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Impact of Demographic Features, Lifestyle, and Comorbidities on the Clinical Expression of Hypertrophic Cardiomyopathy.
Finocchiaro, G, Magavern, E, Sinagra, G, Ashley, E, Papadakis, M, Tome-Esteban, M, Sharma, S, Olivotto, I
Journal of the American Heart Association. 2017;(12)
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Prediction of thrombo-embolic risk in patients with hypertrophic cardiomyopathy (HCM Risk-CVA).
Guttmann, OP, Pavlou, M, O'Mahony, C, Monserrat, L, Anastasakis, A, Rapezzi, C, Biagini, E, Gimeno, JR, Limongelli, G, Garcia-Pavia, P, et al
European journal of heart failure. 2015;(8):837-45
Abstract
AIMS: Atrial fibrillation (AF) and thrombo-embolism (TE) are associated with reduced survival in hypertrophic cardiomyopathy (HCM), but the absolute risk of TE in patients with and without AF is unclear. The primary aim of this study was to derive and validate a model for estimating the risk of TE in HCM. Exploratory analyses were performed to determine predictors of TE, the performance of the CHA2 DS2 -VASc score, and outcome with vitamin K antagonists (VKAs). METHODS AND RESULTS A retrospective, longitudinal cohort of seven institutions was used to develop multivariable Cox regression models fitted with pre-selected predictors. Bootstrapping was used for validation. Of 4821 HCM patients recruited between 1986 and 2008, 172 (3.6%) reached the primary endpoint of cerebrovascular accident (CVA), transient ischaemic attack (TIA), or systemic peripheral embolus within 10 years. A total of 27.5% of patients had a CHA2 DS2 -VASc score of 0, of whom 9.8% developed TE during follow-up. Cox regression revealed an association between TE and age, AF, the interaction between age and AF, TE prior to first evaluation, NYHA class, left atrial (LA) diameter, vascular disease, and maximal LV wall thickness. There was a curvilinear relationship between LA size and TE risk. The model predicted TE with a C-index of 0.75 [95% confidence interval (CI) 0.70-0.80] and the D-statistic was 1.30 (95% CI 1.05-1.56). VKA treatment was associated with a 54.8% (95% CI 31-97%, P = 0.037) relative risk reduction in HCM patients with AF. CONCLUSIONS The study shows that the risk of TE in HCM patients can be identified using a small number of simple clinical features. LA size, in particular, should be monitored closely, and the assessment and treatment of conventional vascular risk factors should be routine practice in older patients. Exploratory analyses show for the first time evidence for a reduction of TE with VKA treatment. The CHA2 DS2 -VASc score does not appear to correlate well with the clinical outcome in patients with HCM and should not be used to assess TE risk in this population.
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MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast.
Baruffini, E, Dallabona, C, Invernizzi, F, Yarham, JW, Melchionda, L, Blakely, EL, Lamantea, E, Donnini, C, Santra, S, Vijayaraghavan, S, et al
Human mutation. 2013;(11):1501-9
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Abstract
We report three families presenting with hypertrophic cardiomyopathy, lactic acidosis, and multiple defects of mitochondrial respiratory chain (MRC) activities. By direct sequencing of the candidate gene MTO1, encoding the mitochondrial-tRNA modifier 1, or whole exome sequencing analysis, we identified novel missense mutations. All MTO1 mutations were predicted to be deleterious on MTO1 function. Their pathogenic role was experimentally validated in a recombinant yeast model, by assessing oxidative growth, respiratory activity, mitochondrial protein synthesis, and complex IV activity. In one case, we also demonstrated that expression of wt MTO1 could rescue the respiratory defect in mutant fibroblasts. The severity of the yeast respiratory phenotypes partly correlated with the different clinical presentations observed in MTO1 mutant patients, although the clinical outcome was highly variable in patients with the same mutation and seemed also to depend on timely start of pharmacological treatment, centered on the control of lactic acidosis by dichloroacetate. Our results indicate that MTO1 mutations are commonly associated with a presentation of hypertrophic cardiomyopathy, lactic acidosis, and MRC deficiency, and that ad hoc recombinant yeast models represent a useful system to test the pathogenic potential of uncommon variants, and provide insight into their effects on the expression of a biochemical phenotype.
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Mutation of mitochondrial DNA G13513A presenting with Leigh syndrome, Wolff-Parkinson-White syndrome and cardiomyopathy.
Wang, SB, Weng, WC, Lee, NC, Hwu, WL, Fan, PC, Lee, WT
Pediatrics and neonatology. 2008;(4):145-9
Abstract
Mutation of mitochondrial DNA (mtDNA) G13513A, encoding the ND5 subunit of respiratory chain complex I, can cause mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) and Leigh syndrome. Wolff-Parkinson-White (WPW) syndrome and optic atrophy were reported in a high proportion of patients with this mutation. We report an 18-month-old girl, with an 11-month history of psychomotor regression who was diagnosed with WPW syndrome and hypertrophic cardiomyopathy, in association with Leigh syndrome. Supplementation with coenzyme Q10, thiamine and carnitine prevented further regression in gross motor function but the patient's heart function deteriorated and dilated cardiomyopathy developed 11 months later. She was found to have a mutation of mtDNA G13513A. We suggest that mtDNA G13513A mutation is an important factor in patients with Leigh syndrome associated with WPW syndrome and/or optic atrophy, and serial heart function monitoring by echocardiography is recommended in this group of patients.
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Impact of ethanol dosing on the long-term outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy: a single-center prospective, and randomized study.
Veselka, J, Duchonová, R, Páleníckova, J, Zemánek, D, Tiserová, M, Linhartová, K, Cervinka, P
Circulation journal : official journal of the Japanese Circulation Society. 2006;(12):1550-2
Abstract
BACKGROUND The impact of ethanol dose on the long-term outcome of alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy was investigated. METHODS AND RESULTS Fifty-four patients (age 24-82 years; 65% women) undergoing ASA were randomized into 2 groups according to the dose of injected ethanol: Group A 1-2 ml, Group B >2 ml. Clinical and echocardiographic data were obtained at baseline and during follow-up. The volume of ethanol injected was 1.50+/-0.4 and 2.60+/-0.6 ml (p<0.001) with a subsequent peak of creatine kinase-MB of 2.25+/-1.00 and 2.62+/-1.57 microkat/L (p=0.02) in Groups A and B, respectively. The median follow-up was 39 (range 6-72) months after ASA, during which 1 patient died and 1 repeat procedure was necessary in both groups of patients. Both groups had a significant and similar improvement in outflow pressure gradient, dyspnea (New York Heart Association functional class) and angina pectoris (Canadian Cardiovascular Society class) (p<0.001). There was a significant decrease in the left ventricular ejection fraction (LVEF) in Group B (81+/-7 vs 75+/-7%; p=0.002), but not in Group A (80+/-7 vs 79+/-7%; p=0.67). Thinning of the basal septum was more pronounced in Group B than in Group A (9.3+/-5.7 vs 6.6+/-3.4 mm; p=0.04). CONCLUSIONS A lower dose of ethanol injected into the target septal branch reduces both the size of necrosis and subsequent thinning of the basal septum, and preserves LVEF during long-term follow-up. Moreover, the low dose (1-2 ml) is as safe and as hemodynamically efficacious as higher doses.
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Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis.
Woo, A, Rakowski, H, Liew, JC, Zhao, MS, Liew, CC, Parker, TG, Zeller, M, Wigle, ED, Sole, MJ
Heart (British Cardiac Society). 2003;(10):1179-85
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Abstract
OBJECTIVES To assess patients with different types of mutations of the beta myosin heavy chain (beta MHC) gene causing hypertrophic cardiomyopathy (HCM) and to determine the prognosis of patients according to the affected functional domain of beta MHC. DESIGN AND SETTING Cohort study of subjects referred to an HCM clinic at an academic hospital. PATIENTS 70 probands from the HCM clinic were screened for mutations of the beta MHC gene and 148 family members of the genotype positive probands were further assessed. The control group for the genetic studies consisted of 106 healthy subjects. MAIN OUTCOME MEASURES Direct DNA sequencing was used to screen 70 probands for mutations of the beta MHC gene. Family members underwent genotypic and detailed clinical, ECG, and echocardiographic assessments. The survival of genotype positive subjects was evaluated according to the type of functional domain affected by the missense mutation and according to phenotypic characteristics. RESULTS A mutation of the beta MHC gene was detected in 15 of 70 probands (21%). Of 148 family members studied in these 15 families, 74 were identified with a beta MHC defect. Eleven mutations were detected, including four novel mutations: Ala196Thr, Pro211Leu, Val404Leu, and Arg870Cys. Median survival was 66 years (95% confidence interval (CI) 64 to 77 years) in all affected subjects. There was a significant difference in survival between subjects according to the affected functional domain (p = 0.02). Significant independent predictors of decreased survival were the non-conservative (that is, associated with a change in the amino acid charge) missense mutations that affected the actin binding site (hazard ratio 4.4, 95% CI 1.6 to 11.8; p = 0.003) and those that affected the rod portion of beta MHC (hazard ratio 4.8, 95% CI 1.2 to 19.4; p = 0.03). No phenotypic characteristics were associated with decreased survival or cardiovascular morbidity. CONCLUSIONS The type of beta MHC functional domain affected by the missense mutation is predictive of overall prognosis in HCM.