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BACKGROUND: In a population under 45 years of age, the predominant causes of sudden cardiac death (SCD) are inherited cardiac diseases. Determining the underlying cause may help identify relatives at risk and prevent further events but is more difficult if an autopsy has not been performed. AIMS: We aimed to assess the diagnostic value of clinical and genetic screening in relatives of young non-autopsied sudden unexplained death (SUD) victims. MATERIAL AND METHODS: Eighty-seven relatives of 65 young non-autopsied SUD victims from 39 families were evaluated from 2016 to 2019. The relatives underwent extensive noninvasive cardiac workup. Genetic examinations were performed in 39 families. RESULTS: The definite diagnoses were made in 17 of 39 (44%) families. Cardiomyopathies were identified in 10 families (5 hypertrophic, 4 dilated, and 1 arrhythmogenic), followed by long QT syndrome (5 families). In 3 families, probable diagnoses were made, whereas in 20 families no diagnosis was achieved. In total, definite and probable diagnoses were made in 18 and 5 patients, respectively. All affected relatives were offered medical management, one of them died of heart failure and one underwent transplantation during the median follow-up of 3 years. Disease-causing variants were found in 7 of 39 (18%) probands; all in families with a definite diagnosis. Variants of unknown significance were found in 2 probands. CONCLUSION: Screening of relatives of SUD victims is warranted and may save lives, even if it is not guided by autopsy results. Genetic testing in families without the disease phenotype has little effectiveness.
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Muerte Súbita Cardíaca , Pruebas Genéticas , Humanos , Femenino , Masculino , Muerte Súbita Cardíaca/etiología , Adulto , Adulto Joven , Adolescente , Persona de Mediana Edad , Niño , Predisposición Genética a la Enfermedad , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnósticoRESUMEN
BACKGROUND: The identification of pathogenic variant in patients with thoracic aortic aneurysms and dissections (TAAD) was previously found to be a significant indicator pointing to earlier need for surgical intervention. In order to evaluate available methods for classifying identified genetic variants we have compared the event-free survival in a cohort of TAAD patients classified as genotype-positive versus genotype-negative by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) criteria or by ClinVar database. METHODS: We analyzed previously unreported cohort of 132 patients tested in the routine clinical setting for genetic variants in a custom panel of 30 genes associated with TAAD or the TruSight Cardio commercial panel of 174 genes associated with cardiac disease. The identified variants were classified using VarSome platform. Kaplan-Meier survival curves were constructed to compare the event-free survival between probands defined as 'genotype-positive' and 'genotype-negative' using different classifications in order to compare their performance. RESULTS: Out of 107 rare variants found, 12 were classified as pathogenic/likely pathogenic by ClinVar, 38 were predicted to be pathogenic/likely pathogenic by ACMG. Variant pathogenicity as assessed by ACMG criteria was a strong predictor of event free survival (event free survival at 50 years 83% vs. 50%, for genotype positive patients vs. reference, respectively, p = 0.00096). The performance of ACMG criteria was similar to that of ClinVar (event free survival at 50 years 87% vs. 50%, for genotype positive patients vs. reference, respectively p = 0.023) but independent from it as shown by analysing variants with no ClinVar record (event free survival at 50 years 80% vs. 50%, p = 0.0039). Variants classified as VUS by ACMG criteria or ClinVar did not affect event-free survival. TAAD specific custom gene panel performed similar to the larger universal cardiac panel. CONCLUSIONS: In our cohort of unrelated TAAD patients ACMG classification tool available at VarSome was useful in assessing pathogenicity of novel genetic variants. Gene panel containing the established genes associated with the highest risk of hereditary TAAD (ACTA1, COL3A1, FBN1, MYH11, SMAD3, TGFB2, TGFBR1, TGFBR2, MYLK) was sufficient to identify prevailing majority of variants most likely to be causative of the disease.
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Aneurisma de la Aorta Torácica , Genética Médica , Aneurisma de la Aorta Torácica/genética , Pruebas Genéticas/métodos , Variación Genética , Genómica , Humanos , Patología Molecular , Estados Unidos , VirulenciaRESUMEN
BACKGROUND: Non-ischemic dilated cardiomyopathy (DCM) can be complicated by sustained ventricular arrhythmias (SVA) and sudden cardiac death (SCD). By now, left-ventricular ejection fraction (LV-EF) is the main guideline criterion for primary prophylactic ICD implantation, potentially leading either to overtreatment or failed detection of patients at risk without severely impaired LV-EF. The aim of the European multi-center study DETECTIN-HF was to establish a clinical risk calculator for individualized risk stratification of DCM patients. METHODS: 1393 patients (68% male, mean age 50.7 ± 14.3y) from four European countries were included. The outcome was occurrence of first potentially life-threatening ventricular arrhythmia. The model was developed using Cox proportional hazards, and internally validated using cross validation. The model included seven independent and easily accessible clinical parameters sex, history of non-sustained ventricular tachycardia, history of syncope, family history of cardiomyopathy, QRS duration, LV-EF, and history of atrial fibrillation. The model was also expanded to account for presence of LGE as the eight8h parameter for cases with available cMRI and scar information. RESULTS: During a mean follow-up period of 57.0 months, 193 (13.8%) patients experienced an arrhythmic event. The calibration slope of the developed model was 00.97 (95% CI 0.90-1.03) and the C-index was 0.72 (95% CI 0.71-0.73). Compared to current guidelines, the model was able to protect the same number of patients (5-year risk ≥8.5%) with 15% fewer ICD implantations. CONCLUSIONS: This DCM-SVA risk model could improve decision making in primary prevention of SCD in non-ischemic DCM using easily accessible clinical information and will likely reduce overtreatment.
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Cardiomiopatía Dilatada , Desfibriladores Implantables , Adulto , Anciano , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/epidemiología , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/epidemiología , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
Titin truncating variants (TTNtv) are known as the leading cause of inherited dilated cardiomyopathy (DCM). Nevertheless, it is unclear whether circulating cardiac biomarkers are helpful in detection and risk assessment. We sought to assess 1) early indicators of cardiotitinopathy including the serum biomarkers high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in clinically stable patients, and 2) predictors of outcome among TTNtv carriers. Our single-center cohort consisted of 108 TTNtv carriers (including 70 DCM patients) from 43 families. Clinical, laboratory and follow-up data were analyzed. The earliest abnormality was left ventricular dysfunction, present in 8, 26 and 47% of patients in the second, third and fourth decade of life, respectively. It was followed by symptoms of heart failure, linked to NT-proBNP elevation and severe left ventricular systolic dysfunction, and later by arrhythmias. Hs-cTnT serum levels were increased in the late stage of the disease only. During the median follow-up of 5.2 years, both malignant ventricular arrhythmia (MVA) and end-stage heart failure (esHF) occurred in 12% of TTNtv carriers. In multivariable analysis, NT-proBNP level ≥650 pg/mL was the best predictor of both composite endpoints (MVA and esHF) and of MVA alone. In conclusion, echocardiographic abnormalities are the first detectable anomalies in the course of cardiotitinopathies. The assessment of circulating cardiac biomarkers is not useful in the detection of the disease onset but may be helpful in risk assessment.
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BACKGROUND: Transthyretin-related familial amyloid polyneuropathy (ATTR-FAP) is a rare, progressive, hereditary, highly disabling multisystem disorder. ATTR-FAP phenotypes differ according to the type of TTR mutation, geographic region and other as yet unidentified factors. The aim of this study was to establish the clinical and genetic characteristics of Polish patients. METHODS AND PATIENTS: Clinical data and necessary examinations were collected from patients diagnosed with ATTR-FAP at the Department of Neurology of Medical University of Warsaw between 1970 and 2019. RESULTS: 16 patients from eight unrelated families with five different TTR mutations were identified. The family with Val71Ala TTR mutation presented with early onset severe progressive polyneuropathy, with marked visual symptoms in a few patients. The next family with Ile73Val TTR mutation developed symptoms in middle age, and presented with mixed neuropathic and cardiologic phenotype. Four unrelated families were found to have the Phe33Leu TTR mutation with mixed neuropathic and cardiologic phenotype and late onset of symptoms. Other TTR mutations identified were: Val30Met and Asp38Val, both with late onset sensory, motor and autonomic neuropathy. CONCLUSION: Polish ATTR-FAP cases presented with heterogeneity typical for non-endemic areas. Phe33Leu TTR mutation was the most common, found in four unrelated families.
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Neuropatías Amiloides Familiares , Prealbúmina , Neuropatías Amiloides Familiares/genética , Humanos , Persona de Mediana Edad , Mutación , Fenotipo , Polonia , Prealbúmina/genéticaRESUMEN
Mono-allelic dominant mutations in the desmoplakin gene (DSP) have been linked to known cardiac disorders, such as arrhythmogenic right ventricular cardiomyopathy and dilated cardiomyopathy. During the course of DSP cardiomyopathy, episodes of acute myocardial injury may occur. While their mechanisms remain unclear, myocarditis has been postulated as an underlying cause. We report on an adolescent girl with arrhythmogenic biventricular cardiomyopathy and three acute myocarditis-like episodes in whom we found a novel truncating DSP variant accompanied by a known low penetrance R490K variant in the NLRP3. Upon family screening, other carriers of the DSP variant have been identified in whom only mild cardiac abnormalities were found. We hypothesized that the uncommon course of cardiomyopathy in the proband as well as striking discrepancies in the phenotype observed in her family may be explained by the co-existence of her low penetrance genetic autoinflammatory predisposition.
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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of causes of sudden cardiac death in the young, especially in athletes. Diagnosis of CPVT may be difficult since all cardiological examinations performed at rest are usually normal, and exercise stress test-induced ventricular tachycardia is not commonly present. The identification of a pathogenic mutation in RYR2 or CASQ2 is diagnostic in CPVT. We report on a 20-year-old athlete who survived two sudden cardiac arrests during swimming. Moreover, he suffered repeated syncopal spells on exercise. The diagnosis was made only following genetic testing using a multi-gene panel, and the p.Arg420Gln RYR2 variant was identified. We present diagnostic and therapeutic issues in this young athlete with CPVT.
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Mutations in the lamin A/C gene are variably phenotypically expressed; however, it is unclear whether circulating cardiac biomarkers are helpful in the detection and risk assessment of cardiolaminopathies. We sought to assess (1) clinical characteristics including serum biomarkers: high sensitivity troponin T (hsTnT) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in clinically stable cardiolaminopathy patients, and (2) outcome among pathogenic/likely pathogenic lamin A/C gene (LMNA) mutation carriers. Our single-centre cohort included 53 patients from 21 families. Clinical, laboratory, follow-up data were analysed. Median follow-up was 1522 days. The earliest abnormality, emerging in the second and third decades of life, was elevated hsTnT (in 12% and in 27% of patients, respectively), followed by the presence of atrioventricular block, heart failure, and malignant ventricular arrhythmia (MVA). In patients with missense vs. other mutations, we found no difference in MVA occurrence and, surprisingly, worse transplant-free survival. Increased levels of both hsTnT and NT-proBNP were strongly associated with MVA occurrence (HR > 13, p ≤ 0.02 in both) in univariable analysis. In multivariable analysis, NT-proBNP level > 150 pg/mL was the only independent indicator of MVA. We conclude that assessment of circulating cardiac biomarkers may help in the detection and risk assessment of cardiolaminopathies.
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The vast majority of cardiomyopathies have an autosomal dominant inheritance; hence, genetic testing is typically offered to patients with a positive family history. A de novo mutation is a new germline mutation not inherited from either parent. The purpose of our study was to search for de novo mutations in patients with cardiomyopathy and no evidence of the disease in the family. Using next-generation sequencing, we analyzed cardiomyopathy genes in 12 probands. In 8 (66.7%), we found de novo variants in known cardiomyopathy genes (TTN, DSP, SCN5A, TNNC1, TPM1, CRYAB, MYH7). In the remaining probands, the analysis was extended to whole exome sequencing in a trio (proband and parents). We found de novo variants in genes that, so far, were not associated with any disease (TRIB3, SLC2A6), a possible disease-causing biallelic genotype (APOBEC gene family), and a de novo mosaic variant without strong evidence of pathogenicity (UNC45A). The high prevalence of de novo mutations emphasizes that genetic screening is also indicated in cases of sporadic cardiomyopathy. Moreover, we have identified novel cardiomyopathy candidate genes that are likely to affect immunological function and/or reaction to stress that could be especially relevant in patients with disease onset associated with infection/infestation.
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We present two symptomatic sisters who had a positive family history of sudden death. None of them had structural heart disease. In the 25-year-old proband, complex ventricular arrhythmia, cardiac conduction system disease, and skeletal muscle weakness were found. Genetic examination showed a pathogenic intronic variant in the desmin gene in the proband only. In the elder sister with palpitations, complex ventricular arrhythmia (>46 000 ectopic beats) was removed by radiofrequency ablation. This family case shows that complex ventricular arrhythmia may have different background within one family, genetic examinations should be performed in a person with broadest spectrum of symptoms.
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Muerte Súbita Cardíaca/prevención & control , Electrocardiografía/métodos , Ablación por Radiofrecuencia/métodos , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/cirugía , Adulto , Femenino , Sistema de Conducción Cardíaco/fisiopatología , Humanos , Taquicardia Ventricular/fisiopatologíaRESUMEN
INTRODUCTION Unexplained sudden cardiac arrest (SCA), occurs in up to 10% of patients and is often attributed to an inherited arrhythmia syndrome. Family screening and genetic testing may help clarify the cause of unexplained SCA. OBJECTIVES We aimed to assess the usefulness of clinical evaluation and genetic testing in patients after unexplained SCA and in their families. PATIENTS AND METHODS In the years 2014-2017, we studied 44 unrelated patients after unexplained SCA and 96 of their relatives. All patients and relatives underwent comprehensive cardiac evaluation. In 31 patients with SCA, next generation sequencing (NGS) was performed. The Kaplan-Meier survival curve was constructed to compare the event-free survival depending on clinical diagnosis or genotype. An adverse event was defined as an adequate implantable cardioverter-defibrillator discharge. RESULTS Based on the clinical evaluation, diagnosis was established in 39% of probands (long QT syndrome 21%; short QT syndrome 7%; Brugada syndrome 7%; catecholaminergic polymorphic ventricular tachycardia, 2%; and early repolarization syndrome, 2%). Ventricular arrhythmia was identified in the relatives of 19% of probands. In 18 of the 31 probands (54.8%), 23 rare gene variants were identified, of which only 2 were classified as pathogenic. The event-free survival over a median of 4.5 years was similar in patients with or without clinical diagnosis and in carriers and noncarriers of a rare genetic variant. CONCLUSIONS This study shows the significance of an extensive clinical assessment in unexplained SCA victims and their relatives. Routine genetic testing by NGS has low diagnostic and prognostic value.
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Muerte Súbita Cardíaca/patología , Predisposición Genética a la Enfermedad , Linaje , Adulto , Anciano , Displasia Ventricular Derecha Arritmogénica/genética , Síndrome de Brugada/genética , Muerte Súbita Cardíaca/etiología , Femenino , Humanos , Síndrome de QT Prolongado/genética , Masculino , Persona de Mediana Edad , Taquicardia Ventricular/genéticaRESUMEN
BACKGROUND: Cardiovascular disease is the leading cause of mortality and morbidity in developed countries, including Poland. Antithrom-botic drugs play a crucial role in the management of acute coronary syndromes (ACS). Recent clinical trials have demonstrated the efficacy and safety profiles of new antiplatelet and anticoagulant agents, which may be used as add-on therapy or replacements for older drugs. The long-t E: rm follow-u P: of antithrombotic management patterns I: n acute COR: onary syndrome patients (EPICOR) is a prospective international observational study (NCT01171404) designed to describe the use of antithrombotic management strategies for the treatment of ACS during the acute phase and over a follow-up period of up to two years from the index event. A total of 608 patients from 26 hospitals in Poland were enrolled into the registry between September 2010 and March 2011. AIM: The aim of this work was to summarise data on pre-hospital and in-hospital and revascularisation therapy in 608 patients enrolled into the registry in Poland. METHODS: The registry collected the records of patients who were hospitalised for ACS within 24 h of symptom onset and who had a final diagnosis of unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (STEMI), and survived to discharge. RESULTS: Among 608 enrolled patients, 291 had a final diagnosis of STEMI and 317 had a final diagnosis of NSTEMI/UA. Patients with NSTEMI/UA were generally at higher cardiovascular risk than patients with STEMI. Before admission to the hospital antiplatelet drugs (acetylsalicylic acid [ASA] and/or clopidogrel) were administered more frequently to STEMI than to NSTEMI/UA patients. Glycoprotein (GP) IIb/IIIa inhibitors were used in almost half of the STEMI patients and in nearly 10% of NSTEMI/UA patients. The combinations of antiplatelet drugs included ASA + clopidogrel (predominantly in NSTEMI/UA) or ASA + clopidogrel + GPIIb/IIIa inhibitor (predominantly in STEMI), while other possible combinations were not used. Almost all STEMI patients (96.2%) and the clear majority of NSTEMI/UA patients (73.8%) were subjected to percutaneous coronary intervention (PCI), while coronary artery bypass grafting was performed in only 2.5% of the NSTEMI/UA patients. At the time of discharge from hospital almost all patients with STEMI received ASA together with clopidogrel, but this strategy was used only in 91.5% of patients with NSTEMI/UA (p < 0.05). Unfractionated heparin was used in 62% of patients, low-molecular weight heparin in 35%, fondaparinux in 0.7%, and bivalirudin in none of the studied patients. CONCLUSIONS: Among patients with ACS enrolled to the EPICOR study in Poland, antiplatelet therapy was started in the pre-hospital phase in approximately one-third of the STEMI patients and in one out of ten of the NSTEMI/UA patients. The initial antiplatelet therapy was mostly based on ASA + clopidogrel and was followed by a combination of ASA + clopidogrel + GPIIb/IIIa inhibitor. Other drugs or combinations, as well as novel antiplatelet drugs, were only used exceptionally. Almost 10% of NSTEMI/UA patients did not receive dual antiplatelet therapy at discharge. PCI plays a dominating role in the first-line treatment for the patients enrolled to this registry in Poland.
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Síndrome Coronario Agudo/tratamiento farmacológico , Fibrinolíticos/uso terapéutico , Revascularización Miocárdica , Síndrome Coronario Agudo/cirugía , Anciano , Angina Inestable/tratamiento farmacológico , Angina Inestable/cirugía , Quimioterapia Combinada , Femenino , Hospitalización , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/cirugía , Polonia , Estudios Prospectivos , Sistema de RegistrosRESUMEN
We report the case of a 70-year-old woman with ST-segment elevation myocardial infarction of the anterior wall, complicated by ventricular septal rupture (two septal defects--VSDs) with symptoms of cardiogenic shock. After 6 weeks of conservative treatment with inotropes and intra-aortic balloon support, the patient underwent surgical repair of VSDs with good clinical outcome.
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Cardiotónicos/uso terapéutico , Infarto del Miocardio/patología , Choque Cardiogénico/tratamiento farmacológico , Choque Cardiogénico/patología , Rotura Septal Ventricular/diagnóstico , Rotura Septal Ventricular/patología , Rotura Septal Ventricular/cirugía , Anciano , Ecocardiografía , Femenino , Humanos , Infarto del Miocardio/complicaciones , Choque Cardiogénico/etiología , Resultado del Tratamiento , Rotura Septal Ventricular/etiologíaRESUMEN
We report the case of a 70-year-old woman with ST-segment elevation myocardial infarction of the anterior wall, complicated by ventricular septal rupture (two septal defects--VSDs) with symptoms of cardiogenic shock. After 6 weeks of conservative treatment with inotropes and intra-aortic balloon support, the patient underwent surgical repair of VSDs with good clinical outcome.