Aims
Atrial fibrillation (AF) and thrombo‐embolism (TE) are associated with reduced survival in hypertrophic cardiomyopathy (HCM), but the absolute risk of TE in patients with and without AF is ...unclear. The primary aim of this study was to derive and validate a model for estimating the risk of TE in HCM. Exploratory analyses were performed to determine predictors of TE, the performance of the CHA2DS2‐VASc score, and outcome with vitamin K antagonists (VKAs).
Methods and results
A retrospective, longitudinal cohort of seven institutions was used to develop multivariable Cox regression models fitted with pre‐selected predictors. Bootstrapping was used for validation. Of 4821 HCM patients recruited between 1986 and 2008, 172 (3.6%) reached the primary endpoint of cerebrovascular accident (CVA), transient ischaemic attack (TIA), or systemic peripheral embolus within 10 years. A total of 27.5% of patients had a CHA2DS2‐VASc score of 0, of whom 9.8% developed TE during follow‐up. Cox regression revealed an association between TE and age, AF, the interaction between age and AF, TE prior to first evaluation, NYHA class, left atrial (LA) diameter, vascular disease, and maximal LV wall thickness. There was a curvilinear relationship between LA size and TE risk. The model predicted TE with a C‐index of 0.75 95% confidence interval (CI) 0.70–0.80 and the D‐statistic was 1.30 (95% CI 1.05–1.56). VKA treatment was associated with a 54.8% (95% CI 31–97%, P = 0.037) relative risk reduction in HCM patients with AF.
Conclusions
The study shows that the risk of TE in HCM patients can be identified using a small number of simple clinical features. LA size, in particular, should be monitored closely, and the assessment and treatment of conventional vascular risk factors should be routine practice in older patients. Exploratory analyses show for the first time evidence for a reduction of TE with VKA treatment. The CHA2DS2‐VASc score does not appear to correlate well with the clinical outcome in patients with HCM and should not be used to assess TE risk in this population.
Background In patients with obstructive hypertrophic cardiomyopathy, surgical myectomy (SM) is indicated for severe symptoms. We sought to compare long-term outcomes of patients with obstructive ...hypertrophic cardiomyopathy where SM was based on guideline-recommended Class I indication (Functional Class or FC ≥3 or angina/exertional syncope despite maximal medical therapy) versus earlier (FC 2 and/or impaired exercise capacity on exercise echocardiography with severe obstruction). Methods and Results We studied 2268 consecutive patients (excluding <18 years, ≥ moderate aortic stenosis and subaortic membrane, 56±14 years, 55% men), who underwent SM at our center between June 2002 and March 2018. Clinical data, including left ventricular outflow tract gradient, were recorded. Death and/or appropriate internal defibrillator discharge were primary composite end points. One thousand three hundred eighteen (58%) patients met Class I indication and 950 (42%) underwent earlier surgery; 222 (10%) had a history of obstructive coronary artery disease. Basal septal thickness, and resting and maximal left ventricular outflow tract gradient were 2.0±0.3 cm, 61±44 mm Hg, and 100±31 mm Hg, respectively. At 6.2±4 years after SM, 248 (11%) had composite events (13 0.6% in-hospital deaths). Age (hazard ratio HR, 1.61; 95% CI, 1.26-1.91), obstructive coronary artery disease (HR, 1.46; 95% CI, 1.06-1.91), and Class I versus earlier SM (HR, 1.61; 95% CI, 1.14-2.12) were associated with higher primary composite events (all
<0.001). Earlier surgery had better longer-term survival (similar to age-sex-matched normal population) versus surgery for Class I indication (76 8% versus 193 15%,
<0.001). Conclusions In patients with obstructive hypertrophic cardiomyopathy, earlier versus surgery for Class I indication had a better long-term survival, similar to the age-sex-matched US population.
vHypertrophic cardiomyopathy (HCM) is the most commonly diagnosed cardiac disease in cats. The complex pathophysiology of HCM is still far from clear, but myocardial remodeling is a key process, and ...cardiomyocyte disarray, interstitial fibrosis, leukocyte infiltration, and vascular dysplasia are described histopathologic features. The present study systematically investigated the pathological processes in HCM, with the aim to shed more light on its pathogenesis. Hearts from 18 HCM cases and 18 cats without cardiac disease (controls) were examined, using light and transmission electron microscopy, immunohistochemistry, and morphometric approaches to identify and quantify the morphological changes. Reverse transcription–quantitative polymerase chain reaction was applied to provide additional mechanistic data on remodeling processes. In HCM, the left and right ventricular free wall and septal myocardium exhibited a significantly reduced overall cellularity, accompanied by a significant increase in interstitial Iba1-positive cells with macrophage morphology. In addition, the myocardium of almost half of the diseased hearts exhibited areas where cardiomyocytes were replaced by cell-rich fibrous tissue with abundant small and medium-sized vessels. HCM hearts also showed significantly higher transcription levels for several inflammatory and profibrotic mediators. Our findings suggest that HCM is the consequence of cardiac remodeling processes that are the result of cardiomyocyte damage and to which macrophages contribute by maintaining an inflammatory and profibrotic environment.
Background:
Hypertrophic cardiomyopathy (HCM) is the main cause of sudden cardiac death among young adults, yet its pathogenesis remains vague. N6-methyladenosine (m6A) methylation modification was ...involved in various cardiovascular diseases such as coronary heart disease and heart failure, although its influence on HCM remains unclear. This study aimed to explore the potential role of m6A in the diagnosis and pathogenesis of HCM.
Methods:
GSE36961 including 106 HCM and 39 controls was used in the study. The HCM-related m6A regulators were selected using support vector machine recursive feature elimination and random forest algorithm. A significant gene signature was then established using least absolute shrinkage and selection operator and then verified by GSE130036. Subgroup classification of HCM was performed based on the expression of m6A biomarkers. Gene set variation analysis was employed to explore the functional difference between distinct subgroups. Weighted gene co-expression network analysis was used to determine the m6A-related hub module. Single-sample gene set enrichment analysis was conducted to assess the immune and mitophagy features between subgroups. Besides, transfection of recombinant plasmids with targeted genes into H9c2 cells was performed to further verify the function of the significant biomarkers.
Results:
Significant difference existed in m6A landscape between HCM and control patients, among which IGFBP3 and YTHDC1 were identified as the independent biomarkers of HCM. Highly infiltrated immune cells (MDSC, macrophages, etc.), more enriched immune-related pathways (TNFα signaling
via
NFκB and IL6-JAK-STAT3 signaling) and cardiac remodeling-associated pathways (epithelial mesenchymal transition, angiogenesis, etc.) were identified in the subgroup with higher IGFBP3. Consistently, overexpression of IGFBP3 in H9c2 cells led to upregulation of extracellular-matrix-related genes (COL1A2, COL3A1 and MMP9) and inflammation-related genes (TNFα and IL6). Besides, higher YTHDC1 expression seemed to be consistent with less-activated mitophagy (PINK1-PRKN mediated mitophagy) and energy metabolism. Further experiments demonstrated that overexpression of YTHDC1 resulted in up-regulation of PINK and PRKN in cardiomyocytes, which are essential genes mediating mitophagy.
Conclusion:
Two m6A readers
(
IGFBP3 and YTHDC1) well distinguished HCM and may facilitate clinical diagnosis. IGFBP3 may play a role in the immune-microenvironments and remodeling of cardiac tissues, while YTHDC1 may influence mitophagy and energy metabolism in HCM.
Abstract
Aims
Idiopathic left ventricular hypertrophy (LVH) is defined as LVH in the absence of myocyte disarray or secondary causes. It is unclear whether idiopathic LVH represents the phenotypic ...spectrum of hypertrophic cardiomyopathy (HCM) or whether it is a unique disease entity. We aimed to ascertain the prevalence of HCM in first-degree relatives of decedents from sudden death with idiopathic LVH at autopsy. Decedents also underwent molecular autopsy to identify the presence of pathogenic variants in genes implicated in HCM.
Methods and results
Families of 46 decedents with idiopathic LVH (125 first-degree relatives) were investigated with electrocardiogram, echocardiogram exercise tolerance test, cardiovascular magnetic resonance imaging, 24-h Holter, and ajmaline provocation test. Next-generation sequencing molecular autopsy was performed in 14 (30%) cases. Decedents with idiopathic LVH were aged 33 ± 14 years and 40 (87%) were male. Fourteen families (30%) comprising 16 individuals were diagnosed with cardiac disease, including Brugada syndrome (n = 8), long QT syndrome (n = 3), cardiomyopathy (n = 2), and Wolff–Parkinson–White syndrome (n = 1). None of the family members were diagnosed with HCM. Molecular autopsy did not identify any pathogenic or likely pathogenic variants in genes encoding sarcomeric proteins. Two decedents had pathogenic variants associated with long QT syndrome, which were confirmed in relatives with the clinical phenotype. One decedent had a pathogenic variant associated with Danon disease in the absence of any histopathological findings of the condition or clinical phenotype in the family.
Conclusion
Idiopathic LVH appears to be a distinct disease entity from HCM and is associated with fatal arrhythmias in individuals with primary arrhythmia syndromes. Family screening in relatives of decedents with idiopathic LVH should be comprehensive and encompass the broader spectrum of inherited cardiac conditions, including channelopathies.
Objectives The objective of this study was to perform a systematic review and meta-analysis of the predictive value of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) for future ...cardiovascular events and death in hypertrophic cardiomyopathy (HCM). Background The utility of LGE for detecting myocardial fibrosis is well established. The prognostic value of LGE in HCM has been described in several studies, but controversy exists given the limited power of these studies to predict future events. Methods We searched multiple databases including PubMed for studies of LGE in HCM that reported selected clinical outcomes (cardiovascular mortality, sudden cardiac death SCD, aborted SCD, and heart failure death). We performed a systematic review of the literature and meta-analysis to determine pooled odds ratios for these clinical events. Results Four studies evaluated 1,063 patients over an average follow-up of 3.1 years. The pooled prevalence of LGE was 60%. The pooled odds ratios (OR) demonstrate that LGE by CMR correlated with cardiac death (pooled OR: 2.92, 95% confidence interval CI: 1.01 to 8.42; p = 0.047), heart failure death (pooled OR: 5.68, 95% CI: 1.04 to 31.07; p = 0.045), and all-cause mortality (pooled OR: 4.46, 95% CI: 1.53 to 13.01; p = 0.006), and showed a trend toward significance for predicting sudden death/aborted sudden death (pooled OR: 2.39, 95% CI: 0.87 to 6.58; p = 0.091). Conclusions Late gadolinium enhancement by CMR has prognostic value in predicting adverse cardiovascular events among HCM patients. There are significant relationships between LGE and cardiovascular mortality, heart failure death, and all-cause mortality in HCM. Additionally, LGE and SCD/aborted SCD displayed a trend toward significance. The assessment of LGE by CMR has the potential to provide important information to improve risk stratification in HCM in clinical practice.
As an RNA binding protein, CUG-BP Elav-like family (CELF) has been shown to be critical for heart biological functions. However, no reports have revealed the function of CELF1 in hypertrophic ...cardiomyopathy (HCM). Hinted by RNA immunoprecipitation-sequencing (RIP-seq) data, the influence of the CELF protein on heme oxygenase-1 (HO-1) expression was tested by modulating CELF1 levels. Cardiac hypertrophy is related to oxidative stress-induced damage. Hence, the cardiovascular system may be protected against further injury by upregulating the expression of antioxidant enzymes, such as HO-1. During the past two decades, research has demonstrated the central role of HO-1 in the protection against diseases. Thus, understanding the molecular mechanisms underlying the modulation of HO-1 expression is profoundly important for developing new strategies to prevent cardiac hypertrophy.
To elucidate the molecular mechanisms underlying HO-1 regulation by the CELF protein, we performed RNA immunoprecipitation (RIP), biotin pull-down analysis, luciferase reporter and mRNA stability assays. We found that the expression of HO-1 was downregulated by CELF1 through the conserved GU-rich elements (GREs) in HO-1 3′UTR transcripts. Correspondingly, CELF1 expression was regulated by controlling the release of carbon monoxide (CO) in H9C2 cells. The CELF1-HO-1-CO regulation axis constituted a novel positive feedback circuit. In addition, we detected the potential involvement of CELF1 and HO-1 in samples from HCM patients. We found that CELF1 and CELF2, but not HO-1, were highly expressed in HCM heart samples. Thus, a manipulation targeting CELF1 could be developed as a potential therapeutic option for cardiac hypertrophy.
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•Understanding HO-1 regulation is profound importance for preventing heart diseases.•Through the conserved GREs, CELF1 negatively regulates HO-1.•CO, the byproduct of HO-1, could modulate CELF1 expression.•A positive feedback circuit in CELF1-HO-1-CO regulation axis•Imply a potential clinical usage and therapeutic method of targeting CELF1 in HCM
Abstract
Disturbed metabolism as a consequence of obesity and diabetes may cause cardiac diseases (recently highlighted in the cardiovascular research spotlight issue on metabolic cardiomyopathies).1 ...In turn, the metabolism of the heart may also be disturbed in genetic and acquired forms of hypertrophic cardiac disease. Herein, we provide an overview of recent insights on metabolic changes in genetic hypertrophic cardiomyopathy and discuss several therapies, which may be explored to target disturbed metabolism and prevent onset of cardiac hypertrophy.
This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.