| BackgroundThe term of coronary artery spasm (CAS) refers to a sudden, intense vasoconstriction of an epicardial coronary artery that causes vascular total occlusion or near to occlusion. CAS is one of the common pathological bases of different coronary artery disease, such as variant angina, myocardial infarction and sudden death. Episodes of CAS tend to occur at rest or the period of between midnight and early morning. Temporary ST-segment elevation on electrocardiogram is a characteristic manifestation of CAS and the key differential point to exertional angina which presents chest pain with ST depression. Depending on the severity and duration of CAS, ST elevation may automatically and completely relieve within minutes.The exact mechanism and precipitating factors of CAS are not well understood. Recent studies have identified a number of precipitating factors that may play a role in the pathogenesis of CAS. They include endothelial dysfunction, smooth muscle cell hypersensitivity to calcium, increased oxidative stress, genetic susceptibility and autonomic nerves system dysfunction. 1. Role of Endothelial Dysfunction. Studies have shown a strong association between endothelial dysfunction and CAS. The endothelium plays an important role in the regulation of vascular tone via the production and release of vasodilative and vasoconstrictive factors. The major vasodilators are nitric oxide (NO) and prostacyclin and the most potent vasoconstrictor is endothelin-1. Intact endothelium is protective against CAS and its disruption predisposes to vasoconstriction. In spastic coronary arteries there is a deficiency in NO activity with an increase of endothelin release.2. Role of smooth muscle cell hypersensitivity. Contraction of vascular smooth muscle cell depends on the concentration of intracellular calcium and the sensitivity of smooth muscle cell to calciumions. The phosphorylation of myosin light chain (MLC), with resultant elevation in intracellular calcium concentration and sensitivity, is the initial regulatory step in contraction.3. Role of reactive oxidative stress. Reactive oxidative stress has been associated with various cardiovascular diseases. Direct evidence of the role of oxidative stress in CAS is lacking. There is indirect evidence that exposure to superoxides predisposes to coronary vasospastic reactivity. Large amounts of oxygen free radicals which can directly damage endothelial cells and inactivate NO leading to vasoconstriction.4. Genetic susceptibility. A number of genetic factors have been linked to susceptibility to CAS mainly in the Japanese population. Abnormalities in the endothelial NO synthase gene is associated with vasoconstriction by a reduction in NO and an increase in superoxide formation. Polymorphisms in the paraoxonase gene that regulates a suppressor of oxidative stress have been associated with a predisposition to oxidative stress.Recent investigations suggested that the imbalance of autonomic nervous activities may cause coronary spasm. Heart rate variability (HRV), as a non-invasive method, is the most sensitive indicator to evaluate autonomic nervous function. More results indicate the acute variation in autonomic tone measured by HRV was associated with spontaneous coronary artery spasm. A reduction in sympathetic nervous activity, and/or the enhancement of vagal activity may play a key role in triggering the spontaneous CAS. While limited data suggest that a decreased vagal activity may be a component of the mechanisms leading to spontaneous coronary artery vasospasm. However, these results were come from self-control studies which were designed to compare the autonomic nervous activities of before and after the episode of coronary artery spasm. The basic feature of the autonomic nervous during non-spastic episode in CAS patients is needed to be investigated. Furthermore, there is no any report on the relation of coronary artery spasm and autonomic nervous system in Chinese population.Calcium channel blocker (CCB) may effectively reduce the episodes of CAS, which was usually ascribed to the mechanism of vasodilation. There is no report to explore the effect of CCB on the activity of autonomic nervous system. We infer that CCB may have some impacts on autonomic nervous tone in CAS patients.Therefore, we designed this study to investigate the characteristics of baseline HRV and the changes after CCB therapy in Chinese CAS patients.Objectives1. To investigate the characteristics of baseline HRV in the patients with CAS during non-spastic episode.2. To evaluate the impact of CCB on HRV in the patients with CAS.Subjects and Methods1. Subjects:The CAS group included25new diagnosed CAS patients,16males and9females. Mean age was51.6±5.2years. The inclusion criteria: Diagnosed by positive acetylcholine provocation test or non-invasive diagnostic criterion. The positive criteria of acetylcholine provocation test includes three conditions as below:firstly, clinical manifestations of chest pain or chest tightness at rest; secondly, no significant coronary stenosis by angiography; thirdly, CAS induced by intracoronary injection of acetylcholine that could result in more than90%coronary artery stenosis, accompanied with similar symptoms of chest pain or chest tightness as usual, which would disappear after the spasm is relieved automatically or by intracoronary nitroglycerol. The criterion of non-invasive diagnostic method is described as below:the patients are diagnosed as CAS if the following three conditions are met simultaneously:①the clinical manifestation of resting chest pain or chest tightness.②negative treadmill exercise electrocardiogram or ischemic electrocardiographic changes during recovery period after exercise.③reverse redistribution on myocardial perfusion scintigraphy.The control group included20healthy persons,12males and8females, which were selected from Healthy Examination Department. Mean age was50.6±7.3years. The inclusion criteria were consisted with the followings:Firstly, medical examinations including physical and lab tests, ECG, transthoracic echocardiography, and chest radiography are normal. And secondly, age and sex were matched to those of CAS group.Case report form was established to record the clinical data including age, sex, BMI, smoking, level of low density lipoprotein cholesterol and so on.2. The exclusion criterion:①Arrhythmia, such as frequent premature beats, atrial flutter, atrial fibrillation, atrioventricular block, tachycardia;②Myocardial infarction, unstable angina;③New York Heart Association class Ⅲ-Ⅳ;④Hyperthyroidism;⑤Diabetes;⑥Hypertension;⑦Sleep apnea syndrome;⑧people who used CCB recently.Following medicines were inhibited or discontinued for at least5half-lives before24-hour Holter electrocardiogram recordings:β-blockers, atropine and analogues, theophylline and ACEI. No smoking and tea or coffee or alcohol drinking during24-hour Holter electrocardiogram recordings.3. Treatment for CAS group:①Smoking cessation;②Antiplatelet drugs: Aspirin is the optimal, and clopidogrel is the succedaneous while aspirin intolerance.③Cholesterol lowering therapy:LDL<2.6mmol/l was considered as an adequate target in CAS group.④CCB treatment:Diltiazem was preferentially prescribed to the CAS patients. However, amlodipine was chosen when the patients had bradycardia.4. The24-hour Holter electrocardiogram recordings and HRV measurement:24-hour Holter electrocardiogram was recorded for all of the CAS patients and healthy controls after included in this study. The Holter electrocardiogram recording was repeated in12CAS patents without smoking after taking CCB for3months. HRV was assessed from24-hour Holter electrocardiogram recordings analyzed by the Grand Pacific Holter Laboratory of American. Arrhythmia which affected analysis of HRV was eliminated automatically by computer. The data include:time domain measures of HRV, SDNN=the standard deviation of N-to-N intervals, in msec; SDANN=the standard deviation of the mean of the5-minute intervals; RMSSD=the root mean square successive differences between adjacent normal R-R intervals that are greater than50msec; PNN50=percent of differences between adjacent normal R-R intervals that are greater than50msec. Frequency domain measures of HRV, high-frequency power(HF), low-frequency power(LF), and calculate the value of low-frequency power/high-frequency power(LF/HF).5. Statistical analysis:Quantitative data were showed as mean±SD and studied by student t test or χ2test. Analysis of covariance was used to adjust for differences about baseline. These statistical analyses were performed on personal computer with SPSS soft-ware.Results1. There were no statistically significant differences in general clinical data between two groups, such as age, gender and BMI(P>0.05). But the proportion of smoking and LDL level in CAS group were higher than those in the control group(P <0.05).2. Among the parameters of HRV, SDNN、SDANN、RMSSD、PNN50、LF and HF were significantly lower in CAS group than in control group(P<0.01). After smoking and LDL level adjustment, statistical differences were still significant(P<0.01). RMSSD and LF/HF were lower in CAS group than in control group, but the differences were not statistical different (P>0.05).3. All the parameters of HRV present a potential to increase in CAS patients after administration of CCB for3months, but the changes were not statistical different (P>0.05).Conclusions1. These results suggest that autonomic nerves dysfunction was closely associated with CAS, the reduction in vagal activity and the enhancement of sympathetic activity may be the baseline features of the CAS patients during non-spastic episode.2. CCB may reduce the episodes of CAS by improving autonomic nerve system in addition to vasodilation. |
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