Thomas Neunteufl

Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain.

In summary, this study shows that CRP levels do not correlate with the extent and severity of coronary narrowing assessed by angiography. Other mechanisms such as acute inflammation with plaque instability and rupture may explain the higher cardiovascular event rate in patients with elevated CRP levels. 1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:

Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease

Flow-mediated vasodilation (FMD) of systemic arteries, a non-invasive parameter of endothelial function, is correlated with cardiovascular risk factors. The relationship between FMD and morphologically and clinically evident coronary artery disease has not been described. This study was performed to test the hypothesis that an impairment of FMD in the brachial artery is related to the presence and/or extent and severity of coronary artery disease (CAD). We examined 74 patients with angina pectoris and 14 control subjects (age 17 36 years). Angiography revealed coronary artery disease (> or = 30% diameter stenosis) in 44 patients (CAD, age 32 67 years) and smooth coronary arteries in 30 patients (non-CAD, age 22-73 years). Vasodilation following reactive hyperemia and after sublingual nitroglycerin (NTG) was assessed in the brachial artery using B-mode high resolution ultrasound. CAD patients showed markedly impaired FMD compared to the non-CAD group (5.7 +/- 4.8 versus 12.6 +/- 6.7%, P < 0.0001) and to controls (5.7 +/- 4.8 versus 15.7 +/- 3.9%, P < 0.00001). NTG induced similar degrees of vasodilation in the CAD and non-CAD groups but less vasodilation in the CAD patients compared to controls (12.2 +/- 6.3 versus 20.4 +/- 6.9%, P < 0.01). On univariate analysis, impaired FMD in CAD patients and non-CAD patients was related to the extent of coronary disease (1-, 2- or 3-vessel disease; r = -0.67, P < 0.0001), to the maximum percent diameter stenosis in one of the major coronary vessels (r = -0.52, P < 0.0001), brachial artery diameter (r = -0.46, P < 0.0001) and plasma cholesterol level (r = -0.34, P < 0.001). On multiple stepwise regression analysis the extent of coronary disease (r = -0.51, P < 0.0001) and the baseline brachial artery diameter (r = -0.37, P < 0.0001) were independently associated with FMD in CAD and non-CAD patients. The present findings suggest that the impairment of FMD in the brachial artery, a marker of systemic endothelial function, is closely related to the angiographic extent of CAD.

Contribution of nicotine to acute endothelial dysfunction in long-term smokers

OBJECTIVES The aim of this study was to determine whether nicotine, a constituent of cigarette smoke, contributes to acute endothelial dysfunction after smoking one cigarette. BACKGROUND Animal studies suggest that nicotine might cause an impairment of endothelium-dependent vasodilation via an increase in oxidative stress. METHODS Sixteen healthy smokers were entered into a randomized, observer-blinded crossover study comparing the effects of nicotine nasal spray (1-mg nicotine) and cigarette smoke (1-mg nicotine, 12 mg tar) on vascular reactivity in the brachial artery. Using high-resolution ultrasound, flow-mediated dilation (FMD) and endothelium-independent, nitroglycerin-induced dilation were assessed at baseline and 20 min after the administration of nicotine (spray or cigarette). RESULTS In response to similar increases in nicotine serum levels, FMD values declined from 10.2 +/- 4.4% to 6.7 +/- 4.0% after the spray (mean difference: -3.6 +/- 2.0%, 95% confidence interval: -4.6; -2.5, p < 0.0001) and from 9.4 +/- 3.8% to 4.3 +/- 2.8% after the cigarette (-5.1 +/- 2.6%, -6.5; -3.7, p < 0.0001). Nitroglycerin-induced dilation remained similar within both periods. Performing a period effect analysis of variance, a significant influence on FMD was found for the mode of administration (p = 0.017) and the baseline value (p = 0.021). The effect on FMD was more pronounced after the cigarette than after the spray (estimated average effect difference: 1.9% FMD). Oxidation parameters did not increase significantly after nicotine spray or tobacco exposure. CONCLUSIONS These results demonstrate that nicotine alone causes acute endothelial dysfunction, although to a lesser extent than smoking a cigarette of the same nicotine yield. However, the precise mechanisms by which nicotine leads to this altered vascular reactivity remain unclear.

Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men.

OBJECTIVES The aim of this study was to determine whether the combination of lipid-lowering therapy and vitamin E supplementation improves peripheral endothelial function and whether it is more effective than lipid-lowering therapy alone. BACKGROUND Endothelium-dependent vasodilation is impaired in coronary and peripheral arteries of patients with hypercholesterolemia. Coronary endothelial function has been shown to improve under lipid-lowering and antioxidant therapy, but the effect of additive vitamin E supplementation in the brachial artery is unknown. METHODS Seven patients with hypercholesterolemia (mean+/-SD; age 51+/-10 yr) were studied. Endothelium-dependent, flow-mediated dilation (FMD) and endothelium-independent nitroglycerin-induced dilation (NMD) were assessed in the brachial artery using high resolution ultrasound 1) at baseline (BL I), 2) after 8 weeks of simvastatin (20 mg) and vitamin E (300 IU) therapy (Comb I), 3) after withdrawal of vitamin E for 4 weeks (Statin), 4) after therapy as in #2 for 4 weeks (Comb II) and 5) after withdrawal of both drugs for 4 weeks (BL II). RESULTS Combined simvastatin and vitamin E therapy reduced total cholesterol (Comb I vs. BL I: 276+/-22 vs. 190+/-14 mg/dl, p < 0.0001) and low-density lipoprotein (LDL)-C (197+/-22 vs. 106+/-22 mg/dl, p < 0.00001), augmented alpha tocopherol levels normalized to LDL (12.2+/-4.1 vs. 4.9+/-0.9 microg alpha-T/100 mg% LDL-C, p < 0.01) and resulted in significant improvements in FMD (16.4+/-4.7 vs. 4.9+/-2.5%, p < 0.001) as well as NMD (17.9+/-4.3 vs. 11.2+/-2.8%, p < 0.01). The ratio of FMD to NMD (0.92+/-0.17 vs. 0.46+/-0.24%, p < 0.05) also increased under combination therapy, indicating a greater improvement of FMD than that of NMD. After withdrawal of vitamin E, both FMD (Comb I vs. Statin: 16.4+/-4.7 vs. 7.9+/-4.7%, p < 0.01) and NMD (17.9+/-4.3 vs. 10.9+/-4.5%, p < 0.05) decreased significantly such that simvastatin alone only tended to improve FMD and did not change NMD. Results under combination therapy (Comb II vs. BL II) were reproducible. CONCLUSIONS Combined vitamin E and simvastatin therapy leads to an improvement of FMD and NMD in the brachial artery of patients with hypercholesterolemia. The improvement of FMD is more pronounced after combination therapy than after lipid-lowering therapy alone, similar to previous findings in the coronary circulation.

Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias

Objective To compare the rate-lowering effect of diltiazem and two amiodarone regimens in critically ill patients with recent-onset atrial tachyarrhythmias. Design Prospective, randomized, controlled study. Setting Medical cardiologic intensive care unit in a university hospital. Patients Sixty critically ill patients (Acute Physiology and Chronic Health Evaluation [APACHE] III score 70 ± 30, age 67 ± 10 yrs). Interventions Patients with atrial fibrillation (n = 57), atrial flutter (n = 2), or atrial tachycardia (n = 1, and a heart rate consistently >120 beats/min over 30 mins were randomly assigned to one of three intravenous treatment regimens. Group 1 received diltiazem in a 25-mg bolus followed by a continuous infusion of 20 mg/hr for 24 hrs, group 2 received amiodarone in a 300-mg bolus, and group 3 received amiodarone in a 300-mg bolus followed by 45 mg/hr for 24 hrs. Measurements and Main Results The primary study end point was a >30% rate reduction within 4 hrs. The secondary study end point was a heart rate <120 beats/min (a patient was considered to have uncontrolled tachycardia if heart rate was >120 beats/min 4 hrs after study drug). The primary study end point was achieved in 14/20 (70%), 11/20 (55%), and 15/20 (75%) of patients in groups 1, 2, and 3, respectively (&khgr;2 = 1.95, p = .38). Uncontrolled tachycardia was more frequently observed in group 2 (0/20, 9/29 [55%], and 1/20 [5%] of patients in groups 1, 2, and 3, respectively; &khgr;2 = 17, p = .00016). In patients achieving tachycardia control, diltiazem showed a significantly better rate reduction (p = .0001 group 1 vs. group 3, p = .0001 over time;p = .0001 group 1 vs. group 2, p = .001 over time) when compared with the amiodarone groups. Premature drug discontinuation due to hypotension was required significantly more often in group 1 (6/20 [30%], 0/20, and 1/20 [5%] for groups 1, 2, and 3, respectively; &khgr;2 = 10, p = .01). Conclusion Sufficient rate control can be achieved in critically ill patients with atrial tachyarrhythmias using either diltiazem or amiodarone. Although diltiazem allowed for significantly better 24-hr heart rate control, this effect was offset by a significantly higher incidence of hypotension requiring discontinuation of the drug. Amiodarone may be an alternative in patients with severe hemodynamic compromise.

Effects of vitamin E on chronic and acute endothelial dysfunction in smokers

OBJECTIVES The aims of this study were to determine whether chronic or acute impairment of flow mediated vasodilation (FMD) in the brachial artery of smokers can be restored or preserved by the antioxidant vitamin E. BACKGROUND Transient impairment of endothelial function after heavy cigarette smoking and chronic endothelial dysfunction in smokers result at least in part from increased oxidative stress. METHODS We studied 22 healthy male smokers (mean +/- SD, 23 +/- 9 cigarettes per day) randomly assigned to receive either 600 IU vitamin E per day (n = 11, age 28 +/- 6 years) or placebo (n = 11, age 27 +/- 6 years) for four weeks and 11 age-matched healthy male nonsmokers. Flow mediated vasodilation and endothelium-independent, nitroglycerin-induced dilation were assessed in the brachial artery using high resolution ultrasound (7.5 MHz) at baseline and after therapy. Subjects stopped smoking 2 h before the ultrasound examinations. At the end of the treatment period, a third scan was obtained 20 min after smoking a cigarette (0.6 mg nicotine, 7 mg tar) to estimate transient impairment of FMD. RESULTS Flow mediated vasodilation at baseline was abnormal in the vitamin E (5.3 +/- 3.8, p < 0.01) and in the placebo group (6.4 +/- 3.5, p < 0.05) compared with nonsmoking controls (11.6 +/- 4.7). Using a two-way repeated measures analysis of variance (ANOVA) to examine the effects of vitamin E on FMD, we found no effect for the grouping factor (p = 0.5834) in the ANOVA over time but a highly significant difference with respect to time (p = 0.0065). The interaction of the time factor and the grouping factor also proved to be significant (p = 0.0318). Flow mediated vasodilation values remained similar after treatment for four weeks in both groups but declined faster after smoking a cigarette in subjects taking placebo compared with those receiving vitamin E (p values from successive differences for the time/group factor: 0.0001/0.0017). The transient attenuation of FMD (calculated as the percent change in FMD) was related to the improvement of the antioxidant status, estimated as percent changes in thiobarbituric acid-reactive substances (r = -0.67, p = 0.0024). Nitroglycerin-induced dilation did not differ between study groups at baseline or after therapy. CONCLUSIONS These results demonstrate that oral supplementation of vitamin E can attenuate transient impairment of endothelial function after heavy smoking due to an improvement of the oxidative status but cannot restore chronic endothelial dysfunction within four weeks in healthy male smokers.

Hemodynamic effects of a continuous infusion of levosimendan in critically ill patients with cardiogenic shock requiring catecholamines

Background:  Levosimendan, a novel inodilator, has been shown to improve hemodynamic function in patients with decompensated heart failure with preserved arterial blood pressure. Data on its use in patients with cardiogenic shock are rare. The present series describes the 24‐h hemodynamic effects of levosimendan as add‐on therapy in desperately ill patients with cardiogenic shock requiring catecholamines.

Prognosis of patients who develop acute renal failure during the first 24 hours of cardiogenic shock after myocardial infarction.

PURPOSE Acute renal failure has important prognostic implications in critically ill patients, but the effects of acute renal failure on in-hospital mortality in the subset of patients with cardiogenic shock are not known. SUBJECTS AND METHODS All consecutive patients who presented with acute coronary syndrome at our cardiovascular intensive care unit from 1993 to 2000 and who were in cardiogenic shock were enrolled. Acute renal failure was defined as a urine volume < 20 mL/h associated with an increase in serum creatinine level > or = 0.5 mg/dL or > 50% above the baseline value. RESULTS There were 118 patients (83 men [70%]; mean [+/- SD] age, 66 +/- 10 years), 39 (33%) of whom developed acute renal failure within 24 hours after the onset of shock. In-hospital mortality was 87% (34/39) in patients with acute renal failure and 53% (42/79) in patients without acute renal failure (odds ratio [OR] = 6.0; 95% confidence interval [CI]: 2.1 to 17; P < 0.001). Other significant univariate predictors of mortality included the peak serum lactate level, epinephrine dose, and the maximum serum creatinine level. Multivariate logistic regression analysis identified acute renal failure as the only independent predictor of mortality. CONCLUSION Acute renal failure was common in patients with cardiogenic shock and strongly associated with in-hospital mortality.

Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study

Summary.  Background: Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies.Objectives: To compare different assays for prediction of events during long‐term follow‐up.Methods: In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator‐stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA‐100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12‐month follow‐up.Results: Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c‐index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA‐100 (c‐index < 0.70; P > 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c‐index < 0.56; P > 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra‐metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status.Conclusions: Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping.

Is oxidative stress causally linked to unstable angina pectoris? A study in 100 CAD patients and matched controls

OBJECTIVE Unstable angina pectoris often leads to acute myocardial infarction. Since lipid peroxidation is thought to be causally related to chronic and acute events in atherosclerosis and coronary artery disease, we measured lipid peroxidation products and vitamin E in 100 patients with coronary artery disease and compared them to a matched control group. METHODS 50 consecutive patients with stable angina pectoris (SAP) and 50 consecutive patients with unstable angina pectoris (UAP) were studied and compared to 100 clinically healthy individuals. In addition to conventional lipid and lipoprotein analysis, malondialdehydes were measured as thiobarbituric acid reactive substances (TBARS). Lipid hydroperoxides were assayed with the colorimetric methylene blue method. alpha-Tocopherol was quantitated by HPLC after extraction of serum with hexane-ethanol. In the patient group conjugated dienes were also measured. RESULTS As expected, patients had significantly higher cholesterol, triglyceride LDL-C and Lp(a) values and lower HDL-C values than controls. When patients were divided into groups with SAP and UAP respectively, peroxides and TBARS were significantly higher in the latter group as compared to patients with SAP and to controls. Conjugated dienes were also significantly higher in patients with UAP as compared to patients with SAP. Total plasma alpha-tocopherol was comparable in all three groups, whereas the alpha-tocopherol content per LDL particle was lowest in patients with UAP, followed by patients with SAP and then controls. CONCLUSION It is concluded that lipid peroxidation parameters are increased in patients with UAP and discriminate SAP from UAP patients.