Matthew Nayor

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

Mutations in sarcomere protein genes can cause hypertrophic cardiomyopathy (HCM), a disorder characterized by myocyte enlargement, fibrosis, and impaired ventricular relaxation. Here, we demonstrate that sarcomere protein gene mutations activate proliferative and profibrotic signals in non-myocyte cells to produce pathologic remodeling in HCM. Gene expression analyses of non-myocyte cells isolated from HCM mouse hearts showed increased levels of RNAs encoding cell-cycle proteins, Tgf-β, periostin, and other profibrotic proteins. Markedly increased BrdU labeling, Ki67 antigen expression, and periostin immunohistochemistry in the fibrotic regions of HCM hearts confirmed the transcriptional profiling data. Genetic ablation of periostin in HCM mice reduced but did not extinguish non-myocyte proliferation and fibrosis. In contrast, administration of Tgf-β-neutralizing antibodies abrogated non-myocyte proliferation and fibrosis. Chronic administration of the angiotensin II type 1 receptor antagonist losartan to mutation-positive, hypertrophy-negative (prehypertrophic) mice prevented the emergence of hypertrophy, non-myocyte proliferation, and fibrosis. Losartan treatment did not reverse pathologic remodeling of established HCM but did reduce non-myocyte proliferation. These data define non-myocyte activation of Tgf-β signaling as a pivotal mechanism for increased fibrosis in HCM and a potentially important factor contributing to diastolic dysfunction and heart failure. Preemptive pharmacologic inhibition of Tgf-β signals warrants study in human patients with sarcomere gene mutations.

Heterogeneous myocyte enhancer factor-2 (Mef2) activation in myocytes predicts focal scarring in hypertrophic cardiomyopathy

Unknown molecular responses to sarcomere protein gene mutations account for pathologic remodeling in hypertrophic cardiomyopathy (HCM), producing myocyte growth and increased cardiac fibrosis. To determine if hypertrophic signals activated myocyte enhancer factor-2 (Mef2), we studied mice carrying the HCM mutation, myosin heavy-chain Arg403Gln, (MHC403/+) and an Mef2-dependent β-galactosidase reporter transgene. In young, prehypertrophic MHC403/+ mice the reporter was not activated. In hypertrophic hearts, activation of the Mef2-dependent reporter was remarkably heterogeneous and was observed consistently in myocytes that bordered fibrotic foci with necrotic cells, MHC403/+ myocytes with Mef2-dependent reporter activation reexpressed the fetal myosin isoform (βMHC), a molecular marker of hypertrophy, although MHC403/+ myocytes with or without βMHC expression were comparably enlarged over WT myocytes. To consider Mef2 roles in severe HCM, we studied homozygous MHC403/403 mice, which have accelerated remodeling, widespread myocyte necrosis, and neonatal lethality. Levels of phosphorylated class II histone deacetylases that activate Mef2 were substantially increased in MHC403/403 hearts, but Mef2-dependent reporter activation was patchy. Sequential analyses showed myocytes increased Mef2-dependent reporter activity before death. Our data dissociate myocyte hypertrophy, a consistent response in HCM, from heterogeneous Mef2 activation and reexpression of a fetal gene program. The temporal and spatial relationship of Mef2-dependent gene activation with myocyte necrosis and fibrosis in MHC403/+ and MHC403/403 hearts defines Mef2 activation as a molecular signature of stressed HCM myocytes that are poised to die.

Recent Update to the US Cholesterol Treatment Guidelines A Comparison With International Guidelines

The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guideline advocated several changes from the previous Adult Treatment Panel III guidelines. Assuming full implementation, the 2013 ACC/AHA guideline would identify ≈13 million Americans as newly eligible for consideration of statin therapy. Three features of the 2013 ACC/AHA guideline primarily responsible for these differences are the specific risk assessment tool endorsed, the risk threshold considered sufficient to warrant primary prevention statin therapy, and the decision not to include cholesterol treatment targets. There is no consensus among international guidelines on the optimal approach to these 3 components. The 2013 ACC/AHA guideline recommends assessing absolute risk with the Pooled Cohort equations, which were developed to improve on previous risk assessment models by including stroke as an outcome and by broadening racial and geographic diversity. Each of the leading international guidelines recommends a different equation for absolute risk assessment. The 2013 ACC/AHA guideline advises consideration of statin therapy for an estimated 10-year risk of atherosclerotic vascular disease of ≥7.5%, which is lower than the thresholds recommended by other leading international guidelines. Lastly, the 2013 ACC/AHA guideline does not endorse a treat-to-target strategy but instead specifies the appropriate intensity of statin for each risk category. This approach is shared by the National Institute for Health and Care Excellence guidelines but differs from other international guidelines. In this review, we summarize the 2013 ACC/AHA cholesterol guideline recommendations and compare them with recommendations from Adult Treatment Panel III and other leading international guidelines.

Cardiovascular Health Status and Incidence of Heart Failure in the Framingham Offspring Study.

Background—The American Heart Association Cardiovascular Health (CVH) score is inversely associated with cardiovascular disease, but its relations to cardiac remodeling traits and heart failure (HF) incidence have not been examined. Methods and Results—A 14-point score was constructed for each participant based on the presence of poor, intermediate, or ideal status on each of the 7 CVH metrics (ideal score=14). We related the CVH score to echocardiographic traits cross-sectionally and to HF incidence prospectively in the Framingham Offspring Study. In age- and sex-adjusted models, a higher CVH score was associated with lower left ventricular (LV) mass, LV wall thickness, LV diastolic dimension, and left atrial dimension (P<0.01 for all; n=2392; mean age, 58 years; 56% women), and with a 12% to 15% lower odds of prevalent LV concentric remodeling and concentric hypertrophy, respectively (P<0.0001 for both). On follow-up (mean, 12.3 years), 188 incident HF events were observed in 3201 participants (mean age, 59 years; 53% women). In age- and sex-adjusted Cox proportional hazard models, the CVH score was inversely associated with HF incidence (hazard ratio per 1-point higher CVH score, 0.77; 95% confidence interval, 0.72–0.83). This association was partially attenuated upon adjustment for LV mass and interim myocardial infarction (hazard ratio, 0.84; 95% confidence interval, 0.76–0.93), and it was consistent for HF with preserved and reduced ejection fractions. Conclusions—In our community-based sample, comprised predominantly of middle-aged white individuals of European descent, better CVH was associated with lower HF incidence, in part due to a lower prevalence of adverse cardiac remodeling.

Circulating Galectin‐3 Is Associated With Cardiometabolic Disease in the Community

Background Circulating Galectin‐3 (Gal‐3) concentrations are associated with an increased incidence of heart failure, atrial fibrillation, chronic kidney disease, and mortality. Recent evidence suggests that Gal‐3 may also be an important modulator of cardiometabolic traits such as adiposity, insulin resistance, and hyperglycemia. We examined the associations of blood Gal‐3 concentrations and cardiometabolic disease traits in the Framingham Heart Study. Methods and Results In cross‐sectional analyses of 2946 Framingham Heart Study participants (mean age 59 years, 55% women), higher Gal‐3 concentrations were associated with higher body mass index, waist circumference, and triglycerides (P<0.0001 for all). Higher Gal‐3 was associated with greater odds of obesity (multivariable‐adjusted odds ratio 1.16 per 1‐SD increase in log–Gal‐3, 95% CI 1.06–1.28, P=0.002) and hypertension (odds ratio 1.18, 95% CI 1.07–1.29, P=0.0006). In prospective analyses, Gal‐3 was associated with incident metabolic syndrome (hazard ratio 1.22, 95% CI 1.10–1.36, P=0.0002) and diabetes (hazard ratio 1.21, 95% CI 1.04–1.41, P=0.02), in age‐ and sex‐adjusted, but not multivariable‐adjusted models. Conclusions In this large, community‐based sample, circulating Gal‐3 was associated with abdominal adiposity, dyslipidemia, and hypertension in cross‐sectional analyses, but Gal‐3 did not predict incident cardiometabolic disease after adjusting for cardiometabolic risk factors. Future investigations should focus on further elucidating mechanisms linking Gal‐3 with cardiometabolic disease and on assessing whether modulation of the Gal‐3 pathway might have positive cardiometabolic effects.

Preventing heart failure: the role of physical activity.

Purpose of review Heart failure prevention is an important public health goal. Increased physical activity and exercise may help to prevent heart failure, as they are associated with reduced heart failure incidence and potentially act through a variety of mechanisms to slow disease progression. Recent findings Increased physical activity, higher cardiorespiratory fitness, and lower sedentary time are associated with reduced heart failure incidence. These associations are consistent for occurrence of heart failure with both preserved and reduced ejection fraction, the common subphenotypes of the condition. Physiologic cardiac and vascular remodeling occurs across the normal range of physical activity in the community, and regular exercise (four to five sessions per week) is necessary to mitigate age-associated reductions in ventricular compliance and cardiac mass. Summary Greater physical activity, less sedentary time, and improved cardiorespiratory fitness are associated with reductions in heart failure risk. Various mechanisms may explain these findings, including: reducing the prevalence of standard and novel cardiovascular risk factors, inhibiting pathologic cardiovascular remodeling, promoting physiologic remodeling, and improving cardiac, neurohormonal, skeletal muscle, pulmonary, renal, and vascular performance. Future research is needed to elucidate the optimal timing, duration, and modality of physical activity and exercise training necessary to prevent the development of heart failure.

Association of Cardiovascular Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction

Importance Nearly half of all patients with heart failure have preserved ejection fraction (HFpEF) as opposed to reduced ejection fraction (HFrEF), yet associations of biomarkers with future heart failure subtype are incompletely understood. Objective To evaluate the associations of 12 cardiovascular biomarkers with incident HFpEF vs HFrEF among adults from the general population. Design, Setting, and Participants This study included 4 longitudinal community-based cohorts: the Cardiovascular Health Study (1989-1990; 1992-1993 for supplemental African-American cohort), the Framingham Heart Study (1995-1998), the Multi-Ethnic Study of Atherosclerosis (2000-2002), and the Prevention of Renal and Vascular End-stage Disease study (1997-1998). Each cohort had prospective ascertainment of incident HFpEF and HFrEF. Data analysis was performed from June 25, 2015, to November 9, 2017. Exposures The following biomarkers were examined: N-terminal pro B-type natriuretic peptide or brain natriuretic peptide, high-sensitivity troponin T or I, C-reactive protein (CRP), urinary albumin to creatinine ratio (UACR), renin to aldosterone ratio, D-dimer, fibrinogen, soluble suppressor of tumorigenicity, galectin-3, cystatin C, plasminogen activator inhibitor 1, and interleukin 6. Main Outcomes and Measures Development of incident HFpEF and incident HFrEF. Results Among the 22 756 participants in these 4 cohorts (12 087 women and 10 669 men; mean [SD] age, 60 [13] years) in the study, during a median follow-up of 12 years, 633 participants developed incident HFpEF, and 841 developed HFrEF. In models adjusted for clinical risk factors of heart failure, 2 biomarkers were significantly associated with incident HFpEF: UACR (hazard ratio [HR], 1.33; 95% CI, 1.20-1.48; P < .001) and natriuretic peptides (HR, 1.27; 95% CI, 1.16-1.40; P < .001), with suggestive associations for high-sensitivity troponin (HR, 1.11; 95% CI, 1.03-1.19; P = .008), plasminogen activator inhibitor 1 (HR, 1.22; 95% CI, 1.03-1.45; P = .02), and fibrinogen (HR, 1.12; 95% CI, 1.03-1.22; P = .01). By contrast, 6 biomarkers were associated with incident HFrEF: natriuretic peptides (HR, 1.54; 95% CI, 1.41-1.68; P < .001), UACR (HR, 1.21; 95% CI, 1.11-1.32; P < .001), high-sensitivity troponin (HR, 1.37; 95% CI, 1.29-1.46; P < .001), cystatin C (HR, 1.19; 95% CI, 1.11-1.27; P < .001), D-dimer (HR, 1.22; 95% CI, 1.11-1.35; P < .001), and CRP (HR, 1.19; 95% CI, 1.11-1.28; P < .001). When directly compared, natriuretic peptides, high-sensitivity troponin, and CRP were more strongly associated with HFrEF compared with HFpEF. Conclusions and Relevance Biomarkers of renal dysfunction, endothelial dysfunction, and inflammation were associated with incident HFrEF. By contrast, only natriuretic peptides and UACR were associated with HFpEF. These findings highlight the need for future studies focused on identifying novel biomarkers of the risk of HFpEF.

Contemporary Approach to Paradoxical Embolism

A 63-year-old man with a history of systemic hypertension presented to the emergency department for evaluation of acute chest pain and shortness of breath that occurred while he was shoveling heavy snow. His heart rate was 114 bpm and blood pressure was 142/78 mm Hg. Peripheral oxyhemoglobin saturation was 91%, and his respiratory rate was 20 breaths per minute. During the physical examination, he developed severe left arm pain associated with complete loss of the left radial and brachial pulses. Urgent upper-extremity angiography demonstrated acute thromboembolism of the proximal left axillary artery (Figure 1A). Percutaneous transluminal embolectomy, followed by catheter-directed thrombolysis, was performed to successfully treat the arterial thrombus. However, thoracic computed tomographic (CT) angiography identified bilateral pulmonary emboli (Figure 1B). Coincidental venous and arterial thromboemboli raised suspicion for a paradoxical embolism. To evaluate this further, transthoracic echocardiography with agitated saline contrast was performed and demonstrated a patent foramen ovale (PFO) with evidence of right-to-left intracardiac shunt (Figure 1C). Three recent studies provide, for the first time, data from prospective, randomized trials to guide treatment in patients with PFO and paradoxical embolism.1–3 Figure 1. Clinical studies demonstrating paradoxical embolism. A 63-year-old man presented with chest pain and subsequently developed left arm ischemia from an axillary artery thromboembolism. Clinical investigation revealed the presence of a pulmonary embolism and patent foramen ovale, supporting a diagnosis of paradoxical embolism. A , Selective angiography demonstrates occlusive thrombus in the left axillary artery (arrowhead). B , Computed tomographic angiography of the pulmonary arteries identifies a filling defect within the right lower lobe pulmonary artery (arrowhead) extending into the segmental branches of the right lower lobes. Filling defects were also observed in the left lower lobe pulmonary artery and within the segmental branches of the left lower lobe. C , Transthoracic echocardiography performed ≈5 seconds …

Predictors and outcomes of heart failure with mid-range ejection fraction

While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid‐range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community.

Incidental Statin Use and the Risk of Stroke or Transient Ischemic Attack after Radiotherapy for Head and Neck Cancer

Background and Purpose Interventions to reduce the risk for cerebrovascular events (CVE; stroke and transient ischemic attack [TIA]) after radiotherapy (RT) for head and neck cancer (HNCA) are needed. Among broad populations, statins reduce CVEs; however, whether statins reduce CVEs after RT for HNCA is unclear. Therefore, we aimed to test whether incidental statin use at the time of RT is associated with a lower rate of CVEs after RT for HNCA. Methods From an institutional database we identified all consecutive subjects treated with neck RT from 2002 to 2012 for HNCA. Data collection and event adjudication was performed by blinded teams. The primary outcome was a composite of ischemic stroke and TIA. The secondary outcome was ischemic stroke. The association between statin use and events was determined using Cox proportional hazard models after adjustment for traditional and RT-specific risk factors. Results The final cohort consisted of 1,011 patients (59±13 years, 30% female, 44% hypertension) with 288 (28%) on statins. Over a median follow-up of 3.4 years (interquartile range, 0.1 to 14) there were 102 CVEs (89 ischemic strokes and 13 TIAs) with 17 in statin users versus 85 in nonstatins users. In a multivariable model containing known predictors of CVE, statins were associated with a reduction in the combination of stroke and TIA (hazard ratio [HR], 0.4; 95% confidence interval [CI], 0.2 to 0.8; P=0.01) and ischemic stroke alone (HR, 0.4; 95% CI, 0.2 to 0.8; P=0.01). Conclusions Incidental statin use at the time of RT for HNCA is associated with a lower risk of stroke or TIA.