International Gargellen Conference.
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Adrenergic beta-Antagonists↗
Biomedical subjects
H Just
Publications and source records attributed to H Just.
Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients.
BACKGROUND: There is evidence for increased formation of free radicals in patients with hypertension, raising the possibility that NO is inactivated by free radicals, which impairs coronary endothelial function. Therefore, we tested the hypothesis that the antioxidant vitamin C could improve abnormal endothelial function of coronary arteries in patients with hypertension. METHODS AND RESULTS: In 22 hypertensive patients without relevant coronary artery stenoses, endothelium-dependent vascular responses of the left anterior descending coronary artery (LAD) to acetylcholine (0.01, 0.1, and 1.0 micromol/L) were determined before and immediately after intravenous infusion of 3 g vitamin C (17 patients) or placebo (5 patients). In a subgroup of 10 patients, papaverine-induced flow-dependent vasodilation (FDD) was measured before and after vitamin C (5 patients) or placebo (5 patients) infusion. Segmental responses of the coronary artery luminal area were analyzed with quantitative coronary angiography. Before vitamin C infusion, the mean changes of LAD luminal areas at increasing doses of acetylcholine were -6.1+/-2.2%, -15.2+/-4.9%, and -33.9+/-8.1% (negative numbers symbolize vasoconstriction) and during FDD, 5.4+/-1.0%. The vasoconstrictor response during acetylcholine was reduced and FDD was augmented by vitamin C. After vitamin C infusion, LAD luminal areas changed by -3.2+/-2.3%, -5.8+/-3.6%, and -10.2+/-5.6% (P<.05, acetylcholine) and 17.8+/-2.8% (P<.05, FDD). Doppler flow velocity (during baseline, acetylcholine, and FDD) was not significantly affected by vitamin C. CONCLUSIONS: Vitamin C improves the endothelium-dependent vasomotor capacity of coronary arteries in patients with hypertension and patent coronary arteries. These findings suggest that increased oxidative stress contributes to endothelial dysfunction in hypertensive patients.
Acetylcholine↗
Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry.
BACKGROUND: Thrombolytic treatment has been shown to accelerate resolution of major pulmonary embolism and lead to a rapid improvement of right-side hemodynamics. However, the association between these favorable effects and the clinical outcome of patients who have no severe hemodynamic compromise at presentation remains unknown. METHODS AND RESULTS: The present multicenter registry included 719 consecutive patients with major pulmonary embolism according to clinical, echocardiographic, scintigraphic, and cardiac catheterization criteria. Symptom onset was acute (<48 hours) in 63% of patients. All patients were hemodynamically stable (ie, without evidence of cardiogenic shock) at presentation. Primary thrombolytic treatment (within 24 hours of diagnosis) was given to 169 patients (23.5%), whereas the remaining 550 patients were initially treated with heparin alone. Overall 30-day mortality was significantly lower in the patients who received thrombolytic agents (4.7 versus 11.1%, P=.016). Clinical factors associated with a higher death rate were syncope (P=.012), arterial hypotension (P=.021), history of congestive heart failure (P=.013), and chronic pulmonary disease (P=.032). However, only primary thrombolysis was found by multivariate analysis to be an independent predictor of survival (odds ratio for in-hospital death, 0.46; 95% confidence interval, 0.21 to 1.00). Patients who underwent early thrombolytic treatment had a reduced rate of recurrent pulmonary embolism (7.7 versus 18.7%, P<.001) but also a higher frequency of major bleeding episodes (21.9% versus 7.8%, P<.001). Cerebral bleeding occurred in 2 patients in each treatment group, and 1 patient in each group died of a bleeding complication. CONCLUSIONS: The results of our study suggest that thrombolysis may favorably affect the clinical outcome of hemodynamically stable patients with major pulmonary embolism.
Adolescent↗
Differential effects of kinins on cardiomyocyte hypertrophy and interstitial collagen matrix in the surviving myocardium after myocardial infarction in the rat.
BACKGROUND: Left ventricular remodeling after myocardial infarction (MI) involves the hypertrophic growth of cardiomyocytes and the accumulation of fibrillar collagen in the interstitial space. We evaluated the role of kinins in postinfarction ventricular remodeling and their potential contribution to the antiremodeling effects of ACE inhibition and angiotensin II type 1 (AT1) receptor blockade. METHODS AND RESULTS: Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant. Additional groups of infarcted rats were treated with the ACE inhibitor lisinopril or the AT1 receptor antagonist ZD7155, each separately and in combination with icatibant. B2 kinin receptor blockade enhanced the interstitial deposition of collagen after MI, whereas morphological and molecular markers of cardiomyocyte hypertrophy (cardiac weight, myocyte cross-sectional area, prepro-atrial natriuretic factor mRNA expression) were not affected. Chronic ACE inhibition and AT1 receptor blockade reduced collagen deposition and cardiomyocyte hypertrophy after MI. The inhibitory action of ACE inhibition and AT1 receptor blockade on interstitial collagen was partially reversed by B2 kinin receptor blockade. However, B2 kinin receptor blockade did not attenuate the effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy. CONCLUSIONS: (1) Kinins inhibit the interstitial accumulation of collagen but do not modulate cardiomyocyte hypertrophy after MI. (2) Kinins contribute to the reduction of myocardial collagen accumulation by ACE inhibition and AT1 receptor blockade. (3) The effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy are related to a reduced generation/receptor blockade of angiotensin II.
Adrenergic beta-Antagonists↗
Propafenone during acute myocardial ischemia in patients: a double-blind, randomized, placebo-controlled study.
OBJECTIVES: The proarrhythmic risk of class I antiarrhythmic agents in combination with myocardial ischemia is mainly the result of their effects on ventricular repolarization. This study was designed to evaluate the effect of class Ic antiarrhythmic agents on QT dispersion during myocardial ischemia. BACKGROUND: QT interval dispersion on the 12-lead electrocardiogram (ECG) has been suggested as a noninvasive marker of inhomogeneous ventricular repolarization and susceptibility to ventricular arrhythmias. METHODS: In a randomized, double-blind study, 98 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) were pretreated with propafenone or placebo. QT dispersion was defined as a maximal minus minimal QT interval on the 12-lead ECG before and after PTCA. The power of the study to detect clinically meaningful differences in QT dispersion was 0.75, and a twofold increase in QT dispersion in the propafenone group compared with the placebo group was considered clinically relevant. RESULTS: The QT and corrected QT (QTc) intervals increased significantly during occlusion of the left anterior descending coronary artery (LAD) (9% and 11%, respectively, p < 0.05), whereas occlusion of the circumflex and right coronary arteries had no effect. QTc dispersion increased significantly in the propafenone group during ischemia (+52%, p = 0.002, vs. +23%, p = 0.15). The most considerable effect on QT dispersion was observed during LAD occlusion and ischemia of the anterior wall (+74%, p = 0.025). Corrected JT dispersion (+57%, p = 0.017, vs. +24%, p = 0.23) and the QT dispersion ratio (+1.6%, p = 0.031, vs. 0.9%, p = 0.34) showed similar effects. Plasma levels of propafenone (522 +/- 165 micrograms/liter) did not influence the results. CONCLUSIONS: During myocardial ischemia, particularly during LAD occlusion, propafenone results in a significant increase in QT dispersion. The results indicate that QT interval prolongation and enhanced QT dispersion reflect inhomogeneous ventricular repolarization generated by the ischemic anterior wall of the myocardium. These observations may demonstrate a clinically important interaction between myocardial ischemia, repolarization variables and propafenone.
Adult↗
Ca(2+)-dependent and Ca(2+)-independent regulation of contractility in isolated human myocardium.
UNLABELLED: Changes in contractile force of the myocardium may depend on changes in the intracellular Ca2+ concentration, changes in the responsiveness of the myofibrils for Ca2+, or a combination of both. We investigated in isolated muscle strip preparations from human nonfailing and endstage failing hearts the influence of physical (changes in preload, stimulation rate, or rhythm), and pharmacological interventions (alpha- or beta-adrenoceptor-stimulation, endothelin) on developed force of contraction and the corresponding intracellular Ca2+ transients. METHODS: Isometric contraction, electrical stimulation, 37 degrees C. Simultaneous registration of force of contraction and intracellular Ca2+ transients (aequorin method). RESULTS: Increases in preload, alpha- and endothelin-receptor stimulation resulted in increases in force of contraction without increasing aequorin light emission. Increasing stimulation rate or increasing rest intervals resulted in parallel increases (nonfailing myocardium) or decreases (failing myocardium) of force of contraction and aequorin light emission. beta-Adrenoceptor-stimulation exerted inotropic and lusitropic effects in human failing myocardium associated with a large, overproportional increase in aequorin light emission. CONCLUSION: The human heart regulates intrinsic contractility via several subcellular mechanisms. Increases in preload (Frank-Starling-mechanism) and alpha- or endothelin-receptor-stimulation enhance myocardial contractility by increasing the Ca2+ responsiveness of the myofilaments; rate- and rhythm-dependent modulation of the contractile state directly depend on changes in the intracellular Ca(2+)-transients; beta-adrenoceptor stimulation results in an overproportional large increase in intracellular Ca2+ transients, probably due to additional cAMP-dependent Ca(2+)-desensitizing effects on the level of the myofibrils.
Calcium↗
Calcium handling proteins in the failing human heart.
There is accumulating evidence that disturbed calcium homeostasis may play a key role in the pathophysiology of human heart failure. Because disturbed calcium handling could result from altered protein expression, levels of calcium handling proteins were quantitated by Western Blot analysis in failing and nonfailing human myocardium from hearts with endstage failing dilated or ischemic cardiomyopathy. Protein levels of the sarcoplasmic reticulum calcium release channel (ryanodine receptor) and of calcium storage proteins (calsequestrin and calreticulin) were similar in failing and nonfailing human myocardium. However, proteins involved in calcium removal from the cytosol were significantly altered in the failing human heart: 1) SR-Ca(2+)-ATPase, relevant for removal of calcium from the cytosol into the lumen of the sarcoplasmic reticulum, was decreased; 2) phospholamban, which inhibits the SR-Ca(2+)-ATPase in the basal unphosphorylated state, was slightly decreased; 3) the ratio of SR-Ca(2+)-ATPase to phospholamban was decreased; 4) the sarcolemmal Na(+)-Ca(2+)-exchanger, relevant for transsarcolemmal calcium extrusion was increased in the failing hearts. In summary, altered levels of proteins involved in calcium removal from the cytosol suggest an increase in transsarcolemmal calcium elimination relative to sarcoplasmic reticulum calcium removal. These findings support the concept that reduced function of the sarcoplasmic reticulum to accumulate calcium may reflect a major defect in excitation-contraction coupling in human heart failure.
Calcium↗
[Magnesium deficiency and magnesium substitution. Effect on ventricular cardiac arrhythmias of various etiology].
During recent years there has been an increasing but still controversial discussion on the antiarrhythmic effects and overall benefit of magnesium when directed to patients with various types of ventricular tachyarrhythmias. While magnesium is considered to be a simple, safe and cost-effective approach and many casuistic and empiric reports have indicated antiarrhythmic properties of magnesium in patients with suspected or manifest ventricular arrhythmias, controlled studies proving the antiarrhythmic and overall benefit and justifying a broader use of magnesium in treating various types of ventricular arrhythmias are missing or rare. At present, antiarrhythmic properties and clinical benefit of magnesium application has only been established in patients with torsade de pointes and digitalis-induced ventricular tachyarrhythmias. In perioperative patients at risk for ventricular tachyarrhythmias and in patients suffering from manifest heart failure, data may also indicate some antiarrhythmic properties of magnesium, however, in this case with a wide consensus that the prevention of magnesium deficit is more effective and preferred in most patients over the therapeutic application of magnesium. Another group of patients who may profit from such a therapeutic approach are patients with frequent ventricular arrhythmias and stable underlying heart disease, in whom a recently published double-blind, randomized study documented an antiarrhythmic effect of a 3 week treatment with potassium and magnesium. For all other types of ventricular tachyarrhythmias, the therapeutic use of magnesium can be considered as not harmful, but also as not proven to be effective.
Anti-Arrhythmia Agents↗
["Myxoma syndrome"--a "benign" disease with "malignant" course].
We are reporting on a 36 year-old woman who presented with recurrent cardiac myxomas over a period of nine years. Two of the tumors typically originated in the left atrium and one in the right atrium. Tumor embolization was the presenting symptom twice, leading to reversible cerebral ischemia and minor pulmonary embolism, respectively. The third tumor remained asymptomatic and was detected during routine echocardiographic examination. Based on a positive family history of cardiac tumors, a facially pronounced hyperpigmentation of the skin and the presence of a thyroid adenoma, the diagnosis of a "myxoma syndrome" was established. Patients with "myxoma syndrome" are generally younger than their counterparts with "sporadic myxoma" (mean age at diagnosis 25 vs. 56 years) and have a high frequency of unusual skin freckling (68%). Familial clustering of cardiac myxomas is also frequent (25%). The tumors may be located in any of the cardiac chambers (87% in the atrias, 13% in the ventricles, 50% at multiple sites simultaneously) and have relatively high (18%) 5-year recurrence rate after surgical excision. Since the clinical signs of cardiac tumors are non-specific, diagnosis essentially relies on cardiac imaging by echocardiography, computer tomography, or angiography. The superiority of transesophageal echocardiography is emphasized in this report.
Adult↗
Antiarrhythmic effects of increasing the daily intake of magnesium and potassium in patients with frequent ventricular arrhythmias. Magnesium in Cardiac Arrhythmias (MAGICA) Investigators.
OBJECTIVES: This study sought to assess potential antiarrhythmic effects of an increase in the daily oral intake of magnesium and potassium in patients with frequent ventricular arrhythmias. BACKGROUND: Magnesium and potassium contribute essentially to the electrical stability of the heart. Despite experimental and clinical evidence for the antiarrhythmic properties of the two minerals, controlled data in patients with stable ventricular arrhythmias are lacking. METHODS: In a randomized, double-blind study, 232 patients with frequent ventricular arrhythmias (> 720 ventricular premature beats [VPBs]/24 h) confirmed at baseline and after 1 week of placebo therapy were subsequently treated over 3 weeks with either 6 mmol of magnesium/12 mmol of potassium-DL-hydrogenaspartate daily or placebo. RESULTS: Compared with placebo pretreatment, active therapy resulted in a median reduction of VPBs by -17.4% (p = 0.001); the suppression rate was 2.4 times greater than that in patients randomized to 3 weeks of placebo therapy (-7.4%, p = 0.038). The likelihood of a > or = 60% (predefined criterion) or > or = 70% suppression rate (calculated from the placebo-controlled run-in period) was 1.7 (25% vs. 15%, p = 0.044) and 1.5 times greater in the active than in the placebo group (20% vs. 13%, p = 0.085), respectively. No effect of magnesium and potassium administration was observed on the incidence of repetitive and supraventricular arrhythmias and clinical symptoms of the patients. CONCLUSIONS: To our knowledge, this study is the first to provide controlled data on the antiarrhythmic effect of oral administration of magnesium and potassium salts when directed to patients with frequent and stable ventricular tachyarrhythmias. A 50% increase in the recommended minimum daily dietary intake of the two minerals for 3 weeks results in a moderate but significant antiarrhythmic effect. However, with the given therapeutic regimen, repetitive tachyarrhythmias and patient symptoms remain unchanged.
Adult↗
Noninvasive estimation of right ventricular systolic pressure in postinfarction ventricular septal rupture: an assessment of two Doppler echocardiographic methods.
OBJECTIVE: To evaluate the diagnostic accuracy of Doppler echocardiography in the assessment of right heart hemodynamics and the diagnosis of pulmonary hypertension in patients with ventricular septal rupture due to acute myocardial infarction. DESIGN: A prospective, echocardiographic and right-heart catheterization study. SETTING: Medical intensive care unit (ICU) of a university hospital. PATIENTS: Twelve consecutive patients admitted to the ICU with the diagnosis of ventricular septal rupture in the setting of acute myocardial infarction. Confirmation of diagnosis was made during surgery (11 patients) or by autopsy (one patient). INTERVENTIONS: All patients were examined by two-dimensional and Doppler echocardiography on admission and subsequently underwent bedside right-heart catheterization. MEASUREMENTS AND MAIN RESULTS: After identification and localization of the rupture site by two-dimensional echocardiography and/or color flow Doppler mapping, the maximal flow velocity of the transseptal jet was measured by continuous-wave Doppler and was used to calculate the peak interventricular pressure gradient by the modified Bernoulli equation. This value was subtracted from the systolic arterial blood pressure value to estimate right ventricular systolic pressure. The values obtained correlated well with catheter-derived measurements (r2 = .71; p = .001). Furthermore, in eight (67%) patients, right ventricular systolic pressure could also be determined by Doppler interrogation of the tricuspid regurgitant jet. Direct comparison of the results of the two echocardiographic methods yielded a good correlation (r2 = .66; p = .016). CONCLUSION: Doppler examination of the transseptal and tricuspid regurgitant jets is applicable to patients with ventricular septal rupture for rapid, noninvasive prediction of right ventricular hemodynamics.
Aged↗
Prognostic significance of right ventricular afterload stress detected by echocardiography in patients with clinically suspected pulmonary embolism.
OBJECTIVE: To investigate the prognostic value of echocardiographic findings in patients who present with symptoms suggestive of acute pulmonary embolism. DESIGN: 317 patients with clinically suspected pulmonary embolism were prospectively evaluated by echocardiography for the presence of right ventricular afterload stress and right heart or pulmonary artery thrombi. Objective confirmation of pulmonary embolism by lung scan or pulmonary angiography was obtained in 164 (52%). The presence of deep venous thrombosis was established in 90 of 158 patients (57%) who underwent phlebographic or Doppler sonographic studies. RESULTS: Right ventricular afterload stress was diagnosed in 87 patients (27%). Objective confirmation of pulmonary embolism and diagnosis of deep venous thrombosis was more common in patients with right ventricular afterload stress than in those without (83% v 40% and 46% v 22%, respectively; P < 0.001). This was also true for the detection of thrombi in the right heart and major pulmonary arteries (12 patients v 1 patient; P < 0.001) as well as for the in-hospital mortality from venous thromboembolism (13% v 0.9%; P < 0.001). One year mortality from pulmonary embolism was 13% in patients with right ventricular afterload stress at presentation compared with 1.3% in those without (P < 0.001). CONCLUSIONS: The presence of right ventricular afterload stress detected by echocardiography is a major determinant of short term prognosis in patients with clinically suspected acute pulmonary embolism.
Acute Disease↗
Influence of isoproterenol and ouabain on excitation-contraction coupling, cross-bridge function, and energetics in failing human myocardium.
BACKGROUND: In patients with heart failure, long-term treatment with catecholamines and phosphodiesterase inhibitors, both of which increase cyclic AMP levels, may be associated with increased mortality, whereas mortality may not be increased with glycoside treatment. Differences in clinical benefit between cyclic AMP-dependent inotropic agents and cardiac glycosides may be related to differences of these drugs on calcium cycling and myocardial energetics. METHODS AND RESULTS: Isometric heat and force measurements were used to investigate the effects of isoproterenol and ouabain on myocardial performance, cross-bridge function, excitation-contraction coupling, and energetics in myocardium from end-stage failing human hearts. Isoproterenol (1 mumol/L) increased peak twitch tension by 55% and decreased time to peak tension and relaxation time by 30% and 26%, respectively (P < .005). Ouabain (0.38 +/- 0.11 mumol/L) increased peak twitch tension and relaxation time by 41% and 20%, respectively, and decreased time to peak tension by 12% (P < .05). With isoproterenol, the amount of excitation-contraction coupling-related heat evolution (tension-independent heat) increased by 246% (P < .05) and the economy of excitation-contraction coupling decreased by 61% (P < .05). Ouabain increased tension-independent heat by only 61% (P < .05) and did not significantly influence economy of excitation-contraction coupling. The effects of isoproterenol on excitation-contraction coupling resulted in a 21% (P < .005) decrease of overall contraction economy, which was not significantly changed with ouabain. Neither isoproterenol nor ouabain influenced energetics of cross-bridge cycling or recovery metabolism. CONCLUSIONS: Major differences between the effects of isoproterenol and ouabain in failing human myocardium are related to calcium cycling with secondary effects on myocardial energetics.
Cardiomyopathies↗
Existence of the Frank-Starling mechanism in the failing human heart. Investigations on the organ, tissue, and sarcomere levels.
BACKGROUND: The Frank-Starling mechanism is one of the most important physiological principles for regulation of contractile performance. We therefore studied the question of whether this mechanism may be absent or attenuated in end-stage failing human left ventricular myocardium. METHODS AND RESULTS: Different methodological approaches were used to analyze the effects of this mechanism on the organ, tissue, and sarcomere levels: (1) In excised human whole left ventricles (2 donor hearts, 5 failing hearts), diastolic and systolic pressure-volume relationships were obtained. (2) In isolated muscle strip preparations from the left ventricular wall of donor hearts (n = 14) and failing hearts from patients with idiopathic dilated cardiomyopathy (n = 21) and ischemic cardiomyopathy (n = 11), peak developed force was measured at different muscle lengths of the preparation. (3) Skinned fiber preparations were obtained from failing right and left ventricles (n = 12). In all three studies, we clearly observed the existence of the Frank-Starling mechanism: (1) In isolated failing human left ventricles, peak developed isometric pressure is increased when the preload is elevated. (2) Peak developed tension is increased by approximately 50% to 70% (P < .01) in left ventricular preparations of failing and nonfailing ventricles when the muscles are stretched from 90% to 100% optimum length. (3) An increase in sarcomere length leads to a sensitization of contractile proteins of ventricular skinned fiber preparations from failing human hearts. At 1.9-microns sarcomere length, the EC50 value was 5.56 +/- 0.06, and at 2.3 microns it was 5.70 +/- 0.05 (P < .01; n = 7). CONCLUSIONS: The Frank-Starling mechanism is maintained in end-stage failing human hearts, whereas significant alterations of diastolic myocardial distensibility are evident in chronic heart failure.
Analysis of Variance↗
Diminished post-rest potentiation of contractile force in human dilated cardiomyopathy. Functional evidence for alterations in intracellular Ca2+ handling.
Post-rest contractile behavior of isolated myocardium indicates the capacity of the sarcoplasmic reticulum (SR) to store and release Ca2+. We investigated post-rest behavior in isolated muscle strips from nonfailing (NF) and endstage failing (dilated cardiomyopathy [DCM]) human hearts. At a basal stimulation frequency of 1 Hz, contractile parameters of the first twitch after increasing rest intervals (2-240 s) were evaluated. In NF (n = 9), steady state twitch tension was 13.7 +/- 1.8 mN/mm2. With increasing rest intervals, post-rest twitch tension continuously increased to maximally 29.9 +/- 4.1 mN/mm2 after 120s (P < 0.05) and to 26.7 +/- 4.5 mN after 240 s rest. In DCM (n = 22), basal twitch tension was 10.0 +/- 1.5 mN/mm2 and increased to maximally 13.6 +/- 2.2 mN/mm2 after 20 s rest (P < 0.05). With longer rest intervals, however, post-rest twitch tension continuously declined (rest decay) to 4.7 +/- 1.0 mN/mm2 at 240 s (P < 0.05). The rest-dependent changes in twitch tension were associated with parallel changes in intracellular Ca2- transients in NF and DCM (aequorin method). The relation between rest-induced changes in twitch tension and aequorin light emission was similar in NF and DCM, indicating preserved Ca(2-)-responsiveness of the myofilaments. Ryanodine (1 microM) completely abolished post-rest potentiation. Increasing basal stimulation frequency (2 Hz) augmented post-rest potentiation, but did not prevent rest decay after longer rest intervals in DCM. The altered post-rest behavior in failing human myocardium indicates disturbed intracellular Ca2- handling involving altered function of the SR.
Adult↗
Antioxidant vitamin C improves endothelial dysfunction in chronic smokers.
BACKGROUND: Chronic smoking is associated with endothelial dysfunction, an early stage of atherosclerosis. It has been suggested that endothelial dysfunction may be a consequence of enhanced degradation of nitric oxide secondary to formation of oxygen-derived free radicals. To test this hypothesis, we investigated the effects of the antioxidant vitamin C on endothelium-dependent responses in chronic smokers. METHODS AND RESULTS: Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine (7.5, 15, 30, and 60 micrograms/min) and the endothelium-independent vasodilator sodium nitroprusside (1, 3, and 10 micrograms/min) were measured by venous occlusion plethysmography in 10 control subjects and 10 chronic smokers. Drugs were infused into the brachial artery, and forearm blood flow was measured for each drug before and during concomitant intra-arterial infusion of the antioxidant vitamin C (18 mg/min). In control subjects, vitamin C had no effect on forearm blood flow in response to acetylcholine and sodium nitroprusside. In contrast, in chronic smokers the attenuated forearm blood flow responses to acetylcholine were markedly improved by concomitant administration of vitamin C, whereas the vasodilator responses to sodium nitroprusside were not affected. CONCLUSIONS: The present studies demonstrate that the antioxidant vitamin C markedly improves endothelium-dependent responses in chronic smokers. This observation supports the concept that endothelial dysfunction in chronic smokers is at least in part mediated by enhanced formation of oxygen-derived free radicals.
Acetylcholine↗
Role of the cardiac sarcolemmal Na(+)-Ca2+ exchanger in end-stage human heart failure.
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Adult↗
Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia. Role of oxidized LDL.
BACKGROUND: Risk factors for atherosclerosis such as hypercholesterolemia and hypertension are associated with endothelial dysfunction of conduit and resistance vessels; however, the interaction of these risk factors and underlying mechanisms affecting endothelial function remain to be determined. The present study investigated the role of long-term smoking and hypercholesterolemia and their impact on endothelial function of peripheral resistance vessels in relation to plasma levels of autoantibodies against oxidized LDL, which has been implicated in the development of endothelial dysfunction and atherosclerosis. METHODS AND RESULTS: The vascular responses to the endothelium-dependent agent acetylcholine (7.5, 15, 30, and 60 micrograms/min) and the endothelium-independent agent sodium nitroprusside (1,3, and 10 micrograms/min) were studied in normal control subjects (n = 10), patients with hypercholesterolemia (n = 15), long-term smokers (n = 15), and hypercholesterolemic patients who smoked (n = 15). Drugs were infused into the brachial artery, and forearm blood flow (FBF) was measured by venous occlusion plethysmography. The FBF responses to acetylcholine were significantly blunted in all three patient groups compared with normal control subjects (P < .05). The acetylcholine-induced increase in FBF was significantly attenuated in patients with hypercholesterolemia who smoked compared with hypercholesterolemic nonsmokers and normocholesterolemic smokers (P < .05 for both). The response to sodium nitroprusside was not statistically different in all four groups. Plasma levels of autoantibody titer against oxidized LDL were inversely related to acetylcholine-induced changes in FBF (r = -.53, P < .002) and were substantially increased in the group with both risk factors. CONCLUSIONS: These results demonstrate that cigarette smoking and hypercholesterolemia synergistically impair endothelial function and that their combined presence is associated with increased plasma levels of autoantibodies against oxidized LDL. These observations raise the possibility that long-term smoking potentiates endothelial dysfunction in hypercholesterolemic patients by enhancing the oxidation of LDL.
Acetylcholine↗