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1.
Circ Genom Precis Med ; 11(10): e001797, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30354299

RESUMO

BACKGROUND: Accurate estimates of survival are indispensable for cardiologists, clinical geneticists, and genetic counselors dealing with families with an inherited cardiac disease. However, a bias towards a more severe disease with a worse outcome in the first publications may not accurately represent the actual survival forecast. We, therefore, evaluated the effect of ascertainment bias on survival in 3 different inherited cardiac diseases (idiopathic ventricular fibrillation, SCN5A overlap syndrome, and arrhythmogenic cardiomyopathy) caused by a founder mutation. METHODS: We collected mortality data from mutation-positive subjects with either DPP6-associated idiopathic ventricular fibrillation, SCN5A overlap syndrome, and PLN-R14del-mediated arrhythmogenic cardiomyopathy >2 to 10 years of ongoing clinical/cascade genetic screening. RESULTS: The median age of survival in DPP6 mutation-positive subjects increased from 44.6 years in the original cohort from 2008 (n=60; 95% CI, 36.8-52.4 years) to 68.2 years in the extended cohort from 2012 (n=235; 95% CI, 64.6-71.7 years; P<0.001). In the SCN5A overlap syndrome, survival increased from 56.1 years in 1999 (n=86; 95% CI, 48.0-64.2 years) to 69.7 years in 2009 (n=197; 95% CI, 61.3-78.2 years; P=0.049). In PLN-R14del positive patients, the median age of survival increased from 63.5 years in 2010 (n=89; 95% CI, 59.1-68.0 years) to 65.2 years in 2012 (n=370; 95% CI, 62.0-68.3 years; P=0.046). CONCLUSIONS: The median age of survival in 3 different inherited cardiac diseases with an established pathogenic substrate significantly increased once genetic testing and cascade screening extended, after the first publication that elucidated the discovery of the disease-susceptibility gene/mutation. This underscores the direct and negative influence of ascertainment bias on survival forecasts and the importance of ongoing clinical/genetic follow-up to establish the most accurate disease prognosis for genetically mediated heart diseases.


Assuntos
Cardiomiopatias , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Doenças Genéticas Inatas , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Fibrilação Ventricular , Adulto , Idoso , Cardiomiopatias/genética , Cardiomiopatias/mortalidade , Intervalo Livre de Doença , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Fibrilação Ventricular/genética , Fibrilação Ventricular/mortalidade
2.
Eur J Heart Fail ; 19(4): 512-521, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27813223

RESUMO

AIMS: Truncating titin mutations (tTTN) occur in 25% of dilated cardiomyopathy (DCM) cases, but the phenotype and severity of disease they cause have not yet been systematically studied. We studied whether tTTN variants are associated with a clinically distinguishable form of DCM. METHODS AND RESULTS: We compared clinical data on DCM probands and relatives with a tTTN mutation (n = 45, n = 73), LMNA mutation (n = 28, n = 29), and probands who tested negative for both genes [idiopathic DCM (iDCM); n = 60]. Median follow-up was at least 2.5 years in each group. TTN subjects presented with DCM at higher age than LMNA subjects (probands 47.9 vs. 40.4 years, P = 0.004; relatives 59.8 vs. 47.0 years, P = 0.01), less often developed LVEF <35% [probands hazard ratio (HR) 0.38, P = 0.002], had higher age of death (probands 70.4 vs. 59.4 years, P < 0.001; relatives 74.1 vs. 58.4 years, P = 0.008), and had better composite outcome (malignant ventricular arrhythmia, heart transplantation, or death; probands HR 0.09, P < 0.001; relatives HR 0.21, P = 0.02) than LMNA subjects and iDCM subjects (HR 0.36, P = 0.07). An LVEF increase of at least 10% occurred in 46.9% of TTN subjects after initiation of standard heart failure treatment, while this only occurred in 6.5% of LMNA subjects (P < 0.001) and 18.5% of iDCM subjects (P = 0.02). This was confirmed in families with co-segregation, in which the 10% point LVEF increase occurred in 55.6% of subjects (P = 0.003 vs. LMNA, P = 0.079 vs. iDCM). CONCLUSIONS: This study shows that tTTN-associated DCM is less severe at presentation and more amenable to standard therapy than LMNA mutation-induced DCM or iDCM.


Assuntos
Cardiomiopatia Dilatada/genética , Conectina/genética , Adulto , Idoso , Arritmias Cardíacas , Cardiomiopatia Dilatada/mortalidade , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/terapia , Estudos de Casos e Controles , Feminino , Seguimentos , Genótipo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Transplante de Coração , Coração Auxiliar , Humanos , Lamina Tipo A/genética , Masculino , Pessoa de Meia-Idade , Mortalidade , Mutação , Fenótipo , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Índice de Gravidade de Doença , Volume Sistólico
3.
Circ Cardiovasc Genet ; 7(4): 455-65, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24909667

RESUMO

BACKGROUND: The pathogenic phospholamban R14del mutation causes dilated and arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of phospholamban R14del mutation carriers. METHODS AND RESULTS: Using the family tree mortality ratio method in a cohort of 403 phospholamban R14del mutation carriers, we found a standardized mortality ratio of 1.7 (95% confidence interval, 1.4-2.0) with significant excess mortality starting from the age of 25 years. Cardiological data were available for 295 carriers. In a median follow-up period of 42 months, 55 (19%) individuals had a first episode of malignant ventricular arrhythmias and 33 (11%) had an end-stage heart failure event. The youngest age at which a malignant ventricular arrhythmia occurred was 20 years, whereas for an end-stage heart failure event this was 31 years. Independent risk factors for malignant ventricular arrhythmias were left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia with hazard ratios of 4.0 (95% confidence interval, 1.9-8.1) and 2.6 (95% confidence interval, 1.5-4.5), respectively. CONCLUSIONS: Phospholamban R14del mutation carriers are at high risk for malignant ventricular arrhythmias and end-stage heart failure, with left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia as independent risk factors. High mortality and a poor prognosis are present from late adolescence. Genetic and cardiac screening is, therefore, advised from adolescence onwards.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Proteínas de Ligação ao Cálcio/genética , Adulto , Fatores Etários , Idoso , Displasia Arritmogênica Ventricular Direita/mortalidade , Displasia Arritmogênica Ventricular Direita/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Estudos de Coortes , Eletrocardiografia , Feminino , Seguimentos , Deleção de Genes , Humanos , Falência Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e Questionários , Análise de Sobrevida
4.
Eur J Heart Fail ; 15(6): 628-36, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23349452

RESUMO

AIMS: With more than 40 dilated cardiomyopathy (DCM)-related genes known, genetic analysis of patients with idiopathic DCM is costly and time-consuming. We describe the yield from genetic analysis in DCM patients in a large Dutch cohort. METHODS AND RESULTS: We collected cardiological and neurological evaluations, family screenings, and genetic analyses for 418 index patients with idiopathic DCM. We identified 35 (putative) pathogenic mutations in 82 index patients (20%). The type of DCM influenced the yield, with mutations found in 25% of familial DCM cases, compared with 8% of sporadic DCM cases and 62% of cases where DCM was accompanied by neuromuscular disease. A PLN founder mutation (43 cases) and LMNA mutations (19 cases, 16 different mutations) were most prevalent and often demonstrated a specific phenotype. Other mutations were found in: MYH7, DES, TNNT2, DMD, TPM1, DMPK, SCN5A, SGCB (homozygous), and TNNI3. After a median follow-up of 40 months, the combined outcome of death from any cause, heart transplantation, or malignant ventricular arrhythmias in patients with a mutation was worse than in those without an identified mutation (hazard ratio 2.0, 95% confidence interval 1.4-3.0). This seems to be mainly attributable to a high prevalence of malignant ventricular arrhythmias and end-stage heart failure in LMNA and PLN mutation carriers. CONCLUSION: The yield of identified mutations in DCM index patients with clinical clues, such as associated neuromuscular disease or familial occurrence, is higher compared with those without these clues. For sporadic DCM, specific clinical characteristics may be used to select cases for DNA analysis.


Assuntos
Cardiomiopatia Dilatada/genética , Mutação/genética , Adulto , Proteínas de Ligação ao Cálcio/genética , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/mortalidade , Estudos de Coortes , Feminino , Testes Genéticos , Humanos , Lamina Tipo A/genética , Masculino , Pessoa de Meia-Idade , Doenças Neuromusculares/complicações , Doenças Neuromusculares/genética , Fenótipo , Prevalência
5.
Int J Cardiol ; 168(1): 472-7, 2013 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-23073275

RESUMO

BACKGROUND: Lamin A/C (LMNA) mutation carriers suffer from a variety of clinical phenotypes, including dilated cardiomyopathy (DCM). Although it has been suggested that carriers are at risk for thromboembolic complications, it is unknown whether this risk is higher than can be expected from the underlying cardiac abnormalities. The purpose of this study was to determine whether a LMNA mutation is associated with an increased risk of thromboembolic complications. METHODS: We compared a cohort of 76 LMNA mutation carriers with a cohort of 224 idiopathic DCM patients without a LMNA mutation, with respect to the prevalence of arterial and venous thromboembolic complications. Furthermore, we carried out a case-control study to explore whether a prothrombotic phenotype was present in LMNA mutation carriers without DCM or atrial tachyarrhythmias (n=14) and compared this with mutation negative relatives (n=13). RESULTS: The prevalence of thromboembolic complications was higher in the cohort of LMNA mutation carriers than in DCM patients (22 vs 11%; p<0.05), after respectively mean follow-up of 42 ± 12 and 49 ± 12 years. After adjustment for possible confounders, including atrial tachyarrhythmias and left ventricular ejection fraction, LMNA mutation carriership was independently associated with an increased risk of thromboembolic complications (HR 4.8, 95% CI: 2.2-10.6). The results of the case-control study suggested a prothrombotic phenotype in LMNA mutation carriers, as reflected by an altered platelet function and increased thrombin generation. CONCLUSIONS: LMNA mutation is independently associated with an increased risk of arterial and venous thromboembolic complications. Laboratory research in LMNA mutation carriers without severe cardiac abnormalities suggests a prothrombotic phenotype.


Assuntos
Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Lamina Tipo A/genética , Mutação/genética , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/genética , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Vasos Coronários/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
6.
Eur J Heart Fail ; 15(4): 376-84, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23183350

RESUMO

AIMS: Mutations in the lamin A/C gene (LMNA) cause a variety of clinical phenotypes, including dilated cardiomyopathy. LMNA is one of the most prevalent mutated genes in dilated cardiomyopathy, and is associated with a high risk of arrhythmias, sudden cardiac death, and heart failure. There are few data on the impact of age and gender on cardiac disease penetrance and mortality. METHODS AND RESULTS: In a multicentre cohort of 269 LMNA mutation carriers, we evaluated gender-specific penetrance of cardiac involvement and major cardiac events. All-cause mortality of mutation carriers [standardized mortality ratio (SMR)] was determined. Cardiac disease penetrance was age dependent and almost complete at the age of 70 years. The presence of an LVEF ≤45% was significantly higher in men (P < 0.001). However, there was no difference between genders in the prevalence of atrioventricular block, atrial tachyarrhythmias, and non-sustained ventricular tachycardia. Malignant ventricular arrhythmias (26% vs. 8%) and end-stage heart failure (28% vs. 14%) were more common in men than in women (P < 0.001 and P = 0.006, respectively). All-cause mortality of mutation carriers was significantly increased [SMR 4.0, 95% confidence interval (CI) 2.8-5.2] between the ages of 15 and 75 years. Mortality in men was higher than in women (hazard ratio 2.2, 95% CI 1.2-4.3). CONCLUSIONS: This large cohort of LMNA mutation carriers demonstrates a high cardiac disease penetrance and a high mortality in mutation carriers. Male mutation carriers have a worse prognosis due to a higher prevalence of malignant ventricular arrhythmias and end-stage heart failure.


Assuntos
Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/mortalidade , Heterozigoto , Lamina Tipo A/genética , Adulto , Fatores Etários , Arritmias Cardíacas/genética , Arritmias Cardíacas/mortalidade , Estudos de Coortes , Feminino , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prevalência , Estudos Retrospectivos , Fatores Sexuais
7.
Eur J Heart Fail ; 14(11): 1199-207, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22820313

RESUMO

AIMS: To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM). METHODS AND RESULTS: We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 % of R14del carriers. Compared with R14del- DCM patients, R14del+ DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 % , P < 0.001), cardiac transplantation (18 % vs. 2 % , P < 0.001), and a family history for sudden cardiac death (SCD) at < 50 years (36 % vs. 16 % , P = 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 %) R14del+ ARVC samples, but in only one of nine (11 %) R14del+ DCM samples (P = 0.03). CONCLUSIONS: The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del+ patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of 'arrhythmogenic cardiomyopathy'.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Proteínas de Ligação ao Cálcio/genética , Cardiomiopatia Dilatada/genética , Adulto , Morte Súbita Cardíaca , Feminino , Humanos , Masculino , Mutação , Fenótipo , Estudos Retrospectivos , Estatística como Assunto
8.
J Am Coll Cardiol ; 59(5): 493-500, 2012 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-22281253

RESUMO

OBJECTIVES: The purpose of this study was to determine risk factors that predict malignant ventricular arrhythmias (MVA) in Lamin A/C (LMNA) mutation carriers. BACKGROUND: LMNA mutations cause a variety of clinical phenotypes, including dilated cardiomyopathy and conduction disease. Many LMNA mutation carriers have a poor prognosis, because of a high frequency of MVA and progression to end-stage heart failure. However, it is unclear how to identify mutation carriers that are at risk for MVA. METHODS: In this multicenter cohort of 269 LMNA mutation carriers, we evaluated risk factors for MVA, defined as sudden cardiac death, resuscitation, and appropriate implantable cardioverter-defibrillator (ICD) treatment. RESULTS: In a median follow-up period of 43 months (interquartile range: 17 to 101 months), 48 (18%) persons experienced a first episode of MVA: 11 persons received successful cardiopulmonary resuscitation, 25 received appropriate ICD treatment, and 12 persons died suddenly. Independent risk factors for MVA were nonsustained ventricular tachycardia, left ventricular ejection fraction <45% at the first clinical contact, male sex, and non-missense mutations (ins-del/truncating or mutations affecting splicing). MVA occurred only in persons with at least 2 of these risk factors. There was a cumulative risk for MVA per additional risk factor. CONCLUSIONS: Carriers of LMNA mutations with a high risk of MVA can be identified using these risk factors. This facilitates selection of LMNA mutation carriers who are most likely to benefit from an ICD.


Assuntos
DNA/genética , Predisposição Genética para Doença , Lamina Tipo A/genética , Mutação , Taquicardia Ventricular/genética , Adulto , Análise Mutacional de DNA , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Lamina Tipo A/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Taquicardia Ventricular/epidemiologia , Taquicardia Ventricular/metabolismo
9.
Ned Tijdschr Geneeskd ; 155: A3159, 2011.
Artigo em Holandês | MEDLINE | ID: mdl-21418704

RESUMO

The diagnosis of heart failure has improved in the renewed heart failure practice guideline of the Dutch College of General Practitioners (NHG), of which the contents correspond to the multidisciplinary guideline 'Heart failure 2010'. This guideline recommend cut-off values for NT-proBNP for exclusion of heart failure and an echocardiogram for confirming diagnosis. In our opinion, however, the guideline will refer too many patients to hospital - partly due to the low cut-off values for NT-proBNP for excluding chronic heart failure - risking unnecessary diagnostic measures. The selection of patients requiring referral may be improved by refining both the risk estimation of heart failure and the use of cut-off values. The purpose of an echocardiogram is also still a matter for debate. We propose that patients be selected for echocardiography both for the diagnosis of heart failure and to investigate the underlying cause, implying referral to a cardiologist prior to echocardiography. Echocardiography for the diagnosis of heart failure alone may delay the institution of appropriate therapies.


Assuntos
Insuficiência Cardíaca/sangue , Peptídeo Natriurético Encefálico/sangue , Biomarcadores/sangue , Medicina de Família e Comunidade , Insuficiência Cardíaca/diagnóstico , Humanos , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Valores de Referência , Sensibilidade e Especificidade
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