Acute Effects of Cocoa Flavanols on Blood Pressure and Peripheral Vascular Reactivity in Type 2 Diabetes Mellitus and Essential Hypertension: A Protocol for an Acute, Randomized, Double-Blinded, Placebo-Controlled Cross-Over Trial.

Anouk Tanghe,Patrick Calders,Koen D Reesink,Bert Celie,Elsa Heyman,Ernst Rietzschel,Samyah Shadid,Jos Op ‘T Roodt

doi:10.3389/fcvm.2021.602086

Abstract

Introduction: Patients with type 2 diabetes mellitus are at high risk to develop vascular complications resulting in high morbidity and mortality. Cocoa flavanols are promising nutraceuticals with possible beneficial vascular effects in humans. However, limited research is currently available on the vascular effects in a diabetic population with inconsistent results. Possible reasons for this inconsistency might be heterogeneity in the given intervention (dose per time and day, single dose vs. split-dose, placebo formula) and the studied population (blood pressure at baseline, duration of diabetes, use of vasoactive antihypertensive and antidiabetic drugs, sex). Therefore, we aimed to develop a randomized, double-blinded, placebo-controlled cross-over trial to investigate whether cocoa flavanols have an acute impact on blood pressure and vascular reactivity in patients with type 2 diabetes with and without arterial hypertension.Methods and Analysis: We will include participants in four groups: (i) patients with type 2 diabetes without arterial hypertension, (ii) patients with type 2 diabetes with arterial hypertension and 1 antihypertensive drug, (iii) non-diabetic participants with essential hypertension and 1 antihypertensive drug, and (iv) healthy controls. All participants will complete the same protocol on both testing days, consuming high-flavanol cocoa extract (790 mg flavanols) or placebo. Macrovascular endothelial function (flow-mediated dilation) and blood pressure will be measured before and after capsule ingestion. Forearm muscle vasoreactivity (near-infrared spectroscopy) and brachial artery blood flow (echo-doppler) will be assessed in response to a dynamic handgrip exercise test after capsule ingestion. Data will be analyzed with a random intercept model in mixed models.Clinical Trial Registration: www.Clinicaltrials.gov, identifier: NCT03722199.

Highlights

Patients with type 2 diabetes mellitus are at high risk to develop vascular complications resulting in high morbidity and mortality
Type 2 diabetes (T2DM) is the most prevalent type [90% [6, 7]] of diabetes mellitus, a highly prevalent disorder [estimated at 425 million people worldwide in 2017 and is expected to be 629 million in 2045 [8]] and poses a challenge to global health. It is characterized by chronic hyperglycemia, which increases oxidative stress
Free radicals bind with and simultaneously deactivate nitric oxide to form peroxynitrite. Both high amounts of oxidative stress and nitric oxide depletion increase the risk for developing micro- and macrovascular complications [9, 10]

Summary

Introduction

Patients with type 2 diabetes mellitus are at high risk to develop vascular complications resulting in high morbidity and mortality. Free radicals bind with and simultaneously deactivate nitric oxide to form peroxynitrite Both high amounts of oxidative stress and nitric oxide depletion increase the risk for developing micro- (retinopathy, nephropathy, and neuropathy) and macrovascular (cardiovascular, cerebrovascular, and peripheral artery diseases) complications [9, 10]. These complications decrease quality of life and increase the global burden of T2DM in terms of health care costs, morbidity [hypertension is present in >60% of all patients with T2DM [11]], and even mortality [12,13,14,15]. The past years researchers have been investigating products to limit or delay the onset of diabetic vascular complications with special attention for nonpharmacological approaches to counter polypharmacy

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