Understanding Ambulatory Arterial Pressure Index and Circadian Rhythm Abnormalities

Introduction Primary hypertension (PH) and coronary artery disease (CAD) are two of the most prevalent and interrelated cardiovascular conditions worldwide.1 Hypertension contributes significantly to the development and progression of CAD, while the coexistence of CAD often complicates blood pressure (BP) control.2 In clinical practice, patients with CAD may present with borderline or low BP due to myocardial ischemia or aggressive anti-ischemic therapy, which can limit the use or titration of β-blockers and non-dihydropyridine calcium channel blockers—mainstay agents for angina and rate control. This therapeutic dilemma underscores the need for refined hemodynamic evaluation tools in hypertensive patients with CAD.3,4 Circadian BP variation plays a critical role in cardiovascular homeostasis, and disruption of the normal nocturnal BP decline is a well-established predictor of adverse cardiovascular outcomes.5 Moreover, an exaggerated early-morning BP surge—common in hypertensive patients with CAD—has been associated with increased myocardial oxygen demand, plaque instability, a higher incidence of myocardial infarction, and major adverse cardiovascular events (MACE).6 Accumulating evidence indicates that patients exhibiting an abnormal dipping pattern and heightened morning BP surge are at particularly elevated risk of ischemic events and sudden cardiac death, especially those with underlying CAD.3–6 Therefore, identifying BP rhythm abnormalities in this population is crucial for individualized management and cardiovascular risk reduction. Ambulatory blood pressure monitoring (ABPM) offers a more comprehensive assessment of BP dynamics compared to office BP measurement, allowing for the evaluation of diurnal variability and related indices.7,8 Among these, the ambulatory arterial pressure index (AAPI)—defined as the ratio of diastolic to systolic pressure load over a 24-hour period—has emerged as a novel integrative marker that reflects the cumulative hemodynamic burden experienced by the arterial wall during daily activities and nocturnal periods.9 Unlike traditional mean BP values, AAPI captures the interplay between systolic and diastolic stress and may better correlate with arterial stiffness, end-organ damage, and risk of major adverse cardiovascular events.10 In patients with established CAD receiving contemporary medical therapy—including β-blockers, ACEIs/ARBs, calcium channel blockers, and statins—ambulatory BP profiles still demonstrate substantial heterogeneity and prognostic relevance. Prior studies have shown that even under optimized pharmacological treatment, CAD patients frequently exhibit impaired nocturnal BP fall, blunted morning BP surge, and persistent 24-hour BP variability, all of which remain strongly associated with recurrent ischemic events and long-term cardiovascular mortality.1–3 For instance, intensive BP-lowering trials in CAD populations revealed that the magnitude and timing of ambulatory BP reduction, rather than clinic BP alone, predicted plaque regression and future cardiovascular events.4,5 Moreover, abnormalities in circadian BP regulation may persist despite adequate office BP control, underscoring the importance of dynamic BP assessment for residual risk stratification in CAD patients.5,8 Hence, evaluating metrics that better capture 24-hour hemodynamic burden in treated CAD cohorts is clinically meaningful, as it may help identify high-risk individuals who could benefit from personalized BP-lowering strategies or chronotherapy. Recent studies suggest that abnormal AAPI levels are associated with subclinical organ dysfunction and poorer cardiovascular outcomes, particularly in patients with metabolic comorbidities or autonomic dysfunction.11 However, limited data are available regarding the association between AAPI and circadian BP patterns, especially in the context of PH complicated by CAD—a clinical setting that is inherently predisposed to autonomic dysregulation and impaired nocturnal BP dipping.12 To the best of our knowledge, this is the first study to investigate the relationship between ambulatory arterial pressure index and circadian BP rhythm patterns in patients with PH and concomitant coronary artery disease. The novelty of this study lies in its focus on a high-risk cohort and the use of AAPI as a potentially more sensitive marker of hemodynamic disturbance compared to traditional BP metrics. We hypothesized that patients with disrupted circadian BP rhythms (non-dipper or reverse-dipper types) would exhibit significantly different AAPI values compared to those with a normal dipper pattern, reflecting underlying autonomic imbalance or vascular dysfunction. By systematically evaluating the distribution of circadian BP profiles and corresponding AAPI values in this population, this study aims to (1) characterize the clinical and hemodynamic profile of patients with abnormal BP rhythms, (2) assess the predictive value of AAPI for circadian rhythm disruption, and (3) explore the potential of AAPI as a noninvasive indicator for early detection of BP rhythm disorders in patients with coexisting PH and CAD. The findings may offer new insights into the integrative pathophysiology of BP regulation and support the utility of AAPI in risk assessment and therapeutic decision-making in this vulnerable population. Methods Study Design and Participants This retrospective observational study was conducted at a tertiary cardiovascular center and included 430 hospitalized patients diagnosed with PH and concomitant CAD between January 2022 and December 2023. Inclusion criteria were as follows: (1) age ≥ 18 years; (2) diagnosis of PH based on the 2018 ESC/ESH guidelines;13 (3) confirmed diagnosis of CAD, including chronic coronary syndrome or acute myocardial infarction (AMI); and (4) completion of 24-hour ambulatory blood pressure monitoring (ABPM) during hospitalization. Patients were excluded if they had secondary hypertension, incomplete ABPM data, or comorbid conditions that significantly affect autonomic regulation (eg, Parkinson’s disease, advanced heart failure, or severe renal impairment). Heart failure was excluded by clinical assessment, echocardiographic left ventricular function evaluation, and natriuretic peptide testing. Patients with reduced ejection fraction (LVEF < 50%), acute pulmonary congestion, or structural heart disease causing hemodynamic instability were eliminated. The study protocol was approved by the Institutional Ethics Committee, and all procedures complied with the Declaration of Helsinki. In our institution, patients with chronic coronary syndrome are frequently admitted for comprehensive cardiovascular evaluation, exclusion of acute ischemic events, and optimization of anti-ischemic or antihypertensive therapy. Hospitalization is also common in those with newly diagnosed or poorly controlled hypertension complicated by coronary artery disease, as inpatient management allows standardized monitoring and timely medication adjustment. Therefore, the included patients underwent ABPM during their routine inpatient evaluation prior to discharge. Chronic coronary syndrome patients were hospitalized for comprehensive cardiovascular evaluation, optimization of anti-ischemic therapy, and blood pressure control. For patients with acute coronary syndrome (ACS), only those with non–ST–elevation ACS or stabilized ST-elevation myocardial infarction after revascularization were included. Patients with acute decompensated heart failure or Killip class ≥ II on admission were excluded based on clinical examination, B-type natriuretic peptide levels, and echocardiographic evaluation. Data Collection Demographic and clinical data, including age, sex, comorbidities, and biochemical parameters (eg, glucose, lipid profile, homocysteine, C-reactive protein), were extracted from the hospital’s electronic medical record system. All ABPM recordings were performed using a validated oscillometric device (Model: ABPM6100, Welch Allyn, USA), calibrated before each use. Blood pressure was measured at 30-minute intervals over 24 hours. Although ABPM is traditionally considered an out-of-office technique, our center routinely initiates ABPM during hospitalization to ensure appropriate device placement, calibration, and patient education. During monitoring, patients followed routine ward activities rather than strict bed rest, reflecting real-life BP fluctuations. This inpatient ABPM protocol has been widely applied in high-risk cardiovascular populations in clinical practice. Measurements were categorized into daytime (6:00–22:00) and nighttime (22:00–6:00) periods, as per standardized ABPM guidelines. Assessment of Circadian Blood Pressure Patterns Circadian BP rhythm patterns were classified into three categories based on the nocturnal decline in mean systolic BP (SBP): Dipper pattern: nighttime SBP reduced by 10–20% compared to daytime; Non-dipper pattern: nighttime SBP reduced by <10%; Reverse-dipper pattern: nighttime SBP higher than daytime SBP.14,15 Patients with non-dipper and reverse-dipper patterns were collectively categorized as having a disrupted circadian rhythm, while those with a dipper pattern were considered to have a normal rhythm. Calculation of the Ambulatory Arterial Pressure Index (AAPI) AAPI was defined as the ratio of diastolic pressure load to systolic pressure load over a 24-hour period, calculated automatically by the ABPM software. Pressure load was defined as the percentage of valid readings exceeding the conventional threshold (SBP > 135 mmHg or DBP > 85 mmHg for daytime; SBP > 120 mmHg or DBP > 70 mmHg for nighttime). The final AAPI value was extracted from the report summary and recorded to three decimal places. Reproducibility and Quality Control of ABPM To minimize measurement variability and ensure reproducibility, all ambulatory BP recordings were performed by trained technicians using the same validated oscillometric ABPM device. Calibration was completed before each test, and recordings with >20% invalid readings or technical artifacts were repeated prior to data entry. In accordance with expert consensus recommendations, we required ≥70% valid measurements over the 24-hour period to be considered eligible. Although a repeated ABPM session was not performed for each participant due to the retrospective nature of the study, these standardized procedures aimed to reduce technical variability and improve the reliability of circadian BP rhythm classification and AAPI calculation. Statistical Analysis Statistical analyses were performed using SPSS software (version 26.0; IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation (SD) or median with interquartile range (IQR), as appropriate. Categorical variables were presented as counts and percentages. Independent samples t-tests were used to compare AAPI between normal and disrupted circadian rhythm groups, after confirming normal distribution via the Shapiro–Wilk test. Categorical variables were compared using the Chi-square test or Fisher’s exact test. Information on concomitant medications, including β-blockers, ACEIs/ARBs, calcium-channel blockers, nitrates, antiplatelets, and statins, was collected. The proportions of patients receiving these medications did not differ significantly across circadian rhythm subgroups (all p > 0.05), and major pharmacologic classes were included in multivariate adjustment. Pearson or Spearman correlation analyses were performed to examine the relationship between AAPI and circadian BP types. A two-tailed p-value < 0.05 was considered statistically significant. Results Baseline Characteristics of the Study Population A total of 430 patients with PH and concomitant coronary artery disease were included in the final analysis. The mean age was 69.1 ± 17.8 years, and 273 (63.5%) were male. All patients underwent 24-hour ambulatory blood pressure monitoring (ABPM), with complete data available for the classification of circadian blood pressure (BP) rhythm and the calculation of the Ambulatory Arterial Pressure Index (AAPI). The average 24-hour systolic and diastolic blood pressures across the cohort were 121.0 ± 9.0 mmHg and 68.8 ± 13.8 mmHg, respectively. The mean AAPI was 0.395 ± 0.041. The average estimated glomerular filtration rate (eGFR) was 94.6 ± 18.7 mL/min/1.73 m2, and the mean serum creatinine level was 70.6 ± 11.7 μmol/L. Regarding metabolic parameters, the average total cholesterol was 4.6 ± 1.2 mmol/L, LDL was 2.9 ± 1.3 mmol/L, HDL was 1.0 ± 0.2 mmol/L, and triglycerides averaged 1.3 ± 0.4 mmol/L. Mean fasting blood glucose was 5.6 ± 0.7 mmol/L. No significant differences were identified among the three circadian rhythm groups with respect to age, sex distribution, or key biochemical parameters. Similarly, in-hospital cardiovascular events — including recurrent ischemia, arrhythmias, and escalation of anti-ischemic or antihypertensive therapy — did not differ significantly between the dipper, non-dipper, and reverse-dipper subgroups (all p > 0.05), indicating comparable clinical stability during the monitoring period. Detailed baseline demographic and clinical characteristics stratified by circadian BP rhythm category are presented in Table 1. Distribution of the Circadian Blood Pressure Patterns Based on nocturnal systolic BP decline, patients were classified into three categories: dipper (n = 51, 11.9%), non-dipper (n = 266, 61.9%), and reverse-dipper (n = 113, 26.3%). Collectively, 379 patients (88.1%) exhibited a disrupted circadian BP rhythm (non-dipper or reverse-dipper), indicating a high prevalence of abnormal BP regulation in this comorbid population. Figure 1 presents the distribution of patients across the three circadian BP rhythm types. Distribution of Ambulatory Arterial Pressure Index The AAPI ranged from 0.300 to 0.500, with a mean of 0.395 ± 0.041 and a median of 0.390 (interquartile range: 0.360–0.430). When stratified by circadian rhythm type, AAPI values were lower in dipper patients compared to non-dipper and reverse-dipper subgroups. Descriptive statistics and group-wise comparisons of AAPI are shown in Table 2. Figure 2 illustrates the distribution of AAPI values across the three rhythm categories, with a visible upward shift in the disrupted rhythm groups. Comparison of AAPI Between Normal and Disrupted Circadian Rhythm Groups Patients were dichotomized into a normal circadian rhythm group (dipper, n = 51) and a disrupted rhythm group (non-dipper or reverse-dipper, n = 379). The mean AAPI in the disrupted group was significantly higher than in the dipper group (0.396 ± 0.041 vs 0.387 ± 0.043; t = –2.297, p = 0.022). These results support a statistically significant association between elevated AAPI and disrupted BP rhythm, suggesting that AAPI may serve as a sensitive hemodynamic marker of circadian dysregulation. Details are provided in Table 2, and the difference is visualized in Figure 2. Correlation Between AAPI and Circadian Blood Pressure Patterns To further explore the graded relationship between AAPI and circadian rhythm disruption, ordinal rhythm categories were numerically coded (dipper = 1, non-dipper = 2, reverse-dipper = 3). Pearson correlation analysis revealed a statistically significant positive association between rhythm type and AAPI (Pearson’s r = 0.18, p = 0.004). Figure 3 displays the scatterplot with fitted linear regression and 95% confidence intervals. The ascending trend in AAPI across rhythm severity categories supports a potential dose–response relationship. Adjustment for Confounding Variables To assess the independent association between AAPI and circadian rhythm disruption, multivariable logistic regression was performed, adjusting for clinically relevant covariates including age, sex, BMI, smoking status, eGFR, fasting glucose, lipid profile, and 24-hour mean systolic BP. Higher AAPI remained independently associated with disrupted circadian rhythm (adjusted OR = 1.42, 95% CI: 1.12–1.81, p = 0.004). The association persisted in a sensitivity analysis excluding patients with acute myocardial infarction (adjusted OR = 1.39, 95% CI: 1.08–1.79, p = 0.007), underscoring the robustness of the findings. Detailed regression coefficients and model parameters are presented in Table 3. Subgroup Analysis According to Clinical Variables Stratified analyses demonstrated that the association between elevated AAPI and disrupted circadian rhythm was robust across subgroups. The difference in AAPI between rhythm groups remained statistically significant in both males and females, as well as in patients aged ≥65 and <65 years. Similarly, patients with acute myocardial infarction and those with stable CAD showed consistent patterns. Figure 4 presents a forest plot summarizing the subgroup analyses, with point estimates favoring higher AAPI in the disrupted rhythm group across all categories. Discussion This study investigated the relationship between the AAPI and circadian BP rhythm in patients with PH and concomitant CAD. The results demonstrate that patients with disrupted circadian BP rhythms—defined as non-dipper or reverse-dipper patterns—exhibited significantly higher AAPI values compared to those with a normal dipper profile. Additionally, a graded, positive correlation between AAPI and the severity of circadian rhythm disruption was observed, suggesting a dose–response relationship. These findings support the hypothesis that AAPI may serve as a sensitive, noninvasive indicator of circadian hemodynamic imbalance in this high-risk population, with potential utility in risk stratification and therapeutic monitoring. Moreover, after adjusting for key demographic, metabolic, and hemodynamic variables, the association between higher AAPI levels and abnormal circadian BP patterns remained robust, indicating that this relationship is unlikely to be explained by confounding factors alone. Our study builds upon prior research emphasizing the prognostic value of circadian BP variation. While disrupted BP rhythms are known to be associated with increased cardiovascular morbidity and mortality independent of mean BP levels, traditional metrics such as nocturnal dipping status or average systolic/diastolic values may fail to capture the full complexity of 24-hour vascular stress.15–17 The AAPI, by incorporating both systolic and diastolic pressure loads over the entire circadian cycle, provides a more integrative representation of vascular burden. Previous studies have shown AAPI to be associated with arterial stiffness, left ventricular hypertrophy, and renal dysfunction.14,15 Our findings extend this knowledge by demonstrating that AAPI is not only elevated in patients with circadian BP abnormalities but also correlates linearly with rhythm severity, thus bridging a gap between 24-hour pressure load metrics and circadian physiology. The clinical implications of these findings are manifold. In patients with coexisting PH and CAD—a subgroup particularly vulnerable to autonomic dysregulation and impaired nocturnal BP dipping—accurate detection of circadian rhythm abnormalities is essential.18 Given that ABPM is already a cornerstone of hypertension management, integrating AAPI into routine ABPM interpretation may offer added value without additional testing burden.19 AAPI may also aid in identifying patients at higher risk of vascular complications who would benefit from chronotherapeutic interventions such as timed antihypertensive dosing or autonomic modulation therapies.20,21 Furthermore, its simplicity and reproducibility make AAPI an attractive candidate for broader implementation in primary care settings and longitudinal monitoring. Despite its strengths, this study has several limitations. First, the retrospective and single-center design may limit generalizability. Although the cohort was relatively large (n = 430), selection bias cannot be excluded, particularly since only hospitalized patients undergoing ABPM were included. Second, while we identified significant associations between AAPI and circadian rhythm disruption, causal relationships cannot be established. Longitudinal studies are required to determine whether elevated AAPI predicts future cardiovascular events or responds to interventions. Third, the reproducibility of ABPM is an important consideration when evaluating circadian BP patterns. Although our protocol incorporated strict quality-control criteria to improve reliability, repeated ABPM assessments were not available for this cohort. Performing a second ABPM after achieving tighter BP control would have provided deeper insight into whether AAPI changes dynamically with circadian rhythm normalization. Future prospective studies, including longitudinal ABPM assessments before and after therapeutic optimization, are warranted to validate the temporal stability of AAPI and its responsiveness to treatment. Fourth, other ABPM-derived metrics such as blood pressure variability, morning surge, and nocturnal BP load were not evaluated in this study and may further influence circadian BP phenotypes and AAPI. Finally, AAPI calculation is currently device-specific, and may not be standardized across different monitoring platforms, which could limit generalizability and cross-device comparability. Alternative approaches to investigate the pathophysiological link between vascular pressure load and circadian rhythm include continuous beat-to-beat BP monitoring, analysis of baroreflex sensitivity, and the incorporation of wearable technology for real-time autonomic assessment.22–24 However, these methods are either technically demanding or lack widespread clinical applicability. Biomarkers such as natriuretic peptides or plasma catecholamines may provide complementary insights but are influenced by numerous confounders and require blood sampling. In contrast, AAPI offers a pragmatic compromise—easily derived, physiologically relevant, and suitable for large-scale screening. Our findings also have implications for the design and evaluation of future antihypertensive drug trials. Current cardiovascular drug trials primarily focus on office blood pressure or mean 24-hour BP reduction as primary endpoints. However, given the strong association observed between AAPI and circadian BP dysregulation, incorporating AAPI as an exploratory or secondary endpoint may help identify therapies that not only lower BP but also optimize 24-hour hemodynamic load and restore physiological dipping patterns. For clinical trial populations characterized by concomitant hypertension and CAD—who frequently exhibit nondipping phenotypes—stratification based on baseline AAPI or circadian rhythm status may improve risk enrichment strategies and allow more precise assessment of treatment benefit. Moreover, monitoring dynamic changes in AAPI could help evaluate chronotherapy regimens and emerging pharmacologic agents targeting autonomic balance or vascular compliance. These applications may ultimately support more personalized therapeutic approaches and enhance the translational relevance of antihypertensive drug studies. Future research should focus on validating the predictive utility of AAPI for cardiovascular outcomes in prospective multicenter cohorts, particularly in diverse ethnic and age groups. Interventional studies should assess whether strategies that reduce AAPI (eg, nocturnal BP targeting, lifestyle interventions) lead to improved rhythm restoration and clinical endpoints. Moreover, integration of AAPI into machine learning models alongside traditional risk factors and circadian data may enhance personalized risk profiling in complex cardiovascular populations. As precision medicine continues to evolve, metrics such as AAPI—grounded in pathophysiological relevance and ease of use—will likely play an increasingly central role in hypertension and vascular care paradigms. Conclusion In patients with PH and concomitant CAD, higher AAPI values were significantly associated with abnormal circadian blood pressure patterns. AAPI demonstrated a graded relationship with rhythm severity and remained independently associated with disrupted nocturnal dipping after multivariable adjustment. These findings highlight AAPI as a simple, noninvasive, and integrative hemodynamic marker that may aid in early identification and risk stratification of patients with circadian blood pressure dysregulation. Prospective studies are warranted to evaluate its prognostic value and responsiveness to targeted chronotherapy interventions.