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AIMS: Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up. METHODS AND RESULTS: We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6-3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79-0.87) and calibration slope of 0.97. CONCLUSION: The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)-positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up.
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Arritmias Cardíacas , Desfibriladores Implantáveis , Feminino , Humanos , Masculino , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/terapia , Proteínas de Ligação ao Cálcio/genética , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , Reprodutibilidade dos Testes , Fatores de Risco , Adulto , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC. METHODS: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22â 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124â 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers. RESULTS: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22â 773; 0.004%) and external comparison groups (4/124â 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias. CONCLUSIONS: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.
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Cardiomiopatia Dilatada , Cardiopatias Congênitas , Masculino , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Feminino , Cardiomiopatia Dilatada/patologia , Cardiopatias Congênitas/genética , Arritmias Cardíacas , Fenótipo , Proteínas com Domínio T/genéticaRESUMO
BACKGROUND: The complex genetics underlying human cardiac disease is evidenced by its heterogenous manifestation, multigenic basis, and sporadic occurrence. These features have hampered disease modeling and mechanistic understanding. Here, we show that 2 structural cardiac diseases, left ventricular noncompaction (LVNC) and bicuspid aortic valve, can be caused by a set of inherited heterozygous gene mutations affecting the NOTCH ligand regulator MIB1 (MINDBOMB1) and cosegregating genes. METHODS: We used CRISPR-Cas9 gene editing to generate mice harboring a nonsense or a missense MIB1 mutation that are both found in LVNC families. We also generated mice separately carrying these MIB1 mutations plus 5 additional cosegregating variants in the ASXL3, APCDD1, TMX3, CEP192, and BCL7A genes identified in these LVNC families by whole exome sequencing. Histological, developmental, and functional analyses of these mouse models were carried out by echocardiography and cardiac magnetic resonance imaging, together with gene expression profiling by RNA sequencing of both selected engineered mouse models and human induced pluripotent stem cell-derived cardiomyocytes. Potential biochemical interactions were assayed in vitro by coimmunoprecipitation and Western blot. RESULTS: Mice homozygous for the MIB1 nonsense mutation did not survive, and the mutation caused LVNC only in heteroallelic combination with a conditional allele inactivated in the myocardium. The heterozygous MIB1 missense allele leads to bicuspid aortic valve in a NOTCH-sensitized genetic background. These data suggest that development of LVNC is influenced by genetic modifiers present in affected families, whereas valve defects are highly sensitive to NOTCH haploinsufficiency. Whole exome sequencing of LVNC families revealed single-nucleotide gene variants of ASXL3, APCDD1, TMX3, CEP192, and BCL7A cosegregating with the MIB1 mutations and LVNC. In experiments with mice harboring the orthologous variants on the corresponding Mib1 backgrounds, triple heterozygous Mib1 Apcdd1 Asxl3 mice showed LVNC, whereas quadruple heterozygous Mib1 Cep192 Tmx3;Bcl7a mice developed bicuspid aortic valve and other valve-associated defects. Biochemical analysis suggested interactions between CEP192, BCL7A, and NOTCH. Gene expression profiling of mutant mouse hearts and human induced pluripotent stem cell-derived cardiomyocytes revealed increased cardiomyocyte proliferation and defective morphological and metabolic maturation. CONCLUSIONS: These findings reveal a shared genetic substrate underlying LVNC and bicuspid aortic valve in which MIB1-NOTCH variants plays a crucial role in heterozygous combination with cosegregating genetic modifiers.
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Doença da Válvula Aórtica Bicúspide , Cardiomiopatias , Cardiopatias Congênitas , Células-Tronco Pluripotentes Induzidas , Humanos , Animais , Camundongos , Cardiopatias Congênitas/complicações , Cardiomiopatias/etiologia , Miócitos Cardíacos , Valva Aórtica/diagnóstico por imagem , Fatores de Transcrição , Proteínas Cromossômicas não HistonaRESUMO
BACKGROUND: Infection by the SARS-Cov-2 virus produces in humans a disease of highly variable and unpredictable severity. The presence of frequent genetic single nucleotide polymorphisms (SNPs) in the population might lead to a greater susceptibility to infection or an exaggerated inflammatory response. SARS-CoV-2 requires the presence of the ACE2 protein to enter in the cell and ACE2 is a regulator of the renin-angiotensin system. Accordingly, we studied the associations between 8 SNPs from AGTR1, ACE2 and ACE genes and the severity of the disease produced by the SARS-Cov-2 virus. METHODS: 318 (aged 59.6±17.3 years, males 62.6%) COVID-19 patients were grouped based on the severity of symptoms: Outpatients (n = 104, 32.7%), hospitalized on the wards (n = 73, 23.0%), Intensive Care Unit (ICU) (n = 84, 26.4%) and deceased (n = 57, 17.9%). Comorbidity data (diabetes, hypertension, obesity, lung disease and cancer) were collected for adjustment. Genotype distribution of 8 selected SNPs among the severity groups was analyzed. RESULTS: Four SNPs in ACE2 were associated with the severity of disease. While rs2074192 andrs1978124showed a protector effectassuming an overdominant model of inheritance (G/A vs. GG-AA, OR = 0.32, 95%CI = 0.12-0.82; p = 0.016 and A/G vs. AA-GG, OR = 0.37, 95%CI: 0.14-0.96; p = 0.038, respectively); the SNPs rs2106809 and rs2285666were associated with an increased risk of being hospitalized and a severity course of the disease with recessive models of inheritance (C/C vs. T/C-T/T, OR = 11.41, 95% CI: 1.12-115.91; p = 0.012) and (A/A vs. GG-G/A, OR = 12.61, 95% CI: 1.26-125.87; p = 0.0081). As expected, an older age (OR = 1.47), male gender (OR = 1.98) and comorbidities (OR = 2.52) increased the risk of being admitted to ICU or death vs more benign outpatient course. Multivariable analysis demonstrated the role of the certain genotypes (ACE2) with the severity of COVID-19 (OR: 0.31, OR 0.37 for rs2074192 and rs1978124, and OR = 2.67, OR = 2.70 for rs2106809 and rs2285666, respectively). Hardy-Weinberg equilibrium in hospitalized group for I/D SNP in ACE was not showed (p<0.05), which might be due to the association with the disease. No association between COVID-19 disease and the different AGTR1 SNPs was evidenced on multivariable, nevertheless the A/A genotype for rs5183 showed an higher hospitalization risk in patients with comorbidities. CONCLUSIONS: Different genetic variants in ACE2 were associated with a severe clinical course and death groups of patients with COVID-19. ACE2 common SNPs in the population might modulate severity of COVID-19 infection independently of other known markers like gender, age and comorbidities.
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Enzima de Conversão de Angiotensina 2/genética , COVID-19/patologia , Peptidil Dipeptidase A/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Angiotensina/genética , SARS-CoV-2/genética , Índice de Gravidade de Doença , Idoso , COVID-19/genética , COVID-19/virologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS: This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model. METHODS AND RESULTS: Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27-55]. During a median follow-up of 4.3 years (IQR 1.7-7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78-0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61-0.75). CONCLUSION: This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach.
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Arritmias Cardíacas , Proteínas de Ligação ao Cálcio/genética , Desfibriladores Implantáveis , Função Ventricular Esquerda , Adulto , Arritmias Cardíacas/genética , Morte Súbita Cardíaca/etiologia , Feminino , Humanos , Masculino , Mutação , Fatores de Risco , Volume SistólicoRESUMO
Left ventricular non-compaction (LVNC) is defined by an increase of trabeculations in left ventricular (LV) endomyocardium. Although LVNC can be in isolation, an increase in hypertrabeculation often accompanies genetic cardiomyopathies. Current methods for quantification of LV trabeculae have limitations. Several improvements are proposed and implemented to enhance a software tool to quantify the trabeculae degree in the LV myocardium in an accurate and automatic way for a population of patients with genetic cardiomyopathies (QLVTHCI). The software tool is developed and evaluated for a population of 59 patients (470 end-diastole cardiac magnetic resonance images). This tool produces volumes of the compact sector and the trabecular area, the proportion between these volumes, and the left ventricular and trabeculated masses. Substantial enhancements are obtained over the manual process performed by cardiologists, so saving important diagnosis time. The parallelization of the detection of the external layer is proposed to ensure real-time processing of a patient, obtaining speed-ups from 7.5 to 1500 with regard to QLVTHCI and the manual process used traditionally by cardiologists. Comparing the method proposed with the fractal proposal to differentiate LVNC and non-LVNC patients among 27 subjects with previously diagnosed cardiomyopathies, QLVTHCI presents a full diagnostic accuracy, while the fractal criteria achieve 78%. Moreover, QLTVHCI can be installed and integrated in hospitals on request, whereas the high cost of the license of the fractal method per year of this tool has prevented reproducibility by other medical centers.
RESUMO
BACKGROUND: Phospholamban (PLN) p.Arg14del mutation carriers are known to develop dilated and/or arrhythmogenic cardiomyopathy, and typical electrocardiographic (ECG) features have been identified for diagnosis. Machine learning is a powerful tool used in ECG analysis and has shown to outperform cardiologists. OBJECTIVES: We aimed to develop machine learning and deep learning models to diagnose PLN p.Arg14del cardiomyopathy using ECGs and evaluate their accuracy compared to an expert cardiologist. METHODS: We included 155 adult PLN mutation carriers and 155 age- and sex-matched control subjects. Twenty-one PLN mutation carriers (13.4%) were classified as symptomatic (symptoms of heart failure or malignant ventricular arrhythmias). The data set was split into training and testing sets using 4-fold cross-validation. Multiple models were developed to discriminate between PLN mutation carriers and control subjects. For comparison, expert cardiologists classified the same data set. The best performing models were validated using an external PLN p.Arg14del mutation carrier data set from Murcia, Spain (n = 50). We applied occlusion maps to visualize the most contributing ECG regions. RESULTS: In terms of specificity, expert cardiologists (0.99) outperformed all models (range 0.53-0.81). In terms of accuracy and sensitivity, experts (0.28 and 0.64) were outperformed by all models (sensitivity range 0.65-0.81). T-wave morphology was most important for classification of PLN p.Arg14del carriers. External validation showed comparable results, with the best model outperforming experts. CONCLUSION: This study shows that machine learning can outperform experienced cardiologists in the diagnosis of PLN p.Arg14del cardiomyopathy and suggests that the shape of the T wave is of added importance to this diagnosis.
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Algoritmos , Displasia Arritmogênica Ventricular Direita/diagnóstico , Proteínas de Ligação ao Cálcio/genética , Cardiologistas/normas , Eletrocardiografia , Aprendizado de Máquina , Mutação , Adolescente , Adulto , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Proteínas de Ligação ao Cálcio/metabolismo , Competência Clínica , Computadores , DNA/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto JovemRESUMO
Hypertrophic cardiomyopathy (HCM) is characterized by an abnormal increase in myocardial mass that affects cardiac structure and function. HCM is the most common inherited cardiovascular disease in humans (0.2%) and the most common cardiovascular disease in cats (14.7%). Feline HCM phenotype is very similar to the phenotype found in humans, but the time frame for the development of the disease is significantly shorter. Similar therapeutic agents are used in its treatment and it has the same complications, such as heart failure, thromboembolism and sudden cardiac death. In contrast to humans, in whom thousands of genetic variants have been identified, genetic studies in cats have been limited to fragment analysis of two sarcomeric genes identifying two variants in MYBPC3 and one in MYH7. Two of these variants have also been associated with human disease. The high prevalence of the reported variants in non-affected cats hinders the assumption of their pathogenicity in heterozygotes. An in-depth review of the literature about genetic studies on feline HCM in comparison with the same disease in humans is presented here. The close similarity in the phenotype and genotype between cats and humans makes the cat an excellent model for the pathophysiological study of the disease and future therapeutic agents.
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Cardiomiopatia Hipertrófica/genética , Doenças do Gato/genética , Predisposição Genética para Doença , Sarcômeros/genética , Animais , Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/fisiopatologia , Proteínas de Transporte/genética , Doenças do Gato/tratamento farmacológico , Doenças do Gato/fisiopatologia , Gatos , Modelos Animais de Doenças , Humanos , Cadeias Pesadas de Miosina/genética , Sarcômeros/patologiaRESUMO
With the development of deep sequencing, a significant proportion of mutations already listed in studies have inconclusive pathogenicity. We aim to establish the proportion of cases in which familial studies are possible and cosegregation analysis is informative. We also compare cosegregation analysis with in silico software and a proposed pathogenicity score. 204 consecutive positive tests were reviewed. 4 different in silico software programs were used. Spaendonck-Zwarts' pathogenicity score was also calculated. A total of 73 of the missense variants could be classified by the score as being likely or definitively pathogenic. A high percentage of nonsense variants were found in desmosomal genes and missense variants in sarcomeric genes. 36.3% of the missense variants in our cohort classified as very likely or definitively pathogenic were novel. Cosegregation analysis was positive in 19.5% and could be discarded in 15.6%. There was a significant discrepancy between the in silico tools used in the setting of inherited heart disease. Multiparametric scoring systems which include cosegregation and functional studies seem to perform better than individual prediction software.
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BACKGROUND: The intermediate group of patients with heart failure (HF) and mid-range left ventricular ejection fraction (HFmrEF) may constitute a specific phenotype, but a direct evidence is lacking. This study aimed to know whether this HF category is accompanied by a particular clinical phenotype and prognosis. METHODS AND RESULTS: This study includes 3446 ambulatory patients with chronic HF from two national registries. According to EF at enrollment, patients were classified as reduced (HFrEF, <40%), mid-range (HFmrEF, 40-49%) or preserved (HFpEF, ≥50%). Patients were followed-up for a median of 41months and the specific cause of death was prospectively registered. Patients with HFmrEF represented 13% of population and they exhibited a phenotype closer to HFrEF, except for a higher rate of coronary revascularization and diabetes, and a less advanced HF syndrome. The observed all-cause mortality was higher among HFrEF (33.0%), and similar between HFmrEF (27.8%) and HFpEF (28.0%) (p=0.012); however, the contribution of each cause of death differed significantly between categories (p<0.001). After propensity score matching, the risk of cardiovascular death, HF death or sudden cardiac death did not differ between HFmrEF and HFrEF in paired samples; however, patients with HFmrEF were at higher risk of cardiovascular death (sHR 1.71, 95% CI 1.13-2.57, p=0.011) and sudden cardiac death (sHR 2.73, 95% CI 1.07-6.98, p=0.036) than patients with HFpEF. CONCLUSIONS: Patients in the intermediate category of HFmrEF conform a phenotype closer to the clinical profile of HFrEF, and associated to higher risk of sudden cardiac death and cardiovascular death than patients with HFpEF.
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Assistência Ambulatorial , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Função Ventricular Esquerda/fisiologia , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial/tendências , Causas de Morte , Doença Crônica , Estudos de Coortes , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de RegistrosRESUMO
INTRODUCTION AND OBJECTIVES: Patients with congenital long QT syndrome (LQTS) have an abnormal QT adaptation to sudden changes in heart rate provoked by standing. The present study sought to evaluate the standing test in a cohort of LQTS patients and to assess if this QT maladaptation phenomenon is ameliorated by beta-blocker therapy. METHODS: Electrographic assessments were performed at baseline and immediately after standing in 36 LQTS patients (6 LQT1 [17%], 20 LQT2 [56%], 3 LQT7 [8%], 7 unidentified-genotype patients [19%]) and 41 controls. The corrected QT interval (QTc) was measured at baseline (QTcsupine) and immediately after standing (QTcstanding); the QTc change from baseline (ΔQTc) was calculated as QTcstanding - QTcsupine. The test was repeated in 26 patients receiving beta-blocker therapy. RESULTS: Both QTcstanding and ΔQTc were significantly higher in the LQTS group than in controls (QTcstanding, 528 ± 46ms vs 420 ± 15ms, P < .0001; ΔQTc, 78 ± 40ms vs 8 ± 13ms, P < .0001). No significant differences were noted between LQT1 and LQT2 patients. Typical ST-T wave patterns appeared after standing in LQTS patients. Receiver operating characteristic curves of QTcstanding and ΔQTc showed a significant increase in diagnostic value compared with the QTcsupine (area under the curve for both, 0.99 vs 0.85; P < .001). Beta-blockers attenuated the response to standing in LQTS patients (QTcstanding, 440 ± 32ms, P < .0001; ΔQTc, 14 ± 16ms, P < .0001). CONCLUSIONS: Evaluation of the QTc after the simple maneuver of standing shows a high diagnostic performance and could be important for monitoring the effects of beta-blocker therapy in LQTS patients.
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Teste de Esforço/métodos , Síndrome do QT Longo/diagnóstico , Antagonistas Adrenérgicos beta , Adulto , Estudos de Casos e Controles , Feminino , Frequência Cardíaca , Humanos , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/fisiopatologia , Masculino , Testes Imediatos , Postura , Curva ROCRESUMO
BACKGROUND: Filamin C (encoded by the FLNC gene) is essential for sarcomere attachment to the plasmatic membrane. FLNC mutations have been associated with myofibrillar myopathies, and cardiac involvement has been reported in some carriers. Accordingly, since 2012, the authors have included FLNC in the genetic screening of patients with inherited cardiomyopathies and sudden death. OBJECTIVES: The aim of this study was to demonstrate the association between truncating mutations in FLNC and the development of high-risk dilated and arrhythmogenic cardiomyopathies. METHODS: FLNC was studied using next-generation sequencing in 2,877 patients with inherited cardiovascular diseases. A characteristic phenotype was identified in probands with truncating mutations in FLNC. Clinical and genetic evaluation of 28 affected families was performed. Localization of filamin C in cardiac tissue was analyzed in patients with truncating FLNC mutations using immunohistochemistry. RESULTS: Twenty-three truncating mutations were identified in 28 probands previously diagnosed with dilated, arrhythmogenic, or restrictive cardiomyopathies. Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 patients with hypertrophic cardiomyopathy. Fifty-four mutation carriers were identified among 121 screened relatives. The phenotype consisted of left ventricular dilation (68%), systolic dysfunction (46%), and myocardial fibrosis (67%); inferolateral negative T waves and low QRS voltages on electrocardiography (33%); ventricular arrhythmias (82%); and frequent sudden cardiac death (40 cases in 21 of 28 families). Clinical skeletal myopathy was not observed. Penetrance was >97% in carriers older than 40 years. Truncating mutations in FLNC cosegregated with this phenotype with a dominant inheritance pattern (combined logarithm of the odds score: 9.5). Immunohistochemical staining of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations. CONCLUSIONS: Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death. Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC.
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Cardiomiopatias/genética , DNA/genética , Filaminas/genética , Mutação , Taquicardia Ventricular/genética , Adolescente , Adulto , Idoso , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Filaminas/metabolismo , Genótipo , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taquicardia Ventricular/complicações , Taquicardia Ventricular/metabolismo , Adulto JovemAssuntos
Cardiomiopatia Hipertrófica/diagnóstico , Eletrocardiografia , Hipertensão/fisiopatologia , Adulto , Cardiomiopatia Hipertrófica/etiologia , Cardiomiopatia Hipertrófica/fisiopatologia , Diagnóstico Diferencial , Ecocardiografia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION AND OBJECTIVES: Long QT syndrome is an inherited ion channelopathy that leads to syncope and sudden death. Because of the heterogeneous phenotype of this disease, genetic testing is fundamental to detect individuals with concealed long QT syndrome. In this study, we determined the features of a family with 13 carriers of the KCNH2-H562R missense mutation, which affects the pore region of the HERG channel. METHODS: We identified the KCNH2-H562R mutation in a 65-year-old man with a prolonged QTc interval who had experienced an episode of torsade de pointes. Subsequently, a total of 13 mutation carriers were identified in the family. Carriers (age 48 [26] years; 46% males) underwent clinical evaluation, electrocardiography and echocardiography. RESULTS: The mean (standard deviation) QTc in carriers was 493 (42) ms (3 [23%] showed normal QTc); 6 (46%) had symptoms (4, syncope; 1, sudden death; 1, aborted sudden death [proband]). While under treatment with beta-blockers, 11 of 12 carriers (92%) remained asymptomatic at 5 years of follow-up (1 patient required left cardiac sympathectomy). The QTc shortening with beta-blockers was 50 (37) ms. There was 1 sudden death in a patient who refused treatment. CONCLUSIONS: Family study is essential in the interpretation of a genetic testing result. This article describes the heterogeneous and variable phenotype of a large family with the KCNH2-H562R mutation and highlights the role of genetic study for the appropriate identification of at-risk individuals who would benefit from treatment.
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DNA/genética , Canal de Potássio ERG1/genética , Eletrocardiografia , Sistema de Condução Cardíaco/fisiopatologia , Síndrome do QT Longo/genética , Mutação , Linhagem , Idoso , Idoso de 80 Anos ou mais , Pré-Escolar , Análise Mutacional de DNA , Canal de Potássio ERG1/metabolismo , Feminino , Testes Genéticos , Heterozigoto , Humanos , Síndrome do QT Longo/fisiopatologia , Masculino , Fenótipo , Adulto JovemAssuntos
Morte Súbita Cardíaca/patologia , Fibroelastose Endocárdica/patologia , Cardiopatias/patologia , Mixedema/patologia , Adulto , Autopsia , Morte Súbita Cardíaca/etiologia , Diagnóstico Diferencial , Fibroelastose Endocárdica/complicações , Endocárdio/patologia , Evolução Fatal , Feminino , Humanos , Miocárdio/patologia , Mixedema/complicaçõesRESUMO
BACKGROUND AND OBJECTIVE: Fabry disease is an X-linked multisystemic lysosomal-storage condition. We describe a large family with a novel GLA mutation: p.M187R/g7219 T>G. PATIENTS AND METHODS: Anamnesis/physical-exam, blood/urine analysis, α-Gal-A activity and/or genetic study of at-risk individuals and multidisciplinary evaluation in confirmed cases. RESULTS: 4 males and 13 heterozygous-females displayed the mutation. Cardiac/renal/neurological disease was diagnosed at a mean age of 41/29/39 years in males and 51/56/46 years in females. Onset mean age was 20 years versus 42 years. 9/15 had cardiomyopathy. Delta wave suggestive of accessory pathway was identified in 1 male and 2 females. 1 female had cardiac arrest (ventricular fibrillation, 61 years). 2 females and 1 male died suddenly (63, 64 and 57 years). Cardiac-subscore of Mainz Severity-Score-Index was severe for males and females over 40 years. 4/15(26%) developed early renal disease. 2 males needed dialysis. 1 male died at 69 years in spite of kidney-heart transplant. CONCLUSION: We describe the largest genetically confirmed Spanish family using multidisciplinary evaluation and MSSI calculation. The novel mutation p.M187R/g7219 T>G is associated with a particularly malignant cardiac phenotype in males and females over 40 years. Severity was higher than that of the largest Spanish FOS-cohort. Short-PR with delta is being reported for the first time.
Assuntos
Doença de Fabry/epidemiologia , Mutação de Sentido Incorreto , Mutação Puntual , alfa-Galactosidase/genética , Adulto , Idade de Início , Substituição de Aminoácidos , Arritmias Cardíacas/etiologia , Encéfalo/patologia , Terapia de Reposição de Enzimas , Oftalmopatias/etiologia , Doença de Fabry/complicações , Doença de Fabry/tratamento farmacológico , Doença de Fabry/genética , Doença de Fabry/patologia , Feminino , Genótipo , Parada Cardíaca/etiologia , Transplante de Coração , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Rim/patologia , Doenças Renais Císticas/etiologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgia , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Linhagem , Espanha/epidemiologia , alfa-Galactosidase/uso terapêuticoRESUMO
INTRODUCTION AND OBJECTIVES: Using gadolinium-enhanced cardiovascular magnetic resonance, it is possible to evaluate the presence of myocardial fibrosis in hypertrophic cardiomyopathy. Classical disease markers are weak predictors of functional disability in affected patients. Our objective was to study the relationship between the degree of myocardial fibrosis observed by cardiac magnetic resonance and exercise capacity. METHODS: We performed cardiac magnetic resonance, echocardiography, exercise testing and Holter monitoring, along with the usual clinical assessments, in 98 patients (age, 46.3+/-15.4 years, 71.4% male) referred from two specialist hypertrophic cardiomyopathy clinics. Cardiac magnetic resonance assessment included quantifying the degree of fibrosis (i.e., the percentage of the myocardium showing enhancement) 10 min after gadolinium infusion. Symptom-limited exercise testing was used to determine exercise capacity (in metabolic equivalent [MET] units). In 71 patients, the basal N-terminal probrain natriuretic peptide (NT-proBNP) level was also measured. RESULTS: Late enhancement was observed on cardiac magnetic resonance in 67 (68.4%) patients. These patients had a lower exercise capacity (8.04+/-3.56 MET vs. 10.41+/-3.57 MET; P=.003). There was an inverse correlation between the percentage of fibrosis and exercise capacity (r=-0.21; P=.044). The best predictor of exercise capacity was the logarithm of the NT-proBNP level (r=-0.5; P< .0001). Multivariate analysis confirmed that age, a history of atrial fibrillation, the basal NT-proBNP level and the presence of fibrosis were independent predictors of exercise capacity (r2 for the model=0.47). CONCLUSIONS: The observation of areas of late gadolinium enhancement on cardiac magnetic resonance was independently associated with poor exercise capacity in patients with hypertrophic cardiomyopathy.
Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Meios de Contraste , Teste de Esforço , Gadolínio , Imageamento por Ressonância Magnética , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-IdadeRESUMO
Today, cardiovascular disease is the principal cause of death and hospitalization in Spain, and accounts for an annual healthcare budget of more than 4000 million euros. Consequently, early diagnosis, effective prevention, and the optimum treatment of cardiovascular disease present a significant social and healthcare challenge for the country. In this context, combining all available resources to increase the efficacy and healthcare benefits of scientific research is a priority. This rationale prompted the establishment of the Spanish Cooperative Cardiovascular Disease Research Network, or RECAVA (Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares), 5 years ago. Since its foundation, RECAVA's activities have focused on achieving four objectives: a) to facilitate contacts between basic, clinical and epidemiological researchers; b) to promote the shared use of advanced technological facilities; c) to apply research results to clinical practice, and d) to train a new generation of translational cardiovascular researchers in Spain. At present, RECAVA consists of 41 research groups and seven shared technological facilities. RECAVA's research strategy is based on a scientific design matrix centered on the most important cardiovascular processes. The level of RECAVA's research activity is reflected in the fact that 28 co-authored articles were published in international journals during the first six months of 2007, with each involving contributions from at least two groups in the network. Finally, RECAVA also participates in the work of the Spanish National Center for Cardiovascular Research, or CNIC (Centro Nacional de Investigación Cardiovascular), and some established Biomedical Research Network Centers, or CIBER (Centros de Investigación Biomédica en RED), with the aim of consolidating the development of a dynamic multidisciplinary research framework that is capable of meeting the growing challenge that cardiovascular disease will present in the future.