Jan Balzer

Sustained Benefits in Vascular Function Through Flavanol-Containing Cocoa in Medicated Diabetic Patients: A Double-Masked, Randomized, Controlled Trial

OBJECTIVES Our goal was to test feasibility and efficacy of a dietary intervention based on daily intake of flavanol-containing cocoa for improving vascular function of medicated diabetic patients. BACKGROUND Even in fully medicated diabetic patients, overall prognosis is unfavorable due to deteriorated cardiovascular function. Based on epidemiological data, diets rich in flavanols are associated with a reduced cardiovascular risk. METHODS In a feasibility study with 10 diabetic patients, we assessed vascular function as flow-mediated dilation (FMD) of the brachial artery, plasma levels of flavanol metabolites, and tolerability after an acute, single-dose ingestion of cocoa, containing increasing concentrations of flavanols (75, 371, and 963 mg). In a subsequent efficacy study, changes in vascular function in 41 medicated diabetic patients were assessed after a 30-day, thrice-daily dietary intervention with either flavanol-rich cocoa (321 mg flavanols per dose) or a nutrient-matched control (25 mg flavanols per dose). Both studies were undertaken in a randomized, double-masked fashion. Primary and secondary outcome measures included changes in FMD and plasma flavanol metabolites, respectively. RESULTS A single ingestion of flavanol-containing cocoa was dose-dependently associated with significant acute increases in circulating flavanols and FMD (at 2 h: from 3.7 +/- 0.2% to 5.5 +/- 0.4%, p < 0.001). A 30-day, thrice-daily consumption of flavanol-containing cocoa increased baseline FMD by 30% (p < 0.0001), while acute increases of FMD upon ingestion of flavanol-containing cocoa continued to be manifest throughout the study. Treatment was well tolerated without evidence of tachyphylaxia. Endothelium-independent responses, blood pressure, heart rate, and glycemic control were unaffected. CONCLUSIONS Diets rich in flavanols reverse vascular dysfunction in diabetes, highlighting therapeutic potentials in cardiovascular disease.

Nitric oxide synthase-derived plasma nitrite predicts exercise capacity

Background: Nitrite is the main oxidation product of nitric oxide (NO) in plasma. It sensitively reflects changes in endothelial NO synthase (eNOS) activity under fasting conditions and serves as an endocrine NO donor, contributing to the regulation of blood flow through reaction with haemoglobin. As NO is necessary to maintain an adequate vascular response to the increased demands of blood flow, it is believed to be important for vasodilation induced by exercise. Objective: To investigate whether the capacity of the vasculature to produce nitrite is associated with exercise performance. Design: With the use of chemiluminescence detection, nitrite concentrations in 55 healthy subjects (mean (SEM) age 40 (2) years; 22 men) were studied before and after an exercise test, and endothelial function was determined by measuring flow-mediated dilation of the brachial artery using high-resolution ultrasound. In a subset of subjects, the NOS inhibitor, NG-monomethyl-l-arginine, was applied to elucidate the effect of eNOS on changes in nitrite. Results: Exercise significantly (p<0.001) increased plasma nitrite from 97 (6) to 125 (8) nM. The relative increase in plasma nitrite was related to flow-mediated dilation (6.1 (0.3)%; r = 0.36; p = 0.01). NG-Monomethyl-l-arginine blocked increases in nitrite. Post-exercise nitrite concentration correlated with exercise performance, as determined by maximally reached stress power (r = 0.37; p<0.007), and inversely with age. Multivariate analysis showed that both age and post-exercise nitrite concentration were independent predictors of stress endurance and power. Conclusion: The results suggest a role for plasma nitrite in the adaptation of haemodynamics during exercise. An impaired increase in plasma nitrite may limit exercise capacity.

Real-time transesophageal three-dimensional echocardiography for guidance of percutaneous cardiac interventions: first experience

Recently, a new generation of transesophageal echocardiography (TEE) probes with a novel matrix array technique was introduced, allowing three-dimensional (3D) presentation of cardiac structures in real-time. This article aims to describe our first experiences with this new technique in the guidance of percutaneous cardiac interventions in the catheter laboratory. We used a matrix array 3D TEE probe connected to a 3D-capable echocardiographic system. The 3D TEE system provides exact imaging of the pathomorphology of cardiac structures as well as intracardiac catheters and devices in real-time. We applied this innovative technique to monitor percutaneous cardiac interventions in the catheter laboratory, such as atrial septal defect (ASD) or patent foramen ovale (PFO) closures, revalving procedures such as percutaneous transvenous mitral valve annuloplasty (PTMA), aortic valve replacements, and electrophysiological procedures. Our findings demonstrate that real-time 3D TEE provides a novel imaging technique to guide interventions in the catheter laboratory, providing fast and complete information about the underlying pathomorphology, improving spatial orientation, and additionally monitoring online the procedure without loss of image quality. These benefits may accelerate the learning curve and improve confidence of the interventional cardiologist in order to increase safety, accuracy, and efficacy of interventional cardiac procedures.

Impact of infarct transmurality on layer-specific impairment of myocardial function: a myocardial deformation imaging study.

AIMS To evaluate deformation parameters of an endocardial, mid-myocardial, and epicardial myocardial layer in different transmurality of myocardial infarction and assess whether layer-specific deformation analysis allows definition of infarct transmurality. METHODS AND RESULTS Fifty-six patients (mean age 55 +/- 9 years, 38 men) with chronic ischaemic left ventricular (LV) dysfunction underwent two-dimensional echocardiography and contrast-enhanced magnetic resonance imaging (ceMRI). The extent of myocardial infarction was determined as relative amount of hyperenhancement by ceMRI in a 16-segment LV model (0%, no infarction; 1-50%, non-transmural infarction; 51-100%, transmural infarction). On the basis of two-dimensional echocardiographic parasternal short-axis views peak systolic circumferential strain was determined for the total wall thickness and for each of three myocardial layers (endocardial, mid-myocardial, and epicardial) using an automatic frame-by-frame tracking system of acoustic echocardiographic markers (EchoPAC, GE Ultrasound). In non-transmural infarction impairment of circumferential strain was greater in the endocardial than the epicardial layer, relative reduction compared with control segments, 45% vs. 28% (P < 0.001), respectively. In transmural infarction additional impairment of circumferential strain was greater in the epicardial than the endocardial layer, relative reduction compared with non-transmural infarction 29% vs. 7% (P < 0.001), respectively. Endocardial layer circumferential strain allowed distinction of non-transmural vs. no infarction with higher accuracy than total wall thickness strain [area under the curve (AUC) 0.842 vs. 0.774, respectively, P = 0.001]. Epicardial layer circumferential strain allowed distinction of transmural from non-transmural infarction with higher accuracy than total wall thickness strain (AUC 0.819 vs. 0.762, respectively, P = 0.005). CONCLUSION Non-transmural infarction results in greater functional impairment of the endocardial than of the epicardial myocardial layer. In transmural infarction both layers are affected similarly compared with controls. A layer-specific analysis of myocardial deformation allows accurate discrimination between different transmurality categories of myocardial infarction.

Age-dependent endothelial dysfunction is associated with failure to increase plasma nitrite in response to exercise

Age-dependent alterations of the vessel wall may predispose older individuals to increased cardiovascular pathology. Aging is associated with an impaired bioactivity of nitric oxide (NO). Plasma nitrite reflects NO-synthase activity under fasting conditions and is an important storage pool of NO. To test the hypothesis that aging is associated with an impaired capacity of the vasculature to increase plasma nitrite during exercise, 29 young and 28 old healthy individuals (25 ± 1 years and 58 ± 2 years; P < 0.001) without major cardiovascular risk factors were enrolled. Exercise stress was similar in both groups. Baseline nitrite did not differ (107 ± 8 vs. 82 ± 10 nmol/l, young vs. old; n.s.) although a trend toward higher nitrite levels in young individuals was seen. In young subjects, exercise increased plasma nitrite by 38 ± 7% (P < 0.001) compared to only 13 ± 8% (P = n.s.) in older subjects. L-NMMA blocked increases of nitrite. Endothelial function, as defined by flow–mediated-dilation (FMD) of the brachial artery via ultrasound, was impaired in older subjects (5.4 ± 0.4% vs. 6.7 ± 0.3%; P < 0.01). Multivariate analysis showed that age (P = 0.007), BMI (P = 0.010), and LDL (P = 0.021) were independent predictors of nitrite increase. The fact that aging is associated with an impaired capacity of the vasculature to adequately increase nitrite to physiological stimuli may contribute to attenuated maintenance and further deterioration of vascular homeostasis with aging.

Endothelial function, nitric oxide, and cocoa flavanols.

Endothelial dysfunction is the pathophysiologic principle involved in the initiation and progression of arteriosclerosis, thus endothelial function serves as a “barometer” for cardiovascular health that can be used for the evaluation of new therapeutic strategies. This review provides an introduction to the concept of endothelial dysfunction, and it explores the importance of this prognostic marker in the context of clinical, dietary interventions in humans. Moreover, we summarize and evaluate the findings of various clinical trials that demonstrated an improvement of endothelial dysfunction in subjects with cardiovascular risk factors after the acute and chronic consumption of flavanol-rich foods, including cocoa products, red wine, and tea.

Real-time three-dimensional transoesophageal echocardiography for guidance of non-coronary interventions in the catheter laboratory

The growing need for less invasive therapies of cardiac disease creates the necessity for improved imaging guidance. Although two-dimensional transthoracic and transoesophageal echocardiography (TEE) have been shown to be essential tools for planning and execution of cardiac interventions, the benefit of three-dimensional TEE for the guidance of interventional procedures still needs to be evaluated. This review aims to describe our first experiences with real-time (RT) three-dimensional TEE for the guidance of percutaneous non-coronary interventions in the catheter laboratory. We used a matrix array TEE probe capable of generating three-dimensional images of cardiac structures in RT. We applied this innovative technique to monitor atrial septal defects or patent foramen ovale closures, valve procedures such as mitral and aortic valve interventions, and electrophysiological procedures. Our first experience using RT three-dimensional TEE for the guidance of percutaneous cardiac interventions in the catheter laboratory demonstrates that this technique is feasible to guide interventions, providing fast and complete information about the underlying pathomorphology, improving spatial orientation, and additionally allowing the online monitoring of the procedure. These benefits may accelerate the learning curve and improve confidence of the interventional cardiologist in order to increase safety, accuracy, and efficacy of interventional cardiac procedures.

Hemodialysis-Induced Release of Hemoglobin Limits Nitric Oxide Bioavailability and Impairs Vascular Function

OBJECTIVES This study sought to characterize the impact of hemodialysis (HD)-induced release of hemoglobin on the bioavailability of nitric oxide (NO) and endothelial function. BACKGROUND Patients on chronic HD suffer from endothelial dysfunction and a massively increased risk for cardiovascular events. Although dialysis-dependent and -independent factors are discussed, the exact mechanisms are not fully understood. METHODS In 14 HD patients (56+/-15 years of age), endothelial function was determined by measuring flow-mediated dilation (FMD) of the brachial artery using high-resolution ultrasound before and after treatment. The NO consumption activity of plasma isolated from patients before and after hemodialysis was studied with an NO-sensitive electrode. RESULTS HD impaired FMD (3.5+/-2.6% to 1.7+/-1.4%, p=0.04) without affecting brachial artery diameter (4.7+/-0.6 mm vs. 4.4+/-0.9 mm, p=0.27). This was accompanied by an increase in cell-free plasma hemoglobin (196+/-43 mg/l to 285+/-109 mg/l, p=0.01), which led to a decrease in the bioavailability of free NO by more than 70%. Oxidation of the released plasma ferrous hemoglobin prevented the consumption of NO. The amount of decompartmentalized hemoglobin after HD correlated inversely with the change in FMD (r=-0.65, p=0.041). CONCLUSIONS Our data support a role of HD-induced release of hemoglobin in the pathogenesis of endothelial dysfunction in patients with end-stage renal disease. Approaches that oxidize free plasma hemoglobin may restore NO bioavailability and may have potential beneficial effects on vascular function. (Influence of Hemodialysis on Endothel-Depending Dilatation of Peripheral Arteries; NCT00764192).

Reduction of peripheral flow reserve impairs endothelial function in conduit arteries of patients with essential hypertension

Background A diminished flow reserve in resistance vessels is a hallmark of hypertensive microvascular disease. Hypertension is associated with structural alterations in the microcirculation and a reduced endothelium-dependent dilation in conduit arteries. Both have been demonstrated to predict future cardiovascular events. Objective We hypothesized that a reduced peripheral flow reserve impairs endothelial function in upstream conduit arteries in patients with arterial hypertension. Design In 43 hypertensive patients (HT) and 38 normotensive controls (NT) endothelial function of the brachial artery was assessed by measurement of flow-mediated dilatation (FMD), using high-resolution ultrasound. Peripheral flow reserve (FR) was determined via measurements of forearm blood flow at rest and during increments of reactive hyperaemia, using venous occlusion plethysmography. Results FMD was markedly impaired in HT (3.6 ± 0.3%) as compared with NT (10.2 ± 0.3%), whereas maximum brachial artery diameter following endothelium-independent dilatation was similar in both groups. In hypertensive patients FR was significantly reduced (HT, 3.2 versus NT, 6.0) during reactive hyperaemia after 5 min of ischaemia. FR was associated with FMD (r = 0.68, P < 0.01). Multiple stepwise regression analysis identified FR as a strong independent variable determining the extent of FMD (r2 = 0.46, P < 0.01). In HT the dose–response curve of FMD upon stepwise increases of FR was shifted significantly to the right. Normalization of FR improved FMD in HT by more than 60%. Conclusions In essential hypertension a reduced FR contributes to the endothelial dysfunction of upstream conduit arteries. These findings may have therapeutic and prognostic implications in patients with arterial hypertension.

Vascular dysfunction of brachial artery after transradial access for coronary catheterization: impact of smoking and catheter changes.

OBJECTIVES The aim of this study was to investigate the effect of diagnostic transradial catheterization on vascular function of upstream brachial artery (BA). BACKGROUND The transradial access has recently become an alternative to transfemoral cardiac catheterization. A potential caveat of this approach lies in possible sustained physical radial artery (RA) damage. METHODS We studied 30 patients (age 61 +/- 11 years) undergoing diagnostic coronary angiography with the transradial access (5-F). Endothelium-dependent, flow-mediated vasodilation (FMD) was measured before and at 6 and 24 h after catheterization of the right-sided RA and BA with high-resolution ultrasound. The left-sided RA served as a control. RESULTS Transradial catheterization significantly decreased FMD in the RA (overall mean 8.5 +/- 1.7% to 4.3 +/- 1.6%) and the upstream BA (overall mean 4.4 +/- 1.6% to 2.9 +/- 1.6%) at 6 h. Subgroup analysis showed that FMD of both arteries at 6 h was significantly lower in active smokers and that it only remained impaired at 24 h in this group, whereas nonsmoker FMD fully recovered. The degree of BA but not RA FMD dysfunction was related to the number of catheters used, with no change after 2 catheters, 1.9 +/- 1.2% decrease (6 h) and recovery (24 h) after 3 catheters, and 3.9 +/- 1.2% decrease (6 h) without recovery (24 h) after 4 to 5 catheters. The RA dysfunction correlated with the baseline diameter. The contralateral control RA exhibited no change ruling out systemic effects. CONCLUSIONS Transradial catheterization not only leads to dysfunction of the RA but also the upstream BA, which is more severe and sustained in smokers and with increasing numbers of catheters.