Dominik Schuler

Cocoa flavanol intake improves endothelial function and Framingham Risk Score in healthy men and women: a randomised, controlled, double-masked trial: the Flaviola Health Study.

Cocoa flavanol (CF) intake improves endothelial function in patients with cardiovascular risk factors and disease. We investigated the effects of CF on surrogate markers of cardiovascular health in low risk, healthy, middle-aged individuals without history, signs or symptoms of CVD. In a 1-month, open-label, one-armed pilot study, bi-daily ingestion of 450 mg of CF led to a time-dependent increase in endothelial function (measured as flow-mediated vasodilation (FMD)) that plateaued after 2 weeks. Subsequently, in a randomised, controlled, double-masked, parallel-group dietary intervention trial (Clinicaltrials.gov: NCT01799005), 100 healthy, middle-aged (35–60 years) men and women consumed either the CF-containing drink (450 mg) or a nutrient-matched CF-free control bi-daily for 1 month. The primary end point was FMD. Secondary end points included plasma lipids and blood pressure, thus enabling the calculation of Framingham Risk Scores and pulse wave velocity. At 1 month, CF increased FMD over control by 1·2 % (95 % CI 1·0, 1·4 %). CF decreased systolic and diastolic blood pressure by 4·4 mmHg (95 % CI 7·9, 0·9 mmHg) and 3·9 mmHg (95 % CI 6·7, 0·9 mmHg), pulse wave velocity by 0·4 m/s (95 % CI 0·8, 0·04 m/s), total cholesterol by 0·20 mmol/l (95 % CI 0·39, 0·01 mmol/l) and LDL-cholesterol by 0·17 mmol/l (95 % CI 0·32, 0·02 mmol/l), whereas HDL-cholesterol increased by 0·10 mmol/l (95 % CI 0·04, 0·17 mmol/l). By applying the Framingham Risk Score, CF predicted a significant lowering of 10-year risk for CHD, myocardial infarction, CVD, death from CHD and CVD. In healthy individuals, regular CF intake improved accredited cardiovascular surrogates of cardiovascular risk, demonstrating that dietary flavanols have the potential to maintain cardiovascular health even in low-risk subjects.

Macrovascular and microvascular function after implantation of left ventricular assist devices in end-stage heart failure: Role of microparticles

BACKGROUND The hemodynamic vascular consequences of implanting left ventricular assist devices (LVADs) have not been studied in detail. We investigated the effect of LVAD implantation compared with heart transplant (HTx) on microvascular and macrovascular function in patients with end-stage heart failure and evaluated whether microparticles may play a role in LVAD-related endothelial dysfunction. METHODS Vascular function was assessed in patients with end-stage heart failure awaiting HTx, patients who had undergone implantation of a continuous-flow centrifugal LVAD, and patients who had already received a HTx. Macrovascular function was measured by flow-mediated vasodilation (FMD) using high-resolution ultrasound of the brachial artery. Microvascular function was assessed in the forearm during reactive hyperemia using laser Doppler perfusion imaging and pulsed wave Doppler. Age-matched patients without heart failure and without coronary artery disease (CAD) (healthy control subjects) and patients with stable CAD served as control subjects. Circulating red blood cell (CD253(+)), leukocyte (CD45(+)), platelet (CD31(+)/CD41(+)), and endothelial cell (CD31(+)/CD41(-), CD62e(+), CD144(+)) microparticles were determined by flow cytometry and free hemoglobin by enzyme-linked immunosorbent assay. RESULTS FMD and microvascular function were significantly impaired in patients with end-stage heart failure compared with healthy control subjects and patients with stable CAD. LVAD implantation led to recovery of microvascular function, but not FMD. In parallel, increased free hemoglobin was observed along with red and white cell microparticles and endothelial and platelet microparticles. This finding indicates destruction of blood cells with release of hemoglobin and activation of endothelial cells. HTx and LVAD implantation led to similar improvements in microvascular function. FMD increased and microparticle levels decreased in patients with HTx, whereas shear stress during reactive hyperemia was similar in patients with LVADs and patients with HTx. CONCLUSIONS Our data suggest that LVAD support leads to significant improvements in microvascular perfusion and hemodynamics. However, destruction of blood cells may contribute to residual endothelial dysfunction potentially by increasing nitric oxide scavenging capacity.

Measurement of Endothelium-Dependent Vasodilation in Mice

Objective— Endothelium-dependent, flow-mediated vasodilation after an increase in shear stress at the endothelial lining of conduit arteries during reactive hyperemia after ischemia is a fundamental principle of vascular physiology adapting blood flow to demand of supplied tissue. Flow-mediated vasodilation measurements have been performed in human studies and are of diagnostic and prognostic importance, but have been impossible because of technical limitations in transgenic mice to date, although these represent the most frequently used animal model in cardiovascular research. Approach and Results— Using high-frequency ultrasound, we visualized, quantified, and characterized for the first time endothelium-dependent dilation of the femoral artery after temporal ischemia of the lower part of the hindlimb and demonstrated that the signaling was almost exclusively dependent on stimulation of endothelial nitric oxide synthase, similar to acetylcholine, completely abolished after pharmacological or genetic inhibition of endothelial nitric oxide synthase and endothelial denudation, substantially impaired in mice of increasing age and cholesterol-fed ApoE knock outs and increased by the dietary polyphenol (−)-epicatechin. Intra- and interindividual variability were similar to the human methodology. Conclusions— The physiology of flow-mediated vasodilation in mice resembles that in humans underscoring the significance of this novel technology to noninvasively, serially, and reliably quantify flow-mediated vasodilation in transgenic mice.

Measurement of Endothelium-Dependent Vasodilation in Mice—Brief Report

Objective— Endothelium-dependent, flow-mediated vasodilation after an increase in shear stress at the endothelial lining of conduit arteries during reactive hyperemia after ischemia is a fundamental principle of vascular physiology adapting blood flow to demand of supplied tissue. Flow-mediated vasodilation measurements have been performed in human studies and are of diagnostic and prognostic importance, but have been impossible because of technical limitations in transgenic mice to date, although these represent the most frequently used animal model in cardiovascular research. Approach and Results— Using high-frequency ultrasound, we visualized, quantified, and characterized for the first time endothelium-dependent dilation of the femoral artery after temporal ischemia of the lower part of the hindlimb and demonstrated that the signaling was almost exclusively dependent on stimulation of endothelial nitric oxide synthase, similar to acetylcholine, completely abolished after pharmacological or genetic inhibition of endothelial nitric oxide synthase and endothelial denudation, substantially impaired in mice of increasing age and cholesterol-fed ApoE knock outs and increased by the dietary polyphenol (−)-epicatechin. Intra- and interindividual variability were similar to the human methodology. Conclusions— The physiology of flow-mediated vasodilation in mice resembles that in humans underscoring the significance of this novel technology to noninvasively, serially, and reliably quantify flow-mediated vasodilation in transgenic mice.

Is there a Role for Antioxidants in the Treatment of Stable Angina

Medical treatment plays an important role in the therapy of coronary artery disease and stable angina. Whereas nitrates are used to improve symptoms, beta-blockers, statins, and ACE-inhibitors/angiotensin receptor blockers are given also to target prognosis in part by slowing the progression of disease. Major cardiovascular risk factors including tobacco smoking, physical inactivity, obesity, arterial hypertension, hyperlipidemia, and diabetes mellitus were associated with overproduction of reactive oxygen species (ROS). In animal models, increased ROS production was associated with the initial steps of atherosclerosis including vascular cell dysfunction, intimal hypertrophy, the formation and destabilization of plaque. As a consequence, ROS were believed to be major contributors to the development of cardiovascular diseases and antioxidant treatments were proposed as promising therapeutic strategies. Nevertheless, intervention studies with antioxidant vitamins have failed to positively affect cardiovascular outcome in prospective trials. Specific inhibitors of prooxidant enzymes are being developed but their efficacy to improve cardiovascular endpoints has not been tested so far. Newer evidence suggests that phytonutrients including flavanols may posses vascular protective effects that are independent of their antioxidant properties observed in vitro. Taken together, there is currently not enough evidence that treatment with antioxidants per se will play a role in cardiovascular medicine.

Repetitive remote occlusion (RRO) stimulates eNOS-dependent blood flow and collateral expansion in hindlimb ischemia

Objective: Collateral expansion is an important compensatory mechanism to alleviate tissue ischemia after arterial occlusion. We investigated the efficacy and mechanisms of temporary remote hindlimb occlusion to stimulate contralateral blood flow and collateral expansion after hindlimb ischemia in mice and evaluated translation to peripheral artery disease in humans. Methods and results: We induced unilateral hindlimb ischemia via femoral artery excision in mice. We studied central hemodynamics, blood flow, and perfusion of the ischemic hindlimb during single and repetitive remote occlusion (RRO) of the contralateral non‐ischemic hindlimb with a pressurized cuff. Similar experiments were performed in patients with unilateral peripheral artery disease (PAD). Contralateral occlusion of the non‐ischemic hindlimb led to an acute increase in blood flow to the ischemic hindlimb without affecting central blood pressure and cardiac output. The increase in blood flow was sustained even after deflation of the pressure cuff. RRO over 12 days (8/day, each 5 min) led to significantly increased arterial inflow, lumen expansion of collateral arteries, and increased perfusion of the chronically ischemic hindlimb as compared to control. In NOS3‐/‐ and after inhibition of NOS (L‐NAME), and NO (ODQ), the acute and chronic effects of contralateral occlusion were abrogated and stimulation of guanylyl cyclase with cinaciguate exhibited a similar response as RRO and was not additive. Pilot studies in PAD patients demonstrated that contralateral occlusion increased arterial inflow to ischemic limbs and improved walking distance. Conclusions: Repetitive remote contralateral occlusion stimulates arterial inflow, perfusion, and functional collateral expansion in chronic hindlimb ischemia via an eNOS‐dependent mechanism underscoring the potential of remote occlusion as a novel treatment option in peripheral artery disease. Graphical abstract Figure. No caption available. HighlightsOcclusion of the non‐ischemic hindlimb acutely increased blood flow to the ischemic hindlimb without affecting central hemodynamics.Repetitive remote occlusion chronically increased arterial inflow, lumen expansion of collateral arteries, and increased perfusion of ischemic hindlimb.Chronic response to RRO twas attenuated in NOS3‐/‐, NOS‐inhibition, NO scavenging and similar, but not additive to guanylyl cyclase activation.In a pilot study in PAD patients, contralateral occlusion increased arterial inflow to ischemic limbs and improved walking distance.Repetitive remote occlusion has potential as a novel treatment option in PAD.

Endothelial microparticles and vascular parameters in subjects with and without arterial hypertension and coronary artery disease

Endothelial microparticles (EMPs) are markers of endothelial injury and activation. The role of EMPs in arterial hypertension is not well understood and EMPs are increased both in arterial hypertension and coronary artery disease (CAD). The data presented here show EMPs as defined by CD31+/41−, CD62e+, and CD144+ surface markers and vascular hemodynamic parameters including office and central blood pressure, heart rate, aortic augmentation index, pulse wave velocity, flow-mediated dilation, nitroglycerin-mediated dilation, brachial artery diameter, hyperemic wall shear stress, and laser Doppler perfusion of the cutaneous microcirculation of normotensives and hypertensives with and without CAD.

Micro-And Macrovascular Function in End Stage Heart Failure: Influence of Mechanical Circulatory Support and of Heart Transplant

Purpose End stage heart failure causes a critical inability of the heart to supply the organism’s blood demand even under resting conditions. Left ventricular assist devices represent a therapeutic option to assist the failing circulation. The hemodynamic consequences with regard to vascular adaptation after implanting LVADs have not been studied in detail. The effect of LVAD implantation and heart transplant (HTx) on micro- and macrovascular function in patients with end stage heart failure should be investigated. Methods and Materials Vascular function was assessed in patients with end-stage heart failure (NYHA IV) that underwent implantation of a continuous flow LVAD, or received HTx. Macrovascular function was measured by flow-mediated vasodilation (FMD) using high resolution ultrasound of the brachial artery. Mircovascular function was assessed as flow reserve (FR) of the forearm during reactive hyperemia using laser Doppler perfusion imaging (LDPI). Healthy age-matched patients (C) with and without coronary artery disease (CAD) served as controls. Results in NYHA IV, FMD (2.4±0.7%) and FR (2.3±0.6) were significantly impaired as compared to C (5.5±1.1%, 6.0±0.9, p Conclusions Whereas LVAD can restore microcirculation function, HTx may be necessary to improve conduit artery endothelial function potentially through supplying pulsatile flow, decrease hemolysis, or decreased platelet activation.