Heart Failure in Patients with Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited cardiomyopathy characterized as fibro-fatty replacement, and a common cause for sudden cardiac death in young athletes. Development of heart failure (HF) has been an under-recognized complication of ACM for a long time. The current clinical management guidelines for HF in ACM progression have nowadays been updated. Thus, a comprehensive review for this great achievement in our understanding of HF in ACM is necessary. In this review, we aim to describe the research progress on epidemiology, clinical characteristics, risk stratification and therapeutics of HF in ACM.

Implantable loop recorders in patients with heart disease: comparison between patients with and without syncope

ObjectivePatients with heart disease are at increased risk for sudden cardiac death. Guidelines recommend an implantable loop recorder (ILR) for symptomatic patients when symptoms are sporadic and possibly arrhythmia-related. In clinical practice, an ILR is mainly used in patients with unexplained syncope. We aimed to compare the clinical value of an ILR in patients with heart disease and a history of syncope versus those with non-syncopal symptoms.MethodsIn this observational single-centre study, we included symptomatic patients with heart disease who received an ILR. The primary endpoint was an actionable event which was defined as an arrhythmic event leading to a change in clinical management. The secondary endpoint was an event leading to device implantation.ResultsOne hundred and twenty patients (mean age 47±17 years, 49% men) were included. The underlying disease substrate was inherited cardiomyopathy (31%), congenital heart disease (28%), channelopathy (23%) and other (18%). Group A consisted of 43 patients with prior syncope and group B consisted of 77 patients with palpitations and/or near-syncope. The median follow-up duration was 19 months (IQR 8–36). The 3-year cumulative event rate was similar between groups with regard to the primary endpoint (38% vs 39% for group A and B, respectively, logrank p=0.54). There was also no difference in the 3-year cumulative rate of device implantation (21% vs 13% for group A and B, respectively, logrank p=0.65).ConclusionIn symptomatic patients with heart disease, there is no difference in the yield of an ILR in patients presenting with or without syncope.

Health-related quality of life and physical activity in children with inherited cardiac arrhythmia or inherited cardiomyopathy: the prospective multicentre controlled QUALIMYORYTHM study rationale, design and methods

Background Advances in paediatric cardiology have improved the prognosis of children with inherited cardiac disorders. However, health-related quality of life (QoL) and physical activity have been scarcely analysed in children with inherited cardiac arrhythmia or inherited cardiomyopathy. Moreover, current guidelines on the eligibility of young athletes with inherited cardiac disorders for sports participation mainly rely on expert opinions and remain controversial. Methods The QUALIMYORYTHM trial is a multicentre observational controlled study. The main objective is to compare the QoL of children aged 6 to 17 years old with inherited cardiac arrhythmia (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, or arrhythmogenic right ventricular dysplasia), or inherited cardiomyopathy (hypertrophic, dilated, or restrictive cardiomyopathy), to that of age and gender-matched healthy subjects. The secondary objective is to assess their QoL according to the disease’s clinical and genetic characteristics, the level of physical activity and motivation for sports, the exercise capacity, and the socio-demographic data. Participants will wear a fitness tracker (ActiGraph GT3X accelerometer) for 2 weeks. A total of 214 children are required to observe a significant difference of 7 ± 15 points in the PedsQL, with a power of 90% and an alpha risk of 5%. Discussion After focusing on the survival in children with inherited cardiac disorders, current research is expanding to patient-reported outcomes and secondary prevention. The QUALIMYORYTHM trial intends to improve the level of evidence for future guidelines on sports eligibility in this population. Trial registration ClinicalTrials.gov Identifier: NCT04712136, registered on January 15th, 2021 (https://clinicaltrials.gov/ct2/show/NCT04712136).

Arrhythmia Mechanism and Dynamics in a Humanized Mouse Model of Inherited Cardiomyopathy Due to Phospholamban R14del Mutation

Background: Arginine (Arg) 14 deletion (R14del) in the calcium regulatory protein phospholamban (hPLN R14del ) has been identified as a disease-causing mutation in patients with an inherited cardiomyopathy. Mechanisms underlying the early arrhythmogenic phenotype that predisposes carriers of this mutation to sudden death with no apparent structural remodeling remain unclear. Methods: To address this, we performed high spatio-temporal resolution optical mapping of intact hearts from adult knock-in mice harboring the human PLN WT (WT, N=12) or the heterozygous human PLN R14del mutation (R14del, N=12) before and after ex-vivo challenge with isoproterenol and rapid pacing. Results: Adverse electrophysiological remodeling was evident in the absence of significant structural or hemodynamic changes. R14del hearts exhibited increased arrhythmia susceptibility compared to WT. Underlying this susceptibility was preferential right ventricular (RV) action potential prolongation that was unresponsive to β-adrenergic stimulation. A steep repolarization gradient at the LV/RV interface provided the substrate for inter-ventricular activation delays and ultimately local conduction block during rapid pacing. This was followed by the initiation of macroreentrant circuits supporting the onset of VT. Once sustained, these circuits evolved into high frequency rotors, which in their majority were pinned to the RV. Importantly, these rotors exhibited unique spatio-temporal dynamics that promoted their increased stability in R14del compared to WT hearts. Conclusions: Our findings highlight the crucial role of primary electrical remodeling caused by the hPLNR14del mutation. These inherently arrhythmogenic features form the substrate for adrenergic-mediated VT at early stages of PLN R14del induced cardiomyopathy.

Uncovering Inherited Cardiomyopathy With Human Induced Pluripotent Stem Cells

In the past decades, researchers discovered the contribution of genetic defects to the pathogenesis of primary cardiomyopathy and tried to explain the pathogenesis of these diseases by establishing a variety of disease models. Although human heart tissues and primary cardiomyocytes have advantages in modeling human heart diseases, they are difficult to obtain and culture in vitro. Defects developed in genetically modified animal models are notably different from human diseases at the molecular level. The advent of human induced pluripotent stem cells (hiPSCs) provides an unprecedented opportunity to further investigate the pathogenic mechanisms of inherited cardiomyopathies in vitro using patient-specific hiPSC-derived cardiomyocytes. In this review, we will make a summary of recent advances in in vitro inherited cardiomyopathy modeling using hiPSCs.

MiRNAs as Biomarkers in Hypertrophic Cardiomyopathy: Current State of the Art

Background: Hypertrophic Cardiomyopathy (HCM) is the most common inherited Cardiomyopathy. The hallmark of HCM is myocardial fibrosis that contributes to heart failure, arrhythmias and sudden cardiac death. Objective: Currently there are no reliable serum biomarkers for detection of myocardial fibrosis, while cardiac magnetic resonance (CMR) is an imaging technique to detect myocardial fibrosis. MicroRNAs (miRNAs) have been increasingly suggested as biomarkers in cardiovascular diseases. However, in HCM there is as yet no identified and verified specific circulating miRNA signature. Methods: We conducted a review of literature to identify the studies that indicate the possible roles of miRNAs in HCM. Results: From studies in transgenic mice with HCM, miR-1, -133 may identify HCM in the early asymptomatic phase. Human miR-29a could be used as a circulating biomarker for detection of both myocardial hypertrophy and fibrosis in HCM, while it could also have a possible additional role in discrimination of hypertrophic obstructive cardiomyopathy from non-obstructive HCM. Additionally, miR-29a-3p is associated with diffuse myocardial fibrosis in HCM while miR-1-3p could discriminate end-stage HCM from dilated cardiomyopathy and left ventricle dilation. Another role of miRNAs could also be the contribution in differential diagnosis between HCM and phenocopies. Moreover, miRNA-targeted therapy (miR-133 mimics) is promising in inhibiting cardiac hypertrophy but this is still in the early stages. Conclusion: A more reliable and specific signature of miRNAs is expected with forthcoming studies in samples from HCM patients and correlation of miRNAs with CMR and serum markers of fibrosis may implicate novel diagnostic and therapeutic pathways.

Phenotypic Diversity of Cardiomyopathy Caused by an MYBPC3 Frameshift Mutation in a Korean Family: A Case Report

Restrictive cardiomyopathy (RCM) is one of the rarest cardiac disorders, with a very poor prognosis, and heart transplantation is the only long-term treatment of choice. We reported that a Korean family presented different cardiomyopathies, such as idiopathic RCM and hypertrophic cardiomyopathy (HCM), caused by the same MYBPC3 mutation in different individuals. A 74-year-old male was admitted for the evaluation of exertional dyspnea, palpitations, and pitting edema in both legs for several months. Transthoracic echocardiography (TTE) showed RCM with biatrial enlargement and pericardial effusion. Cardiac magnetic resonance (CMR) images revealed normal left ventricular chamber size, borderline diffuse left ventricular hypertrophy and very large atria. In contrast to the proband, CMR images showed asymmetric septal hypertrophy of the left ventricle, consistent with a diagnosis of HCM in the proband’s two daughters. Of the five heterozygous variants identified as candidate causes of inherited cardiomyopathy by whole exome sequencing in the proband, Sanger sequencing confirmed the presence of a heterozygous frameshift mutation (NM_000256.3:c.3313_3314insGG; p.Ala1105Glyfs*85) in MYBPC3 in the proband and his affected daughters, but not in his unaffected granddaughter. There is clinical and genetic overlap of HCM with restrictive physiology and RCM, especially when HCM is combined with severe myocardial fibrosis. Family screening with genetic testing and CMR imaging could be excellent tools for the evaluation of idiopathic RCM.

Extended septal myectomy and left ventricular outflow tract intervention for hypertrophic obstructive cardiomyopathy

Hypertrophic obstructive cardiomyopathy is the most common inherited cardiomyopathy. Septal myectomy is a low-risk operation and remains the first septal reduction therapeutic option. We present a patient with hypertrophic obstructive cardiomyopathy requiring extended septal myectomy and concomitant left ventricular outflow tract intervention. In addition to septal reduction therapy, this patient also underwent anterior mitral valve plication, trigonal release, and secondary chordal division to relieve the obstruction. A tailored approach to hypertrophic obstructive cardiomyopathy with a comprehensive left ventricular outflow tract intervention is necessary to ensure the best hemodynamic outcome. Preoperative heart failure and recurrent syncope fully resolved after this intervention.

Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression

Background: Inherited cardiomyopathy associates with a range of phenotype, mediated by genetic and non-genetic factors. Non-inherited cardiomyopathy also displays varying progression and outcomes. Expression of cardiomyopathy genes is under the regulatory control of promoters and enhancers, and human genetic variation in promoters and enhancers may contribute to this variability. Methods: We superimposed epigenomic profiling from hearts and cardiomyocytes, including promoter-capture chromatin conformation information, to identify enhancers for two cardiomyopathy genes, MYH7 and LMNA . Enhancer function was validated in human cardiomyocytes derived from induced pluripotent stem cells. We also conducted a genome-wide search to ascertain genomic variation in enhancers positioned to alter cardiac expression and correlated one of these variants to cardiomyopathy progression using biobank data. Results: Multiple enhancers were identified and validated for LMNA and MYH7 , including a key enhancer that regulates the switch from MYH6 expression to MYH7 expression. Deletion of this enhancer resulted in a dose-dependent increase in MYH6 and faster contractile rate in engineered heart tissues. We searched for genomic variation in enhancer sequences across the genome, with focus on nucleotide changes that create or interrupt transcription factor binding sites. rs875908 disrupts a TBX5 binding motif and maps to an enhancer region 2KB from the transcriptional start site of MYH7 . Gene editing to remove the enhancer harboring this variant markedly reduced MYH7 expression in human cardiomyocytes. Using biobank-derived data, rs875908 associated with longitudinal echocardiographic features with cardiomyopathy. Conclusions: Enhancers regulate cardiomyopathy gene expression, and genomic variation within these enhancer regions associates with cardiomyopathic progression over time. This integrated approach identified noncoding modifiers of cardiomyopathy and is applicable to other cardiac genes.