442 Original research
Effect of percutaneous coronary intervention on heart rate recovery in patients with coronary artery disease Jianguo Liu, Aibin Xu, Lili Niu and Junxia Li Objective This study aimed to investigate the effect of percutaneous coronary intervention (PCI) on heart rate recovery (HRR) in patients with angiographically defined coronary artery disease, and to search for a noninvasive method for evaluating the effect of revascularization. Methods From June 2012 to July 2013, 56 consecutive male patients with coronary artery disease were enrolled in the PCI group. Correspondingly, in the control group there were 56 consecutive male patients with chest pain but a normal coronary artery verified by angiography. The exercise treadmill test was performed 3 days before and 7 days after intervention in the PCI group, and 3 days before angiography in the control group. Results The peak heart rate, metabolic equivalents, and the Duke score were notably lower in the PCI group before intervention compared with the control group (P < 0.01). In contrast, preintervention ST depression in the PCI group was significantly higher than that in the control group (P < 0.01). Preintervention HRR values from 1 to 6 min were much lower in the PCI group compared with the control group (P < 0.01). HRR values from 1 to 6 min in the PCI
Introduction The prognostic value of abnormal heart rate recovery (HRR) after exercise with regard to predicting cardiovascular disease as well as mortality is well established [1]. After initiation of the exercise test, heart rate (HR) during the first few minutes increases because of withdrawal of parasympathetic tone. Several studies have demonstrated that delayed HRR is an independent predictor of increased mortality among patients undergoing the exercise treadmill test (ETT) [2,3]. Moreover, a previous prospective study has indicated that HRR is an independent predictor of all-cause mortality, even if the severity of coronary artery disease (CAD), exercise capacity, and left ventricular function are taken into consideration [4]. However, the potential association between slow HRR and cardiovascular morbidity is still not known. Recently, a prospective cross-sectional study showed that abnormal postexercise HRR at 1 min (< 18 bpm) was independently associated with the extent of CAD after multivariable logistic regression analysis adjusting for established CAD risk factors [5]. Unfortunately, it has not been ascertained whether HRR is affected by different coronary involvement, extent of major epicardial coronary involvement, or revascularization. Furthermore, there are few data on the 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
group post intervention increased significantly compared with preintervention HRR values (P < 0.01), especially at 3, 4, 5, and 6 min. HRR values at 1, 2, and 3 min increased sharply post intervention. Conclusion Successful revascularization through PCI could improve HRR in patients with major coronary artery involvement. Moreover, HRR measurement may be used as a noninvasive method for evaluating the effect of revascularization. Coron Artery Dis 26:442–447 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Coronary Artery Disease 2015, 26:442–447 Keywords: coronary artery disease, heart rate recovery, revascularization Department of Cardiology, General Hospital, Beijing Military Area Command, Beijing, China Correspondence to Jianguo Liu, PhD, Department of Cardiology, General Hospital, Beijing Military Area Command, Dongcheng District, Beijing 100700, China Tel/fax: + 86 010 6400 6459; e-mail: [email protected] Received 31 January 2015 Revised 13 April 2015 Accepted 15 April 2015
effect of coronary revascularization on HRR in patients with CAD. The aim of this study was to evaluate the effect of percutaneous coronary intervention (PCI) on HRR after ETT in patients with CAD verified by coronary angiography, as well as to explore a noninvasive method for evaluating the effect of revascularization.
Methods Study population and exclusion criteria
Our study originally enrolled 480 attendees from June 2012 to July 2013. Of these attendees, 424 were excluded because of the following reasons: acute coronary syndrome (n = 179), female (n = 125), 65 years or older and inability or reluctance to perform ETT (n = 98), left ventricular hypertrophy and substantial changes in STsegment depression (n = 9), Angiographic Rentrop Scores of collateral circulation greater than 1 and refusal to sign study consent forms (n = 13). Finally, a total of 56 consecutive male patients with angiographically defined CAD (aged 45–60 years) were enrolled in the PCI group. In brief, 43 patients (76.8%) received nitrate, 11 (19.6%) with nondihydropyridine calcium channel blockers as antihypertensive agents, six (10.7%) with the application DOI: 10.1097/MCA.0000000000000264
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Effect of PCI on HRR Liu et al. 443
of angiotensin-converting enzyme inhibitors, and 34 (60.7%) with β-blockers. Among these 34 patients using beta blockers, 27 (48.2%) were treated with metoprolol tartaric acid at a dose of 25 mg twice daily, and seven patients were administered bisoprolol fumarate pesos at a dose of 2.5 mg once daily. Angiographic Rentrop Scores of collateral circulation in the PCI group were less than 1 [6], and all patients in the PCI group achieved complete revascularization by percutaneous coronary angioplasty. Correspondingly, in the control group there were 56 consecutive male patients with chest pain but with a normal coronary artery verified by angiography. Among the 56 patients in the control group, eight (14.3%) were treated with a nondihydropyridine calcium channel blocker as an antihypertensive agent, four (7.1%) with angiotensin-converting enzyme inhibitors, and seven (12.5%) with metoprolol tartaric acid at a dose of 25 mg twice daily. To avoid the effect of β-blockers on HRR, they were discontinued for more than five half-life periods before ETT in both the PCI and the control groups. According to the American College of Cardiology/ American Heart Association 2002 guideline update for exercise testing, patients with absolute or relative contraindications including acute myocardial infarction, symptomatic severe aortic stenosis, and hypertrophic cardiomyopathy were excluded [7]. The study protocol was approved by the Institutional Review Committee on Human Research at our hospital. All participants gave their informed consent.
Angiographic analysis and definitions
Patients were eligible when coronary angiography was demonstrated by ETT results on the basis of American College of Cardiology/American Heart Association guidelines [8]. Radial artery access was chosen for coronary artery angiography and interventional procedures [9]. Cardiologists who were blinded to Duke treadmill scores and the patients’ HRR, as well as to the hypothesis of this study, semiquantitatively analyzed the degree of coronary artery luminal stenosis. Moreover, the reference lumen diameter was calculated by selecting end-diastolic frames to demonstrate stenosis in its most severe and nonforeshortened projection [10]. More than 50% diameter narrowing of the major coronary arteries was considered as significant CAD [11]. In our study, PCI was performed when stenosis was of at least 70% of the vessel diameter in at least one coronary artery. The definition of a successful PCI procedure was the achievement of a minimum stenosis diameter of less than 20% in the presence of Thrombolysis in Myocardial Infarction grade 3 flow. Furthermore, patients who had no major clinical complication and no signs of myocardial ischemia during hospitalization were relieved after undergoing the PCI procedure [12].
Exercise treadmill test protocols and heart rate recovery analysis
The ETT was performed 3 days before and 7 days after the PCI intervention in the PCI group, and 3 days before coronary artery angiography in the control group. The participants were forbidden from smoking or engaging in strenuous physical activity for at least 3 h before the examination. Thereafter, the ETT was performed on a Quinton T50 treadmill system (Quinton Cardiology Inc., Seattle, Washington, USA) according to a submaximal Bruce’s protocol, with continuous ECG monitoring. Blood pressure was measured and recorded at rest, at the end of each stress stage, at peak stress, and at recovery, respectively. In addition, data on symptoms in metabolic equivalents (METs) were acquired. ST-segments were considered as abnormal if at least 1 mm of horizontal or down-sloping ST-segment depression at 80 ms was found after the J point in at least three consecutive beats in two contiguous leads. ST-segment depression was also examined. Moreover, the Duke treadmill exercise score was calculated on the basis of the following formula: Duke treadmill exercise score ¼ exercise time½ð5max ST deviationÞ ð4treadmill angina indexÞ: The test was terminated for any of the following reasons: a rating of perceived exertion greater than 17 (Borg scale), achievement of a greater than 85% age-predicted maximum heart rate, inability to safely continue walking on the treadmill because of fatigue, systolic blood pressure greater than 250 mmHg, typical chest discomfort, severe arrhythmias, or more than 1 mm horizontal or downsloping ST-segment depression. Following peak exercise, patients walked for a 2 min cool-down period at 1.5 mph at a 2.5% grade [1], and the values of HRR at each time point from 1 to 6 min were defined as HR reduction from that at peak exercise to the rate at 1, 2, 3, 4, 5, and 6 min after cessation of exercise. The HRR values at each time point from 1 to 6 min were marked as HRR1, HRR2, HRR3, HRR4, HRR5, and HRR6, respectively. The maximal predicted HR was calculated based on the equation subtracting the patient’s age from 220. HRR values were analyzed using a Q-STRESS/Cardiac stress system (American International Medical, Bothell, Washington, USA) software.
Estimation of sample size
Sufficiency of samples is very important to guarantee reliability of the conclusion. Thus, in the current study, we applied Power and Sample Size Calculation version 3.1.2, 2014 software to carry out power analysis to estimate the sample size.
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Statistical analysis
Statistical analysis was carried out using SPSS statistical software for Windows version 22.0 (SPSS for Windows, version 22.0; SPSS Inc., Chicago, Illinois, USA). Data were expressed as mean ± SD or % (n) of patients. Differences in continuous variables were analyzed using independent t-tests, and differences in categorical variables were analyzed using the χ2-test. A two-sided Pvalue of less than 0.05 was considered to be statistically significant. Spearman’s analysis was used to determine which variables were associated with the presence of obstructive CAD on cardiac catheterization, on the basis of baseline clinical variables, along with HRR and other ETT variables.
Results Baseline characteristics and angiographic findings
There was no significant difference in age, total cholesterol level, and prevalence of hypertension between the two groups (Table 1). However, low-density lipoproteincholesterol and lipoprotein(a) levels of the control group were significantly lower than those of the PCI group (P < 0.001). Moreover, BMI and prevalence of diabetes mellitus were found to be significantly higher in the PCI group compared with the control group (BMI, P = 0.012; diabetes mellitus, P = 0.018). Similarly, smoking rate was remarkably elevated in the PCI group compared with the control group (P < 0.001). With regard to the use of nitrates, no patient was treated with nitrates in the control group, whereas 43 patients (76.8%) were treated with nitrates in the PCI group before intervention. Among the 56 patients in the PCI group, 15 had singlevessel disease in the left anterior descending coronary artery, 16 had double-vessel disease in the left anterior descending and left circumflex coronary arteries, 12 had double-vessel disease in the left anterior descending and right coronary arteries, and 13 in both left circumflex and right coronary arteries. All patients in the PCI group achieved complete revascularization with PCI. Table 1
Baseline characteristics
Variables Age (years) BMI (kg/m2) TC (mmol/l) LDL-C (mmol/l) LP(a) (mmol/l) DM2 Hypertension Smoking Nitrates
Control group (n = 56)
PCI group (preintervention, n = 56)
51.8 ± 3.8 25.9 ± 2.8 5.1 ± 1.1 2.6 ± 0.8 112.6 ± 27.8 7.2% (4) 25.0% (14) 12.5% (7) 0
52.4 ± 4.2 27.2 ± 3.4* 5.5 ± 1.4 3.5 ± 1.1** 243.5 ± 46.3** 23.2% (13)** 32.1% (18) 41.1% (23) 76.8% (43)
P-value 0.430 0.012 0.096 < 0.001 < 0.001 0.018 0.403 < 0.001
β-blockers were discontinued before the treadmill exercise test for five half-life periods in all patients. Data are expressed as mean ± SD or % (n) of patients. DM2, diabetes mellitus 2; LDL-C, low-density lipoprotein-cholesterol; LP(a), lipoprotein(a); PCI, percutaneous coronary intervention; TC, total cholesterol. *P < 0.05. **P < 0.01 versus control group.
Furthermore, the patients had no major cardiovascular complication during hospitalization. Comparison of peak heart rate and pertinent exercise treadmill test data between the control and percutaneous coronary intervention groups
The peak HR and the pertinent ETT data of the control and PCI groups are shown in Table 2. There was no difference in resting HR between the control and PCI groups. Preintervention peak HR and METs of the PCI group were significantly lower than those of the control group (P < 0.01). At the same time, postintervention peak HR and METs in the PCI group increased significantly compared with the control group (P < 0.01). However, postintervention peak HR in the PCI group was lower than that in the control group (P < 0.001), whereas no significant difference in METs was found between the two groups (P > 0.05). The Duke score was significantly higher in the control group compared with the PCI group before intervention. After intervention, the Duke score in the PCI group increased significantly compared with that before intervention (P < 0.01). In contrast, ST depression before intervention was significantly higher in the PCI group than in the control group (P < 0.01), whereas ST depression in the PCI group after intervention reduced significantly compared with that before intervention (P < 0.01). However, ST depression in the PCI group after intervention was higher than that in the control group, but without statistical significance (P > 0.05). Change in heart rate recovery in the percutaneous coronary intervention group before and after intervention
As shown in Fig. 1, there existed a significant statistical difference in HRR values in the PCI group before and after intervention at each time point from 1 to 6 min (P < 0.01). HRR values were significantly increased at 1, 2, and 3 min after intervention compared with those before intervention in the PCI group, and were stable after 3 min. Table 2 Comparison of the peak heart rate between the control group and the PCI group (bpm)
Peak HR METs ST depression (mm) Duke score
n
Control group
PCI group before PCI
PCI group after PCI
56 56 56
156.7 ± 10.4 11.2 ± 1.5 0.5 ± 0.1
128.8 ± 16.1a 9.8 ± 1.7a 1.5 ± 0.5a
135.8 ± 10.4a,b 10.8 ± 1.2b 0.6 ± 0.2b
56
10.7 ± 1.2
− 6.8 ± 2.3
6.7 ± 2.1a
HR, heart rate; MET, metabolic equivalent; PCI, percutaneous coronary intervention. a P < 0.01 versus control group. b P < 0.01 versus PCI group before PCI.
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Effect of PCI on HRR Liu et al. 445
Fig. 1
Fig. 2
80
80 70
∗
∗
∗
∗
40 ∗
20
∗
∗
∗
∗
50 40 30
∗
20 PCI group preintervention PCI group postintervention
10 0
∗
60
50
30
70
HRR (bpm)
HRR (bpm)
60
∗
1
2
3 4 Time post-ETT (min)
5
10 0
6
HRR values of the PCI group after successful revascularization increased significantly compared with those of the PCI group before intervention at each time point from 1 to 6 min (*P < 0.01), especially at 3, 4, 5, and 6 min. HRR values at 1, 2, and 3 min increased sharply post intervention, and apparently at 1 and 2 min before intervention. ETT, exercise treadmill test; HRR, heart rate recovery; PCI, percutaneous coronary intervention.
Comparison of heart rate recovery between the control and percutaneous coronary intervention groups
HRR values at each time point from 1 to 6 min were much lower in the PCI group before intervention compared with the control group (Fig. 2; P < 0.01). HRR values from 1 to 3 min increased sharply in the control group; similarly, HRR values in the PCI group before the procedure obviously increased from 1 to 2 min. However, no statistical differences in HRR1, HRR2, HRR3, and HRR4 were found between the PCI group after intervention and the control group. However, postintervention HRR5 and HRR6 of the PCI group were significantly lower than those of the control group (P < 0.001; Table 3). On univariate analysis, HRR1 (r, − 0.86, P < 0.001) was found to be related to the presence of obstructive CAD. Furthermore, total cholesterol (r, 0.64, P = 0.024), lowdensity lipoprotein-cholesterol (r, 0.75, P = 0.013), peak HR (r, − 0.81, P < 0.001), Duke score (r, 0.88, P < 0.001), and ST depression (r, 0.72, P < 0.001) were found to be remarkably associated with the presence of obstructive CAD. The results of power analysis
Statistical power values of HRR1, HRR2, HRR3, HRR4, HRR5, and HRR6 of the PCI group between before and after intervention (bpm, n = 56) were 0.926, 0.838, 1.0, 1.0, 1.0, and 1.0, respectively. Moreover, statistical power values of HRR1, HRR2, HRR3, HRR4, HRR5, and HRR6 between the control group and the PCI group before intervention (bpm, n = 56) were 0.867, 0.979, 1.0, 1.0, 1.0 and 1.0, respectively. In addition, statistical power values of HRR1, HRR2, HRR3, HRR4, HRR5 and HRR6 between the control group and the PCI group after
Control group PCI group preintervention 1
2
3
4
5
6
Time post-ETT (min) HRR values of the control group at each time point from 1 to 6 min were significantly greater than those of the PCI group before intervention (*P < 0.01), especially at 3, 4, 5, and 6 min. HRR values at 1, 2, and 3 min increased sharply in the control group. ETT, exercise treadmill test; HRR, heart rate recovery; PCI, percutaneous coronary intervention.
Table 3 Comparison of HRR among the control group, the PCI group before intervention, and the PCI group after intervention (bpm, n = 56) HRR
Control group
PCI group before intervention
PCI group after intervention
HRR1 HRR2 HRR3 HRR4 HRR5 HRR6
22.4 ± 7.1 39.6 ± 8.1 53.8 ± 7.9 56.6 ± 9.3 59.8 ± 8.4 60.2 ± 9.1
18.0 ± 6.5a 33.2 ± 4.5a 35.8 ± 8.8a 38.8 ± 8.2a 39.4 ± 9.2a 40.2 ± 11.0a
23.0 ± 7.8b 38.4 ± 9.2b 52.0 ± 10.3b 53.6 ± 13.7b 53.8 ± 12.4b,c 53.8 ± 13.3b,c
HRR1, HRR2, HRR3, HRR4, HRR5, and HRR6 were the values of HRR at each time point from 1 to 6 min, which were defined as heart rate reduction from that at peak exercise to that 1, 2, 3, 4, 5, and 6 min after cessation of exercise. HRR, heart rate recovery; PCI, percutaneous coronary intervention. a P < 0.001 versus control group. b P < 0.001 versus PCI group before intervention. c P < 0.01 versus control group.
intervention (bpm, n =56) were 0.07, 0.11, 0.173, 0.258, 0.773, and 0.788, respectively. Importantly, statistical power values of peak HR, METs, ST depression, and Duke score between the PCI group and the control group before intervention were 1.0, 0.983, 1.0, and 1.0 respectively, and they were 0.784. 0.926, 1.0, and 1.0 after intervention, respectively. On the basis of these results, we thought the overall power value was relatively good and the sample size was sufficient for our study.
Discussion In the current study, we investigated the impact of coronary revascularization on HRR in patients with CAD
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who had undergone PCI. First, the peak HR and HRR values of patients with CAD were much lower than those of the control group. Thereafter, we observed that successful coronary revascularization through PCI improved HRR in the patients with CAD. These results suggest that HRR might provide a novel noninvasive index to evaluate the effect of coronary revascularization on CAD patients. HRR measurement serves as a simple and pragmatic method to investigate the risk for cardiovascular and all-cause mortality in patients with CAD. At present, it is controversial whether abnormal HRR can predict CAD. In an older male population, Cole et al. [13] showed that slow HRR was an independent predictor of mortality among patients with CAD. In contrast, Lipinski et al. [14] showed that HRR was not significantly affected by CAD, but patients with reduced HRR had a significantly greater number of narrowed coronary arteries than those without reduced HRR. The results obtained by Ghaffari and colleagues were consistent with those obtained by Lipinski and colleagues. However, another study demonstrated that delayed HRR was not helpful in predicting the presence of significant angiographic coronary disease [15]. These paradoxical findings might be explained, in part, by different recovering styles post peak exercise adopted in different studies [5]. In the study by Cole and colleagues, a 2 min ‘cool down’ after reaching peak exercise was performed in the test protocol. There are other studies indicating that the value of HRR might be affected by ‘cool down’, which decreases the sensitivity of the diagnosis [16,17]. In the study by Ghaffari et al. [5], HRR measurements were performed in the sitting position in the patients who did not undergo a ‘cool-down’ period. Watanabe et al. [17] measured HRR in the supine position immediately after reaching peak exercise. However, examining HRR in the supine position after cessation of the ETT might have a negative effect on the sensitivity for the detection of CAD [5]. Therefore, different recovering styles after termination of exercise associated with discrepant cardiac burden and venous return may have had an influence on HRR in previous studies. Our study also adopted a ‘cool-down’ stage after reaching peak exercise as part of the study protocol. This study showed that HRR values in patients with CAD significantly decreased at each time point from 1 to 6 min after exercise compared with control patients. HRR values at 1, 2, and 3 min after exercise increased sharply in the control and PCI groups after successful revascularization. However, HRR values in the PCI group before intervention apparently increased at 1 and 2 min. Although our results indicate that HRR3 may be appropriate for evaluating the effect of coronary revascularization in CAD patients, these findings should be explained with caution because direct comparisons among these studies are not possible given the discrepancies in their methods.
Initial increases in HR during exercise are mainly due to the reduction in parasympathetic tone, whereas sympathetic activation is responsible for HR greater than 100 bpm. Moreover, the rapid decrease in HR is also principally determined by parasympathetic tone in the early stage after termination of exercise [3,18]. In the present study, HRR values of patients with CAD improved significantly at each time point from 1 to 6 min after successful coronary revascularization. Significantly, HRR values of the PCI group increased more remarkably at each time point from 3 to 6 min after intervention compared with preintervention values. In light of these results, we infer that the reduction in HRR in the patients with CAD is mainly relevant to sympathetic activation [19]. Importantly, successful revascularization through PCI decreases sympathetic activation [20], and provides the evidence for application of PCI in the treatment of the patients with angiographically defined CAD. Researchers have measured cardiac autonomic functions derived from short-term HR variability recordings related to HRR after ETT in young individuals [21]. Further study will be beneficial to clarify the mechanisms underlying the change in HRR and autonomic tone during ETT in patients with CAD. Sengul and Duman [22] found that HRR at the first minute after exercise was significantly reduced in patients with metabolic syndrome compared with healthy controls. Furthermore, blunted HRR was strongly correlated with increased epicardial fat thickness in patients with metabolic syndrome. Yamada et al. [23] investigated the relationship between silent myocardial ischemia and HRR in patients with type 2 diabetes, and found that HRR was significantly associated with silent myocardial ischemia even after adjusting several confounding factors of type 2 diabetes. Turker et al. [24] also showed a significantly decreased HRR after exercise in patients with coronary artery ectasia. In our study, the incidence of type 2 diabetes was much higher in patients with CAD than in the control group, and the BMI of CAD patients was significantly higher than that of the control group. Although HRR in CAD patients improved after successful coronary revascularization, there still remained metabolic dysfunction and atherosclerosis. Therefore, postintervention HRR5 and HRR6 of the PCI group were still lower than those of the control group. However, more data are needed to determine whether metabolic syndrome or diabetes is an independent predictor of reduced HRR. Study limitations
The current study can be considered as a pilot study searching for a noninvasive method to evaluate the effect of revascularization in patients with CAD. If HRR values were investigated over the follow-up period, it would be helpful to reveal the relationship between HRR and the rate of re-stenosis in the PCI group. Moreover, the
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Effect of PCI on HRR Liu et al. 447
sample size is small, and our findings need to be confirmed in a larger cohort of patients. In addition, patients were limited to male only because of the differences in the features of ETT between male and female patients that have previously been exhibited. Significantly, HRR values will be measured immediately after reaching peak exercise in future work.
10
11
12
Conclusion
Successful revascularization through PCI could improve HRR in patients with major coronary artery involvement. Moreover, HRR measurement may be used as a noninvasive method for evaluating the effect of revascularization.
13
Acknowledgements 14
Conflicts of interest
There are no conflicts of interest.
References
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Effect of percutaneous coronary intervention on heart rate recovery in patients with coronary artery disease Jianguo Liu, Aibin Xu, Lili Niu and Junxia Li Objective This study aimed to investigate the effect of percutaneous coronary intervention (PCI) on heart rate recovery (HRR) in patients with angiographically defined coronary artery disease, and to search for a noninvasive method for evaluating the effect of revascularization. Methods From June 2012 to July 2013, 56 consecutive male patients with coronary artery disease were enrolled in the PCI group. Correspondingly, in the control group there were 56 consecutive male patients with chest pain but a normal coronary artery verified by angiography. The exercise treadmill test was performed 3 days before and 7 days after intervention in the PCI group, and 3 days before angiography in the control group. Results The peak heart rate, metabolic equivalents, and the Duke score were notably lower in the PCI group before intervention compared with the control group (P < 0.01). In contrast, preintervention ST depression in the PCI group was significantly higher than that in the control group (P < 0.01). Preintervention HRR values from 1 to 6 min were much lower in the PCI group compared with the control group (P < 0.01). HRR values from 1 to 6 min in the PCI
Introduction The prognostic value of abnormal heart rate recovery (HRR) after exercise with regard to predicting cardiovascular disease as well as mortality is well established [1]. After initiation of the exercise test, heart rate (HR) during the first few minutes increases because of withdrawal of parasympathetic tone. Several studies have demonstrated that delayed HRR is an independent predictor of increased mortality among patients undergoing the exercise treadmill test (ETT) [2,3]. Moreover, a previous prospective study has indicated that HRR is an independent predictor of all-cause mortality, even if the severity of coronary artery disease (CAD), exercise capacity, and left ventricular function are taken into consideration [4]. However, the potential association between slow HRR and cardiovascular morbidity is still not known. Recently, a prospective cross-sectional study showed that abnormal postexercise HRR at 1 min (< 18 bpm) was independently associated with the extent of CAD after multivariable logistic regression analysis adjusting for established CAD risk factors [5]. Unfortunately, it has not been ascertained whether HRR is affected by different coronary involvement, extent of major epicardial coronary involvement, or revascularization. Furthermore, there are few data on the 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
group post intervention increased significantly compared with preintervention HRR values (P < 0.01), especially at 3, 4, 5, and 6 min. HRR values at 1, 2, and 3 min increased sharply post intervention. Conclusion Successful revascularization through PCI could improve HRR in patients with major coronary artery involvement. Moreover, HRR measurement may be used as a noninvasive method for evaluating the effect of revascularization. Coron Artery Dis 26:442–447 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Coronary Artery Disease 2015, 26:442–447 Keywords: coronary artery disease, heart rate recovery, revascularization Department of Cardiology, General Hospital, Beijing Military Area Command, Beijing, China Correspondence to Jianguo Liu, PhD, Department of Cardiology, General Hospital, Beijing Military Area Command, Dongcheng District, Beijing 100700, China Tel/fax: + 86 010 6400 6459; e-mail: [email protected] Received 31 January 2015 Revised 13 April 2015 Accepted 15 April 2015
effect of coronary revascularization on HRR in patients with CAD. The aim of this study was to evaluate the effect of percutaneous coronary intervention (PCI) on HRR after ETT in patients with CAD verified by coronary angiography, as well as to explore a noninvasive method for evaluating the effect of revascularization.
Methods Study population and exclusion criteria
Our study originally enrolled 480 attendees from June 2012 to July 2013. Of these attendees, 424 were excluded because of the following reasons: acute coronary syndrome (n = 179), female (n = 125), 65 years or older and inability or reluctance to perform ETT (n = 98), left ventricular hypertrophy and substantial changes in STsegment depression (n = 9), Angiographic Rentrop Scores of collateral circulation greater than 1 and refusal to sign study consent forms (n = 13). Finally, a total of 56 consecutive male patients with angiographically defined CAD (aged 45–60 years) were enrolled in the PCI group. In brief, 43 patients (76.8%) received nitrate, 11 (19.6%) with nondihydropyridine calcium channel blockers as antihypertensive agents, six (10.7%) with the application DOI: 10.1097/MCA.0000000000000264
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Effect of PCI on HRR Liu et al. 443
of angiotensin-converting enzyme inhibitors, and 34 (60.7%) with β-blockers. Among these 34 patients using beta blockers, 27 (48.2%) were treated with metoprolol tartaric acid at a dose of 25 mg twice daily, and seven patients were administered bisoprolol fumarate pesos at a dose of 2.5 mg once daily. Angiographic Rentrop Scores of collateral circulation in the PCI group were less than 1 [6], and all patients in the PCI group achieved complete revascularization by percutaneous coronary angioplasty. Correspondingly, in the control group there were 56 consecutive male patients with chest pain but with a normal coronary artery verified by angiography. Among the 56 patients in the control group, eight (14.3%) were treated with a nondihydropyridine calcium channel blocker as an antihypertensive agent, four (7.1%) with angiotensin-converting enzyme inhibitors, and seven (12.5%) with metoprolol tartaric acid at a dose of 25 mg twice daily. To avoid the effect of β-blockers on HRR, they were discontinued for more than five half-life periods before ETT in both the PCI and the control groups. According to the American College of Cardiology/ American Heart Association 2002 guideline update for exercise testing, patients with absolute or relative contraindications including acute myocardial infarction, symptomatic severe aortic stenosis, and hypertrophic cardiomyopathy were excluded [7]. The study protocol was approved by the Institutional Review Committee on Human Research at our hospital. All participants gave their informed consent.
Angiographic analysis and definitions
Patients were eligible when coronary angiography was demonstrated by ETT results on the basis of American College of Cardiology/American Heart Association guidelines [8]. Radial artery access was chosen for coronary artery angiography and interventional procedures [9]. Cardiologists who were blinded to Duke treadmill scores and the patients’ HRR, as well as to the hypothesis of this study, semiquantitatively analyzed the degree of coronary artery luminal stenosis. Moreover, the reference lumen diameter was calculated by selecting end-diastolic frames to demonstrate stenosis in its most severe and nonforeshortened projection [10]. More than 50% diameter narrowing of the major coronary arteries was considered as significant CAD [11]. In our study, PCI was performed when stenosis was of at least 70% of the vessel diameter in at least one coronary artery. The definition of a successful PCI procedure was the achievement of a minimum stenosis diameter of less than 20% in the presence of Thrombolysis in Myocardial Infarction grade 3 flow. Furthermore, patients who had no major clinical complication and no signs of myocardial ischemia during hospitalization were relieved after undergoing the PCI procedure [12].
Exercise treadmill test protocols and heart rate recovery analysis
The ETT was performed 3 days before and 7 days after the PCI intervention in the PCI group, and 3 days before coronary artery angiography in the control group. The participants were forbidden from smoking or engaging in strenuous physical activity for at least 3 h before the examination. Thereafter, the ETT was performed on a Quinton T50 treadmill system (Quinton Cardiology Inc., Seattle, Washington, USA) according to a submaximal Bruce’s protocol, with continuous ECG monitoring. Blood pressure was measured and recorded at rest, at the end of each stress stage, at peak stress, and at recovery, respectively. In addition, data on symptoms in metabolic equivalents (METs) were acquired. ST-segments were considered as abnormal if at least 1 mm of horizontal or down-sloping ST-segment depression at 80 ms was found after the J point in at least three consecutive beats in two contiguous leads. ST-segment depression was also examined. Moreover, the Duke treadmill exercise score was calculated on the basis of the following formula: Duke treadmill exercise score ¼ exercise time½ð5max ST deviationÞ ð4treadmill angina indexÞ: The test was terminated for any of the following reasons: a rating of perceived exertion greater than 17 (Borg scale), achievement of a greater than 85% age-predicted maximum heart rate, inability to safely continue walking on the treadmill because of fatigue, systolic blood pressure greater than 250 mmHg, typical chest discomfort, severe arrhythmias, or more than 1 mm horizontal or downsloping ST-segment depression. Following peak exercise, patients walked for a 2 min cool-down period at 1.5 mph at a 2.5% grade [1], and the values of HRR at each time point from 1 to 6 min were defined as HR reduction from that at peak exercise to the rate at 1, 2, 3, 4, 5, and 6 min after cessation of exercise. The HRR values at each time point from 1 to 6 min were marked as HRR1, HRR2, HRR3, HRR4, HRR5, and HRR6, respectively. The maximal predicted HR was calculated based on the equation subtracting the patient’s age from 220. HRR values were analyzed using a Q-STRESS/Cardiac stress system (American International Medical, Bothell, Washington, USA) software.
Estimation of sample size
Sufficiency of samples is very important to guarantee reliability of the conclusion. Thus, in the current study, we applied Power and Sample Size Calculation version 3.1.2, 2014 software to carry out power analysis to estimate the sample size.
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Statistical analysis
Statistical analysis was carried out using SPSS statistical software for Windows version 22.0 (SPSS for Windows, version 22.0; SPSS Inc., Chicago, Illinois, USA). Data were expressed as mean ± SD or % (n) of patients. Differences in continuous variables were analyzed using independent t-tests, and differences in categorical variables were analyzed using the χ2-test. A two-sided Pvalue of less than 0.05 was considered to be statistically significant. Spearman’s analysis was used to determine which variables were associated with the presence of obstructive CAD on cardiac catheterization, on the basis of baseline clinical variables, along with HRR and other ETT variables.
Results Baseline characteristics and angiographic findings
There was no significant difference in age, total cholesterol level, and prevalence of hypertension between the two groups (Table 1). However, low-density lipoproteincholesterol and lipoprotein(a) levels of the control group were significantly lower than those of the PCI group (P < 0.001). Moreover, BMI and prevalence of diabetes mellitus were found to be significantly higher in the PCI group compared with the control group (BMI, P = 0.012; diabetes mellitus, P = 0.018). Similarly, smoking rate was remarkably elevated in the PCI group compared with the control group (P < 0.001). With regard to the use of nitrates, no patient was treated with nitrates in the control group, whereas 43 patients (76.8%) were treated with nitrates in the PCI group before intervention. Among the 56 patients in the PCI group, 15 had singlevessel disease in the left anterior descending coronary artery, 16 had double-vessel disease in the left anterior descending and left circumflex coronary arteries, 12 had double-vessel disease in the left anterior descending and right coronary arteries, and 13 in both left circumflex and right coronary arteries. All patients in the PCI group achieved complete revascularization with PCI. Table 1
Baseline characteristics
Variables Age (years) BMI (kg/m2) TC (mmol/l) LDL-C (mmol/l) LP(a) (mmol/l) DM2 Hypertension Smoking Nitrates
Control group (n = 56)
PCI group (preintervention, n = 56)
51.8 ± 3.8 25.9 ± 2.8 5.1 ± 1.1 2.6 ± 0.8 112.6 ± 27.8 7.2% (4) 25.0% (14) 12.5% (7) 0
52.4 ± 4.2 27.2 ± 3.4* 5.5 ± 1.4 3.5 ± 1.1** 243.5 ± 46.3** 23.2% (13)** 32.1% (18) 41.1% (23) 76.8% (43)
P-value 0.430 0.012 0.096 < 0.001 < 0.001 0.018 0.403 < 0.001
β-blockers were discontinued before the treadmill exercise test for five half-life periods in all patients. Data are expressed as mean ± SD or % (n) of patients. DM2, diabetes mellitus 2; LDL-C, low-density lipoprotein-cholesterol; LP(a), lipoprotein(a); PCI, percutaneous coronary intervention; TC, total cholesterol. *P < 0.05. **P < 0.01 versus control group.
Furthermore, the patients had no major cardiovascular complication during hospitalization. Comparison of peak heart rate and pertinent exercise treadmill test data between the control and percutaneous coronary intervention groups
The peak HR and the pertinent ETT data of the control and PCI groups are shown in Table 2. There was no difference in resting HR between the control and PCI groups. Preintervention peak HR and METs of the PCI group were significantly lower than those of the control group (P < 0.01). At the same time, postintervention peak HR and METs in the PCI group increased significantly compared with the control group (P < 0.01). However, postintervention peak HR in the PCI group was lower than that in the control group (P < 0.001), whereas no significant difference in METs was found between the two groups (P > 0.05). The Duke score was significantly higher in the control group compared with the PCI group before intervention. After intervention, the Duke score in the PCI group increased significantly compared with that before intervention (P < 0.01). In contrast, ST depression before intervention was significantly higher in the PCI group than in the control group (P < 0.01), whereas ST depression in the PCI group after intervention reduced significantly compared with that before intervention (P < 0.01). However, ST depression in the PCI group after intervention was higher than that in the control group, but without statistical significance (P > 0.05). Change in heart rate recovery in the percutaneous coronary intervention group before and after intervention
As shown in Fig. 1, there existed a significant statistical difference in HRR values in the PCI group before and after intervention at each time point from 1 to 6 min (P < 0.01). HRR values were significantly increased at 1, 2, and 3 min after intervention compared with those before intervention in the PCI group, and were stable after 3 min. Table 2 Comparison of the peak heart rate between the control group and the PCI group (bpm)
Peak HR METs ST depression (mm) Duke score
n
Control group
PCI group before PCI
PCI group after PCI
56 56 56
156.7 ± 10.4 11.2 ± 1.5 0.5 ± 0.1
128.8 ± 16.1a 9.8 ± 1.7a 1.5 ± 0.5a
135.8 ± 10.4a,b 10.8 ± 1.2b 0.6 ± 0.2b
56
10.7 ± 1.2
− 6.8 ± 2.3
6.7 ± 2.1a
HR, heart rate; MET, metabolic equivalent; PCI, percutaneous coronary intervention. a P < 0.01 versus control group. b P < 0.01 versus PCI group before PCI.
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Effect of PCI on HRR Liu et al. 445
Fig. 1
Fig. 2
80
80 70
∗
∗
∗
∗
40 ∗
20
∗
∗
∗
∗
50 40 30
∗
20 PCI group preintervention PCI group postintervention
10 0
∗
60
50
30
70
HRR (bpm)
HRR (bpm)
60
∗
1
2
3 4 Time post-ETT (min)
5
10 0
6
HRR values of the PCI group after successful revascularization increased significantly compared with those of the PCI group before intervention at each time point from 1 to 6 min (*P < 0.01), especially at 3, 4, 5, and 6 min. HRR values at 1, 2, and 3 min increased sharply post intervention, and apparently at 1 and 2 min before intervention. ETT, exercise treadmill test; HRR, heart rate recovery; PCI, percutaneous coronary intervention.
Comparison of heart rate recovery between the control and percutaneous coronary intervention groups
HRR values at each time point from 1 to 6 min were much lower in the PCI group before intervention compared with the control group (Fig. 2; P < 0.01). HRR values from 1 to 3 min increased sharply in the control group; similarly, HRR values in the PCI group before the procedure obviously increased from 1 to 2 min. However, no statistical differences in HRR1, HRR2, HRR3, and HRR4 were found between the PCI group after intervention and the control group. However, postintervention HRR5 and HRR6 of the PCI group were significantly lower than those of the control group (P < 0.001; Table 3). On univariate analysis, HRR1 (r, − 0.86, P < 0.001) was found to be related to the presence of obstructive CAD. Furthermore, total cholesterol (r, 0.64, P = 0.024), lowdensity lipoprotein-cholesterol (r, 0.75, P = 0.013), peak HR (r, − 0.81, P < 0.001), Duke score (r, 0.88, P < 0.001), and ST depression (r, 0.72, P < 0.001) were found to be remarkably associated with the presence of obstructive CAD. The results of power analysis
Statistical power values of HRR1, HRR2, HRR3, HRR4, HRR5, and HRR6 of the PCI group between before and after intervention (bpm, n = 56) were 0.926, 0.838, 1.0, 1.0, 1.0, and 1.0, respectively. Moreover, statistical power values of HRR1, HRR2, HRR3, HRR4, HRR5, and HRR6 between the control group and the PCI group before intervention (bpm, n = 56) were 0.867, 0.979, 1.0, 1.0, 1.0 and 1.0, respectively. In addition, statistical power values of HRR1, HRR2, HRR3, HRR4, HRR5 and HRR6 between the control group and the PCI group after
Control group PCI group preintervention 1
2
3
4
5
6
Time post-ETT (min) HRR values of the control group at each time point from 1 to 6 min were significantly greater than those of the PCI group before intervention (*P < 0.01), especially at 3, 4, 5, and 6 min. HRR values at 1, 2, and 3 min increased sharply in the control group. ETT, exercise treadmill test; HRR, heart rate recovery; PCI, percutaneous coronary intervention.
Table 3 Comparison of HRR among the control group, the PCI group before intervention, and the PCI group after intervention (bpm, n = 56) HRR
Control group
PCI group before intervention
PCI group after intervention
HRR1 HRR2 HRR3 HRR4 HRR5 HRR6
22.4 ± 7.1 39.6 ± 8.1 53.8 ± 7.9 56.6 ± 9.3 59.8 ± 8.4 60.2 ± 9.1
18.0 ± 6.5a 33.2 ± 4.5a 35.8 ± 8.8a 38.8 ± 8.2a 39.4 ± 9.2a 40.2 ± 11.0a
23.0 ± 7.8b 38.4 ± 9.2b 52.0 ± 10.3b 53.6 ± 13.7b 53.8 ± 12.4b,c 53.8 ± 13.3b,c
HRR1, HRR2, HRR3, HRR4, HRR5, and HRR6 were the values of HRR at each time point from 1 to 6 min, which were defined as heart rate reduction from that at peak exercise to that 1, 2, 3, 4, 5, and 6 min after cessation of exercise. HRR, heart rate recovery; PCI, percutaneous coronary intervention. a P < 0.001 versus control group. b P < 0.001 versus PCI group before intervention. c P < 0.01 versus control group.
intervention (bpm, n =56) were 0.07, 0.11, 0.173, 0.258, 0.773, and 0.788, respectively. Importantly, statistical power values of peak HR, METs, ST depression, and Duke score between the PCI group and the control group before intervention were 1.0, 0.983, 1.0, and 1.0 respectively, and they were 0.784. 0.926, 1.0, and 1.0 after intervention, respectively. On the basis of these results, we thought the overall power value was relatively good and the sample size was sufficient for our study.
Discussion In the current study, we investigated the impact of coronary revascularization on HRR in patients with CAD
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who had undergone PCI. First, the peak HR and HRR values of patients with CAD were much lower than those of the control group. Thereafter, we observed that successful coronary revascularization through PCI improved HRR in the patients with CAD. These results suggest that HRR might provide a novel noninvasive index to evaluate the effect of coronary revascularization on CAD patients. HRR measurement serves as a simple and pragmatic method to investigate the risk for cardiovascular and all-cause mortality in patients with CAD. At present, it is controversial whether abnormal HRR can predict CAD. In an older male population, Cole et al. [13] showed that slow HRR was an independent predictor of mortality among patients with CAD. In contrast, Lipinski et al. [14] showed that HRR was not significantly affected by CAD, but patients with reduced HRR had a significantly greater number of narrowed coronary arteries than those without reduced HRR. The results obtained by Ghaffari and colleagues were consistent with those obtained by Lipinski and colleagues. However, another study demonstrated that delayed HRR was not helpful in predicting the presence of significant angiographic coronary disease [15]. These paradoxical findings might be explained, in part, by different recovering styles post peak exercise adopted in different studies [5]. In the study by Cole and colleagues, a 2 min ‘cool down’ after reaching peak exercise was performed in the test protocol. There are other studies indicating that the value of HRR might be affected by ‘cool down’, which decreases the sensitivity of the diagnosis [16,17]. In the study by Ghaffari et al. [5], HRR measurements were performed in the sitting position in the patients who did not undergo a ‘cool-down’ period. Watanabe et al. [17] measured HRR in the supine position immediately after reaching peak exercise. However, examining HRR in the supine position after cessation of the ETT might have a negative effect on the sensitivity for the detection of CAD [5]. Therefore, different recovering styles after termination of exercise associated with discrepant cardiac burden and venous return may have had an influence on HRR in previous studies. Our study also adopted a ‘cool-down’ stage after reaching peak exercise as part of the study protocol. This study showed that HRR values in patients with CAD significantly decreased at each time point from 1 to 6 min after exercise compared with control patients. HRR values at 1, 2, and 3 min after exercise increased sharply in the control and PCI groups after successful revascularization. However, HRR values in the PCI group before intervention apparently increased at 1 and 2 min. Although our results indicate that HRR3 may be appropriate for evaluating the effect of coronary revascularization in CAD patients, these findings should be explained with caution because direct comparisons among these studies are not possible given the discrepancies in their methods.
Initial increases in HR during exercise are mainly due to the reduction in parasympathetic tone, whereas sympathetic activation is responsible for HR greater than 100 bpm. Moreover, the rapid decrease in HR is also principally determined by parasympathetic tone in the early stage after termination of exercise [3,18]. In the present study, HRR values of patients with CAD improved significantly at each time point from 1 to 6 min after successful coronary revascularization. Significantly, HRR values of the PCI group increased more remarkably at each time point from 3 to 6 min after intervention compared with preintervention values. In light of these results, we infer that the reduction in HRR in the patients with CAD is mainly relevant to sympathetic activation [19]. Importantly, successful revascularization through PCI decreases sympathetic activation [20], and provides the evidence for application of PCI in the treatment of the patients with angiographically defined CAD. Researchers have measured cardiac autonomic functions derived from short-term HR variability recordings related to HRR after ETT in young individuals [21]. Further study will be beneficial to clarify the mechanisms underlying the change in HRR and autonomic tone during ETT in patients with CAD. Sengul and Duman [22] found that HRR at the first minute after exercise was significantly reduced in patients with metabolic syndrome compared with healthy controls. Furthermore, blunted HRR was strongly correlated with increased epicardial fat thickness in patients with metabolic syndrome. Yamada et al. [23] investigated the relationship between silent myocardial ischemia and HRR in patients with type 2 diabetes, and found that HRR was significantly associated with silent myocardial ischemia even after adjusting several confounding factors of type 2 diabetes. Turker et al. [24] also showed a significantly decreased HRR after exercise in patients with coronary artery ectasia. In our study, the incidence of type 2 diabetes was much higher in patients with CAD than in the control group, and the BMI of CAD patients was significantly higher than that of the control group. Although HRR in CAD patients improved after successful coronary revascularization, there still remained metabolic dysfunction and atherosclerosis. Therefore, postintervention HRR5 and HRR6 of the PCI group were still lower than those of the control group. However, more data are needed to determine whether metabolic syndrome or diabetes is an independent predictor of reduced HRR. Study limitations
The current study can be considered as a pilot study searching for a noninvasive method to evaluate the effect of revascularization in patients with CAD. If HRR values were investigated over the follow-up period, it would be helpful to reveal the relationship between HRR and the rate of re-stenosis in the PCI group. Moreover, the
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Effect of PCI on HRR Liu et al. 447
sample size is small, and our findings need to be confirmed in a larger cohort of patients. In addition, patients were limited to male only because of the differences in the features of ETT between male and female patients that have previously been exhibited. Significantly, HRR values will be measured immediately after reaching peak exercise in future work.
10
11
12
Conclusion
Successful revascularization through PCI could improve HRR in patients with major coronary artery involvement. Moreover, HRR measurement may be used as a noninvasive method for evaluating the effect of revascularization.
13
Acknowledgements 14
Conflicts of interest
There are no conflicts of interest.
References
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