Longitudinal quantitative assessment of coronary atherosclerosis related to normal systolic blood pressure maintenance in the absence of established cardiovascular disease

Abstract Background Atherosclerosis‐related adverse events are commonly observed even in conditions with low cardiovascular (CV) risk. Longitudinal data regarding the association of normal systolic blood pressure maintenance (SBPmaintain) with coronary plaque volume changes (PVC) has been limited in adults without traditional CV disease. Hypothesis Normal SBPmaintain is important to attenuate coronary atherosclerosis progression in adults without baseline CV disease. Methods We analyzed 95 adults (56.7 ± 8.5 years; 40.0% men) without baseline CV disease who underwent serial coronary computed tomographic angiography with mean 3.5 years of follow‐up. All participants were divided into two groups of normal SBPmaintain (follow‐up SBP < 120 mm Hg) and ≥elevated SBPmaintain (follow‐up SBP ≥ 120 mm Hg). Annualized PVC was defined as PVC divided by the interscan period. Results Compared to participants with normal SBPmaintain, those with ≥elevated SBPmaintain had higher annualized total PVC (mm3/year) (0.0 [0.0–2.2] vs. 4.1 [0.0–13.0]; p < .001). Baseline total plaque volume (β = .10) and the levels of SBPmaintain (β = .23) and follow‐up high‐density lipoprotein cholesterol (β = −0.28) were associated with annualized total PVC (all p < .05). The optimal cutoff of SBPmaintain for predicting plaque progression was 118.5 mm Hg (sensitivity: 78.2%, specificity: 62.5%; area under curve: 0.700; 95% confidence interval [CI]: 0.59–0.81; p < .05). SBPmaintain ≥ 118.5 mm Hg (odds ratio [OR]: 4.03; 95% CI: 1.51–10.75) and baseline total plaque volume (OR: 1.03; 95% CI: 1.01–1.06) independently influenced coronary plaque progression (all p < .05). Conclusion Normal SBPmaintain is substantial to attenuate coronary atherosclerosis progression in conditions without established CV disease.


| INTRODUCTION
Coronary atherosclerosis is strongly associated with an increase in cardiovascular (CV) morbidity and mortality. 1,2 CV risk has been stratified on the basis of conventional CV risk factors (CVRFs). 3 However, atherosclerosis-related adverse events are commonly developed even in adults with low CV risk. [4][5][6] Considering that subclinical atherosclerosis underlies most CV events, it is important to identify independent predictors for subclinical atherosclerosis in conditions with a low CV risk burden.
The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines lowered the blood pressure thresholds for defining hypertension. 7 Although this enhanced guideline could cause overdiagnosis of hypertension and result in unnecessary treatment, recent studies have reported the usefulness of this guideline, especially in subjects with a low CV risk burden. 8,9 However, the consensus on this issue is not yet been reached in clinical practice. Recently, the Systolic Blood Pressure Intervention Trial (SPRINT) study finally reported that targeting a systolic blood pressure (SBP) of <120 mm Hg resulted in lower rates of major adverse CV events and mortality than targeting an SBP of <140 mm Hg in 9361 patients with an increased risk of CV disease who had no diabetes or previous stroke during a median of 3.3 years of followup. 10 Although this finding emphasizes the significance of strict SBP control with the consistent concept of reinforced guideline for hypertension, little is known about the optimal SBP levels to attenuate the progression of coronary atherosclerosis in conditions without established CV disease.
Serial assessment of coronary plaques using intravascular ultrasound (IVUS) has contributed to understanding the pathophysiology of coronary artery disease. 11,12 However, it is hard to perform IVUS in a low CV risk population because of its invasiveness and high cost.
Recently improved technology in coronary computed tomographic angiography (CCTA) has allowed noninvasive evaluation and comprehension of coronary atherosclerosis. [13][14][15][16][17][18] Therefore, this study aimed to evaluate the association of normal SBP maintenance (SBP maintain ) with coronary plaque volume changes (PVC) in adults without baseline CV disease using the quantitative measurement by serial CCTA.

| study population
The study design and protocol of the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging (PARADIGM) registry has been reported previously. 19 Briefly, the PARADIGM is a prospective, international, and observational registry guidelines. 20,21 Among them, at index CCTA, 909 participants were identified as having no diabetes, and 814 participants were consecutively excluded because of the previous diagnosis of hypertension (n = 501), hyperlipidemia (n = 125), and atrial fibrillation (n = 23); obesity or unavailable body mass index (BMI) data (n = 10); current smoking (n = 53); any medication history (n = 91); and previous history of revascularization (n = 2) or cerebrovascular disease (n = 1), and unavailable follow-up blood pressure data (n = 8). Finally, 95 participants without established CV disease at index CCTA were included in the present study. All participants were divided into two groups of normal SBP maintain (follow-up SBP < 120 mm Hg) (n = 40) and more than elevated SBP maintain (follow-up SBP ≥ 120 mm Hg) (n = 55) based on the follow-up SBP levels, as per the 2017 ACC/AHA guidelines.
Laboratory tests were conducted within 1 month of all CCTA examinations. All blood samples were collected after a minimum of 8 h fasting period. SBP and diastolic blood pressure (DBP) were measured on the right arm using an automatic manometer with an appropriate cuff size after the participants rested for ≥5 min.

| statistical analysis
Continuous variables are expressed as mean ± SD or medians [interquartile range], as appropriate. Categorical variables are presented as absolute values and proportions. Continuous variables between two groups were compared using the independent t-test or Mann-Whitney U test, as appropriate. Categorical variables were compared using the χ 2 -test or Fisher's exact test, as appropriate. Linear regression models were used to identify the association between clinical variables and annualized total PVC. Logistic regression models were used to identify the independent predictors of coronary plaque progression. Variables with p < .05 in the univariate analyses were considered confounding variables and entered into multivariate regression analyses, respectively. Except for the nonmodifiable variables of age, gender, and baseline plaque volume, other independent variables achieved at follow-up CCTA were included in the regression models. In the receiver operating characteristic analysis, the optimal cutoffs of follow-up SBP maintain for predicting coronary plaque progression was determined using the Youden index. All statistical analyses were performed using the Statistical Package for the Social Sciences version 19 and SAS (version 9.1.3; SAS Institute Inc.). A p value of <.05 was considered significant for all analyses.

| Baseline characteristics
The mean age of participants was 56.7 ± 8.5 years and the proportion of men was 40.0%. The mean interscan period was 3.5 ± 1.4 years.  p < .001) (Table S1).  Abbreviations: SBP, systolic blood pressure; SBP maintain, systolic blood pressure maintenance.

| Independent predictors for coronary plaque progression
The optimal SBP maintain cut-off for predicting coronary plaque progression was found to be 118. 5   A recent experimental study has suggested that high blood pressure per se exacerbates atherogenesis of coronary arteries in the  (1) the usefulness of coronary artery calcium score (CACS) to determine therapeutic targets in various clinical conditions [29][30][31][32] and (2)  stable CAD who had no heart failure or substantial hypertension. 36 The Aliskiren Quantitative Atherosclerosis Regression Intravascular UltrasoundStudy (AQUARIUS) showed that the use of aliskiren compared with placebo did not result in improving or slowing the coronary atherosclerosis progression after at least 72 weeks of randomization among 613 patients with CAD with prehypertension. 37 Unlike the studies mentioned above, the present study identified the optimal SBP level for attenuating subclinical coronary atherosclerosis in conditions without established CV disease after adjusting for baseline plaque burden of coronary arteries which is known as the most important factor for rapid plaque progression. 38 The present study has some limitations. First, consecutive changes of clinical variables during follow-up periods were not available. Second, this study only included an extreme selection of participants from the PARADIGM registry who had no established CV disease. Therefore, the characteristics of our participants could not represent the overall participant characteristics of the PARADIGM registry. Third, the major proportion of the overall PARADIGM registry was East Asians. In this PARADIGM substudy, all participants were East Asians; hence, this might limit the generalizability of the findings. Fourth, the target blood pressure might be somewhat different in an elderly population. 39 However, this study could not evaluate this issue because only five (4.9%) participants aged over 70 years. Finally, the small sample size and relatively short-term followup periods were the weaknesses of the present study. Despite these limitations, this is the first longitudinal study to evaluate the association of clinical factors with coronary atherosclerotic changes in the absence of established CV disease using serial CCTA.
In conclusion, compared to subjects with normal SBP maintain , annualized total PVC was significantly higher in subjects with ≥elevated SBP maintain in the absence of baseline CV disease. Both baseline total plaque volume and SBP maintain had an independent association with the risk of coronary plaque progression. The present study suggests that the endeavor to maintain normal SBP is important to attenuate coronary atherosclerosis progression even in conditions without established CV disease. Further prospective studies with larger sample sizes and longer follow-up durations should be necessary.