Vagal neurostimulation in patients with coronary artery disease.

We tested the hypotheses that (1) progression of coronary artery disease (CAD) increases sympathetic inflow to the heart, thus impairing cardiac blood supply, and (2) reduced sympathetic tone improves cardiac microcirculation and ameliorates severity of anginal symptoms. Electrical irritation of the nerve auricularis--a sensitive ramus of the vagus nerve--provides a central sympatholytic action. Using this technique, we studied the effects of vagal neurostimulation (VNS) on hemodynamics, the content of atrial noradrenergic nerves and the microcirculatory bed of CAD patients. VNS was performed in the preoperative period of CAD patients with severe angina pectoris. The comparison groups consisted of untreated patients with CAD or Wolff-Parkinson-White syndrome. Atrial tissue of patients with this syndrome (n = 6); with effort angina (n = 14); with angina at rest (n = 10); and with severe angina treated with VNS (n = 8) contained the following volume percentages of noradrenergic nerves: 1.7+/-0.1%, 1.3+/-0.3%, 0.5+/-0.1% (p < 0.05 vs. the other groups) and 1.3+/-0.2%, respectively. In these groups, cardiac microcirculatory vessels (diameter, 10-20 microm) had the following densities: 2.7+/-0.2%, 3.4+/-0.2%, 2.0+/-0.4% (p < 0.05 vs. the other groups) and 3.3+/-0.3%, respectively. VNS treatment abolished angina at rest, decreased heart rate and blood pressure. It improved left ventricular ejection fraction from 50+/-1.5% to 58+/-1.0% (p < 0.05), also changing left ventricular diastolic filling. The ratio of time velocity integrals of the early (Ei) to late (Ai) waves increased from 1.07+/-0.12 to 1.65+/-0.17 after VNS (p < 0.05). In electrocardiograms of VNS-treated patients, QRS- and QT-duration were shortened. the PQ-interval did not change, but T-wave configuration improved. In the postoperative period, heart failure occurred in 90% of the control group. vs. 12% in patients treated with VNS (p < 0.05). We conclude that CAD is characterized by overactivity of sympathetic cardiac tone. Vagal stimulation reduced sympathetic inflow to the heart, seemingly via an inhibition of norepinephrine release from sympathetic nerves. VNS' sympatholytic/vagotonic action dilated cardiac microcirculatory vessels and improved left ventricular contractility in patients with severe CAD.

Effects of electrostimulation of the vagus afferent endings in patients with coronary artery disease.

BACKGROUND: In rats, low-frequency electroneurostimulation (ENS) of the ear afferent vagus endings and brainstem structures via transauricular electroacupuncture increases the parasympathetic tone of the autonomic nervous system. We examined the effects of ENS applied in the preoperative period in patients with coronary artery disease (CAD) who underwent coronary artery bypass grafting operations. METHODS: ENS was performed in a group of 10 patients with CAD who were classified as Canadian Cardiovascular Society class IV before operation. A second group of 10 patients with a similar degree of CAD comprised a control group. The efficacy of the procedure was evaluated on the basis of improvement in the patient's clinical course before and after operation. The presence of major inducible stress protein (HSP 70i) and the ATP content of the myocardium was determined in atrial tissue (part of the right heart auricle) from both groups of patients. Tissue from patients with Wolff-Parkinson-White (WPW) syndrome served as a control, non-ischemic, cardiac tissue. RESULTS: A course of 10 ENS procedures improved the patients' preoperative clinical course, producing a rapid reduction in their angina. By the end of the course, the patients no longer developed angina either at rest or after a moderate physical load, and their dependence on treatment with vasodilators had decreased considerably. Atrial tissue from patients with CAD who were treated with ENS was similar to that from patients with WPW in lcaking HSP 70i and in ATP content. In contrast, tissue from the control group of patients with CAD contained HSP 70i and had an increased content of ATP. The antianginal effect of neurostimulation lasted for at least 2-3 weeks after completion of the procedures. The postoperative recovery of patients treated with ENS was characterized by stable hemodynamics and sinus rhythm. CONCLUSION: We conclude that ENS had a central vagotonic/sympatholytic influence on the heart, leading to the development of three main effects in patients with CAD: relief of anginal symptoms, diminution of some biochemical myocardial signs of the disease, and an increase in the heart's tolerance of operative reperfusion damage.

The role of hsp70 and IP3-DAG mechanism in the adaptive stabilization of structures and heart protection.

This study has shown that the maximal activation of the IP3-DAG regulatory circuit is observed on the 14th day of adaptation to repeated stresses. This activation is characterized by increased activity of phospholipase C and of the positive inotropic response of isolated heart to an alpha-agonist. Simultaneously, this activation is accompanied by the accumulation of five heat shock protein 70 (hsp70) isoforms. The IP3-DAG circuit activation and the hsp70 accumulation are accompanied by a significant increase in the cardiac resistance to post-ischemic reperfusion, as evidenced by a considerable decrease in the contracture, arrhythmias and the creatine kinase release into the perfusate. Continuation of the adaptation to repeated stresses for 28 days leads to complete reversal of the observed shifts.

Phenomenon of the adaptive stabilization of structures and protection of the heart.

OBJECTIVE: To study the role of heat shock proteins in the mechanism of adaptive stabilization of structures. DESIGN: Double-blind randomized trial. ANIMALS: Wistar male rats weighting between 250 and 300 g. INTERVENTIONS: Adaptation to restraint stress. Animals were heparinized and anesthetized with nembutal. Experiments on isolated heart included ischemia, reperfusion, adrenergic damage and heat shock. Biochemical investigations studied calcium transport from sarcoplasmic reticulum and mitochondria, and cytofluorimetrical analysis of DNA using the O'Farrell method. MAIN RESULTS: In reperfusion, the contraction amplitude of the hearts from adapted animals was 8.8 times higher than control. This acceleration of the contractile function recovery was due to a more rapid disappearance of the contracture. The duration of ventricular tachycardia and fibrillation was 246 +/- 16 s in control and 119 +/- 12 s in adaptation (P < 0.001). The creatine kinase release was 719 +/- 34 mU/min/g wet weight in control and 302 +/- 120 mU/min/g wet weight in adaptation (P < 0.05). In adaptation, the heat shock-induced contraction amplitude was 2.4 times higher than control and the enzyme yield was practically absent. Adaptation reduced the duration of atrioventricular blockade from 385 to 233 s per group and decreased the number of extrasystoles by 6.5 times. The calcium leakage from intracellular stores during storage proceeded slower in adaptation than in control. During storage of mitochondria at 4 degrees C, oxygen consumption fell much slower in adaptation than in control. As a result, the capacity of mitochondria (isolated from hearts of adapted animals stored for two days) to consume oxygen was 50% higher than in controls; in controls, almost one-half of nuclei were already damaged at one-chain DNA concentration of 50 micrograms/mL, while this phenomenon was 5.5 times less pronounced in adaptation. Adaptation resulted in the accumulation of five polypeptides (molecular weight 72 kDa and pl from 6.3 to 5.7). CONCLUSIONS: The mechanism providing adaptive increase of the heart resistance is apparent both at the central level and at the level of heart cells, and is accompanied by accumulation of inducible polypeptides.

Differences in adaptive stabilization of structures in response to stress and hypoxia relate with the accumulation of hsp70 isoforms.

The phenomenon of adaptive stabilization of structures (PhASS) develops during adaptation of the organism to intermittent restraint stress. The PhASS manifests itself in a considerably increased resistance of the heart to a broad spectrum of harmful factors. In the present work, the content of hsp70 and their role in the development of PhASS during adaptation to intermittent restraint stress and to intermittent hypoxia were studied. In adaptation to restraint stress, five hsp70 isoforms with pI ranging from 5.7 to 6.3 were accumulated in the myocardium. The heart simultaneously became strikingly resistant to reperfusion paradox and heat shock. In adaptation to hypoxia, only two hsp70 isoforms with pI about 5.8 were accumulated. The resistance to reperfusion paradox was not increased and the resistance to heat shock was increased only moderately. These data suggest a role of different hsp70 isoforms in the mechanism of PhASS as well as adaptive protection of the heart.

Adaptive protection of the heart and stabilization of myocardial structures.

Adaptation of animals to short-term stress exposure (ASE) protected the heart against arrhythmias in acute ischemia and reperfusion and eliminated the decrease in threshold of fibrillation and arrhythmias is acute myocardial infarction and postinfarction cardiosclerosis. Cardioprotective effect of ASE was provided not only by the activation of GABAergic, opioidergic and cholinergic stress-limiting system but also by a mechanism formed at the level of heart itself. Isolated hearts of animals adapted to short-term stress exposure possessed a strikingly enhanced resistance to toxic doses of catecholamines, Ca2+, and to reperfusion damage following total ischemia. Contracture-inducing and arrhythmogenic effects of these factors and the release of CK into the perfusate were manifold reduced in ASE. Mitochondria and elements of SR Ca-pump isolated from the hearts of adapted animals were much more resistant to autolysis. This phenomenon of adaptive stabilization of structures (PhASS) was accompanied by the accumulation of HSP 71 and a simultaneous increase in the heart thermal stability. In the coronary artery ligation the PhASS lacked the anti-ischemic effect, but it provided a decrease of the necrotic zone by more than 40%, the ischemic zone being unchanged, due to its cytoprotective effect.