Clinical and epidemiological studies from the applicant and others have established that 40-50% of patients with incident or prevalent heart failure (HF) in the community have a normal ejection fraction. This syndrome is referred to as diastolic HF (DHF) and disporportionately affects the elderly, women and persons with hypertension. Morbidity and mortality are similar to that reported for HF with a reduced ejection fraction and substantial. DHF has been presumed to be due to impairment in diastolic function of the heart. However, few studies have characterized diastolic function in patients with DHF and no large animal model of DHF has been established. Further, recent clinical studies have suggested alternative pathogenic mechanisms. Controversy over the pathogenesis of DHF has hampered development of effective therapy. The broad objective of this competitive renewal application remains to investigate the integrative pathophysiology of diastolic dysfunction (DD) and diastolic heart failure (DHF) and to translate this knowledge into therapeutic strategies for this common and highly morbid condition. We utilize in vivo studies in the elderly hypertensive canine model (experimental DHF, ExDHF) to test 2 broad hypotheses which are based on our preliminary studies in the human and in ExDHF. First, we hypothesize that arterial elastance (Ea) is increased in experimental and human DHF and is coupled to increases in both LV systolic (Ees) and LV diastolic (Ed) elastance via the intrinsic myocardial properties which dictate arterio-ventricular coupling. The clinical relevance of this hypothesis is that indeed, an increase in arterial stiffness can, in and of itself, cause not only impairment in LV relaxation but also increases in passive diastolic stiffness, the types of """"""""diastolic dysfunction"""""""" postulated to cause DHF. Second, we hypothesize that in addition to afterload mediated increases in Ees and Ed, hypertension leads to increases in ventricular fibrosis which contributes to chronic increases in Ees and Ed, above and beyond those associated with increased load. Studies are proposed to address 4 specific aims: 1) Determine the specific perturbations in vascular function (increased peripheral resistance and/or increased aortic impedance) which lead to increased arterial elastance (Ea) in ExDHF; 2) Determine the alterations in aortic structure which mediate increases in Ea in ExDHF; 3) Determine the effect of increases in Ea on LV systolic (Ees) and diastolic (Ed) elastance and 4) Determine the role of altered ventricular structure in mediating chronic increases in Ees and Ed in ExDHF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063281-06
Application #
7031631
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Evans, Frank
Project Start
2000-04-10
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
6
Fiscal Year
2006
Total Cost
$363,746
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Bishu, Kalkidan; Hamdani, Nazha; Mohammed, Selma F et al. (2011) Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo. Circulation 124:2882-91
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Mohammed, Selma F; Ohtani, Tomohito; Korinek, Josef et al. (2010) Mineralocorticoid accelerates transition to heart failure with preserved ejection fraction via ""nongenomic effects"". Circulation 122:370-8
Borlaug, Barry A; Nishimura, Rick A; Sorajja, Paul et al. (2010) Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 3:588-95
Borlaug, Barry A; Lam, Carolyn S P; Roger, Véronique L et al. (2009) Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction. J Am Coll Cardiol 54:410-8
Lam, Carolyn S P; Roger, Véronique L; Rodeheffer, Richard J et al. (2009) Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol 53:1119-26
Lam, Carolyn S P; Borlaug, Barry A; Kane, Garvan C et al. (2009) Age-associated increases in pulmonary artery systolic pressure in the general population. Circulation 119:2663-70

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