Krystyna Herbaczyńska-Cedro

Effect of Supplemental Oral l-Arginine on Exercise Capacity in Patients With Stable Angina Pectoris

A randomized, double-blind, placebo-controlled study in patients with clinical symptoms of stable angina pectoris and healed myocardial infarction (n = 22) has shown that oral supplementation with L-arginine (6 g/day for 3 days) increases exercise capacity (tested on a Marquette case 12 treadmill according to the modified Bruce protocol). Results suggest that the inefficient L-arginine/nitric oxide system contributes to limitation of myocardial perfusion and/or peripheral vasodilation during maximum exercise in patients with stable angina pectoris.

Effects of oral L-arginine supplementation on exercise-induced QT dispersion and exercise tolerance in stable angina pectoris.

We assessed the effects of L-arginine (an endogenous precursor of nitric oxide) on the magnitude of exercise-induced QT dispersion in patients with coronary artery disease. The study had a randomized double-blind cross-over design. Twenty-five patients with stable coronary artery disease underwent two separate exercise tests: after oral administration of L-arginine (6 g/24 h for 3 days) or placebo. Indications for cessation of exercise included: pulse limit, exhaustion, chest pain, ST segment depression >2 mm. We found that arginine significantly increased exercise duration from 604+/-146 to 647+/-159 s (P<0.03). However, it had no effect on the sum of exercise-induced ST segment depressions (1.9+/-2.3 and 2.4+/-3.3 on and off arginine, respectively, NS). Exercise shortened QT interval to a similar extent in patients treated with placebo or arginine. QT dispersion changed during exercise from 55+/-21 to 60+/-19 ms (NS) and from 60+/-21 to 53+/-17 ms (NS), respectively. We conclude that, in patients with coronary artery disease, oral supplementation of L-arginine does not affect exercise-induced changes in QT interval duration, QT dispersion or the magnitude of ST segment depression. However, it significantly increases exercise tolerance, most likely due to improved peripheral vasomotion. These results may be of clinical and therapeutic importance.

NG-monomethyl-l-arginine increases platelet deposition on damaged endothelium in vivo. A scanning electron microscopic study

There is increasing evidence that nitric oxide (NO) synthetized in vascular endothelium and in platelets by NO synthase influences vascular tone, down regulates platelet function and platelet-vessel wall interaction both in vitro and in vivo. We investigated the effect of a NO synthase inhibitor, NG-mono-methyl-L-arginine (L-NMMA, 100 mg/kg iv) on platelet-endothelial cell interaction in rabbit arteries ex vivo using scanning electron microscope (SEM). The effect of L-NMMA was examined on intact endothelium and on that damaged by arterial constriction. The infusion of L-NMMA increased systemic blood pressure and decreased carotid blood flow, however, it did not change the appearance of an intact endothelium and did not result in platelet activation on intact endothelial cells. In contrast, SEM of endothelial areas damaged by constriction showed extensive platelet adhesion and aggregation on subendothelium. These morphological changes were not detected in control animals with intact or damaged by arterial constriction endothelium. These results show that under physiological conditions, the inhibition of NO synthase alone does not result in platelet activation in vivo. However, when combined with endothelial injury it may lead to platelet activation and thrombosis.

Effects of antioxidant vitamins C and E on signal-averaged electrocardiogram in acute myocardial infarction

Experimental studies indicate that oxygen-free radicals contribute to ischemic myocardial damage and affect electric properties of cellular membranes. We hypothesize that an association exists between an oxygen-free radical-induced component of myocardial ischemic injury and altered electric function that underlies the genesis of ventricular late potentials in the course of myocardial infarction. If so, antioxidant vitamins C and E may prevent alterations in the signal-averaged electrocardiogram (SAECG). To test this hypothesis, we investigated the effect of supplementation with vitamins C and E on the indices of the SAECG in patients with acute myocardial infarction (AMI). Sixty-one patients with AMI were randomized to receive conventional treatment and vitamins C and E, each 600 mg/day, orally for 14 days (supplemented group, n = 33) or conventional treatment only (control group, n = 28). SAECG was recorded on days 1 or 2 and between days 9 and 13 (mean 10). Serum ascorbic acid, tocopherol, plasma lipid peroxides, and oxygen-free radical production by isolated leukocytes were measured on days 1 or 2 and between days 12 and 14. In the control group, SAECG showed an increase in mean QRS and low-amplitude ( < 40 microV) signal durations, from 99 +/- 10 to 111 +/- 13 ms (p < 0.001) and from 31 +/- 8 to 38 +/- 10 ms (p < 0.001), respectively, and a decrease in the root-mean-square voltage of the last 40 ms of the QRS complex, from 36 +/- 25 to 21 +/- 11 microV (p < 0.002). In vitamin-supplemented patients, all these indices remained unchanged. Oxygen-free radical production by isolated leukocytes was decreased compared with that in controls (p < 0.02). Supplementation was confirmed by elevation of serum ascorbic acid and tocopherol. Results support the hypothesis that in patients with AMI, oxygen-free radical-induced cellular damage contributes to alterations in electric function of the heart as seen on the SAECG.

Effects of vitamins C and E on the outcome after acute myocardial infarction in diabetics: a retrospective, hypothesis-generating analysis from the MIVIT study.

Background: There is significant evidence that reactive oxygen species play an important role in endothelial dysfunction, ischemia/reperfusion injury as well as in the pathogenesis of diabetes mellitus (DM). It is also known that vitamins C and E have substantial antioxidant properties. However, clinical evidence concerning this topic is insufficient so far. The aim of the present study was to determine if the administration of vitamins C and E influences the outcome in diabetic patients with acute myocardial infarction (AMI). Methods: Among 800 patients with AMI included in the MIVIT (Myocardial Infarction and Vitamins) study, 122 patients (15%) had confirmed DM. A retrospective analysis of the influence of vitamins C and E on 30-day cardiac mortality in patients with or without DM was performed. Results: There was a significant reduction in 30-day cardiac mortality in diabetic patients treated with antioxidant vitamins C and E [5 (8%) vs. 14 (22%); OR 0.32, 95% CI 0.11–0.93; p = 0.036]. Such an effect has not been observed in patients without DM [19 (6%) vs. 19 (6%); OR 0.97, 95% CI 0.51–1.85; p = 0.94]. Conclusion: The results suggest that early administration of antioxidant vitamins C and E in patients with AMI and concomitant DM reduces cardiac mortality.

Release of matrix metalloproteinase-9 during balloon angioplasty in patients with stable angina.: A preliminary study

BACKGROUND Vascular wall remodeling is a major factor contributing to restenosis after angioplasty that involves migration and proliferation of vascular smooth muscle cells. The release of matrix-degrading metalloproteinases, including metalloproteinase-2 and metalloproteinase-9, facilitates remodeling. Experimental data suggest that nitric oxide (NO) decreases the activity of metalloproteinases and this may attenuate arterial remodeling after balloon injury. We investigated whether metalloproteinase-2, metalloproteinase-9 and NO are released into the coronary sinus blood during angioplasty in coronary patients. METHODS In 10 patients with stable angina undergoing elective percutaneous transluminal coronary angioplasty of an isolated stenosis of the proximal left anterior descending coronary artery, blood was sampled from the coronary sinus at baseline, immediately and 1 min after each balloon deflation. Plasma release of metalloproteinase-2 and metalloproteinase-9 was assayed by their gelatinolytic activity using zymography, while the liberation of NO metabolites was measured by high-performance liquid chromatography. RESULTS Two consecutive balloon inflations each of 60 s duration, resulted in an immediate increase (P<0.05) of metalloproteinase-9, but not metalloproteinase-2 activity, followed by normalization of metalloproteinase-9 levels to the baseline within 1 min. Plasma levels of NO metabolites remained unchanged. CONCLUSIONS Rapid release of metalloproteinase-9 after balloon inflation may both contribute to remodeling and protect the vascular wall from post-angioplasty thrombosis.

Suppression of the release of prostaglandin-like substances by hydrocortisone in vivo.

Muscular exercise of the dogs hind leg evokes the release of prostaglandin-like substances/PG-like substances/into femoral venous blood. The release of PG-like substances detected by the bioassay method was significantly greater in adrenalectomized as compared to normal dogs. To test the possibility that this difference may be related to the deficiency of adrenocortical secretion in adrenalectomized dogs, the effect of hydrocortisone/HC/and aldosterone/AS/upon the release of PG-like substances induced by muscular work of the dogs hind leg was investigated. The doses of HC and AS infused intravenously or intraarterially were close to the range of physiological secretion rate of these hormones. HC suppressed the release of PG-like material by 30 to 60%, whereas AS had no effect upon the rate and duration of the release. The rate of removal of exogenous PGE2 in the hind limb circulation was not influenced by HC, suggesting that the diminution of PG release by HC results from the suppression of PG generation rather than from the enhancement of degradation. It is suggested that PG-like substances may be related to the membrane-stabilizing properties of this hormone. The difference in the intensity of the release of PG-like substances between normal and adrenalectomized dogs suggests that, at least in some conditions, the release of endogenous PGs from tissues may be influenced by the state of adrenocortical activity.

Platelet adhesion is related to heart rhythm disturbances in the acute phase of myocardial infarction

This study examines the relationship between platelet adhesion, aggregation and the occurrence of heart rhythm disturbances in 43 consecutive patients (mean age 58) admitted to a coronary care unit with acute myocardial infarction. Blood for platelet studies was taken prior to institution of any medication and heart rhythm was monitored (Holter) for 24 h after admission. The control group consisted of 22 healthy subjects (mean age 55 yr). Platelet adhesion to collagen was measured in EDTA-platelet rich plasma by recording the changes in light transmission in an optical aggregometer. Platelet aggregation was measured by the Born method. Platelet adhesion was increased in the group of patients with acute myocardial infarction as compared to controls and was significantly higher in the patients with complex ventricular arrhythmias (Lown 3-4b, n = 18) than in the patients with stable rhythm. Platelet aggregation in the patients with acute myocardial infarction did not differ significantly from the controls and was not related to heart rhythm disturbances. The causal relationship of increased platelet adhesiveness to collagen and heart rhythm disturbances in acute myocardial infarction remains to be established.

Increased activity of circulating polymorphonuclear leukocytes in acute myocardial infarction.

Acute myocardial infarction results in an increased sensitivity of circulating polymorphonuclear leukocytes to ex vivo aggregation. This increase was prevented by pretreatment of leukocytes with BW755, but not with aspirin, suggesting that the activation of blood leukocytes in infarction is due to a stimulation of cellular lipoxygenase.

Elective coronary angioplasty with 60 s balloon inflation does not cause peroxidative injury.

Background The aim of this study was to evaluate the ongoing controversial issue of whether ischemia/reperfusion during elective coronary angioplasty evokes myocardial peroxidative injury.