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Project

Genetic and mtDNA contributions to early cardiovascular ageing and disease: a population study

Heart failure (HF) is a progressive disorder that begins with cardiovascular risk factors, proceeds to asymptomatic maladaptive left ventricular (LV) remodelling and dysfunction, and then evolves into clinically overt HF and disability.  The genetic and molecular drivers that underlie progressive cardiac dysfunction and remodelling are only partially understood.

The progression of LV dysfunction is associated with changes in cardiac energy production as well as consumption. Mitochondria, main myocardial adenosine triphosphate (ATP) producing organelles, contain several copies of circular mitochondrial DNA (mtDNA) molecules that are susceptible to oxidative damage. Accumulation of mtDNA damage in dysfunctional mitochondria might result in decreased overall cellular mitochondrial-to-nuclear DNA ratio (mtDNA content) early in the course of HF.  On the other hand, cardiomyocyte contraction and relaxation depend on the balance of important electrolytes across the cellular membranes in cardiomyocytes. The electrolyte gradients are maintained by trans-membrane channels and active ATP dependent pumps. Marked decrease in mitochondrial ATP production leads to the inhibition of the Na-K-ATPase and to impaired LV function.  Considering the known pathophysiological roles of both energy producing mitochondria and energy consuming electrolyte pumps in determination of LV function, biomarkers of mitochondrial function and genetic polymorphism of the Na/K ATPase require further study.

To investigate the genetic and mitochondrial contributions to early changes in LV structure and/or function, this doctoral project builds on large-scale European population studies of cardiovascular phenotypes and outcomes. Using an epidemiological approach we will: (1) determine whether genetic factors contribute to LV diastolic function as assessed by echocardiographic Doppler velocities, (2) evaluate the possible association between LV function and polymorphisms in ATP12A gene encoding a subunit of an ATPase that can function as a Na+/K+ pump, (3) measure the peripheral blood mtDNA content in a general population sample and describe its distribution and determinants, (4) investigate whether echocardiographic indexes of LV structure and function are associated with mtDNA content measured in peripheral blood cells, (5) explore the relations between mtDNA content, circulating metabolites and markers of inflammation, (6) test the correlation between mtDNA content measured in cardiomyocytes and peripheral blood cells in patients with symptomatic HF. 

Date:1 Oct 2013 →  28 Jun 2017
Keywords:Cardiovascular epidemiology, Cardiovascular genetics, Mitochondrial DNA
Disciplines:Public health care, Public health sciences, Public health services, Genetics, Systems biology, Molecular and cell biology, Morphological sciences, Cardiac and vascular medicine
Project type:PhD project