Intracranial Atherosclerosis and Stage 1 Hypertension Defined by the 2017 ACC/AHA Guideline

Abstract

Background

In 2017, the American College of Cardiology (ACC)/American Heart Association (AHA) released a new, stricter definition of stage 1 hypertension which was previously considered prehypertension. However, impacts of the novel stage 1 hypertension on deleterious target-organ outcomes are still controversial. In this study, we evaluated the relationship between this newly defined stage 1 hypertension and the presence of intracranial atherosclerosis (ICAS) lesions in neurologically healthy participants.

Methods

We assessed consecutive participants in routine health checkups between January 2006 and December 2013. Blood pressure (BP) was classified according to the 2017 ACC/AHA hypertension guideline, and ICAS was defined as occlusion or ≥50% stenosis of intracranial vessels on flight magnetic resonance angiography.

Results

Among 3,111 healthy participants (mean age: 56 years, sex: 54% men), 85 (3%) had ICAS lesions. In multivariate analysis, stage 1 hypertension (adjusted odds ratio: 2.46, 95% confidence interval: 1.10–5.51, P = 0.029) remained an independent predictor of ICAS after adjustment for confounders. Stage 2 hypertension showed a higher odds ratio and a lower P value, indicating a dose–response effect. Age and HbA1c level were also significantly associated with ICAS, independent of the BP categories. The ICAS lesion burden showed a dose–response effect across the BP categories (P for trend <0.001), whereas ICAS lesion location did not (P for trend = 0.699).

Conclusions

We demonstrated that stage 1 hypertension, defined according to the 2017 ACC/AHA guideline, was associated with a higher prevalence and burden of ICAS lesions in a neurologically healthy population.

atherosclerosis, blood pressure, cerebrovascular disease, hypertension, prehypertension

Blood pressure (BP) is a well-known risk factor for cardiovascular or cerebrovascular disease.^1–3 In clinical practice, the term “hypertension” is defined arbitrarily for cost-benefit reasons, however, BP is directly correlated with risk of vascular complications, beginning at values of 115/75 mm Hg with no definable threshold for hypertension.^4–6 Various studies have shown that patients with BP levels between optimal and hypertension also have a heightened risk of cardiovascular or cerebrovascular diseases and atherosclerosis.^6–10 For this reason, the 2003 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) defined these patients as having “prehypertension,” ^4,10,11 and recommended close follow-up and lifestyle modification.^9,12,13 However, the use of antihypertensive medication in patients with prehypertension is still controversial.^5,9,10,12

With improvements in hypertension self-awareness and accompanying antihypertensive medication, the prevalence of severe hypertension has been declining over time.¹⁴ In this situation, many studies focusing on more strict BP control and better outcomes had appeared and the American College of Cardiology (ACC)/American Heart Association (AHA) changed their definition of hypertension in the 2017 guidelines.^15,16 Patients with a systolic BP (SBP) of 130–139 mm Hg or a diastolic BP (DBP) of 80–89 mm Hg are now classified as having “stage 1 hypertension.” ¹⁵ This change emphasizes the need for early intensive treatment of BP levels that were previously managed using lifestyle modification only. However, it is not yet clear how this newly defined stage 1 hypertension is associated with the risk of vascular complication.⁴

Intracranial atherosclerosis (ICAS) is a well-documented risk factor for cerebrovascular diseases and it shows considerable prevalence between 10% and 30% in general population.^17–19 Although it has been associated with a high risk of ischemic stroke, the pathophysiological mechanisms underlying ICAS development are not yet fully understood. As a form of atherosclerosis, several known mechanisms of hypertension on atherosclerosis developments may be applicable to ICAS.^20–22 Indeed, there are several studies that hypertension contributes to ICAS via target-organ damage.^23,24 However, it is unclear whether the newly defined stage 1 hypertension, which was previously regarded as prehypertension, can also lead to ICAS. In this study, we aimed to evaluate the relationship between stage 1 hypertension, as defined by the 2017 ACC/AHA hypertension guidelines, and ICAS in neurologically healthy participants. We also assessed the dose–response relationship in participants with higher BP categories to support additional scientific evidence about close relationship between 2.

Methods

Patients and population

The study involved 3,317 consecutive subjects who had visited Seoul National University Hospital Health Promotion Center between January 2006 and December 2013 to undergo a routine health checkup. We immediately excluded 57 of them who had a history of stroke or severe neurological deficit and then sequentially excluded others according to the following exclusion criteria: (i) younger than 30 years (n = 27), (ii) missing data on covariates (n = 86), and (iii) Extracranial atherosclerosis (n = 36)—these participants were excluded to ensure that the effect of BP only on ICAS lesions was identified. Ultimately, 3,111 neurologically healthy participants were included the analyses (Figure 1). This study was approved by the institutional review board at Seoul National University Hospital (IRB No. 1502-026-647). The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Figure 1.

Flow chart of participants inclusion.

Clinical assessment

Clinical information and cardiovascular risk factors were evaluated in all participants, and brain magnetic resonance imaging, brain magnetic resonance angiography (MRA), and laboratory examinations were conducted as parts of routine health checkups.²⁵ Age, sex, body mass index, BP categories, diabetes, hyperlipidemia, current smoking, current alcohol use, and use of antihypertensive medication, antidiabetic medication, and lipid-lowering agents were assessed as clinical factors and cardiovascular risk factors.²⁵ Laboratory examination of glucose profile, lipid profile, white blood cell count, and high-sensitivity C-reactive protein was also carried out after 12 hours of overnight fasting.²⁵

We measured BP using the recommended standard protocol.⁵ BP was measured on the left arm using an automated BP measurement (EASY-X800; JAWON Medical, Korea) after the patient had rested for 5 minutes in a chair. Both SBP and DBP were rated twice, with a 5-minute interval between measurements, and the average of the 2 readings was used in the analysis. BP was categorized according to the 2017 ACC/AHA hypertension guidelines¹⁵: (i) normal group, SBP < 120 mm Hg and DBP < 80 mm Hg; (ii) elevated group, SBP of 120–129 mm Hg and DBP < 80 mm Hg; (iii) stage 1 hypertension group, SBP of 130–139 mm Hg or DBP of 80–89 mm Hg; and (iv) stage 2 hypertension group, SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg or history of antihypertensive medication use.

Radiological assessment

All participants in this study underwent brain magnetic resonance imaging and MRA using a 1.5-Tesla MR scanner (Signa; GE Healthcare, Milwaukee, WI, or Magnetom Sonata; Siemens, Munich, Germany). We broadly examined the magnetic resonance imaging and MRA images as follows: 3-dimensional time-of-flight MRA images (repetition time [TR]/echo time [TE] = 24/3.5 ms, slice thickness = 1.2 mm), T1-weighted images (TR/TE = 500/11 ms), T2-weighted images (TR/TE = 5000/127 ms), T2 fluid-attenuated inversion recovery images (TR/TE = 8,800/127 ms), and T2 gradient echo images (TR/TE = 57/20 ms). The basic slice thickness was 5 mm in the axial plane in all images, except the time-of-flight MRA images. ICAS was defined as occlusion or more than 50% stenosis of the intracranial vessels, as seen on the flight MRA images.^26,27 To evaluate the dose–response relationship between BP and ICAS lesions, we classified ICAS lesion burden into absent, single, or multiple groups according to the number of lesions.²⁵ We also categorized ICAS lesion locations as anterior circulation, posterior circulation, or both.²⁵ All radiological markers were rated by 2 well-trained neurologists (K.-W.N. and H.-Y.J.) and disagreements were resolved by discussion with a third rater (H.-M.K.)

Statistical analysis

We presented continuous variables with normal distribution as mean ± standard deviation and those with non-normal distribution as median (interquartile range). Continuous variables with skewed data were transformed into log scale. Univariate analyses of continuous variables were performed using either the Student’s t-test or Mann–Whitney U-test, as appropriate, and the chi-squared test or Fisher’s exact test were used to analyze categorical variables, where appropriate. To find possible predictors of ICAS, we conducted multivariate analysis using binary logistic regression. Variables with P < 0.10, as well as sex and body mass index, were introduced as confounders.

To assess the dose–response relationship between BP and ICAS lesion burden, we compared the proportions of the BP categories among the absent, single, and multiple ICAS groups using the chi-squared test and linear-by-linear association analysis. The relationship between the BP categories and the ICAS lesion location was analyzed in the same way. All statistical analyses were performed using IBM SPSS, version 21 (IBM, Chicago, IL). P values <0.05 were considered statistically significant.

Results

A total of 3,111 participants were evaluated (mean age: 56 years, male sex: 54%, mean body mass index: 24.16 kg/m²), and 85 (3%) of them had ICAS lesions (single: 57, multiple: 28). The BP categories, as defined by the 2017 ACC/AHA hypertension guidelines were distributed as follows: normal group, 982 (32%); elevated group, 420 (14%); stage 1 hypertension group, 575 (19%); stage 2 hypertension group, 1,134 (37%). The baseline characteristics of the patients with and without ICAS are presented in Table 1. ICAS was closely associated with age, BP category, use of antiplatelet agent, and levels of HbA1c and fasting glucose.

Table 1.

Baseline characteristics of patients with and without ICAS

	ICAS (−) (n = 3,026)	ICAS (+) (n = 85)	P value
Age, y [IQR]	56 [50–62]	62 [55–70]	<0.001
Sex, male, %	1,631 (54)	44 (52)	0.697
BMI, kg/m2 [IQR]	24.00 [22.10–25.93]	24.19 [22.67–25.95]	0.249
BP categories, %			<0.001
Normal	972 (32)	10 (12)
Elevated	410 (14)	10 (12)
Stage 1 hypertension	559 (18)	16 (19)
Stage 2 hypertension	1,085 (36)	49 (58)
Diabetes, %	437 (14)	18 (21)	0.083
Hyperlipidemia, %	770 (25)	25 (29)	0.408
Current smoker, %	544 (18)	14 (16)	0.721
Current alcohol drinker, %	1,472 (49)	37 (44)	0.352
Antiplatelet agent, %	298 (10)	16 (19)	0.007
Antidiabetic, %	195 (6)	7 (8)	0.509
Statin, %	244 (8)	9 (11)	0.401
HbA1c, % [IQR]	5.7 [5.5–6.0]	5.9 [5.6–6.3]	0.001
Fasting glucose, mg/dl [IQR]	91 [84–101]	94 [89–105]	0.009
Total-c, mg/dl [IQR]	198 [174–223]	196 [181–223]	0.610
LDL-c, mg/dl [IQR]	125 [102–147]	122 [97–148]	0.834
HDL-c, mg/dl [IQR]	53 [45–63]	55 [47–63]	0.195
Triglycerides, mg/dl [IQR]	99 [73–144]	94 [78–130]	0.814
WBC count, ×103/µl [IQR]	5.30 [4.39–6.37]	5.59 [4.51–6.53]	0.260
hs-CRP, mg/dl [IQR]	0.04 [0.01–0.15]	0.07 [0.01–0.17]	0.075

Abbreviations: BMI, body mass index; BP, blood pressure; HDL-c, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; ICAS, intracranial atherosclerosis; IQR, interquartile range; LDL-c, low-density lipoprotein cholesterol; Total-c, total cholesterol; WBC, white blood cell.

In the multivariate analysis, stage 1 hypertension (adjusted odds ratio = 2.46, 95% confidence interval = 1.10–5.51, P = 0.029) remained an independent predictor of ICAS, after adjustment for confounders. Stage 2 hypertension showed a higher adjusted odds ratio (3.09, 95% confidence interval = 1.52–6.28) and a lower P value (P = 0.002), constituting a dose–response effect across the BP categories (P for trend = 0.019). Age and HbA1c level were also significantly associated with ICAS, independent of BP category (Table 2). These associations continued when we conducted additional multivariate sensitivity analysis, excluding 685 patients who were prescribed antihypertensive medication Supplementary Table 1.

Table 2.

Multivariate analysis of possible predictors of ICAS

	Crude OR [95% CI]	P value	Adjusted OR [95% CI]	P valuea
Age	1.08 [1.05–1.10]	<0.001	1.06 [1.03–1.09]	<0.001
Sex, male	0.92 [0.60–1.41]	0.697	0.86 [0.56–1.34]	0.515
BMI	1.03 [0.97–1.11]	0.335	1.00 [0.93–1.07]	0.921
BP categories		<0.001b		0.019b
Normal	Ref	Ref	Ref	Ref
Elevated	2.37 [0.98–5.74]	0.056	2.05 [0.84–5.03]	0.116
Stage 1 HTN	2.78 [1.25–6.17]	0.012	2.46 [1.10–5.51]	0.029
Stage 2 HTN	4.39 [2.21–8.71]	<0.001	3.09 [1.52–6.28]	0.002
Antiplatelet agent	2.12 [1.22–3.70]	0.008	1.35 [0.75–2.41]	0.315
HbA1cc	14.73 [3.92–55.36]	<0.001	6.00 [1.32–27.38]	0.021
hs-CRPc	1.13 [0.98–1.29]	0.089	1.06 [0.92–1.22]	0.428

Abbreviations: BMI, body mass index; BP, blood pressure; CI, confidence interval; hs-CRP, high-sensitivity C-reactive protein; HTN, hypertension; ICAS, intracranial atherosclerosis; IQR, interquartile range; OR, odds ratio.

^aAdjusted in variables with a P value <0.10 in the univariate analysis (age, sex, body mass index, blood pressure categories, antiplatelet agent, HbA1c, and high-sensitivity C-reactive protein).

^bP values for linear trend across BP categories.

^cThese variables were transformed into log scales.

In the assessment of dose-dependent relationship between BP categories and ICAS lesion burden, the multiple ICAS lesion group showed higher frequencies of stage 1 and stage 2 hypertension than the single-lesion or absent groups (P < 0.001), constituting a dose–response effect (P for trend <0.001). Conversely, there was no association between the BP categories and the location of ICAS lesions (P for trend = 0.699; Figure 2).

Figure 2.

Distribution of BP categories according to ICAS lesion burden. (a) The burden of ICAS lesion showed a dose–response manner across the BP categories (P for trend <0.001). (b) Meanwhile, there was no association between BP categories and the location of ICAS lesions (P for trend = 0.699). Abbreviations: BP, blood pressure; DBP, diastolic BP; ICAS, intracranial atherosclerosis; SBP, systolic BP.

When we compared vascular risk factors among the BP categories, higher BP categories tended, in a linear fashion, to show older age, higher frequencies of male sex, diabetes, and hyperlipidemia, lower frequencies of current smoking, higher levels of body mass index, HbA1c, fasting glucose, triglycerides, white blood cell count, and high-sensitivity C-reactive protein, and lower levels of high-density lipoprotein cholesterol (Table 3).

Table 3.

Distributions of risk factors between blood pressure categories

	Normal	Elevated	Stage 1 HTN	Stage 2 HTN
Age, y [IQR]*	54 [48–59]	57 [50–63]	56 [50–63]	58 [53–65]
Sex, male, %*	445 (45)	237 (56)	329 (57)	664 (59)
BMI, kg/m2 [IQR]*	23.08 [21.14–24.70]	24.13 [22.42–26.05]	24.02 [22.28–25.90]	24.74 [22.99–26.80]
Diabetes, %*	93 (9)	41 (10)	78 (14)	243 (21)
Hyperlipidemia, %*	204 (21)	95 (23)	139 (24)	357 (31)
Current smoker, %*	201 (20)	71 (17)	116 (20)	170 (15)
Current alcohol drinker, %	468 (48)	195 (46)	288 (50)	558 (49)
HbA1c, % [IQR]*	5.7 [5.4–5.9]	5.7 [5.5–6.0]	5.7 [5.5–6.0]	5.8 [5.6–6.2]
Fasting glucose, mg/dl [IQR]*	89 [82–96]	90 [84–98]	92 [85–101]	95 [88–107]
Total-c, mg/dl [IQR]	196 [173–220]	203 [178–224]	203 [181–228]	194 [172–221]
LDL-c, mg/dl [IQR]	123 [102–146]	130 [104–152]	128 [107–155]	121 [98–145]
HDL-c, mg/dl [IQR]*	55 [46–65]	53 [44–63]	54 [44–63]	51 [44–61]
TG, mg/dl [IQR]*	89 [66–127]	98 [76–140]	104 [74–145]	110 [79–156]
WBC count, ×103/µl [IQR]*	5.08 [4.20–6.13]	5.22 [4.28–6.30]	5.33 [4.45–6.39]	5.49 [4.56–6.67]
hs-CRP, mg/dl [IQR]*	0.03 [0.01–0.13]	0.05 [0.01–0.15]	0.04 [0.01–0.13]	0.06 [0.01–0.18]

Abbreviations: BMI, body mass index; HDL-c, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; HTN, hypertension; IQR, interquartile range; LDL-c, low-density lipoprotein cholesterol , TG, triglycerides; Total-c, total cholesterol; WBC, white blood cell.

^*P for trend <0.05 in these variables.

Discussion

This study found that stage 1 hypertension, as defined by the 2017 ACC/AHA hypertension guidelines, was associated with a higher prevalence of ICAS compared to normal BP levels in a neurologically healthy population. In addition, the BP categories were associated with both prevalence and burden of ICAS lesions in a dose–response manner. The systematic influence of elevated BP seemed important in the pathophysiology of ICAS lesion development.

The exact mechanisms connecting elevated BP and ICAS are unclear. However, we suggest several plausible explanations: First, vascular smooth muscle cell hyperplasia and hypertrophy may be involved. When elevated BP acts on the arterial walls, cellular hyperplasia occurs via the proliferation of smooth muscle cells and these cells infiltrate into subendothelial areas.^11,20,22 In addition, various extracellular matrix proteins accumulate, such as elastin, collagen, and mucopolysaccharides, leading to arterial intimal thickening.^11,20,22,28 These changes are proportional to tangential or stretching force on the wall, and these forces depend, in turn, on the systemic BP.²⁸ The results of this study also indicate that SBP values of 130–139 mm Hg or DBP values of 80–89 mm Hg also induce intimal thickening in intracranial vessels; Second, elevated BP can increase levels of oxidized lipoprotein, which is a main component of the atherosclerotic lipid core. Increased luminal pressure increases the influx of low-density lipoprotein cholesterol and the production of superoxide.^20,23,29 There was also indirect evidence that oxidized low-density lipoprotein cholesterol was positively associated with both SBP and DBP levels.²⁹ We could not directly measure histological parameters in this study. However, increased oxidized-lipid deposition on the wall could be one possible mechanism, forming fibrous fatty plaques. Third, endothelial dysfunction may play a role. In stage 1 hypertension, endothelial function can be impaired through the following mechanisms: (i) oxidative stress, (ii) subclinical inflammation, and (iii) vasoactive materials.^{20–22,28,30,31} Increased vascular permeability caused by endothelial dysfunction allows more inflammatory and lipid materials into the arterial walls, leading to atheroma; ³¹ Finally, stage 1 hypertension may indicate that subjects have a higher burden of risk factors, which are also risk factors for ICAS development. In previous studies, 90% of patients with prehypertension, defined as stage 1 hypertension in this study, had at least one other cardiovascular risk factor.^5,6 In this study, 42% of participants in the stage 1 hypertension group have other cardiovascular risk factors, and the frequencies of risk factors increased across the BP categories in a dose–response manner (Table 3). Thus, subjects with stage 1 hypertension may have a more hostile environment that contributes to ICAS development than those with normal BP levels.

We found a dose–response relationship between the BP categories and ICAS lesion burden. As mentioned, it is already known that cardiovascular and cerebrovascular disease risk proportionally increases with BP level, beginning at 115/75 mm Hg.^4–6 Furthermore, several studies have shown the clues that this novel stage 1 hypertension has an increased risk of ischemic stroke compared to optimal BP. However, our main findings are novel in that they confirm the newly defined stage 1 hypertension confers significant risk with regards to the prevalence and even burden of ICAS. Once ischemic stroke events occur, they commonly induce persistent neurological disability. Thus, it is very important to know the preclinical stage and prevent stroke in advance. Our confirmation of risk of novel stage 1 hypertension on a potent risk factor of stroke (e.g., ICAS) may give important insights to further studies. Conversely, ICAS lesion location seemed to have no association with BP categories, implying that hypertension is a systemic disease.

There were several caveats in this study. First, the design was retrospective, and the study was carried out in a single center. Although we included a large number of participants and examined a broad range of clinical and radiological information, the possibility of selection bias remains. Second, due to the limitations of cross-sectional analysis, we could only confirm the association, but not causality. For this reason, large prospective studies should be carried out in future. Third, the prevalence of ICAS is relatively small in this study. It may result from the traits of our registry, which contains younger median age and smaller burden of vascular risk factors. However, despite of low frequencies of ICAS, we proved definite correlation between stage 1 hypertension and ICAS. Fourth, we should also consider the genetic factors. As previous studies have shown, East Asians have high frequencies of RNF213 R4810K variants, leading to intracranial vascular vulnerability to hemodynamic stress.³² Thus, our results should be confirmed in non-Asian population. Finally, because we reviewed data from past routine health checkups, we could only use the baseline BP data measured on a single day. This may have led to BP group misclassification. However, as previous epidemiological evidence has confirmed, BP measurements taken on a single day are adequate.³³ Thus, our main results would not be different.

We demonstrated that stage 1 hypertension according to the 2017 ACC/AHA guidelines was associated with higher prevalence and burden of ICAS in neurologically healthy participants. To identify a high-risk group about ICAS development, the new, stricter BP guideline seems to be plausible.

Acknowledgments

None.

Disclosure

The authors declared no conflict of interest.

Author notes

*These authors contributed equally