Electro-mechanical dysfunction in long QT syndrome: Role for arrhythmogenic risk prediction and modulation by sex and sex hormones.

Long QT syndrome (LQTS) is a congenital arrhythmogenic channelopathy characterized by impaired cardiac repolarization. Increasing evidence supports the notion that LQTS is not purely an "electrical" disease but rather an "electro-mechanical" disease with regionally heterogeneously impaired electrical and mechanical cardiac function. In the first part, this article reviews current knowledge on electro-mechanical (dys)function in LQTS, clinical consequences of the observed electro-mechanical dysfunction, and potential underlying mechanisms. Since several novel imaging techniques - Strain Echocardiography (SE) and Magnetic Resonance Tissue Phase Mapping (TPM) - are applied in clinical and experimental settings to assess the (regional) mechanical function, advantages of these non-invasive techniques and their feasibility in the clinical routine are particularly highlighted. The second part provides novel insights into sex differences and sex hormone effects on electro-mechanical cardiac function in a transgenic LQT2 rabbit model. Here we demonstrate that female LQT2 rabbits exhibit a prolonged time to diastolic peak - as marker for contraction duration and early relaxation - compared to males. Chronic estradiol-treatment enhances these differences in time to diastolic peak even more and additionally increases the risk for ventricular arrhythmia. Importantly, time to diastolic peak is particularly prolonged in rabbits exhibiting ventricular arrhythmia - regardless of hormone treatment - contrasting with a lack of differences in QT duration between symptomatic and asymptomatic LQT2 rabbits. This indicates the potential added value of the assessment of mechanical dysfunction in future risk stratification of LQTS patients.

The vulnerable myocardium.

Cardiovascular disease is the major cause of morbidity and mortality in subjects suffering from diabetes mellitus. While coronary artery disease is the leading cause of cardiac complications in diabetics, it is widely recognized that diabetes increases the risk for the development of heart failure independently of coronary heart disease and hypertension. This increased susceptibility of the diabetic heart to develop structural and functional impairment is termed diabetic cardiomyopathy. The number of different mechanisms proposed to contribute to diabetic cardiomyopathy is steadily increasing and underlines the complexity of this cardiac entity.In this review the mechanisms that account for the increased myocardial vulnerability in diabetic cardiomyopathy are discussed.

The vulnerable myocardium. Diabetic cardiomyopathy.

Cardiovascular disease is the major cause of morbidity and mortality in subjects suffering from diabetes mellitus. While coronary artery disease is the leading cause of cardiac complications in diabetics, it is widely recognized that diabetes increases the risk for the development of heart failure independently of coronary heart disease and hypertension. This increased susceptibility of the diabetic heart to develop structural and functional impairment is termed diabetic cardiomyopathy. The number of different mechanisms proposed to contribute to diabetic cardiomyopathy is steadily increasing and underlines the complexity of this cardiac entity. In this review the mechanisms that account for the increased myocardial vulnerability in diabetic cardiomyopathy are discussed.

Differential gene expression in response to ventricular unloading in rat and human myocardium.

UNLABELLED: Left ventricular unloading by mechanical assist devices induces myocardial atrophy. We aimed to systematically identify differentially expressed genes in a model of physiological atrophy (unloading of healthy rat myocardium) and compare these changes to those in a unloaded, failing human heart. METHODS: Atrophy in rat hearts was induced by heterotopic transplantation of a donor heart into the abdomen of an isogenic recipient. After one week, donor and recipient RNA was isolated. Differential gene expression was assessed by subtractive hybridization. Two screens with radioactive probes were performed to verify differentially expressed clones. Positive clones were sequenced and cDNA of genes of known homology were used as probes for hybridization with RNA from separate atrophied rat hearts and human tissue from a normal, failing or failing and unloaded left ventricle. RESULTS: We picked 1880 clones from the subtractive hybridization procedure (940/940: forward/reverse runs assessing up- or down-regulation, respectively). The first screen verified 465/140 and the second screen verified 67/30 clones. 24/23 clones were sequenced and 14/10 homologies to known genes were found. In the atrophied heart, respiratory chain and metabolic genes were down-regulated (NADH-DH, cytochrome c oxidase, acetyl-CoA synthetase, myoglobin) and cellular recognition and stress genes were up-regulated (MHC1 and 2, HSP70). In the human heart, cytochrome c oxidase, acetyl-CoA synthetase, and myoglobin expression was increased in the failing heart and returned to normal with unloading. Unloading also resulted in up-regulation of HSP70. CONCLUSIONS: The genetic responses of failing human and healthy rat myocardium to mechanical unloading show similarities that appear to be independent of species differences and/or underlying disease. Thus, heterotopic heart transplantation is a relevant model for investigating the mechanisms of mechanical unloading.