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A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na+ current (INa) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic-phenotypic relationships in patients carrying SCN5A mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak INa generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (-69.4 ± 9.0 pA/pF) or in combination with WT (-62.2 ± 14.6 pA/pF), was significantly (n ≥ 17, p < 0.05) reduced compared to that generated by WT channels alone (-199.1 ± 44.1 pA/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of INa, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the INa and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of SCN5A loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies.
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Cricetulus , Canal de Sódio Disparado por Voltagem NAV1.5 , Linhagem , Penetrância , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Humanos , Animais , Células CHO , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Espanha , Mutação com Perda de Função , Fenótipo , MutaçãoRESUMO
BACKGROUND: Identification of people with hypertrophic cardiomyopathy (HCM) who are at risk of sudden cardiac death (SCD) and require a prophylactic implantable cardioverter defibrillator is challenging. In 2014, the European Society of Cardiology proposed a new risk stratification method based on a risk prediction model (HCM Risk-SCD) that estimates the 5-year risk of SCD. The aim was to externally validate the 2014 European Society of Cardiology recommendations in a geographically diverse cohort of patients recruited from the United States, Europe, the Middle East, and Asia. METHODS: This was an observational, retrospective, longitudinal cohort study. RESULTS: The cohort consisted of 3703 patients. Seventy three (2%) patients reached the SCD end point within 5 years of follow-up (5-year incidence, 2.4% [95% confidence interval {CI}, 1.9-3.0]). The validation study revealed a calibration slope of 1.02 (95% CI, 0.93-1.12), C-index of 0.70 (95% CI, 0.68-0.72), and D-statistic of 1.17 (95% CI, 1.05-1.29). In a complete case analysis (n= 2147; 44 SCD end points at 5 years), patients with a predicted 5-year risk of <4% (n=1524; 71%) had an observed 5-year SCD incidence of 1.4% (95% CI, 0.8-2.2); patients with a predicted risk of ≥6% (n=297; 14%) had an observed SCD incidence of 8.9% (95% CI, 5.96-13.1) at 5 years. For every 13 (297/23) implantable cardioverter defibrillator implantations in patients with an estimated 5-year SCD risk ≥6%, 1 patient can potentially be saved from SCD. CONCLUSIONS: This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD.
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Cardiologia , Cardiomiopatia Hipertrófica/epidemiologia , Morte Súbita Cardíaca/prevenção & controle , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/diagnóstico , Estudos de Coortes , Morte Súbita Cardíaca/etiologia , Desfibriladores Implantáveis/estatística & dados numéricos , Europa (Continente)/epidemiologia , Seguimentos , Humanos , Incidência , Guias de Prática Clínica como Assunto , Prognóstico , Projetos de Pesquisa , Estudos Retrospectivos , Risco , Sociedades MédicasRESUMO
AIMS: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome with multiple underlying causes. Wild-type transthyretin (TTR) amyloidosis (ATTRwt) is an underdiagnosed cause of HFpEF that might benefit from new specific treatments. ATTRwt can be diagnosed non-invasively by (99m)Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) scintigraphy. We sought to determine the prevalence of ATTRwt among elderly patients admitted due to HFpEF. METHODS AND RESULTS: We prospectively screened all consecutive patients ≥60 years old admitted due to HFpEF [left ventricular (LV) ejection fraction ≥50%] with LV hypertrophy (≥12 mm). All eligible patients were offered a (99m)Tc-DPD scintigraphy. The study included 120 HFpEF patients (59% women, 82 ± 8 years). A total of 16 patients (13.3%; 95% confidence interval: 7.2-19.5) showed a moderate-to-severe uptake on the (99m)Tc-DPD scintigraphy. All patients with a positive scan underwent genetic testing of the TTR gene, and no mutations were found. An endomyocardial biopsy was performed in four patients, confirming ATTRwt in all cases. There were no differences in age, gender, hypertension, diabetes, coronary artery disease, or atrial fibrillation between ATTRwt patients and patients with other HFpEF forms. Although patients with ATTRwt exhibited higher median N-terminal pro-brain natriuretic peptide (6467 vs. 3173 pg/L; P = 0.019), median troponin I (0.135 vs. 0.025 µg/L; P < 0.001), mean LV maximal wall thickness (17 ± 3.4 vs. 14 ± 2.5 mm; P = 0.001), rate of pericardial effusion (44 vs. 19%; P = 0.047), and rate of pacemakers (44 vs. 12%; P = 0.004), clinical overlap between ATTRwt and other HFpEF forms was high. CONCLUSION: ATTRwt is an underdiagnosed disease that accounts for a significant number (13%) of HFpEF cases. The effect of emerging TTR-modifying drugs should be evaluated in these patients.
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Neuropatias Amiloides Familiares/complicações , Insuficiência Cardíaca/etiologia , Idoso , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/fisiopatologia , Estudos Transversais , Difosfonatos , Ecocardiografia , Eletrocardiografia , Feminino , Genótipo , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Compostos de Organotecnécio , Estudos Prospectivos , Cintilografia , Compostos Radiofarmacêuticos , Volume Sistólico/fisiologiaRESUMO
BACKGROUND: Genetic disease has recently emerged as a cause of cardiac conduction disorders (CCDs), but the diagnostic yield of genetic testing and the contribution of the different genes to CCD is still unsettled. OBJECTIVES: This study sought to determine the diagnostic yield of genetic testing in young adults with CCD of unknown etiology requiring pacemaker implantation. We also studied the prevalence of rare protein-altering variants across individual genes and functional gene groups. METHODS: We performed whole exome sequencing in 150 patients with CCD of unknown etiology who had permanent pacemaker implanted at age ≤60 years at 14 Spanish hospitals. Prevalence of rare protein-altering variants in patients with CCD was compared with a reference population of 115,522 individuals from gnomAD database (control subjects). RESULTS: Among 39 prioritized genes, patients with CCD had more rare protein-altering variants than control subjects (OR: 2.39; 95% CI: 1.75-3.33). Significant enrichment of rare variants in patients with CCD was observed in all functional gene groups except in the desmosomal genes group. Rare variants in the nuclear envelope genes group exhibited the strongest association with CCD (OR: 6.77; 95% CI: 3.71-13.87). Of note, rare variants in sarcomeric genes were also enriched (OR: 1.73; 95% CI: 1.05-3.10). An actionable genetic variant was detected in 21 patients (14%), with LMNA being the most frequently involved gene (4.6%). CONCLUSIONS: Unrecognized rare genetic variants increase the risk of CCD in young adults with CCD of unknown etiology. Genetic testing should be performed in patients age ≤60 years with CCD of unknown etiology. The role of genetic variants in sarcomeric genes as a cause of CCD should be further investigated.
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BACKGROUND: Disease penetrance in genotype-positive (G+) relatives of families with dilated cardiomyopathy (DCM) and the characteristics associated with DCM onset in these individuals are unknown. OBJECTIVES: This study sought to determine the penetrance of new DCM diagnosis in G+ relatives and to identify factors associated with DCM development. METHODS: The authors evaluated 779 G+ patients (age 35.8 ± 17.3 years; 459 [59%] females; 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers. RESULTS: After a median follow-up of 37.1 months (Q1-Q3: 16.3-63.8 months), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 per 100 person-years; 95% CI: 2.3-3.5 per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank P = 0.015 and P <0.01, respectively). In a multivariable model excluding CMR parameters, independent predictors of DCM development were: older age (HR per 1-year increase: 1.02; 95% CI: 1.0-1.04), an abnormal electrocardiogram (HR: 2.13; 95% CI: 1.38-3.29); presence of variants in motor sarcomeric genes (HR: 1.92; 95% CI: 1.05-3.50); lower left ventricular ejection fraction (HR per 1% increase: 0.86; 95% CI: 0.82-0.90) and larger left ventricular end-diastolic diameter (HR per 1-mm increase: 1.10; 95% CI: 1.06-1.13). Multivariable analysis in individuals with cardiac magnetic resonance and late gadolinium enhancement assessment (n = 360, 45%) identified late gadolinium enhancement as an additional independent predictor of DCM development (HR: 2.52; 95% CI: 1.43-4.45). CONCLUSIONS: Following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years. Older age, an abnormal electrocardiogram, lower left ventricular ejection fraction, increased left ventricular end-diastolic diameter, motor sarcomeric genetic variants, and late gadolinium enhancement are associated with a higher risk of developing DCM.
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Cardiomiopatia Dilatada , Genótipo , Penetrância , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Conectina/genética , Eletrocardiografia , Seguimentos , Espanha/epidemiologia , Estudos RetrospectivosRESUMO
BACKGROUND AND OBJECTIVE: Cardiac transthyretin amyloidosis (CA-ATTR) is a prevalent disease with age. Genetic study is recommended, even in eldest patients. We aim to analyze the prevalence of hereditary transthyretin amyloidosis (ATTRv) in elderly patients (≥75years) with CA-ATTR and its implications. PATIENTS AND METHODOLOGY: Retrospective observational study of the cohort of elderly patients with CA-ATTR diagnosed according to the international recommended protocol. We analyze the results of sequencing TTR gene, the differential characteristics and their clinical implications. RESULTS: Between 2016 and 2022, 130 elderly patients (89% cohort) were diagnosed with CA-ATTR (85% male). In 8 of the 123 patients with a genetic study, a pathogenic variant in TTR was identified (6.5%), initiating specific treatment in 4 subjects (50%). The family study identified another case and 6 asymptomatic carriers. There were no significant differences between baseline characteristics or in clinical events. CONCLUSIONS: The prevalence of ATTRv in elderly patients with CA-ATTR was 6.5% without observing differential characteristics that allow guiding a selective indication of genetic analysis.
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AIMS: Late gadolinium enhancement (LGE) is frequently found in patients with dilated cardiomyopathy (DCM); there is little information about its frequency and distribution pattern according to the underlying genetic substrate. We sought to describe LGE patterns according to genotypes and to analyse the risk of major ventricular arrhythmias (MVA) according to patterns. METHODS AND RESULTS: Cardiac magnetic resonance findings and LGE distribution according to genetics were performed in a cohort of 600 DCM patients followed at 20 Spanish centres. After exclusion of individuals with multiple causative gene variants or with variants in infrequent DCM-causing genes, 577 patients (34% females, mean age 53.5 years, left ventricular ejection fraction 36.9 ± 13.9%) conformed to the final cohort. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. Significant differences were found comparing LGE patterns between genes (P < 0.001). LGE was absent or rare in patients with variants in TNNT2, RBM20, and MYH7 (0, 5, and 20%, respectively). Patients with variants in DMD, DSP, and FLNC showed a predominance of LGE subepicardial patterns (50, 41, and 18%, respectively), whereas patients with variants in TTN, BAG3, LMNA, and MYBPC3 showed unspecific LGE patterns. The genetic yield differed according to LGE patterns. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. CONCLUSION: LGE patterns in DCM have a specific distribution according to the affected gene. Certain LGE patterns are associated with an increased risk of MVA and with an increased yield of genetic testing.
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Cardiomiopatia Dilatada , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/complicações , Meios de Contraste , Gadolínio , Volume Sistólico , Função Ventricular Esquerda , Arritmias Cardíacas , Estudos de Associação Genética , Valor Preditivo dos Testes , Imagem Cinética por Ressonância Magnética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genéticaRESUMO
AIMS: Genotype and left ventricular scar on cardiac magnetic resonance (CMR) are increasingly recognized as risk markers for adverse outcomes in non-ischaemic dilated cardiomyopathy (DCM). We investigated the combined influence of genotype and late gadolinium enhancement (LGE) in assessing prognosis in a large cohort of patients with DCM. METHODS AND RESULTS: Outcomes of 600 patients with DCM (53.3 ± 14.1 years, 66% male) who underwent clinical CMR and genetic testing were retrospectively analysed. The primary endpoints were end-stage heart failure (ESHF) and malignant ventricular arrhythmias (MVA). During a median follow-up of 2.7 years (interquartile range 1.3-4.9), 24 (4.00%) and 48 (8.00%) patients had ESHF and MVA, respectively. In total, 242 (40.3%) patients had pathogenic/likely pathogenic variants (positive genotype) and 151 (25.2%) had LGE. In survival analysis, positive LGE was associated with MVA and ESHF (both, p < 0.001) while positive genotype was associated with ESHF (p = 0.034) but not with MVA (p = 0.102). Classification of patients according to genotype (G+/G-) and LGE presence (L+/L-) revealed progressively increasing events across L-/G-, L-/G+, L+/G- and L+/G+ groups and resulted in optimized MVA and ESHF prediction (p < 0.001 and p = 0.001, respectively). Hazard ratios for MVA and ESHF in patients with either L+ or G+ compared with those with L-/G- were 4.71 (95% confidence interval: 2.11-10.50, p < 0.001) and 7.92 (95% confidence interval: 1.86-33.78, p < 0.001), respectively. CONCLUSION: Classification of patients with DCM according to genotype and LGE improves MVA and ESHF prediction. Scar assessment with CMR and genotyping should be considered to select patients for primary prevention implantable cardioverter-defibrillator placement.
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Cardiomiopatia Dilatada , Insuficiência Cardíaca , Arritmias Cardíacas , Cicatriz , Meios de Contraste , Feminino , Gadolínio , Genótipo , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/genética , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Valor Preditivo dos Testes , Prognóstico , Estudos RetrospectivosRESUMO
INTRODUCTION AND OBJECTIVES: Hereditary transthyretin amyloidosis (hATTR) is a disease caused by mutations in the transthyretin gene that frequently shows cardiac involvement due to amyloid deposition in the myocardium. Our objective was to identify cardiac involvement in a Spanish cohort. METHODS: Retrospective multicenter study of patients diagnosed with hATTR with cardiac involvement from Spanish centers. We collected demographic, clinical, and genetic data. RESULTS: A total of 181 patients from 26 centers were included (65.2% men, with a median age at diagnosis of 62 years). The most frequent mutations were Val50Met (67.7%) and Val142Ile (12.4%). The main reason for consultation was extracardiac symptoms (69%), mainly neurological. The mean N-terminal pro-B-type natriuretic peptide level was 2145±3586 pg/mL. The most characteristic electrocardiogram findings were a pseudoinfarct pattern (25.9%) and atrioventricular block (25.3%). Mean ventricular thickness was 15.4±4.1mm. Longitudinal strain was reduced in basal segments by 29.4%. Late diffuse subendocardial enhancement was observed in 58.8%. Perugini grade 2 or 3 uptake was observed in 75% of scintigraphy scans. During follow-up, 24.9% of the patients were admitted for heart failure, 34.3% required a pacemaker, and 31.6% required a liver transplant. One third (32.5%) died during follow-up, mainly due to heart failure (28.8%). The presence of non-Val50Met mutations was associated with a worse prognosis. CONCLUSIONS: HATTR cardiac amyloidosis in Spain shows heterogeneous genetic and clinical involvement. The prognosis is poor, mainly due to cardiac complications. Consequently early diagnosis and treatment are vital.
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Neuropatias Amiloides Familiares , Cardiomiopatias , Insuficiência Cardíaca , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/genética , Cardiomiopatias/diagnóstico , Cardiomiopatias/epidemiologia , Cardiomiopatias/genética , Feminino , Insuficiência Cardíaca/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Pré-Albumina/genética , Espanha/epidemiologiaRESUMO
AIMS: To describe the natural history of SARS-CoV-2 infection in patients with hypertrophic cardiomyopathy (HCM) compared with a control group and to identify predictors of adverse events. METHODS AND RESULTS: Three hundred and five patients [age 56.6 ± 16.9 years old, 191 (62.6%) male patients] with HCM and SARS-Cov-2 infection were enrolled. The control group consisted of 91 131 infected individuals. Endpoints were (i) SARS-CoV-2 related mortality and (ii) severe clinical course [death or intensive care unit (ICU) admission]. New onset of atrial fibrillation, ventricular arrhythmias, shock, stroke, and cardiac arrest were also recorded. Sixty-nine (22.9%) HCM patients were hospitalized for non-ICU level care, and 21 (7.0%) required ICU care. Seventeen (5.6%) died: eight (2.6%) of respiratory failure, four (1.3%) of heart failure, two (0.7%) suddenly, and three (1.0%) due to other SARS-CoV-2-related complications. Covariates associated with mortality in the multivariable were age {odds ratio (OR) per 10 year increase 2.25 [95% confidence interval (CI): 1.12-4.51], P = 0.0229}, baseline New York Heart Association class [OR per one-unit increase 4.01 (95%CI: 1.75-9.20), P = 0.0011], presence of left ventricular outflow tract obstruction [OR 5.59 (95%CI: 1.16-26.92), P = 0.0317], and left ventricular systolic impairment [OR 7.72 (95%CI: 1.20-49.79), P = 0.0316]. Controlling for age and sex and comparing HCM patients with a community-based SARS-CoV-2 cohort, the presence of HCM was associated with a borderline significant increased risk of mortality OR 1.70 (95%CI: 0.98-2.91, P = 0.0600). CONCLUSIONS: Over one-fourth of HCM patients infected with SARS-Cov-2 required hospitalization, including 6% in an ICU setting. Age and cardiac features related to HCM, including baseline functional class, left ventricular outflow tract obstruction, and systolic impairment, conveyed increased risk of mortality.
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Fibrilação Atrial , COVID-19 , Cardiomiopatia Hipertrófica , Disfunção Ventricular Esquerda , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Feminino , COVID-19/complicações , COVID-19/epidemiologia , SARS-CoV-2 , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/epidemiologia , Sistema de Registros , Disfunção Ventricular Esquerda/complicações , Fibrilação Atrial/complicaçõesRESUMO
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.
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Cardiomiopatia Dilatada , Insuficiência Cardíaca , Cadeias Pesadas de Miosina , Adolescente , Adulto , Arritmias Cardíacas/complicações , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/genética , Miosinas Cardíacas/genética , Cardiomiopatia Dilatada/genética , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/genética , Humanos , Masculino , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/genética , Fenótipo , Remodelação Ventricular/genética , Adulto JovemRESUMO
BACKGROUND: Although genotyping allows family screening and influences risk-stratification in patients with nonischemic dilated cardiomyopathy (DCM) or isolated left ventricular systolic dysfunction (LVSD), its result is negative in a significant number of patients, limiting its widespread adoption. OBJECTIVES: This study sought to develop and externally validate a score that predicts the probability for a positive genetic test result (G+) in DCM/LVSD. METHODS: Clinical, electrocardiogram, and echocardiographic variables were collected in 1,015 genotyped patients from Spain with DCM/LVSD. Multivariable logistic regression analysis was used to identify variables independently predicting G+, which were summed to create the Madrid Genotype Score. The external validation sample comprised 1,097 genotyped patients from the Maastricht and Trieste registries. RESULTS: A G+ result was found in 377 (37%) and 289 (26%) patients from the derivation and validation cohorts, respectively. Independent predictors of a G+ result in the derivation cohort were: family history of DCM (OR: 2.29; 95% CI: 1.73-3.04; P < 0.001), low electrocardiogram voltage in peripheral leads (OR: 3.61; 95% CI: 2.38-5.49; P < 0.001), skeletal myopathy (OR: 3.42; 95% CI: 1.60-7.31; P = 0.001), absence of hypertension (OR: 2.28; 95% CI: 1.67-3.13; P < 0.001), and absence of left bundle branch block (OR: 3.58; 95% CI: 2.57-5.01; P < 0.001). A score containing these factors predicted a G+ result, ranging from 3% when all predictors were absent to 79% when ≥4 predictors were present. Internal validation provided a C-statistic of 0.74 (95% CI: 0.71-0.77) and a calibration slope of 0.94 (95% CI: 0.80-1.10). The C-statistic in the external validation cohort was 0.74 (95% CI: 0.71-0.78). CONCLUSIONS: The Madrid Genotype Score is an accurate tool to predict a G+ result in DCM/LVSD.
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Cardiomiopatia Dilatada , Disfunção Ventricular Esquerda , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Estudos de Coortes , Genótipo , Humanos , Fatores de RiscoRESUMO
INTRODUCTION AND OBJECTIVES: HCN4 variants have been reported to cause combined sick sinus syndrome (SSS) and left ventricular noncompaction (LVNC) cardiomyopathy. This relationship has been proven in few cases and no previous patients have associated left atrial dilatation (LAD). Our objective was to study a familial disorder characterized by SSS, LAD, and hypertrabeculation/LVNC and to identify the underlying genetic and electrophysiological characteristics. METHODS: A family with SSS and LVNC underwent a clinical, genetic, and electrophysiological assessment. They were studied via electrocardiography, Holter recording, echocardiography, and exercise stress tests; cardiac magnetic resonance imaging was additionally performed in affected individuals. Genetic testing was undertaken with targeted next-generation sequencing, as well as a functional study of the candidate variant in Chinese hamster ovary cells. RESULTS: Twelve members of the family had sinus bradycardia, associated with complete criteria of LVNC in 4 members and hypertrabeculation in 6 others, as well as LAD in 9 members. A HCN4 c.1123C>T;(p.R375C) variant was present in heterozygosis in all affected patients and absent in unaffected individuals. Electrophysiological analyses showed that the amplitude and densities of the HCN4 currents (IHCN4) generated by mutant p.R375C HCN4 channels were significantly lower than those generated by wild-type channels. CONCLUSIONS: The combined phenotype of SSS, LAD, and LVNC is associated with the heritable HCN4 c.1123C>T;(p.R375C) variant. HCN4 variants should be included in the genetic diagnosis of LVNC cardiomyopathy and of patients with familial forms of SSS, as well as of individuals with sinus bradycardia and LAD.
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Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Síndrome do Nó Sinusal , Animais , Bradicardia/diagnóstico , Bradicardia/genética , Células CHO , Cricetinae , Cricetulus , Dilatação , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Proteínas Musculares/genética , Fenótipo , Canais de Potássio/genética , Síndrome do Nó Sinusal/diagnóstico , Síndrome do Nó Sinusal/genéticaRESUMO
BACKGROUND: The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled. OBJECTIVES: The study sought to assess the prognostic impact of disease-causing genetic variants in DCM. METHODS: Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR). RESULTS: After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.09-2.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction ≤35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene. CONCLUSIONS: In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene.
Assuntos
Cardiomiopatia Dilatada/genética , Variação Genética , Insuficiência Cardíaca/genética , Adulto , Idoso , Arritmias Cardíacas/fisiopatologia , Feminino , Genótipo , Ventrículos do Coração , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco , Volume Sistólico/genética , Resultado do Tratamento , Disfunção Ventricular/fisiopatologia , Função Ventricular Esquerda , Remodelação VentricularRESUMO
INTRODUCTION AND OBJECTIVES: According to sudden cardiac death guidelines, an implantable cardioverter-defibrillator (ICD) should be considered in patients with LMNA-related dilated cardiomyopathy (DCM) and ≥ 2 risk factors: male sex, left ventricular ejection fraction (LVEF) <45%, nonsustained ventricular tachycardia (NSVT), and nonmissense genetic variants. In this study we aimed to describe the clinical characteristics of carriers of LMNA genetic variants among individuals from a Spanish cardiac-laminopathies cohort (REDLAMINA registry) and to assess previously reported risk criteria. METHODS: The relationship between risk factors and cardiovascular events was evaluated in a cohort of 140 carriers (age ≥ 16 years) of pathogenic LMNA variants (54 probands, 86 relatives). We considered: a) major arrhythmic events (MAE) if there was appropriate ICD discharge or sudden cardiac death; b) heart failure death if there was heart transplant or death due to heart failure. RESULTS: We identified 11 novel and 21 previously reported LMNA-related DCM variants. LVEF <45% (P=.001) and NSVT (P <.001) were related to MAE, but not sex or type of genetic variant. The only factor independently related to heart failure death was LVEF <45% (P <.001). CONCLUSIONS: In the REDLAMINA registry cohort, the only predictors independently associated with MAE were NSVT and LVEF <45%. Therefore, female carriers of missense variants with either NSVT or LVEF <45% should not be considered a low-risk group. It is important to individualize risk stratification in carriers of LMNA missense variants, because not all have the same prognosis.
Assuntos
Laminopatias , Adolescente , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Desfibriladores Implantáveis , Feminino , Humanos , Masculino , Sistema de Registros , Fatores de Risco , Volume Sistólico , Taquicardia Ventricular , Função Ventricular EsquerdaRESUMO
BACKGROUND: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. METHODS: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). RESULTS: Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P=0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; P=0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; P<0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (P=0.07). CONCLUSIONS: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.
Assuntos
Cardiomiopatia Dilatada/genética , Conectina/genética , Variação Genética , Disfunção Ventricular Esquerda/genética , Função Ventricular Esquerda/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/terapia , Europa (Continente) , Feminino , Predisposição Genética para Doença , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , New South Wales , Fenótipo , Prognóstico , Medição de Risco , Fatores de Risco , Fatores Sexuais , Volume Sistólico/genética , Fatores de Tempo , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/terapia , Remodelação VentricularRESUMO
INTRODUCTION AND OBJECTIVES: The cardiology day hospital (CDH) is an alternative to hospitalization for scheduled cardiological procedures. The aims of this study were to analyze the activity, quality of care and the cost-effectiveness of a CDH. METHODS: An observational descriptive study was conducted of the health care activity during the first year of operation of DHHA. The quality of care was analyzed through the substitution rate (outpatient procedures), cancellation rates, complications, and a satisfaction survey. For cost-effectiveness, we calculated the economic savings of avoided hospital stays. RESULTS: A total of 1646 patients were attended (mean age 69 ± 15 years, 60% men); 2550 procedures were scheduled with a cancellation rate of 4%. The most frequently cancelled procedure was electrical cardioversion. The substitution rate for scheduled invasive procedures was 66%. Only 1 patient required readmission after discharge from the CDH due to heart failure. Most surveyed patients (95%) considered the care received in the CDH to be good or very good. The saving due to outpatient-converted procedures made possible by the CDH was 219 199.55, higher than the cost of the first year of operation. CONCLUSIONS: In our center, the CDH allowed more than two thirds of the invasive procedures to be performed on an outpatient basis, while maintaining the quality of care. In the first year of operation, the expenses due to its implementation were offset by a significant reduction in hospital admissions.
Assuntos
Hospital Dia/normas , Qualidade da Assistência à Saúde , Idoso , Procedimentos Cirúrgicos Ambulatórios/economia , Procedimentos Cirúrgicos Ambulatórios/normas , Unidades de Cuidados Coronarianos/economia , Unidades de Cuidados Coronarianos/normas , Análise Custo-Benefício , Hospital Dia/economia , Atenção à Saúde/economia , Atenção à Saúde/normas , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Satisfação do Paciente , Complicações Pós-Operatórias/economia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Espanha , Procedimentos Cirúrgicos Torácicos/economia , Procedimentos Cirúrgicos Torácicos/normas , Procedimentos Cirúrgicos Torácicos/estatística & dados numéricosRESUMO
Magnetic resonance (MR) is considered the gold standard in the assessment of myocardial morphology, function, perfusion, and viability. However, its main limitation is its scarce availability. In 2014, we installed the first MR scanner exclusively managed by a cardiology department within the publicly-funded Spanish healthcare system with the aim of improving patient-care, training and research in the department. In the time interval analyzed, July 2014 to May 2017, 3422 cardiac MR scans were performed (32minutes used per study; 96% with good quality; 75% with contrast media administration). The most prevalent clinical indications were cardiomyopathy (29%) and ischemic heart disease (12%). Twenty-five percent of studies were conducted in the context of research protocols. Follow-up studies predominated among outpatients, while pretherapeutic assessment was more common in hospitalized patients. The presumptive diagnosis was changed by cardiac MR scanning in up to 20% of patients investigated for ischemic heart disease. The installation and operative management of an MR scanner in our cardiology department has allowed us to integrate this technique into daily clinical practice, modify our clinical protocols, optimize access to this technology among cardiac patients, improve training, and conduct clinical research.
Assuntos
Institutos de Cardiologia/organização & administração , Doença da Artéria Coronariana/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética/métodos , Isquemia Miocárdica/diagnóstico por imagem , Programas Nacionais de Saúde/organização & administração , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Saúde Pública , Melhoria de Qualidade , Estudos Retrospectivos , EspanhaRESUMO
INTRODUCTION AND OBJECTIVES: Myocardial interstitial fibrosis, a hallmark of hypertrophic cardiomyopathy (HCM), has been proposed as an arrhythmic substrate. Fibrosis is associated with increased extracellular volume (ECV), which can be quantified by computed tomography (CT). We aimed to analyze the association between CT-determined ECV and malignant ventricular arrhythmias. METHODS: A retrospective case-control observational study was conducted in HCM patients with implantable cardioverter-defibrillator, undergoing a CT-protocol with continuous iodine contrast infusion to determine equilibrium ECV. Left ventricular septal and lateral CT-determined ECV was compared between prespecified cases (malignant arrhythmia any time before CT scan) and controls (no prior malignant arrhythmias) and among ECV tertiles. RESULTS: A total of 78 implantable cardioverter-defibrillator HCM patients were included; 24 were women, with a mean age of 52.1 ± 15.6 years. Mean ECV ± standard deviation in the septal left ventricular wall and was 29.8% ± 6.3% in cases (n = 24) vs 31.9% ± 8.5% in controls (n = 54); P = .282. Mean ECV in the lateral wall was 24.5% ± 6.8% in cases vs 28.2% ± 7.4% in controls; P = .043. On comparison of the entire population according to septal ECV tertiles, no significant differences were found in the number of patients receiving appropriate shocks. Conversely, we found a trend (P = .056) for a higher number of patients receiving appropriate shocks in the lateral ECV lowest tertile. CONCLUSIONS: Extracellular volume was not increased in implantable cardioverter-defibrillator HCM patients with malignant ventricular arrhythmias vs those without arrhythmias. Our findings do not support the use of ECV (a surrogate of diffuse fibrosis) as a predictor of arrhythmias in high-risk HCM patients.