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Tham Y.K.,Baker IDI Heart and Diabetes Institute | Tham Y.K.,Monash University | Bernardo B.C.,Baker IDI Heart and Diabetes Institute | Ooi J.Y.Y.,Baker IDI Heart and Diabetes Institute | And 3 more authors.
Archives of Toxicology | Year: 2015

The onset of heart failure is typically preceded by cardiac hypertrophy, a response of the heart to increased workload, a cardiac insult such as a heart attack or genetic mutation. Cardiac hypertrophy is usually characterized by an increase in cardiomyocyte size and thickening of ventricular walls. Initially, such growth is an adaptive response to maintain cardiac function; however, in settings of sustained stress and as time progresses, these changes become maladaptive and the heart ultimately fails. In this review, we discuss the key features of pathological cardiac hypertrophy and the numerous mediators that have been found to be involved in the pathogenesis of cardiac hypertrophy affecting gene transcription, calcium handling, protein synthesis, metabolism, autophagy, oxidative stress and inflammation. We also discuss new mediators including signaling proteins, microRNAs, long noncoding RNAs and new findings related to the role of calcineurin and calcium-/calmodulin-dependent protein kinases. We also highlight mediators and processes which contribute to the transition from adaptive cardiac remodeling to maladaptive remodeling and heart failure. Treatment strategies for heart failure commonly include diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and β-blockers; however, mortality rates remain high. Here, we discuss new therapeutic approaches (e.g., RNA-based therapies, dietary supplementation, small molecules) either entering clinical trials or in preclinical development. Finally, we address the challenges that remain in translating these discoveries to new and approved therapies for heart failure. © 2015, Springer-Verlag Berlin Heidelberg.

PubMed | Kings College London British Heart Foundation Center
Type: Journal Article | Journal: Hypertension (Dallas, Tex. : 1979) | Year: 2015

Myocardial wall stress (MWS) is thought to be the mechanical stimulus to ventricular hypertrophy. The objective of this study was to examine whether MWS is elevated in children with chronic kidney disease (CKD) who are at high risk of developing adverse cardiovascular events related to left ventricular (LV) hypertrophy. MWS, a function of left ventricular pressure, myocardial wall volume, and cavity volume, was obtained using carotid tonometry to estimate ventricular pressure and 2-dimensional transthoracic echocardiographic wall-tracking to obtain LV cavity and wall volumes. Ninety-two children (50 boys) aged 11.23.2 (meanSD) years, including healthy controls (n=16), and those with CKD disease divided into 3 groups according to estimated glomerular filtration rate (mL/min per 1.73 m2) >90 (CKD 1, n=26), 60 to 90(CKD 2, n=23), and <60 (CKD3, n=27) were studied. There was no significant difference in age, height, weight, central or peripheral blood pressure, LV mass, or mass index in the 4 study groups. By contrast, peak, mean, and end-systolic MWS were higher in children with CKD and increased across stages of CKD (peak MWS, 338.818.5 and 397.514.3 s/cm2 in controls and CKD3, respectively; P=0.01). Higher systolic MWS was explained by a form of LV dysfunction whereby dynamic values of the ratio of wall volume/cavity size during systole were lower in children with CKD than in those without (P=0.001). Children with CKD exhibit blood pressureindependent LV dysfunction which results in increased systolic MWS and which may predispose to LV hypertrophy in later life.

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