Christian Binggeli

High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men

Background—Hypercholesterolemia is a risk factor for atherosclerosis-causing endothelial dysfunction, an early event in the disease process. In contrast, high-density lipoprotein (HDL) cholesterol inversely correlates with morbidity and mortality representing a protective effect. Therefore, we investigated the effects of reconstituted HDL on endothelial function in hypercholesterolemic men. Methods and Results—Endothelium-dependent and -independent vasodilation to intraarterial acetylcholine and sodium nitroprusside (SNP), respectively, was measured by forearm venous occlusion plethysmography in healthy normo- and hypercholesterolemic men. In hypercholesterolemics, the effects of reconstituted HDL (rHDL; 80 mg/kg IV over 4 hours) on acetylcholine- and SNP-induced changes in forearm blood flow were assessed in the presence or absence of the nitric oxide (NO) synthase inhibitor L-NMMA. Hypercholesterolemics showed reduced vasodilation to acetylcholine but not to SNP compared with normocholesterolemics (P <0.0001). rHDL infusion increased plasma HDL cholesterol from 1.3±0.1 to 2.2±0.1 mmol/L (P <0.0001, n=18) and significantly enhanced the acetylcholine-induced increase in forearm blood flow without affecting that induced by SNP. rHDL infusion also improved flow-mediated dilation of the brachial artery (to 4.5±0.9% from 2.7±0.6%, P =0.02). NO synthase inhibition prevented the improvement in acetylcholine-induced vasodilation while leaving the response to SNP unchanged. Albumin infusion in an equivalent protein dose had no effect on vasomotion or lipid levels. Conclusions—In hypercholesterolemic patients, intravenous rHDL infusion rapidly normalizes endothelium-dependent vasodilation by increasing NO bioavailability. This may in part explain the protective effect of HDL from coronary heart disease and illustrates the potential therapeutic benefit of increasing HDL in patients at risk from atherosclerosis.

Increased Activation of Sympathetic Nervous System and Endothelin by Mental Stress in Normotensive Offspring of Hypertensive Parents

BACKGROUND The pathogenesis of essential hypertension is still uncertain, but genetic factors and the sympathetic nervous system are likely to be involved. Sympathetic nerve activity and hormonal circulatory control mechanisms, however, are affected by blood pressure itself. Hence, early functional changes are best investigated in normotensive subjects at risk to develop hypertension, such as normotensive offspring of hypertensive parents. METHODS AND RESULTS Muscle sympathetic nerve activity (MSA) was measured in the peroneal nerve of 10 normotensive offspring of parents with essential hypertension and 8 offspring of normotensive parents. Measurements were performed under resting conditions, during a 10-minute period of hypoxia (12.5% O2/87.5% N2) and during a 3-minute mental stress test. The tests were separated by a 30-minute resting period. Plasma samples for determination of norepinephrine and endothelin were collected before and after the tests. Baseline values of MSA were comparable in offspring of hypertensive and normotensive parents. During hypoxia, MSA, heart rate, and norepinephrine and endothelin plasma levels increased in offspring of hypertensive and normotensive parents to a comparable degree, whereas no significant changes in blood pressure and plasma norepinephrine levels were observed in either group. During mental stress, MSA and plasma norepinephrine and endothelin increased only in offspring of hypertensive parents (P < .001 to .01). In parallel, blood pressure increased significantly only in offspring of hypertensive parents (P < .001 to .05) but heart rate increased in both groups (P < .001 to .05). CONCLUSIONS The activity of the sympathetic nervous system and plasma norepinephrine and endothelin levels are increased during mental stress only in offspring of hypertensive parents, whereas the response to hypoxia was similar in offspring of hypertensive and normotensive parents, suggesting a genetically determined abnormal regulation of the sympathetic nervous system to certain stressful stimuli in offspring of hypertensive parents. This may play a role in the pathogenesis of essential hypertension.

Coffee Acutely Increases Sympathetic Nerve Activity and Blood Pressure Independently of Caffeine Content Role of Habitual Versus Nonhabitual Drinking

Background—Coffee is the most abundantly consumed stimulant worldwide. However, its cardiovascular safety remains controversial. Possible health hazards have been related to its main ingredient, caffeine. Activation of the sympathetic nervous system by coffee may enhance cardiovascular risk; however, it is unclear whether this effect of coffee is related to caffeine or other substance(s) also contained in decaffeinated coffee. Methods and Results—In 15 healthy volunteers (6 habitual and 9 nonhabitual coffee drinkers) arterial blood pressure (BP), heart rate, and muscle sympathetic nervous activity (MSA) were continuously recorded before and after drinking a triple espresso or a decaffeinated triple espresso or after intravenous administration of caffeine (250 mg) or placebo (saline) in the same subjects. There was a significant time × condition interaction for the intravenous caffeine and placebo conditions for MSA, with caffeine showing a significant increase in MSA at 60 minutes (53.2±14.1% total activity) and the placebo group showing no effect. A similar significant time effect was found for coffee drinking (54.1±22.5% total activity). Habitual and nonhabitual coffee drinkers demonstrated similar changes in MSA and BP after intravenous caffeine, whereas coffee drinking increased BP in nonhabitual drinkers only, despite comparable increases of MSA and plasma caffeine levels. Nonhabitual coffee drinkers showed similar activation of MSA and BP after caffeine infusion, coffee, or decaffeinated coffee. Conclusions—Acutely, coffee and caffeine induced comparable increases in MSA and BP in nonhabitual coffee drinkers, whereas habitual coffee drinkers exhibited lack of BP increase despite MSA activation to coffee. Because decaffeinated coffee also increases BP and MSA in nonhabitual drinkers, ingredients other than caffeine must be responsible for cardiovascular activation.

Dark chocolate improves endothelial and platelet function

The effects of chocolate on cardiovascular health are still a matter of debate. Chocolate may adversely affect cardiovascular risk because of its effects on glucose, lipids, and body weight or potentially favour cardiovascular health through antioxidative effects of chocolate ingredients, such as flavonoids (present in dark but not white chocolate). Endothelial dysfunction and platelet activation are cornerstones in the pathogenesis of atherothrombosis, leading to vasoconstriction, thrombus formation, and inflammation. Smoking is a major cardiovascular risk factor. The mechanisms promoting atherothrombosis in smokers primarily include increased oxidative stress that enhances proatherogenic processes such as low density lipoprotein oxidation and inactivation of endothelium derived nitric oxide. Platelets contribute both to acute coronary syndromes and to the progression of atherothrombosis. Both active and passive cigarette smoking has consistently been shown to induce endothelial dysfunction. Therefore, smokers serve as an ideal model to study the beneficial vascular effects of antioxidant strategies such as dark chocolate.1 The goal of the present study was to investigate whether the beneficial antioxidant effect of polyphenol-rich dark chocolate can induce an improvement of endothelial and platelet function in healthy volunteers with known endothelial dysfunction and platelet hyperreactivity. Twenty five male smokers were enrolled in the study after giving written informed consent. Women were excluded for known sex hormone induced differences in vascular tone and reactivity. All study participants did not take any medication, including vitamins or dietary supplements. The local institutional ethical review board approved the protocol. To assess the effect of dark …

Statins enhance postischemic hyperemia in the skin circulation of hypercholesterolemic patients: A monitoring test of endothelial dysfunction for clinical practice?☆

OBJECTIVES The present study aims to investigate whether laser Doppler flowmetry can be used to monitor improvements in vascular function during statin therapy. BACKGROUND Endothelial dysfunction is an early feature of atherosclerosis in hypercholesterolemic patients and can be improved by statins. There are several methods to assess endothelial function in vivo, none of them being feasible in everyday practice. METHODS Skin perfusion, measured by laser Doppler flowmetry, was assessed at rest and during reactive hyperemia. Nineteen hypercholesterolemic patients (age 42 to 73 years, total cholesterol 5.4 to 9.6 mmol/l) were studied before and during statin therapy. To further investigate the mechanisms, postischemic skin hyperemia was measured before and after intradermal injection of the nitric oxide synthase inhibitor L-NAME and its inactive isoform D-NAME (0.5 micromol/10 microl each). On a separate day, the healthy volunteers were reexamined before and 2 h after 1,000 mg aspirin. RESULTS Postischemic skin blood flow was markedly reduced in hypercholesterolemic patients (45 +/- 11%) compared with healthy controls (238 +/- 20%, p < 0.0001) and improved after statin therapy (113 +/- 15%, p = 0.0005 vs. pre-treatment). In the healthy volunteers, the hyperemic responses were not significantly different after L-NAME and D-NAME. Aspirin reduced hyperemia from 274 +/- 49% to 197 +/- 40% (p = 0.025). CONCLUSIONS Reactive hyperemia of the skin microcirculation can be easily and reproducibly assessed by laser Doppler flowmetry. Vasodilator prostaglandins are the major mediators of postischemic skin hyperemia, which is impaired in hypercholesterolemic patients and can be enhanced by cholesterol-lowering therapy. Thus, laser Doppler flowmetry may represent a tool to assess and monitor vascular function during therapy in everyday practice.

Differential Activation of Cardiac and Peripheral Sympathetic Nervous System by Nifedipine: Role of Pharmacokinetics

OBJECTIVES We sought to study the effects of short-acting and long-acting nifedipine on the sympathetic nervous system (SNS), heart rate (HR) and blood pressure (BP) of normotensive subjects under baseline conditions and during SNS stimulation. BACKGROUND Calcium channel antagonists in different pharmacokinetic formulations are widely used in patients with coronary artery disease or hypertension. Short-acting formulations activate the SNS, an action that may be disadvantageous in patients with coronary disease, especially if left ventricular function is impaired. The effects of slow-release formulations on the SNS are unknown. METHODS We used microneurography to investigate the influence of nifedipine (5 mg; 10 mg; and slow-release [GITS], 60 mg) on muscle sympathetic nerve activity (MSA) and skin sympathetic nerve activity (SSA) in healthy volunteers. RESULTS Peak plasma levels after short-acting and slow-release nifedipine were achieved within 60 min and 330 min, respectively. Short-acting (10 mg, n = 10) and slow-release (n = 10) nifedipine, but not placebo, markedly activated MSA and increased plasma norepinephrine; plasma endothelin increased only with slow-release nifedipine. HR increased after short-acting nifedipine, but not after nifedipine GITS. Nifedipine had no effect on SSA (n = 6). Blockade of cardiac sympathetic activity (with esmolol) led to similar decreases in HR with or without nifedipine, whereas parasympatholysis (with atropine) led to similar increases in HR with or without nifedipine. The cold pressor test markedly increased MSA in all treatment groups and further increased MSA beyond the increase induced by nifedipine. CONCLUSIONS Nifedipine markedly increased MSA, but not SSA, independently of drug release formulation. In contrast, HR increased with short-acting, but not with slow-release, nifedipine. Therefore, nifedipine activates cardiac and peripheral sympathetic nerves differently depending on pharmacokinetics. These effects of nifedipine may be disadvantageous in cardiac patients with increased sympathetic activity or congestive heart failure, or both.

Dysfunctional Baroreflex Regulation of Sympathetic Nerve Activity in Patients With Vasovagal Syncope

Background—The interplay of resting muscle sympathetic nerve activity (MSA) and the baroreceptor reflex in patients with vasovagal syncope remains elusive. Hence, the aim of the present study was to investigate MSA, baroreceptor sensitivity, heart rate, and blood pressure under resting conditions and during orthostatic stress in patients with a history of vasovagal syncope. Methods and Results—MSA was measured using microneurography at rest and during lower body negative pressure (LBNP) to mimic orthostatic stress in patients with a history of vasovagal syncope (n=10) and in age-matched healthy controls (n=8). Heart rate and blood pressure were simultaneously recorded. Cardiac baroreceptor sensitivity was calculated with the spectral technique (&agr; coefficient). Resting MSA in the patients with syncope was significantly increased as compared with controls (42.4±2.3 versus 26.5±3.6 bursts/min, P =0.001), whereas activation of MSA during orthostatic stress in the patient group was significantly blunted (5.1±1.6 versus 15.2±2.1 bursts/min at LBNP −50 mm Hg, P =0.002). In the patients with syncope, cardiac baroreceptor sensitivity was significantly reduced under supine resting conditions (8.5±0.7 versus 13.0±1.1 ms/mm Hg, P =0.001), as well as under orthostatic stress (7.3±0.7 versus 13.4±1.5 ms/mm Hg, P =0.003). Conclusions—This study shows that in patients with vasovagal syncope, resting MSA is increased and baroreflex regulation during orthostatic stress is blunted, thus leading to impaired MSA adaptation. These results provide new insights into mechanisms of vasovagal syncope and suggest that pharmacological modulation of baroreceptor sensitivity may represent a promising treatment of neuromediated syncope.

Baroreceptor dysfunction induced by nitric oxide synthase inhibition in humans

OBJECTIVES We sought to investigate baroreceptor regulation of sympathetic nerve activity and hemodynamics after inhibition of nitric oxide (NO) synthesis. BACKGROUND Both the sympathetic nervous system and endothelium-derived substances play essential roles in cardiovascular homeostasis and diseases. Little is known about their interactions. METHODS In healthy volunteers, we recorded muscle sympathetic nerve activity (MSA) with microneurography and central hemodynamics measured at different levels of central venous pressure induced by lower body negative pressure. RESULTS After administration of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 1 mg/kg/min), systolic blood pressure increased by 24 mm Hg (p = 0.01) and diastolic blood pressure by 12 mm Hg (p = 0.009), while stroke volume index (measured by thermodilution) fell from 53 to 38 mL/min/m2 (p < 0.002). Administration of L-NMMA prevented the compensatory increase of heart rate, but not MSA, to orthostatic stress. The altered response of heart rate was not due to higher blood pressure, because heart rate responses were not altered during infusion of the alpha-1-adrenoceptor agonist phenylephrine (titrated to an equal increase of systolic blood pressure). In the presence of equal systolic blood pressure and central venous pressure, we found no difference in MSA during phenylephrine and L-NMMA infusion. CONCLUSIONS This study demonstrates a highly specific alteration of baroreceptor regulation of heart rate but not muscle sympathetic activity after inhibition of NO synthesis in healthy volunteers. This suggests an important role of NO in reflex-mediated heart rate regulation in humans.

Effects of Chronic Calcium Channel Blockade on Sympathetic Nerve Activity in Hypertension

The sympathetic nervous system (SNS) is an important regulator of the circulation. Its activity is increased in hypertension and heart failure and adversely affects prognosis. Although certain drugs inhibit SNS, dihydropyridine calcium antagonists may stimulate the system. Phenylalkylamine calcium antagonists such as verapamil have a different pharmacological profile. We therefore tested the hypothesis of whether amlodipine, nifedipine, or verapamil differs in the effects on muscle sympathetic nerve activity (MSA). Forty-three patients (31 men, 12 women) with mild to moderate hypertension were randomly assigned to 1 drug for 8 weeks. Blood pressure, heart rate, and MSA (by microneurography) were measured at baseline and after 8 weeks of treatment. All calcium antagonists led to a similar decrease in blood pressure of 5.0±1.5 to 6.4±1.4 mm Hg at 8 weeks (P <0.001 versus baseline). There were no significant differences in MSA between groups. With amlodipine, MSA averaged 49±3 bursts/min (3 versus baseline); with nifedipine, 48±3 bursts/min (2 versus baseline); and with verapamil, 49±2 bursts/min (all, P =NS). With verapamil, norepinephrine decreased by 4% but tended to increase by about one third with amlodipine or nifedipine (P =NS). Thus, in hypertension slow release forms of verapamil, nifedipine, and amlodipine exert comparable antihypertensive effects and do not change MSA, although there was a trend toward decreased MSA and plasma norepinephrine with verapamil.

Coffee Blunts Mental Stress-Induced Blood Pressure Increase in Habitual but Not in Nonhabitual Coffee Drinkers

Coffee is widely consumed, especially during mental stress conditions. Cardiovascular impact of coffee remains debated because the underlying mechanisms of action are complex. We reported previously differential cardiovascular stimulation of coffee at rest depending on habitual consumption. The present study was designed to evaluate the effects of coffee on cardiovascular response to mental stress. In 15 healthy volunteers (6 habitual, 9 nonhabitual coffee drinkers), we assessed the effect of mental stress on blood pressure (BP), heart rate (HR), and muscle sympathetic activity (MSA) before and after a triple espresso, intravenous caffeine, and placebo in the same subjects. Under baseline conditions, mental stress significantly increases MSA (+2.5±0.7 volts per minute; +14.1±10.3%), systolic (+11.6±4.1 mm Hg) and diastolic BP (+6.4±2.0 mm Hg), and HR (+9.6±1.8 minutes−1). In nonhabitual coffee drinkers, a triple espresso but not caffeine induced an additional increase in systolic BP (+9±6.3 mm Hg; P=0.003) during mental stress, whereas in habitual drinkers, the stress-induced BP increase was blunted (+4±3.9 mm Hg; P=NS). As a result, nonhabitual coffee drinkers experienced significantly higher BP during mental stress than habitual drinkers (151±17.9/83±5.6 mm Hg versus 130±7.8/74±6.7 mm Hg; P<0.05). Caffeine induced similar effects in habitual and nonhabitual coffee drinkers at rest and during mental stress. The response to the cold pressor test was not influenced by coffee drinking in both groups. In conclusion, in nonhabitual coffee drinkers, coffee enhances the cardiovascular response to mental stress with an additional increase in systolic BP, whereas in habitual drinkers, the response is blunted. Caffeine alone does not exert any potentiating effect, confirming that ingredients other than caffeine are partially responsible for the stimulating effect of coffee on the cardiovascular system.