Physiological Effects of Grape Seed Extract in Diastolic Heart Failure

Study Overview
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Brief Summary
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Diastolic heart failure (also known as heart failure with normal ejection fraction or heart failure with preserved ejection fraction) occurs even though the heart muscle's pumping function is normal. In many cases diastolic heart failure is related to stiffening of the heart and blood vessels in people who have high blood pressure. Current guidelines suggest that patients should limit the salt content of their diet, as too much salty food can cause fluid retention and other problems in diastolic heart failure. Studies in animals with diastolic heart failure suggest that antioxidant chemicals found in grapes can block some of the harmful effects of salty diets. Because it is often difficult for patients with diastolic heart failure to maintain a low salt diet, the investigators are researching the effects of the antioxidant properties of grape seed extract, a natural supplement made from grape seeds. The investigators hypothesize that supplementing the diet with grape seed extract (GSE) can decrease the levels of harmful chemicals and improve heart and blood vessel function in patients with diastolic heart failure and a history of high blood pressure. The University of Michigan research group plans to enroll 25 patients with a history of high blood pressure and diastolic heart failure in a research study. The study will assess the effects of GSE on hormones and other chemicals that can cause heart and blood vessel damage. The investigators will also study the effects of GSE on the ability of the blood vessels and heart muscles to relax at the proper time and speed. Finally, the investigators will observe how GSE affects participants' overall ability to exercise, quality of life, and blood pressure control. Study participants will be randomly assigned to take either GSE or placebo (looks like but does not contain GSE) capsules twice a day for six weeks. After a two-week break, all subjects will cross over to the opposite group of capsules for an additional six-week period. At the start of the study and at the end of each six-week time period study participants will have non-invasive heart and blood vessel testing, blood work and urine tests, and blood pressure monitoring.

Official Title
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GRAPe Seed Extract and Ventriculovascular Investigation in Normal Ejection-Fraction Heart Failure

Conditions
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Diastolic Heart Failure, Hypertensive Heart Disease, Heart Failure With Preserved Ejection Fraction, Hypertension, Oxidative Stress

Intervention / Treatment
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* Drug: grape seed extract (MegaNatural BP, Polyphenolics, Inc.)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion: Signs and symptoms of heart failure Left ventricular ejection fraction ≥ 50% (contrast ventriculography, echocardiography, nuclear scintigraphy, MRI or CT imaging) Diastolic dysfunction on previous echocardiogram/catheterization, or indeterminate diastolic function with supporting evidence of heart failure (HF) (as per European Society of Cardiology guidelines) History of systemic hypertension Age ≥ 50 years Willing to adhere to prescribed course of supplementation Informed consent Exclusion Criteria: Daily intake of antioxidant supplements or vitamins beyond that provided in a standard daily multivitamin (e.g. high-dose vitamin E or vitamin C) NYHA Class IV heart failure symptoms (except during previous hospitalization) Hospitalization for decompensated heart failure within past one month Severely uncontrolled hypertension (SBP ≥ 180 and.or DBP ≥ 100 at rest, on current antihypertensive regimen Uncontrolled diabetes mellitus (hemoglobin A1C > 9%) Severe renal (estimated GFR < 30 ml/min) or hepatic disease/failure Severe anemia (Hgb < 9) Primary exercise limitation due to severe pulmonary disease Unacceptably poor echocardiographic images for analysis Worse than moderate mitral or aortic stenosis or insufficiency. Non-hypertensive cause of HFpEF (e.g. valvular disease, congenital heart disease, amyloidosis, sarcoidosis, constrictive pericardial syndromes) Myocardial infarction or unstable angina, including new or worsening anginal syndrome, within the past three months Uncontrolled arrhythmia (including non rate-controlled atrial fibrillation) Terminal illness expected to result in death within six months or active solid-organ cancer Psychiatric disorder (or dementia) with potential to compromise adherence Changes in medical regimen for heart disease or hypertension within past 1 month (except diuretic dose adjustment)

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: grape seed extract capsule<br>Grape seed extract (MegaNatural BP, Polyphenolics, Inc.) 300 milligram capsules twice daily for six weeks | Drug: grape seed extract (MegaNatural BP, Polyphenolics, Inc.)<br>* Subjects will be randomized in double-blind fashion to either grape seed extract (GSE) or maltodextrin placebo capsules for for 6 weeks. Patient will take 300 mg GSE/placebo twice a day for 6 weeks. Patient will have a 2 week washout period and then cross over to the opposite group for an additional 6 weeks.<br>* Other names: antioxidants;|
| Placebo Comparator: maltodextrin capsule<br>Maltodextrin capsules (matched for appearance and taste to grape seed extract capsules) twice daily for six weeks | Drug: grape seed extract (MegaNatural BP, Polyphenolics, Inc.)<br>* Subjects will be randomized in double-blind fashion to either grape seed extract (GSE) or maltodextrin placebo capsules for for 6 weeks. Patient will take 300 mg GSE/placebo twice a day for 6 weeks. Patient will have a 2 week washout period and then cross over to the opposite group for an additional 6 weeks.<br>* Other names: antioxidants;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brachial artery flow-mediated dilation (FMD) | Ultrasound measure of conduit artery endothelial function | Pre-six weeks of investigational drug and placebo intervention | 
| Brachial artery flow-mediated dilation (FMD) | Ultrasound measure of conduit artery endothelial function | Post-six weeks of investigational drug and placebo intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-hour blood pressure | Mean and diurnal variation | Pre-six weeks of investigational drug and placebo intervention | 
| EndoPAT arterial endothelial function | Plethysmographic measure of resistance arterial endothelial function | Pre-six weeks of investigational drug and placebo intervention | 
| Carotid-femoral pulse wave velocity |  | Pre-six weeks of investigational drug and placebo intervention | 
| Maximal exercise capacity and oxygen consumption |  | Pre-six weeks of investigational drug and placebo intervention | 
| Resting and post-exercise ventricular systolic and diastolic function | Standard and novel echocardiographic measures including strain/strain rate | Pre-six weeks of investigational drug and placebo intervention | 
| Urinary 8-isoprostanes | Measure of oxidative stress | Pre-six weeks of investigational drug and placebo intervention | 
| Heart failure related quality of life | Minnesota Living With Heart Failure Questionnaire | Pre-six weeks of investigational drug and placebo intervention | 
| 24-hour blood pressure | Mean and diurnal variation | Post-six weeks of investigational drug and placebo intervention | 
| EndoPAT arterial endothelial function | Plethysmographic measure of resistance arterial endothelial function | Post-six weeks of investigational drug and placebo intervention | 
| Carotid-femoral pulse wave velocity |  | Post-six weeks of investigational drug and placebo intervention | 
| Maximal exercise capacity and oxygen consumption |  | Post-six weeks of investigational drug and placebo intervention | 
| Resting and post-exercise ventricular systolic and diastolic function | Standard and novel echocardiographic measures including strain/strain rate | Post-six weeks of investigational drug and placebo intervention | 
| Urinary 8-isoprostanes | Measure of oxidative stress | Post-six weeks of investigational drug and placebo intervention | 
| Heart failure related quality of life | Minnesota Living With Heart Failure Questionnaire | Post-six weeks of investigational drug and placebo intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, Endothelial function, Antioxidants, Oxidative stress, Grapes, Polyphenols, Resveratrol, Quercetin, Anthocyanins, Flavanols, Flavonols, Congestive heart failure, Heart failure with normal ejection fraction, Heart failure with preserved systolic function, HFNEF, HFPSF, HFPEF, DHF