Dipping Pattern and 1-year stroke functional outcome in ischemic stroke or transient ischemic attack

ABSTRACT

Aims

This study aimed to explore whether a relationship exists between dipping patterns and 1-year functional outcome in patients with acute ischemic stroke (IS) or transient ischemic attack (TIA).

Methods

Data from the Blood Pressure and Clinical Outcome in TIA or Ischemic Stroke Study (BOSS), a nationwide, hospital-based, longitudinal cohort study, was used for this study. Patients with acute IS or TIA were recruited within 7 days after onset and ambulatory blood pressure monitoring was performed during hospitalization. Patients were defined as dippers if nocturnal systolic blood pressure fell by ≥10%, non-dippers if 0–10%, and reverse dippers if < 0%. Poor functional outcome was defined as a modified Rankin Scale (mRS) score of 3–5. Logistic regression analysis was used to test the association between dipping patterns and 1-year functional outcome.

Results

Among the 1808 IS/TIA patients, 19.19% were dippers, 53.21% were non-dippers, and 27.60% were reverse dippers. Poor functional outcome occurred in 22.44% of reverse dippers, which was significantly higher than that of dippers (16.14%) and non-dippers (16.53%) (P = .014). A univariate analysis revealed that reverse dipping was a risk factor for poor functional outcome (Odds ratio 1.504, 95% confidence interval 1.055–2.145, P = .024). However, this significance disappeared after adjusting for confounders.

Conclusions

Reverse dipping was prevalent in patients with IS/TIA. The higher incidence of 1-year poor functional outcome in reverse dippers warrants further investigation.

KEYWORDS:

• Dipping pattern
• reverse dipping
• acute ischemic stroke
• transient ischemic attack
• functional outcome

Introduction

Elevated blood pressure (BP) is the most important modifiable risk factor for acute stroke (1–4). Recently, an abundance of studies have found that certain BP profiles acquired by ambulatory blood pressure monitoring (ABPM), such as non- and reverse dipping patterns, predicted increased hypertensive target organ damage and poor cardiovascular prognosis in general as well as in hypertensive populations (2,4–6). While abnormal dipping pattern might affect vascular health independent of BP level, there was considerable controversy surrounding the prognostic value of dipping patterns in patients with acute ischemic stroke (IS) or transient ischemic attack (TIA). Several studies have revealed poor outcomes in non-dippers and reverse dippers (2,7), while others have noted no significant association between dipping patterns and stroke outcomes (8,9). Furthermore, there is a paucity of data from large stroke cohort studies. Therefore, we investigated the relationship between dipping patterns early after acute IS/TIA onset and 1-year stroke functional outcome in a large cohort study.

Materials and methods

Patients

The methodology of the blood pressure and clinical outcome in the TIA or ischemic stroke study (BOSS) has been reported in detail elsewhere (10–12). Briefly, the BOSS was a nationwide hospital-based longitudinal cohort study conducted at 61 hospitals in China. The participating hospitals were selected from 16 provinces and 4 municipalities across mainland China. Patients were recruited if the following conditions were met: age of 18 years or older, diagnosis of acute IS or TIA, and hospitalization within 7 days of the index event. The exclusion criteria for the present study were as follows: less than 70% of valid BP readings on ABPM, atrial fibrillation, thrombolysis treatment, and loss to follow-up at 1 year. Finally, 1808 patients were included in this study. This study was approved by the ethics committee of each study center. Written informed consent was obtained from all participants or their designated relatives.

24-hour ABPM

ABPM was performed over 24 hours during hospitalization using a validated device. The ABPM device was attached ipsilateral to the intracranial lesion. Daytime episodes were defined as those occurring between 6:00 am to 9:59 pm and nighttime episodes as those occurring between 10:00 pm to 5:59 am. BP measurements were taken every 15 min during the day and every 30 min during the night. Nocturnal systolic blood pressure (SBP) fall was calculated according to the standard formula: (daytime SBP – nighttime SBP)/daytime SBP×100%. Patients were defined as dippers if their nocturnal SBP fell by ≥10% (patients with a nocturnal SBP fall ≥20% accounted for only 2% of the entire population; thus, they were classified into the dipper group), non-dippers if their nocturnal SBP fell by < 10%, and reverse dippers if their nocturnal SBP fell by < 0% (average nighttime SBP was higher than daytime SBP).

Baseline data collection

Baseline data collection included the following (1): demographics (2); risk factors including history of hypertension, coronary heart disease, diabetes mellitus, dyslipidemia, peripheral vascular disease, current or previous smoking, and moderate or heavy drinking (3); other clinical features including National Institutes of Health Stroke Scale (NIHSS) score at admission and creatinine obtained from a venous blood sample. The estimated glomerular filtration rate (eGFR) was calculated using the Chinese modification of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.

Follow-up and functional outcome

Functional outcome of acute IS/TIA was assessed using the modified Rankin Scale (mRS). Poor functional outcome was defined as an mRS 3–5. Patients were followed-up for 1 year by telephone. A standard electronic data collection system was developed by Goodwill Information Technology Co., Ltd., and electronic case report forms were used for follow-up data collection.

Statistical analysis

Continuous variables are expressed as means with standard deviations or medians with interquartile ranges, as appropriate. Categorical data are presented as proportions. Before further analysis, a comparison of the characteristics among dippers, non-dippers, and reverse dippers was performed using the Kruskal-Wallis test for continuous variables and the chi-square test for categorical variables. Dippers were used as the reference category and were separately compared with non-dippers and reverse dippers using univariate and multivariate analyses. Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated using multivariate logistic regression analysis to evaluate the association between dipping patterns and 1-year functional outcome. The multivariable model was adjusted for age, sex, hypertension, diabetes mellitus, coronary heart disease, antihypertensive treatment, baseline NIHSS score, eGFR and average 24 h SBP value. Data were analyzed using SAS version 9.1.3 statistical software (SAS Institute, Cary, NC, USA). Two-tailed P values <.05 were considered statistically significant.

Results

The demographic and clinical baseline values of the participants enrolled in this study are shown in Table 1. Of the 1808 patients included, their mean age was 62.03 ± 10.95 years, 32.28% were female, 70.95% were diagnosed with hypertension, 54.38% received anti-hypertensive medication, and 21.39% were diagnosed with diabetes. The mean 24-h SBP was 141.6 ± 18.14 mmHg (Table 1).

Table 1. Baseline characteristics according to dipping patterns.

Characteristics	All (N = 1808)	Dipper (N = 347)	Non-dipper (N = 962)	Reverse dipper (N = 499)	P value
Age (y)	62.03 ± 10.95	60.63 ± 10.53	61.50 ± 11.03	64.04 ± 10.72	<.001
Women (%)	32.28%	34.01%	31.29%	32.87%	.612
History of hypertension (%)	70.95%	65.13%	72.66%	71.54%	.031
History of diabetes (%)	21.39%	15.85%	21.62%	24.85%	.006
History of CHD (%)	10.56%	7.20%	11.64%	10.82%	.055
History of PVD (%)	1.75%	1.73%	1.87%	1.40%	.807
History of dyslipidemia (%)	10.67%	10.09%	12.06	8.42%	.088
Smoke	33.37%	32.85%	34.62%	31.06%	.384
Drink	32.39%	33.43%	32.12%	31.86%	.879
Baseline NIHSS	2.00 (1.00, 4.00)	2.00 (1.00, 4.00)	2.00 (1.00, 4.00)	2.00 (1.00, 5.00)	.019
Anti-hypertensive treatment (%)	54.38%	47.55%	54.89%	57.72%	.012
Mean eGFR(ml/min/1.73 m^2)	91.76 (79.06, 101.27)	94.02 (81.58, 101.88)	92.04 (79.50, 101.96)	89.22 (75.29, 99.80)	<.001
Average 24 h SBP (mmHg)	141.60 ± 18.14	138.08 ± 17.24	141.69 ± 18.72	143.98 ± 17.31	<.001
daytime SBP (mmHg)	142.87 ± 18.22	142.60 ± 17.92	143.29 ± 18.91	142.25 ± 17.12	.702
nighttime SBP (mmHg)	137.39 ± 20.48	122.42 ± 15.70	136.45 ± 18.37	149.62 ± 19.80	<.001

Values are presented as “mean ± standard deviation” or “median with interquartile range” for continuous variables, and as percentages for categorical variables. The Kruskal-Wallis test was used for continuous variables, and Chi-square tests were used for categorical variables.

NHISS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure; eGFR, estimated glomerular filtration rate; PVD, peripheral vascular disease; CHD, coronary heart disease.

ABPM revealed dipping, non-dipping, and reverse dipping in 19.19%, 53.21%, and 27.60% of the patients, respectively. Compared to dippers and non-dippers, reverse dippers were older and more likely to have a higher prevalence of diabetes, higher rate of antihypertensive treatment, higher baseline NIHSS score, higher nighttime SBP, and lower eGFR at admission (all P < .05) (Table 1).

Poor 1-year functional outcome was observed in 327 (18.09%) patients. Reverse dippers were more likely to have poor functional outcome as the rate of poor functional outcome was 22.44% for reverse dippers, 16.14% for dippers, and 16.53% for non-dippers (P = .014). The univariate analysis revealed that reverse dipping was a significant risk factor for poor functional outcome compared with dipping (OR 1.504, 95%CI 1.055–2.145, P = .024). However, after adjusting for age, sex, history of hypertension, diabetes, coronary heart disease, baseline NIHSS score, antihypertensive treatment, eGFR, and average 24 h SBP, reverse dipping was no longer associated with 1-year functional outcome (Table 2).

Table 2. Dipping profiles of systolic blood pressure on 1-year functional outcome in IS/TIA patients.

		Dipper	Non-dipper OR (95% CI)	Reverse dipper OR (95% CI)
Poor functional outcome	unadjusted	1.0(reference)	1.029(0.738–1.435)	1.504(1.055–2.145) *
	Adjusted^§	1.0(reference)	0.817(0.563–1.186)	0.972(0.648–1.458)

IS, ischemic stroke; TIA, transient ischemic attack. ^§Adjusted for age, sex, history of hypertension, diabetes, coronary heart disease, baseline. NIHSS, antihypertensive treatment, eGFR and average 24-hour systolic blood pressure value. *P < 0.

Discussion

BP in healthy individuals exhibits diurnal variation, with a nighttime dip of 10–20%. Reverse dipping, a condition characterized by an increased nighttime SBP compared to daytime SBP, represents an extreme alteration in circadian BP rhythm and is regarded as a particularly harmful BP phenotype (4,6,7,9). In the BOSS study, we found that reverse dipping was highly prevalent in patients with acute IS or TIA and was associated with a higher incidence of poor functional outcome.

Previous studies have reported that the prevalence of reverse dipping is higher in hypertensive individuals than in normotensive individuals (13,14). In a Belgian database including 3648 patients with hypertension from 4 European studies, reverse dippers accounted for 12.14% of the pooled population (15). Reverse dipping has also been reported to be significantly more common in stroke patients (24.1–40%) than in community control subjects (2,7,8). In the present study, this proportion was 27.6%.

Diabetes was frequent in the reverse dippers in the present study. Notably, a previous study found that diabetes was particularly associated with elevated nighttime blood pressure (13), which often coincides with non- and reverse-dipping. Insulin resistance in diabetes may play an important role in the development of abnormal circadian BP rhythms (15,16). Hyperinsulinemia may activate the mitogen-activated protein kinase pathway, leading to smooth muscle cell proliferation, increased stiffness, and elevated BP variations (17).

We found that the reverse dippers were significantly older than those in the other two groups. Importantly, a study by Sakakura et al. found that aging increases blood pressure variability (18). Moreover, the NIHSS score at baseline was significantly higher in the reverse dipping group than in the dipping and non-dipping groups. A previous study that analyzed 35 patients with acute ischemic stroke also found that reverse dippers had the highest NIHSS score at baseline, which was in line with our findings (7). Therefore, reverse dipping might be associated with a worse baseline status.

In our study, we observed that reverse dippers had a significantly higher nighttime SBP. Importantly, a previous study found that for each 10 mmHg increase in mean nighttime SBP, the risk of cardiovascular events increased by 21% (19).

In the present study, the eGFR was lower in reverse dippers than in dippers. Previous studies have reported that reverse dippers were prevalent among the chronic kidney disease (CKD) population (13,20). In fact, a study assessing CKD patients not undergoing dialysis found that the reverse dipping pattern demonstrated an independent prognosis for cardiovascular events and deaths after adjustment for 24-hour SBP (21). In view of the good renal function of the patients enrolled in this study (median eGFR 91.76 ml/min/1.73 m², interquartile range 79.06–101.27 ml/min/1.73 m²), the effects of renal function on reverse dipping and stroke prognosis should be assessed in future studies.

It has been reported that reverse dipping is associated with the initial formation of carotid plaque in individuals with hypertension and is considered an important marker for accelerated atherosclerosis, aortic stiffness, coronary artery disease, and stroke (13,15,16,22–24). For example, a meta-analysis of 3468 hypertensive patients without major cardiovascular disease at baseline found that the incidence of cardiovascular events was higher in reverse dippers (15). Furthermore, in a prospective study performed in 426 patients with cerebral infarction followed up for an average period of 7.6 years, reverse dipping was associated with an increased mortality rate (25). However, in a study of 173 acute stroke patients in which BP was measured every 4 hours for 48 hours, reverse dipping was not associated with 3-month death or stroke disability (8). Another study found no significant association between dipping patterns and 3-month functional outcome in 304 patients with acute ischemic stroke treated with intravenous thrombolysis (9). Although we found that reverse dipping was associated with a higher incidence of 1-year poor functional outcome in the univariate analysis; this association disappeared after adjusting for confounders. These conflicting results may be due in part to differences in methodology and study design. Additionally, the low incidence rate of poor functional outcome during the 1-year follow-up in our study might also have influenced the results. Nevertheless, reverse dipping may still have a higher burden of poor outcomes, and deserves further investigation.

The mechanisms underlying the relationship between the dipping patterns and prognosis of IS/TIA remains unclear and is probably multifactorial. Notably, stable cerebral blood flow after stroke requires SBP to remain within the limits required for proper cerebral auto-regulation. Reverse dipping along with sustained hypertensive stress to the vascular endothelium is accompanied by persistent activation of the autonomic nervous system, sympathetic tone and α1-adrenergic activities, disturbed baroreflex sensitivity, sleep apnea, increased salt sensitivity, and nocturnal volume overload, which likely leads to injured brain blood vessels and changes in cerebral perfusion (14,25,26). A lack of adequate nocturnal dipping has also been reported to be associated with greater common carotid intima-media thickness (27), slower gait speed, and greater brain atrophy (6). Combined, these findings may partially explain the association between abnormal dipping patterns and poor functional outcome in IS/TIA. There was also a hypothetical question of whether reverse dipping preceded stroke prognosis or was a consequence of a cerebrovascular event. Some researchers have suggested that reverse dipping may be caused by damage to the autonomic centers in the brain, resulting in pathological sympathetic activation. However, in either case, reverse dipping was found to be prevalent in patients with IS/TIA and might be an important risk factor for poor functional outcome.

The strengths of this study were the inclusion of a large, representative acute IS/TIA patient population, the use of ABPM, and the provision of data on functional outcome for 1-year post-stroke. However, our study had some limitations. Different types of ABPM devices were used at each site. Given this, the original BP data of all patients were reentered into EpiData, and all BP-composite parameters were recalculated using SAS software. Moreover, our results among patients with IS/TIA should not necessarily be extrapolated to all types of stroke patients. As such, future studies should be conducted with different populations.

Conclusions

Based on a nationwide, hospital-based, multicenter, longitudinal cohort study of patients with acute ischemic stroke/TIA, we found that reverse dipping was prevalent and may be related to a higher incidence of poor functional outcome. The influence of abnormal circadian BP rhythm on stroke prognosis requires further study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/10641963.2022.2139384

Additional information

Funding

This study was supported by grants from the Ministry of Science and Technology of the Peoples Republic of China (2011BAI08B01, 2013BAI09B02, 2017YFC1310901, 2017YFC1310902, 2016YFC0901001, 2016YFC0901002, 2018YFC1311700, and 2018YFC1311706), a grant from Beijing Municipal Administration of Hospitals’ Youth Program (QML20150504), grants from the Beijing Municipal Commission of Health and Family Planning (No.2016-1-2041, SML20150502), Beijing Multiple Administration of Hospital Clinical Medicine Development of Special Funding Support (ZYLX201820), Beijing Health Scientific and Technological Achievements, and appropriate technology promotion projects (2018-TG-32).