RESUMO
BACKGROUND: PPKs represent a heterogeneous group of disorders with hyperkeratosis of palmar and/or plantar skin. PPK, hair shaft abnormalities, cardiomyopathy and arrhythmias can be caused by mutations in desmosomal genes, e.g. desmoplakin (DSP). PPK should trigger genetic testing to reveal mutations with possible related cardiac disease. OBJECTIVES: To report a large multigenerational family with a novel DSP mutation associated with early-onset PPK and adult-onset cardiomyopathy and arrhythmias. METHODS: A custom-designed in-house panel of 35 PPK related genes was used to screen mutations in the index patient with focal PPK. The identified DSP mutation was verified by Sanger sequencing. DNA samples from 20 members of the large multigenerational family were sequenced for the DSP mutation. Medical records were reviewed. Clinical dermatological evaluation was performed, including light microscopy of hair samples. Cardiac evaluation included clinical examination, echocardiography, cardiac magnetic resonance imaging (CMR), electrocardiogram (ECG), Holter monitoring and laboratory tests. RESULTS: We identified a novel autosomal dominant truncating DSP c.2493delA p.(Glu831Aspfs*33) mutation associated with dilated cardiomyopathy (DCM) with arrhythmia susceptibility and focal PPK as an early cutaneous sign. The mutation was found in nine affected family members, but not in any unaffected members. Onset of dermatological findings preceded cardiac symptoms which were variable and occurred at adult age. CONCLUSIONS: We report a novel truncating DSP mutation causing focal PPK with varying severity and left ventricular dilatation and ventricular extrasystoles. This finding emphasizes the importance of genetic diagnosis in patients with PPK for clinical counselling and management of cardiomyopathies and arrhythmias.
Assuntos
Cardiomiopatias , Cardiomiopatia Dilatada , Desmoplaquinas , Ceratodermia Palmar e Plantar , Adulto , Cardiomiopatias/complicações , Cardiomiopatias/genética , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/genética , Desmoplaquinas/genética , Humanos , Ceratodermia Palmar e Plantar/complicações , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/genética , MutaçãoRESUMO
Dilated cardiomyopathy (DCM), a genetically heterogeneous cardiac disease characterized by left ventricular dilatation and systolic dysfunction, is caused majorly by truncations of titin (TTN), especially in A-band region. Clinical interpretation of TTN-truncating variants (TTNtv) has been challenged by the existing inaccurate variant assessment strategies and uncertainty in the true frequency of TTNtv across the general population. We aggregated TTNtv identified in 1788 DCM patients and compared the variants with those reported in over 60,000 Exome Aggregation Consortium reference population. We implemented our current variant assessment strategy that prioritizes TTNtv affecting all transcripts of the gene, and observed a decline in the prevalence of TTNtv in DCM. Despite this decline, TTNtv are more prevalent in DCM patients compared with reference population (p = 4.1 × 10(-295) ). Moreover, our extended analyses confirmed the enrichment of TTNtv not only in the A-band but also in the I/A-band junction of TTN. We estimated the probability of pathogenicity of TTNtv affecting all transcripts of TTN, identified in unselected DCM patients to be 97.8% (likelihood ratio (LR) = 42.2). We emphasize that identifying a TTNtv, especially in the A-band region, has a higher risk of being disease-causing than previously anticipated, and recommend prioritizing TTNtv affecting at least five transcripts of the gene.
Assuntos
Cardiomiopatia Dilatada/genética , Conectina/genética , Mutação , RNA Mensageiro/genética , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/patologia , Estudos de Coortes , Bases de Dados Genéticas , Exoma , Regulação da Expressão Gênica , Humanos , Transcrição GênicaRESUMO
Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A enzyme activity. Decreased enzyme activity leads to accumulation of glycosphingolipids in different tissues including endothelial cells and smooth-muscle cells and cardiomyocytes, and cardiovascular complications are common in the disease. Since 2001, specific enzyme replacement therapy (ERT) with alpha-galactosidase A has been available. It has been reported to improve clinical symptoms and quality of life. However, limited and controversial data on its efficacy to cardiac involvement have been published. Nine patients (5 male) with Fabry disease were included in an open-label prospective follow-up study of 24-month ERT. Comprehensive cardiovascular evaluation was performed by MRI, stress echocardiography and quality of life assessment. Plasma globotriaosylceramide decreased from 6.2 to 1.4 microg/ml during ERT (p<0.05). The only other measured parameters that changed significantly were resting heart rate that decreased from 79 to 67 bpm (p<0.01) and end-systolic volume that decreased by 12.4 ml (p<0.05). The other parameters consisting of quality of life, self-estimated cardiovascular condition, diastolic function, exercise capacity, ECG parameters, ejection fraction and ventricular mass did not change. ERT has only minimal effect on symptoms and cardiovascular morphology and function in Fabry disease. Therefore, effective conventional medical therapy is still of major importance in Fabry disease. Larger ERT studies are warranted, especially in women, to solve current open questions, such as the age at which ERT should be started, optimal dosage and intervals between infusions. Furthermore, longer follow-up studies are needed to assess the effects of ERT on prognosis.
Assuntos
Doença de Fabry/tratamento farmacológico , Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/tratamento farmacológico , alfa-Galactosidase/uso terapêutico , Adulto , Idoso , Pressão Sanguínea , Ecocardiografia sob Estresse , Eletrocardiografia , Exercício Físico , Doença de Fabry/complicações , Doença de Fabry/fisiopatologia , Feminino , Seguimentos , Frequência Cardíaca , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de VidaRESUMO
We investigated the capability of transthoracic Doppler echocardiography (TTE) to detect and quantify the severity of restenosis in the left anterior descending coronary artery (LAD) after percutaneous transluminal coronary angioplasty (PTCA). We studied 10 consecutive patients assigned for quantitative coronary angiography (qCA) due to a recurrent angina pectoris after PTCA of the LAD. The LAD was visualized by TTE, and the presence of local turbulence and an increase in the blood flow velocity was regarded to indicate coronary stenosis. To assess the severity of the stenosis, the increase of blood flow velocity was measured. Angiography showed stenoses of various degrees (27-100%) in all patients. All stenoses were detectable using TTE. Moreover, the ratio of maximal blood flow velocity at the site of stenosis to the pre-stenotic blood flow velocity (M/P-ratio) correlated significantly with the reduction of the luminal diameter of LAD (r = 0.85, P < 0.003). A M/P-ratio higher than 3.0 predicted a diameter reduction of 50% or higher with sensitivity and specificity of 100% in patients with a subtotal stenosis (n = 9). Our results indicate that stenoses in the LAD could be found and the severity of the stenoses could be quantified reliably with TTE. This approach is totally non-invasive and less expensive than coronary angiography and can be used clinically in clarifying restenosis after coronary angioplasty.
Assuntos
Angioplastia Coronária com Balão , Circulação Coronária , Doença das Coronárias/diagnóstico por imagem , Doença das Coronárias/terapia , Ecocardiografia Doppler/métodos , Idoso , Velocidade do Fluxo Sanguíneo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico por imagem , Recidiva , Sensibilidade e EspecificidadeRESUMO
Coronary flow reserve (CFR) measurements have been widely used in assessing the functional significance of coronary artery stenosis because they are more sensitive in predicting major cardiac events than angiographically detected reductions of coronary arteries. Myocardial blood flow can be determined by measuring coronary sinus (CS) flow with velocity-encoded cine magnetic resonance imaging (VEC-MRI). The purpose of this study was to compare global myocardial blood flow (MBF) and CFR measured using VEC-MRI with MBF and CFR measured using positron emission tomography (PET). We measured MBF at baseline and after dipyridamole-induced hyperemia in 12 male volunteers with VEC-MRI and PET. With VEC-MRI, MBF was 0.64 +/- 0.09 (ml/min/g) at baseline and 1.59 +/- 0.79 (ml/min/g) at hyperemia, which yielded an average CFR of 2.51 +/- 1.29. With PET, MBF was 0.65 +/- 0.20 (ml/min/g) at baseline and 1.78 +/- 0.72 (ml/min/g) at hyperemia, which yielded an average CFR of 2.79 +/- 0.97. The correlation of MBFs between these two methods was good (r = 0.82, P < 0.001). The CFRs measured by MRI correlated well with those measured using PET (r = 0.76, P < 0.004). These results suggest that MRI is a useful and accurate method to measure global MBF and CFR. Therefore, it would be suitable for studying risk factor modifications of vascular function at an early stage in healthy volunteers.
Assuntos
Circulação Coronária/fisiologia , Imagem Cinética por Ressonância Magnética , Infarto do Miocárdio/diagnóstico , Fluxo Sanguíneo Regional/fisiologia , Tomografia Computadorizada de Emissão , Adulto , Circulação Colateral/fisiologia , Dipiridamol , Teste de Esforço , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Valores de Referência , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Previous studies using intravascular Doppler sonography and positron emission tomography (PET) have shown that the hemodynamic significance of coronary artery stenosis can be evaluated by measuring coronary flow reserve. The purpose of this study was to assess whether MR imaging measurements of coronary flow reserve in the left anterior descending artery are comparable with those obtained with PET in the corresponding territory. SUBJECTS AND METHODS: MR imaging and PET flow measurements were obtained in 10 healthy volunteers. Blood flow velocity in the left anterior descending artery was measured with breath-hold velocity-encoded cine MR imaging before and after IV administration of dipyridamole. The coronary flow velocity reserve measured by MR imaging was compared with the myocardial perfusion reserve in the anterior myocardium quantified on using PET and (15)O-labeled water. RESULTS: The average flow velocity reserve in the left anterior descending artery measured on MR imaging was 2.44+/-1.14 in healthy volunteers, which was comparable with the myocardial perfusion reserve measured by PET (2.52+/-0.84). MR imaging and PET measurements of the coronary flow reserve showed a significant correlation (r = 0.79, p<0.01). CONCLUSION: MR imaging measurement of the flow velocity reserve in the proximal left anterior descending artery correlates well with the myocardial perfusion reserve obtained with PET and (15)O-labeled water.
Assuntos
Circulação Coronária/fisiologia , Imagem Cinética por Ressonância Magnética , Tomografia Computadorizada de Emissão , Adulto , Velocidade do Fluxo Sanguíneo/fisiologia , Vasos Coronários/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: This study was performed to determine whether MR imaging can be used to reliably measure global myocardial blood flow and coronary flow reserve in patients with coronary artery disease as compared with such measurements obtained by positron emission tomography (PET). SUBJECTS AND METHODS: We measured myocardial blood flow first at baseline and then after dipyridamole-induced hyperemia in 20 patients with coronary artery disease. Myocardial blood flow as revealed by MR imaging was calculated by dividing coronary sinus flow by the left ventricular mass. Coronary flow reserve was calculated by dividing the rate of hyperemic flow by the rate of baseline flow. RESULTS: Using MR imaging, myocardial blood flow at baseline was 0.73 +/- 0.23 mL x min(-1) x g(-1), and at hyperemia the blood flow was 1.43 +/- 0.37 mL x min(-1) x g(-1), yielding an average coronary flow reserve of 1.99 +/- 0.47. Using PET, myocardial blood flow was 0.89 +/- 0.21 mL x min(-1) x g(-1) at baseline and 1.56 +/- 0.42 mL x min(-1) x g(-1) at hyperemia, yielding an average coronary flow reserve of 1.77 +/- 0.36. The correlation of myocardial blood flow and coronary flow reserve measurements for these two methods was an r of 0.80 (p < 0.01) and an r of 0.50 (p < 0.05), respectively. CONCLUSION: This study shows that myocardial blood flow measurements obtained using MR imaging have a good correlation with corresponding PET measurements. Coronary flow reserve measurements obtained using MR imaging had only moderate correlation with PET-obtained measurements. Our results suggest that MR imaging flow quantification could potentially be used for measuring global myocardial blood flow in patients in whom interventional treatment for coronary artery disease is being evaluated.
Assuntos
Circulação Coronária/fisiologia , Estenose Coronária/diagnóstico , Imagem Cinética por Ressonância Magnética , Tomografia Computadorizada de Emissão , Adulto , Idoso , Velocidade do Fluxo Sanguíneo/fisiologia , Estenose Coronária/fisiopatologia , Dipiridamol , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional/fisiologia , Reprodutibilidade dos Testes , Função Ventricular Esquerda/fisiologiaRESUMO
There is an increasing need for new, functional and more quantitative parameters to assess coronary arterial function, for the purposes of evidence-based medicine. Coronary arterial function has been widely studied using pharmacological stimulation induced by dipyridamole or adenosine. Coronary flow reserve (CFR), defined as the ratio of pharmacologically induced hyperemic flow divided by basal flow, has been found to be an important functional index in both the clinical and subclinical stages of cardiovascular diseases. Ten healthy male volunteers were studied to compare transthoracic Doppler echocardiography (TTE) and MRI for measuring left anterior descending coronary artery (LAD) flow velocity and CFR. Additionally, the time-response curve of dipyridamole infusion was studied in five healthy males using TTE. Assessment of blood flow velocity, measured as MDV, PDV and VTI indicated Pearson's correlation coefficients of 0.88, 0.85 and 0.70, respectively, between flow velocity measurements performed using TTE and MRI. The results indicate that, despite minor differences in LAD diastolic velocities measured by TTE and MRI, the correlation of the LAD diastolic velocities measured using both methods are good and both methods are feasible for measuring CFR. Moreover, TTE has the unique capability of continuous measurement of LAD flow velocity, which allowed assessment of the time-response curve for dipyridamole-induced increase in LAD flow velocity in this study. This study indicates that the TTE method may be used in sequential or on-line monitoring of LAD blood flow velocity and therefore can be applied to evaluate the time- or dose-response effects of infused drugs in the coronary circulation of humans.