The Relationship Between Resting Heart Rate and SYNTAX Score in Patients With Stable Coronary Artery Disease

Abstract

We investigated the relationship between resting heart rate (HR) and The Synergy between percutaneous coronary intervention with Taxus and cardiac surgery (SYNTAX) score in patients with stable coronary artery disease (SCAD). A total of 420 patients who were admitted to our outpatient clinic for stable angina pectoris with sinus rhythm and had at least 50% narrowing in at least 1 coronary artery after coronary angiography were included in the study. Patients were divided into 3 tertiles based on the resting HR: HR of tertile 1 was ≤65 (n = 138), tertile 2 was between 66 and 76 (n = 139), and tertile 3 was ≥77 beats/min (n = 143). The SYNTAX score (7.6 ± 4.6, 12.4 ± 5.6, 20.3 ± 8.1; P < .001) was significantly higher for those in tertile 3 than for those in tertiles 1 and 2. Leukocyte count (7.8 ± 2.2, 7.9 ± 2.2, 8.4 ± 2.3 × 10⁹/L; P = .035) and C-reactive protein (CRP) levels (2.4 ± 0.5, 3.2 ± 0.7, 4.5 ± 1.2 mg/L, P < .001) were increasing from the lowest to the highest tertile. Using multiple logistic regression analysis, CRP (odds ratio [OR] 1.54 [1.17-2.11], P = .001) and resting HR (OR 1.67 [1.25-2.19], P < .001) emerged as independent predictors of SYNTAX score. Resting HR is related to SYNTAX score in patients with SCAD.

Keywords

resting heart rate coronary artery disease SYNTAX score

Introduction

A significant association between resting heart rate (HR) and all-cause and cardiovascular (CV) mortality has been reported in numerous epidemiologic studies over the last 35 years.^1
–3 Resting HR, which is a simple and easily measurable clinical parameter, predicts both CV and non-CV death in general populations,^4
–6 in patients with acute coronary syndromes (ACSs),^7,8 stable coronary artery disease (SCAD),^9,10 heart failure,¹¹ hypertension,¹² and stroke.¹³ These studies demonstrated a strong, graded, and independent relationship between resting HR and incident CV disease.

The Synergy between percutaneous coronary intervention with Taxus and cardiac surgery (SYNTAX) score, which was established during the SYNTAX trial, is a helpful tool for treatment decisions regarding the complexity of the coronary artery disease (CAD). The SYNTAX score is an anatomical-based tool that quantitatively characterizes the coronary vasculature with respect to the number, location, complexity, and functional impact of angiographically obstructive lesions.¹⁴ Depending on the location and several angiographic characteristics, the lesion is given a corresponding point value, and finally scores of individual lesions are summed via the Internet-based SYNTAX calculator to derive the final score.¹⁵ Retrospective analyses suggest that CAD severity by SYNTAX scoring might help to guide the selection of revascularization strategies and, therefore, improve treatment decisions.^16,17 The SYNTAX score has been shown to be able to predict mortality and morbidity at early and late follow-up in patients with CAD, irrespective of clinical presentation, including ACS^18,19 and SCAD.²⁰

In this study, we aimed to investigate the usefulness of resting HR in predicting severity and complexity of coronary atherosclerosis as assessed by the SYNTAX score in patients with SCAD who underwent coronary angiography (CAG).

Methods

A total of 420 patients who admitted to our tertiary center outpatient clinic for stable angina pectoris with sinus rhythm and had at least 50% narrowing in at least 1 coronary artery after CAG were included in the study. Patients with a history of coronary artery bypass graft surgery, history of percutaneous coronary intervention, heart failure (ejection fraction <50%), acute or chronic infectious disease, rheumatologic diseases, thyroid diseases, severe kidney or liver failure, and psychiatric diseases were excluded from the study. Other than these exclusion criteria, patients with a permanent pacemaker, sick sinus syndrome, sinoatrial block, total atrioventricular block, and atrial fibrillation were also excluded from the study (Figure 1). Written informed consent was obtained from all the participants, and the local ethics committee approved the study.

Baseline characteristics, including age, sex, smoking status, hyperlipidemia, hypertension, diabetes mellitus (DM), family history and previous medications, systolic blood pressure (BP), diastolic BP, body mass index (BMI), and angina grade according to Canadian Cardiovascular Society (CCS) angina scale, were obtained retrospectively in all patients. Hypertension was defined as systolic BP >140 mm Hg and/or a diastolic BP >90 mm Hg at least 2 times or if the individual was taking antihypertensive medications. The diagnosis of DM was based on the previous history of DM treated with or without drug therapies. Hyperlipidemia was defined as total cholesterol >200 mg/dL or treatment with a lipid-lowering agent. Furthermore, on admission, each patient was evaluated for serum glucose, creatinine, lipid profile, C-reactive protein (CRP), and hematological indices.

Resting HR was noted in first clinical outpatient contact. Resting HR was determined by performing routine 12-lead electrocardiography (ECG) after resting for 10 minutes. Mean time between first outpatient clinical contact and CAG was 73 ± 18 hours.

Judkins technique was used through femoral or radial approach in the implementation of selective CAG. Left anterior descending and left circumflex coronary arteries were evaluated in at least 4 angiographic views, while right coronary artery was being evaluated in at least 2 angiographic views. The coronary angiograms were examined by 2 specialists blinded to the clinical and laboratory findings of the cases. Each coronary lesion producing a ≥50% luminal obstruction in vessels ≥1.5 mm was separately scored and added to provide the SYNTAX score. The calculation was performed with the Internet-based SYNTAX calculator version 2.10 (www.syntaxscore.com).

Analyses were performed using SPSS 20.0 (SPSS, Inc, Chicago, Illinois). Continuous data were presented as mean ± standard deviation. The Kolmogorov-Smirnov test was used to test the distribution pattern. The study population was assigned into tertiles based on resting HR at admission. Comparisons of multiple mean values were carried out by Kruskal-Wallis tests or analysis of variance as appropriate. Categorical variables were summarized as percentages and compared with chi-square test. Pearson correlation coefficient was computed to examine the association between 2 continuous variables. Effects of different variables on SYNTAX score were calculated using univariate linear regression analysis for each. The SYNTAX score was accepted as the ordinal-dependent variable (SYNTAX score >22 or not), and variables for which the unadjusted P value was <.10 in linear regression analysis were identified as potential risk markers and included in the full model. We reduced the model using stepwise multivariate logistic regression analyses and eliminated potential risk markers using likelihood ratio tests. A 2-sided P value <.05 was considered significant, and the confidence interval was 95%.

Results

A total of 420 patients (mean age 62.08 ± 9.55 years, 72% men) were divided into 3 tertiles according to resting HR. Tertile 1 composed of patients with HR ≤65 (n = 138), tertile 2 composed of patients with HR between 66 and 76 (n = 139), and tertile 3 composed of patients with HR ≥ 77 beats/min (n = 143). Mean HR of tertiles were 60.9 ± 3.6 in tertile 1, 69.8 ± 3.4 in tertile 2, and 86.3 ± 6.9 in tertile 3 (P < .001).

The baseline clinical characteristics of the study population are summarized in Table 1. Compared to tertiles 1 and 2, tertile 3 had more patients with DM (36.2%, 51.1%, and 62.2%; P < .001) and smokers (42.7%, 55.3%, and 61.5%; P = .006). Angina severity assessed by CCS angina classification (1.8 ± 0.5 vs 2.0 ± 0.6 vs 2.4 ± 0.6, P < .001) and BMI (22.1 ± 1.9 vs 23.1 ± 2.0 vs 25.8 ± 2.3, P < .001) were significantly increasing when going from lowest to highest tertile. The SYNTAX score of patients in tertile 3 was significantly higher than that of patients in tertiles 2 and 1 (20.3 ± 8.1 vs 12.4 ± 5.6 vs 7.6 ± 4.6, respectively, P < .001; Figure 2). Of the 420 patients, 354 had an SYNTAX score of <22.

Table 1.

Clinical Characteristics of the Study Population.^a

Variables	Tertile 1 (n = 138, HR ≤ 65)	Tertile 2 (n = 139, 65 < HR <77)	Tertile 3 (n = 143, HR ≥ 77)	P
Age, years	60.3 ± 9.3	61.3 ± 9.3	62.5 ± 9.9	.158
Male (%)	94 (68.1)	97 (69.7)	112 (78.3)	.112
Diabetes mellitus (%)	50 (36.2)	71 (51.1)	89 (62.2)	<.001
Hypertension (%)	77 (55.7)	91 (65.4)	86 (60.1)	.257
Smoking (%)	59 (42.7)	77 (55.3)	88 (61.5)	.006
Family history (%)	21 (15.2)	24 (17.2)	27 (18.8)	.421
Body mass index, kg/m²	22.1 ± 1.9	23.1 ± 2.0	25.8 ± 2.3	<.001
CCS angina class	1.8 ± 0.5	2.0 ± 0.6	2.4 ± 0.6	<.001
Medications
Aspirin (%)	65 (47.1)	67 (48.2)	68 (47.5)	.734
β-blocker (%)	62 (44.9)	57 (41.0)	55 (38.4)	.542
Ca-channel blocker (%)	18 (13.1)	15 (10.7)	16 (11.1)	.702
ACEI/ARB (%)	49 (35.5)	45 (32.3)	47 (32.8)	.735
Statin (%)	39 (28.2)	40 (28.7)	37 (25.8)	.798
LV ejection fraction	61.2 ± 5.4	60.7 ± 5.7	60.9 ± 5.8	.658
Heart rate	60.9 ± 3.6	69.8 ± 3.4	86.3 ± 6.9	<.001
SYNTAX score	7.6 ± 4.6	12.4 ± 5.6	20.3 ± 8.1	<.001

Abbreviations: CCS, Canadian Cardiovascular Society; LV, left ventricular; ACEI/ARB, angiotensin-converting enzyme inhibitor/aldosterone receptor blocker; SYNTAX, The Synergy between percutaneous coronary intervention with Taxus and cardiac surgery; HR, heart rate; SD, standard deviation.

^aData are expressed as mean ± SD and number (percentage).

Laboratory parameters of the patients are shown in Table 2. There were no significant difference in terms of glucose, creatinine, hemoglobin, and lipid parameters between the tertiles. However, leukocyte count (7.8 ± 2.2 vs 7.9 ± 2.2 vs 8.4 ± 2.3 × 10⁹/L, P = .035) and CRP levels (2.4 ± 0.5 vs 3.2 ± 0.7 vs 4.5 ± 1.2 mg/L, P < .001) significantly increased when going from lowest to highest tertile.

Table 2.

Laboratory Parameters of Study Population.^a

Variables	Tertile 1 (n = 138, HR ≤ 65)	Tertile 2 (n = 139, 65 < HR < 77)	Tertile 3 (n = 143, HR ≥ 77)	P
Glucose, mg/dL	120 ± 39	124 ± 56	129 ± 58	.358
Creatinine, mg/dL	0.9 ± 0.3	0.9 ± 0.2	1.0 ± 0.5	.209
Uric acid, mg/dL	6.0 ± 1.6	5.6 ± 1.4	5.5 ± 1.5	.213
Total cholesterol, mg/dL	181 ± 41	184 ± 44	189 ± 45	.311
LDL cholesterol, mg/dL	108 ± 36	112 ± 39	115 ± 40	.328
HDL cholesterol, mg/dL	42 ± 12	43 ± 16	41 ± 11	.335
Triglyceride, mg/dL	158 ± 81	155 ± 81	169 ± 97	.447
Hemoglobin, g/L	14.1 ± 3.1	14.2 ± 2.7	13.7 ± 1.9	.201
Platelets, ×10⁹/L	257.1 ± 60.1	262.5 ± 66.3	255.2 ± 75.6	.647
Leukocyte count, ×10⁹/L	7.8 ± 2.2	7.9 ± 2.2	8.4 ± 2.3	.035
C-reactive protein, mg/L	2.4 ± 0.5	3.2 ± 0.7	4.5 ± 1.2	<.001

Abbreviations: HR, heart rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation.

^aData are expressed as mean ± SD.

There was significant correlation between resting HR and SYNTAX score (r = .690, P < .001) and between resting HR and CRP levels (r = .735, P < .001; Figure 3). According to multivariate stepwise logistic regression analyses, CRP (odds ratio [OR] 1.54 [1.17-2.11], P = .001) and resting HR (OR 1.67 [1.25-2.19], P < .001) reached statistical significance (Table 3).

Table 3.

Predictors of SYNTAX Score in Univariate and Multivariate Logistic Regression Analysis.

Variables	Univariate		Multivariate
Variables	OR (95% CI)	P Value	OR (95% CI)	P Value
Age	1.20 (0.99-1.05)	.193
Diabetes mellitus	2.08 (1.15-3.76)	.015	1.12 (0.98-1.76)	.078
Hypertension	1.17 (0.65-2.10)	.607
Smoking	1.37 (0.77-2.44)	.289
Body mass index	1.75 (1.52-2.03)	<.001	1.14 (0.99-1.74)	.064
Low-density lipoprotein	1.05 (0.97-1.22)	.102
C-reactive protein	2.68 (2.06-3.48)	<.001	1.54 (1.17-2.11)	.001
Leukocyte count	1.12 (0.98-1.22)	.051	1.17 (0.88-1.38)	.162
Heart rate	1.24 (1.17-1.31)	<.001	1.67 (1.25-2.19)	<.001

Abbreviations: CI, confidence interval; OR, odds ratio; SYNTAX, The Synergy between percutaneous coronary intervention with Taxus and cardiac surgery.

Discussion

In the present study, we demonstrated that resting HR is strongly related to severity and complexity of coronary atherosclerosis as assessed by the SYNTAX score in patients with SCAD.

Since the publication that showed an interesting correlation between resting HR and life expectancy among mammals in 1997, several studies have been conducted to define the relationship between HR and CV disease in humans.²¹ In the past 2 decades, there has been growing evidence that resting HR might be a marker or even a risk factor for CV morbidity and mortality. Recently, the FINRISK (Cardiovascular risk factor changes in Finland) study, a large prospective population-based observational study, demonstrated strong, graded, and independent relationship between resting HR and incident CV disease both in healthy men and in healthy women.²² The Coronary Artery Surgery Study registry assessed the relationship between resting HR and CV mortality in approximately 25 000 patients with suspected or proven CAD over a median follow-up of 15 years. Multivariate analysis revealed that patients with a resting HR >83 beats/min had a significantly higher risk of CV mortality than patients with a resting HR ≤62 beats/min.²³ In the Framingham study, CV and coronary mortality increased progressively with resting HR in a cohort of 5070 patients free from CV disease at the time of entry into the study, and the effect of HR on mortality was independent of other traditional CV risk factors.²⁴

Recent evidence suggests an important role of HR in the pathophysiology of atherosclerosis. Elevated HR can indirectly be proatherosclerotic by expressing sympathetic system over reactivity.²⁵ A direct effect has also been described. First, it enhances the magnitude and the frequency of the mechanical load on arterial wall, which cause increased tensile stress on endothelial cells and upregulate proatherogenic gene expression.²⁶ By inducing shortening of diastolic period and increasing systolic time due to increased HR prolong exposure of endothelium to the proatherogenic effects of shear stress.²⁷ Enhanced low and oscillatory shear stress and phasic tensile stress stimulate both migration and proliferation of smooth muscle cells from the media to intima, increasing arterial stiffness.²⁸

Inflammation plays an important role in the initiation and progression of atherosclerosis.²⁹ We found an increase in leukocyte count, and CRP levels parallel to resting HR and SYNTAX score. These findings support the hypothesis that elevated HR may also be a sign of increased inflammation, and HR is not the sole reason for an increased SYNTAX score.

Heart rate also plays an important role in plaque instability and rupture. An angiographic human study in patients who underwent 2 CAG procedures within 6 months showed that an HR >80 bpm facilitated plaque disruption.³⁰ In this study, regression analysis identified a positive association between the presence of plaque disruption in the second angiogram and a mean HR >80 bpm. These data indicate that hemodynamic forces may play a crucial role in the pathogenesis of plaque disruption. Heart rate is also a prognostic factor in other clinical syndromes related to CAD such as patients with left ventricular systolic dysfunction. A subgroup analysis of the placebo arm of the BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with CAD and left ventricUlar dysfunction) trial, composed of patients with CAD and systolic dysfunction, showed that patients with an HR >70 bpm had increased risk of CV death (34%), hospital admission for heart failure (53%), hospital admission for myocardial infarction (46%), and coronary revascularization (38%).¹⁰ However, in patients with heart failure, elevated HR is accepted as a physiological and beneficial compensatory response and because of that results of that trial may not show the direct effect of HR on CV mortality and morbidity.

The mean resting HR of our study population was 72. Angina grade according to CCS angina scale was increasing while moving on to higher HR tertiles. Ischemia may be a consequence of high resting HR, where myocardial oxygen demand will increase and coronary perfusion will decrease.

Conclusion

The relationship between HR and CV events is now well known. In our study, we demonstrated that resting HR is a powerful and independent predictor of severity and complexity of coronary atherosclerosis as assessed by the SYNTAX score in patients with SCAD. Therapeutic targets to decrease HR to prevent CV mortality and morbidity need further studies.

Limitations

Our study has some limitations. First, we determined the HR with a resting ECG. However, HR inherently varies during the day. The resting HR recorded at any particular time of the day may be a limitation. Second, we excluded patients with other than sinus rhythm from the study. Due to this, our results cannot be generalized to all patients with SCAD. Third, although we excluded patients with systemic and psychiatric diseases that affect resting HR, the results in some patients may be influenced by undetermined factors.

Footnotes

Authors’ Note

All authors contributed substantially to the conception and design or acquisition of data or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and the final approval of the version to be published.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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