RESUMO
Aims: The p.Arg14del founder mutation in the gene encoding phospholamban (PLN) is associated with an increased risk of malignant ventricular arrhythmia (VA) and heart failure. It has been shown to lead to calcium overload, cardiomyocyte damage, and eventually to myocardial fibrosis. This study sought to investigate ventricular function, the extent and localization of myocardial fibrosis and the associations with ECG features and VA in PLN p.Arg14del mutation carriers. Methods and results: Cardiovascular magnetic resonance (CMR) data of 150 mutation carriers were analysed retrospectively. Left ventricular (LV) and right ventricular (RV) volumes, mass, and ejection fraction were measured. The extent of late gadolinium enhancement (LGE) was expressed as a percentage of myocardial mass. All standard ECG parameters were measured. Occurrence of VA was analysed on ambulatory 24-h and/or exercise electrocardiography, if available. Mean age was 40 ± 15 years, 42% males, and 7% were index patients while 93% were pre-symptomatic carriers identified after family cascade screening. Mean LV ejection fraction (LVEF) and RV ejection fraction were 58 ± 9% and 55 ± 9%, respectively. LV-LGE was present in 91% of mutation carriers with reduced LVEF (<45%) and in 30% of carriers with preserved LVEF. In carriers with positive LV-LGE, its median extent was 5.9% (interquartile range 3.2-12.7). LGE was mainly observed in the inferolateral wall. Carriers with inverted T-waves in the lateral ECG leads more often had LV-LGE (P < 0.01) than carriers without. Finally, the presence of LV-LGE, but not attenuated R-waves and inverted lateral T-waves, was independently associated with VA. Conclusion: LV myocardial fibrosis is present in many PLN p.Arg14del mutation carriers, and who still have a preserved LVEF. It is seen predominantly in the LV inferolateral wall and corresponds with electrocardiographic repolarization abnormalities. Although preliminary, myocardial fibrosis was found to be independently associated with VA. Our findings support the use of CMR with LGE early in the diagnostic work-up.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/genética , Imagem Cinética por Ressonância Magnética/métodos , Miocárdio/patologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Adulto , Meios de Contraste , Eletrocardiografia , Feminino , Fibrose/patologia , Predisposição Genética para Doença , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Meglumina , Pessoa de Meia-Idade , Mutação , Países Baixos , Compostos Organometálicos , Fenótipo , Estudos Retrospectivos , Taquicardia Ventricular/diagnóstico por imagem , Taquicardia Ventricular/genéticaRESUMO
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 SistólicoRESUMO
Increasing numbers of patient relatives at risk of developing dilated or hypertrophic cardiomyopathy (DCM/HCM) are being identified and followed up by cardiologists according to the ACC/ESC guidelines. However, given limited healthcare resources, good-quality low-cost alternative approaches are needed. Therefore, we have compared conventional follow-up by a cardiologist with that provided at a cardiogenetic clinic (CGC) led by a genetic counsellor. Phenotype-negative first-degree relatives at risk for DCM/HCM were randomly assigned to see either a cardiologist or to attend a CGC. Uptake and resource use were recorded. For 189 participants, we evaluated quality of care experienced, patient satisfaction and perceived personal control (PPC) using validated questionnaires and estimated the average cost difference of these two modes of care. Maximum patient satisfaction scores were achieved more frequently at the CGC (86% vs 45%, P<0.01). In terms of follow-up care provided, the genetic counsellor did not perform worse than the cardiologist (95% vs 59%, P<0.01). The genetic counsellor more often enquired about the relative-at risk's health (100% vs 65%, P<0.01) and family health (97% vs 33%, P<0.01), measured blood pressure (98% vs 29%, P<0.01) and gave disease-specific information (77% vs 52%, P<0.01). Although PPC scores were equal in both groups, the average cost per patient of CGC follow-up was 25% lower. Follow-up of phenotype-negative relatives at risk for DCM/HCM at a CGC led to greater patient satisfaction and is well-appreciated at lower cost. CGC care is a good alternative to conventional cardiological follow-up for this growing group of patients.
Assuntos
Assistência ao Convalescente/métodos , Cardiomiopatia Dilatada/genética , Custos e Análise de Custo , Aconselhamento Genético/métodos , Hipertrofia/genética , Núcleo Familiar , Adolescente , Adulto , Assistência ao Convalescente/economia , Assistência ao Convalescente/psicologia , Idoso , Cardiomiopatia Dilatada/diagnóstico , Feminino , Aconselhamento Genético/economia , Aconselhamento Genético/psicologia , Humanos , Hipertrofia/diagnóstico , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Distribuição AleatóriaRESUMO
BACKGROUND: Familial forms of primary sinus bradycardia have sometimes been attributed to mutations in HCN4, SCN5A, and ANK2. In these studies, no structural cardiac alterations were reported in mutation carriers. However, a cluster of reports in the literature describe patients presenting with sinus bradycardia in association with left ventricular noncompaction cardiomyopathy (LVNC), pointing to a shared genetic cause. OBJECTIVES: This study sought to identify the genetic defect underlying the combined clinical presentation of bradycardia and LVNC, hypothesizing that these 2 clinical abnormalities have a common genetic cause. METHODS: Exome sequencing was carried out in 2 cousins from the index family that were affected by the combined bradycardia-LVNC phenotype; shared variants thus identified were subsequently overlaid with the chromosomal regions shared among 5 affected family members that were identified using single nucleotide polymorphism array analysis. RESULTS: The combined linkage analysis and exome sequencing in the index family identified 11 novel variants shared among the 2 affected cousins. One of these, p.Gly482Arg in HCN4, segregated with the combined bradycardia and LVNC phenotype in the entire family. Subsequent screening of HCN4 in 3 additional families with the same clinical combination of bradycardia and LVNC identified HCN4 mutations in each. In electrophysiological studies, all found HCN4 mutations showed a more negative voltage dependence of activation, consistent with the observed bradycardia. CONCLUSIONS: Although mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence to our knowledge that mutations in this ion channel gene also may be associated with structural abnormalities of the myocardium.
Assuntos
Cardiopatias Congênitas/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Proteínas Musculares/genética , Canais de Potássio/genética , Síndrome do Nó Sinusal/congênito , Adolescente , Adulto , Idoso , Animais , Células CHO , Cricetulus , Análise Mutacional de DNA , Exoma , Feminino , Ligação Genética , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Masculino , Potenciais da Membrana , Pessoa de Meia-Idade , Síndrome do Nó Sinusal/diagnóstico por imagem , Síndrome do Nó Sinusal/genética , Síndrome , Ultrassonografia , Adulto JovemRESUMO
AIMS: To investigate whether skin autofluorescence (AF), a non-invasive marker for advanced glycation end products (AGEs), is elevated in stable coronary artery disease (sCAD) and to investigate its relationship with serum levels of the soluble receptor for AGEs (sRAGE), neopterin and C-reactive protein (CRP). METHODS AND RESULTS: Skin AF and serum levels of sRAGE, neopterin and CRP were assessed in 63 sCAD patients (mean age: 64.7+/-10.5 years), comprising 78% males, 19% subjects with diabetes, and 22% current smokers and in 33 (mean age: 63.4+/-10.0 years) healthy non-diabetic and non-smoking age and gender matched controls. Skin AF was significantly increased in sCAD compared with controls, irrespective of diabetes, current smoking and renal function. Levels of sRAGE (standardized beta: 0.43 (explaining 17% of variance in skin AF); P<0.001), neopterin (beta: 0.36 (11%); P=0.003) and glucose (beta: 0.29 (8%); P=0.0011) as well as current smoking (beta: 0.26 (6%); P=0.024) were independently associated with skin AF (R(2) 0.42), whereas the association of gender, former smoking, body mass index, CRP, lipids, creatinine clearance and pulse pressure with skin AF was not significant in this model. CONCLUSION: These data demonstrate that skin AF is elevated in sCAD and is related to sRAGE and neopterin, making it an easily applicable tool to improve our understanding of inflammatory and oxidative stress in cardiovascular disease.
Assuntos
Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/metabolismo , Fluorescência , Neopterina/sangue , Receptores Imunológicos/sangue , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Estresse Oxidativo/fisiologia , Receptor para Produtos Finais de Glicação Avançada , Pele/metabolismo , Solubilidade , Vasculite/diagnóstico , Vasculite/metabolismoRESUMO
PURPOSE: Recent trial results are in favor of aggressive lipid lowering using high dose statins in patients needing secondary prevention. It is unclear whether these effects are solely due to more extensive lipid lowering or the result of the potentially anti-inflammatory properties of statins. We aimed to determine whether aggressive compared with conventional statin therapy is more effective in reducing systemic markers of inflammation and oxidative stress. MATERIALS AND METHODS: This was a multi-centre, double-blind, placebo-controlled trial. Patients with previous cardiovascular disease, who did not achieve low density lipoprotein (LDL) cholesterol levels <2.6 mmol/l on conventional statin therapy (simvastatin 40 mg) were randomized to continue with simvastatin 40 mg or to receive atorvastatin 40 mg for 8 weeks and thereafter atorvastatin 80 mg for the final 8 weeks (aggressive treatment). Lipids, C-reactive protein, soluble cellular adhesion molecules, neopterin, von Willebrand Factor, and antibodies against oxidized LDL were measured at baseline and after 16 weeks. RESULTS: Lipid levels decreased significantly in the aggressive treatment group (LDL-C reduction 20.8%; P < 0.001), whereas a slight increase was observed in the conventional group (LDL-C increase 3.7%; P = 0.037). A significant reduction in antibodies against oxidized LDL was seen in the aggressive (13.4%; P < 0.001) and the conventional (26.8%; P < 0.001) group, but there was no difference between groups (P = 0.25). Furthermore, no significant differences in change in other biomarkers was observed between both groups. CONCLUSIONS: This study does not support the hypothesis that a more profound reduction in inflammatory and oxidative stress contributes to the benefits of aggressive statin therapy.
Assuntos
Ácidos Heptanoicos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Pirróis/administração & dosagem , Sinvastatina/administração & dosagem , Adulto , Idoso , Anticorpos/sangue , Atorvastatina , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Moléculas de Adesão Celular/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Método Duplo-Cego , Feminino , Ácidos Heptanoicos/farmacologia , Ácidos Heptanoicos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/sangue , Lipoproteínas LDL/imunologia , Masculino , Pessoa de Meia-Idade , Neopterina/sangue , Pirróis/farmacologia , Pirróis/uso terapêutico , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Fator de von Willebrand/análiseRESUMO
Giant cell myocarditis (GCM) is a serious condition that warrants immediate diagnosis and treatment. It often presents as rapidly progressive heart failure and/or malignant ventricular arrhythmias. Here, we describe a 34-year-old patient with myasthenia gravis who presented with GCM 2 weeks after resection of a thymoma. A cardiac biopsy confirming the diagnosis was done within 3 days after admission. After institution of an aggressive immunosuppressive drug regimen, implantation of an implantable cardioverter defibrillator, and intensive cardiac rehabilitation, the patient recovered dramatically. In control biopsies after 4 weeks and 6 months, no more giant cells were found. We conclude that, in the case of nonischemic acute heart failure in young patients, a biopsy should be performed as soon as possible to prevent an unfavourable outcome of this often fatal disease.
Assuntos
Baixo Débito Cardíaco/patologia , Endocárdio/patologia , Células Gigantes/patologia , Miocardite/patologia , Miocárdio/patologia , Doença Aguda , Adulto , Biópsia/métodos , Baixo Débito Cardíaco/etiologia , Ventrículos do Coração/patologia , Humanos , Masculino , Miocardite/complicações , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/patologiaRESUMO
OBJECTIVES: The renin-angiotensin system (RAS) is thought to play a major role in the pathophysiology of de-novo restenotic lesions and in-stent restenosis after percutaneous coronary intervention (PCI). Heme oxygenase-1 (HO-1), is thought to beneficially influence these processes. We examined the effect of pharmacologic as well as genetic RAS interactions on restenosis in a large population of consecutive patients undergoing PCI, and evaluated possible gene-gene interactions in both systems. METHODS: The GENDER project is a multicenter prospective follow-up study, including 3146 patients after successful PCI. Genotyping in these patients was performed for the ACE gene insertion/deletion, the angiotensinogen 235Met/Thr, T174M and A(-6)G, the angiotensin-II type 1 receptor (AT1R) 1166A/C and T810A, the angiotensin-II type 2 receptor (AT2R) 1675G/A and 3123A polymorphisms and the length polymorphism in the HO-1 promoter region. RESULTS: A total of 3104 patients were followed for 10 months. In 2975 patients at least one of the nine genotypes could be determined. The AT1R 1166 CC genotype showed a significant association with TVR; the other polymorphisms did not. RAS-inhibitory drugs were not associated with the incidence of TVR, nor did they interact with any of the investigated polymorphisms. Patients with the ACE I/I polymorphism showed a trend towards a better outcome if they had a short number of repeats in the HO-1 promoter. This relationship was inversely present in carriers of the ACE D/D polymorphism. CONCLUSION: We could only establish a role for the AT1R 1166A/C polymorphism in restenosis after PCI. However, significant gene-gene interaction was suggested for the ACE gene and the HO-1 promotor. The RAS and HO-1 relation in restenosis merits further investigation.
Assuntos
Angioplastia Coronária com Balão , Doença das Coronárias/terapia , Reestenose Coronária/genética , Polimorfismo Genético , Receptor Tipo 1 de Angiotensina/genética , Alelos , Angiotensinogênio/genética , Doença das Coronárias/genética , Reestenose Coronária/prevenção & controle , Seguimentos , Heme Oxigenase-1/genética , Humanos , Estudos Multicêntricos como Assunto , Peptidil Dipeptidase A/genética , Regiões Promotoras Genéticas , Estudos Prospectivos , Receptores de Angiotensina/genética , Fatores de Tempo , Resultado do TratamentoRESUMO
Disturbed vasomotor function in coronary arteries has clinical importance in early stages of coronary artery disease (CAD), as it may contribute to the potential risk for an ischaemic coronary event. In the present study, we have investigated the relationship between coronary vasomotor function and the extent of CAD. The response to acetylcholine and nitrate infusion was assessed by quantitative coronary angiography. The extent of CAD was categorized into two groups: minor CAD (normal coronary arteries and vessel wall irregularities) and significant CAD (one-, two- and three-vessel disease). A total of 277 patients with stable angina pectoris, referred for a first diagnostic coronary angiography, were eligible for analysis (mean age 57 years, 61% male). The response to nitrate was significantly impaired in patients with significant CAD ( P <0.001). On the other hand, the response to acetylcholine was not different between the two groups ( P =0.12); however, a trend between the response to acetylcholine and the extent of CAD was observed in patients without a previous infarction ( P =0.07), which was a significant interaction variable. Furthermore, a significant relationship between coronary vasomotor response and the number of cardiovascular risk factors was observed ( P <0.05). In conclusion, in a heterogeneous group of patients, coronary vasomotor function measured by nitrate infusion was more strongly associated with the extent of CAD and the number of risk factors than the response to acetylcholine. These data suggest that, in patients with advanced atherosclerosis or multiple risk factors, the vasomotor dysfunction is not solely restricted to the endothelium.
Assuntos
Acetilcolina , Angina Pectoris/fisiopatologia , Angiografia Coronária , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/fisiopatologia , Vasoconstritores , Idoso , Análise de Variância , Angina Pectoris/diagnóstico por imagem , Angina Pectoris/patologia , Distribuição de Qui-Quadrado , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/patologia , Vasos Coronários/efeitos dos fármacos , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Nitroglicerina , Fatores de Risco , VasodilatadoresRESUMO
The value of monocyte/macrophage activity as a prognostic factor in patients with non-Q-wave myocardial infarction (NQMI) has not yet been investigated. Moreover, scarce data are available on the long-term predictive value of markers of inflammation in patients who experience a NQMI. The present study aimed to determine the predictive value of neopterin, alone and in relation to levels of C-reactive protein, on the recurrence of major clinical cardiovascular events in patients who had a NQMI.
Assuntos
Proteína C-Reativa/análise , Ativação de Macrófagos/fisiologia , Monócitos/fisiologia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , Neopterina/sangue , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Valor Preditivo dos Testes , Recidiva , Fatores de TempoRESUMO
Atherosclerosis is characterized by a low-grade systemic inflammatory response and endothelial dysfunction. The aim of the present study was to investigate a possible relationship between systemic markers of inflammation, serum markers of endothelial activation and endothelium-dependent vasodilatation in a group of high-risk patients, and to evaluate the effects of intervention with high doses of simvastatin on these parameters. In patients with heterozygous familial hypercholesterolaemia, without atherosclerotic events, flow-mediated vasodilatation (FMD) of the brachial artery was measured after a wash-out period for lipid-lowering drugs (baseline) and after 6 weeks of treatment with simvastatin 80 mg daily. Levels of C-reactive protein (CRP), soluble intercellular cell-adhesion molecule (s-ICAM) and soluble E-selectin (s-E-selectin) were determined at baseline and again after 6 weeks and 12 months of therapy. A total of 35 subjects participated in the study (mean age 42 years; 60% male). When divided into tertiles according to FMD (<3.9%, 3.9-9.0% and >9.0%), no differences in levels of CRP, s-ICAM-1 and/or s-E-selectin were detected between the groups. Moreover, no changes in FMD, levels of CRP or levels of s-ICAM-1 and/or s-E-selectin were found during treatment with simvastatin. We conclude that endothelial function, as reflected by FMD, does not seem to be related to markers of inflammation in familial hypercholesterolaemia subjects at high risk of, but without clinically overt signs of, atherosclerosis. Moreover, aggressive lipid-lowering therapy with simvastatin does not result in improved endothelial function or in a reduction of markers of inflammation in these patients.
Assuntos
Artéria Braquial/fisiopatologia , Endotélio Vascular/fisiopatologia , Hiperlipoproteinemia Tipo II/fisiopatologia , Vasodilatação , Adulto , Anticolesterolemiantes/uso terapêutico , Biomarcadores/sangue , Artéria Braquial/diagnóstico por imagem , Proteína C-Reativa/análise , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Selectina E/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Seguimentos , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/imunologia , Molécula 1 de Adesão Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Nitroglicerina/uso terapêutico , Sinvastatina/uso terapêutico , Triglicerídeos/sangue , Ultrassonografia , Vasodilatadores/uso terapêuticoRESUMO
BACKGROUND: Endothelial dysfunction is useful in predicting future cardiovascular disease. At present several tests are available to test endothelial function: coronary diameter response to acetylcholine, forearm bloodflow (FBF) response to acetylcholine, and brachial artery flow-mediated dilative (FMD) response to postischemic hyperemia. This study aimed to compare the three most frequently reported endothelial function tests. METHODS: Twenty-eight patients (19 males and nine females, mean age 57 years) referred for diagnostic coronary angiography were considered for endothelial function measurement in the coronary artery as well as in the forearm by FBF and FMD. RESULTS: Acetylcholine decreased the mean coronary diameter by 7.4% (SD 6.3%) and increased the mean FBF by 230% (SD 152%). Hyperemia increased the mean brachial diameter by 6.7% (SD 4.8%). The effect of acetylcholine on forearm resistance vessels was significantly related to the effect of acetylcholine on the coronary conduit vessels (P=0.039). Nonetheless, FMD was not related to FBF nor to the coronary response. CONCLUSION: In patients with mild coronary endothelial dysfunction, forearm vasoreactivity is related to the coronary response, provided that the same stimulus is used.