The 50 most-cited articles in Circulation, 2019

Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. These guidelines, which are based on systematic methods to evaluate and classify evidence, provide a foundation for the delivery of quality cardiovascular care. The ACC and AHA sponsor the development and publication of clinical practice guidelines without commercial support, and members volunteer their time to the writing and review efforts. Clinical practice guidelines provide recommendations applicable to patients with or at risk of developing cardiovascular disease (CVD). The focus is on medical practice in the United States, but these guidelines are relevant to patients throughout the world. Although guidelines may be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with patients’ interests. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances, and should not…

Author(s): Arnett, Donna K; Blumenthal, Roger S; Albert, Michelle A; Buroker, Andrew B; Goldberger, Zachary D; Hahn, Ellen J; Himmelfarb, Cheryl Dennison; Khera, Amit; Lloyd-Jones, Donald; McEvoy, J William; Michos, Erin D; Miedema, Michael D; Muñoz, Daniel; Smith, Sidney C; Virani, Salim S; Williams, Kim A; Yeboah, Joseph; Ziaeian, Boback

1. The most important way to prevent atherosclerotic vascular disease, heart failure, and atrial fibrillation is to promote a healthy lifestyle throughout life. 2. A team-based care approach is an effective strategy for the prevention of cardiovascular disease. Clinicians should evaluate the social determinants of health that affect individuals to inform treatment decisions. 3. Adults who are 40 to 75 years of age and are being evaluated for cardiovascular disease prevention should undergo 10-year atherosclerotic cardiovascular disease (ASCVD) risk estimation and have a clinician–patient risk discussion before starting on pharmacological therapy, such as antihypertensive therapy, a statin, or aspirin. The presence or absence of additional risk-enhancing factors can help guide decisions about preventive interventions in select individuals, as can coronary artery calcium scanning. 4. All adults should consume a healthy diet that emphasizes the intake of vegetables, fruits, nuts, whole grains, lean vegetable or animal protein, and fish and minimizes the intake of trans fats, processed…

Cardiorenal syndrome encompasses a spectrum of disorders involving both the heart and kidneys in which acute or chronic dysfunction in 1 organ may induce acute or chronic dysfunction in the other organ. It represents the confluence of heart-kidney interactions across several interfaces. These include the hemodynamic cross-talk between the failing heart and the response of the kidneys and vice versa, as well as alterations in neurohormonal markers and inflammatory molecular signatures characteristic of its clinical phenotypes. The mission of this scientific statement is to describe the epidemiology and pathogenesis of cardiorenal syndrome in the context of the continuously evolving nature of its clinicopathological description over the past decade. It also describes diagnostic and therapeutic strategies applicable to cardiorenal syndrome, summarizes cardiac-kidney interactions in special populations such as patients with diabetes mellitus and kidney transplant recipients, and emphasizes the role of palliative care in patients with cardiorenal syndrome. Finally, it outlines the need…

It has been 50 years since Francis Fontan pioneered the operation that today bears his name. Initially designed for patients with tricuspid atresia, this procedure is now offered for a vast array of congenital cardiac lesions when a circulation with 2 ventricles cannot be achieved. As a result of technical advances and improvements in patient selection and perioperative management, survival has steadily increased, and it is estimated that patients operated on today may hope for a 30-year survival of >80%. Up to 70 000 patients may be alive worldwide today with Fontan circulation, and this population is expected to double in the next 20 years. In the absence of a subpulmonary ventricle, Fontan circulation is characterized by chronically elevated systemic venous pressures and decreased cardiac output. The addition of this acquired abnormal circulation to innate abnormalities associated with single-ventricle congenital heart disease exposes these patients to a variety of complications. Circulatory failure, ventricular dysfunction, atrioventricular valve regurgitation, arrhythmia,…

Myocardial infarction in the absence of obstructive coronary artery disease is found in ≈5% to 6% of all patients with acute infarction who are referred for coronary angiography. There are a variety of causes that can result in this clinical condition. As such, it is important that patients are appropriately diagnosed and an evaluation to uncover the correct cause is performed so that, when possible, specific therapies to treat the underlying cause can be prescribed. This statement provides a formal and updated definition for the broadly labelled term MINOCA (incorporating the definition of acute myocardial infarction from the newly released "Fourth Universal Definition of Myocardial Infarction") and provides a clinically useful framework and algorithms for the diagnostic evaluation and management of patients with myocardial infarction in the absence of obstructive coronary artery disease.

BACKGROUND: Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined. METHODS: Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration. RESULTS: The median (interquartile range) baseline Lp(a) concentration was 37 (13-165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio…

hydroxymethylglutaryl-CoA reductase inhibitors/statins ◼ hypercholesterolemia ◼ lipids ◼ patient compliance ◼ primary prevention ◼ risk assessment ◼ risk reduction discussion ◼ risk treatment discussion, secondary prevention ◼ ezetimibe ◼ proprotein convertase subtilisin

Identification and management of patients at high bleeding risk undergoing percutaneous coronary intervention are of major importance, but a lack of standardization in defining this population limits trial design, data interpretation, and clinical decision-making. The Academic Research Consortium for High Bleeding Risk (ARC-HBR) is a collaboration among leading research organizations, regulatory authorities, and physician-scientists from the United States, Asia, and Europe focusing on percutaneous coronary intervention-related bleeding. Two meetings of the 31-member consortium were held in Washington, DC, in April 2018 and in Paris, France, in October 2018. These meetings were organized by the Cardiovascular European Research Center on behalf of the ARC-HBR group and included representatives of the US Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, as well as observers from the pharmaceutical and medical device industries. A consensus definition of patients at high bleeding risk was developed that was based on review of the available…

Background: Arterial hypertension and its organ sequelae show characteristics of T cell–mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study (Canakinumab Antiinflammatory Thrombosis Outcome Study) targeting interleukin-1β demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays a pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFAs) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in 2 different mouse models of hypertensive cardiovascular damage. Methods: To investigate the effect of SCFAs on hypertensive cardiac damage and atherosclerosis, wild-type NMRI or apolipoprotein E knockout–deficient mice received propionate (200 mmol/L) or control in the drinking water. To induce hypertension, wild-type NMRI mice were infused with angiotensin II (1.44 mg·kg –1 ·d –1 subcutaneous) for 14 days. To accelerate the…

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as 2 new classes of antihyperglycemic agents that also reduce cardiovascular risk. The relative benefits in patients with and without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs remain undefined. METHODS: We performed a systematic review and trial-level meta-analysis of GLP1-RA and SGLT2i cardiovascular outcomes trials using the PubMed and EMBASE databases (Excerpta Medica Database). The primary outcomes were the composite of myocardial infarction, stroke, and cardiovascular death (MACE); hospitalization for heart failure; and progression of kidney disease. RESULTS: In total, data from 8 trials and 77 242 patients, 42 920 (55.6%) in GLP1-RA trials, and 34 322 (44.4%) in SGLT2i trials, were included. Both drug classes reduced MACE in a similar magnitude with GLP1-RA reducing the risk by 12% (hazard ratio [HR], 0.88; 95% CI, 0.84-0.94; P<0.001) and SGLT2i by 11% (HR, 0.89; 95% CI, 0.83-0.96;…

BACKGROUND: Sex differences are known to exist in the management of older patients presenting with acute myocardial infarction (AMI). Few studies have examined the incidence and risk factors of AMI among young patients, or whether clinical management differs by sex. METHODS: The Atherosclerosis Risk in Communities (ARIC) Surveillance study conducts hospital surveillance of AMI in 4 US communities (MD, MN, MS, and NC). AMI was classified by physician review, using a validated algorithm. Medications and procedures were abstracted from the medical record. Our study population was limited to young patients aged 35 to 54 years. RESULTS: From 1995 to 2014, 28 732 weighted hospitalizations for AMI were sampled among patients aged 35 to 74 years. Of these, 8737 (30%) were young. The annual incidence of AMI hospitalizations increased for young women but decreased for young men. The overall proportion of AMI admissions attributable to young patients steadily increased, from 27% in 1995 to 1999 to 32% in 2010 to 2014 ( P for trend=0.002), with the largest increase observed in young women.…

As early and effective antiretroviral therapy has become more widespread, HIV has transitioned from a progressive, fatal disease to a chronic, manageable disease marked by elevated risk of chronic comorbid diseases, including cardiovascular diseases (CVDs). Rates of myocardial infarction, heart failure, stroke, and other CVD manifestations, including pulmonary hypertension and sudden cardiac death, are significantly higher for people living with HIV than for uninfected control subjects, even in the setting of HIV viral suppression with effective antiretroviral therapy. These elevated risks generally persist after demographic and clinical risk factors are accounted for and may be partly attributed to chronic inflammation and immune dysregulation. Data on long-term CVD outcomes in HIV are limited by the relatively recent epidemiological transition of HIV to a chronic disease. Therefore, our understanding of CVD pathogenesis, prevention, and treatment in HIV relies on large observational studies, randomized controlled trials of HIV therapies that are underpowered to detect CVD end…

BACKGROUND: Subclinical inflammation is associated with an increased risk of heart failure and with adverse prognosis in patients with established heart failure. Yet, treatments specifically directed at reducing inflammation in patients with heart failure have not yet shown improved clinical outcomes. We tested the hypothesis that the interleukin-1β inhibitor canakinumab would prevent hospitalization for heart failure (HHF) and the composite of HHF or heart failure-related mortality. METHODS: We randomized 10 061 patients with prior myocardial infarction and high-sensitivity C-reactive protein ≥2 mg/L to canakinumab 50, 150, or 300 mg or placebo, given subcutaneously once every 3 months. In total, 2173 (22%) reported a history of heart failure at baseline. We tested the hypothesis that canakinumab prevents prospectively collected HHF events and the composite of HHF or heart failure-related mortality. RESULTS: A total of 385 patients had an HHF event during a median follow-up of 3.7 years. Patients who had HHF were older, had higher body mass index, and were more likely to have…

Type 2 diabetes mellitus is a risk factor for incident heart failure and increases the risk of morbidity and mortality in patients with established disease. Secular trends in the prevalence of diabetes mellitus and heart failure forecast a growing burden of disease and underscore the need for effective therapeutic strategies. Recent clinical trials have demonstrated the shared pathophysiology between diabetes mellitus and heart failure, the synergistic effect of managing both conditions, and the potential for diabetes mellitus therapies to modulate the risk of heart failure outcomes. This scientific statement on diabetes mellitus and heart failure summarizes the epidemiology, pathophysiology, and impact of diabetes mellitus and its control on outcomes in heart failure; reviews the approach to pharmacological therapy and lifestyle modification in patients with diabetes mellitus and heart failure; highlights the value of multidisciplinary interventions to improve clinical outcomes in this population; and outlines priorities for future research.

BACKGROUND: Valvular heart disease (VHD) is an important cause of mortality and morbidity and has been subject to important changes in management. The VHD II survey was designed by the EURObservational Research Programme of the European Society of Cardiology to analyze actual management of VHD and to compare practice with guidelines. METHODS: Patients with severe native VHD or previous valvular intervention were enrolled prospectively across 28 countries over a 3-month period in 2017. Indications for intervention were considered concordant if the intervention was performed or scheduled in symptomatic patients, corresponding to Class I recommendations specified in the 2012 European Society of Cardiology and in the 2014 American Heart Association/American College of Cardiology VHD guidelines. RESULTS: A total of 7247 patients (4483 hospitalized, 2764 outpatients) were included in 222 centers. Median age was 71 years (interquartile range, 62-80 years); 1917 patients (26.5%) were ≥80 years; and 3416 were female (47.1%). Severe native VHD was present in 5219 patients (72.0%): aortic…

BACKGROUND: Women with a history of certain pregnancy complications are at higher risk for cardiovascular (CVD) disease. However, most clinical guidelines only recommend postpartum follow-up of those with a history of preeclampsia, gestational diabetes mellitus, or preterm birth. This systematic review was undertaken to determine if there is an association between a broader array of pregnancy complications and the future risk of CVD. METHODS: We systematically searched PubMed, MEDLINE and EMBASE (via Ovid), CINAHL, and the Cochrane Library from inception to September 22, 2017, for observational studies of the association between the hypertensive disorders of pregnancy, placental abruption, preterm birth, gestational diabetes mellitus, low birth weight, small-for-gestational-age birth, stillbirth, and miscarriage and subsequent CVD. Likelihood ratio meta-analyses were performed to generate pooled odds ratios (OR) and 95% intrinsic confidence intervals (ICI). RESULTS: Our systematic review included 84 studies (28 993 438 patients). Sample sizes varied from 250 to 2 000 000, with a…

Background: SGLT2 (sodium-glucose cotransporter 2) inhibitors lower cardiovascular events in type 2 diabetes mellitus but whether they promote direct cardiac effects remains unknown. We sought to determine if empagliflozin causes a decrease in left ventricular (LV) mass in people with type 2 diabetes mellitus and coronary artery disease. Methods: Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5% to 10.0%, known coronary artery disease, and estimated glomerular filtration rate ≥60mL/min/1.73m 2 . The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed to body surface area from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to body surface area, ejection fraction, 24-hour ambulatory blood pressure, hematocrit, and NT-proBNP (N-terminal pro b-type natriuretic peptide). Results:…

Background: Advanced generation ablation technologies have been developed to achieve more effective pulmonary vein isolation (PVI) and minimize arrhythmia recurrence after atrial fibrillation (AF) ablation. Methods: We randomly assigned 346 patients with drug-refractory paroxysmal AF to contact force–guided radiofrequency ablation (CF-RF; n=115), 4-minute cryoballoon ablation (Cryo-4; n=115), or 2-minute cryoballoon ablation (Cryo-2; n=116). Follow-up was 12 months. The primary outcome was time to first documented recurrence of symptomatic or asymptomatic atrial tachyarrhythmia (AF, atrial flutter, or atrial tachycardia) between days 91 and 365 after ablation or a repeat ablation procedure at any time. Secondary end points included freedom from symptomatic arrhythmia and AF burden. All patients received an implantable loop recorder. Results: One-year freedom from atrial tachyarrhythmia defined by continuous rhythm monitoring was 53.9%, 52.2%, and 51.7% with CF-RF, Cryo-4, and Cryo-2, respectively ( P =0.87). One-year freedom from symptomatic atrial tachyarrhythmia defined by…

Cardiac rehabilitation (CR) is an evidence-based intervention that uses patient education, health behavior modification, and exercise training to improve secondary prevention outcomes in patients with cardiovascular disease. CR programs reduce morbidity and mortality rates in adults with ischemic heart disease, heart failure, or cardiac surgery but are significantly underused, with only a minority of eligible patients participating in CR in the United States. New delivery strategies are urgently needed to improve participation. One potential strategy is home-based CR (HBCR). In contrast to center-based CR services, which are provided in a medically supervised facility, HBCR relies on remote coaching with indirect exercise supervision and is provided mostly or entirely outside of the traditional center-based setting. Although HBCR has been successfully deployed in the United Kingdom, Canada, and other countries, most US healthcare organizations have little to no experience with such programs. The purpose of this scientific statement is to identify the core components, efficacy,…

BACKGROUND: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. METHODS: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. RESULTS: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF…

BACKGROUND: Risk of cardiovascular disease (CVD) and mortality for patients with versus without type 2 diabetes mellitus (T2DM) appears to vary by the age at T2DM diagnosis, but few population studies have analyzed mortality and CVD outcomes associations across the full age range. METHODS: With use of the Swedish National Diabetes Registry, everyone with T2DM registered in the Registry between 1998 and 2012 was included. Controls were randomly selected from the general population matched for age, sex, and county. The analysis cohort comprised 318 083 patients with T2DM matched with just <1.6 million controls. Participants were followed from 1998 to 2013 for CVD outcomes and to 2014 for mortality. Outcomes of interest were total mortality, cardiovascular mortality, noncardiovascular mortality, coronary heart disease, acute myocardial infarction, stroke, heart failure, and atrial fibrillation. We also examined life expectancy by age at diagnosis. We conducted the primary analyses using Cox proportional hazards models in those with no previous CVD and repeated the work in the entire…

Risk assessment is a critical step in the current approach to primary prevention of atherosclerotic cardiovascular disease. Knowledge of the 10-year risk for atherosclerotic cardiovascular disease identifies patients in higher-risk groups who are likely to have greater net benefit and lower number needed to treat for both statins and antihypertensive therapy. Current US prevention guidelines for blood pressure and cholesterol management recommend use of the pooled cohort equations to start a process of shared decision-making between clinicians and patients in primary prevention. The pooled cohort equations have been widely validated and are broadly useful for the general US clinical population. But, they may systematically underestimate risk in patients from certain racial/ethnic groups, those with lower socioeconomic status or with chronic inflammatory diseases, and overestimate risk in patients with higher socioeconomic status or who have been closely engaged with preventive healthcare services. If uncertainty remains for patients at borderline or intermediate risk, or if the…

Background: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone–system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. Methods: We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: ≤22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. Results: Among 13 195…

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure in older individuals. We sought to characterize the natural history of ATTR-CM and compare outcomes and quality of life among patients with acquired and hereditary forms of the disease. METHODS: We studied 711 patients with wild-type ATTR-CM, 205 with hereditary ATTR-CM associated with the V1221 variant (V122I-hATTR-CM), and 118 with non-V122I-hATTR-CM at the UK National Amyloidosis Center between 2000 and 2017. Patients underwent prospective protocolized evaluations comprising assessment of cardiac parameters, functional status by 6-minute walk test, quality of life according to the Kansas City Cardiomyopathy Questionnaire, and survival. Hospital service usage pre- and postdiagnosis was established using English central health records in a subset of patients. RESULTS: There was substantial diagnostic delay, with patients using hospital services a median (interquartile range) of 17 (9-27) times during the 3 years before diagnosis, by which time quality of life was…

Pulmonary embolism (PE) represents the third leading cause of cardiovascular mortality. The technological landscape for management of acute intermediate- and high-risk PE is rapidly evolving. Two interventional devices using pharmacomechanical means to recanalize the pulmonary arteries have recently been cleared by the US Food and Drug Administration for marketing, and several others are in various stages of development. The purpose of this document is to clarify the current state of endovascular interventional therapy for acute PE and to provide considerations for evidence development for new devices that will define which patients with PE would derive the greatest net benefit from their use in various clinical settings. First, definitions and limitations of commonly used risk stratification tools for PE are reviewed. An adjudication of risks and benefits of available interventional therapies for PE follows. Next, considerations for optimal future evidence development in this field are presented in the context of the current US regulatory framework. Finally, the document concludes…

Background: Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors’ aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO 2 ); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers. Methods: Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were…

BACKGROUND: Percutaneous mechanical circulatory support devices are increasingly used in acute myocardial infarction complicated by cardiogenic shock (AMI-CS), despite limited evidence for their effectiveness. The aim of this study was to evaluate outcomes associated with use of the Impella device compared with intra-aortic balloon pump (IABP) and medical treatment in patients with AMI-CS. METHODS: Data of patients with AMI-CS treated with the Impella device at European tertiary care hospitals were collected retrospectively. All patients underwent early revascularization and received optimal medical treatment. Using IABP-SHOCK II (Intraaortic Balloon Pump in Cardiogenic Shock II) trial inclusion and exclusion criteria, 372 patients were identified and included in this analysis. These patients were matched to 600 patients from the IABP-SHOCK II trial. The following baseline criteria were used as matching parameters: age, sex, mechanical ventilation, ejection fraction, prior cardiopulmonary resuscitation, and lactate. Primary end point was 30-day all-cause mortality. RESULTS: In…

Hypertriglyceridemia (triglycerides 200-499 mg/dL) is relatively common in the United States, whereas more severe triglyceride elevations (very high triglycerides, ≥500 mg/dL) are far less frequently observed. Both are becoming increasingly prevalent in the United States and elsewhere, likely driven in large part by growing rates of obesity and diabetes mellitus. In a 2002 American Heart Association scientific statement, the omega-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were recommended (at a dose of 2-4 g/d) for reducing triglycerides in patients with elevated triglycerides. Since 2002, prescription agents containing EPA+DHA or EPA alone have been approved by the US Food and Drug Administration for treating very high triglycerides; these agents are also widely used for hypertriglyceridemia. The purpose of this advisory is to summarize the lipid and lipoprotein effects resulting from pharmacological doses of n-3 FAs (>3 g/d total EPA+DHA) on the basis of new scientific data and availability of n-3 FA agents. In treatment of very high…

Cardiovascular disease is a competing cause of death in patients with cancer with early-stage disease. This elevated cardiovascular disease risk is thought to derive from both the direct effects of cancer therapies and the accumulation of risk factors such as hypertension, weight gain, cigarette smoking, and loss of cardiorespiratory fitness. Effective and viable strategies are needed to mitigate cardiovascular disease risk in this population; a multimodal model such as cardiac rehabilitation may be a potential solution. This statement from the American Heart Association provides an overview of the existing knowledge and rationale for the use of cardiac rehabilitation to provide structured exercise and ancillary services to cancer patients and survivors. This document introduces the concept of cardio-oncology rehabilitation, which includes identification of patients with cancer at high risk for cardiac dysfunction and a description of the cardiac rehabilitation infrastructure needed to address the unique exposures and complications related to cancer care. In this statement, we also…

BACKGROUND: -Methyladenosine (m6A) methylation is the most prevalent internal posttranscriptional modification on mammalian mRNA. The role of m6A mRNA methylation in the heart is not known. METHODS: To determine the role of m6A methylation in the heart, we isolated primary cardiomyocytes and performed m6A immunoprecipitation followed by RNA sequencing. We then generated genetic tools to modulate m6A levels in cardiomyocytes by manipulating the levels of the m6A RNA methylase methyltransferase-like 3 (METTL3) both in culture and in vivo. We generated cardiac-restricted gain- and loss-of-function mouse models to allow assessment of the METTL3-m6A pathway in cardiac homeostasis and function. RESULTS: We measured the level of m6A methylation on cardiomyocyte mRNA, and found a significant increase in response to hypertrophic stimulation, suggesting a potential role for m6A methylation in the development of cardiomyocyte hypertrophy. Analysis of m6A methylation showed significant enrichment in genes that regulate kinases and intracellular signaling pathways. Inhibition of METTL3…

Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor–associated myocarditis. Although the full spectrum of immune checkpoint inhibitor–associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor–associated myocarditis, have made ascertainment and identification of myocarditis with…

BACKGROUND: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed. METHODS: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO…

Outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) have improved because of advancements in equipment and techniques. With global collaboration and knowledge sharing, we have identified 7 common principles that are widely accepted as best practices for CTO-PCI. 1. Ischemic symptom improvement is the primary indication for CTO-PCI. 2. Dual coronary angiography and in-depth and structured review of the angiogram (and, if available, coronary computed tomography angiography) are key for planning and safely performing CTO-PCI. 3. Use of a microcatheter is essential for optimal guidewire manipulation and exchanges. 4. Antegrade wiring, antegrade dissection and reentry, and the retrograde approach are all complementary and necessary crossing strategies. Antegrade wiring is the most common initial technique, whereas retrograde and antegrade dissection and reentry are often required for more complex CTOs. 5. If the initially selected crossing strategy fails, efficient change to an alternative crossing technique increases the likelihood of eventual PCI success,…

BACKGROUND: circRNAs (circular RNAs) are emerging as powerful regulators of cardiac development and disease, but their roles in cardiac regeneration are still unknown. This study used superenhancers to distinguish key circRNAs in the regulation of cardiac regeneration and explored the mechanisms underlying circRNA functions. METHODS: We used integrated bioinformatics analysis of RNA sequencing data and superenhancer catalogs to identify superenhancer-associated circRNAs. Quantitative polymerase chain reactions and in situ hybridization were performed to determine the circRNA expression patterns in hearts. Gain- and loss-of-function assays were conducted to detect the role of circRNAs in cardiomyocyte proliferation and cardiac repair after myocardial infarction. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays were used to determine the binding of Meis1 (Meis homeobox 1) on circNfix-associated superenhancers. RNA pulldown and luciferase reporter assays were used to study circRNA interactions with proteins and miRNAs (micro RNAs). RESULTS: We identified a…

Background: The role of intraaortic balloon counterpulsation (IABP) in cardiogenic shock is still a subject of intense debate despite the neutral results of the IABP-SHOCK II trial (Intraaortic Balloon Pump in Cardiogenic Shock II) with subsequent downgrading in international guidelines. So far, randomized data on the impact of IABP on long-term clinical outcomes in patients with cardiogenic shock complicating acute myocardial infarction are lacking. Furthermore, only limited evidence is available on general long-term outcomes of patients with cardiogenic shock treated by contemporary practice. Methods: The IABP-SHOCK II trial is a multicenter, randomized, open-label trial. Between 2009 and 2012, 600 patients with cardiogenic shock complicating acute myocardial infarction undergoing early revascularization were randomized to IABP versus control. Results: Long-term follow-up was performed 6.2 years (interquartile range 5.6–6.7) after initial randomization. Follow-up was completed for 591 of 600 patients (98.5%). Mortality was not different between the IABP and the control group…

This scientific statement presents considerations for clinical management regarding the assessment and risk reduction of select pediatric populations at high risk for premature cardiovascular disease, including acquired arteriosclerosis or atherosclerosis. For each topic, the evidence for accelerated acquired coronary artery disease and stroke in childhood and adolescence and the evidence for benefit of interventions in youth will be reviewed. Children and adolescents may be at higher risk for cardiovascular disease because of significant atherosclerotic or arteriosclerotic risk factors, high-risk conditions that promote atherosclerosis, or coronary artery or other cardiac or vascular abnormalities that make the individual more vulnerable to the adverse effects of traditional cardiovascular risk factors. Existing scientific statements and guidelines will be referenced when applicable, and suggestions for risk identification and reduction specific to each setting will be described. This statement is directed toward pediatric cardiologists, primary care providers, and subspecialists…

Background: Improvements have been made in the treatment and control of some but not all major cardiovascular risk factors in the United States. It remains unclear whether women and men have benefited equally. Methods: Data from the 2001 to 2002 through the 2015 to 2016 US National Health and Nutrition Examination Survey on adults aged 20 to 79 years were used. We assessed sex differences in temporal trends in the levels of systolic blood pressure, body mass index, smoking status, high-density lipoprotein and total cholesterol, and hemoglobin A 1c . Trends in treatment and control rates of hypertension, diabetes mellitus, and dyslipidemia were also assessed. Results: Overall, 35 416 participants (51% women) were included. Trends in systolic blood pressure, smoking status, high-density lipoprotein cholesterol, and hemoglobin A 1c were similar between the sexes. Body mass index increased more in women than men ( P =0.006). Mean levels were 28.1 and 29.6 kg/m 2 in women and 27.9 and 29.0 kg/m 2 in men in 2001 to 2004 and 2013 to 2016, respectively. Total cholesterol decreased more in…

Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as DNMT3A or TET2 . In humans, CHIP associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6/IL-1β expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk. Methods: We analyzed exome sequences from 35 416 individuals in the UK Biobank without prevalent CVD, to identify participants with DNMT3A or TET2 CHIP. We used the IL6R p.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified by IL6R p.Asp358Ala. Results: We identified 1079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction >10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk…

Significant improvements have been achieved in cardiac arrest resuscitation and postarrest resuscitation care, but mortality remains high. Most of the poor outcomes and deaths of cardiac arrest survivors have been attributed to widespread brain injury. This brain injury, commonly manifested as a comatose state, is a marker of poor outcome and a major basis for unfavorable neurological prognostication. Accurate prognostication is important to avoid pursuing futile treatments when poor outcome is inevitable but also to avoid an inappropriate withdrawal of life-sustaining treatment in patients who may otherwise have a chance of achieving meaningful neurological recovery. Inaccurate neurological prognostication leading to withdrawal of life-sustaining treatment and deaths may significantly bias clinical studies, leading to failure in detecting the true study outcomes. The American Heart Association Emergency Cardiovascular Care Science Subcommittee organized a writing group composed of adult and pediatric experts from neurology, cardiology, emergency medicine, intensive care medicine,…

BACKGROUND: Case studies have suggested the efficacy of catheter-free, electrophysiology-guided noninvasive cardiac radioablation for ventricular tachycardia (VT) using stereotactic body radiation therapy, although prospective data are lacking. METHODS: We conducted a prospective phase I/II trial of noninvasive cardiac radioablation in adults with treatment-refractory episodes of VT or cardiomyopathy related to premature ventricular contractions (PVCs). Arrhythmogenic scar regions were targeted by combining noninvasive anatomic and electric cardiac imaging with a standard stereotactic body radiation therapy workflow followed by delivery of a single fraction of 25 Gy to the target. The primary safety end point was treatment-related serious adverse events in the first 90 days. The primary efficacy end point was any reduction in VT episodes (tracked by indwelling implantable cardioverter defibrillators) or any reduction in PVC burden (as measured by a 24-hour Holter monitor) comparing the 6 months before and after treatment (with a 6-week blanking window after treatment).…

Background: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. Methods: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m 2 , and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of…

BACKGROUND: Impella was approved for mechanical circulatory support (MCS) in 2008, but large-scale, real-world data on its use are lacking. Our objective was to describe trends and variations in Impella use, clinical outcomes, and costs across US hospitals in patients undergoing percutaneous coronary intervention (PCI) treated with MCS (Impella or intra-aortic balloon pump). METHODS: From the Premier Healthcare Database, we analyzed 48 306 patients undergoing PCI with MCS at 432 hospitals between January 2004 and December 2016. Association analyses were performed at 3 levels: time period, hospital, and patient. Hierarchical models with propensity adjustment were used for association analyses. We examined trends and variations in the proportion of Impella use, and associated clinical outcomes (in-hospital mortality, bleeding requiring transfusion, acute kidney injury, stroke, length of stay, and hospital costs). RESULTS: Among patients undergoing PCI treated with MCS, 4782 (9.9%) received Impella; its use increased over time, reaching 31.9% of MCS in 2016. There was wide variation in…

In this scientific statement from the American Heart Association, experts in the field of cardiomyopathy (heart muscle disease) in children address 2 issues: the most current understanding of the causes of cardiomyopathy in children and the optimal approaches to diagnosis cardiomyopathy in children. Cardiomyopathies result in some of the worst pediatric cardiology outcomes; nearly 40% of children who present with symptomatic cardiomyopathy undergo a heart transplantation or die within the first 2 years after diagnosis. The percentage of children with cardiomyopathy who underwent a heart transplantation has not declined over the past 10 years, and cardiomyopathy remains the leading cause of transplantation for children >1 year of age. Studies from the National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry have shown that causes are established in very few children with cardiomyopathy, yet genetic causes are likely to be present in most. The incidence of pediatric cardiomyopathy is ≈1 per 100 000 children. This is comparable to the incidence of such…

BACKGROUND: Whether consumption of sugar-sweetened beverages (SSBs) or artificially sweetened beverages (ASBs) is associated with risk of mortality is of public health interest. METHODS: We examined associations between consumption of SSBs and ASBs with risk of total and cause-specific mortality among 37 716 men from the Health Professional's Follow-up study (from 1986 to 2014) and 80 647 women from the Nurses' Health study (from 1980 to 2014) who were free from chronic diseases at baseline. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals. RESULTS: We documented 36 436 deaths (7896 cardiovascular disease [CVD] and 12 380 cancer deaths) during 3 415 564 person-years of follow-up. After adjusting for major diet and lifestyle factors, consumption of SSBs was associated with a higher risk of total mortality; pooled hazard ratios (95% confidence intervals) across categories (<1/mo, 1-4/mo, 2-6/week, 1-<2/d, and ≥2/d) were 1.00 (reference), 1.01 (0.98, 1.04), 1.06 (1.03, 1.09), 1.14 (1.09, 1.19), and 1.21 (1.13, 1.28; P trend <0.0001).…

BACKGROUND: Procedural results for percutaneous coronary intervention (PCI) in coronary vessels with chronic total occlusion (CTO) have improved in recent years, and PCI strategies have moved toward more complete revascularization with more liberal use of CTO-PCI. However, evidence evaluating CTO-PCI is limited to observational studies and small clinical trials. METHODS: In this open-label, multicenter, randomized, noninferiority trial, PCI-eligible patients were assigned to receive either 1 of 2 strategies: PCI or no PCI for the qualifying de novo CTO lesion with the option for PCI of obstructive non-CTO lesions at the discretion of the operator. The primary end point was a composite of death, myocardial infarction, stroke, or any revascularization. Health-related quality of life was assessed at baseline and at 1, 6, 12, 24, and 36 months. Because of slow recruitment, the trial was stopped before completion of the 1284 planned enrollments. RESULTS: Between March 2010 and September 2016, 834 patients were randomly assigned to the CTO-PCI (n=417) or no CTO-PCI (n=398) strategy. Among…

BACKGROUND: Functional tricuspid regurgitation (FTR) is common in heart failure with reduced ejection fraction and mostly consequent to pulmonary hypertension. However, the intrinsic clinical implications of FTR are not fully understood. METHODS: The cohort of all Mayo Clinic patients from 2003 to 2011 diagnosed with heart failure stage B-C and ejection fraction<50%, with FTR grading and systolic pulmonary artery pressure estimation by Doppler echocardiography was identified and outcomes were analyzed. Patients with pacemakers/defibrillators, organic valve disease, or previous valve surgery were excluded. The primary outcome measure was overall mortality (censored at implantation of a defibrillator, ventricular assist device, or cardiac transplantation), adjusting for clinical and echocardiographic associates with mortality and major comorbidities. RESULTS: Among 13 026 patients meeting inclusion criteria, FTR was detected in 88% (N=11 507: 33% trivial, 32% mild, 17% moderate, and 6% severe), aged 68±14 years, 35% women, ejection fraction 36±10%, systolic pulmonary artery pressure…