Idiopathic Left Ventricular Hypertrophy Research Articles

Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-Year Study.

Understanding the incidence, causes, and trends of sudden cardiac death (SCD) among young competitive athletes is critical to inform preventive policies. This study included National Collegiate Athletic Association athlete deaths during a 20-year time frame (July 1, 2002, through June 30, 2022). Athlete deaths were identified through 4 separate independent databases and search strategies (National Collegiate Athletic Association resolutions list, Parent Heart Watch database and media reports, National Center for Catastrophic Sports Injury Research database, and insurance claims). Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. A total of 143 SCD cases in National Collegiate Athletic Association athletes were identified from 1102 total deaths. The National Collegiate Athletic Association resolutions list identified 117 of 143 (82%), the Parent Heart Watch database or media reports identified 89 of 143 (62%), the National Center for Catastrophic Sports Injury Research database identified 63 of 143 (44%), and insurance claims identified 27 of 143 (19%) SCD cases. The overall incidence of SCD was 1:63 682 athlete-years (95% CI, 1:54 065-1:75 010). Incidence was higher in male athletes than in female athletes (1:43 348 [95% CI, 1:36 228-1:51 867] versus 1:164 504 [95% CI, 1:110 552-1:244 787] athlete-years, respectively) and Black athletes compared with White athletes (1:26 704 [1:20 417-1:34 925] versus 1:74 581 [1:60 247-1:92 326] athlete-years, respectively). The highest incidence of SCD was among Division I male basketball players (1:8188 [White, 1:5848; Black, 1:7696 athlete-years]). The incidence rate for SCD decreased over the study period (5-year incidence rate ratio, 0.71 [95% CI, 0.61-0.82]), whereas the rate of noncardiovascular deaths remained stable (5-year incidence rate ratio, 0.98 [95% CI, 0.94-1.04]). Autopsy-negative sudden unexplained death (19.5%) was the most common postmortem examination finding, followed by idiopathic left ventricular hypertrophy or possible cardiomyopathy (16.9%) and hypertrophic cardiomyopathy (12.7%), in cases with enough information for adjudication (118 of 143). Eight cases of death were attributable to myocarditis over the study period (1 case from January 1, 2020, through June 30, 2022), with none attributed to COVID-19 infection. SCD events were exertional in 50% of cases. Exertional SCD was more common among those with coronary artery anomalies (100%) and arrhythmogenic cardiomyopathy (83%). The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD.

Abstract P2049: Myosin Heavy Chain-7 E848G Mutation-induced Sarcopenia And Hypocontractility In Induced Pluripotent Stem Cell Model Of Hypertrophic Cardiomyopathy Are Rescued By Muscle Ring Finger 1 Ablation

Hypertrophic cardiomyopathy (HCM) presents with idiopathic left ventricular hypertrophy and occasionally systolic dysfunction. In a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of HCM, we previously reported the pathogenic MYH7 E848G variant increased hiPSC-CM size and impaired contractility. To elucidate the mechanisms by which the E848G variant causes HCM, we now examined cardiac tissue from a MYH7 wt/E848G patient. We found reduced expression of the following sarcomeric proteins: β-myosin heavy chain (βMHC) (97.8 ± 1.1% reduction), α-sarcomeric actinin (αSA) (84.8 ± 7.3%), and ventricular myosin light chain (MLC-1v) (45.9 ± 13.9%) relative to healthy patient tissue. Isogenic MYH7 wt/E848G hiPSC-CMs also had reduced protein expression of βMHC (22.8%) and αSA (24.5%) relative to MYH7 wt/wt hiPSC-CMs and unchanged mRNA expression. These results suggest MYH7 E848G HCM induces broad sarcomere component deficiency. We tested hiPSC-CM contractility using single cell traction force microscopy (TFM) and engineered heart tissues (EHT). Single isogenic MYH7 wt/E848G hiPSC-CMs had lower maximum twitch force (80 ± 12 nN) than MYH7 wt/wt hiPSC-CMs (150 ± 20 nN) by TFM. Isogenic MYH7 wt/E848G EHTs had lower maximum twitch force (118.9 ± 23.7 μN) than MYH7 wt/wt EHTs (287.4 ± 27.7 μN). Because MuRF1, an E3 ubiquitin-protein ligase, is known to target βMHC for proteasomal degradation, we hypothesized MuRF1 mediates the sarcopenic and hypocontractile phenotype. Genetic ablation of TRIM63 (encoding MuRF1) significantly reduced MYH7 wt/E848G hiPSC-CM cell size by flow cytometry (6.8 ± 1.7%). MYH7 wt/E848G TRIM63 -/- hiPSC-CMs increased protein expression of βMHC (154.7 ± 51.9%), αSA (44.9 ± 25.6%), and MLC-1v (246.9 ± 57.3%) relative to MYH7 wt/E848G TRIM63 +/+ hiPSC-CMs. MYH7 wt/E848G TRIM63 -/- had significantly higher maximum twitch force by TFM (133 ± 14 nN) and EHTs (178.2 ± 9.8 μN) than MYH7 wt/E848G TRIM63 +/+ by TFM (67 ± 8.0 nN) and EHTs (118.9 ± 23.7 μN). Our results implicate sarcopenia in the pathogenesis of MYH7 E848G HCM and identify MuRF1 as a potential novel therapeutic target for HCM. Further study will determine if these findings are generalizable to other pathogenic HCM variants in MYH7 and other sarcomeric genes.

Abstract P1019: High-throughput Generation And Functional Characterization Of Myosin Heavy Chain 7 Variants In Genome-edited Cardiomyocytes

Hypertrophic cardiomyopathy (HCM), an inheritable cardiac condition characterized by idiopathic left ventricular hypertrophy, can cause sudden cardiac death or heart failure. Autosomal-dominant missense mutations in MYH7 (encoding the sarcomeric βMHC protein) account for 33% of genotype-positive HCM cases. While pathogenic MYH7 variants are clinically-actionable, 75% of MYH7 missense variants in ClinVar are variants of unknown significance (VUS). Gene-editing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can help determine the function of MYH7 VUS, however, the discovery of new variants by genetic testing outpaces the ability to gene-edit hiPSCs. Thus, we developed a novel method called CR ISPR a On- T arget E diting R etrieval (CRaTER) which increases the success of gene-editing by 25-fold compared to current methods. We leveraged CRaTER to enrich for hiPSCs edited with a library of MYH7 missense variants and recovered 113 different heterozygous variants. As deleterious mutations can reduce protein stability, we flow sorted MYH7 variant hiPSC-CMs into bins based on differing βMHC abundance followed by next generation sequencing of each bin to calculate variant abundance scores. This assay identified 31 MYH7 missense variants as functionally abnormal (lower abundance scores than synonymous controls), including all known pathogenic variants in the library. This βMHC depletion phenotype was validated in clonal hiPSC-CMs and supported by western blotting of myocardium from a patient with a pathogenic MYH7 missense mutation. Furthermore, we rescued βMHC protein levels by genetically ablating the gene encoding for Muscle RING-finger protein-1, an E3 protein ligase that targets βMHC for degradation, and found that the cardiomyocyte hypertrophy induced by the pathogenic MYH7 E848G HCM variant was significantly blunted. In summary, CRaTER enables the generation of gene-edited hiPSC lines at unprecedented scale. Functional analysis of MYH7 variant hiPSC-CMs reveals a novel correlation between loss of βMHC protein and clinical pathogenicity that can be leveraged for clinical variant interpretation. Interventions that prevent the loss of βMHC may potentially be therapeutic for MYH7 -associated HCM.

Difficulties in Diagnosing Fabry Disease in Patients with Unexplained Left Ventricular Hypertrophy (LVH): Is the Novel GLA Gene Mutation a Pathogenic Mutation or Polymorphism?

Fabry disease (FD) is an X-linked, lysosomal glycosphingolipid storage disorder that occurs very rarely. Cardiac involvement may comprise of left ventricular hypertrophy (LVH), arrhythmias, conduction abnormalities, heart failure and valvular abnormalities. The goal of this study was to conduct gene analysis for FD in patients suffering from unexplained LVH. 120 patients over the age of 30 who were diagnosed by echocardiography with idiopathic LVH were included in the study. Patients with severe hypertension, intermediate valve disease such as moderate aortic stenosis, known FD, and a family history of autosomal dominant hypertrophic cardiomyopathy were excluded from the study. GLA gene mutations were studied by Sanger sequence analysis in all patients. Of the 120 total patients included in this study, 69 were female (58%) and 51 were male (42%). The mean age was 60.3 ± 15.7. GLA gene mutations were detected in three male patients. The detected mutations are as follows: NM_000169.2:IVS6-10G>A (c.1000-10G>A), NM_000169.2:c.937G>T (p.D313Y) (p.Asp313Tyr) and NM_000169.2:c.941A>T (p.K314M) (p.Lys314Met). Early diagnosis is of vital importance in FD, which can be treated with enzyme replacement. Genetic screening in patients diagnosed with idiopathic LVH by echocardiography is important in the early diagnosis and treatment of FD. Patients over 30 years of age with idiopathic LVH should be screened for FD. Various new polymorphisms can be detected in genetic screening. Identifying new polymorphisms is important for knowing the true mutations in FD.

Sudden Cardiac Death Among Adolescents in the United Kingdom

BackgroundCauses and precipitating factors of sudden cardiac death (SCD) in adolescents are poorly understood. ObjectivesThe authors sought to investigate the etiologies of SCD and their association with physical activity in a large cohort of adolescents. MethodsBetween 1994 and June 2022, 7,675 cases of SCD were consecutively referred to our national cardiac pathology center; 756 (10%) were adolescents. All cases underwent detailed autopsy evaluation by expert cardiac pathologists. Clinical information was obtained from referring coroners. ResultsA structurally normal heart, indicative of sudden arrhythmic death syndrome was the most common autopsy finding (n = 474; 63%). Myocardial diseases were detected in 163 cases (22%), including arrhythmogenic cardiomyopathy (n = 36; 5%), hypertrophic cardiomyopathy (n = 31; 4%), idiopathic left ventricular hypertrophy (n = 31; 4%), and myocarditis (n = 30; 4%). Coronary artery anomalies were identified in 17 cases (2%). Decedents were competitive athletes in 128 cases (17%), and 159 decedents (21%) died during exercise. Arrhythmogenic cardiomyopathy was diagnosed in 8% of athletes compared with 4% of nonathletes (P = 0.05); coronary artery anomalies were significantly more common in athletes (9% vs 1%; P < 0.001), as well as commotio cordis (5% compared with 1% in nonathletes; P = 0.001). The 3 main comorbidities were asthma (n = 58; 8%), epilepsy (n = 44; 6%), and obesity (n = 40; 5%). ConclusionsSudden arrhythmic death syndrome and myocardial diseases are the most common conditions diagnosed at autopsy in adolescent victims of SCD. Among causes of SCD, arrhythmogenic cardiomyopathy, coronary artery anomalies, and commotio cordis are more common in young athletes than in similar age sedentary individuals.

Mitral valve abnormalities in decedents of sudden cardiac death due to hypertrophic cardiomyopathy and idiopathic left ventricular hypertrophy

Abstract Background The sole identification of left ventricular hypertrophy (LVH) in a young individual that died suddenly may often lead to an erroneous diagnosis of hypertrophic cardiomyopathy (HCM). Emerging data suggests that idiopathic LVH (ILVH) and HCM may be separate entities. Aim We aimed to report on the prevalence and nature of mitral valve (MV) abnormalities, in a cohort of sudden cardiac death (SCD) victims with a post-mortem examination consistent with HCM and ILVH. Methods We reviewed 6860 consecutive cases of SCD referred to our specialist cardiac pathology centre between 1994 and 2020. SCD was defined as death from a cardiovascular cause within 12 hours of apparent well-being. HCM was defined by the presence of LVH, in the absence of abnormal loading conditions and characterised by myocyte disarray at histology. ILVH was defined as unexplained LVH (heart weight &amp;gt;500 g in males and &amp;gt;400 g in females) and left ventricular (LV) wall thickness &amp;gt;15mm, in the absence of myocardial disarray or secondary causes of LVH. The MV was examined for patency, circumference, thickening, nodularity, ballooning, bulging between cords, perforation, and the presence of impact lesions in the LV outflow tract (LVOT) and aortic outlet. Results Of the total cases of SCD, 264 (4%) were due to HCM (mean age 41±18 years, 78% males, LV maximal wall thickness 19±6 mm) (Figure 1). Ante-mortem symptoms were reported in 44 (17%) cases and for the majority (n=217, 82%) HCM was established at post-mortem. Death was attributed to ILVH in 253 (3%) cases (mean age 43±16 years, 80% males, LV maximal wall thickness 18±4 mm). MV abnormalities were found in 58 (22%) decedents with HCM (mean age 38±17 years; 72% males) and in 13 (5%) decedents with ILVH (mean age 55±15 years; 77% male), p&amp;lt;0.001. Amongst the 58 (22%) cases with HCM and MV abnormalities, 15 (6%) cases had multiple MV abnormalities. These included impact lesions associated with thickening of the anterior leaflet of the MV (n=39) and degenerative changes (n=34) such as bulging and ballooning; and thickening and nodularity. Decedents with HCM exhibiting MV abnormalities were younger than decedents with a normal MV (38±17 versus 45±19 years; p=0.08). Among the 253 decedents with ILVH, 13 (5%) cases exhibited MV abnormalities, which largely included degenerative changes (n=12). Among decedents with HCM and ILVH exhibiting MV abnormalities, the former was significantly younger (38±17 versus 55±15; p=0.001). Myocardial fibrosis was observed in 162 (61%) cases of HCM and 99 (39%) cases of ILVH, p&amp;lt;0.001. Conclusions MV abnormalities are over four-fold more common in individuals with HCM than those with ILVH and may be considered as additional macroscopic features to differentiate between these two entities. Furthermore, the inherent descriptive terminologies used when assessing the MV, support a greater emphasis on the standardisation and quantification of MV abnormalities as part of the autopsy in victims of SCD. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Acknowledgements: We thank the charitable organisation, Cardiac Risk in the Young (CRY) who fund and support the CRY Cardiovascular Pathology Unit and CRY database.

Mitral valve abnormalities in decedents of sudden cardiac death due to hypertrophic cardiomyopathy and idiopathic left ventricular hypertrophy.

Mitral valve abnormalities in decedents of sudden cardiac death due to hypertrophic cardiomyopathy and idiopathic left ventricular hypertrophy.

A new inherited syndrome causing sudden cardiac death with specific ECG changes and idiopathic left ventricular hypertrophy

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Sudden cardiac death (SCD) is a serious threat. In individuals under the age of 35 years sudden arrhythmic death is the most frequent cause. In younger persons, genetically determined cardiac diseases (e.g., cardiomyopathies, ion-channel diseases) account for an important proportion of these cases. Purpose We discovered a unusual combination of ECG changes and left ventricular hypertrophy that lead to a cumulation of sudden cardiac death in a single family. We therefore did a scientific work-up of this finding. Methods We investigated the case of a 23 year-old male with SCD, specific ECG changes and left ventricular hypertrophy (Figure 1). Family history was significant for SCD in the paternal line. A precise analysis was performed by an international multidisciplinary expert panel including autopsy of the index patient’s heart, molecular autopsy, whole exome sequencing, analysis of the pedigree and examination of available family members (Figure 2). Results Three cases of SCD were reported in paternal relatives. The index patient exhibited specific ECG changes (ST-depression), which were also found in five paternal relatives and the brother of the index Patient (Figure 3). Post-mortem analysis of the heart yielded mild idiopathic concentric hypertrophy without myocardial disarray. The genetic analysis of the index patient showed two nucleotide variations in two different genes (ANK2: c.11791G &amp;gt; A , MYO18B: c.3761G &amp;gt; A), which were also expressed in five relatives. Two family members had showed all indicators of the inherited syndrome including specific ECG changes, genetic changes and left ventricular hypertrophy. Conclusions We described a distinct inheritable syndrome causing SCD, characterized by specific ECG changes, idiopathic left ventricular hypertrophy and mutations of ANK2 and MYO18. As far as we know this is the first description of this syndrom. We hypothesize that if all features (ECG-changes, described genetic mutations, left ventricular hypertrophy) are positive, the risk for SCD may be considerably increased. Abstract Figure. ECG of index patient and pedigree

Causes of sudden cardiac death in young athletes and nonathletes: systematic review and meta-analysis

Abstract Funding Acknowledgements Type of funding sources: None. Introduction. The etiology of sudden cardiac death (SCD) in young people is still debated. The aim of this meta-analysis was to identify the most frequent causes of SCD in individuals aged ≤35 years, the differences between athletes and nonathletes and among geographic areas. Methods. Studies published between 01/01/1990 and 01/31/2020 and evaluating post-mortem the etiology of SCD in young individuals (≤35 years) were included. Individuals were divided in athletes and nonathletes. Studies that did not report separately data between athletes and nonathletes were excluded. Results. Thirty-four studies met the inclusion criteria and a total population of 5,060 victims of SCD were analysed (2,890 athletes, 2,170 nonathletes). Structurally normal heart, hypertrophic cardiomyopathy (HCM), idiopathic left ventricular hypertrophy, and anomalous origin of coronary arteries (AOCA) were the most frequent causes of SCD in athletes while coronary artery disease (CAD), arrhythmogenic cardiomyopathy (ACM), and channelopathies were frequent causes of SCD in nonathletes. The number of SCDs due to ischemic heart disease (19.6% vs. 9.1%, p = 0.009), ACM (11.5% vs. 4.7%, p = 0.03) and channelopathies (8.4% vs. 1.9%, p = 0.02) was higher in nonathletes comparing with athletes. SCD due to non-ischemic left ventricular scar (5.1% vs. 1.1%, p = 0.01) was more frequent in athletes. HCM (p = 0.01) and AOCA (p = 0.004) were more frequently cause of SCD in US while ACM (p = 0.001), structurally normal heart (p = 0.02), and channelopathies (p = 0.02) in Europe. Conclusions. Structurally normal heart, HCM, AOCA were frequent causes of SCD in athletes while CAD, ACM and channelopathies in nonathletes. The causes of SCD differ between US and Europe.

Diagnostic Yield of Genetic Testing in Sudden Cardiac Death with Autopsy Findings of Uncertain Significance.

Background: Sudden death (SD) in the young usually has an underlying genetic cause. In many cases, autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy (LVH), nonsignificant coronary atherosclerosis (CA), and primary myocardial fibrosis (PMF). Their pathogenicity and their relation to SD cause is unknown. This study aims to evaluate the diagnostic yield of genetic testing in these cases. Methods: SD cases, between 1 and 50 years old, with findings of uncertain significance (idiopathic LVH, nonsignificant CA and PMF) on autopsy were evaluated prospectively, including information about medical and family history and circumstances of death. Genetic testing was performed. Results: In a series of 195 SD cases, we selected 31 cases presenting idiopathic LVH (n = 16, 51.61%), nonsignificant CA (n = 17, 54.84%), and/or PMF (n = 24, 77.42%) in the autopsy. Mean age was 41 ± 7.2 years. Diagnostic yield of genetic test was 67.74%, considering variants of unknown significance (VUS), pathogenic variants (PV) and likely pathogenic variants (LPV); 6.45% including only PV and LPV. Structural genes represented 41,93% (n = 13) of cases, while 38,7% (n = 12) were related to channelopathies. Conclusion: Molecular autopsy in SD cases between 1 and 50 years old, with findings of uncertain significance, has a low diagnostic yield, being VUS the most frequent variant observed.

Update on the Diagnostic Pitfalls of Autopsy and Post-Mortem Genetic Testing in Cardiomyopathies.

Inherited cardiomyopathies are frequent causes of sudden cardiac death (SCD), especially in young patients. Despite at the autopsy they usually have distinctive microscopic and/or macroscopic diagnostic features, their phenotypes may be mild or ambiguous, possibly leading to misdiagnoses or missed diagnoses. In this review, the main differential diagnoses of hypertrophic cardiomyopathy (e.g., athlete’s heart, idiopathic left ventricular hypertrophy), arrhythmogenic cardiomyopathy (e.g., adipositas cordis, myocarditis) and dilated cardiomyopathy (e.g., acquired forms of dilated cardiomyopathy, left ventricular noncompaction) are discussed. Moreover, the diagnostic issues in SCD victims affected by phenotype-negative hypertrophic cardiomyopathy and the relationship between myocardial bridging and hypertrophic cardiomyopathy are analyzed. Finally, the applications/limits of virtopsy and post-mortem genetic testing in this field are discussed, with particular attention to the issues related to the assessment of the significance of the genetic variants.

Aetiology and incidence of sudden cardiac arrest and death in young competitive athletes in the USA: a 4-year prospective study

ObjectiveTo investigate the aetiology and incidence of sudden cardiac arrest and death (SCA/D) in US competitive athletes.MethodsProspective surveillance was conducted from 1 July 2014 to 30 June 2018 through the...

Sudden cardiac death in persons aged 50 years or younger: diagnostic yield of a regional molecular autopsy program using massive sequencing

Introduction and objectivesSudden cardiac death (SCD) in young people often has a genetic cause. Consequently, the results of “molecular autopsy” may have important implications for their relatives. Our objective was to evaluate the diagnostic yield of a molecular autopsy program using next-generation sequencing. MethodsWe performed a prospective study of a cohort of consecutive patients who died from nonviolent SCD, aged ≤ 50 years, and who underwent molecular autopsy using large panels of next-generation sequencing, with subsequent clinical and genetic family screening. We analyzed demographic, clinical, toxicological, and genetic data. ResultsWe studied 123 consecutive cases of SCD in persons aged ≤ 50 years. The incidence of SCD was 5.8 cases/100 000 individuals/y, mean age was 36.15±12.7 years, and 95 were men (77%). The cause was cardiac in 53%, unexplained SCD in 24%, toxic in 10.6%, and infant SCD in 4%. Among cardiac causes, ischemic heart disease accounted for 38% of deaths, arrhythmogenic cardiomyopathy for 7%, hypertrophic cardiomyopathy for 5%, and idiopathic left ventricular hypertrophy for 11%. Genetic analysis was performed in 62 cases (50.4%). Genetic variants were found in 42 cases (67.7%), with a mean of 3.4±4 genetic variants/patient, and the variant found was considered to be pathogenic or probably pathogenic in 30.6%. In unexplained SCD, 70% showed some genetic variant. Family screening diagnosed 21 carriers or affected individuals, 5 of whom were at risk, indicating an implantable cardiac defibrillator. ConclusionsProtocol-based and exhaustive study of SCD from cardiac causes in persons aged ≤ 50 years is feasible and necessary. In a high percentage of cases, the cause is genetic, indicating the existence of relatives at risk who could benefit from early diagnosis and treatment to avoid complications.

Muerte súbita de jóvenes: rendimiento diagnóstico de un programa autonómico de autopsia molecular con secuenciación masiva

Introduction and objectivesSudden cardiac death (SCD) in young people often has a genetic cause. Consequently, the results of “molecular autopsy” may have important implications for their relatives. Our objective was to evaluate the diagnostic yield of a molecular autopsy program using next-generation sequencing. MethodsWe performed a prospective study of a cohort of consecutive patients who died from nonviolent SCD, aged ≤ 50 years, and who underwent molecular autopsy using large panels of next-generation sequencing, with subsequent clinical and genetic family screening. We analyzed demographic, clinical, toxicological, and genetic data. ResultsWe studied 123 consecutive cases of SCD in persons aged ≤ 50 years. The incidence of SCD was 5.8 cases/100 000 individuals/y, mean age was 36.15±12.7 years, and 95 were men (77%). The cause was cardiac in 53%, unexplained SCD in 24%, toxic in 10.6%, and infant SCD in 4%. Among cardiac causes, ischemic heart disease accounted for 38% of deaths, arrhythmogenic cardiomyopathy for 7%, hypertrophic cardiomyopathy for 5%, and idiopathic left ventricular hypertrophy for 11%. Genetic analysis was performed in 62 cases (50.4%). Genetic variants were found in 42 cases (67.7%), with a mean of 3.4±4 genetic variants/patient, and the variant found was considered to be pathogenic or probably pathogenic in 30.6%. In unexplained SCD, 70% showed some genetic variant. Family screening diagnosed 21 carriers or affected individuals, 5 of whom were at risk, indicating an implantable cardiac defibrillator. ConclusionsProtocol-based and exhaustive study of SCD from cardiac causes in persons aged ≤ 50 years is feasible and necessary. In a high percentage of cases, the cause is genetic, indicating the existence of relatives at risk who could benefit from early diagnosis and treatment to avoid complications.Full English text available from: www.revespcardiol.org/en

Diagnostic yield of hypertrophic cardiomyopathy in first-degree relatives of decedents with idiopathic left ventricular hypertrophy.

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. 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. 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.

The Prevalence of Fabry Disease Among Turkish Patients with Non-Obstructive Hypertrophic Cardiomyopathy: Insights from a Screening Study

Aims:Fabry disease is an X-linked lysosomal storage disorder due to a deficiency of the α-galactosidase A enzyme. Cardiac involvement is present in over 60% of adult cases of Fabry disease. Hypertrophic cardiomyopathy without left ventricular outflow tract obstruction is the most common phenotype. The aim of the study was to screen adult patients with hypertrophic cardiomyopathy without left ventricular outflow tract.Methods:A total of 80 patients between the ages of 18 and 65 years old, were referred to a tertiary center for trans-thoracic echocardiography for various clinical indications. They were investigated for the presence of idiopathic left ventricular hypertrophy without resting or dynamic left ventricular outflow tract obstruction. Plasma α-galactosidase A enzyme activity and α-galactosidase GLA gene mutations were investigated.Results:The mean age was 41.5±12.7 years and 66.25% of patients were males. The mean echocardiographic parameters were as follows: left ventricular ejection fraction 60.7±7.4%, interventricular septum thickness 18.2±4.4 mm, left ventricular posterior wall 13.5±2.1 mm, left ventricular end-diastolic diameter 47.4±6.2 mm, left ventricular end-systolic diameter 27.8±6.5 mm, and left ventricular mass index 171.05±48.5 g/m². Hemizygous mutations associated with Fabry disease were detected in two male patients (2.50% of the screened population): NM_000169.2:c.334C>T(p.Arg112Cys), NM_000169.2:c.902G>A(p.Arg301Gln).Conclusion:Fabry disease should be considered in the differential diagnosis in a highly selected patient population with unexplained left ventricular hypertrophy. The cardiologist may play an important role in the screening and diagnosis of the disease.

Sports-related sudden cardiac death due to myocardial diseases on a population from 1–35 years: a multicentre forensic study in Spain

This is a multicentre forensic study that identifies all sports-related sudden deaths (SRSDs) in young people, due to myocardial diseases (MDs) that occurred in a large area of Spain. The aim of the study is to assess the epidemiology, causes of death, and sport activities associated with these fatalities. This is a retrospective study based on forensic autopsies performed in the provinces of Biscay, Seville, Valencia and in the jurisdiction covered by the National Institute of Toxicology and Forensic Sciences in Madrid (Spain). The retrospective study encompasses from 2010 to 2017. All sudden cardiac deaths (SCDs) in persons 1–35 years old were selected. The total number of SCDs were divided into death occurred during exercise (SRSD) and death during rest, sleep or normal activities (non-SRSD). Each of these two groups was subdivided according to the cause of death into MD (primary cardiomyopathies and myocarditis) and non-MD. Clinic-pathological, toxicological and genetic characteristics of SRSD due to MD were analysed. Over the 8-year study period, we identified 645 cases of SCD in the young: 75 SRSD (11.6%) and 570 non-SRSD (88.4%). MD was diagnosed in 33 (44.0%) of the SRSD and in 112 (19.6%) of the non-SRSD cases. All cases of SRSD due to MD were males (mean age (24.0 ± 7.6) years) practicing recreational sports (85%). SRSDs were more frequent in arrhythmogenic cardiomyopathy (ACM) (37%) and hypertrophic cardiomyopathy (HCM) (24%), followed by myocarditis (15%) and idiopathic left ventricular hypertrophy (ILVH) (9%). Only in five cases of SRSD the MD responsible of death (HCM) had been diagnosed in life. Cardiovascular symptoms related to the disease were present in other seven patients (six of them with ACM). Postmortem genetic studies were performed in 15/28 (54%) primary cardiomyopathies with positive results in 12 (80%) cases. The most frequent sports disciplines were football (49%) followed by gymnastics (15%) and running (12%). In Spain, SRSD in young people due to MDs occurs in males who perform a recreational activity. Compared with control group we observed a strong association between MDs and exertion. One in three SRSDs are due to cardiomyopathy, especially ACM, which reinforces the need for preparticipation screening to detect these pathologies in recreational sport athletes. Further studies are warranted to understand the causes and circumstances of sudden death to facilitate the development of preventive strategies.

Ratio of Fabry disease in patients with idiopathic left ventricular hypertrophy: A single-center study in Turkey.

Objective:Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism which arises due to deficient or absent activity of lysosomal α-galactosidase A (α-Gal A). This may be associated with increased left ventricular (LV) wall thickness and may mimic the morphological features of hypertrophic cardiomyopathy. The purpose of this study was to define the ratio of occurrence of FD to the manifestation of unexplained left ventricular hypertrophy (LVH).Methods:We studied a prospectively assembled a consecutive cohort of 190 patients with unexplained LVH on echocardiography. The criterion for LVH diagnosis was a maximum LV wall thickness of 13 mm or greater. All patients were tested for mutations in the GLA gene.Results:The majority of patients were male (n=119, 63%) and the mean patient age was 47.2±15 years. In 190 patients diagnosed with LVH, we identified 2 patients (1.05%) with documented GLA mutations [c.427G>A (p.A143T)(p.Ala143Thr)] and [c.937G>T (p.D313Y)(p.Asp313Tyr)]. After the family screening, 3 additional patients with FD were identified in 2 families, including 5 individuals who are now receiving enzyme replacement therapy.Conclusion:We identified 2 index patients with FD and unexplained LVH. Cardiologists should, therefore, be aware of FD in cases of unexplained LVH. Family screening is crucial for the earlier identification of unaffected new patients who may benefit from enzyme replacement therapy.

Incidence and Etiology of Sudden Cardiac Arrest and Death in High School Athletes in the United States

ObjectiveTo determine the incidence and etiology of sudden cardiac arrest and death (SCA/D) in US high school athletes. Patients and MethodsA prospective media database of SCA/D was queried for cases aged 14 to 18 years from 7 states over 6 school years (September 1, 2007, to August 30, 2013). Event details were investigated to determine participation on a high school athletic team, sex, sport, and occurrence during school-sponsored activity or exertion. National sports participation numbers were used and a conversion factor was applied to account for multisport athletes. Autopsy reports were reviewed and cause of death was adjudicated by an expert panel. ResultsA total of 16,390,409 million athlete-seasons representing 6,974,640 athlete-years (AY) were examined, encompassing 36% of the total US high school athlete population. A total of 104 cases of SCA/D were identified (35 SCA with survival and 69 sudden cardiac deaths [SCDs]). The rate of SCD was 1:101,082 AY and of SCA/D 1:67,064 AY. Eighty-eight percent (92) of events occurred in male athletes. The rate of SCA/D in male athletes was 1:44,832 AY and in female athletes 1:237,510 AY (incidence rate ratio, 5.3; 95% CI, 2.9-10.6; P<.001). Men's basketball was the highest risk sport with an SCA/D incidence of 1:37,087 AY followed by men's football at 1:86,494 AY. Men's basketball and football athletes accounted for 57% (39) of deaths. Eighty percent of SCDs (55 of 69) were exertional and 55% (38 of 69) occurred while playing for a school-sponsored team. Autopsy reports were obtained in 73% (50) of cases. The most common findings of autopsy were idiopathic left ventricular hypertrophy or possible cardiomyopathy (13 of 50 [26%]), autopsy-negative sudden unexplained death (9 of 50 [18%]), hypertrophic cardiomyopathy (7 of 50 [14%]), and myocarditis (7 of 50 [14%]). ConclusionThe rate of SCA/D in male high school athletes was 1:44,832 AY, with almost half due to possible or confirmed cardiomyopathy disease. It is likely that many cases were not identified because of reliance on media reports, and these numbers represent a minimum estimate.

Etiology of Sudden Death in Sports: Insights From a United Kingdom Regional Registry

BackgroundAccurate knowledge of causes of sudden cardiac death (SCD) in athletes and its precipitating factors is necessary to establish preventative strategies. ObjectivesThis study investigated causes of SCD and their association with intensive physical activity in a large cohort of athletes. MethodsBetween 1994 and 2014, 357 consecutive cases of athletes who died suddenly (mean 29 ± 11 years of age, 92% males, 76% Caucasian, 69% competitive) were referred to our cardiac pathology center. All subjects underwent detailed post-mortem evaluation, including histological analysis by an expert cardiac pathologist. Clinical information was obtained from referring coroners. ResultsSudden arrhythmic death syndrome (SADS) was the most prevalent cause of death (n = 149 [42%]). Myocardial disease was detected in 40% of cases, including idiopathic left ventricular hypertrophy (LVH) and/or fibrosis (n = 59, 16%); arrhythmogenic right ventricular cardiomyopathy (ARVC) (13%); and hypertrophic cardiomyopathy (HCM) (6%). Coronary artery anomalies occurred in 5% of cases. SADS and coronary artery anomalies affected predominantly young athletes (≤ 35 years of age), whereas myocardial disease was more common in older individuals. SCD during intense exertion occurred in 61% of cases; ARVC and left ventricular fibrosis most strongly predicted SCD during exertion. ConclusionsConditions predisposing to SCD in sports demonstrate a significant age predilection. The strong association of ARVC and left ventricular fibrosis with exercise-induced SCD reinforces the need for early detection and abstinence from intense exercise. However, almost 40% of athletes die at rest, highlighting the need for complementary preventive strategies.