Hypertension remains one of the leading modifiable risk factors for cardiovascular morbidity and mortality worldwide (1). Among the hypertensive population, resistant hypertension—a condition defined as blood pressure that remains above target despite the concurrent use of three or more antihypertensive medications of different classes, including a diuretic—is associated with significantly higher cardiovascular risk (2). Patients with resistant hypertension often exhibit abnormal circadian blood pressure patterns, particularly nocturnal hypertension, which has been increasingly recognized as an independent predictor of adverse outcomes, including stroke (3,4).

Nocturnal hypertension is characterized by elevated blood pressure during sleep and can be accurately identified through 24-hour ambulatory blood pressure monitoring (ABPM) (5). Unlike daytime hypertension, elevated nighttime blood pressure has been shown to have a stronger association with target organ damage, such as left ventricular hypertrophy, chronic kidney disease, and cerebrovascular events (6,7). The normal physiological dipping pattern—where nighttime blood pressure falls by 10–20% compared to daytime values—is frequently blunted or absent in individuals with resistant hypertension, further exacerbating their risk profile (8).

Previous studies have demonstrated that nocturnal hypertension is associated with an increased risk of stroke in the general hypertensive population (9). However, data specifically examining the prognostic significance of nocturnal hypertension among patients with resistant hypertension are limited. Given the high baseline risk in this population, understanding the impact of nocturnal blood pressure elevations on stroke outcomes is critical for optimizing management strategies.

Therefore, the present longitudinal study was conducted to evaluate the association between nocturnal hypertension and the risk of stroke in patients with resistant hypertension, with the aim of highlighting the importance of nocturnal blood pressure monitoring in this vulnerable cohort.

Study Design and Population

This was a prospective, longitudinal cohort study conducted at a tertiary care teaching hospital. Patients aged 30–75 years who were diagnosed with resistant hypertension, according to the American Heart Association criteria (blood pressure ≥140/90 mmHg despite adherence to a regimen of three or more antihypertensive drugs of different classes, including a diuretic), were eligible for inclusion (1). Patients with secondary hypertension, recent myocardial infarction, known atrial fibrillation, severe valvular heart disease, or advanced renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m²) were excluded.

Baseline Assessment

Demographic data, clinical history, medication usage, lifestyle factors (smoking status, alcohol use), and comorbidities such as diabetes mellitus and dyslipidemia were recorded at enrollment. Body mass index (BMI) and standard office blood pressure measurements were obtained according to the European Society of Hypertension guidelines (2).

Ambulatory Blood Pressure Monitoring (ABPM)

All participants underwent 24-hour ABPM at baseline using a validated oscillometric device (Spacelabs 90217A). Blood pressure readings were recorded every 20 minutes during daytime (6:00 AM to 10:00 PM) and every 30 minutes during nighttime (10:00 PM to 6:00 AM). Nocturnal hypertension was defined as a mean nighttime systolic blood pressure ≥120 mmHg or diastolic blood pressure ≥70 mmHg, as per current recommendations (3).

Follow-up and Outcome Assessment

Participants were followed up every six months via clinic visits or telephone interviews for a maximum of 36 months. The primary outcome was the occurrence of a first stroke event, confirmed through clinical evaluation and neuroimaging (CT or MRI scan). Stroke was classified as ischemic or hemorrhagic based on imaging findings.

Statistical Analysis

Continuous variables were expressed as mean ± standard deviation or median (interquartile range) as appropriate, and categorical variables were presented as frequencies and percentages. Group comparisons were performed using the independent t-test or Mann–Whitney U test for continuous variables and the chi-square test for categorical variables. Kaplan–Meier survival analysis was used to estimate the cumulative incidence of stroke, and the log-rank test was used to compare groups. Multivariate Cox proportional hazards regression analysis was performed to assess the association between nocturnal hypertension and risk of stroke after adjusting for potential confounders. A p-value <0.05 was considered statistically significant. Statistical analyses were conducted using SPSS version 25.0 (IBM Corp., Armonk, NY, USA).

A total of 312 patients with resistant hypertension were enrolled, of whom 176 (56.4%) had nocturnal hypertension and 136 (43.6%) did not. Baseline characteristics of the two groups are summarized in Table 1.

Patients with nocturnal hypertension were older (mean age 58.7 ± 9.4 years) compared to those without nocturnal hypertension (mean age 54.2 ± 8.6 years, p = 0.001). The nocturnal hypertension group also had a higher prevalence of diabetes mellitus (62.5% vs. 44.1%, p = 0.003) and dyslipidemia (71.0% vs. 53.6%, p = 0.002). Mean daytime systolic and diastolic blood pressures were not significantly different between the groups (p > 0.05).

During a median follow-up period of 36 months, 42 stroke events were recorded: 34 events (15.3%) occurred in the nocturnal hypertension group and 8 events (5.9%) in the non-nocturnal hypertension group (Table 2). The cumulative incidence of stroke was significantly higher in patients with nocturnal hypertension compared to those without (log-rank test, p < 0.001).

In multivariate Cox proportional hazards analysis (Table 3), after adjusting for age, sex, diabetes, dyslipidemia, smoking, and baseline daytime blood pressure, nocturnal hypertension remained an independent predictor of stroke (adjusted hazard ratio [aHR] 3.78, 95% confidence interval [CI]: 2.01–7.12, p < 0.001).

Table 1: Baseline Characteristics of Study Participants

(SBP = Systolic Blood Pressure; DBP = Diastolic Blood Pressure)

Table 2: Stroke Incidence in Study Groups

Table 3: Multivariate Cox Proportional Hazards Analysis for Risk of Stroke

In this longitudinal study, we observed that nocturnal hypertension was strongly associated with an increased risk of stroke in patients with resistant hypertension. Patients exhibiting elevated nighttime blood pressure had a more than threefold higher risk of stroke compared to those without nocturnal hypertension, even after adjustment for major confounding factors.

Our findings are consistent with previous studies demonstrating that nocturnal blood pressure is a superior predictor of cardiovascular events compared to daytime or office measurements (1,2). The concept of "non-dipping" or "reverse-dipping" blood pressure patterns has been linked with heightened sympathetic activity, impaired sodium handling, and endothelial dysfunction, all of which contribute to target organ damage (3,4). Resistant hypertension, by its nature, often reflects a more advanced pathophysiological stage, and the coexistence of nocturnal hypertension appears to exacerbate vascular injury, leading to an increased stroke risk (5).

Ambulatory blood pressure monitoring (ABPM) provides unique insights into 24-hour blood pressure profiles, uncovering masked nocturnal hypertension that would be missed in clinic readings (6). Our study reinforces the clinical importance of incorporating ABPM into the routine evaluation of patients with resistant hypertension, especially considering that almost 56% of our cohort exhibited nocturnal hypertension at baseline.

The mechanisms linking nocturnal hypertension with stroke are multifactorial. Persistent nocturnal elevations in blood pressure promote arterial stiffness, accelerate atherosclerosis, and impair cerebrovascular autoregulation, thereby increasing the likelihood of both ischemic and hemorrhagic events (7,8). Additionally, abnormal nocturnal blood pressure patterns are associated with a higher prevalence of left ventricular hypertrophy and microalbuminuria, which further reflect systemic vascular dysfunction (9).

Previous research has emphasized the role of nighttime blood pressure control in reducing cardiovascular risk. For instance, the Hygia Chronotherapy Trial demonstrated that bedtime administration of antihypertensive medication significantly reduced nighttime blood pressure and improved cardiovascular outcomes, including stroke (10). However, specific evidence focusing on resistant hypertension populations remains limited. Our study adds to the growing body of literature suggesting that optimal nocturnal blood pressure control may be crucial in this high-risk group.

Interestingly, while daytime blood pressure values were not significantly different between groups in our study, nighttime measurements revealed significant disparities in stroke incidence. This underscores the limitations of relying solely on daytime or office blood pressure readings when evaluating risk profiles in resistant hypertension (11,12).

Diabetes mellitus and advanced age were also identified as independent predictors of stroke in our multivariate analysis, in line with existing data (13,14,15). These comorbidities likely interact synergistically with nocturnal hypertension, potentiating vascular injury and increasing the risk of cerebrovascular events.

Our study has several strengths, including a well-characterized cohort, standardized ABPM protocols, and rigorous outcome adjudication. Nevertheless, certain limitations should be acknowledged. First, the study was conducted at a single center, which may limit generalizability. Second, despite adjustment for known confounders, the possibility of residual confounding cannot be entirely excluded. Finally, stroke subtypes (ischemic vs. hemorrhagic) were not analyzed separately due to limited event numbers.

In conclusion, nocturnal hypertension independently predicts stroke in patients with resistant hypertension. ABPM should be routinely employed in this population for better risk stratification. Future interventional studies are warranted to evaluate whether targeted nighttime blood pressure control strategies can reduce stroke incidence in patients with resistant hypertension.

1. Hermida RC, Ríos MT, Crespo JJ, Moyá A, Domínguez-Sardiña M, Otero A, et al. Treatment-time regimen of hypertension medications significantly affects ambulatory blood pressure and clinical characteristics of patients with resistant hypertension. Chronobiol Int. 2013;30(1-2):192–206. doi:10.3109/07420528.2012.701460. PMID: 23098160.
2. Moyá A, Crespo JJ, Ayala DE, Ríos MT, Pousa L, Callejas PA, et al. Effects of time-of-day of hypertension treatment on ambulatory blood pressure and clinical characteristics of patients with type 2 diabetes. Chronobiol Int. 2013;30(1-2):116–31. doi:10.3109/07420528.2012.702587. PMID: 23181613.
3. Crespo JJ, Piñeiro L, Otero A, Castiñeira C, Ríos MT, Regueiro A, et al. Administration-time-dependent effects of hypertension treatment on ambulatory blood pressure in patients with chronic kidney disease. Chronobiol Int. 2013;30(1-2):159–75. doi:10.3109/07420528.2012.701459. PMID: 23098134.
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