OBJECTIVE:Recent studies have demonstrated a greater prevalence of coronary atherosclerosis in male masters endurance athletes, but the underlying contributors remain unclear. We explored the relationship between occult resting and exercise-induced hypertension with coronary atherosclerosis characteristics. METHODS:198 male masters endurance athletes with a low Framingham risk score (<10%) and no clinical diagnosis of hypertension underwent 24-hour ambulatory blood pressure (ABP) monitoring and exercise BP assessment. Coronary CT angiography assessed coronary artery calcification (CAC) score, luminal stenosis and high-risk plaque features. RESULTS:Seventy-eight (39%) athletes were hypertensive on ABP monitoring and 93 (47%) demonstrated a hypertensive response to exercise. A CAC score of 1-99 Agatston units (AU), 100-399 AU and ≥400 AU was present in 94 (47%), 32 (16%) and 15 (8%) athletes, respectively. Twenty-four (12%) athletes had coronary stenoses >50%. Sixty-two athletes (31%) had calcified plaque, 32 (16%) had mixed plaque, 2 (1%) had non-calcified plaque and 26 (13%) had markers of high-risk plaque. Hypertension on ABP monitoring was significantly associated with a CAC score ≥100 AU (OR: 2.56; 1.08 to 6.04) and coronary stenosis >50% (OR: 2.92; 1.17 to 7.33). A hypertensive response to exercise was significantly associated with coronary stenosis >50% (OR: 4.72; 1.65 to 13.5) and the presence of high-risk plaque (OR: 3.27; 1.27 to 8.43). CONCLUSION:Masters male endurance athletes have a high prevalence of occult hypertension, which is associated with high-risk features of coronary atherosclerosis. Both ambulatory and exercise-induced hypertension are associated with a higher prevalence of atherosclerotic coronary artery disease in male endurance athletes. Early identification and timely clinical management of this classic cardiovascular disease risk factor may reduce the burden of coronary atherosclerosis in athletes.

AIMS:Sudden arrhythmic death syndrome (SADS) refers to a sudden death, which remains unexplained despite comprehensive post-mortem examination and a toxicological screen. We aimed to investigate the impact of age and sex on the overall diagnostic yield and underlying aetiology in decedents with SADS using a combined approach of familial evaluation (FE) and molecular autopsy (MA). METHODS AND RESULTS:Consecutive referrals to a single centre for FE only, MA only or both, following a SADS death were included. First-degree family members underwent comprehensive FE and decedents with post-mortem DNA were sequenced with a 36 cardiac gene panel for MA. A Bayesian framework for analysis was performed to identify associations. Among 760 SADS decedents (66% male; mean age 31 ± 12 years) the overall diagnostic yield for an inherited cardiac condition was 37% (32-42%) and 9% (6-12%) for FE and MA cohorts. In a subset where both FE and MA were performed the diagnostic yield was 45% (38-61%). The relative risk of an FE diagnosis of long QT syndrome (LQTS) or Catecholaminergic polymorphic ventricular tachycardia (CPVT) vs. remaining unexplained declined by 5.6% [RR 0.94 (0.91-0.98)] and by 11% [RR 0.89 (0.81-0.97)], for each year increase in age. Females were more likely to have a diagnosis by both FE [40% (34-45%) vs. 36% (31-41%)] and MA [15% (10-21%) vs. 6% (3-8%)]. Females [8.1% (4.1-13.4%)], were more likely to be diagnosed with LQTS than males [1.2% (0.2-2.7%)] in the MA cohort. CONCLUSION:After a SADS death, the diagnostic yield of comprehensive FE, MA, or both in an expert setting can be up to 45% with a combined approach. Females had higher diagnostic yield than males, most notable with LQTS. CPVT and LQTS diagnoses declined with increasing age. These data highlight the relative utility of FE and MA depending on age and sex for determining underlying diagnoses following SADS deaths.

BACKGROUND:Cardiac involvement is the main determinant of adverse outcomes in Fabry disease. The study aimed to investigate cardiovascular outcomes in patients with Fabry disease. METHODS:This was a multicenter, retrospective, longitudinal study of consecutively referred adult patients with Fabry disease. The primary end point was the occurrence of major adverse cardiovascular events defined as a composite of cardiovascular death, major arrhythmic events, bradyarrhythmias requiring pacemaker implantation, and stroke. RESULTS:A total of 680 patients (age, 42.3±15.9 years; 41.0% male; 68.7% on disease-specific therapy) were included. During a median follow-up of 7.1 (interquartile range, 3.9-11.6) years, 92 patients (13.5%) experienced a major adverse cardiovascular event. At 10 years, freedom from major adverse cardiovascular event was 85.1% (95% CI, 81.3-88.2) and was lower in men compared with women (76.1% [95% CI, 68.9-81.9] versus 91.3% [95% CI, 87.0-94.2]; log-rank χ2=26.9; P<0.001). On multivariable analysis, age (hazard ratio, 1.04 [95% CI, 1.01-1.06] per 1 year; P<0.001), estimated glomerular filtration rate (hazard ratio, 0.99 [95% CI, 0.98-0.99] per 1 mL/min per 1.73 m2; P<0.001), QRS interval (hazard ratio, 1.02 [95% CI, 1.01-1.03] per 1 ms; P=0.002), and left ventricular mass index (hazard ratio, 1.01 [95% CI, 1.00-1.01] per 1 g/m2; P=0.032) were independent predictors of major adverse cardiovascular events during follow-up. CONCLUSIONS:This study shows that the prevention and treatment of cardiovascular disease remain an unmet need for patients with Fabry disease.

Naxos disease is a rare autosomal recessive condition combining arrhythmogenic right ventricular cardiomyopathy, woolly hair, and palmoplantar keratoderma. The first identified causative variant was in the gene encoding the desmosomal protein plakoglobin. Naxos disease exhibits fibro-fatty myocardial replacement with immunohistological abnormalities in cardiac protein and signaling pathways, highlighting the role of inflammation and potential anti-inflammatory treatments. Childhood cutaneous signs precede cardiac features, which are diagnosed by familial and genetic evaluation, electrocardiography and cardiac imaging. Disease progression necessitates holistic care with risk management and lifestyle adjustments, often needing treatment for arrhythmia and heart failure. Similar phenotypes have been linked to desmoplakin and rarely desmocollin2 gene variants, highlighting the importance of familial and genetic evaluation. This document summarizes current knowledge on Naxos disease and related cardiocutaneous syndromes and initiates an international endeavor to collect and study all global cases, aiming to improve understanding, treatment, and patient care through shared data and research.

ObjectiveTransthyretin amyloid cardiomyopathy (ATTR-CM) is an infiltrative cardiac disorder caused by deposition of wild type or mutated transthyretin. As ATTR-CM is associated with conduction disease, we sought to determine its prevalence in patients with idiopathic high-degree atrioventricular (AV) block requiring permanent pacemaker (PPM) implantation.MethodsConsecutive patients aged 70–85 years undergoing PPM implantation for idiopathic high-degree AV block between November 2019 and November 2021 were offered a 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scan. Demographics, comorbidities, electrocardiographic and imaging data from the time of device implantation were retrospectively collected.Results39 patients (79.5% male, mean (SD) age at device implantation 76.2 (2.9) years) had a DPD scan. 3/39 (7.7%, all male) had a result consistent with ATTR-CM (Perugini grade 2 or 3). Mean (SD) maximum wall thickness of those with a positive DPD scan was 19.0 mm (3.6 mm) vs 11.4 mm (2.7 mm) in those with a negative scan (p=0.06). All patients diagnosed with ATTR-CM had spinal canal stenosis and two had carpal tunnel syndrome.ConclusionsATTR-CM should be considered in older patients requiring permanent pacing for high-degree AV block, particularly in the presence of left ventricular hypertrophy, carpal tunnel syndrome or spinal canal stenosis.

ABSTRACT BACKGROUND Studies in ostensibly healthy male master athletes have revealed a greater prevalence of coronary artery calcification (CAC) and coronary plaques compared with relatively sedentary counterparts. In contrast, data relating to potentially adverse coronary remodelling in female master athletes is sparse and conflicting. We investigated the prevalence of coronary atherosclerosis in a cohort of predominantly post-menopausal female master athletes with a low atherosclerotic risk profile. METHODS 196 female athletes with a mean age of 55±7 years-old and median exercise duration of 33 years (25-39) and 59 relatively sedentary females of similar age underwent cardiovascular investigations including a coronary computed tomogram angiography with assessment of CAC scores, coronary plaques, and pericoronary adipose tissue attenuation. 70% of the athletes and 68% of the control group were post-menopausal. RESULTS Athletes and controls had a similarly low Framingham 10-year risk (1.49% versus 2.1%; P=0.68), but body mass index and blood pressure were lower and HDL-C was higher in the athletes. The prevalence of CAC score >0 Agatston units (AU) was low and did not differ between athletes and controls (21% versus 32%;P=0.073). Female athletes had a lower prevalence of a CAC score >50 th centile (19% versus 32%;P<0.03) and >75 th centile (14% versus 25%;P=0.045) for age compared with controls, but the prevalence of a CAC score >100 AU did not differ between the groups (3.6% versus 8.5%;P=0.12). There were also no differences between the groups in the prevalence of individuals with coronary plaques (21% versus 32%;P=0.09), total plaque volume (16 mm 3 [IQR 3-56] versus 49 [5-142] mm 3 ;P=0.08), or plaque burden (10.8% [2.8-21] versus 15.4% [4.6-28];P=0.46). Coronary plaques were predominantly calcified in both athletes and controls (80% versus 63%;P=0.08). Age, blood pressure and HDL-C were independent predictors for a CAC score >0 AU among athletes. CONCLUSIONS In contrast with previous studies in male master athletes, lifelong exercise in female counterparts does not appear to be associated with increased CAC score, coronary plaque burden or any qualitative differences in coronary plaque compared with relatively sedentary healthy counterparts. Coronary atherosclerosis in master female athletes is mainly driven by traditional risk factors.

Hypertrophic cardiomyopathy (HCM) is a common myocardial disease defined by increased left ventricular wall thickness unexplained by loading conditions. HCM frequently is caused by pathogenic variants in sarcomeric protein genes, but several other syndromic, metabolic, infiltrative, and neuromuscular diseases can result in HCM phenocopies. This review summarizes the current understanding of these HCM mimics, highlighting their importance across the life course. The central role of a comprehensive, multiparametric diagnostic approach and the potential of precision medicine in tailoring treatment strategies are emphasized.

BackgroundLeft ventricular hypertrophy (LVH) is the principal cardiac manifestation of Fabry disease (FD). This study aimed to determine the incidence and predictors of LVH development in a contemporary cohort of patients with FD and no LVH at baseline evaluation.MethodsConsecutively referred adult (aged ≥16 years) patients with FD were enrolled into an observational cohort study. Patients were prospectively followed in a specialist cardiomyopathy centre and the primary endpoint was the first detection of LVH (left ventricular mass index (LVMi) ≥115 g/m2in men and ≥95 g/m2in women).ResultsFrom a cohort of 393 patients, 214 (aged 35.8±13.8 years; 61 (29%) males) had no LVH at first evaluation. During a median follow-up of 9.4 years (IQR 4.7–12.7), 55 patients (24.6%) developed LVH. The estimated incidence of LVH was 11.3% (95% CI 6.5% to 16.1%) at 5 years, 29.1% (95% CI 21.5% to 36.7%) at 10 years and 45.0% (95% CI 33.8% to 62.4%) at 15 years of follow-up. On multivariable analysis, independent predictors for LVH development were age (HR 1.04 (95% CI 1.02 to 1.06) per 1-year increase, p<0.001), male sex (HR 2.90 (95% CI 1.66 to 5.09), p<0.001) and an abnormal ECG (HR 3.10 (95% CI 1.72 to 5.57), p<0.001). The annual rate of change in LVMi was +2.77 (IQR 1.45–4.62) g/m2/year in males and +1.38 (IQR 0.09–2.85) g/m2/year in females (p<0.001).ConclusionsApproximately one-quarter of patients with FD developed LVH during follow-up. Age, male sex and ECG abnormalities were associated with a higher risk of developing LVH in patients with FD.

Hypertrophic cardiomyopathy is a myocardial disease defined by an increased left ventricular wall thickness not solely explained by abnormal loading conditions. It is often genetically determined, with sarcomeric gene mutations accounting for around 50% of cases. Several conditions, including syndromic, metabolic, infiltrative, and neuromuscular diseases, may present with left ventricular hypertrophy, mimicking the hypertrophic cardiomyopathy phenotype but showing a different pathophysiology, clinical course, and outcome. Despite being rare, they are collectively responsible for a large proportion of patients presenting with hypertrophic heart disease, and their timely diagnosis can significantly impact patients' management. The understanding of disease pathophysiology has advanced over the last few years, and several therapeutic targets have been identified, leading to a new era of tailored treatments applying to different etiologies associated with left ventricular hypertrophy. This review aims to provide an overview of the existing and emerging therapies for the principal causes of hypertrophic heart disease, discussing the potential impact on patients' management and clinical outcome.

BACKGROUND AND AIMS:Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants. METHODS:Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC). RESULTS:Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers [mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively]. Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2-60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P = .49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P = .09). CONCLUSIONS:Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.

Journal Article The never-ending hunt for risk predictors in hypertrophic cardiomyopathy: the role of cardiac magnetic resonance tissue characterization Get access Athanasios Bakalakos, Athanasios Bakalakos Institute of Cardiovascular Science, University College London, 5 University St., London WC1E 6JF, UKBarts Heart Centre, St. Bartholomew’s Hospital, W Smithfield, London EC1A 7BE, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Perry M Elliott Perry M Elliott Institute of Cardiovascular Science, University College London, 5 University St., London WC1E 6JF, UKBarts Heart Centre, St. Bartholomew’s Hospital, W Smithfield, London EC1A 7BE, UK Corresponding author. E-mail: perry.elliott@ucl.ac.uk Search for other works by this author on: Oxford Academic PubMed Google Scholar European Heart Journal - Cardiovascular Imaging, Volume 24, Issue 7, July 2023, Pages 885–886, https://doi.org/10.1093/ehjci/jead091 Published: 08 May 2023 Article history Corrected and typeset: 08 May 2023 Published: 08 May 2023

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups—overt, either genotype-positive (G+LVH+) or genotype-negative (G−LVH+), and subclinical (G+LVH−) HCM—exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G−LVH+), 77 patients with G+LVH−, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P <0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P <0.001). Patients with G−LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle ( P <0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G− patients (100% [51/51] versus 82% [41/50]; P =0.001). Patients with G+LVH− compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P <0.001), and MVD (reduced stress myocardial blood flow [ P =0.015] with perfusion defects in 28% versus 0 healthy volunteers [ P =0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P =0.01; stress myocardial blood flow: odds ratio, 2.8, P =0.015; subclinical: fractional anisotropy odds ratio, 4.0, P =0.001; myocardial perfusion reserve odds ratio, 2.2, P =0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G− patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.

BACKGROUND:Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. METHODS:Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. RESULTS:Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. CONCLUSIONS:RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.

BACKGROUND:The diagnosis of Fabry disease (FD) has relevant implications related to the management. Thus, a clear assignment of GLA variant pathogenicity is crucial. This systematic review and meta-analysis aimed to investigate the prevalence of FD in high-risk populations and newborns and evaluate the impact of different GLA variant classifications on the estimated prevalence of FD. METHODS:We searched the EMBASE and PubMed databases on February 21, 2023. Observational studies evaluating the prevalence of FD and reporting the identified GLA variants were included. GLA variants were re-evaluated for their pathogenicity significance using the American College of Medical Genetics and Genomics criteria and the ClinVar database. The pooled prevalence of FD among different settings was calculated. The study was registered on PROSPERO (CRD42023401663) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. RESULTS:Of the 3941 studies identified, 110 met the inclusion criteria. The pooled prevalence of FD was significantly different according to the clinical setting and criteria used for the pathogenicity assessment. Using the American College of Medical Genetics and Genomics criteria, the pooled prevalence was 1.2% in patients with left ventricular hypertrophy/hypertrophic cardiomyopathy (26 studies; 10 080 patients screened), 0.3% in end-stage renal disease/chronic kidney disease (38 studies; 62 050 patients screened), 0.7% in stroke (25 studies; 15 295 patients screened), 0.7% in cardiac conduction disturbance requiring pacemaker (3 studies; 1033 patients screened), 1.0% in small-fiber neuropathy (3 studies; 904 patients screened), and 0.01% in newborns (15 studies; 11 108 793 newborns screened). The pooled prevalence was different if the GLA variants were assessed using the ClinVar database, and most patients with a discrepancy in the pathogenicity assignment carried 1 of the following variants: p.A143T, p.D313Y, and p.E66Q. CONCLUSIONS:This systematic review and meta-analysis describe the prevalence of FD among newborns and high-risk populations, highlighting the need for a periodic reassessment of the GLA variants in the context of recent clinical, biochemical, and histological data. REGISTRATION:URL: https://crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42023401663.

BACKGROUND:Malonyl-CoA decarboxylase deficiency (MLYCDD) is an ultra-rare inherited metabolic disorder, characterized by multi-organ involvement manifesting during the first few months of life. Our aim was to describe the clinical, biochemical, and genetic characteristics of patients with later-onset MLYCDD.METHODS:Clinical and biochemical characteristics of two patients aged 48 and 29 years with a confirmed molecular diagnosis of MLYCDD were examined. A systematic review of published studies describing the characteristics of cardiovascular involvement of patients with MLYCDD was performed.RESULTS:Two patients diagnosed with MLYCDD during adulthood were identified. The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction. No other clinical manifestation typical of MLYCDD was observed. Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity. During follow-up, no deterioration of LV systolic function was observed. The systematic review identified 33 individuals with a genetic diagnosis of MLYCDD (median age 6 months [IQR 1-12], 22 males [67%]). Cardiovascular involvement was observed in 64% of cases, with DCM the most common phenotype. A modified diet combined with levocarnitine supplementation resulted in the improvement of LV systolic function in most cases. After a median follow-up of 8 months, 3 patients died (two heart failure-related and one arrhythmic death).CONCLUSIONS:For the first time this study describes a later-onset phenotype of MLYCDD patients, characterized by single-organ involvement, mildly reduced enzyme activity, and a benign clinical course.