Heart Rate Variability in Patients With Stable Coronary Artery Disease and Aspirin Resistance Tahir DURMAZ,1 MD, Telat KELES,1 MD, Ozcan OZDEMIR,2 MD, Nihal Akar BAYRAM,1 MD, Murat AKCAY,1 MD, Ekrem YETER,1 MD, and Engin BOZKURT,1 MD SUMMARY Aspirin resistance as defined by failure to effectively inhibit thromboxane synthesis is associated with a higher risk of recurrent myocardial ischemia and cardiovascular death. Heart rate variability (HRV) analysis has been extensively used to identify patients at risk for increased cardiac mortality. The aim of this study was to evaluate the association between HRV and aspirin resistance in patients with stable coronary artery disease (CAD). Sixty-nine (69) consecutive patients with stable CAD were included in this study. Of the 69 patients, 18 (26%) were aspirin nonresponders. When the aspirin responders were compared with the nonresponders, there was no significant difference between the groups with respect to most clinical parameters, major cardiovascular risk factors, medical treatments, and aspirin dosages. However, the patients with aspirin resistance had a higher previous myocardial infarction history and lower left ventricular ejection fraction. Moreover, mean platelet volume, CT/EPI, CT/ADP values, LF and LF/HF ratio were higher while HF, SDNN, SDANN, and RMSSD were lower in the nonresponder group than the responders. Regarding HRV parameters, CT/ADP time was negatively correlated with SDNN (r = -0.5, P = 0.02) and HF (r = -0.4, P = 0.03), and positively correlated with LF (r = 0.6, P = 0.01) and LF/HF (r = 0.7, P = 0.001). Similarly, CT/EPI time was negatively correlated with SDNN (r = -0.4, P = 0.03), and positively correlated with LF (r = 0.5, P = 0.02) and the LF/HF ratio (r = 0.5, P = 0.02). Regression analysis revealed that the only parameters affecting SDNN and LF/HF ratio were left ventricle ejection fraction and aspirin resistance. The heart rate variability decreased and sympathetic activity increased in the patients with aspirin resistance and stable CAD. This may contribute to a higher risk of recurrent myocardial ischemia and cardiovascular death in patients with aspirin resistance. (Int Heart J 2008; 49: 413-422) Key words: Heart rate variability, Aspirin resistance, Coronary artery disease

ASPIRIN is the cornerstone of antiplatelet therapy in cardiovascular medicine From the 1 Ataturk Education and Research Hospital, and 2 Private Akay Hospital, Cardiology Clinics, Ankara, Turkey. Address for correspondence: Ozcan Ozdemir, MD, Private Akay Hospital, Cardiology Clinics, Ilkyerlesim Mah. Sayginlar Sitesi C3/4, Batikent 06370, Ankara, Turkey. Received for publication January 7, 2008. Revised and accepted June 2, 2008. 413

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today. Despite the demonstrated benefits of aspirin in coronary heart disease, a large segment of the population does not benefit from aspirin.1) Aspirin resistance as defined by failure to effectively inhibit thromboxane synthesis is associated with a higher risk of recurrent myocardial ischemia and cardiovascular death.2) Assessment of heart rate variability (HRV) may provide quantitative information about the modulation of cardiac sympathetic and parasympathetic nerve activities.3) Impaired autonomic nervous activity has been recognized as a considerable symptom of cardiac dysfunction and is strongly associated with an increased risk of overall mortality in patients with heart disease.4,5) Some HRV parameters such as decreased SDNN and increased LF/HF ratio are associated with an increased cardiac mortality in almost all clinical conditions characterized by an autonomic imbalance and therefore heart rate variability (HRV) analysis has been extensively used to evaluate autonomic modulation of sinus node and to identify patients at risk for increased cardiac mortality.6-8) Although it is well-known that either HRV or aspirin resistance is associated with cardiovascular events, the association between HRV and aspirin resistance has not been elucidated. The aim of the present study was to evaluate the heart rate variability in patients with aspirin resistance and stable coronary artery disease (CAD). The decreased heart rate variability in these patients may explain the increased cardiac mortality. METHODS Study population: Sixty-nine (69) consecutive patients diagnosed with stable

coronary heart disease in our clinics were enrolled. Patients with acute or chronic inflammatory disease, myeloproliferative disorders, malignancies, renal, hepatic or thyroid disease, acute coronary syndromes within 3 months, a hematocrit < 0.30 or > 0.52 and a platelet count < 100 G/L, or those treated with immunosuppressive or cytotoxic drugs were excluded. Written consent was obtained from all patients and our Institutional Review Board (IRB) approved the study. Heart rate variability analysis: All subjects underwent 3 channel 24-hour Holter ambulatory ECG monitoring (Biomedical System Century 2000/3000 Holter System, Version 1.32). Recordings were analyzed using a Biomedical Systems Century 2000/3000 HRV Package System, following manual adjustment of RR intervals. Analog data were digitized at 200 Hz and edited by a cardiologist. The validation procedure consisted of beat labeling and tagging of noisy regions. A continuous series of RR (NN) intervals (tachogram) was obtained and all 5minute segments with at most 5 isolated ectopic beats were retained for spectral analysis. Recordings with < 18 hours of data or < 85% of qualified sinus beats were excluded. The time and frequency-domain analysis of HRV were performed

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according to the recommendation of the task force.3) The mean heart rate, standard deviation of all NN intervals (SDNN), the standard deviation of the 5minute mean RR intervals (SDANN), and root mean square of successive differences (RMSSD) were measured in the time domain analysis of HRV. A reduced SDNN has been considered to reflect diminished vagal and increased sympathetic modulation of the sinus node. The power spectrum of HRV was measured using fast-Fourier transform analysis in 4 frequency bands: < 0.0033 Hz (ultra low frequency, ULF), 0.0033 to 0.04 (very low frequency, VLF), 0.04 to 0.15 (low frequency, LF) and 0.15 to 0.40 (high frequency, HF). HF was used as a marker of the parasympathetic nervous system and LF was used as a marker of the parasympathetic nervous system and sympathetic activity.3) We also measured the ratio of low to high frequency power (LF/HF) reflecting the sympathovagal balance. High values indicate dominant sympathetic activity.9) For frequency domain parameters 3 circadian periods were considered, the complete 24 hours, and the diurnal and nocturnal periods defined on the basis of patient diaries. Diurnal periods covered lengths of at least 6 hours to a maximum of 10 hours; nocturnal periods covered a minimum of 4 hours to a maximum of 6 hours. Blood sampling and laboratory determinations: Blood samples were drawn from each subject in the morning between 8 and 10 AM (2-4 hours after aspirin intake) in the fasting state. They were withdrawn by antecubital venipuncture and the first several mL of blood were discarded to avoid spontaneous platelet activation. Citrated blood (0.129 M trisodium citrate in dilution 1:10) was used for analysis by PFA-100® (Platelet Function Analyzer, Dade Behring, Germany) and 4.5 mL of blood was collected in ethylene diamine tetra acetic acid (EDTA) tubes for platelet counts and hematocrit. Mean platelet volume was measured using a Coulter S+ resistive particle counting system. All analyses were performed within a range of 1-2 hours after blood collection. Total cholesterol, HDL cholesterol and triglyceride levels were measured enzymatically by an autoanalyzer (Hitachi 911, Japan). LDL cholesterol levels were determined using the Friedewald formula. Leukocyte and platelet counts were performed using a BCD autoanalyzer (Dade Behring, Germany). PFA-100® system: The PFA-100® system is a novel, rapid, simple, and reproducible platelet function test that allows for simple quantitative assessment of in vitro platelet aggregation and for identification of aspirin nonresponder status in a clinical setting.10,11) The PFA-100® test represents a highly sensitive and specific in vitro system for the assessment of platelet aggregation in small samples of citrated whole blood.12) It consists of a microprocessor-controlled instrument and a disposable test cartridge containing a biologically active membrane with either collagen and epinephrine or with collagen and ADP. The instrument aspirates citrated whole blood under constant vacuum conditions at a high shear stress of

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5000-6000 s-1 through a capillary tube and a precisely defined aperture in the membrane mimicking the microcapillary system of human circulation. The time required to obtain full occlusion of the aperture is reported as the closure time (CT). Normal closure times range between 85-165 seconds for collagen/epinephrine (CT/EPI) membrane coating and 71-118 seconds for collagen/ADP (CT/ ADP) coating using central 90% intervals (5th to 95th percentile) in our laboratory. If the CT/EPI was > 300 seconds, the result was reported as 300 seconds. Aspirin

Table I. Characteristics of the Aspirin Responder and Nonresponder Groups

Age (years) Male/female BMI (kg/m2) Hypertension Diabetes mellitus Smoking Hyperlipidemia History of myocardial infarction Ejection fraction (%) Aspirin dose (mg/day) Beta-blockers ACE inhibitors Statins Nitrates Platelets Mean platelet volume (dL) Fibrinogen (mg/dL) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) CT/EPI CT/ADP Ventricular premature contractions/day SDNN SDANN RMSSD LF day LF night LF 24 hours HF day HF night HF 24 hours LF/HF day LF/HF night

Nonresponders (n = 18)

Responders (n = 51)

P

65.1 ± 8.8 14/4 25.8 ± 6.4 10 (56%) 7 (39%) 6 (33%) 12 (67%) 7 (39%) 48.3 ± 18.1 225.5 ± 93.4 13 (72%) 10 (56%) 6 (46%) 6 (33%) 238.6 ± 59.6 11.1 ± 0.810 3.9 ± 1.4 240.2 ± 48.3 149.9 ± 62.6 37.4 ± 9.2 170.8 ± 70.2 124.9 ± 26.3 78.5 ± 10.7 346 ± 124 54.2 ± 31.7 47.3 ± 20.2 35.9 ± 18.1 1420 ± 506 1087 ± 416 1263 ± 467 283 ± 102 329 ± 113 298 ± 98 6.4 ± 2.6 3.6 ± 1.5

63.7 ± 9.3 40/11 24.9 ± 5.9 24 (47%) 18 (36%) 16 (32%) 31 (69%) 9 (18%) 52.4 ± 14.7 220.7 ± 104.8 36 (71%) 27 (53%) 25 (49%) 16 (31%) 242.4 ± 82.5 10.4 ± 1.2 3.8 ± 2.1 231.8 ± 54.1 151.9 ± 41.3 36.5 ± 7.1 177.9 ± 100.3 276.3 ± 40.9 113.1 ± 56.9 136 ± 45 108.2 ± 61.7 106.6 ± 42.2 44.7 ± 26.8 805 ± 431 683 ± 227 728 ± 325 428 ± 304 526 ± 238 458 ± 154 2.9 ± 1.8 1.6 ± 1.8

0.1 0.5 0.5 0.5 0.5 0.7 0.7 0.02 0.03 0.4 0.4 0.3 0.5 0.7 0.4 0.03 0.8 0.4 0.5 0.5 0.4 0.001 0.001 0.001 0.001 0.001 0.002 0.001 0.001 0.001 0.001 0.003 0.004 0.001 0.001

CT/EPI indicates clasure time for collagen/epinephrine; CT/ADP, closure time for collagen/ ADP; SDNN, standard deviation of all NN intervals; SDANN, standard deviation of the 5-minute mean RR intervals; RMSSD, root mean square of successive differences; LF, Low frequency; and HF, high frequency.

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resistance is defined as CT/EPI < 186 seconds. For all patients, PFA-100 system measurements were performed in duplicate. The mean percent error for each patient was < 2%. RESULTS Sixty-nine (69) consecutive patients (54 males, 15 females, age range, 41 to 77 years) were included in this study. Of the 69 patients, 18 (26%) were aspirin Table II. Correlation Between CT/ADP, CT/EPI and Some Clinical, Laboratory, and Heart Rate Variability Parameters CT/ADP Age Hematocrit Fibrinogen Platelet count Mean platelet volume BMI Total cholesterol LDL cholesterol HDL cholesterol Triglycerides SDNN LF HF LF/HF

r = -0.4 r = -0.1 r = 0.1 r = -0.09 r = 0.02 r = -0.3 r = 0.2 r = 0.2 r = 0.1 r = 0.2 r = -0.5 r = 0.6 r = -0.4 r = 0.7

P = 0.03 P = 0.06 P = 0.5 P = 0.6 P = 0.9 P = 0.2 P = 0.6 P = 0.4 P = 0.4 P = 0.5 P = 0.02 P = 0.01 P = 0.03 P = 0.001

CT/EPI r = -0.04 r = -0.2 r = -0.08 r = -0.2 r = -0.5 r = -0.2 r = 0.3 r = 0.1 r = 0.3 r = 0.3 r = -0.4 r = 0.5 r = -0.2 r = 0.5

P = 0.8 P = 0.04 P = 0.6 P = 0.2 P = 0.02 P = 0.3 P = 0.5 P = 0.7 P = 0.5 P = 0.4 P = 0.03 P = 0.02 P = 0.4 P = 0.02

SDNN indicates standard deviation of all NN intervals; LF, Lowfrequency; and HF, high frequency. Table III. Factors Affecting Heart Rate Variability (SDNN) in Multivariate Analysis

Age Gender Smoking DM HT HL Previous MI β-Blocker Use ACE-I use Aspirin dose (mg/day) LVEF ASA resistance

SE

β

t

P

0.2 4.1 4.5 4.3 3.9 4.1 3.9 0.07 0.05 0.1 13.3 4.3

-0.04 0.2 -0.1 -0.04 -0.06 -0.3 0.2 -0.02 -0.04 0.07 -0.5 -0.3

-0.5 0.4 -0.9 -0.4 -0.8 -0.4 0.3 -0.3 -0.6 1.03 -2.7 -2.8

0.6 0.7 0.4 0.7 0.6 0.7 0.8 0.7 0.6 0.3 0.01 0.008

LVEF indicates left ventricular ejection fraction; ASA, Aspirin (acetylsalicylic acid); DM, diabetes mellitus; HT, hypertension; and HL, hyperlipidemia.

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Table IV. Independent Variables Affecting the LF/HF Ratio

Age Gender Smoking DM HT HL Previous angina β-Blocker treatment ACE-I treatment Aspirin dose (mg/day) LVEF ASA resistance

SE

β

t

P

0.007 0.1 0.1 0.1 0.1 0.1 0.1 0.02 0.2 0.1 0.01 0.11

-0.1 -0.1 0.04 0.04 0.01 0.08 -0.8 0.2 -0.2 -0.1 -0.4 -0.7

-1.7 0.6 0.4 0.5 0.1 1.1 -1.1 2.2 -1.7 -1.1 -2.9 -8.8

0.07 0.5 0.7 0.06 0.8 0.3 0.3 0.3 0.09 0.3 0.005 0.001

DM indicates diabetes mellitus; HT, hypertension; and HL, hyperlipidemia.

nonresponders. When we compared the aspirin responders and nonresponders, there was no significant difference between the 2 groups with respect to most of the clinical parameters, major cardiovascular risk factors, medical treatments, and aspirin dosages. However, the patients with aspirin resistance had a higher incidence of a previous myocardial infarction and a lower left ventricular ejection fraction compared to those without aspirin resistance. Moreover, mean platelet volume, CT/EPI, CT/ADP values, LF and the LF/HF ratio were higher and HF, SDNN, SDANN, and RMSSD were lower in the nonresponder group than in the responder group (Table I). The patients with aspirin resistance had a higher number of ventricular premature complexes during a 24-hour period than those without aspirin resistance. Correlation analysis revealed that CT/ADP was negatively correlated (r = 0.4, P = 0.003) with age. CT/EPI was negatively correlated (r = -0.5, P = 0.02) with mean platelet volume and with hematocrit levels (r = -0.2, P = 0.04). Regarding HRV parameters, CT/ADP time was negatively correlated with SDNN (r = -0.5, P = 0.02) and HF (r = -0.4, P = 0.03) and positively correlated with LF (r = 0.6, P = 0.01) and LF/HF (r = 0.7, P = 0.001). Similarly, CT/EPI time was negatively correlated with SDNN (r = -0.4, P = 0.03) and positively correlated with LF (r = 0.5, P = 0.02) and the LF/HF ratio (r = 0.5, P = 0.02) (Table II). Regression analysis revealed that the only parameters affecting SDNN and the LF/HF ratio were left ventricular ejection fraction and aspirin resistance (Tables III and IV).

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DISCUSSION The main findings of our study were 1) heart rate variability decreased; 2) sympathetic activity increased or there is a sympatho-vagal imbalance; 3) the number of ventricular premature beats was higher in the patients with aspirin resistance and CAD; and 4) heart rate variability is associated with aspirin resistance in patients with CAD. Assessment of HRV is based on the analysis of consecutive sinus rhythm RR intervals and may provide quantitative information about the modulation of cardiac sympathetic and parasympathetic nerve activities. Although heart rate variability can be measured in a number of ways, the techniques of conventional time domain (statistical and geometrical) and frequency domain measurements (power spectral density) are predominantly used.3) Significantly altered HRV can be found not only in cardiac diseases but also in a wide variety of pathophysiologic disorders characterised by neurohumoral activation.13) The instantaneous RR interval depends on the continuous interplay between vagal and sympathetic efferent activity to the SA node and the intrinsic heart rate.14) Increased sympathetic activity or decreased vagal modulation of cardiac function assessed by HRV analysis has been associated with an increased risk of coronary heart disease and mortality15) and angiographic progression of coronary atherosclerosis,16) as well as arrhythmia and sudden cardiac death.17) Aspirin exerts its antithrombotic effect primarily by interfering with the biosynthesis of thromboxane A218) and several studies have demonstrated a beneficial role for aspirin in primary or secondary prevention of heart disease.19,20) However, the antiplatelet effect of aspirin is not uniform in all patients.21) Aspirin resistance as defined by failure to effectively inhibit thromboxane synthesis is associated with a higher risk of recurrent myocardial ischemia and cardiovascular death,2) as well as recurrent cerebral ischemic attacks.10) Gum, et al 22) reported that aspirin resistance is associated with a 4.1-fold excess adjusted hazard of serious vascular events, independent of age, gender, and conventional vascular risk factors. The incidence of aspirin resistance ranges between 8-45% depending on timing and technique of examination, time of the last aspirin intake, dose of aspirin, and heterogenecity of patient population.23-26) Several proposals have been put forward to explain the aspirin resistance; 1) lack of accommodation with aspirin treatment,27) 2) impaired adsorption,28) 3) use of other nonsteoridal antiinflammatory drugs,28) 4) increased thromboxane production especially resistant to aspirin,22) 5) increased platelet activation and/or turnover,29) and 6) genetic polymorphism.30) Grotemeyer, et al 26) found that patients with elevated platelet reactivity despite aspirin are more likely to experience vascular death, MI, or a cerebrovascular accident. The major adverse cardiovascular event prevalence is found to be increased in patients with stable CAD having detected aspirin resis-

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tance after cessation of clopidogrel therapy.31) Recently, Chent, et al 32) showed that aspirin resistance is associated with an increased risk of adverse clinical outcomes in stable patients with CAD. The adrenergic system affects both peripheral platelet activation and thrombocytopoiesis in bone marrow.33,34) Platelet activation causes shape change and thereby increases MPV.35) Lande, et al 36) showed that MPV significantly increased during adrenaline infusion, reflecting either swelling and shape change of platelets due to platelet activation or release of larger, activated platelets from spleen. Andersen, et al 25) demonstrated that P-selectin but not β -thromboglobulin is significantly higher in the nonresponders, suggesting the increased activation of platelets in this group. Similarly, we found higher mean platelet volumes reflecting more reactive platelets37) in the nonresponders. Therefore, sympathetic overactivity in patients with aspirin resistance may cause platelet activation and may contribute to aspirin resistance in the patients with CAD. Similarly, Hurlen, et al 38) found that the antiplatelet action of aspirin is decreased during exercise although this effect is normal during rest in patients who previously experienced a myocardial infarction. They concluded that aspirin is not sufficiently effective when platelets are activated by catecholamines. Moreover, experimental studies have indicated that the antiplatelet effect of aspirin is counteracted by catecholamines.39) Ersoz, et al 40) found that aspirin does not sufficiently inhibit ADP and collagen-induced platelet aggregation in patients with CAD. Furthermore, they suggested that aspirin may be less effective due to sympathoadrenal activation in these patients. Therefore, the association between increased aspirin resistance and sympathetic overactivity may be explained by less vulnerability of the platelets to aspirin during increased catecholamines. This study is, to the best of our knowledge, the first to evaluate the association between heart rate variability and aspirin resistance in patients with stable coronary artery disease. We found that the heart rate variability is associated with aspirin resistance in patients with stable CAD. This may contribute to a higher risk of recurrent myocardial ischemia and cardiovascular death in patients with aspirin resistance. Limitations: The most important limitation of the study is the lack of blood concentrations of catecholamines in these patients. We did not evaluate platelet aggregation by thromboxanes and the correlation between bleeding time and CT/ EPI. REFERENCES 1.

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