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INTRODUCTION AND OBJECTIVES: Missense mutations in the filamin C (FLNC) gene have been reported as cause of inherited cardiomyopathy. Knowledge of the pathogenicity and genotype-phenotype correlation remains scarce. Our aim was to describe a distinctive cardiac phenotype related to rare missense FLNC variants in the ROD2 domain. METHODS: We recruited 21 unrelated families genetically evaluated because of hypertrophic cardiomyopathy (HCM)/restrictive cardiomyopathy (RCM) phenotype carrying rare missense variants in the ROD2 domain of FLNC (FLNC-mRod2). Carriers underwent advanced cardiac imaging and genetic cascade screening. Myocardial tissue from 3 explanted hearts of a missense FLNC carrier was histologically analyzed and compared with an FLNC-truncating variant heart sample and a healthy control. Plasmids independently containing 3 FLNC missense variants were transfected and analyzed using confocal microscopy. RESULTS: Eleven families (52%) with 20 assessed individuals (37 [23.7-52.7]) years showed 15 cases with a cardiac phenotype consisting of an overlap of HCM-RCM and left ventricular hypertrabeculation (saw-tooth appearance). During a median follow-up of 6.49 years, they presented with advanced heart failure: 16 (80%) diastolic dysfunction, 3 heart transplants, 3 heart failure deaths) and absence of cardiac conduction disturbances or skeletal myopathy. A total of 6 families had moderate genotype-phenotype segregation, and the remaining were de novo variants. Differential extracellular matrix remodeling and FLNC distribution among cardiomyocytes were confirmed on histology. HT1080 and H9c2 cells did not reveal cytoplasmic aggregation of mutant FLNC. CONCLUSIONS: FLNC-mRod2 variants show a high prevalence of an overlapped phenotype comprising RCM, HCM and deep hypertrabeculation with saw-tooth appearance and distinctive cardiac histopathological remodeling.
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Cardiomiopatias , Cardiomiopatia Hipertrófica , Cardiomiopatia Restritiva , Insuficiência Cardíaca , Humanos , Cardiomiopatia Restritiva/genética , Mutação de Sentido Incorreto , Mutação , Filaminas/genética , Fenótipo , Miocárdio , Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genéticaRESUMO
INTRODUCTION AND OBJECTIVES: Study of inherited heart diseases (IHD) involves performing diagnostic tests, which are sometimes inconvenient or stressful, in asymptomatic relatives. The aim of this study was to analyze refusal to undergo various diagnostic tests and follow therapeutic recommendations. METHODS: We assessed 1992 consecutive families with IHD to analyze refusal to undergo family screening. The study included 1539 individuals who were recommended to undergo cardiac magnetic resonance, and 837 who were recommended a drug challenge test. To study treatment refusal, we assessed 395 patients with an indication for an implantable cardioverter-defibrillator (ICD) and 402 patients with an indication for anticoagulation. RESULTS: A total of 28% of families who were recommended to undergo screening for suspected IHD did not attend, but refusal was lower if there was a family history of sudden cardiac death. In all, 23% did not undergo magnetic resonance, and the 2 main reasons were administrative problems (53%) and claustrophobia (18%). Refusal was more common in older people, women, symptomatic persons, individuals with arrhythmias, and relatives. Nearly one fifth (19%) did not take the drug challenge test, due to fear (46%) or administrative issues (25%). Refusal was more frequent in older individuals, asymptomatic persons, those with a history of arrhythmias, relatives, and those with a positive genetic study. Only a minority of patients rejected the treatments (5.1% ICD, 2.5% anticoagulation). The percentage of sudden cardiac death in persons rejecting ICD implantation was high (4.5% per year). CONCLUSIONS: One fifth of people attending screening for IHD refused to undergo more sophisticated and stressful tests. This study identified several independent predictors associated with refusal. Only a minority of high-risk patients refused treatments such as ICD implantation and anticoagulation.
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Desfibriladores Implantáveis , Testes Diagnósticos de Rotina , Idoso , Arritmias Cardíacas , Morte Súbita Cardíaca , Feminino , HumanosRESUMO
Introduction: Inherited cardiovascular diseases are an important cause of sudden cardiac death (SD). The use of risk scores identify high risk patients who would benefit from an implantable cardioverter-defibrillators (ICDs). The development of automated devices for out-of-hospital cardiac arrest improves early resuscitation. The objective of the study is to quantify prevented SD and the neurological recovery of patients with inherited cardiovascular diseases. Methods: Two hundred fifty-seven cases of SD (age 42 ± 18 years, 79.4% men) of non-ischemic cardiac cause were prospectively collected during the study period (2009-17). Fifty three (20.6%) had a resuscitated cardiac arrest (RCA) (age 40 ± 18 years, 64.2% male). Epidemiological, clinical and autopsy aspects were analyzed. Prevented SD was defined as a combination of RCA and appropriate ICD therapy cases. Results: An autopsy was performed in 157/204 (77.0%) cases who died. There were 19 (12.1%) cases with a negative autopsy. The diagnosis of cardiomyopathy and channelopathy was 58.0 and 18.7%, respectively. Female sex and confirmed or suspected channelopathy were associated with successful resuscitation. The percentage of prevented SD remained low during the study period (mean 35.6%). 60.4% of RCA cases presented good neurological outcome. There was no association between neurological recovery and therapeutic hypothermia, but there was association with time of resuscitation (min). Conclusion: A fifth part of non-ischemic cardiac arrests were resuscitated. Female sex and channelopathies were more prevalent among RCA. Two thirds of RCA had a good neurological recovery.
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BACKGROUND: Left ventricular noncompaction (LVNC) is a heterogeneous entity with uncertain prognosis. OBJECTIVES: This study sought to develop and validate a prediction model of major adverse cardiovascular events (MACE) and to identify LVNC cases without events during long-term follow-up. METHODS: This is a retrospective longitudinal multicenter cohort study of consecutive patients fulfilling LVNC criteria by echocardiography or cardiovascular magnetic resonance. MACE were defined as heart failure (HF), ventricular arrhythmias (VAs), systemic embolisms, or all-cause mortality. RESULTS: A total of 585 patients were included (45 ± 20 years of age, 57% male). LV ejection fraction (LVEF) was 48% ± 17%, and 18% presented late gadolinium enhancement (LGE). After a median follow-up of 5.1 years, MACE occurred in 223 (38%) patients: HF in 110 (19%), VAs in 87 (15%), systemic embolisms in 18 (3%), and 34 (6%) died. LVEF was the main variable independently associated with MACE (P < 0.05). LGE was associated with HF and VAs in patients with LVEF >35% (P < 0.05). A prediction model of MACE was developed using Cox regression, composed by age, sex, electrocardiography, cardiovascular risk factors, LVEF, and family aggregation. C-index was 0.72 (95% confidence interval: 0.67-0.75) in the derivation cohort and 0.72 (95% confidence interval: 0.71-0.73) in an external validation cohort. Patients with no electrocardiogram abnormalities, LVEF ≥50%, no LGE, and negative family screening presented no MACE at follow-up. CONCLUSIONS: LVNC is associated with an increased risk of heart failure and ventricular arrhythmias. LVEF is the variable most strongly associated with MACE; however, LGE confers additional risk in patients without severe systolic dysfunction. A risk prediction model is developed and validated to guide management.
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Arritmias Cardíacas/epidemiologia , Embolia/epidemiologia , Insuficiência Cardíaca/epidemiologia , Miocárdio Ventricular não Compactado Isolado/mortalidade , Modelagem Computacional Específica para o Paciente , Adulto , Idoso , Arritmias Cardíacas/etiologia , Embolia/etiologia , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Miocárdio Ventricular não Compactado Isolado/complicações , Miocárdio Ventricular não Compactado Isolado/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Espanha/epidemiologia , Adulto JovemRESUMO
Cancer therapy-induced cardiomyopathy (CCM) manifests as left ventricular (LV) dysfunction and heart failure (HF). It is associated withparticular pharmacological agents and it is typically dose dependent, but significant individual variability has been observed. History of prior cardiac disease, abuse of toxics, cardiac overload conditions, age, and genetic predisposing factors modulate the degree of the cardiac reserve and the response to the injury. Genetic/familial cardiomyopathies (CMY) are increasingly recognized in general populations with an estimated prevalence of 1:250. Association between cardiac and oncologic diseases regarding genetics involves not only the toxicity process, but pathogenicity. Genetic variants in germinal cells that cause CMY (LMNA, RAS/MAPK) can increase susceptibility for certain types of cancer. The study of mutations found in cancer cells (somatic) has revealed the implication of genes commonly associated with the development of CMY. In particular, desmosomal mutations have been related to increased undifferentiation and invasiveness of cancer. In this article, the authors review the knowledge on the relevance of environmental and genetic background in CCM and give insights into the shared genetic role in the pathogenicity of the cancer process and development of CMY.
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BACKGROUND: Myocardial uptake of bone tracers has emerged as useful tool for the early detection of transthyretin amyloidosis (ATTR). The prevalence of wild-type ATTR (ATTRwt) in individuals remains to be established. METHODS: All whole body bone scans performed in individualsâ¯≥â¯75â¯years with no previous clinical suspicion of ATTR were revised in a population-based university hospital over a 7-year period (1509 studies corresponding to 1114 patients; 80.5⯱â¯4.1â¯years, 65% males). Positive cardiac uptake was defined according to Perugini score as grade 2 or 3. Heart failure (HF) hospitalizations during the follow-up were obtained from regional administrative databases. RESULTS: Thirty-one patientsâ¯≥â¯75â¯years (2.78%) showed cardiac uptake; compared with those without uptake, these patients were older (85⯱â¯5 vs. 80⯱â¯4, pâ¯<â¯0.001) and predominantly males (90% vs. 64%, pâ¯=â¯0.005). The prevalence of cardiac uptake was 3.88% in males and 0.77% in females, and increased with age, reaching 13.9% in males≥85â¯years (2.7% among females). The estimated prevalence for the European standard populationâ¯≥â¯75â¯years was 4.15% in males, 1.03% in females and 2.59% in the general population. HF hospitalizations rates were 14% in patients without uptake and 29% in those with cardiac uptake (pâ¯=â¯0.034). After adjusting for age and gender, cardiac uptake was associated with a higher risk of HF hospitalization (OR 2.60, 95%CI 1.09-5.74, pâ¯=â¯0.022). CONCLUSIONS: Myocardial uptake in bone scan is very prevalent with ageing, mainly affects males and is associated with an increased risk of HF hospitalization. These findings reinforce ATTRwt as a relevant cause of HF in the elderly.
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Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/epidemiologia , Coração/diagnóstico por imagem , Vigilância da População , Cintilografia/métodos , Compostos Radiofarmacêuticos , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea/fisiologia , Feminino , Seguimentos , Humanos , Masculino , Prevalência , Estudos RetrospectivosRESUMO
Hypertrophic cardiomyopathy is the most common inherited cardiovascular disease. It is characterized by increased ventricular wall thickness and is highly complex due to its heterogeneous clinical presentation, several phenotypes, large number of associated causal mutations and broad spectrum of complications. It is caused by mutations in sarcomeric proteins, which are identified in up to 60% of cases of the disease. Clinical manifestations of Hypertrophic Cardiomyopathy include shortness of breath, chest pain, palpitations and syncope, which are related to the onset of diastolic dysfunction, left ventricular outflow tract obstruction, ischemia, atrial fibrillation and abnormal vascular responses. It is associated with an increased risk of sudden cardiac death, heart failure and thromboembolic events. In this article, we discuss the diagnostic and therapeutic aspects of this disease.