Intervention of spironolactone on heart rate variability and its circadian rhythm in patients with heart failure
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《中华医药杂志》英文版
Intervention of spironolactone on heart rate variability and its circadian rhythm in patients with heart failure(pdf)
1 Department of Cardiology,The First Hospital of Jilin University, Changchun, Jilin Province 130021, China
2 The Third Hospital, Qingdao, Shandong Province 266041, China
Correspondence to ZHANG Yu, Department of Cardiology, the First Hospital of Jilin University，Changchun, Jilin Province 130021, China
Tel:+86-431-5612342,E-mail: yzhang@email.jlu.edu.cn
[Abstract] Objective The study was designed to observe heart rate variability (HRV) and its circadian rhythm in patients with heart failure in order to explore the mechanisms of aldosterone blockade in improving patients with heart failure. Methods HRV indices such as the time domain and frequency domain and its circadian rhythm were obtained from 48 -hour continuous electrocardiogram (ECG) recording in 24 heart failure patients and 10 healthy subjects. Results HRV indices were lower in heart failure patients than in healthy subjects, P<0.05. After four-week treatment, increase of HRV indices was more significant in spironolactone group than in routine group, especially HF and NN,P<0.05. In addition, this effect of spironolactone was maximal in the morning (6 am~10 am), including not only increase of HRV but also decrease of heart rate. Conclusions The effects of spironolactone on HRV and its circadian rhythm in patients with heart failure may be by inhibiting the release of aldosterone at 6 am~10 am. It could be one of mechanisms that spironolactone improved heart function.
[Key words] heart failure; heart rate variability; circadian rhythm; spironolactone
INTRODUCTION
Heart rate variability (HRV) is time variability between two successive cardiac cycles. It has been considered as a non-invasive method in evaluation of the cardiac autonomic nervous system. A number of clinical studies have demonstrated [1,2] that the functions of cardiac autonomic nerves were damaged, HRV indices were decreased and the circadian rhythms were disappeared in patients with heart failure. The malignant cardiac arrhythmia, acute myocardial infarction and sudden death were often occurred in the morning. It is because that the sympathetic nerves are most active in the morning [3]. There is evidence that aldosterone may have detrimental effects on the cardiac autonomic nervous system, especially during the morning hours [4]. Therefore, observation of HRV and its circadian rhythms in the morning is of great importance. In order to understand the mechanism of spironolactone in meliorating the prognosis of heart failure, we investigated the effect of spironolactone on HRV and circadian rhythms in patients with heart failure in this paper.
SUBJECTS AND METHODS
Subjects
Twenty-four patients with heart failure (New York Heart Association [NYHA] class III to IV) were recruited from our hospital between March 2004 and March 2005. The patients who predominant cardiac rhythm was not sinus or diabetes or hyperthyroidism or renal failure were excluded. Fifteen males and 9 females, aged 60±13 years old. Five patients were complicated with hypertension, 15 coronary heart diseases, 2 dilated cardiomyopathy, and 2 valvular heart diseases. All the patients had not taken angiotensin-converting enzyme inhibitors (ACEI), spironolactone, beta-blockers, digitoxin two weeks before admission. All 24 selected patients were randomly divided into two groups such as spironolactone treatment group (40 mg /day,n=12) and routine treatment group (n=12). Ten healthy subjects who were approved no heart disease by examination were selected as control. Six males, 4 females with mean age of 58 ± 7 years old.
Methods and Observatory Parameters
Forty-eight hour continuous electrocardiogram (ECG) recordings (supplied by Changchun Times Digital Co.Ltd) were obtained in all subjects using a standard twelve-channel recorder. HRV indices were analyzed with a Holter analysis system in the time domain and frequency domain. The time domain indices included R-R intervals, NN; standard deviation of all normal sinus R-R intervals over 24 hours, SDNN; standard deviation of the average normal sinus R-R intervals for all 5-minute segment, SDANN; root mean square of the successive normal sinus R-R interval difference, rMMSD; percentage of successive normal sinus R-R intervals longer than 50 ms, pNN50%. Frequency domain indices included low frequency, LF (0.04~0.15 Hz), reflecting the common influence of the sympathetic nerves and vagus nerves, while high frequency, HF (0.15~0.40 Hz), reflecting the activity of the vagus nerves. And the biochemical, blood and urine routine examination, blood pressure, heart rate, echocardiography, weight, and the side effects were measured or observed at the same time.
Statistical Analysis
All data was given as mean ± standard deviation. Results were compared by paired t-test.Differences were considered as significant at P<0.05.RESULTS
Compared Heart Failure with Normal Control Group
All the HRV indices of heart failure patients were lowered, indicating the fact that the cardiac autonomic nerves were damaged during heart failure(Table 1).
Table 1 Comparison of Heart Failure with Control in Heart Rate, Blood Potassium and HRV Indices (xx±s)
Note:*P<0.05, **P<0.01 vs. control
Effects of Spironolactone on HRV Indices
After systematic treatment, both the spironolactone treatment group and routine treatment group showed increase of HRV indices. The spironolactone treatment group was more apparent than the routine treatment group, not only HF and NN increase but also heart rate reduction,P<0.05. This fact demonstrated that spironolactone could play an important role in meliorating the activity of vagus nerves(Table 2).
Table 2 Comparison of Routine Group of HRV Indices with Spironolactone Group Pre- and Post- treatment (xx±s)
Note:*P<0.05, vs.pre-treatment, respectively
Effects of Spironolactone on HRV in Different Times
Spironolactone therapy caused a significant increase of HRV indices which were maximal from 6 am to 10 am in the morning. During these hours, standard deviation of the R-R intervals and HF component were significantly increased, indicating the improvement of spironolactone on autonomic nerves' circadian rhythms(Table 3).
Table 3 Comparison of HRV Change Value in Different Time after Treatment
Note:*P<0.05,**P<0.01, Spironolactone vs. routine therapy after treatment
Side Effects
No high blood potassium and renal failure.
DISCUSSION
It has been established that an important factor which leads to high mortality of heart failure is the damage and unbalance of the autonomic nervous function, such as increase of sympathetic nerves and decrease of vagus nerves. Consistent with previous findings [4], our results showed that the time domain and frequency domain were lower in heart failure patients than in healthy subjects. Elevated aldosterone levels in heart failure may have a detrimental effect on the autonomic nervous system. First, aldosterone infusion directly reduced baroreceptor discharge from the carotid sinus in dog [5]. Second, aldosterone blunts the human baroreflex response [6,7]. Third, aldosterone may potentiate the effects of catecholamine [8]. Fourth, aldosterone blocks myocardial uptake of norepinephrine (NA) in vivo in an animal model [9]. Therefore, administration of spironolactone, antagonist of aldosterone, in heart failure is provided with important clinic significance [10]. Our results showed that spironolactone improved not only heart rate itself but also HRV. These effects appear to be maximal between 6 am and 10 am. It is time when aldosterone secretion, activity of sympathetic nerves and morbidity of cardiovascular events are also maximal [4，11]. Mechanisms of spironolactone include following aspects [11~13], antagonizing over-activated renin-angiotensin-system (RAS), decreasing the heart burden by diuresis, decreasing incidence of arrhythmia and sudden death from low blood potassium and magnesium, inhibiting ventricle remodeling, alleviating fibrosis of myocardial and vascular which lead to arrhythmia, increasing synthesis of nitric oxide (NO) by melioration of vascular endothelial function, increasing activity of vagus nerves and circadian rhythms of HRV, decreasing the incidence of sudden death by increase of myocardial NA uptake.
In brief, the activity of SNS and RAAS is increased in heart failure, which the regulation of autonomic nerves and the reflex of baroreceptor were damaged by elevated aldosterone levels. Aldosterone antagonist - spironolactone can antagonize harmful effects of aldosterone, especially in preventing cardiovascular events in the morning. It could be one of the mechanisms of spironolactone in improving the prognosis of heart failure. The measurement of HRV was considered as a sensitive and specific parameter in evaluating severity, prognosis of heart failure and efficacy of drugs.
REFERENCES
1. Song YC, Wan LL, Hu TH, et al. The Analysis of Heart Rate Variability in Patients with Congestive Heart Failure. Chinese Journal of Cardiology, 1995, 23:107-110.
2. Adamopoulos S, Ponikowsky P, Cerquetani E, et al. Circadian pattern of heart rate variability in chronic heart failure patients: effects of physical training. Eur Heart J, 1995, 16:1380-6.
3. Liu J and Zhang Y. Intervention of Spironolactonein on Circadian Rhythms of Heart Rate Variability in Heart Failure Patients (review). Chinese Journal of Practical Internal Medicine, 2005，5：419-420.
4. Kok-Meng Yee, MRCP, Stuart D, Pringle, MD, et al. Circadian Variation in the Effects of Aldosterone Blockade on Heart Rate Variability and QT Dispersion in Congestive Heart Failure. JACC, 2001, 37(7):1800-1807.
5. Wang M, Macclaim JM, Zucker IH. Aldosterone reduces baroreceptor discharge in the dog. Hypertension, 1994, 19: 270-277.
6. Yee KM, Struthers AD. Aldosterone blunts the baroreflex response in man. Clin Sci, 1998, 95: 678-692.
7. Hoffman J, Grimm W, Menz V, et al. Heart rate variability and baroreflex sensitivity in idiopathic dilated cardiomyopathy. Heart, 2000, 83(5): 531-538.
8. Weber, MA, Purdy RE. Catecholamine mediated constrictor effects of aldosterone on vascular smooth muscle. Life Sci, 1982, 30:2009-17.
9. Barr CS, Lang CC, Hanson J, et al. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol, 1995, 76:1259-65.
10. Wei M and Liu KS. The Influence of spironolactone on Autonomic Nervous System in Congestive Heart Failure. Hebei Medicine,2004，26(5)：379-380.
11. Mac Fadyen RJ, Barr CS, Struthers AD. Aldosterone blocker reduces vascular collagen turnover, improves heart rate variability and reduce early morning rise in heart rate in heart failure patients. Cardiovasc Res, 1997, 35(1):30-34.
12. Li SY and Chen JH. The Application of different dose Aldoterone Antagonist in Refractory Heart Failure. Chinese Journal of Misdiagnostics, 2003, 3:892-93.
13. Cheng YZ. The Mechanism and Advance of Aldoterone Antagonist- Spironolactone in Chronic Heart Failure. Chinese Journal of Cardiology, 2003,31:69-71.
(Editor Anne)(ZHANG Yu1, LIU Jie2, WANG)
1 Department of Cardiology,The First Hospital of Jilin University, Changchun, Jilin Province 130021, China
2 The Third Hospital, Qingdao, Shandong Province 266041, China
Correspondence to ZHANG Yu, Department of Cardiology, the First Hospital of Jilin University，Changchun, Jilin Province 130021, China
Tel:+86-431-5612342,E-mail: yzhang@email.jlu.edu.cn
[Abstract] Objective The study was designed to observe heart rate variability (HRV) and its circadian rhythm in patients with heart failure in order to explore the mechanisms of aldosterone blockade in improving patients with heart failure. Methods HRV indices such as the time domain and frequency domain and its circadian rhythm were obtained from 48 -hour continuous electrocardiogram (ECG) recording in 24 heart failure patients and 10 healthy subjects. Results HRV indices were lower in heart failure patients than in healthy subjects, P<0.05. After four-week treatment, increase of HRV indices was more significant in spironolactone group than in routine group, especially HF and NN,P<0.05. In addition, this effect of spironolactone was maximal in the morning (6 am~10 am), including not only increase of HRV but also decrease of heart rate. Conclusions The effects of spironolactone on HRV and its circadian rhythm in patients with heart failure may be by inhibiting the release of aldosterone at 6 am~10 am. It could be one of mechanisms that spironolactone improved heart function.
[Key words] heart failure; heart rate variability; circadian rhythm; spironolactone
INTRODUCTION
Heart rate variability (HRV) is time variability between two successive cardiac cycles. It has been considered as a non-invasive method in evaluation of the cardiac autonomic nervous system. A number of clinical studies have demonstrated [1,2] that the functions of cardiac autonomic nerves were damaged, HRV indices were decreased and the circadian rhythms were disappeared in patients with heart failure. The malignant cardiac arrhythmia, acute myocardial infarction and sudden death were often occurred in the morning. It is because that the sympathetic nerves are most active in the morning [3]. There is evidence that aldosterone may have detrimental effects on the cardiac autonomic nervous system, especially during the morning hours [4]. Therefore, observation of HRV and its circadian rhythms in the morning is of great importance. In order to understand the mechanism of spironolactone in meliorating the prognosis of heart failure, we investigated the effect of spironolactone on HRV and circadian rhythms in patients with heart failure in this paper.
SUBJECTS AND METHODS
Subjects
Twenty-four patients with heart failure (New York Heart Association [NYHA] class III to IV) were recruited from our hospital between March 2004 and March 2005. The patients who predominant cardiac rhythm was not sinus or diabetes or hyperthyroidism or renal failure were excluded. Fifteen males and 9 females, aged 60±13 years old. Five patients were complicated with hypertension, 15 coronary heart diseases, 2 dilated cardiomyopathy, and 2 valvular heart diseases. All the patients had not taken angiotensin-converting enzyme inhibitors (ACEI), spironolactone, beta-blockers, digitoxin two weeks before admission. All 24 selected patients were randomly divided into two groups such as spironolactone treatment group (40 mg /day,n=12) and routine treatment group (n=12). Ten healthy subjects who were approved no heart disease by examination were selected as control. Six males, 4 females with mean age of 58 ± 7 years old.
Methods and Observatory Parameters
Forty-eight hour continuous electrocardiogram (ECG) recordings (supplied by Changchun Times Digital Co.Ltd) were obtained in all subjects using a standard twelve-channel recorder. HRV indices were analyzed with a Holter analysis system in the time domain and frequency domain. The time domain indices included R-R intervals, NN; standard deviation of all normal sinus R-R intervals over 24 hours, SDNN; standard deviation of the average normal sinus R-R intervals for all 5-minute segment, SDANN; root mean square of the successive normal sinus R-R interval difference, rMMSD; percentage of successive normal sinus R-R intervals longer than 50 ms, pNN50%. Frequency domain indices included low frequency, LF (0.04~0.15 Hz), reflecting the common influence of the sympathetic nerves and vagus nerves, while high frequency, HF (0.15~0.40 Hz), reflecting the activity of the vagus nerves. And the biochemical, blood and urine routine examination, blood pressure, heart rate, echocardiography, weight, and the side effects were measured or observed at the same time.
Statistical Analysis
All data was given as mean ± standard deviation. Results were compared by paired t-test.Differences were considered as significant at P<0.05.RESULTS
Compared Heart Failure with Normal Control Group
All the HRV indices of heart failure patients were lowered, indicating the fact that the cardiac autonomic nerves were damaged during heart failure(Table 1).
Table 1 Comparison of Heart Failure with Control in Heart Rate, Blood Potassium and HRV Indices (xx±s)
Note:*P<0.05, **P<0.01 vs. control
Effects of Spironolactone on HRV Indices
After systematic treatment, both the spironolactone treatment group and routine treatment group showed increase of HRV indices. The spironolactone treatment group was more apparent than the routine treatment group, not only HF and NN increase but also heart rate reduction,P<0.05. This fact demonstrated that spironolactone could play an important role in meliorating the activity of vagus nerves(Table 2).
Table 2 Comparison of Routine Group of HRV Indices with Spironolactone Group Pre- and Post- treatment (xx±s)
Note:*P<0.05, vs.pre-treatment, respectively
Effects of Spironolactone on HRV in Different Times
Spironolactone therapy caused a significant increase of HRV indices which were maximal from 6 am to 10 am in the morning. During these hours, standard deviation of the R-R intervals and HF component were significantly increased, indicating the improvement of spironolactone on autonomic nerves' circadian rhythms(Table 3).
Table 3 Comparison of HRV Change Value in Different Time after Treatment
Note:*P<0.05,**P<0.01, Spironolactone vs. routine therapy after treatment
Side Effects
No high blood potassium and renal failure.
DISCUSSION
It has been established that an important factor which leads to high mortality of heart failure is the damage and unbalance of the autonomic nervous function, such as increase of sympathetic nerves and decrease of vagus nerves. Consistent with previous findings [4], our results showed that the time domain and frequency domain were lower in heart failure patients than in healthy subjects. Elevated aldosterone levels in heart failure may have a detrimental effect on the autonomic nervous system. First, aldosterone infusion directly reduced baroreceptor discharge from the carotid sinus in dog [5]. Second, aldosterone blunts the human baroreflex response [6,7]. Third, aldosterone may potentiate the effects of catecholamine [8]. Fourth, aldosterone blocks myocardial uptake of norepinephrine (NA) in vivo in an animal model [9]. Therefore, administration of spironolactone, antagonist of aldosterone, in heart failure is provided with important clinic significance [10]. Our results showed that spironolactone improved not only heart rate itself but also HRV. These effects appear to be maximal between 6 am and 10 am. It is time when aldosterone secretion, activity of sympathetic nerves and morbidity of cardiovascular events are also maximal [4，11]. Mechanisms of spironolactone include following aspects [11~13], antagonizing over-activated renin-angiotensin-system (RAS), decreasing the heart burden by diuresis, decreasing incidence of arrhythmia and sudden death from low blood potassium and magnesium, inhibiting ventricle remodeling, alleviating fibrosis of myocardial and vascular which lead to arrhythmia, increasing synthesis of nitric oxide (NO) by melioration of vascular endothelial function, increasing activity of vagus nerves and circadian rhythms of HRV, decreasing the incidence of sudden death by increase of myocardial NA uptake.
In brief, the activity of SNS and RAAS is increased in heart failure, which the regulation of autonomic nerves and the reflex of baroreceptor were damaged by elevated aldosterone levels. Aldosterone antagonist - spironolactone can antagonize harmful effects of aldosterone, especially in preventing cardiovascular events in the morning. It could be one of the mechanisms of spironolactone in improving the prognosis of heart failure. The measurement of HRV was considered as a sensitive and specific parameter in evaluating severity, prognosis of heart failure and efficacy of drugs.
REFERENCES
1. Song YC, Wan LL, Hu TH, et al. The Analysis of Heart Rate Variability in Patients with Congestive Heart Failure. Chinese Journal of Cardiology, 1995, 23:107-110.
2. Adamopoulos S, Ponikowsky P, Cerquetani E, et al. Circadian pattern of heart rate variability in chronic heart failure patients: effects of physical training. Eur Heart J, 1995, 16:1380-6.
3. Liu J and Zhang Y. Intervention of Spironolactonein on Circadian Rhythms of Heart Rate Variability in Heart Failure Patients (review). Chinese Journal of Practical Internal Medicine, 2005，5：419-420.
4. Kok-Meng Yee, MRCP, Stuart D, Pringle, MD, et al. Circadian Variation in the Effects of Aldosterone Blockade on Heart Rate Variability and QT Dispersion in Congestive Heart Failure. JACC, 2001, 37(7):1800-1807.
5. Wang M, Macclaim JM, Zucker IH. Aldosterone reduces baroreceptor discharge in the dog. Hypertension, 1994, 19: 270-277.
6. Yee KM, Struthers AD. Aldosterone blunts the baroreflex response in man. Clin Sci, 1998, 95: 678-692.
7. Hoffman J, Grimm W, Menz V, et al. Heart rate variability and baroreflex sensitivity in idiopathic dilated cardiomyopathy. Heart, 2000, 83(5): 531-538.
8. Weber, MA, Purdy RE. Catecholamine mediated constrictor effects of aldosterone on vascular smooth muscle. Life Sci, 1982, 30:2009-17.
9. Barr CS, Lang CC, Hanson J, et al. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol, 1995, 76:1259-65.
10. Wei M and Liu KS. The Influence of spironolactone on Autonomic Nervous System in Congestive Heart Failure. Hebei Medicine,2004，26(5)：379-380.
11. Mac Fadyen RJ, Barr CS, Struthers AD. Aldosterone blocker reduces vascular collagen turnover, improves heart rate variability and reduce early morning rise in heart rate in heart failure patients. Cardiovasc Res, 1997, 35(1):30-34.
12. Li SY and Chen JH. The Application of different dose Aldoterone Antagonist in Refractory Heart Failure. Chinese Journal of Misdiagnostics, 2003, 3:892-93.
13. Cheng YZ. The Mechanism and Advance of Aldoterone Antagonist- Spironolactone in Chronic Heart Failure. Chinese Journal of Cardiology, 2003,31:69-71.
(Editor Anne)(ZHANG Yu1, LIU Jie2, WANG)