Arterial blood pressure (BP) follows a circadian

Transcription

1 Original Paper Relationship Between Exercise Heart Rate Recovery and Circadian Blood Pressure Pattern Sercan Okutucu, MD; Giray Kabakci, MD; Onur Sinan Deveci, MD; Hakan Aksoy, MD; Ergun Baris Kaya, MD; Kudret Aytemir, MD; Ali Oto, MD The aim of the present cross-sectional study was to evaluate heart rate recovery (HRR) in normotensive and hypertensive individuals with either nondipper or dipper type circadian rhythm of blood pressure. Eighty-five patients were divided into 4 groups according to the presence of hypertension and pattern of circadian blood pressure as follows: (1) normotensive dipper, n=20; (2) normotensive nondipper, n=21; (3) hypertensive dipper, n=22; and (4) hypertensive nondipper, n=22. HRR indices were calculated by subtracting first, second, and third minute heart rates from the maximal heart rate obtained during stress testing and designated as HRR1, HRR2, and HRR3. Mean HRR1 values ( vs , P=.016) were significantly higher in the normotensive dipper group than the normotensive nondipper group. Mean HRR1 values ( vs beats per minute, P=.007) were higher in the hypertensive dipper group than the hypertensive nondipper group. Spearman s correlation analyses revealed a positive correlation between degree of nighttime dipping and HRR1 (r=.600, P=.001). From the Department of Cardiology, Hacettepe University Faculty of Medicine, Ankara, Turkey Address for correspondence: Sercan Okutucu, MD, Hacettepe University Faculty of Medicine, Department of Cardiology, Sıhhiye Ankara, 06100, Turkey sercanokutucu@yahoo.com doi: /j x The correlation coefficient between degree of nighttime dipping and HRR1 was higher in the hypertensive group than the normotensive group (r=.676, P=.001 and r=.575, P=.001, respectively). Blunting of the nocturnal fall in blood pressure associates with a delayed recovery of heart rate after graded maximal exercise in both normotensive and hypertensive groups. J Clin Hypertens (Greenwich). 2010;12: ª 2010 Wiley Periodicals, Inc. Arterial blood pressure (BP) follows a circadian type rhythm. 1 3 Most people present a decline in arterial BP between 10% 20% during nighttime intervals which is called a dipper pattern. 1,4 It has been reported that the lack of nocturnal BP fall which is called nondipping is associated with more serious end organ damages when compared to hypertensives with a dipping pattern. 5 9 Although pathologic mechanisms responsible for blunted nocturnal fall in BP are still unclear, it has been suggested that nondippers show impairment in the autonomic system that includes abnormal parasympathetic activity. 10,11 Since a decrease in vagal activity has been known as a powerful independent predictor of overall mortality, the decline in vagal tone might explain the increase in cardiovascular risk in nondipper subjects. 12 Meanwhile, an impaired recovery of heart rate (HRR) during the first minute after graded exercise has been considered to reflect diminished vagal activity that may be associated with a worse cardiovascular outcome inde- VOL. 12 NO. 6 JUNE 2010 THE JOURNAL OF CLINICAL HYPERTENSION 407

2 pendent of workload and changes in heart rate during exercise The aim of the present cross-sectional study was to evaluate HRR in normotensive and hypertensive individuals with either nondipper or dipper type circadian rhythm of BP. METHODS The study population included 85 individuals. All patients underwent 24-hour ambulatory BP monitorization, treadmill exercise testing, and transthoracic echocardiographic examination. Patients with a history of cardiovascular, cerebrovascular, or other systemic disease were excluded. Ambulatory BP Monitorization Ambulatory BP monitoring studies were carried out using a Tracker NIBP2 (Del Mar Reynolds Medical Ltd, Hertford, UK) monitoring device. The first hour was discarded from analysis. BP readings were obtained automatically at 15-minute intervals during the daytime and nighttime. Recordings were accepted only if more than 85% of the raw data were valid. The absolute and the percentage of the decrease of nighttime systolic BP vs daytime systolic BP were calculated in all subjects. Time in bed was defined based on the patient-kept diary that documented the exact time of getting into and arising from bed. The average BP for this time in bed was calculated from the ambulatory monitoring data (termed nighttime BP). Daytime BP was defined as the average BP during the remainder of the 24-hour period. Mean BP was calculated as the diastolic pressure plus one-third of the pulse pressure. The percentage decline in nighttime BP was calculated as follows: (mean daytime BP mean nighttime BP mean daytime BP 100). Patients with a decline in mean nighttime BP of less than 10% were accepted as nondippers. Patients were accepted as hypertensive if the following were present: (1) current use of antihypertensive drugs; (2) presence of resting systolic BP of 140 mm Hg and or diastolic BP of 90 mm Hg; and (3) an average 24-hour BP value above mm Hg. Treadmill Exercise Testing and Transthoracic Echocardiographic Examination A treadmill exercise testing was conducted in all patients using modified Bruce protocol. Twelve lead electrocardiography (Mason-Likar modification) was recorded at 25 mm s paper speed. All patients achieved an exercise time of more than 6 minutes, and a maximum heart rate of at least 85% of age-predicted maximal heart rate response. After achieving peak workload, all patients spent at least 3 minutes recovery without cool-down period. Exercise capacity is measured in metabolic equivalent levels (METs) at peak exercise. Systolic BP (SBP ME ) and diastolic BP (DBP ME ) at maximum exercise were recorded. HRR indices were calculated by subtracting first, second, and third minute heart rates from the maximal heart rate obtained during stress testing and designated as HRR1, HRR2, and HRR3. Transthoracic echocardiographic examination was performed on all subjects by using a SystemFive (GE Vingmed Ultrasound, Horten, Norway) cardiac ultrasound scanner with MHz transducers. The study was approved by the local ethics committee, and patients gave informed written consent. Statistical Analyses Statistical analyses were performed using SPSS for Windows 15 (SPSS Inc., Chicago, IL). Numerical variables with a normal distribution were presented as the mean standard deviation, and numerical variables with a skewed distribution were presented as the median (minimum and maximum), and categorical variables were presented as percentages. For numerical variables, an independent sample t-test and Mann-Whitney U test were used for intergroup comparisons. A chi-square test and Fischer s exact chi-square test were used for comparisons of categorical variables. Multivariate linear regression analysis was performed to evaluate the effects of various variables, such as age, basal heart rate (BHR), maximal heart rate (MHR), SBP ME, DBP ME, exercise time, exercise capacity, and average systolic (AvSBP) and average diastolic (AvDBP) 24-hour ambulatory BP monitorization values on HRR. The correlation between the decline in nighttime BP and HRR was examined with Spearman s correlation analysis. Two-tailed P values <.05 were considered as significant. RESULTS Eighty-five patients were enrolled and divided into 4 groups according to the presence of hypertension and circadian BP pattern as follows: (1) normotensive dipper, n=20; (2) normotensive nondipper, n=21; (3) hypertensive dipper, n=22; and (4) hypertensive nondipper, n=22. Thus, dipper and nondipper cases were compared with their respective groups. Demographic characteristics, distribution of conventional risk factors, BP, and exercise test parameters of the groups are summarized in Table I and Table II. 408 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 12 NO. 6 JUNE 2010

3 Table I. Demographic Characteristics and Clinical Parameters of Normotensive Group Normotensive Dipper (n=20) Normotensive Nondipper (n=21) Age, y NS Gender (male female%) NS Smokers (%) NS Basal heart rate, bpm NS Left ventricular ejection fraction (%) NS Average systolic 24-h ABPM, mm Hg Average diastolic 24-h ABPM, mm Hg Decline in nighttime BP (%) Numeric variables with a normal distribution were presented as the mean standard deviation. Abbreviations: ABPM, ambulatory blood pressure monitoring; BP, blood pressure; bpm, beats per minute; NS, not significant. Table II. Demographic Characteristics and Clinical Parameters of Hypertensive Group Hypertensive Dipper Hypertensive Nondipper Age, y NS Gender (male female%) NS Smokers (%) NS Basal heart rate, bpm NS Left ventricular ejection fraction (%) NS Average systolic 24-h ABPM, mm Hg NS Average diastolic 24-h ABPM, mm Hg Decline in nighttime BP (%) Numeric variables with a normal distribution were presented as the mean standard deviation. Abbreviations: ABPM, ambulatory blood pressure monitoring; BP, blood pressure; bpm, beats per minute; NS, not significant. The dipper and nondipper subgroups of normotensive cases were similar with respect to age ( vs years), gender distribution ([male female] 13 7 vs12 9), smoking status (30% vs 28%), BHR ( vs beats per minute [bpm]), and left ventricular ejection fraction ( % vs %). In the normotensive dipper group, AvSBP ( vs , P=.044) and AvDBP ( vs , P=.010) values were significantly lower than the normotensive nondipper group. Mean HRR1 values ( vs , P=.016) were significantly higher in the normotensive dipper group than the normotensive nondipper group (Figure 1). The duration of the treadmill exercise test ( vs minutes), peak exercise capacity ( vs METs), MHR ( vs bpm), SBP ME ( mm Hg vs mmHg),DBP ME ( mm Hg vs mm Hg), HRR2 ( vs ), and HRR3 ( vs ) were similar in dipper and nondipper subgroups of normotensive group, respectively (Table III). Figure 1. Distribution of heart rate recovery in four subgroups according to dipping status and hypertension. bpm indicates beats per minute. The dipper and nondipper subgroups of hypertensive cases were also similar with respect to age ( vs years), gender distribution VOL. 12 NO. 6 JUNE 2010 THE JOURNAL OF CLINICAL HYPERTENSION 409

4 Table III. Treadmill Exercise Test Parameters of Normotensive Group Normotensive Dipper (n=20) Normotensive Nondipper (n=21) Duration of exercise test, min NS Peak exercise capacity (METs) NS Maximal heart rate, bpm NS SBP ME, mm Hg NS DBP ME, mm Hg NS HRR1, bpm HRR2, bpm NS HRR3, bpm NS Numeric variables with a normal distribution were presented as the mean standard deviation. Abbreviations: bpm, beats per minute; HRR1 3, heart rate recovery indices (see text for full description); DBP ME, diastolic blood pressure at maximum exercise; METs, metabolic equivalent levels; NS, not significant; SBP ME, sytolic blood pressure at maximum exercise. Table IV. Treadmill Exercise Test Parameters of Hypertensive Group Hypertensive Dipper Hypertensive Nondipper Duration of exercise test, min NS Maximal heart rate (bpm) NS Peak exercise capacity, METs NS SBP ME, mm Hg NS DBP ME, mm Hg NS HRR1, bpm HRR2, bpm NS HRR3, bpm NS Numeric variables with a normal distribution were presented as the mean standard deviation. Abbreviations: bpm, beats per minute; HRR1 3, heart rate recovery indices (see text for full description); DBP ME, diastolic blood pressure at maximum exercise; METs, metabolic equivalent levels; NS, not significant; SBP ME, sytolic blood pressure at maximum exercise. ([male female] vs 10 12), smoking status (32% vs 32%), BHR ( vs bpm), left ventricular ejection fraction ( % vs %), and AvSBP ( mm Hg vs mm Hg).In hypertensive dipper group, AvDBP ( mm Hg vs mm Hg, P=.007) was significantly lower than the hypertensive nondipper group. Mean HRR1 values ( vs bpm, P=.007) were higher in hypertensive dipper group than the hypertensive nondipper group (Figure 1). The duration of the treadmill exercise test ( vs minutes), MHR ( vs bpm), peak exercise capacity ( vs METs), SBP ME ( mm Hg vs mm Hg), DBP ME ( mm Hg vs mm Hg), HRR2 ( vs ), and HRR3 ( vs ) were similar in the dipper and nondipper subgroups of the normotensive group, respectively (Table IV). Effects of age, BHR, MHR, SBP ME, DBP ME, exercise time, exercise capacity, AvSBP, AvDBP, and decline in nighttime BP on HRR1 were examined in a multivariate linear regression analysis and it was determined that the degree of dipping and DBP ME were independent predictors of HRR1. In this model, the influence of nighttime dipping on HRR1 was found to be more prominent than the other factors (P=.001, b=0.642). Spearman s correlation analyses revealed a positive correlation between degree of nighttime dipping and HRR1 (r=.600, P=.001) (Figure 2). The correlation coefficient between degree of nighttime dipping and HRR1 for the hypertensive group was higher than the normotensive group (r=.676, P=.001 and r=.575, P=.001, respectively) (Figure 3). DISCUSSION To the best of our knowledge our study is the first to suggest that the presence and degree of dipping 410 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 12 NO. 6 JUNE 2010

5 Figure 2. Correlation between heart rate recovery and decline in nighttime blood pressure (BP) in all the study population. r indicates correlation coefficient. in nighttime BP were associated with a higher HRR1 both in normotensive and hypertensive individuals. We have found that both in normotensives and mild-to-moderate hypertensives, the percentage of the fall of nighttime BP is positively correlated with the decrease in the heart rate during the first minute after graded exercise. It has been shown that some cardiovascular complications of essential hypertension such as left ventricular hypertrophy, 17,18 microalbuminuria, 19,20 and cerebrovascular damage 8,21 tend to be more common in patients whose 24-hour BP profile is blunted. Although the underlying mechanisms of nocturnal decrease of BP are not yet fully understood, withdrawal of sympathetic activity during sleep probably plays an important role. 22,23 Abnormalities on autonomic nervous activity, particularly of the sympathovagal balance as seen in patients with autonomic neuropathy are thought to explain the blunting of the normal nighttime BP decline. 24,25 HRR after graded exercise is one of the commonly used techniques that reflect autonomic activity. 26,27 An attenuated HRR, which is defined as the decrease in heart rate immediately after exercise, reflects reduced parasympathetic nervous system (PNS) activity. 28,29 Kannankeril and colleagues 30 demonstrated that sympathetic withdrawal also contributes significantly to early HRR, as evidenced by brisk HRR even after atropine administration at maximal exercise. Based on these findings, they suggested that abnormal HRR might be attributable to a defect in sympathetic withdrawal, PNS reactivation, or both of them. When sympathetic hyperactivity is amplified, the increased cardiovascular workload and hemodynamic stress result in endothelial dysfunction, coronary artery spasm, left ventricular hypertrophy, serious arrhythmias, stroke, and increased cardiac mortality. However, increased parasympathetic activity is protective against ischemia related dysrhythmias, and also reduces heart rate and BP. 31 Furthermore, Chaitman 32 showed that, the finding of an abnormal HRR response was a surrogate for underlying autonomic dysfunction and that the mechanism of increased mortality associated with this finding might be more related to autonomic dysfunction than to the presence or extent of coronary artery disease. HRR indices immediately after the completion of an exercise stress test were found as predictors of all cause mortality. 33,34 Schwartz and colleagues 35 reported that increased PNS activity had been associated with a decrease in the risk of deathbyprotecting theheart against lethal arrhythmias. Other studies have also shown that abnormal HRR, defined as failure of heart rate to decrease 12 beats or more during the first minute after peak Figure 3. Correlation between heart rate recovery and decline in nighttime blood pressure (BP) in normotensive and hypertensive groups. bpm indicates beats per minute; r, correlation coefficient. VOL. 12 NO. 6 JUNE 2010 THE JOURNAL OF CLINICAL HYPERTENSION 411

6 exercise, independently predicted an increased mortality. 13,36 Furthermore, Morshedi-Meibodi and colleagues 37 demonstrated that the greater HRR in the first minute of recovery the lower the subsequent mortality. Corroborating our results, Polonia and colleagues 16 have reported an association between the blunting of the nocturnal fall of BP and delayed HRR after graded maximal exercise, but different from our study normotensive individuals were not involved. CONCLUSIONS The blunting of the nocturnal fall in BP was associated with a delayed recovery of heart rate after graded maximal exercise in both normotensive and hypertensive groups. This relationship was more prominent in the hypertensive group. When the prognostic significance of HRR is considered, hypertensives and normotensives with a nondipping pattern should be followed closely for adverse cardiovascular outcomes. The main strength of the present study was the selection of patients from the most frequently encountered patients in the daily practice of cardiology. The major limitations of the present study are the relatively small number of patients and that the results are based on a single center. Disclosures: The authors have nothing to disclose. REFERENCES 1 Biaggioni I. Circadian clocks, autonomic rhythms, and blood pressure dipping. Hypertension. 2008;52: O Brien E. Dipping comes of age: the importance of nocturnal blood pressure. Hypertension. 2009;53: Pickering TG. Should we be evaluating blood pressure dipping status in clinical practice? J Clin Hypertens (Greenwich). 2005;7: Fukutomi M, Matsui Y, Shimada K. Dipper and nondipper. Nippon Rinsho. 2006;64(suppl 6): Izzedine H, Launay-Vacher V, Deray G. Abnormal blood pressure circadian rhythm: a target organ damage? Int J Cardiol. 2006;107: Pierdomenico SD, Lapenna D, Guglielmi MD, et al. Arterial disease in dipper and nondipper hypertensive patients. Am J Hypertens. 1997;10: Kohno I, Takusagawa M, Yin D, et al. Qt dispersion in dipper- and nondipper-type hypertension. Am J Hypertens. 1998;11: Shimada K, Kario K. Altered circadian rhythm of blood pressure and cerebrovascular damage. Blood Press Monit. 1997;2: Zweiker R, Eber B, Schumacher M, et al. Non-dipping related to cardiovascular events in essential hypertensive patients. Acta Med Austriaca. 1994;21: Abate G, D Andrea L, Battestini M, et al. Autonomic nervous activity in elderly dipper and non-dipper patients with essential hypertension. Aging (Milano). 1997;9: Ragot S, Herpin D, Siche JP, et al. Autonomic nervous system activity in dipper and non-dipper essential hypertensive patients. What about sex differences? J Hypertens. 1999;17: Nakano Y, Oshima T, Ozono R, et al. Non-dipper phenomenon in essential hypertension is related to blunted nocturnal rise and fall of sympatho-vagal nervous activity and progress in retinopathy. Auton Neurosci. 2001; 88: Pierpont GL, Voth EJ. Assessing autonomic function by analysis of heart rate recovery from exercise in healthy subjects. Am J Cardiol. 2004;94: Imai K, Sato H, Hori M, et al. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol. 1994;24: Pierpont GL, Stolpman DR, Gornick CC. Heart rate recovery post-exercise as an index of parasympathetic activity. J Auton Nerv Syst. 2000;80: Polonia J, Amaral C, Bertoquini S, et al. Attenuation of heart rate recovery after exercise in hypertensive patients with blunting of the nighttime blood pressure fall. Int J Cardiol. 2006;106: Verdecchia P, Schillaci G, Guerrieri M, et al. Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation. 1990;81: Klein W, Zweiker R, Eber B, et al. Circadian blood pressure pattern in patients with treated hypertension and left ventricular hypertrophy. Angiology. 1991;42: Redon J, Liao Y, Lozano JV, et al. Ambulatory blood pressure and microalbuminuria in essential hypertension: role of circadian variability. J Hypertens. 1994;12: Hishiki S, Tochikubo O, Miyajima E, et al. Circadian variation of urinary microalbumin excretion and ambulatory blood pressure in patients with essential hypertension. J Hypertens. 1998;16: Shimamura T, Nakajima M, Iwasaki T, et al. Analysis of circadian blood pressure rhythm and target-organ damage in stroke-prone spontaneously hypertensive rats. J Hypertens. 1999;17: Sherwood A, Steffen PR, Blumenthal JA, et al. Nighttime blood pressure dipping: the role of the sympathetic nervous system. Am J Hypertens. 2002;15: Baumgart P. Circadian rhythm of blood pressure: internal and external time triggers. Chronobiol Int. 1991;8: Mann S, Altman DG, Raftery EB, et al. Circadian variation of blood pressure in autonomic failure. Circulation. 1983;68: Kohara K, Nishida W, Maguchi M, et al. Autonomic nervous function in non-dipper essential hypertensive subjects. Evaluation by power spectral analysis of heart rate variability. Hypertension. 1995;26: Cay S. Heart rate recovery after exercise: an important prognostic criterion. Int J Cardiol. 2009;137: Georgoulias P, Valotassiou V, Tsougos I. Heart-rate recovery as a clinical marker of cardiovascular autonomic dysfunction in diabetic patients. Eur J Nucl Med Mol Imaging. 2009;36: Vivekananthan DP, Blackstone EH, Pothier CE, et al. Heart rate recovery after exercise is a predictor of mortality, independent of the angiographic severity of coronary disease. J Am Coll Cardiol. 2003;42: Arena R, Guazzi M, Myers J, et al. Prognostic value of heart rate recovery in patients with heart failure. Am Heart J. 2006;151:851 e Kannankeril PJ, Le FK, Kadish AH, et al. Parasympathetic effects on heart rate recovery after exercise. J Investig Med. 2004;52: Curtis BM, O Keefe JH Jr. Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight. Mayo Clin Proc. 2002;77: THE JOURNAL OF CLINICAL HYPERTENSION VOL. 12 NO. 6 JUNE 2010

7 32 Chaitman BR. Abnormal heart rate responses to exercise predict increased long-term mortality regardless of coronary disease extent: the question is why? J Am Coll Cardiol. 2003;42: Gibbons RJ. Abnormal heart-rate recovery after exercise. Lancet. 2002;359: Nishime EO, Cole CR, Blackstone EH, et al. Heart rate recovery and treadmill exercise score as predictors of mortality in patients referred for exercise ECG. JAMA. 2000;284: Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation. 1992;85:I77 I Mora S, Redberg RF, Cui Y, et al. Ability of exercise testing to predict cardiovascular and all-cause death in asymptomatic women: a 20-year follow-up of the lipid research clinics prevalence study. JAMA. 2003;290: Morshedi-Meibodi A, Larson MG, Levy D, et al. Heart rate recovery after treadmill exercise testing and risk of cardiovascular disease events (The Framingham Heart Study). Am J Cardiol. 2002;90: VOL. 12 NO. 6 JUNE 2010 THE JOURNAL OF CLINICAL HYPERTENSION 413