Genetics of systolic and diastolic heart failure.
Heart failure accounts for a significant portion of heart diseases. Molecular mechanisms gradually emerge that participate in pathways leading to left ventricular dysfunction in common systolic heart failure (SHF) and diastolic heart failure (DHF). A human genome-wide association study (GWAS) identified two markers for SHF and no GWAS on DHF has been documented. However, genetic analyses in rat models of SHF and DHF have begun to unravel the genetic components known as quantitative trait loci (QTLs) initiating systolic and diastolic function. A QTL for systolic function was detected and the gene responsible for it is identified to be that encoding the soluble epoxide hydrolase. Diastolic function is determined by multiple QTLs and the Ccl2/monocyte chemotactic protein gene is the strongest candidate. An amelioration on diastolic dysfunction is merely transient from changing such a single QTL accompanied by a blood pressure reduction. A long-term protection can be achieved only via combining alleles of several QTLs. Thus, distinct genes in synergy are involved in physiological mechanisms durably ameliorating or reversing diastolic dysfunction. These data lay the foundation for identifying causal genes responsible for individual diastolic function QTLs and the essential combination of them to attain a permanent protection against diastolic dysfunction, and consequently will facilitate the elucidation of pathophysiological mechanisms underlying hypertensive diastolic dysfunction. Novel pathways triggering systolic and diastolic dysfunction have emerged that will likely provide new diagnostic tools, innovative therapeutic targets and strategies in reducing, curing and even reversing SHF and DHF.
Research Centre, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada.
Alan Y
AY
Deng
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D055106:Genome-Wide Association Study; D054144:Heart Failure, Diastolic / Q000150:complications / Q000235:genetics*; D054143:Heart Failure, Systolic / Q000150:complications / Q000235:genetics*; D006801:Humans; D040641:Quantitative Trait Loci; D051381:Rats; D018487:Ventricular Dysfunction, Left / Q000209:etiology
D018932:Chemokine CCL2; D005819:Genetic Markers; D004851:Epoxide Hydrolases