Search

Arrhythmogenic cardiomyopathy is a familial heart muscle disease characterized by structural, electrical, and pathological abnormalities. Recognition of left ventricular (LV) involvement in arrhythmogenic right ventricular cardiomyopathy (ARVC) has led to the newer term of arrhythmogenic cardiomyopathy (ACM). We report on a family with autosomal dominant desmoplakin (DSP) related ACM to illustrate the broad clinical spectrum of disease. The importance of evaluation of relatives with cardiac magnetic resonance imaging and consideration of genetic testing in the absence of Task Force diagnostic criteria is discussed. The practical and ethical issues of access to the Guthrie collection for deoxyribonucleic acid (DNA) testing are considered.

In 2022, the British Cardiovascular Society celebrates the centenary of its foundation. Starting out as a small group of government-appointed physicians interested in heart disease, the Cardiac Club has grown and adapted to represent all those working in cardiovascular care and research. The historical stages of the organisation’s development are outlined, alongside major innovations in science and technology providing context for a rapidly changing medical world. Only a small part of the history of cardiology in Britain is told, with greater emphasis on describing the broader need for services, skilled workforce, healthcare policy and continuing education. Above all, the history of the British Cardiovascular Society is a story of people and places. The people are those with vision, attitude and leadership to improve the care of communities across the world. The places are those that enabled conversation, innovation and freedom to bring about change. It is hard to believe the remarkable progress in diagnosis, prevention and treatment of heart disease over 100 years, but a thriving modern Society must be the greatest legacy of its founders.

Background Myocardial fibrosis is a common feature of hypertrophic cardiomyopathy (HCM) but its pathophysiology has yet to be elucidated. Purpose In this study, we used a multiplex approach to examine the genetic regulation of pathways associated with fibrosis in patients undergoing septal myectomy. Methods Myocardial tissue was collected at time of surgical intervention. Control biopsy samples were obtained from the left ventricular free wall from structurally normal hearts during autopsy following non-cardiac related death. Tissue was either snap frozen in liquid nitrogen and subsequently stored at −80 degrees or collected in RNA laterTM and frozen 24 hours later at −80 degrees. Total RNA was extracted from HCM tissue samples using the Qiagen RNeasy fibrous tissues mini kit and from control samples using mirVana isolation kit (Ambion), according to the manufacturer's protocol. Quantitative PCR (qPCR) was performed on the extracted RNA using a RT. Profiler™ Human finrosis PCR Array. Results The study cohort comprised 22 HCM samples and 5 controls. The relative regulation of genes involved in myocardial fibrosis in patients with HCM compared to controls is shown in figure 1. In patients with HCM, there was increased expression of genes involved in collagen synthesis. A significant two-fold upregulation in type III procollagen mRNA was observed relative to controls (p=0.013) with a similar trend identified for type I procollagen (1.5 fold up-regulation, p=0.081). The gene expression of MMP3 (−1.5 fold, p=0.029) and MMP8 (−1.8, p=0.002) which are involved in collaged degradation were downregulated in the HCM group. The gene expression of pro-fibrotic mediators TGF-β2 (4.8 fold, p=0.008) and CCN2 (2.9 fold, p=0.021) was also significantly elevated. Within the HCM group, there was a correlation between the fold regulation of TGF-β1 (r=0.570, p=0.006; r=0.528, p=0.012), TGF-β2 (r=0.569, p=0.006; r=0.514, p=0.014) and TGF-β3 (r=0.738, p The expression of BMP-7 which has been shown to reduce myocardial fibrosis by antagonising TGF- β mediated endothelial – mesothelial transformation of fibroblasts was also down-regulated in HCM (−3.8, p=0.015). Conclusions Genetic expression of procollagen is significantly upregulated in patients with HCM relative to controls. TGF-β and CCN2 mediated signalling appear to be key mediators in promoting collagen expression. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Heart Hospital Charitable Grant, UK Figure 1. Gene expression in HCM

Background— Exercise testing is performed in patients with hypertrophic cardiomyopathy to evaluate blood pressure response, a risk factor for sudden cardiac death. The prognostic role of exercise gas exchange variables is unknown. Methods and Results— Between 1998 and 2010, 1898 patients (age 47±15 years, range 16–86 years; 67% male) with hypertrophic cardiomyopathy underwent cardiopulmonary exercise testing. A total of 178 (9.4%) patients reached the primary end point of all-cause mortality or heart transplant (death/transplant) during a median follow-up of 5.6 years (interquartile range 2.6–8.9), giving an annual event rate of 1.6% per person year. Peak oxygen consumption (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.77–0.88, P P =0.049), and ventilatory anaerobic threshold (adjusted HR 0.82, 95% CI 0.70–0.96, P =0.016) were predictors of the primary outcome after correction for age, sex, left atrial size, nonsustained ventricular tachycardia, and ejection fraction. The overall adjusted death/transplant estimates for patients in the lowest quartile with peak oxygen consumption ≤15.3 mL/kg/min were 14% at 5 years and 31% at 10 years. Peak oxygen consumption (HR 0.81, 95% CI 0.77–0.86, P P Conclusions— Cardiopulmonary exercise testing provides prognostic information in patients with hypertrophic cardiomyopathy. Submaximal exercise parameters, such as ventilatory efficiency and anaerobic threshold, measured alone or in combination with peak oxygen consumption, predict death from heart failure.

Cardiomyopathies are an important cause of sudden cardiac death in young people and are responsible for arrhythmias and premature heart failure in all age groups. Although many cardiomyopathies are inherited, biochemical markers are a fundamental part of the diagnostic work-up and are useful in the prognostic assessment of disease. In this article, the authors review the rationale and evidence for important biomarkers according to their role in patient management. Emerging biomarkers are briefly reviewed, alongside modern scientific approaches to biomarker discovery.

Background Anderson–Fabry Disease (AFD) is an X linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Some mutations are associated with prominent and, in many cases, exclusive cardiac involvement. The primary aims of this study were to determine the incidence of major cardiac events in AFD and to identify clinical and genetic predictors of adverse outcomes. Methods and results We studied 207 patients with AFD (47% male, mean age 44 years, mean follow-up 7.1 years). Fifty-eight (28%) individuals carried mutations that have been previously associated with a cardiac predominant phenotype. Twenty-one (10%) developed severe heart failure (New York Heart Association functional class (NYHA) ≥3), 13 (6%) developed atrial fibrillation (AF), 13 (6%) received devices for the treatment of bradycardia; there were a total of 7 (3%) cardiac deaths. The incidence of the primary endpoint (a composite of new onset AF, NYHA ≥ 3 symptoms, device insertion for bradycardia and cardiac death) was 2.64 per 100 person-years (CI 1.78 to 3.77). Age (HR 1.04, CI 1.01 to 1.08, p=0.004), Mainz Severity Score Index score (HR 1.05, CI 1.01 to 1.09, p=0.012) and QRS duration (HR 1.03, CI 1.00 to 1.05, p=0.020) were significant independent predictors of the primary endpoint. The presence of a cardiac genetic variant did not predict the primary end point. Conclusions AFD is associated with a high burden of cardiac morbidity and mortality. Adverse cardiac outcomes are associated with age, global disease severity and advanced cardiac disease but not the presence of cardiac genetic variants.

Importance Hypertrophic cardiomyopathy causes limiting symptoms in patients, mediated partly through inefficient myocardial energy use. There is conflicting evidence for therapy with inhibitors of myocardial fatty acid metabolism in patients with nonobstructive hypertrophic cardiomyopathy. Objective To determine the effect of oral therapy with trimetazidine, a direct inhibitor of fatty acid β-oxidation, on exercise capacity in patients with symptomatic nonobstructive hypertrophic cardiomyopathy. Design, Setting, and Participants This randomized, placebo-controlled, double-blind clinical trial at The Heart Hospital, University College London Hospitals, London, United Kingdom was performed between May 31, 2012, and September 8, 2014. The trial included 51 drug-refractory symptomatic (New York Heart Association class ≥2) patients aged 24 to 74 years with a maximum left ventricular outflow tract gradient 50 mm Hg or lower and a peak oxygen consumption during exercise of 80% or less predicted value for age and sex. Statistical analysis was performed from March 1, 2016 through July 4, 2018. Interventions Participants were randomly assigned to trimetazidine, 20 mg, 3 times daily (n = 27) or placebo (n = 24) for 3 months. Main Outcomes and Measures The primary end point was peak oxygen consumption during upright bicycle ergometry. Secondary end points were 6-minute walk distance, quality of life (Minnesota Living with Heart Failure questionnaire), frequency of ventricular ectopic beats, diastolic function, serum N-terminal pro–brain natriuretic peptide level, and troponin T level. Results Of 49 participants who received trimetazidine (n = 26) or placebo (n = 23) and completed the study, 34 (70%) were male; the mean (SD) age was 50 (13) years. Trimetazidine therapy did not improve exercise capacity, with patients in the trimetazidine group walking 38.4 m (95% CI, 5.13 to 71.70 m) less than patients in the placebo group at 3 months after adjustment for their baseline walking distance measurements. After adjustment for baseline values, peak oxygen consumption was 1.35 mL/kg per minute lower (95% CI, −2.58 to −0.11 mL/kg per minute;P = .03) in the intervention group after 3 months. Conclusions and Relevance In symptomatic patients with nonobstructive hypertrophic cardiomyopathy, trimetazidine therapy does not improve exercise capacity. Pharmacologic therapy for this disease remains limited. Trial Registration ClinicalTrials.gov identifier:NCT01696370

The modern description of hypertrophic cardiomyopathy is credited to the London pathologist, Robert Donald Teare who likened the disease to "a tumour of the heart" and published his observations in the British Heart Journal 50 years ago. Teare recognised asymmetrical hypertrophy and myocyte disarray as a familial condition associated with premature and sudden death in young people. He rightly deserves the accolade for bringing a poorly understood, but well recognised phenomenon into the public domain. Thick and heavy hearts had been of interest and investigation to physicians and pathologists for many centuries. This article reviews the early history of hypertrophic cardiomyopathy and reflects on several centuries of progress in our understanding of the condition.

Aims To determine the relation between serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and prognosis in patients with hypertrophic cardiomyopathy (HCM). Methods and results In total, 847 patients (53 ± 15 years; 67% male) with HCM (28% with left ventricular outflow tract obstruction ≥30 mmHg at rest) were followed for 3.5 years (IQR 2.5–4.5 years). The median NT-proBNP concentration was 78 pmol/L (range

The European Society of Cardiology recently recommended a new tool 1 to estimate 5 year risk of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). We investigated the relationship between serum cardiac troponin I (cTnI) levels and HCM-risk score in 100 consecutive patients referred to the West of Scotland Inherited Cardiac Conditions Clinic. The 20 most recent patients had a high sensitivity cTnI assay performed (limit of detection (LOD) 1.2 ng/L) and the remaining 80 had the traditional assay (LOD 10 ng/L). Demographic, clinical, genetic and imaging parameters were collected at first assessment. HCM-risk was calculated retrospectively. Cardiac TnI was elevated in 27% of the population (n = 100, 60% male, mean age 56 ± 14, left ventricular outflow tract (LVOT) obstruction (i.e. resting gradient ≥30 mmHg) in 20%) and they had significantly higher overall HCM-risk score (3.7% v 2.2%, p In conclusion, serum cTnI is elevated in a significant proportion of patients with HCM and is associated with clinical markers of disease severity. Biomarkers may be useful as an adjunct to current risk models in identifying patients with adverse cardiac remodelling and underlying atrial fibrillation. Reference O’Mahony C et al . A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM risk-SCD). Eur Heart J . 2014;35(30):2010-–20

Enzyme replacement therapy has the potential to delay or reverse adverse cardiac remodeling in Anderson-Fabry disease (AFD); however, the current indications for enzyme replacement therapy rely on detecting relatively advanced features of the disease. We aimed to determine the relation between the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration and cardiac abnormalities in patients with AFD. We hypothesized that it might help to detect early disease. NT-proBNP was measured under at rest conditions in 117 patients with AFD (age 48 ± 15 years, 46.2% men). All patients underwent clinical evaluation with electrocardiography and echocardiography. The median NT-proBNP concentration was 24 pmol/L (range

A 46-year-old woman was admitted following three episodes of collapse. She had no past medical history but her cousin had died suddenly in her 30s from an unknown heart condition. Physical examination and blood pressure were normal. An electrocardiogram (ECG) showed diffuse T wave inversion (figure 1), and troponin I measured at 12 h was 0.96 μg/l. Routine blood tests, inflammatory markers, coronary angiography and 24 h Holter …

A 53-year-old white man was identified through family screening as having arrhythmogenic right ventricular cardiomyopathy caused by a frameshift mutation in the desmoplakin gene (DSP S1015fsX1017). Direct questioning revealed a previously undisclosed history of palpitations. The electrocardiogram (ECG) showed anterolateral T-wave inversion (Figure 1). Holter monitoring detected an asymptomatic 11-beat run of nonsustained ventricular tachycardia, 2 triplets, 11 couplets, and 1754 multifocal ventricular ectopics. These ectopics were of left ventricular (LV) origin when captured on 12-lead ECG. There were no late potentials on signal-averaged ECG. Figure 1. ECG …

To the Editor: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by mutations in the gene encoding alpha-galactosidase A. The resultant deficiency in alpha-galactosidase A leads to progressive intracellular accumulation of neutral glycosphingolipids throughout the body

Background Exercise testing is commonly performed in patients with hypertrophic cardiomyopathy (HCM) to evaluate blood pressure response, a conventional risk factor for sudden cardiac death. The 2011 ACCF/AHA guidelines state “the role of metabolic stress testing in the evaluation of patients with HCM remains to be decided, particularly with regard to clinical outcome. Methods and results Between 1998 and 2010, 1,898 patients (age 47 ± 15 years, 67% male) with HCM underwent cardiopulmonary exercise testing (CPX). During a mean follow-up of 5.8 ± 4 years, 178 (9.4%) patients reached the primary endpoint of all-cause mortality or orthotropic heart transplant. Peak oxygen consumption, V˙O 2 (HR 0.91 95% CI 0.89–0.93, p 2 (HR 1.08 95% CI 1.06–1.09), and ventilatory anaerobic threshold V˙AT (HR 0.88 95% CI 0.84–0.92) were predictors of the primary outcome. A progressively worse prognosis was associated with higher ventilatory class (Figure 1). V˙EV˙CO 2 was a good predictor of heart failure death or transplantation (HR 1.1 95% CI 1.07–1.14 p Conclusions CPX provides important prognostic information in patients with HCM. Sub-maximal exercise parameters are potentially more useful than peak VO 2 alone. Patients with an enhanced ventilatory response have a substantially higher risk of death or transplantation. Reference 1 Gersh, et al . JACC 2011;58(25):212–60

Objective To evaluate the role of diffuse myocardial fibrosis (DMF) in familial Dilated Cardiomyopathy (fDCM) using Equilibrium Contrast-CMR (EQ-CMR). Background Post mortem/biopsy studies have shown that DMF occurs in DCM, but its clinical significance remains largely unknown as its assessment requires invasive biopsy. EQ-CMR is a recently described technique that permits the non-invasive and accurate assessment of DMF by measuring the myocardial contrast volume of distribution (Vd(m)) at equilibrium contrast [1]. Methods Using international diagnostic guidelines we identified 28 patients with fDCM (mean age 42, 61% male, 89% NYHA class I, 11% NYHA class II). This cohort excluded the most severe cases of fDCM due to the high prevalence of permanent pacemakers or ICDs. The Vd(m) (a measure of DMF) was compared to that obtained in healthy volunteers (mean age 35, 63% male) and also to other indexed CMR parameters, including left atrial area and echocardiographic parameters of diastolic function (tissue doppler and strain imaging). Results fDCM patients had increased LV size (95mls/m2 vs 73mls/m2 , p=0.0001), worse ejection fraction (55% vs 69%, p