Heart rate variability after long-term treatment with atorvastatin in hypercholesterolaemic patients with or without coronary artery disease

Transcription

1 Atherosclerosis 157 (2001) Heart rate variability after long-term treatment with atorvastatin in hypercholesterolaemic patients with or without coronary artery disease Anthimos N. Pehlivanidis, Vasilios G. Athyros *, Dimokritos S. Demitriadis, Athanasios A Papageorgiou, Vasilios J. Bouloukos, Athanasios G. Kontopoulos Di ision of Cardiology, 2nd Propedeutic Department of Internal Medicine, Aristotelian Uni ersity, Hippocration Hospital, 49 Konstantinoupoleos Street, 54642, Thessaloniki, Greece Received 26 July 2000; received in revised form 14 November 2000; accepted 21 November 2000 Abstract Low heart rate variability (HRV) level, indicative of impaired autonomic function, is associated with an increased risk of cardiovascular morbidity and mortality and is negatively affected by hypercholesterolaemia. In order to test the hypothesis that significant low density lipoprotein (LDL) cholesterol reduction after treatment with a statin will have a beneficial effect on HRV level in hypercholesterolaemic patients with or without coronary artery disease (CAD), forty consecutive patients (28 men and 12 women) with a median age of 61, range (17 70) years were studied. Twenty had stable CAD and 20 were free of CAD at baseline. Twenty healthy volunteers, of similar age and gender as the patients, were used as controls. Patients were treated with atorvastatin (20 mg/day) for 2 years. Changes in lipid parameters and HRV indices were assessed at baseline and 2 years later in all subjects. In both patient subgroups a significant beneficial change in all lipid parameters (more pronounced in the CAD+ subgroup) and a significant beneficial modification in HRV time and frequency domain indices was recorded (more pronounced in the CAD subgroup), while lipid parameters and HRV indices remained unchanged in the control group. A correlation between LDL concentrations and most of the HRV indices was found at baseline in both patient subgroups, while no such correlation was found between values or their percent changes after hypolipidaemic treatment. These data suggest that treatment with atorvastatin improves autonomic function, as reflected by an increase in HRV level, and this may be a likely mechanism, at least in part, for the reduction in clinical events reported by the landmark survival studies with statins in primary and secondary CAD prevention. Perhaps, if this finding is confirmed by larger studies, HRV level may prove to be a useful tool for risk-stratification and treatment guide in high-risk patients with hypercholesterolaemia, regardless of CAD Elsevier Science Ireland Ltd. All rights reserved. Keywords: Atorvastatin; Hypercholesterolaemia; Heart rate variability 1. Introduction In clinical practice indices of heart rate variability (HRV) have been proved to be good predictors of arrhythmic events, sudden death, and acute ischaemic syndromes [1,2] suggesting that low HRV is associated * Corresponding author. Present address: 15 Marmara Street, Thessaloniki, , Greece; Tel.: /454237; fax: / address: athyros@med.auth.gr (V.G. Athyros). with increased risk of cardiovascular morbidity and mortality. Moreover, low HRV predicts progression of coronary artery disease (CAD), providing information beyond that obtained by traditional risk markers of atherosclerosis [3] and is associated with events even in patients with stable CAD and preserved left ventricular function [4]. Hypercholesterolaemia is associated with a decreased HRV in men with [5] or without CAD [5,6] and in patients with type 1 diabetes [7]. The data in the literature on the effect of serum cholesterol reduction /01/$ - see front matter 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S (00)

2 464 A.N. Pehli anidis et al. / Atherosclerosis 157 (2001) on HRV level is limited and controversial. Hypolipidaemic diet leads to a moderate decrease in serum lipids, but does not affect HRV indices [8]. In antithesis, the REGRESS Study Group reported a significant reduction in HRV level (mainly time domain indices), after long-term administration of pravastatin in patients with stable angina pectoris, in comparison to placebo [9]. To date no evaluation of statin treatment effect on HRV indices in hypercholesterolaemic CAD( ) patients has been published. The present study was based on the hypothesis that since increased total and low density lipoprotein (LDL) cholesterol concentrations are inversely related to HRV level [5,6], a substantial reduction of these lipids with a statin might lead to a beneficial increase in HRV level. 2. Study population methods 2.1. Patients Forty consecutive patients (28 men and 12 women) with a median age of 61 (range 17 70) years were studied. Twenty patients with stable CAD and 20 without CAD were recruited. The inclusion criteria were hypercholesterolaemia (LDL 200 mg/dl), positive exercise tolerance test (ETT) for the CAD( +) patients, negative ETT for the CAD( ) ones, and age 70 years. The exclusion criteria were diabetes mellitus, presence of other systemic disease(s), atrial fibrillation, and bundle branch block. All patients were treated with atorvastatin (20 mg/day) for a period of 2 years. Twenty healthy volunteers were used as controls. These were recruited from our general practice out-patient clinic, among persons coming forward for a check-up or a health certificate. For each patient enrolled a control subject of similar age and of the same gender as the patient was included in the study over the same time period. Informed consent approved by the Ethical Committee of the Aristotelian University was obtained from all patients before enrollment Protocol Patients and controls had an ETT and a 24-h electrocardiogram (ECG) recording at baseline. Lipid parameters were assessed before enrollment. Diagnosis of CAD was based on coronary angiography in CAD(+) patients, while CAD absence was based on history, physical examination, ECG, and exercise tolerance test (ETT) in CAD( ) patients. Patients were assigned to atorvastatin (20 mg/day) after baseline examinations. Most patients were receiving a statin for the first time. Those on statin prior to enrolment (n=6) had a washout period of 6 weeks. The dosage of drugs that the CAD( +) patients were receiving at baseline remained unchanged throughout the study. Two years later, and while patients were still on the same medical management, a second 24-h ECG monitoring was carried out and a new ETT was performed. Controls underwent the same tests at baseline and 2 years later, during the same time period as the hypercholesterolaemic patients Lipid profile Assessment of lipid parameters were performed at months 1, 3, 6, 12, 18, and 24 for patients and 1 and 24 for controls, using standard methods ETT This was performed according to the Bruce protocol using the Marquette, Case 16, (Marquette Electronics, Milwaukee, WI) treadmill HRV analyses These were performed blindly by one of the investigators (VGA) at baseline and 2 years after treatment with 20 mg/day of atorvastatin. The Cardiolight system (Medset, Hamburg, Germany) was used. This consists of a solid state digital ECG recorder and an IBM compatible computer using the Medset software (version 8.2p). Time accuracy of the recording and the ability for detection of abnormal QRS beats have been validated previously [10 12]. Parameters of heart rate variability can be defined in the time and frequency domains. The following time domain indexes were used: (1) the S.D. of coupling intervals (SDNN), (2) the S.D. of the mean R R intervals during all 5-min periods that constitute the 24-h day (SDANN), (3) percent of R R intervals differing more than 50 ms from each other (pnn50), and (4) the root mean square of successive differences (RMSSD). In the frequency domain, we analysed: (5) total spectral power, defined as the spectral power between 0.01 and 1.00 Hz, (6) low-frequency power, the power between 0.04 to 0.15 Hz, and (7) high-frequency power, that is, power between 0.15 and 0.40 Hz. Normalisation of spectral powers was obtained through dividing by total power Statistical analysis All parameters were expressed as mean value 1 S.E. The paired 2-tailed Student s t-test (CI 95%) was used to compare baseline and 2 years values within the same group. The unpaired 2-tailed Student s t-test (CI 95%) was used to compare values between groups at baseline and 2 years later. Percent change of values at 2 years, in comparison to baseline, was calculated. Pearson s cor-

3 A.N. Pehli anidis et al. / Atherosclerosis 157 (2001) relation co-efficient was used to assess correlations between lipid parameters and HRV indices at baseline and after treatment as well as their percent changes. In addition, stepwise logistic analysis was used to test the hypothesis that changes in HRV indices were independent of age, gender, baseline heart rate and blood pressure. Two-tailed P-values 0.05 were considered statistically significant. For all forms of statistical analysis the SPSS, ver. 8.0, programme was used. 3. Results 3.1. Concomitant treatment No other hypolipidaemic drug, besides atorvastatin, was administered during the 2-year follow-up. Most of CAD( +) patients were receiving concomitant treatment: 16 were on aspirin, 15 on a blocker, and six on an ACE inhibitor. The regimen for each patient was established at least 6 months prior to enrollment and was maintained throughout the 2-year follow-up without any change in drug dosage Baseline data At baseline, lipid parameters of both patient subgroups (CAD( ) and CAD( +)) were significantly different from those of controls (P 0.01), but had no differences between them (Table 1). HRV level was significantly lower than that of controls (P 0.001), but no differences between the two treatment subgroups were recorded (Table 2). A correlation between LDL cholesterol and HRV indices was detected at baseline (Table 3) The mean duration of ETT of hyperlipidaemic patients was s Effect of therapy Lipid parameters These were beneficially modified in both treatment subgroups (Table 1). Mean percent change in lipid parameters in the CAD( +) subgroup modifications was more profound than in the CAD( ) subgroup (Fig. 1a) ETT The mean duration of the ETT was significantly prolonged in both subgroups. Pooled data showed an increase of ETT duration of 75.8 s, ( vs ), P Three CAD(+) patients had a negative ETT after 2 years of treatment with atorvastatin HRV All time and frequency domain indices of HRV were significantly improved after treatment (Table 2). Percent change in most HRV indices of the CAD( ) subgroup was more profound as shown in Fig. 1b. No correlation was found between LDL cholesterol levels and HRV indices values or their percent changes, after 2 years of treatment (Table 3) Heart rate and blood pressure There were no significant changes in heart rate and blood pressure (systolic and diastolic) in all patients and control subjects. During the study period, there were no complications related to CAD or side-effects related to therapy. None of the patients required cardiac catheterization or interventional therapy during the 2 year period. Table 1 Lipid parameters at baseline and after 24 months of treatment with 20 mg/day of atorvastatin in hypercholesterolaemic patients with or without CAD and normal volunteers a CAD(+) CAD( ) Controls CAD(+) treatment CAD( ) treatment baseline baseline baseline Controls 2 years after Total cholesterol * * **, *** *** Triglycerides * * *, ** ** HDL * * *, ** *** cholesterol LDL * * *, **, *** ** cholesterol LDL/HDL * * **, *** ** ratio a Values are expressed in means 1 S.E. LDL, low density lipoprotein; HDL, high density lipoprotein. * P 0.05 vs. controls; **P 0.05 vs. baseline; ***P 0.05 vs. CAD( ).

4 466 A.N. Pehli anidis et al. / Atherosclerosis 157 (2001) Table 2 Heart rate variability indices at baseline and after 24 months of treatment with 20 mg/day of atorvastatin in hypercholesterolaemic patients with or without CAD a CAD(+) baseline CAD( ) baseline Controls baseline CAD(+) treatment CAD( ) treatment Controls 2 years after SDNN * * *,** ** SDANN * * *,** ** pnn * * ** *,** RMSSD * * *,** *,** Total power * * *,** ** HFP nu * * ** ** LFP nu * * ** ** LFP/HFP ratio * * *, **, *** ** a Values are expressed in means 1 S.E. SDNN, S.D. of R R intervals; SDANN, S.D. of mean R R intervals during all 5-min periods that constitute the 24-h day; pnn50, percent of R R intervals differing more than 50 ms from each other; RMSSD, root mean square of successive differences of R R intervals; HFP, high frequency power; LFP, low frequency power; nu, normalised units. * P 0.05 vs. controls; **P 0.05 vs. baseline; ***P 0.05 vs. CAD( ). 4. Discussion The results of the present study demonstrated for the first time that therapy with a statin increased HRV level in patients with hypercholesterolaemia, with or without CAD. These changes in HRV indices may predict a beneficial effect of atorvastatin on autonomic function. The latter might contribute to a decline in cardiovascular morbidity and mortality in such patients and might be a possible mechanism, at least in part, for the reduction in clinical events reported by the landmark survival studies with statins in primary or secondary CAD prevention. Concomitant treatment of the patients was established at least 6 months prior to the entry in the study and was maintained throughout the treatment period. Thus, changes in HRV level could not be attributed to concomitant treatment. The effect of atorvastatin on lipid profile is consistent with that reported by numerous previous studies. In CAD( +) patients, the beneficial change of lipid profile was more pronounced than that in CAD( ) patients. This might be due to better compliance of these patients to life-style changes, hypolipidaemic diet and drug treatment. The study showed a beneficial effect of atorvastatin on ETT. An increase in duration of the test was recorded both in patients with and without CAD. Three of the CAD patients with positive ETT at baseline, had a negative ETT after 24 months. These findings were attributed to improvement of either physical condition or myocardial perfusion by atorvastatin treatment. This is consistent with the findings of a previous study with lovastatin or simvastatin versus hypolipidaemic diet, in hypercholesterolaemic patients with positive ETT and normal coronary arteries [13]. In that study, patients returned to previous status in terms of ETT after 20 weeks of drug discontinuation, suggesting that statins reduce myocardial ischaemia related to coronary microcirculation, as shown by the beneficial effects on ETT, in a reversible manner. Previous studies have shown that the enhancement of parasympathetic tone may decrease the incidence of malignant ventricular arrhythmias and sudden cardiac death [14], although decreased HRV was mostly associated with coronary events such as myocardial infarction and progressive angina requiring revascularisation. In the experimental pacing induced heart failure, vagally mediated coronary vasodilation is selectively attenuated, reflecting an impaired coronary endothelial function [15]. Another study demonstrated a strong relation between autonomic function and myocardial ischaemia [16]. Considering the autonomic regulation of coronary flow, a report using positron emission tomography demonstrated a correlation between time domain HRV and myocardial perfusion [17]. These data suggest that a low HRV, indicative of deficient autonomic function, may be related to coronary endothelial dysfunction and/or vasomotor disorders. Thus, impaired HRV level could be the result of a deficient coronary perfusion and its improvement may come through the increase of coronary flow, which in turn may be further improved by better autonomic regulation. The improvement of HRV level, seen in this study, could be attributed to either the hypolipidaemic action or the pleiotropic effects of atorvastatin. Significant reduction of LDL cholesterol, seen in the present study, is a possible mechanism of action. Endothelial dysfunction in humans is associated with cholesterol levels in hyperlipidaemic patients [18] or even in subjects in the high normal range [19]. In a

5 A.N. Pehli anidis et al. / Atherosclerosis 157 (2001) Cholesterol and Recurrent Events (CARE) subgroup study [20] the magnitude of the endothelium-dependent vasodilation was significantly correlated with the percent change in LDL cholesterol after pravastatin administration from baseline to final visit. This study concluded that improvement in endothelium-dependent vasoreactivity by pravastatin may be a likely mechanism, at least in part, for the reduction in clinical events reported by the CARE study. The fact that the reduction in LDL cholesterol levels was not analogous to that of most HRV indices, may indicate that the pleiotropic effects of atorvastatin might have additionally contributed to the improvement in HRV level. There are data providing support for the idea that statins enhance endothelial function independent of their lipid-lowering effects in patients with [21] or without CAD [22]. These studies showed that patients, regardless of CAD, who were on statin therapy have better vascular endothelial function [23] or less CAD related clinical events [22] than patients without this medication, although there were no differences in serum lipid profile between the study groups. This finding supports the idea that some of the beneficial effects of statins, in primary and secondary prevention of CAD, may be mediated via some other mechanism(s) than cholesterol lowering alone. Moreover, it has been shown in bovine aortic cells [23] that atorvastatin and simvastatin inhibited pre-proendothelin-1 mrna. In another study [24], atorvastatin, pravastatin, and cerivastatin, inhibited phorbol esterstimulated superoxide anion formation in endotheliumintact segments of the rat aorta, resulting in a shift in the balance between NO and O(2)( ) in the endothelium that improves endothelial function even in healthy blood vessels. Also, atorvastatin is shown to upregulate endothelial NO synthase (enos) and inhibit inducible NO synthase (inos), significantly elevating the intraplatelet NO levels in hyperlipidaemic patients without affecting inos expression [25]. The data suggest that treatment with atorvastatin in patients with or without CAD has a beneficial effect on autonomic function, as reflected by improvement in HRV indices. The above mentioned effects of statins, hypolipidaemic or pleotropic, may be a possible explanation for HRV improvement mainly through endothelial-depended blood flow in coronary vasculature. Our findings are in antithesis to those reported for pravastatin in patients with stable angina pectoris by the REGRESS Study Group. This might be attributed to significant differences in: baseline LDL-C levels, extend of LDL-C reduction, specific properties of the two statins, characteristics of study populations, and technology employed to assess HRV indices Study limitations The study was not randomised, because it included only one treatment group and it could not be placebocontrolled, because of ethical issues Clinical implications HRV is easily derived from a 24-h ECG recording, together with information regarding transient ischaemia and arrhythmias. Considering that, we believe that in the absence of markers to predict a clinical event in dyslipidaemic patients without CAD and those with CAD but preserved left ventricular function, the assessment of HRV may become increasingly important in clinical practice. Our findings on the effect of a statin on HRV must be confirmed by larger studies. If this is the case, HRV may additionally be used to risk-stratify dyslipidaemic patients with or without CAD. It may Table 3 Correlations between LDL cholesterol and heart rate variability indices at baseline and after 24 months of treatment with 20 mg/day of atorvastatin in hypercholesterolaemic patients with or without CAD a LDL cholesterol baseline (n=40) P-value LDL-cholesterol treatment (n=40) P-value SDNN NS SDANN NS pnn NS RMSSD NS Total power NS HFP nu NS LFP nu NS LFP/HFP ratio NS a Pooled data n=40. SDNN, S.D. of R R intervals; SDANN, S.D. of mean R R intervals during all 5-min periods that constitute the 24-h day; pnn50, percent of R R intervals differing more than 50 ms from each other; RMSSD, root mean square of successive differences of R R intervals; HFP, high frequency power; LFP, low frequency power; nu, normalised units.

6 468 A.N. Pehli anidis et al. / Atherosclerosis 157 (2001) Fig. 1. (a) Mean percent change (vs. baseline) in lipid parameters, after 24 months of treatment with 20 mg of atorvastatin, in hypercholesterolaemic patients with or without CAD, and mean percent change in lipid parameters in normal volunteers at the same time period. LDL, low density lipoprotein; HDL, high density lipoprotein. (b) Percent change (vs. baseline) in heart rate variability time and frequency domain indices, after 24 months of treatment with 20 mg of atorvastatin, in hypercholesterolaemic patients with or without CAD, and percent change in the same parameters in normal volunteers over the same time period. SDNN, S.D. of coupling intervals; SDANN, S.D. of mean R R intervals during all 5-min periods that constitute the 24-h day; pnn50, percent of R R intervals differing more than 50 ms from each other; RMSSD, root mean square of successive differences of R R intervals; HFP, high frequency power; LFP, low frequency power; nu, normalised units. provide additional evidence for the efficacy of hypolipidaemic treatment and contribute to the achievement of specific treatment goals for each patient, with proper drug selection and dose titration in high risk patients. Acknowledgements No company or institution other than the Hippocration Hospital has financed this study.

7 A.N. Pehli anidis et al. / Atherosclerosis 157 (2001) References [1] Cripps TR, Malik M, Farell T, Camm AJ. Prognostic value of reduction of heart rate variability after acute myocardial infarction: clinical evaluation of a new analysis method. Br Heart J 1991;65:14 9. [2] Quintana M, Storck N, Lindblad LE, Lindvall K, Ericson M. Heart rate variability as a means of assessing prognosis after acute myocardial infarction. Eur Heart J 1997;18: [3] Huikuri HV, Jokinen V, Syvanne M, et al. Heart rate variability and progression of coronary atherosclerosis. Arterioscler Thromb Vasc Biol 1999;19: [4] van Boven AJ, Jukema JW, Haaksma J, Zwinderman AH, Crijns HJ, Lie KI. Depressed heart rate variability is associated with events in patients with stable coronary artery disease and preserved left ventricular function. REGRESS Study Group. Am Heart J 1998;135: [5] Christensen JH, Toft E, Christensen MS, Schmidt EB. Heart rate variability and plasma lipids in men with and without ischaemic heart disease. Atherosclerosis 1999;45: [6] Kupari M, Virolainen J, Koskinen P, Tikkanen MJ. Short-term heart rate variability and factors modifying the risk of coronary artery disease in a population sample. Am J Cardiol 1993;72: [7] Burger AJ, Hamer AW, Weinrauch LA, D Elia JA. Relation of heart rate variability and serum lipoproteins in type 1 diabetes mellitus and chronic stable angina pectoris. Am J Cardiol 1998;81: [8] Danev S, Nikolova R, Kerekovska M, Svetoslavov S. Relationship between heart rate variability and hypercholesterolaemia. Cent Eur J Public Health 1997;5: [9] The REGRESS Study Group, van Boven AJ. Pravastatin but not placebo reduces heart rate variability after 2 years in patients with stable angina pectoris. Circulation 1995;92(Suppl. 1):I145. [10] Kontopoulos A, Athyros V, Papageorgiou A, Papadopoulos G, Avramidis M, Boudoulas H. Effect of quinapril or metoprolol on heart rate variability in post-myocardial infarction patients. Am J Cardiol 1996;77: [11] Kontopoulos A, Athyros V, Papageorgiou A, Skeberis V, Basagiannis E, Boudoulas H. Effect of angiotensin converting enzyme inhibitors on power spectrum of heart rate variability in post-myocardial infarction patients. Coron Artery Dis 1997;8: [12] Kontopoulos A, Athyros V, Papageorgiou A, Boudoulas H. Effect of quinapril or metoprolol on circadian sympathetic and parasympathetic modulation after acute myocardial infarction. Am J Cardiol 1999;84: [13] Mansur AP, Serrano CV Jr, Nicolau JC, Cesar LA, Ramires JA. Effect of cholesterol lowering treatment on positive exercise tests in patients with hypercholesterolaemia and normal coronary angiograms. Heart 1999;82: [14] Rich MW, Saini JS, Kleiger RE, Carney RM, ten Velde A, Freedland KE. Correlation of heart rate variability with clinical and angiographic variables and late mortality after coronary angiography. Am J Cardiol 1988;62: [15] Zhao G, Shen W, Xiaobin X, Ochoa M, Bernstein R, Hintze TH. Selective impairment of vagally mediated, nitric oxide-dependent coronary vasodilation in conscious dogs after pacing induced heart failure. Circulation 1995;91: [16] van Boven AJ, Brouwer J, Crijns HJGM, Haaksma J, Lie KI. Differential autonomic mechanisms underlying early morning and daytime transient myocardial ischemia in patients with stable coronary artery disease. Br Heart J 1995;73: [17] Meeder JG, Blanksma PK, Crijns HJ, et al. Mechanisms of angina pectoris in syndrome X assessed by myocardial perfusion dynamics and heart rate variability. Eur Heart J 1995;16: [18] Chowienczyk PJ, Watts GF, Cockcroft JR, Ritter JM. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolemia. Lancet 1992;340: [19] Steinberg HO, Bayazeed B, Hook G, Johnson A, Cronin J, Baron AD. Endothelial dysfunction is associated with cholesterol levels in the high normal range in humans. Circulation 1997;96: [20] Cohen JD, Drury JH, Ostdiek J, et al. Benefits of lipid lowering on vascular reactivity in patients with coronary artery disease and average cholesterol levels: a mechanism for reducing clinical events? Am Heart J 2000;139: [21] Jarvisalo MJ, Toikka JO, Vasankari T, et al. HMG CoA reductase inhibitors are related to improved systemic endothelial function in coronary artery disease. Atherosclerosis 1999;147: [22] Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. New Engl J Med 1995;333: [23] Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998;101: [24] Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M. Improvement of nitric oxide-dependent vasodilatation by HMG- CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 2000;20:61 9. [25] Tannous M, Cheung R, Vignini A, Mutus B. Atorvastatin increases ecnos levels in human platelets of hyperlipidemic subjects. Thromb Haemost 1999;82: