Dietary Prevention of Heart Failure in Hypertensive Metabolic Syndrome

Tens of thousands of Veterans have heart failure with preserved ejection fraction (HFpEF), and suffer poor quality of life, frequent hospitalizations, and high death rates. Older Veterans and those with high blood pressure, obesity, and the metabolic syndrome (abnormal cholesterol and resistance to insulin's effects) are particularly at risk for HFpEF. However, it is not clear why only some Veterans in this risk group eventually develop HFpEF. Extensive information from experimental animal models and some human studies suggests that dietary patterns in vulnerable 'salt-sensitive' people could contribute to the risk for HFpEF. Reducing salt intake and increasing overall dietary quality in at-risk Veterans could prevent heart and blood vessel damage that ultimately leads to HFpEF. Reducing the development of HFpEF, which currently has no definitive treatment, is highly relevant to the VA's mission to emphasize prevention of disease and population health.

COVID-19 in-person visit hold has been removed- screening and actively enrolling. We are not currently performing sublingual darkfield microscopy because of the need for close face-to-face contact with an open-mouthed patient for several minutes in the setting of COVID-19 pandemic. Patients with heart failure (HF) account for over 1,200,000 VA outpatient visits per year, and HF remains the most common cause for hospital admission in the VA. Approximately 1/3 of Veterans with HF have 'preserved' ejection fraction (HFpEF), or relatively normal contractile function of the heart; such patients suffer functional decline and poor quality of life, and half die within 5 years after diagnosis. Risk factors for developing HFpEF are more common in Veterans than the general population, and the burden of HFpEF to the VA system will rise in the years ahead as these Veterans age. Preventive efforts are critical, but are hampered by gaps in knowledge related to HFpEF pathophysiology. The long term goal of this proposal is to prevent the onset of HFpEF in at-risk Veterans. Hypertension (HTN) confers the highest population-attributable risk for HFpEF, particularly when accompanied by the metabolic syndrome, a constellation of obesity, insulin resistance, and dyslipidemia. Animal models of HTN and metabolic syndrome develop HFpEF due to microvascular oxidative stress and inflammation induced by high sodium intake. Recent data from cardiac biopsies confirm similar mechanisms in human HFpEF. Dietary sodium restriction is widely recommended to prevent HTN-associated heart disease in humans, but this advice is now controversial. Few studies have examined how individual differences in response to sodium intake affect risk. "Salt-sensitive" persons have blood pressure (BP) that changes in parallel with sodium intake, and commonly develop cardiovascular abnormalities associated with HFpEF. The overall objective of this proposal is to evaluate salt-sensitivity as a novel, diet-responsive risk factor for incident HFpEF in Veterans with HTN and metabolic syndrome. The central hypothesis is that the sodium-restricted Dietary Approaches to Stop Hypertension (DASH/SRD) eating pattern will improve cardiovascular functional and structural risk factors for HFpEF in Veterans with the salt-sensitive phenotype. Guided by findings in experimental models, cohort studies, and strong preliminary evidence from the investigators' research group, this hypothesis will be tested in a two-phase study and by pursuing three specific aims: 1) Determine effects of DASH/SRD on functional and structural cardiovascular HFpEF risk factors in salt-sensitive vs. salt-resistant Veterans, 2) measure the effect of an electronically-delivered tailored-messaging intervention on DASH/SRD adherence, and 3) determine effects of DASH/SRD intervention and adoption on microvascular function and assess the endothelial glycocalyx as a biomarker of cardiovascular response to DASH/SRD. Phase 1 of the study is a crossover-randomized comparison of DASH/SRD vs. control diet for two weeks each, and Phase 2 a 6-month extension to promote DASH/SRD adherence. The salt-sensitive phenotype will be defined by between-diet changes in 24-hour mean BP during Phase 1. In Phase 2, the efficacy of motivational interviewing-based counseling and the Women's and Men's Hypertension Experiences and Emerging Lifestyles Intervention (WHEELS-I), a tailored messaging program, to sustain DASH/SRD adherence, will be compared. Echocardiography and arterial tonometry will be used to assess HFpEF-related cardiovascular parameters during short- and longer-term dietary modification and their interaction with salt-sensitivity. In vivo microscopy and novel blood testing will assess microvascular function and the integrity of the endothelial glycocalyx, a blood vessel lining that is sodium-responsive and may mediate the adverse effects of salt-sensitivity. This proposal is innovative because it represents the first study to examine salt-sensitivity as a factor promoting HFpEF in Veterans with HTN and metabolic syndrome, the highest risk group for incident HFpEF. Moreover, it aims to link microvascular dysfunction, an important pathway in human HFpEF, with endothelial glycocalyx damage, a potential biomarker for sodium-mediated vascular risk. The proposed research is significant because it will vertically advance the investigators' understanding of how dietary factors contribute to the pathophysiology of HFpEF, a major and growing health threat to Veterans.

Phase 1 of study: randomized crossover design, 14 days each of control vs. sodium-restricted DASH diet Phase 2 of study: randomized assignment, 6 months of motivational interviewing vs. motivational interviewing plus mobile application-based promotion of dietary adherence

In addition to motivational interviewing-based counseling with a registered dietitian to promote adoption of the sodium-restricted Dietary Approaches to Stop Hypertension (DASH/SRD) eating plan., participants in this arm will also receive an electronically-delivered tailored messaging intervention called Women's and Men's Hypertension Experiences and Emerging Lifestyle Intervention (WHEELS-I).

Participants in this arm will receive motivational interviewing-based counseling with a registered dietitian to promote adoption of the sodium-restricted Dietary Approaches to Stop Hypertension (DASH/SRD) eating plan.

Participants will receive the WHEELS-I electronically-delivered tailored messaging intervention in addition to motivational interviewing-based counseling.

Effects of a 2-week DASH/SRD intervention vs. control diet on HFpEF functional cardiovascular risk factors

Participants will be randomized to the sequence DASH/SRD-control diet or control diet-DASH/SRD, and consume the diets for 14 days each.

Velocity of pulse wave traveling between carotid and femoral artery; validated measure of arterial stiffness

Velocity of pulse wave traveling between carotid and femoral artery; validated measure of arterial stiffness

Sodium-restricted DASH diet score on Food Frequency Questionnaire, measured by complete or partial adherence to 9 dietary domains

Analysis of 3-day food diaries by a Registered Dietitian, utilizing the Nutrition Data System for Research

Inclusion Criteria: Veterans aged 45 years with HTN here defined as screening systolic BP 130 and/or diastolic BP 85 mmHg, or current use of anti-hypertensive drugs and metabolic syndrome body mass index 30 kg/m2 and/or waist circumference >94 cm Participants must also be willing to participate in the WHEELS-I program by using a smartphone application or email Exclusion Criteria: On-treatment systolic BP of >160 mmHg at screening visit previous history of HF left ventricular ejection fraction <50% moderate or severe valvular heart disease myocardial infarction or stroke within the prior 6 months chronic kidney disease with estimated glomerular filtration rate <45 ml/min/ 1.73m2 unoperated aortic aneurysm for which surgery is indicated, prior hyperkalemia requiring urgent treatment hemoglobin <9 gm/dL investigator-determined factors: severe pulmonary disease, e.g.: oxygen-requiring hepatic disease, e.g.: cirrhosis severely uncontrolled diabetes (hemoglobin A1c >10%) active cancer other than non-melanoma skin or low-risk prostate cancer other comorbidity with expected survival <12 months active alcohol/illicit substance abuse and/or a history of persistent nonadherence to treatment Veterans involved in another study (unless it is survey-only and the other investigator will allow us to invite the person in a survey-only study to consider our study)