Natural History of MYH7-Related Dilated Cardiomyopathy

BACKGROUND Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVES We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 +/- 19.2 years) recruited from 29 international centers. RESULTS At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% +/- 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of <= 35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation

Correlación fenotipo/genotipo en la miocardiopatía hipertrófica y miocardiopatía no compactada

Las miocardiopatías se definen como enfermedades específicas del músculo cardiaco. Son patologías cardiacas relativamente frecuentes, y suponen una importante causa de mortalidad y morbilidad a nivel global. La miocardiopatía hipertrófica (MCH), una de las miocardiopatías más estudiadas y conocidas, es la enfermedad cardíaca hereditaria más frecuente, afectando a 1 de cada 500 personas. Aunque el estudio genético se recomienda para el cribado familiar, la falta de datos robustos sobre asociaciones genotipo-fenotipo específicas ha reducido su impacto en el manejo clínico más allá del cribado familiar. La nueva variante truncante descrita en nuestra región MYBPC3, p.Gly263*, resulta útil para profundizar en el estudio de posibles asociaciones genotipo-fenotipo. Por otro lado miocardiopatía no compactada (LVNC) es probablemente la miocardiopatía más controvertida, con más lagunas de conocimiento. Asimismo, existen pocos datos sobre el análisis histopatológico en corazones con miocardiopatía no compactada. Existen diferentes clasificaciones que pretenden ayudar a distinguir unas miocardiopatías de otras. Pero, desafortunadamente muchas veces resultan más un factor de confusión que una ayuda en la clasificación. Con estos antecedentes nos propusimos el objetivo de intentar contribuir a establecer correlaciones genotipo-fenotipo, en base al estudio de todos los portadores de variante MYBPC3 p.Gly263*y su comparación con otras variantes truncantes en el mismo gen. Para ello se realizó estudio genético y clínico de una cohorte de casos índice con MCH y de todos los familiares disponibles portadores de la variante MYBPC3 p.Gly263*. Además, nos propusimos intentar contribuir a ampliar el conocimiento sobre la miocardiopatía no compactada, mediante el estudio clínico y genético de una cohorte de pacientes con fenotipo de miocardiopatía no compactada diagnosticados por resonancia cardiaca o anatomía patológica. El estudio genético se realizó mediante técnicas de secuenciación masiva de nueva generación, con paneles diseñados para la MCH y LNVN respectivamente. Y, con estos datos, el objetivo global de aportar una visión integradora de las miocardiopatías a partir de aspectos genéticos comunes y diferenciales. El estudio de todos los portadores de la variante patogénica MYBPC3 p.Gly263*, nos permitió comprobar que al igual que el resto de variantes fundadoras truncantes descritas en este gen, los portadores presentaban un curso clínico relativamente benigno con una presentación tardía (con potenciales complicaciones tardías, pero en general más allá de la edad reproductiva). Se constató la alta penetrancia de la MCH en los portadores de variantes truncantes en MYBPC3 y la resonancia cardiaca resultó una herramienta útil en el cribado clínico familiar. Por otro lado, se profundizó sobre las controversias de la LVNC y se comprobó la existencia de solapamiento fenotípico y genotípico con otras miocardiopatías como la miocardiopatía hipertrófica y dilatada. Se describieron las características fenotípicas y genotípicas de la cohorte de LVNC, en la que se evidenció la importancia del estudio genético, tanto para el estudio familiar como para la posible distinción entre posibles fenocopias. Se encontraron características histopatológicas interés como la hipertrofia de los miocitos y la marcada alteración morfológica nuclear. Se concluye que las clasificaciones existentes de miocardiopatías presentan nomenclaturas confusas que dificultan la distinción entre alteraciones morfológicas idénticas con distintas etiologías. Una clasificación que anteponga la división entre cardiopatías hereditarias o no-hereditarias a los criterios morfológicos facilitaría el manejo clínico de todas las miocardiopatías

Observed and Expected Survival in Men and Women after Suffering a STEMI

Introduction: Mortality caused by ST elevation myocardial infarction (STEMI) has declined because of greater use of primary percutaneous coronary intervention (PCI). It is unknown if patients &gt;75 have similar survival as peers. We aim to know it stratifying by sex and assessing how the sex may impact the survival. Methods: We retrospectively selected all patients &gt;75 who suffered a STEMI treated with primary PCI at our institution. We compared their survival with that of the reference population (general population matched by age, sex, and geographical region). A Cox-regression analysis controlling for clinical factors was performed to know if sex was a risk factor. Results: Total of 450 patients were studied. Survival at 1, 3, and 5 years of follow-up for patients who survived the first 30 days was 91.22% (CI95% 87.80&ndash;93.72), 79.71% (CI95% 74.58&ndash;83.92), and 68.02% (CI95% 60.66&ndash;74.3), whereas in the reference population it was 93.11%, 79.10%, and 65.01%, respectively. Sex was not a risk factor, Hazard Ratio = 1.02 (CI95% 0.67-1.53; p = 0.92). Conclusions: Life expectancy of patients suffering a STEMI is nowadays intimately linked to survival in the first 30 days. After one year, the risk of death for both men and women seems similar to that of the general population

Opportunistic Genetic Screening for Familial Hypercholesterolemia in Heart Transplant Patients

Heart transplantation remains the gold standard for the treatment of advanced heart failure (HF). Identification of the etiology of HF is mandatory, as the specific pathology can determine subsequent treatment. Early identification of familial hypercholesterolemia (FH), the most common genetic disorder associated with premature cardiovascular disease, has a potential important impact on clinical management and public health. We evaluated the genetic information in the genes associated with FH in a cohort of 140 heart-transplanted patients. All patients underwent NGS genetic testing including LDLR, APOB, and PCSK9. We identified four carriers of rare pathogenic variants in LDLR and APOB. Although all four identified carriers had dyslipidemia, only the one carrying the pathogenic variant LDLR c.676T&gt;C was transplanted due to CAD. Another patient with heart valvular disease was carrier of the controversial LDLR c.2096C&gt;T. Two additional patients with non-ischemic dilated cardiomyopathy were carriers of variants in APOB (c.4672A&gt;G and c.5600G&gt;A). In our cohort, we identified the genetic cause of FH in patients that otherwise would not have been diagnosed. Opportunistic genetic testing for FH provides important information to perform personalized medicine and risk stratification not only for patients but also for relatives at concealed high cardiovascular risk. Including the LDLR gene in standard NGS cardiovascular diagnostics panels should be considered

Different Phenotypes in Monozygotic Twins, Carriers of the Same Pathogenic Variant for Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a monogenic disease with autosomal dominant inheritance. Genotype&ndash;phenotype relationships are complex, with variable penetrance even within the same family. The involvement of other modulating genetic and environmental factors is unknown. We aimed to analyze the HCM in monozygotic twins, carriers of the same founder pathogenic variant MYBPC3 p.G263*. The relationship was verified using the PowerPlex 16 HS System kit. Phenotypic differences and environmental differences (overloading conditions, coexistence and location, lifestyle, sport, and intensity) were analyzed. Three pairs of twins genetically identical for all markers and carriers of MYBPC3 G263* were identified. No environmental differences were identified. One of the 89-year-old twins had symptomatic severe obstructive HCM that required septal ablation, while her twin has remained asymptomatic with mild phenotype &gt;80 years. A 49-year-old twin had a severe phenotype of obstructive HCM and pending myectomy, while his twin had a mild asymptomatic phenotype. In the last pair of twins, one presented a much larger left ventricular hypertrophy than his identical twin. In summary, we present three pairs of HCM twin patients sharing not only the genetic cause of the inherited disease but the entire genetic background. Despite identical genetic information and the absence of other known clinical, environmental, or lifestyle differences, the severity of the HCM phenotype is strikingly different. These unexplained differences should prompt the study of other unknown modulating factors, either epigenetic or environmental