Diet and pathophysiology of heart failure with preserved ejection fraction
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DESCRIPTION (provided by applicant): Heart failure with preserved ejection fraction (HFpEF) constitutes half of heart failure in the elderly, but has no evidence-based therapy due to incomplete understanding of pathophysiology. Over 80% of HFpEF patients have hypertension, but the specific aspects that contribute to HFpEF are undefined. In 'salt-sensitive' animal models, high dietary sodium intake induces oxidative stress and inflammation in the heart, kidneys, and vasculature that cause HFpEF. In humans, the predictors of salt-sensitive hypertension match HFpEF demographics. Moreover, high sodium intake in salt-sensitive persons increases systemic oxidative stress and worsens vascular abnormalities associated with HFpEF. Current guidelines recommend dietary sodium restriction in heart failure and hypertension, but no prior studies have reported on the physiological effects of dietary modification in hypertensive HFpEF. We propose that salt-sensitive hypertension and the typical American diet are important driving factors for the initiation and progression of hypertensive HFpEF. We hypothesize that dietary patterns recommended for hypertension will 1) improve cardiovascular physiology, and 2) decrease systemic and cellular oxidative stress and inflammation in patients with hypertensive HFpEF. We will test these hypotheses by providing three weeks of the sodium-restricted Dietary Approaches to Stop Hypertension (DASH) diet to 25 patients with hypertensive HFpEF. We will report diet-induced changes in blood pressure and in vascular and ventricular function using standard and novel non-invasive measures. We will correlate these findings with oxidative stress and inflammatory marker production in the systemic circulation, venous endothelial cells, and peripheral blood mononuclear cells. In an eight-week extension, we will facilitate DASH diet compliance and determine if adherence leads to sustained physiological improvement. The candidate for this mentored Patient-Oriented Career Development Award aims to complement his previous training with additional expertise in noninvasive physiological measurement, bionutritional knowledge and dietary assessment, and interventional clinical research design. In order to facilitate future collaboration with laboratory-based colleagues, in concert with the proposed study the candidate will also pursue didactic and experiential basic science training related to his research aims. The University of Michigan has committed abundant resources to support this proposal including the use of a metabolic kitchen, sample processing laboratory, and biorepository in addition to nursing, bionutrition, and laboratory staff in the NIH CTSA-funded Michigan Clinical Research Unit. The proposal is supported by a multidisciplinary mentorship group comprised of authorities in salt-sensitive hypertension, cardiovascular physiology, vascular and immune cell biology, bionutrition, and clinical trial design. The proposed studies should provide novel information about the importance of dietary factors in hypertensive HFpEF, and could eventually lead to new strategies for the treatment and prevention of this major public health threat.
