensive. We projected the cost-effectiveness of expanded statin prescribing strategies using low-cost generics and identified conditions under which aggressive prescribing ceases to be cost-effective. Methods and results- We simulated expanded statin prescribing strategies with the coronary heart disease policy model, a Markov model of the US population >35 years of age. If statins cost $4/mo, treatment thresholds of low-density lipoprotein cholesterol >160 mg/dL for low-risk persons (0 to 1 risk factor), >130 mg/dL for moderate-risk persons (≥2 risk factors and 10-year risk <10%), and >100 mg/dL for moderately high-risk persons (≥2 risk factors and 10-year risk >10%) would reduce annual healthcare costs by $430 million compared with Adult Treatment Panel III guidelines. Lowering thresholds to >130 mg/dL for persons with 0 risk factors and >100 mg/dL for persons with 1 risk factor and treating all moderate- and moderately high-risk persons regardless of low-density lipoprotein cholesterol would provide additional health benefits for $9900 per quality-adjusted life-year. These findings are insensitive to most adverse effect assumptions (including statin-associated diabetes mellitus and severe hypothetical effects) but are sensitive to large reductions in the efficacy of statins or to a long-term disutility burden for which a patient would trade 30 to 80 days of life to avoid 30 years of statins. Conclusions- Low-cost statins are cost-effective for most persons with even modestly elevated cholesterol or any coronary heart disease risk factors if they do not mind taking a pill daily. Adverse effects are unlikely to outweigh benefits in any subgroup in which statins are found to be efficacious.

Circulation: 28 Jun 2011; epub ahead of print
Lazar LD, Pletcher MJ, Coxson PG, Bibbins-Domingo K, Goldman L
Circulation: 28 Jun 2011; epub ahead of print | PMID: 21709063
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cAMP Phosphodiesterase Inhibitors Increases Nitric Oxide Production by Modulating Dimethylarginine Dimethylaminohydrolases.

Pullamsetti SS, Savai R, Schaefer MB, Wilhelm J, ... Grimminger F, Schermuly RT
Background- Pulmonary arterial hypertension is characterized by a progressive increase in pulmonary vascular resistance caused by endothelial dysfunction, inward vascular remodeling, and severe loss of precapillary pulmonary vessel cross-sectional area. Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) play important roles in endothelial dysfunction. We investigated whether combined phosphodiesterase (PDE) 3 and 4 inhibition ameliorates endothelial function by regulating the ADMA-DDAH axis. Methods and results- We investigated the effects of the PDE3/4 inhibitor tolafentrine in vitro on endothelial cell survival, proliferation, and apoptosis. Effects of tolafentrine on the endothelial nitric oxide synthase/nitric oxide pathway, DDAH expression, DDAH promoter activity, and cytokine release from endothelial cells and their subsequent influence on DDAH expression were investigated. In monocrotaline-induced pulmonary arterial hypertension in rats, the effects of inhaled tolafentrine on DDAH expression and activity were investigated. Real-time-polymerase chain reaction, immunocytochemistry, and PDE activity assays suggested high expression of PDE3 and PDE4 isoforms in endothelial cells. Treatment of endothelial cells with PDE3/4 inhibitor significantly decreased ADMA-induced apoptosis via a cAMP/PKA-dependent pathway by induction of DDAH2. Chronic nebulization of PDE3/4 inhibitor significantly attenuated monocrotaline-induced hemodynamic, gas exchange abnormalities, vascular remodeling, and right heart hypertrophy. Interestingly, PDE3/4 inhibitor treatment reduced ADMA and elevated nitric oxide/cGMP levels. Mechanistically, this could be attributed to direct modulatory effects of cAMP on the promoter region of DDAH2, which was consequently found to be increased in expression and activity. Furthermore, PDE3/4 inhibitor suppressed apoptosis in endothelial cells and increased vascularization in the lung. Conclusion- Combined inhibition of PDE3 and 4 regresses development of pulmonary hypertension and promotes endothelial regeneration by modulating the ADMA-DDAH axis.

Circulation: 08 Mar 2011; epub ahead of print
Pullamsetti SS, Savai R, Schaefer MB, Wilhelm J, ... Grimminger F, Schermuly RT
Circulation: 08 Mar 2011; epub ahead of print | PMID: 21382892
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Ablation of C/EBP Homologous Protein Attenuates Endoplasmic Reticulum-Mediated Apoptosis and Cardiac Dysfunction Induced by Pressure Overload.

Fu HY, Okada KI, Liao Y, Tsukamoto O, ... Kitakaze M, Minamino T
Background: -Apoptosis may contribute to the development of heart failure, but the role of apoptotic signaling initiated by the endoplasmic reticulum in this condition has not been well clarified. Methods and results-In myocardial samples from patients with heart failure, quantitative real-time polymerase chain reaction revealed an increase in messenger RNA for C/EBP homologous protein (CHOP), a transcriptional factor that mediates endoplasmic reticulum-initiated apoptotic cell death. We performed transverse aortic constriction or sham operation on wild-type (WT) and CHOP-deficient mice. The CHOP-deficient mice showed less cardiac hypertrophy, fibrosis, and cardiac dysfunction compared with WT mice at 4 weeks after transverse aortic constriction, although the contractility of isolated cardiomyocytes from CHOP-deficient mice was not significantly different from that in the WT mice. In the hearts of CHOP-deficient mice, phosphorylation of eukaryotic translation initiation factor 2alpha, which may reduce protein translation, was enhanced compared with WT mice. In the hearts of WT mice, CHOP-increased apoptotic cell death with activation of caspase-3 was observed at 4 weeks after transverse aortic constriction. In contrast, CHOP-deficient mice had less apoptotic cell death and lower caspase-3 activation at 4 weeks after transverse aortic constriction. Furthermore, the Bcl2/Bax ratio was decreased in WT mice, whereas this change was significantly blunted in CHOP-deficient mice. Real-time polymerase chain reaction microarray analysis revealed that CHOP could regulate several Bcl2 family members in failing hearts. Conclusions-We propose the novel concept that CHOP, which may modify protein translation and mediate endoplasmic reticulum-initiated apoptotic cell death, contributes to development of cardiac hypertrophy and failure induced by pressure overload.

Circulation: 13 Jul 2010; epub ahead of print
Fu HY, Okada KI, Liao Y, Tsukamoto O, ... Kitakaze M, Minamino T
Circulation: 13 Jul 2010; epub ahead of print | PMID: 20625112
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Familial Evaluation in Arrhythmogenic Right Ventricular Cardiomyopathy: Impact of Genetics and Revised Task Force Criteria.

Quarta G, Muir A, Pantazis A, Syrris P, ... Elliott PM, McKenna WJ
Background- With recognition of disease-causing genes in arrhythmogenic right ventricular cardiomyopathy, mutation analysis is being applied. Methods and results- The role of genotyping in familial assessment for arrhythmogenic right ventricular cardiomyopathy was investigated, including the prevalence of mutations in known causal genes, the penetrance and expressivity in genotyped families, and the utility of the 2010 Task Force criteria in clinical diagnosis. Clinical and molecular genetic evaluation was performed in 210 first-degree and 45 second-degree relatives from 100 families. In 51 families, the proband was deceased. The living probands had a high prevalence of ECG abnormalities (89%) and ventricular arrhythmia (78%) and evidence of more severe disease than relatives. Definite or probable causal mutations were found in 58% of families and 73% of living probands, of whom 28% had an additional desmosomal variant (ie, mutation or polymorphism). Ninety-three relatives had a causal mutation; 33% fulfilled the 2010 criteria, whereas only 19% satisfied the 1994 version (P=0.03). An additional desmosomal gene variant was found in 10% and was associated with a 5-fold increased risk of developing penetrant disease (odds ratio, 4.7; 95% confidence interval, 1.1 to 20.4; P=0.04). Conclusions- Arrhythmogenic right ventricular cardiomyopathy is a genetically complex disease characterized by marked intrafamilial phenotype diversity. Penetrance is definition dependent and is greater with the 2010 criteria compared with the 1994 criteria. Relatives harboring >1 genetic variant had significantly increased risk of developing clinical disease, potentially an important determinant of the phenotypic heterogeneity seen within families with arrhythmogenic right ventricular cardiomyopathy.

Circulation: 24 May 2011; epub ahead of print
Quarta G, Muir A, Pantazis A, Syrris P, ... Elliott PM, McKenna WJ
Circulation: 24 May 2011; epub ahead of print | PMID: 21606390
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Abstract

Ca2+/Calmodulin-Dependent Kinase IIδ Causes Heart Failure by Accumulation of p53 in Dilated Cardiomyopathy.

Toko H, Takahashi H, Kayama Y, Oka T, ... Sasaguri T, Komuro I
Background: -Dilated cardiomyopathy (DCM), characterized by dilatation and dysfunction of the left ventricle, is an important cause of heart failure. Many mutations in various genes, including cytoskeletal protein genes and contractile protein genes, have been identified in DCM patients, but the mechanisms of how such mutations lead to DCM remain unknown. Methods and results-We established the mouse model of DCM by expressing a mutated cardiac alpha-actin gene, which has been reported in patients with DCM, in the heart (mActin-Tg). mActin-Tg mice showed gradual dilatation and dysfunction of the left ventricle, resulting in death by heart failure. The number of apoptotic cardiomyocytes and protein levels of p53 were increased in the hearts of mActin-Tg mice. Overexpression of Bcl-2 or downregulation of p53 decreased the number of apoptotic cardiomyocytes and improved cardiac function. This mouse model showed a decrease in myofilament calcium sensitivity and activation of calcium/calmodulin-dependent kinase IIdelta (CaMKIIdelta). The inhibition of CaMKIIdelta prevented the increase in p53 and apoptotic cardiomyocytes and ameliorated cardiac function. Conclusion-CaMKIIdelta plays a critical role in the development of heart failure in part by accumulation of p53 and induction of cardiomyocyte apoptosis in the DCM mouse model.

Circulation: 17 Aug 2010; epub ahead of print
Toko H, Takahashi H, Kayama Y, Oka T, ... Sasaguri T, Komuro I
Circulation: 17 Aug 2010; epub ahead of print | PMID: 20713897
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Abstract

Ca2+-Related Signaling and Protein Phosphorylation Abnormalities Play Central Roles in a New Experimental Model of Electrical Storm.

Tsuji Y, Hojo M, Voigt N, El-Armouche A, ... Kodama I, Kamiya K
Background- Electrical storm (ES), characterized by recurrent ventricular tachycardia/fibrillation, typically occurs in implantable cardioverter-defibrillator patients and adversely affects prognosis. However, the underlying molecular basis is poorly understood. In the present study, we report a new experimental model featuring repetitive episodes of implantable cardioverter-defibrillator firing for recurrent ventricular fibrillation (VF), in which we assessed involvement of Ca(2+)-related protein alterations in ES. Methods and results- We studied 37 rabbits with complete atrioventricular block for ≈80 days, all with implantable cardioverter-defibrillator implantation. All rabbits showed long-QT and VF episodes. Fifty-three percent of rabbits developed ES (≥3 VF episodes per 24-hour period; 103±23 VF episodes per rabbit). Expression/phosphorylation of Ca(2+)-handling proteins was assessed in left ventricular tissues from rabbits with the following: ES; VF episodes but not ES (non-ES); and controls. Left ventricular end-diastolic diameter increased comparably in ES and non-ES rabbits, but contractile dysfunction was significantly greater in ES than in non-ES rabbits. ES rabbits showed striking hyperphosphorylation of Ca(2+)/calmodulin-dependent protein kinase II, prominent phospholamban dephosphorylation, and increased protein phosphatase 1 and 2A expression versus control and non-ES rabbits. Ryanodine receptors were similarly hyperphosphorylated at Ser2815 in ES and non-ES rabbits, but ryanodine receptor Ser2809 and L-type Ca(2+) channel α-subunit hyperphosphorylation were significantly greater in ES versus non-ES rabbits. To examine direct effects of repeated VF/defibrillation, VF was induced 10 times in control rabbits. Repeated VF tissues showed autophosphorylated Ca(2+)/calmodulin-dependent protein kinase II upregulation and phospholamban dephosphorylation like those of ES rabbit hearts. Continuous infusion of a calmodulin antagonist (W-7) to ES rabbits reduced Ca(2+)/calmodulin-dependent protein kinase II hyperphosphorylation, suppressed ventricular tachycardia/fibrillation, and rescued left ventricular dysfunction. Conclusions- ES causes Ca(2+)/calmodulin-dependent protein kinase II activation and phospholamban dephosphorylation, which can explain the vicious cycle of arrhythmia promotion and mechanical dysfunction that characterizes ES.

Circulation: 10 May 2011; epub ahead of print
Tsuji Y, Hojo M, Voigt N, El-Armouche A, ... Kodama I, Kamiya K
Circulation: 10 May 2011; epub ahead of print | PMID: 21555709
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Abstract

Deletion of Cardiomyocyte Mineralocorticoid Receptor Ameliorates Adverse Remodeling After Myocardial Infarction.

Fraccarollo D, Berger S, Galuppo P, Kneitz S, ... Ertl G, Bauersachs J
Background- Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MR(MLCCre)) that were generated with a conditional MR allele (MR(flox)) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter. Methods and results- Control (MR(flox/flox), MR(flox/wt)) and MR(MLCCre) mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MR(MLCCre) mice. Chronically infarcted MR(MLCCre) mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O(2)(·-) production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MR(MLCCre) mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor-κB and reduced apoptosis early after myocardial infarction. Conclusion- Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression.

Circulation: 18 Jan 2011; epub ahead of print
Fraccarollo D, Berger S, Galuppo P, Kneitz S, ... Ertl G, Bauersachs J
Circulation: 18 Jan 2011; epub ahead of print | PMID: 21242479
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Abstract

Incidence and Prognosis of Resistant Hypertension in Hypertensive Patients.

Daugherty SL, Powers JD, Magid DJ, Tavel HM, ... Selby JV, Ho PM
Background: Despite a recent American Heart Association (AHA) consensus statement emphasizing the importance of resistant hypertension, the incidence and prognosis of this condition is largely unknown. Methods and results: This retrospective cohort study in two integrated health plans included patients with incident hypertension started on treatment from 2002-2006. Patients were followed for the development of resistant hypertension based on AHA criteria of uncontrolled blood pressure despite use of three or more antihypertensive medications using medication fill and blood pressure measurement data. We determined incident cardiovascular events (death or incident myocardial infarction, heart failure, stroke or chronic kidney disease) in patients with and without resistant hypertension adjusting for patient and clinical characteristics. Among 205,750 patients with incident hypertension, 1.9% developed resistant hypertension within a median 1.5 years from initial treatment, or 0.7 cases per 100 person-years of follow-up. These patients were more often men, older, and had higher rates of diabetes compared with non-resistant patients. Over 3.8 years of median follow-up, cardiovascular event rates were significantly higher in those with resistant hypertension (unadjusted: 18.0% vs. 13.5%, p<0.001). After adjusting for patient and clinical characteristics, resistant hypertension was associated with a higher risk of cardiovascular events (HR 1.47, 95% CI 1.33-1.62). Conclusions: Among patients with incident hypertension started on treatment, 1 in 50 patients developed resistant hypertension. Resistant hypertension patients had an increased risk of cardiovascular events supporting the need for greater efforts toward improving hypertension outcomes in this population.

Circulation: 29 Feb 2012; epub ahead of print
Daugherty SL, Powers JD, Magid DJ, Tavel HM, ... Selby JV, Ho PM
Circulation: 29 Feb 2012; epub ahead of print | PMID: 22379110
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Abstract

Auto-Antigenic Protein-DNA Complexes Stimulate Plasmacytoid Dendritic Cells to Promote Atherosclerosis.

Döring Y, Manthey H, Drechsler M, Lievens D, ... Weber C, Zernecke A
Background: Inflammation has been closely linked to auto-immunogenic processes in atherosclerosis. Plasmacytoid DCs (pDCs) are specialized to produce type-I interferons in response to pathogenic single-stranded nucleic acids but can also sense self-DNA released from dying cells or in neutrophil extracellular traps (NETs) complexed to the antimicrobial peptide Cramp/LL37 in autoimmune disease. However, the exact role of pDCs in atherosclerosis remains elusive. Methods and results: Here we demonstrate that pDCs can be detected in murine and human atherosclerotic lesions. Exposure to oxLDL enhanced the capacity of pDCs to phagocytose and prime antigen-specific T cell responses. pDCs can be stimulated to produce IFN-α by Cramp/DNA complexes, and we further identified increased expression of Cramp and formation of NETs in atherosclerotic arteries. Whereas Cramp/DNA complexes aggravated atherosclerotic lesion formation in apolipoprotein E-deficient (Apoe(-/-)) mice, pDC depletion and Cramp-deficiency in bone marrow reduced atherosclerosis and anti-dsDNA antibody titers. Moreover, the specific activation of pDCs and IFN-α treatment promoted plaque growth, associated with enhanced anti-ds-DNA antibody titers. Accordingly, anti-dsDNA-antibodies were elevated in patients with symptomatic versus asymptomatic carotid artery stenosis. Conclusions: Self-DNA, e.g. released from dying cells or in NETs, and an increased expression of the antimicrobial peptide Cramp/LL37 in atherosclerotic lesions may thus stimulate a pDC-driven pathway of autoimmune activation and the generation of anti-ds-DNA antibodies, critically aggravating atherosclerosis lesion formation. These key factors may thus represent novel therapeutic targets.

Circulation: 04 Mar 2012; epub ahead of print
Döring Y, Manthey H, Drechsler M, Lievens D, ... Weber C, Zernecke A
Circulation: 04 Mar 2012; epub ahead of print | PMID: 22388324
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Abstract

Role for Substance-P Based Nociceptive Signaling in Progenitor Cell Activation and Angiogenesis during Ischemia in Mice and in Human Subjects.

Amadesi S, Reni C, Katare R, Meloni M, ... Emanueli C, Madeddu P
Background: Pain triggers homeostatic alarm reaction to injury. It remains unknown however if nociceptive signaling activated by ischemia is relevant for progenitor cells (PC) release from bone marrow. To this end, we investigated the role of the neuropeptide substance-P (SP) and cognate neurokinin 1 (NK1) nociceptor in PC activation and angiogenesis during ischemia in mice and in human subjects. Methods and results: The mouse bone marrow contains sensory fibers and PC that express SP. Moreover, SP-induced migration enriches for PC that express NK1 and promote reparative angiogenesis following transplantation in a mouse model of limb ischemia. Acute myocardial infarction and limb ischemia increase SP levels in peripheral blood, decrease SP levels in bone marrow and stimulate the mobilization of NK1-expressing PC, with these effects being abrogated by systemic administration of the opioid receptor agonist morphine. Moreover, bone marrow reconstitution with NK1-knockout cells results in depressed PC mobilization, delayed blood flow recovery and reduced neovascularization following ischemia. We next asked if SP is instrumental to PC mobilization and homing in patients with ischemia. Human PC express NK1 and SP-induced migration enriches for pro-angiogenic PC. Patients with acute myocardial infarction show high circulating levels of SP and NK1-positive cells that co-express PC antigens, like CD34, KDR and CXCR4. Moreover, NK1-expressing PC are abundant in infarcted hearts, but not in hearts that developed an infarct after transplantation. Conclusions: Our data highlight the role of SP in reparative neovascularization. Nociceptive signaling may represent a novel target of regenerative medicine.

Circulation: 05 Mar 2012; epub ahead of print
Amadesi S, Reni C, Katare R, Meloni M, ... Emanueli C, Madeddu P
Circulation: 05 Mar 2012; epub ahead of print | PMID: 22392530
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Abstract

ACC/AHA/ESC/WHF Universal Definition of Myocardial Infarction Classification System and the Risk of Cardiovascular Death: Observations from the TRITON-TIMI 38 Trial.

Bonaca MP, Wiviott SD, Braunwald E, Murphy SA, ... Antman EM, Morrow DA
Background: The availability of more sensitive biomarkers of myonecrosis and a new classification system from the Universal Definition of Myocardial Infarction (MI) have led to evolution of the classification of MI. The prognostic implications of MI defined in the current era have not been well described. Methods and results: We investigated the association between new or recurrent MI by subtype according to the ACC/AHA/ESC/WHF Task Force for the Redefinition of MI Classification System and the risk of cardiovascular (CV) death among 13,608 patients with acute coronary syndrome (ACS) in TRITON-TIMI 38. The adjusted risk of CV death was evaluated by landmark analysis starting at the time of the MI through 180 days after the event. Patients who experienced an MI during follow up had a higher risk of CV death at 6 months compared to patients without an MI (6.5% vs 1.3% vs, p<0.001). This higher risk was present across all subtypes of MI including Type 4a (Peri-PCI, 3.2%, p<0.001) and Type 4b (stent thrombosis, 15.4%, p<0.001). After adjusting for important clinical covariates, the occurrence of any MI was associated with a 5 fold higher risk of death at 6 months (95% CI 3.8 - 7.1) with similarly increased risk across subtypes. Conclusions: MI is associated with a significantly increased risk of CV death with a consistent relationship across all types as defined by the Universal Classification System. These findings underscore the clinical relevance of these events and the importance of therapies aimed at preventing MI. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov; NCT00097591.

Circulation: 26 Dec 2011; epub ahead of print
Bonaca MP, Wiviott SD, Braunwald E, Murphy SA, ... Antman EM, Morrow DA
Circulation: 26 Dec 2011; epub ahead of print | PMID: 22199016
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Abstract

Sinus Node and Atrial Arrhythmias.

John RM, Kumar S
Although sinus node dysfunction (SND) and atrial arrhythmias frequently coexist and interact, the putative mechanism linking the 2 remain unclear. Although SND is accompanied by atrial myocardial structural changes in the right atrium, atrial fibrillation (AF) is a disease of variable interactions between left atrial triggers and substrate most commonly of left atrial origin. Significant advances have been made in our understanding of the genetic and pathophysiologic mechanism underlying the development and progression of SND and AF. Although some patients manifest SND as a result of electric remodeling induced by periods of AF, others develop progressive atrial structural remodeling that gives rise to both conditions together. The treatment strategy will thus vary according to the predominant disease phenotype. Although catheter ablation will benefit patients with predominantly AF and secondary SND, cardiac pacing may be the mainstay of therapy for patients with predominant fibrotic atrial cardiomyopathy. This contemporary review summarizes current knowledge on sinus node pathophysiology with the broader goal of yielding insights into the complex relationship between sinus node disease and atrial arrhythmias.

Circulation: 10 May 2016; 133:1892-900
John RM, Kumar S
Circulation: 10 May 2016; 133:1892-900 | PMID: 27166347
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Abstract

Cardiac Biomarkers are Associated with an Increased Risk of Stroke and Death in Patients with Atrial Fibrillation: A RELY Substudy.

Hijazi Z, Oldgren J, Andersson U, Connolly SJ, ... Yusuf S, Wallentin L
Background: Cardiac biomarkers are strong predictors of adverse outcomes in several patient populations. We evaluated the prevalence of elevated troponin I and NT-proBNP and their association to cardiovascular events in atrial fibrillation (AF) patients in the RELY trial. Methods and results: Biomarkers at randomization were analyzed in 6189 patients. Outcomes were evaluated by Cox proportional hazards models adjusting for established cardiovascular risk factors and the CHADS(2) and CHA(2)DS(2)-VASc risk scores. Patients were stratified based on troponin I concentrations: <0.010 μg/L, n=2663; 0.010-0.019 μg/L, n=2006; 0.020-0.039 μg/L, n=1023; ≥0.040 μg/L, n=497; and on NT-proBNP concentrations quartiles: <387; 387-800; 801-1402; >1402 ng/L. Rates of stroke were independently related to levels of troponin I with 2.09%/year in the highest and 0.84%/year in the lowest troponin I group (hazard ratio (HR) 1.99 [95% confidence interval (CI) 1.17-3.39], p=0.0040), and to NT-proBNP with 2.30%/year vs. 0.92% in the highest vs. lowest NT-proBNP quartile groups, (HR 2.40 [CI 1.41-4.07], p=0.0014). Vascular mortality was also independently related to biomarker levels with 6.56%/year in the highest and 1.04%/year the lowest troponin I group (HR 4.38 [CI 3.05-6.29] p<0.0001), and 5.00%/year in the highest and 0.61%/year in the lowest NT-proBNP quartile groups (HR 6.73 [3.95-11.49] p<0.0001). Biomarkers increased the C-statistic from 0.68 to 0.72, p<0.0001, for a composite of thromboembolic events. Conclusions: Elevations of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke and mortality. Cardiac biomarkers seem useful for improving risk prediction in AF beyond currently used clinical variables. CLINICAL TRIAL REGISTRATION INFORMATION: www.clinicaltrials.gov; NCT00262600.

Circulation: 28 Feb 2012; epub ahead of print
Hijazi Z, Oldgren J, Andersson U, Connolly SJ, ... Yusuf S, Wallentin L
Circulation: 28 Feb 2012; epub ahead of print | PMID: 22374183
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Abstract

The Polyphenols Resveratrol and S17834 prevent the Structural and Functional Sequelae of Diet-Induced Metabolic Heart Disease in Mice.

Qin F, Siwik DA, Luptak I, Hou X, ... Cohen RA, Colucci WS
Background: Diet-induced obesity is associated with metabolic heart disease characterized by left ventricular (LV) hypertrophy and diastolic dysfunction. Polyphenols such as resveratrol (RSV) and the synthetic flavonoid derivative S17834 exert beneficial systemic and cardiovascular effects in a variety of settings including diabetes and chronic hemodynamic overload. Methods and results: We characterized the structural and functional features of a mouse model of diet-induced metabolic syndrome, and used the model to test the hypothesis that the polyphenols prevent myocardial hypertrophy and diastolic dysfunction. Male C57BL/6J mice were fed a normal diet or a diet high in fat and sugar (HFHS) with or without concomitant treatment with S17834 or RSV for up to 8 months. HFHS diet-fed mice developed progressive LV hypertrophy and diastolic dysfunction with preservation of systolic function in association with myocyte hypertrophy and interstitial fibrosis. In HFHS-fed mice there was increased myocardial oxidative stress with evidence of oxidant-mediated protein modification via tyrosine nitration and 4-OH-2-nonenol (HNE) adduction. HFHS-fed mice also exhibited increases in plasma fasting glucose, insulin and HOMA-IR indicative of insulin resistance. Treatment with S17834 or RSV prevented LV hypertrophy and diastolic dysfunction. For S17834, these beneficial effects were associated with decreases in oxidant-mediated protein modifications and hyper-insulinemia, and increased plasma adiponectin. Conclusions: RSV and S17834 administered concurrently with a HFHS diet prevent the development of LV hypertrophy, interstitial fibrosis and diastolic dysfunction. Multiple mechanisms may contribute to the beneficial effects of the polyphenols including a reduction in myocardial oxidative stress and related protein modifications, amelioration of insulin resistance and increased plasma adiponectin. The polyphenols RSV and S17834 may be of value in the prevention of diet-induced metabolic heart disease.

Circulation: 04 Mar 2012; epub ahead of print
Qin F, Siwik DA, Luptak I, Hou X, ... Cohen RA, Colucci WS
Circulation: 04 Mar 2012; epub ahead of print | PMID: 22388319
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Abstract

Ryanodine Receptor Phosphorylation by Calcium/Calmodulin-Dependent Protein Kinase II Promotes Life-Threatening Ventricular Arrhythmias in Mice With Heart Failure.

van Oort RJ, McCauley MD, Dixit SS, Pereira L, ... Bers DM, Wehrens XH
Background- Approximately half of patients with heart failure die suddenly as a result of ventricular arrhythmias. Although abnormal Ca(2+) release from the sarcoplasmic reticulum through ryanodine receptors (RyR2) has been linked to arrhythmogenesis, the molecular mechanisms triggering release of arrhythmogenic Ca(2+) remain unknown. We tested the hypothesis that increased RyR2 phosphorylation by Ca(2+)/calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias. Methods and results- Mice in which the S2814 Ca(2+)/calmodulin-dependent protein kinase II site on RyR2 is constitutively activated (S2814D) develop pathological sarcoplasmic reticulum Ca(2+) release events, resulting in reduced sarcoplasmic reticulum Ca(2+) load on confocal microscopy. These Ca(2+) release events are associated with increased RyR2 open probability in lipid bilayer preparations. At baseline, young S2814D mice have structurally and functionally normal hearts without arrhythmias; however, they develop sustained ventricular tachycardia and sudden cardiac death on catecholaminergic provocation by caffeine/epinephrine or programmed electric stimulation. Young S2814D mice have a significant predisposition to sudden arrhythmogenic death after transverse aortic constriction surgery. Finally, genetic ablation of the Ca(2+)/calmodulin-dependent protein kinase II site on RyR2 (S2814A) protects mutant mice from pacing-induced arrhythmias versus wild-type mice after transverse aortic constriction surgery. Conclusions- Our results suggest that Ca(2+)/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca(2+) release channels at S2814 plays an important role in arrhythmogenesis and sudden cardiac death in mice with heart failure.

Circulation: 24 Nov 2010; epub ahead of print
van Oort RJ, McCauley MD, Dixit SS, Pereira L, ... Bers DM, Wehrens XH
Circulation: 24 Nov 2010; epub ahead of print | PMID: 21098440
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Abstract

Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia. Proposed Modification of the Task Force Criteria.

Marcus FI, McKenna WJ, Sherrill D, Basso C, ... Wichter T, Zareba W
Background: -In 1994, an International Task Force proposed criteria for the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) that facilitated recognition and interpretation of the frequently nonspecific clinical features of ARVC/D. This enabled confirmatory clinical diagnosis in index cases through exclusion of phenocopies and provided a standard on which clinical research and genetic studies could be based. Structural, histological, electrocardiographic, arrhythmic, and familial features of the disease were incorporated into the criteria, subdivided into major and minor categories according to the specificity of their association with ARVC/D. At that time, clinical experience with ARVC/D was dominated by symptomatic index cases and sudden cardiac death victims-the overt or severe end of the disease spectrum. Consequently, the 1994 criteria were highly specific but lacked sensitivity for early and familial disease. Methods and results-Revision of the diagnostic criteria provides guidance on the role of emerging diagnostic modalities and advances in the genetics of ARVC/D. The criteria have been modified to incorporate new knowledge and technology to improve diagnostic sensitivity, but with the important requisite of maintaining diagnostic specificity. The approach of classifying structural, histological, electrocardiographic, arrhythmic, and genetic features of the disease as major and minor criteria has been maintained. In this modification of the Task Force criteria, quantitative criteria are proposed and abnormalities are defined on the basis of comparison with normal subject data. Conclusions-The present modifications of the Task Force Criteria represent a working framework to improve the diagnosis and management of this condition. Clinical trial registration-clinicaltrials.gov Identifier: NCT00024505.

Circulation: 22 Feb 2010; epub ahead of print
Marcus FI, McKenna WJ, Sherrill D, Basso C, ... Wichter T, Zareba W
Circulation: 22 Feb 2010; epub ahead of print | PMID: 20172911
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The Way to Select a Suitable Patient Population for Thrombin Receptor Antagonist from the Large Clinical Trial Database of the TRA-2P-TIMI50 Trial.

Goto S, Goto S
In this issue of Circulation, Cavender et al presented an interesting report on the prevention of cardiovascular (CV) events in patients with prior myocardial infarction (MI) with and without diabetes mellitus (DM) using Vorapaxar, a new class antiplatelet agent of thrombin receptor (protease activated receptor: PAR)-1 antagonist.(1,2) Platelet cells are known to play crucial roles in both hemostasis and pathological thrombus formation.(3) The efficacy and safety of various antiplatelet agents were tested in many clinical settings including "acute coronary syndrome",(4, 5) "cerebrovascular, coronary and peripheral arterial diseases",(6) "stable out-patients with atherothrombosis"(7) and so on. The complicated and yet to be clarified quantitative relationship between activation/inhibition of each receptor on platelet cells (as shown in Figure 1(8-10)) and the onset of thrombotic and bleeding events makes it difficult to predict the best suitable antiplatelet intervention in individual patients using a constructive logic.(11) Thus, the Evidence-based approach is currently the only available tool to test scientific hypothesis in clinical medicine.

Circulation: 13 Feb 2015; epub ahead of print
Goto S, Goto S
Circulation: 13 Feb 2015; epub ahead of print | PMID: 25681465
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Mechanical Stress Conditioning and Electrical Stimulation Promote Contractility and Force Maturation of Induced Pluripotent Stem Cell-Derived Human Cardiac Tissue.

Ruan JL, Tulloch NL, Razumova MV, Saiget M, ... Regnier M, Murry CE
-Tissue engineering enables the generation of functional human cardiac tissue using cells derived in vitro in combination with biocompatible materials. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes provide a cell source for cardiac tissue engineering; however, their immaturity limits their potential applications. Here we sought to study the effect of mechanical conditioning and electrical pacing on the maturation of hiPSC-derived cardiac tissues. METHODSS: -Cardiomyocytes derived from hiPSCs were used to generate collagen-based bioengineered human cardiac tissue. Engineered tissue constructs were subjected to different mechanical stress and electrical pacing conditions. RESULTSS: -The engineered human myocardium exhibits Frank-Starling-type force-length relationships. After 2 weeks of static stress conditioning, the engineered myocardium demonstrated increases in contractility (0.63±0.10 mN/mm(2) vs 0.055±0.009 mN/mm(2) for no stress), tensile stiffness, construct alignment, and cell size. Stress conditioning also increased SERCA2 expression, which correlated with a less negative force-frequency relationship. When electrical pacing was combined with static stress conditioning, the tissues showed an additional increase in force production (1.34±0.19 mN/mm(2)), with no change in construct alignment or cell size, suggesting maturation of excitation-contraction coupling. Supporting this notion, we found expression of RYR2 and SERCA2 further increased by combined static stress and electrical stimulation.

Circulation: 13 Oct 2016; epub ahead of print
Ruan JL, Tulloch NL, Razumova MV, Saiget M, ... Regnier M, Murry CE
Circulation: 13 Oct 2016; epub ahead of print | PMID: 27737958
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Endurance Exercise and the Right Ventricle: Weak Link, Innocent Bystander, or Key Ingredient?

Wasfy MM, Baggish AL
The cardiovascular response to high intensity exercise has intrigued clinicians and scientists for more than a century. Since the initial reports of cardiac enlargement among Nordic skiers,(1)and rowers,(2)a great deal has been learned about how the heart and vasculature remodel in response to endurance exercise. Through the efforts of many investigators and their athletic subjects, we now recognize the heart as an organ characterized by tremendous plasticity that permits chamber dilation and myocardial hypertrophy in response to the hemodynamic stressors inherent in endurance sporting activity. Our contemporary view of the endurance "athlete\'s heart" includes attributes such as biventricular and biatrial dilation, mild to moderate ventricular hypertrophy, and normal to mildly reduced resting biventricular systolic function (as defined by ejection fractions).(3)Functionally, this remodeling pattern facilitates stroke volume augmentation and thus increases cardiac output reserve during exercise. Yet, are theses adaptations that facilitate successful endurance sport participation and lead to optimal athletic performance cost free? More specifically, do the short-term physiologic benefits of exercise-induced cardiac remodeling come with long-term tradeoffs that have undesirable clinical consequences?

Circulation: 12 Apr 2016; epub ahead of print
Wasfy MM, Baggish AL
Circulation: 12 Apr 2016; epub ahead of print | PMID: 27073130
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Cardiovascular Diseases in India: Current Epidemiology and Future Directions.

Prabhakaran D, Jeemon P, Roy A
Cardiovascular diseases (CVDs) have now become the leading cause of mortality in India. A quarter of all mortality is attributable to CVD. Ischemic heart disease and stroke are the predominant causes and are responsible for >80% of CVD deaths. The Global Burden of Disease study estimate of age-standardized CVD death rate of 272 per 100 000 population in India is higher than the global average of 235 per 100 000 population. Some aspects of the CVD epidemic in India are particular causes of concern, including its accelerated buildup, the early age of disease onset in the population, and the high case fatality rate. In India, the epidemiological transition from predominantly infectious disease conditions to noncommunicable diseases has occurred over a rather brief period of time. Premature mortality in terms of years of life lost because of CVD in India increased by 59%, from 23.2 million (1990) to 37 million (2010). Despite wide heterogeneity in the prevalence of cardiovascular risk factors across different regions, CVD has emerged as the leading cause of death in all parts of India, including poorer states and rural areas. The progression of the epidemic is characterized by the reversal of socioeconomic gradients; tobacco use and low fruit and vegetable intake have become more prevalent among those from lower socioeconomic backgrounds. In addition, individuals from lower socioeconomic backgrounds frequently do not receive optimal therapy, leading to poorer outcomes. Countering the epidemic requires the development of strategies such as the formulation and effective implementation of evidence-based policy, reinforcement of health systems, and emphasis on prevention, early detection, and treatment with the use of both conventional and innovative techniques. Several ongoing community-based studies are testing these strategies.

Circulation: 03 May 2016; 133:1605-20
Prabhakaran D, Jeemon P, Roy A
Circulation: 03 May 2016; 133:1605-20 | PMID: 27142605
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Abstract

Brain in Congenital Heart Disease Across the Lifespan: The Cumulative Burden of Injury.

Marelli A, Miller SP, Marino BS, Jefferson AL, Newburger JW
The number of patients surviving with congenital heart disease (CHD) has soared over the last 3 decades. Adults constitute the fastest-growing segment of the CHD population, now outnumbering children. Research to date on the heart-brain intersection in this population has been focused largely on neurodevelopmental outcomes in childhood and adolescence. Mutations in genes that are highly expressed in heart and brain may cause cerebral dysgenesis. Together with altered cerebral perfusion in utero, these factors are associated with abnormalities of brain structure and brain immaturity in a significant portion of neonates with critical CHD even before they undergo cardiac surgery. In infancy and childhood, the brain may be affected by risk factors related to heart disease itself or to its interventional treatments. As children with CHD become adults, they increasingly develop heart failure, atrial fibrillation, hypertension, diabetes mellitus, and coronary disease. These acquired cardiovascular comorbidities can be expected to have effects similar to those in the general population on cerebral blood flow, brain volumes, and dementia. In both children and adults, cardiovascular disease may have adverse effects on achievement, executive function, memory, language, social interactions, and quality of life. Against the backdrop of shifting demographics, risk factors for brain injury in the CHD population are cumulative and synergistic. As neurodevelopmental sequelae in children with CHD evolve to cognitive decline or dementia during adulthood, a growing population of CHD can be expected to require support services. We highlight evidence gaps and future research directions.

Circulation: 16 May 2016; 133:1951-62
Marelli A, Miller SP, Marino BS, Jefferson AL, Newburger JW
Circulation: 16 May 2016; 133:1951-62 | PMID: 27185022
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Abstract

Can We Make High-Density Lipoproteins Great Again?

Thyagarajan N, Brannan AM, Brown RJ
Elevated levels of circulating high-density lipoprotein cholesterol (HDL-C) have long been thought to be associated with reduced coronary artery disease (CAD) risk.(1,2)This concept has led to the "HDL hypothesis": increasing HDL-C would be a key addendum in the prevention of CAD,(2)in addition to reducing circulating low-density lipoprotein cholesterol levels. In theory, increasing HDL-C should improve the anti-atherosclerotic process of reverse cholesterol transport (RCT). However, repeated attempts to increase HDL-C pharmacologically have shown no changes to the risk of CAD.(3)While discouraging, the concept of "HDL functionality", or its ability to efflux cholesterol from extrahepatic tissues during the RCT process, was shown to be a negative correlate of CAD.(4)Thus, studies of interventions that attempt to target HDL functionality are highly desirable.

Circulation: 14 Apr 2016; epub ahead of print
Thyagarajan N, Brannan AM, Brown RJ
Circulation: 14 Apr 2016; epub ahead of print | PMID: 27081118
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Abstract

Cardiac Raptor Ablation Impairs Adaptive Hypertrophy, Alters Metabolic Gene Expression, and Causes Heart Failure in Mice.

Shende P, Plaisance I, Morandi C, Pellieux C, ... Pedrazzini T, Brink M
Background- Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals. It is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC) 1 and mTORC2. The role of each of these branches of mTOR signaling in the adult heart is currently unknown. Methods and results- We generated mice with deficient myocardial mTORC1 activity by targeted ablation of raptor, which encodes an essential component of mTORC1, during adulthood. At 3 weeks after the deletion, atrial and brain natriuretic peptides and β-myosin heavy chain were strongly induced, multiple genes involved in the regulation of energy metabolism were altered, but cardiac function was normal. Function deteriorated rapidly afterward, resulting in dilated cardiomyopathy and high mortality within 6 weeks. Aortic banding-induced pathological overload resulted in severe dilated cardiomyopathy already at 1 week without a prior phase of adaptive hypertrophy. The mechanism involved a lack of adaptive cardiomyocyte growth via blunted protein synthesis capacity, as supported by reduced phosphorylation of ribosomal S6 kinase 1 and 4E-binding protein 1. In addition, reduced mitochondrial content, a shift in metabolic substrate use, and increased apoptosis and autophagy were observed. Conclusions- Our results demonstrate an essential function for mTORC1 in the heart under physiological and pathological conditions and are relevant for the understanding of disease states in which the insulin/insulin-like growth factor signaling axis is affected such as diabetes mellitus and heart failure or after cancer therapy.

Circulation: 01 Mar 2011; epub ahead of print
Shende P, Plaisance I, Morandi C, Pellieux C, ... Pedrazzini T, Brink M
Circulation: 01 Mar 2011; epub ahead of print | PMID: 21357822
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Abstract

Mitral Valve Prolapse with Mid-Late Systolic Mitral Regurgitation: Pitfalls of Evaluation and Clinical Outcome Compared to Holosystolic Regurgitation.

Topilsky Y, Michelena H, Bichara V, Maalouf J, Mahoney DW, Enriquez-Sarano M
Background: Mitral regurgitation (MR) of mitral valve prolapse (MVP) predominates in late-systole but may be holosystolic (Holo-MR) or purely mid-late systolic (Mid-Late-MR) but the impact of MR-timing on MR left ventricular (LV) atrial (LA) consequences and outcome is unknown. Whether effective-regurgitant-orifice (ERO) by flow-convergence method is similarly linked to outcome in Mid-Late-MR and Holo-MR is uncertain. Methods and results: We comprehensively and prospectively quantified MR in 111 patients with MVP and Mid-Late-MR and matched them to 90 patients with MVP and Holo-MR for age, gender, atrial fibrillation, ejection fraction and ERO (flow-convergence). Mid-Late-MR vs. Holo-MR groups were well-matched including for comorbidity, blood pressure and heart rate (all p>0.10). Mid-Late-MR vs. Holo-MR caused similar color jet-area, mid-systolic regurgitant flow and peak velocity (p>0.40). Despite identical ERO (0.25±0.15 vs.0.25±0.15 cm(2), p=0.53), Mid-Late-MR shorter duration (233±56 vs. 426±50 msec, p<0.0001) yielded lower regurgitant volume (24.8±13.4 vs. 48.6±25.6mL; p<0.0001). MR consequences, systolic pulmonary pressure, LV and LA-volume-index (all p<0.001) were more benign in Mid-Late-MR vs. Holo-MR. Under medical management less cardiac events (5-year 15.8±4.6 vs. 40.4±6.1%, p<0.0001) occurred in Mid-Late-MR vs. Holo-MR requiring less mitral surgery. Multivariable analysis confirmed the independent association of Mid-Late-MR with benign consequences and outcomes (all p<0.01). Absolute ERO was not linked to outcome in contrast to regurgitant volume. Conclusions: MR of MVP purely Mid-Late systolic causes more benign consequences and outcomes than holosystolic MR. Assessment may be misleading as jet area and ERO by flow-convergence appear similar to holosystolic MR. However, shorter MR yields lower RVol, consequences and benign outcomes. Instantaneous ERO by flow-convergence should be interpreted in context and in Mid-Late-MR regurgitant volume provides information more reflective of MR severity. Therefore, clinical management and surgical referral should carefully take into account timing and consequences of MR.

Circulation: 04 Mar 2012; epub ahead of print
Topilsky Y, Michelena H, Bichara V, Maalouf J, Mahoney DW, Enriquez-Sarano M
Circulation: 04 Mar 2012; epub ahead of print | PMID: 22388325
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