Incremental prognostic value of combined information of arterial stiffness and the result of treadmill exercise test in patients with suspected coronary artery disease

doi:10.21203/rs.3.rs-4912915/v1

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Incremental prognostic value of combined information of arterial stiffness and the result of treadmill exercise test in patients with suspected coronary artery disease

https://doi.org/10.21203/rs.3.rs-4912915/v1

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The effectiveness of diagnostic tools can be enhanced by their combination. This study aimed to investigate whether arterial stiffness data, obtained by brachial-ankle pulse wave velocity (baPWV) measurement, could improve prognostic value to exercise treadmill test (ETT) to predict future cardiovascular events. A total of 1,788 consecutive subjects (mean age 55.8 ± 10.7 years, 59.1% men) with suspected of having coronary artery disease (CAD), who underwent ETT and baPWV on the same day were prospectively recruited. The study outcome was major adverse cardiovascular event (MACE), a composite of cardiac death, non-fatal myocardial infarction, and coronary revascularization. During a mean follow-up period of 875 days (interquartile range, 116–2,212 days), there were 88 cases of MACE (4.9%). The elevated baPWV (≥ 1,440 cm/s) (hazard ratio [HR] 5.18, 95% confidence interval [CI] 2.68–10.0, P < 0.001) and positive ETT result (HR 2.81, 95% CI 1.77–4.47, P < 0.001) were associated with MACE even after adjustment for potential confounders. The combination of baPWV to traditional risk factors and ETT result further stratified the subjects’ risk (low baPWV and negative ETT result vs high baPVW and positive ETT result; HR 16.44, 95% CI 6.17–43.78, P < 0.001). Arterial stiffness, assessed by baPWV, had incremental prognostic value to ETT result in patients with suspected of CAD. Combined information of baPWV and ETT result can serve as a useful clinical tool for risk stratification in this high-risk patient population.

Health sciences/Cardiology/Interventional cardiology

Health sciences/Risk factors

cardiovascular disease

pulse wave analysis

risk assessment

treadmill test

vascular stiffness

Coronary artery disease (CAD) is the leading cause of death globally.¹ Therefore, it is important to detect CAD early, start appropriate treatment, and identify high-risk patients. Invasive coronary angiography (ICA) is the gold standard in diagnosing CAD. However, it usually carries potential risks and increases patients’ medical expenses.² Given these limitations of ICA, several methods are used to classify a patient’s risk, such as risk scoring systems.^3,4 These risk scoring systems predict risk based on traditional risk factors. However, a large number of people have reported experiencing cardiovascular events even if they do not have pre-existing risk factors.⁵ The exercise treadmill test (ETT) is an important diagnostic and prognostic prediction tool for assessing patients with suspected CAD regardless of the presence of traditional risk factors. However, given the less than optimal diagnostic accuracy of ETT, some patients might undergo unnecessary ICA, while others may miss out on vital CAD treatment.⁶

Interest in arterial stiffness in the cardiovascular field has been increasing. Arterial stiffness is associated with CAD and serves as a predictor of cardiovascular events, independent of traditional risk factors.^7–9 Arterial stiffness can be measured through several methods. Among them, brachial-ankle pulse wave velocity (baPWV) stands out as a simple and commonly used methods.¹⁰ Recent study have indicated that the prognostic value increases when pulse wave velocity (PWV) information is combined with other diagnostic tools.^11–13 Considering the usefulness of both ETT and baPWV in predicting the prognosis of CAD, it can be speculated that combining the results of these two tests is valuable for the prediction of future cardiovascular events. However, no research has been conducted on this issue. Therefore, this study was conducted to investigate the incremental value of the combination of baPWV to ETT in predicting future cardiovascular events in patients with suspected CAD.

Study population

From January 2010 to April 2020, subjects suspected of having CAD who agreed to participate in the study were prospectively recruited. The study subjects ETT and baPWV on the same day. Initially, 2,242 subjects agreed to participate in the study. However, the following were excluded: 1) 119 subjects with a history of CAD, 2) 16 subjects with a history of stroke, 3) 2 subjects who did not undergo the baPWV measurement, 4) 23 subjects with an ankle-brachial index < 0.9, 5) 122 subjects with inadequate ETT results, and, 6) 82 subjects who underwent percutaneous coronary intervention (PCI) or coronary bypass graft surgery (CABG) within 30 days due to high- risk features. Consequentially, 1,788 subjects were included in the final analysis of the study. This study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the Institutional Review Board (IRB) of Boramae Medical Center (Seoul, Korea) (IRB number, 10-2022-12). Written informed consent was obtained from each study participant.

Data collection

The patient’s height and body weight were measured at the time of admission. The body mass index (BMI) was calculated by dividing weight in kilograms by height squared in meters (kg/m²). A previous history of cardiovascular risk factors, including hypertension, diabetes mellitus (DM), dyslipidemia, current smoking status, and obesity, was obtained. Hypertension was defined as the use of antihypertensive medications or systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg. DM was defined as the use of oral hypoglycemic agents or insulin, or serum fasting glucose level ≥ 126 mg/dL. Dyslipidemia was defined as known but untreated or currently being treated with a lipid-lowering agent. Patients were classified as current smokers if they smoked regularly for the past 12 months. Obesity was defined as BMI ≥ 25 kg/m².¹⁴ Laboratory findings including hemoglobin, fasting glucose, glycated hemoglobin A1c, estimated glomerular filtration rate (GFR) calculated with modification of diet in renal disease equation, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride and C-reactive protein were recorded.¹⁵ Transthoracic echocardiography was performed, and left ventricular ejection fraction (LVEF) were measured according to current practice guideline.¹⁶ Information on cardiovascular medications such as beta-blockers, renin-angiotensin system (RAS) blockers, calcium channel blockers, and statins were also obtained.

ETT

Patients with baseline electrocardiogram (ECG) abnormalities, including preexcitation (Wolff-Parkinson-White) syndrome, electronically paced ventricular rhythm, greater than 1 mm of resting ST depression, and complete left bundle branch block, were excluded from the ETT. ETT was performed according to standard Bruce protocol.¹⁷ The speed and incline of the treadmill were increased every three minutes. The initial stage started at a slope of 10% with a speed of 1.7 mph. The second stage was carried out at a slope of 12% with a speed of 2.5 mph. The third stage was carried out at a slope of 14% with a speed of 3.4 mph. The fourth stage was carried out at a slope of 16% with a speed of 4.2 mph. The fifth stage was carried out at a slope of 18% with a speed of 5 mph. Finally, the sixth stage was carried out at a slope of 20% with a speed of 5.5 mph. Surface 12-lead ECG was monitored continuously throughout the test, and brachial BP was measured at rest, at each stress stage, at peak stress, and at the end of the recovery stage. According to a scientific statement from the American Heart Association, the test was terminated in the following situations. 1) ST-segment elevation (> 1.0 mm) in leads without preexisting Q waves because of prior myocardial infarction (other than aVR, aVL, and V1), 2) drop in systolic blood pressure > 10 mm Hg, despite an increase in workload, when accompanied by any other evidence of ischemia, 3) moderate-to-severe angina, 4) central nervous system symptoms (e.g., ataxia, dizziness, near syncope), 5) signs of poor perfusion (cyanosis or pallor), 6) sustained ventricular tachycardia or other arrhythmia, including second- or third-degree atrioventricular block, that interferes with normal maintenance of cardiac output during exercise, 7) technical difficulties in monitoring the ECG or systolic blood pressure, 8) the subject’s request to stop.¹⁸ ST changes were read at 60 to 80 ms from the J point and considered positive for ischemia if there is a 1 mm (0.1mV) or more horizontal or down-sloping ST depression at any heart rate, and nothing prevents proper interpretation of the test results.

baPWV measurement

On the day of baPWV measurement, subjects abstained from smoking, alcohol, and caffeinated beverages such as coffee or green tea. The patient's usual medications were not interrupted and continued as usual without interruption. The patient rested in bed at least 5 minutes before the examination. Measurements were taken in a quiet, closed room with constant temperature and humidity. The baPWV was measured using a noninvasive automated waveform analyzer (VP-100; Colins, Komaki, Japan).^9,10 Cuffs were wrapped around both upper arms and ankles. Pressure waveforms from the brachial and tibial arteries were recorded simultaneously with plethysmographs and oscillometric pressure sensors using occluding/sensing cuffs. The time interval between the pressure waveforms of the brachial artery and the tibial artery (pulse transit time) were measured, and baPWV was automatically calculated based on the distance estimated from the patient's height. The average of right and left baPWV measurements was used for analysis in this study. All measurements were performed by a single experienced operator, who was blinded to the patients’ clinical data.

Clinical events

Major adverse cardiovascular events (MACE), the composite of cardiac death, non-fatal myocardial infarction, and coronary revascularization including PCI and CABG during the follow-up period were assessed. Cardiac death was defined as death from acute coronary syndrome, ventricular arrhythmia, and end-stage heart failure. Unexplained sudden death was also considered cardiac death. Myocardial infarction was defined as an elevation in cardiac troponin values with at least 1 value above the 99th percentile upper reference limit, with symptoms of myocardial ischemia, new ischemic change of electrocardiography, development of pathologic Q waves, or imaging evidence of myocardial infarction. Clinical events were identified by the physician in charge and confirmed by the principal investigator.

Statistical analysis

Study subjects were stratified into two groups according to the presence of MACE. Continuous variables are expressed as mean ± standard deviation and analyzed using Student’s t-test. Categorical variables are expressed as percentages and analyzed using Pearson’s chi-square test. Receiver operating characteristic (ROC) curve analysis was used to determine optimal baPWV values associated with composite clinical events. To find independent parameters for MACE, multivariable Cox proportional hazards regression analyses were performed, and the following variables were adjusted: age, sex, BMI, hypertension, DM, dyslipidemia, smoking status, renal function, and the use of renin-angiotensin system blockers, beta-blockers, and statins. Global chi-square values were calculated to clarify the incremental prognostic value of ETT and baPWV in combination with other traditional risk factors for prediction future MACE. All analyses were 2-tailed, and clinical significance was defined as p < 0.05. Statistical analyses were performed with the statistical package SPSS version 25.0 (IBM Co., Armonk, NY, USA).

Baseline clinical characteristics

During a mean follow-up period of 875 days (interquartile range, 116–2,212 days), there were 88 cases of MACE (4.9%), which included 1 cardiac death, 8 myocardial infarction, 70 coronary revascularization, and 21 ischemic stroke cases. The mean age was 55.8 ± 10.7 years, and 1,056 (59.1%) were men. Detailed baseline clinical characteristics of the study patient according to the occurrence of MACE are shown in Table 1. Patients who experienced MACE were older (60.8 ± 9.4 vs. 55.5 ± 10.7 years, P < 0.001), and had a higher proportion of men (81.8% vs. 57.9%, P < 0.001). Patients with MACE had more cardiovascular risk factors including hypertension, DM and current cigarette smoking. In laboratory findings, as there were more diabetic patients in the MACE group, leading to higher fasting glucose and glycated hemoglobin A1c levels. Total cholesterol was lower in patients with MACE and was mainly driven by lower HDL-cholesterol. Mean LVEF was lower in patients with MACE than in those without. Regarding the use of cardiovascular medications, patients with MACE had more risk factors, such as hypertension and diabetes, leading to increased usage of cardiovascular drugs across all medication classes, compared to patients without MACE. baPWV was significantly higher in patients with MACE than in those without (1,728 ± 298 vs. 1,455 ± 275 cm/s, P < 0.001). The proportion of positive ETT was also higher in patients with MACE compared to those without (52.3% vs. 16.3%, P < 0.001).

Table 1

Baseline clinical characteristics of study subjects
Characteristics	MACCE (+) (n = 88)	MACCE (−) (n = 1,700)	P value
Age, years	60.8 ± 9.4	55.5 ± 10.7	< 0.001
Men	72 (81.8)	984 (57.9)	< 0.001
BMI, kg/m²	24.7 ± 2.8	24.7 ± 3.2	0.839
SBP, mmHg	128 ± 15	125 ± 15	0.167
DBP, mmHg	76.9 ± 10.1	77.0 ± 10.2	0.901
Cardiovascular risk factors
Hypertension	52 (59.1)	658 (38.7)	< 0.001
Diabetes mellitus	26 (29.5)	232 (13.6)	< 0.001
Dyslipidemia	39 (44.3)	620 (36.5)	0.137
Current smoking	23 (26.1)	303 (17.8)	0.049
Obesity (BMI ≥ 25 kg/m²)	43 (48.9)	732 (43.1)	0.284
Laboratory findings
Hemoglobin, g/dL	14.4 ± 1.7	14.3 ± 1.5	0.413
Fasting glucose, mg/dL	117 ± 30	106 ± 25	< 0.001
Glycated hemoglobin A1c, %	6.29 ± 1.19	5.90 ± 0.87	0.009
Estimated GFR, mL/min/1.73 m²	84.5 ± 17.4	89.5 ± 17.9	0.011
Total cholesterol, mg/dL	177 ± 39	190 ± 40	0.005
LDL-cholesterol, mg/dL	112 ± 37	118 ± 37	0.199
HDL-cholesterol, mg/dL	46.1 ± 11.7	51.2 ± 12.6	< 0.001
Triglyceride, mg/dL	126 ± 56	124 ± 76	0.784
C-reactive protein, mg/dL	0.25 ± 0.47	0.20 ± 0.53	0.406
LVEF, %	64.5 ± 7.9	66.4 ± 7.0	0.030
Cardiovascular medications
RAS blockers	42 (47.7)	278 (16.4)	< 0.001
Calcium channel blockers	34 (38.6)	296 (17.4)	< 0.001
Beta-blockers	44 (50.0)	223 (13.1)	< 0.001
Statins	64 (72.7)	522 (30.7)	< 0.001
Numbers are expressed as mean ± standard deviation or n (%). MACCE, major adverse cardiac and cerebrovascular events; BMI, body mass index; GFR, glomerular filtration rate; LDL, low-density lipoprotein; HDL, high-density lipoprotein; LVEF, left ventricular ejection fraction; RAS, renin-angiotensin system.

Associations of baPWV, ETT, and their combinations with MACE

In ROC analysis, the optimal cut-off value predicting future MACE was 1,440 cm/s with a sensitivity of 87.5% and specificity of 54.4% (Fig. 1). In Kaplan-Meier survival analysis, both ETT result (positive vs. negative, log-rank P < 0.001) and baPWV value (< 1,440 vs. ≥ 1,440 cm/s, log-rank P < 0.001) were significantly associated with the incidence of future MACE events (Fig. 2). When ETT results and baPWV were combined, MACE occurrence could be further subdivided (log-rank P < 0.001) (Fig. 3). To confirm the independent association of ETT and baPWV, multivariable analysis was performed adjusting for various clinical factors. Multivariable analysis showing the independent association of each of ETT and baPWV with MACE and the combination of ETT and baPWV with MACE is shown in Table 2. Positive ETT result (hazard ratio [HR] 2.81, confidence interval [CI] 1.77–4.47, P < 0.001) and high baPWV (HR 5.18, CI 2.68–10.0, P < 0.001) were significantly associated with MACE even after adjustment for potential confounders. The combination of ETT and baPWV further stratified the patient’s risk. Based on the reference to ETT (−) and low baPWV (< 1,440 cm/s), ETT (+) and low baPWV (< 1,440 cm/s) had a 4.65-fold higher risk of subsequent MACE (P = 0.012). ETT (−) and higher baPWV (≥ 1,440 cm/s) had a 6.71-fold higher risk of subsequent MACE (P < 0.001). ETT (+) and higher baPWV (≥ 1,440 cm/s) had a 16.44-fold higher risk of subsequent MACE (P < 0.001).

Table 2

Multivariable analyses showing MACCE risk according to the results of ETT and baPWV
Test results	HR (95% CI)	P value
ETT result
ETT (+)	2.81 (1.77–4.47)	< 0.001
baPWV result
baPWV ≥ 1,440 cm/s	5.18 (2.68–10.0)	< 0.001
ETT + baPWV results
ETT (−) & baPWV < 1,440 cm/s	1
ETT (+) & baPWB < 1,440 cm/s	4.65 (1.40–15.45)	0.012
ETT (−) & baPWV ≥ 1,440 cm/s	6.71 (2.58–17.40)	< 0.001
ETT (+) & baPWV ≥ 1,440 cm/s	16.44 (6.17–43.78)	< 0.001
ETT, baPWV and ETT + baPWV results were one of independent variable in each separate multivariable analysis model. Following variables were adjusted: age, sex, body mass index, hypertension, diabetes mellitus, dyslipidemia, smoking status, renal function, and the use of renin-angiotensin system blockers, beta-blockers and statins. MACCE, major adverse cardiac and cerebrovascular events; ETT, exercise treadmill test; baPWV, brachial-ankle pulse wave velocity; HR, hazard ratio; CI, confidence interval.

Additional prognostic value of baPWV to ETT

The additional prognostic value of baPWV to ETT result was evaluated using global χ² scores. When ETT result was added to traditional risk factors, including age, sex, BMI, hypertension, DM, dyslipidemia, smoking status, renal function, and the use of renin-angiotensin system blockers, beta-blockers, and statins, the prognostic value of the model was significantly increased (global χ² score, 97 to 125, P < 0.001). The addition of baPWV to previous model further increased the prognostic value of the model (global χ² score, 125 to 148, P < 0.001) (Fig. 4).

In this study, both increased arterial stiffness assessed by baPWV and positive ETT result were independent prognostic factors for future cardiovascular events in patients with suspected CAD. By combining the information from these two diagnostic modalities, we were able to further stratify patients’ risk. Furthermore, when baPWV results were added to the clinical and ETT information, the ability to predict future MACE occurrence significantly improved. Our findings suggest that baPWV measurement may have a complementary role in risk stratification among patients with suspected CAD who underwent ETT.

Arteries become stiff with age, and other risk factors such as high blood pressure, high blood sugar, and smoking also contribute to this process. Several studies have documented the prognostic importance of arterial stiffness as an independent predictor of cardiovascular mortality and morbidity, including conditions such as myocardial infarction, hypertension, heart failure, and stroke.^19,20 These studies support the clinical usefulness of arterial stiffness measurement as an indicator of atherosclerotic burden and as a cardiovascular risk stratification tool, as well as an indicator of vascular function. Arterial stiffness can be measured in several ways, including pulse pressure, PWV, and augmentation index.²¹ Among them, PWV is one of the major non-invasive methods and carotid-femoral PWV (cfPWV) is considered the gold standard for assessing central arterial stiffness.²² In several studies, cfPWV was independent predictor of cardiovascular mortality and morbidity.^23–26 However, the relatively high level of technical expertise required and the need to expose the inguinal region may limit the widespread clinical use of cfPWV. On the other hand, baPWV can be used more comfortably as it does not require exposing the inguinal area and the measurement process is simple. Similar to cfPWV, baPWV was also identified as an independent predictor of cardiovascular death and events in both hypertensive subjects and patients with CAD.^27,28 In addition to the previous studies, our study demonstrated the complementary role of baPWV measurements in risk stratification for patients in the intermediate-risk group with suspected CAD. Considering the non-invasiveness, simplicity, and economic feasibility of baPWV measurement, it is a very suitable test for mass screening for cardiovascular risk stratification.

Although ICA is considered the current gold standard for diagnosing CAD, it is not indicated in all patients with chest pain, especially in the early stages of those with low-to-moderate risk. There are several non-invasive testing modalities for the diagnosis of CAD such as ETT, stress echocardiography, radionuclide myocardial perfusion imaging, and coronary computed tomography angiography. These non-invasive testing modalities vary in terms of several factors, including diagnostic accuracy, availability, costs, and radiation exposure.²² Among these modalities, according to the current guidelines for the diagnosis and management of patients with stable ischemic heart disease, ETT is the recommended initial diagnostic test modality for patients with moderate pretest probability who are capable of exercising and have an interpretable resting ECG.²⁹ ETT can assist in identifying and stratifying patients with an intermediate risk probability for cardiac events. However, there are limitations in solely relying on ETT for patient identification due to its relatively low sensitivity and specificity.³⁰ The Duke treadmill score is a useful tool that provides additional prognostic information by combining ST changes and angina symptom during exercise.³¹ However, the Duke treadmill score is less useful when test results are categorized as intermediate or high-risk, necessitating additional imaging tests to enhance diagnostic accuracy.³² Considering this, based on our study results showing additional prognostic value of baPWV to ETT, we believe that baPWV, which can be measured relatively easily, can strengthen the predictive power of ETT for cardiovascular events.

Despite the development of numerous diagnostic methods and risk prediction models, CVD still remains one of the leading causes of mortality and morbidity. Moreover, many people have reported experiencing cardiovascular events even in the absence of pre-existing risk factors.⁵ Therefore, an effective risk stratification tool is needed to classify patients' cardiovascular disease risk in addition to the existing traditional risk factors. In this context, there are studies that enhance the prognostic value by combining the two test results. Specifically, there are intriguing studies that have augmented the prognostic value of patients by combining PWV results with other test results, which included C-reactive protein level, risk scores, single-photon emission tomography, coronary computed tomographic angiography. ^{11–13,33,34} This study is the first and only one to enhance the prognostic value by combining ETT results with baPWV and further expand the application value of baPWV.

Clinical implications

Given its non-invasive nature, ease of measurement, and relatively low cost, baPWV can be useful for cardiovascular risk stratification. By combining the results of ETT, which is non-invasive and relatively easy to perform in an outpatient setting, with baPWV, better risk assessment can be performed, allowing for better screening of high-risk patients for active monitoring and more intensive management. Our findings may encourage further studies exploring the usefulness of baPWV in patients with suspected CAD, especially when used as an adjunctive diagnostic test to evaluate various aspects of cardiovascular disease.

Study limitations

This study has several limitations. First, because our study population consisted of patients with suspected CAD who underwent ETT, the findings may not be generalizable to the entire general population. Second, as the population of this study was only Koreans, it is difficult to generalize the results of this study to other ethnic groups. Lastly, arterial stiffness is strongly related to age and the reference range of baPWV varies depending on the age of the study population.^35,36 Therefore, the cutoff value of baPWV in this study cannot be uniformly applied to all people, and must be interpreted in consideration of the age group of study subjects.

Arterial stiffness assessed by baPWV had incremental prognostic value to ETT. The combined information of baPWV and ETT results may be useful for risk stratification in patients with suspected CAD.

Conflict of interest

The authors declare no competing interests.

Funding

None.

Author Contribution

Conceptualization, J.C. and H-L.K.; Methodology, J.C. and H-L.K.; Software, J.C. and H-L.K.; Validation, J.C., H-L.K., H.S.J., W-H.L., J-B.S., S-H.K., J-H.Z., and M-A.K.; Formal Analysis, J.C.; Investigation, J.C., H-L.K., H.S.J., W-H.L., J-B.S., S-H.K., J-H.Z., and M-A.K.; Re-sources, H-L.K., H.S.J., W-H.L., J-B.S., S-H.K., J-H.Z., and M-A.K.; Data Curation, J.C. and H-L.K.; Writing – Original Draft Preparation, J.C.; Writing – Review & Editing, , J.C., H-L.K., H.S.J., W-H.L., J-B.S., S-H.K., J-H.Z., and M-A.K.; Visualization, J.C.; Supervision, H-L.K.; Project Administration, H-L.K.

Data Availability

The datasets used during the current study available from the corresponding author on reasonable request.

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No competing interests reported.

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Incremental prognostic value of combined information of arterial stiffness and the result of treadmill exercise test in patients with suspected coronary artery disease

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Abstract

Figures

Introduction

Methods

Study population

Data collection

ETT

baPWV measurement

Clinical events

Statistical analysis

Results

Baseline clinical characteristics

Associations of baPWV, ETT, and their combinations with MACE

Additional prognostic value of baPWV to ETT

Discussion

Clinical implications

Study limitations

Conclusions

Declarations

Conflict of interest

Funding

Author Contribution

Data Availability

References

Additional Declarations

Status:

Version 1