A growing body of evidence that, Blood Pressure Variability (BPV), is suggested to be a marker of the alterations in cardiovascular regulatory mechanisms that could result in cardiovascular complications and target organ damage regardless the mean Blood Pressure (BP) level [1]. Coronary artery remodeling is changes in the External Elastic Membrane (EEM), usually occurred in response to atherosclerotic plaque accumulation. Positive remodeling (PR) refers to a larger EEM area at a lesion site than the adjacent reference site, and negative remodeling (NR) refers to a smaller EEM area than the adjacent reference site. Positive remodeling has an index>1.05, while negative remodeling has an index<0.95. Direct evidence of remodeling can only be demonstrated in serial studies showing changes in the EEM cross sectional area over time, since remodeling may also be encountered at the “normal-appearing” reference coronary segment [2]. Several studies have demonstrated that PR is more predominant in patients with Acute Coronary Syndrome (ACS) comparing to patients with stable angina pectoris [3-5]. Previous studies have reported that PR lesion has higher lipid contents and a macrophage count, both markers of plaque vulnerability [6]. Plaques exhibiting positive remodeling had more often thrombus and signs of rupture [7].

Conversely, plaques with negative remodeling have a stable phenotype, but they could be identified only in prospective observations and not in a unique IVUS observation. Nevertheless, the association between increased BPV and coronary artery lesion remodeling is not clear. Herein, we conducted the current study to explore the association between BPV and coronary artery remodeling by Intravascular Ultrasound (IVUS), in patients with stable coronary artery disease.

Our prospective study included 109 patients with stable coronary artery disease, who were prepared for percutaneous coronary intervention under IVUS control. We excluded patients with, valvular heart disease and inflammatory disease. Patients with poor images of IVUS and those with severe calci ication were also excluded.

24-Hour Ambulatory Blood Pressure Monitoring (ABPM)

All subjects underwent ABPM with the use of device (Mobil-OGraph; IEM GmbH, Stolberg, Germany). The blood pressure readings were obtained at 30‐ and one hour intervals in the daytime and at nighttime, respectively. The relevant daytime and nighttime periods were defined as the time intervals, which ranged from 6 am to 10 pm and from 10 pm to 6 am. Any subject lacking ≥ 20% of the readings was excluded. In our study blood pressure variability was considered as the weighted mean SD of both systolic and diastolic daytime and night blood pressure (W-SD). The Weighted systolic-SD_dn is the mean of day and night SD values of systolic blood pressure corrected for the number of hours included in each of these two periods, based on the following formula: SD_dn=([day SD × hours included in the daytime]+ [night SD × hours included in the night time])/(hours included in daytime+nighttime) [8]. Morning Blood Pressure Surge (MBPS) was calculated as the difference between morning systolic blood pressure obtained after waking (averaged systolic blood pressure for 2 hours just after waking up) minus the lowest nocturnal systolic [9]. Participants who showed a nocturnal fall of ≥ 10% in SBP were considered dippers. Likewise, a patient whose nocturnal SBP fell by <10% or even rose was defined as a non-dipper.

IVUS imaging and analyses and definitions of remodeling

All coronary intravascular ultrasound studies were performed with the use of 20-MHz, 2.9 F IVUS system (Eagle Eye, Volcano Corp, Rancho Cordova, CA, USA). The IVUS catheter was advanced >10 mm beyond the lesion and automated pullback was performed to the aorto-ostial junction at a speed of 0.5 mm/s. For evaluation, the proximal reference site and the target lesion site were chosen. The target lesion was defined as the site with the smallest minimal lumen diameter. Whilst, the proximal reference segment was defined as the site with the least amount of plaque proximal to the target lesion without any intervening side branch.

The EEM area at the site of the target lesion was measured and compared with EEM area at the proximal reference site. After that, the coronary artery remodeling index was calculated as the ratio of EEM area at the target lesion site to the area at the proximal segment. In our study, the patterns of coronary artery remodeling were stratified into two groups; the first group with positive remodeling (PR), (Figure 1) and the second group included those with intermediate/negative (IR/ NR), (Figure 2). Positive remodeling was considered, when the remodeling index>1.05, intermediate remodeling (a remodeling index between 0.95 and 1.05) and those with negative remodeling (a remodeling index<0.95) [5].

Figure 1: An example of positive remodeling. A patients with weighted SD_dn=14 mmHg. The remodeling was [1.08], an example of negative remodeling. A patients with weighted SD_dn=8 mmHg. The remodeling was [0.6].

Figure 2: Correlation between weighted SD_dn and triglyceride to high density lipoprotein (TG/HDL-C) ratio. ROC shows that weighted SD_dn ≥ 13 mmHg is the best cut-off value for predicting positive remodeling. AUC=0.91, p<0.001.

Laboratory analysis

Blood samples were obtained before PCI for assessment of serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), highdensity lipoprotein cholesterol (HDL-C), triglyceride levels, blood glucose, high-sensitivity C-reaction protein (hs-CRP). TG/HDL-C ratio was also calculated.

Statistical analysis

Statistical analyses were performed with SPSS version 16.0 (SPSS Inc). Continuous and normally distributed data are presented as mean ± 1 SD and were compared by two-tailed unpaired t tests. Spearman correlation coefficient test was used for correlations analyses. Univariable and multivariable binary logistic regression models were performed to characterize predictors of positive remodeling. ROC curve analysis was performed to obtain the cutoff value of weighted systolic-SD_dn, with the highest sensitivity and specificity, of predicting positive remodeling in patients with patients coronary artery disease.

Patients were stratified into two groups based on the remodeling pattern as positive remodeling group (PR, remodeling index>1.05), which included 59 patients and intermediate remodeling (IR, remodeling index ≤ 1.05 and ≥ 0.95)/negative remodeling (NR, remodeling index<0.95) which included 50 patients. Table 1 represents the demographic data of both groups. There were no significant differences among both groups as regards baseline characteristics except for TG/HDL-C (p<0.01) and hs-CRP (p<0.05).

Table 1: Baseline characteristics of the study cohorts according to the presence or absence of positive remodeling.

Table 1 depicts the ABPM data of patients in group I compared with those in group II. Weighted systolic-SD_dn was significantly higher in group I compared with group II (p<0.001). Furthermore, the weighted systolic day SD was higher in group I patients (p<0.05). Importantly, we found that group I patients had a significant exaggerated MBPS was compared with group II (p<0.003)

The relations between remodeling index and the tested variables are represented in Table 1. Our results showed that weighted systolic-SD_dn and MBPS were significantly correlated with remodeling index (r=0.49, and 0.45 respectively; p<0.001). TG/HDL-C ration had a significant correlation with remodeling index (r=0.39, p<0.003). Besides, TG/HDL-C ratio was significantly correlated with weighted SD_dn (r=0.43, p<0.001).

Correlation analysis showed significant correlations between remodeling index and the weighted systolic-SD_dn (p<0.001), MBPS (p<0.001), day SBP variability (p<0.01), nocturnal SBP variability (p<0.01), TG/HDL-C (p<0.003) and hs-C reactive protein (p<0.05).

Multivariate analysis showed that weighted systolic-SD_dn (p<0.001) and Morning surge (p<0.001), were the independent predictors of positive remodeling in subjects with stable CAD. With ROC carve analysis, we found that BPV index (weighted systolic-SD_dn) value ≥ 13 mm Hg had a sensitivity of 95% a specificity 83% for identification of patients with the positive remodeling. The area under the curve was 0.91 (95% CI, 0.85-0.97). Furthermore, MBPS value>45 mmHg was the optimal cut-off value for predicting positive remodeling with a sensitivity of 93% and a specificity of 81%. The area under curve=0.89(95% CI, 0.83-0.95).

The current study provides an explicit evidence of a significant correlation between blood pressure variability and coronary artery remodeling in subjects with stable coronary artery disease. It implies that BPV index (weighted-SD_dn) and exaggerated MBPS are independent predictors of positive remodeling in patients with stable CAD. Our study provides additional interesting merits. First, weighted SD_dn index value ≥ 13 mmHg was the optimal cut-off value, to predict positive remodeling in subjects with stable CAD, second MBPS ≥ 45 mmHg was the best cut-off value to predict positive remodeling, third, TG/HDL-C ratio was significantly correlated with both blood variability index (weighted systolic-SD_dn) and remodeling index, finally, hs-C reactive protein was significantly higher in patients with positive remodeling and correlated with remodeling index.

Many investigators demonstrated that coronary artery lesions with positive remodeling are more biologically dynamic compared with intermediate or negatively remodeled lesions. Meanwhile, subjects, who have coronary lesion with positive remodeling are more prone to have vulnerable plaque [10,11].

Yet, the clear-cut morphological characteristics for plaque vulnerability, and precise management, which could improve or alter features of coronary plaques vulnerability to be stable, are uncertain. Hence, early detection or prediction of vulnerable plaque before rupture is of great value for the prevention of disastrous clinical outcomes and can be a guide for an adjunctive therapy or early intervention.

Obviously, histopathological researches demonstrated that positive remodeling is associated with abundant of inflammatory cells infiltration, more pro-inflammatory cytokines, and enhanced protease activity [10,12].

IVUS have provided a good in vivo assessment of coronary plaque and demonstrated positive remodeling is correlated with the plaque volume and a larger necrotic core [13,14]. Hence, great plaque burden with positive remodeling determined by IVUS is related to plaque vulnerability and more atherosclerosis burden. For that, coronary remodeling evaluation might be a major risk predictor for plaque rupture.

Kikuya et al. [15] found an independent relation between short term blood pressure variability and increased risk of cardiovascular events in the general population. Furthermore, Cay et al. [16] found a significant correlation between increased short-term blood pressure variability and the risk of in-stent restenosis in normotensive subjects.

Weiss et al. [17] reported that the fourth quartile (BPV ≥ 17.95 mm Hg) was associated with adverse cardiovascular outcomes, when compared with the first quartile (BPV ≤ 10.56 mm Hg) in both normotensive and hypertensive individuals.

Previous experimental studies in animals showed that higher shortterm blood pressure variability was associated with end-organ damage, even at a normal mean blood pressure, consistent with the evidence in humans [18,19].

Li Y et al. [20] found a significant relationship between within-visit diastolic blood pressure variability and the occurrence internal carotid artery plaque and increased intima-media thickness in normotensive subjects. Moreover, they reported that this relation was independent of the impact of mean blood pressure and heart rate on the carotid arteries.

Nagai et al. [21] found an independent relation between subclinical carotid atherosclerosis and visit-to-visit blood pressure fluctuations regardless average blood pressure.

In fact blood pressure variability is a multifaceted incident involving interactions among behavioral, environmental, humoral, and neural effects. The key mechanisms of blood pressure variability are functional impairment of both vascular endothelium and baroreceptor [22]. Moreover, great blood pressure variability might enhance stress on the coronary vasculatures and results in endothelial dysfunction. Consequently, blood pressure variability might have a significant impact on progression of coronary atherosclerotic process.

Another interesting issue, we found a significant higher TG/HDL-C ratio and hs-C reactive protein in subjects with positive remodeling. More so, TG/HDL-C and hs-C reactive protein were correlated with BPV in individuals with positive remodeling. Therefore, TG/HDL-C and hs-C reactive protein could be parts of the determinant links between increased BPV and positive remodeling in normotensive subjects with coronary artery disease.

Da luz et al. [23] demonstrated that TG/HDL-C was an indicator of coronary artery disease progression and is associated with the disease severity. Hence, this ratio is an easily non-invasive predictor of the presence and severity of CAD.

Rodríguez-Morán et al. [24] found a significant association between elevated TG: HDL-C ratios and pre-hypertension in both obese and non-obese children independent of family history of hypertension, insulin levels and HOMA-IR.

Kim et al. [25] demonstrated that high sensitive C-reactive protein was significantly associated with daytime and 24-hour systolic and diastolic BP variability. They concluded that high sensitive C-reactive protein levels were independently predicted by BPV, in spite of clinical confounders.

Implications

The detection of increase of blood pressure variability may predict the early vascular complications, and it could be as a mark of premature cardiovascular morbidity. So, not only keeping the blood pressure in a normal range but also decreasing the blood pressure variability might be of great value to prevent the early cardiovascular morbidity and adverse outcome.

The current study demonstrated blood pressure variability is an independent predictor of plaque vulnerability in patients with stable CAD. We found that BPV index (weighted systolic-SDdn) ≥ 13 mmHg and MBPS ≥ 45 mmHg were the optimal cut-off value for predicting positive remodeling. Hence, we suggest that evaluation of blood pressure variability is important and provides a useful tool for risk stratification for patients with coronary artery disease.

This is a single center study with a small number of patients, hence having the possibility of selection bias. No follow-up study was performed.