A novel mtDNA point mutation in tRNAVal is associated with hypertrophic cardiomyopathy and MELAS

Background. Pathological mutations of mitochondrial (mt) DNA may cause specific diseases such as cardiomyopathies or hearing loss, or syndromes such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome. We describe a novel mtDNA mutation in a patient with severe hypertrophic cardiomyopathy associated with MELAS. The familial phenotype included 1) hypertrophic cardiomyopathy and MELAS, 2) clinically mild cardiac hypertrophy, and 3) deafness. Methods. The proband and her first degree relatives underwent echo and electrocardiograms, and biochemical tests. Magnetic resonance imaging of the brain was performed in the proband. mtDNA was fully analyzed by sequencing. DNA purification, polymerase chain reaction and direct automated sequencing were performed following standard procedures. Heteroplasmy of the novel mutation was quantified by densitometric analysis. Results. A novel G1644A transition affecting the tRNAVal was identified in the proband and maternal relatives. The mutation has been interpreted as pathological because the G at the 1644 position is a highly conserved base, is heteroplasmic with higher levels of mutant DNA in the proband than in the relatives, is located in the unique tRNAVal, is very close to a mutation described as causative of MELAS, and finally has not been found in 100 healthy controls. Conclusions. Although it is rare for patients with MELAS to be referred to cardiological evaluation because of coexisting cardiomyopathy, cardiologists should be aware of this association as well as of the non cardiac signs that may address the diagnosis to mtDNA defect-related disease in families with a variable phenotype. © 2004 CEPI Srl

European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants

Malaltia aòrtica; Dissecció; Aneurisma aòrtic toràcicEnfermedad aórtica; Disección; Aneurisma de aorta torácicaAortic disease; Dissection; Thoracic aortic aneurysmThe ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2-related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits. Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2. The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2-related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.This work was supported by the Dutch Heart Foundation (2014 T007) and by an Erasmus University Rotterdam Fellowship (I.M.B.H. van de Laar)

Balance in patients with Marfan syndrome

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Phenotype commitment in vascular smooth muscle cells derived from coronary atherosclerotic plaques: differential gene expression of endothelial Nitric Oxide Synthase

Unstable angina and myocardial infarction are the clinical manifestations of the abrupt thrombotic occlusion of an epicardial coronary artery as a result of spontaneous atherosclerotic plaque rupture or fissuring, and the exposure of highly thrombogenic material to blood. It has been demonstrated that the proliferation of vascular smooth muscle cells (VSMCs) and impaired bioavailabilty of nitric oxide (NO) are among the most important mechanisms involved in the progression of atherosclerosis. It has also been suggested that a NO imbalance in coronary arteries may be involved in myocardial ischemia as a result of vasomotor dysfunction triggering plaque rupture and the thrombotic response. We used 5' nuclease assays (TaqMan™ PCRs) to study gene expression in coronary plaques collected by means of therapeutic directional coronary atherectomy from 15 patients with stable angina (SA) and 15 with acute coronary syndromes (ACS) without ST elevation. Total RNA was extracted from the 30 plaques and the cDNA was amplified in order to determine endothelial nitric oxide synthase (eNOS) gene expression. Analysis of the results showed that the expression of eNOS was significantly higher (p<0.001) in the plaques from the ACS patients. Furthermore, isolated VSMCs from ACS and SA plaques confirmed the above pattern even after 25 plating passages. In situ RT-PCR was also carried out to co-localize the eNOS messengers and the VSMC phenotype

Restrictive Cardiomyopathy, Atrioventricular Block and Mild to Subclinical Myopathy in Patients With Desmin-Immunoreactive Material Deposits

AbstractObjectives. We present clinical data and heart and skeletal muscle biopsy findings from a series of patients with ultrastructural accumulations of granulofilamentous material identified as desmin.Background. Desmin cardiomyopathy is a poorly understood disease characterized by abnormal desmin deposits in cardiac and skeletal muscle.Methods. Clinical evaluation, endomyocardial and skeletal muscle biopsy, light and electron microscopy and immunohistochemistry were used to establish the presence of desmin cardiomyopathy.Results. Six hundred thirty-one patients with primary cardiomyopathy underwent endomyocardial biopsy (EMB). Ultrastructural accumulations of granulofilamentous material were found in 5 of 12 biopsy samples from patients with idiopathic restrictive cardiomyopathy and demonstrated specific immunoreactivity with anti-desmin antibodies by immunoelectron microscopy. Immunohistochemical findings on light microscopy were nonspecific because of a diffuse intracellular distribution of desmin. All five patients had atrioventricular (AV) block and mild or subclinical myopathy. Granulofilamentous material was present in skeletal muscle biopsy samples in all five patients, and unlike the heart biopsy samples, light microscopic immunohistochemical analysis demonstrated characteristic subsarcolemmal desmin deposits. Two patients were first-degree relatives (mother and son); another son with first-degree AV block but without myopathy or cardiomyopathy demonstrated similar light and ultrastructural findings in skeletal muscle. Electrophoretic studies demonstrated two isoforms of desmin—one of normal and another of lower molecular weight—in cardiac and skeletal muscle of the familial cases.Conclusions. Desmin cardiomyopathy must be considered in the differential diagnosis of restrictive cardiomyopathy, especially in patients with AV block and myopathy. Diagnosis depends on ultrastructural examination of EMB samples or light microscopic immunohistochemical studies of skeletal muscle biopsy samples. Familial desminopathy may manifest as subclinical disease and may be associated with abnormal isoforms of desmin

Incidence of Second Primary Cancer in Transplanted Patients

Background. Solid organ transplanted patients have a three-to fourfold higher lifetime risk of developing a cancer than the general population. However, the incidence of a second primary cancer in transplanted patients has never been studied, despite the fact that the presence of regular follow-ups and the increased survival of these patients make them a very attractive model. Methods. We investigated the incidence of a second primary cancer (SPC) in 7,636 patients who underwent a kidney, liver, lung or heart transplant between 1970 and 2004, and were followed-up for 51,819 person-years. Results. During the follow-up, 499 subjects developed a first cancer (annual incidence: 98.6ϫ10,000 PY), and 22 of them developed a SPC (annual incidence: 3.9ϫ10,000 PY). The annual incidence of a SPC in the transplanted patients who developed a first cancer was 107.8ϫ10,000 PY, giving a standardized incidence ratio of 1.1 (95% CI: 0.83-1.41). Conclusions. This result shows that the incidence of the SPC was the same as the incidence of a first cancer. Our study does not indicate an increased risk of SPC in transplanted subjects who already suffered a first malignancy

Correction: Age-specific reference values for carotid arterial stiffness estimated by ultrasonic wall tracking

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Mitochondrial cardiomyopathies: how to identify candidate pathogenic mutations by mitochondrial DNA sequencing, MITOMASTER and phylogeny

Pathogenic mitochondrial DNA (mtDNA) mutations leading to mitochondrial dysfunction can cause cardiomyopathy and heart failure. Owing to a high mutation rate, mtDNA defects may occur at any nucleotide in its 16 569 bp sequence. Complete mtDNA sequencing may detect pathogenic mutations, which can be difficult to interpret because of normal ethnic/geographic-associated haplogroup variation. Our goal is to show how to identify candidate mtDNA mutations by sorting out polymorphisms using readily available online tools. The purpose of this approach is to help investigators in prioritizing mtDNA variants for functional analysis to establish pathogenicity. We analyzed complete mtDNA sequences from 29 Italian patients with mitochondrial cardiomyopathy or suspected disease. Using MITOMASTER and PhyloTree, we characterized 593 substitution variants by haplogroup and allele frequencies to identify all novel, non-haplogroup-associated variants. MITOMASTER permitted determination of each variant's location, amino acid change and evolutionary conservation. We found that 98% of variants were common or rare, haplogroup-associated variants, and thus unlikely to be primary cause in 80% of cases. Six variants were novel, non-haplogroup variants and thus possible contributors to disease etiology. Two with the greatest pathogenic potential were heteroplasmic, nonsynonymous variants: m.15132T>C in MT-CYB for a patient with hypertrophic dilated cardiomyopathy and m.6570G>T in MT-CO1 for a patient with myopathy. In summary, we have used our automated information system, MITOMASTER, to make a preliminary distinction between normal mtDNA variation and pathogenic mutations in patient samples; this fast and easy approach allowed us to select the variants for traditional analysis to establish pathogenicity