ABSTRACT
Resistant hypertension (RH) is characterized by uncontrolled blood pressure (BP) despite optimal antihypertensive treatment. This study investigated the clinical characteristics and target organ damage (TOD) in patients with RH, examining their relationships with BP and heart rate variability (HRV). Among 386 hypertensive patients—including those with RH, controlled hypertension, and inadequately treated hypertension—clinical data, laboratory results, and 24‐h ambulatory BP monitoring were analyzed. Patients with RH showed higher body mass index, blood glucose, serum uric acid levels, and longer hypertension duration compared to other groups. Notably, in patients with uncontrolled RH, markers of TOD such as urinary albumin‐creatinine ratio and pulse wave velocity measures were significantly elevated. Multivariate regression revealed that earlier onset of hypertension, elevated serum uric acid and creatinine, and increased arterial stiffness independently predicted RH. Additionally, TOD indicators were closely correlated with 24‐h systolic and diastolic BP as well as HRV parameters. Increased BP variability and arterial stiffness were identified as important factors contributing to TOD, suggesting a bidirectional relationship that may hasten disease progression. These findings emphasize that RH is strongly associated with severe TOD, particularly when BP remains uncontrolled. Effective management of both BP levels and their variability is essential to reduce TOD, and further studies are needed to clarify underlying mechanisms and improve therapeutic strategies.
Keywords: arterial stiffness, blood pressure variability, renal impairment, resistant hypertension, target organ damage
1. Introduction
Hypertension remains a major global public health issue, affecting an estimated 30%–50% of adults worldwide [1]. Within this population, resistant hypertension (RH) constitutes a high‐risk subgroup. RH is defined as persistently elevated blood pressure (BP) despite the use of at least three antihypertensive agents, including a diuretic, at optimal doses—or requiring four or more medications to achieve adequate control [2]. This condition is associated with a significantly increased risk of cardiovascular complications, such as stroke, myocardial infarction, and heart failure, when compared with controlled hypertension [3]. The urgent need for early detection and effective management of RH arises from its strong association with target organ damage (TOD). TOD manifestations include renal impairment, arterial stiffness, and left ventricular hypertrophy—factors that contribute to adverse clinical outcomes [4, 5, 6].
Among these, renal dysfunction and arterial stiffness are among the most commonly observed features. Long‐standing hypertension damages renal microvasculature, leading to increased urinary albumin excretion and, eventually, chronic kidney disease [7]. Arterial stiffness results from structural changes in the arterial wall due to sustained high BP, which compromises blood flow regulation and end‐organ perfusion [8]. In this study, several indicators were used to quantify TOD. The urinary albumin‐creatinine ratio (ACR) was adopted as a marker of renal impairment, with elevated ACR levels reflecting glomerular injury [9]. Arterial stiffness was assessed via pulse wave velocity (PWV), including both carotid‐femoral PWV (cf‐PWV) and brachial‐ankle PWV (ba‐PWV), which evaluate central and peripheral arterial stiffness, respectively [10]. Serum creatinine concentration served as an additional measure of renal function, providing insights into filtration capacity decline [11]. Blood pressure variability (BPV) and heart rate variability (HRV) were also examined for their relevance in TOD development. RH patients frequently present with elevated BPV, which destabilizes vascular homeostasis and promotes structural arterial changes [12, 13]. BPV has been recognized as an independent predictor of cardiovascular events and may exacerbate TOD in RH by imposing cyclic mechanical stress on end organs.
The primary aim of this study is to characterize the clinical features and severity of TOD in RH patients, with an emphasis on distinguishing between controlled and uncontrolled RH. Furthermore, the study investigates how BPV and HRV relate to TOD markers—particularly renal dysfunction and arterial stiffness. Through comprehensive multivariate analysis, the study also seeks to identify independent predictors of RH and its complications, focusing on hypertension duration, biochemical indices, and hemodynamic variables. These findings are expected to improve risk stratification and guide more targeted therapeutic strategies for RH management.
2. Methods
2.1. Study Design and Setting
This cross‐sectional observational study was conducted at the Hypertension Outpatient Clinic of Chongqing Three Gorges Medical College. The study period spanned 12 months, from January to December 2023, encompassing data collection, analysis, and interpretation.
2.2. Study Population
Eligible participants were adults (≥18 years) with a confirmed diagnosis of hypertension. Patients were divided into three groups: RH, controlled hypertension, and inadequately treated hypertension. RH was defined as a clinic BP ≥140/90 mmHg despite concurrent use of at least three antihypertensive agents (including a diuretic), or as BP controlled with four or more medications. Controlled hypertension refers to patients achieving BP <140/90 mmHg with fewer than four drugs. Inadequately treated hypertension included patients with BP ≥140/90 mmHg who were taking fewer than three antihypertensive agents.
Patients with secondary hypertension—such as that caused by primary aldosteronism, Cushing's syndrome, pheochromocytoma, or renovascular disease—were excluded. Other exclusion criteria included incomplete clinical or laboratory data, and the presence of severe comorbidities that might confound outcomes (e.g., advanced malignancy, severe heart failure, or chronic infections).
2.3. Data Collection
Comprehensive clinical, laboratory, and TOD‐related data were collected. Demographic and clinical variables included age, sex, body mass index (BMI), smoking and alcohol use, hypertension duration, and the presence of comorbid conditions (e.g., diabetes mellitus and chronic kidney disease). Laboratory assessments covered fasting plasma glucose, serum uric acid, serum creatinine, and a full lipid panel (total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, and triglycerides). Urinary ACR was obtained from spot urine samples to assess renal damage. All biochemical analyses were performed using standardized automated methods in the hospital's central laboratory.
Each patient underwent 24‐h ambulatory blood pressure monitoring (ABPM) using a validated oscillometric device (SpaceLabs 90217A, SpaceLabs Healthcare, Issaquah, WA, USA). BP measurements were recorded every 30 min during the daytime (6:00–22:00) and every 60 min during the nighttime (22:00–6:00), a compromise to ensure participant comfort and compliance. The average valid reading rate was 89.6%. Data from participants with <70% valid readings, or with <14 daytime and <7 nighttime measurements, were excluded based on established quality criteria. All ABPM data were manually reviewed to remove artifacts and ensure accurate BP classification.
Classification of uncontrolled RH was based on ABPM values rather than clinic BP. Patients were considered to have uncontrolled RH if their mean 24‐h systolic BP was ≥130 mmHg and/or diastolic BP was ≥80 mmHg while taking three or more antihypertensive agents (including a diuretic), or if four or more drugs were needed to maintain control.
TOD was evaluated using multiple indices: Arterial stiffness was measured using cf‐PWV and ba‐PWV via a validated non‐invasive device. Renal function: Estimated glomerular filtration rate (eGFR) was calculated using the CKD‐EPI equation. Urinary ACR was used to quantify albuminuria. Central augmentation index (AI): Measured using the SphygmoCor XCEL system (AtCor Medical, Sydney, Australia). Measurements were conducted in a temperature‐controlled room following at least 10 min of rest in a supine position. Radial artery waveforms were captured and transformed into central aortic waveforms using a generalized transfer function. AI was expressed as a percentage of central pulse pressure. Measurements with a quality index <80% were repeated. Central AI was considered abnormal if >30% in men or >35% in women, based on established sex‐ and age‐adjusted norms.
2.4. Definitions and Categorization
TOD indices were classified using established clinical thresholds: Urinary ACR: Normal (<30 mg/g), microalbuminuria (30–300 mg/g), macroalbuminuria (>300 mg/g) [14]. Arterial stiffness: cf‐PWV ≥10 m/s and ba‐PWV ≥14 m/s indicated significant stiffness [15]. Renal impairment: Defined as eGFR <60 mL/min/1.73 m2 [16].
2.5. Statistical Analysis
All statistical analyses were performed using SPSS software. Continuous variables were expressed as mean ± standard deviation (SD) or median (interquartile range, IQR), depending on normality. Categorical variables were summarized as counts and percentages. Between‐group comparisons (e.g., controlled vs. uncontrolled RH) were made using Student's t‐tests or Mann–Whitney U tests for continuous data, and chi‐square or Fisher's exact tests for categorical data. Multivariate logistic regression was applied to identify independent predictors of RH and associated TOD. Variables were selected based on clinical relevance and univariate analysis results, with adjustments for confounders such as age, sex, BMI, hypertension duration, and biochemical markers. Correlation analyses were conducted to examine relationships between BP variability, HRV, and TOD parameters (e.g., ACR, cf‐PWV, ba‐PWV). Pearson or Spearman correlation coefficients were calculated based on data distribution. A p value <0.05 was considered statistically significant. Corrections for multiple comparisons were applied when appropriate.
3. Results
3.1. Characteristics of the Study Population
A total of 386 patients were included in this study, comprising 65 with RH, 163 with controlled hypertension, and 158 with inadequately treated hypertension. The demographic and clinical characteristics of the three groups are summarized in Table 1. The proportion of males was significantly higher in the RH group compared to the controlled hypertension group (46.9% vs. 31.2%, p < 0.05). Patients with RH had significantly higher body weight, BMI, blood glucose levels, and uric acid levels than the other groups. Additionally, the duration of hypertension was markedly longer in the RH group compared to the controlled and inadequately treated groups (13.8 years vs. 5.3 years vs. 12.1 years, p < 0.05). Regarding lifestyle factors, the smoking rate was higher in the RH group (17.3%) compared to the controlled hypertension group (8.1%, p < 0.05), while the drinking rate was lower (9.9% vs. 20.1%, p < 0.05). No significant differences in age or height were observed among the groups (p > 0.05). Other clinical parameters, such as diabetes prevalence, carotid plaque, and snoring rates, were higher in the RH group, although statistical significance varied. Antihypertensive medication use patterns, including drug class distribution and average number of agents used per patient, are detailed in Table S1.
TABLE 1.
Characteristics of the study population.
| Characteristic | Resistant hypertension (n = 65) | Controlled hypertension (n = 163) | Inadequately treated hypertension (n = 158) | p |
|---|---|---|---|---|
| Age (years) | 57.8 ± 9.6 | 59.3 ± 8.5 | 58.6 ± 10.1 | 0.866 |
| Male (%) | 46.9 | 31.2 * | 46.2 | <0.05 |
| Height (cm) | 165 ± 8.3 | 163 ± 8.5 | 165.2 ± 8.1 | 0.937 |
| Weight (kg) | 70.9 ± 12.2 | 65.9 ± 10.5 * | 69.1 ± 12.1 | <0.05 |
| BMI (kg/m2) | 25.9 ± 3.3 | 24.8 ± 2.8 * | 25.2 ± 3.1 | <0.05 |
| Heart rate (bpm) | 78.2 ± 9.1 | 74.5 ± 8.4 | 75.9 ± 8.7 | 0.032 |
| Blood glucose (mmol/L) | 5.5 (4.6–7.6) | 5.2 (4.5–6.3) * | 5.1 (4.4–6.8) * | <0.05 |
| Uric acid (µmol/L) | 375.2 ± 92.8 | 325.2 ± 71.1 * | 346 ± 83.3 * | <0.05 |
| Cretinine (µmol/L) | 86.3 ± 15.7 | 75.4 ± 12.9 | 80.1 ± 13.3 | <0.05 |
| eGFR (mL/min/1.73 m2) | 75.8 ± 14.5 | 89.1 ± 15.3 | 83.6 ± 14.7 | <0.05 |
| LDL (mmol/L) | 3.2 ± 0.8 | 2.9 ± 0.7 | 3.1 ± 0.8 | 0.041 |
| HDL (mmol/L) | 1.1 ± 0.3 | 1.3 ± 0.3 | 1.2 ± 0.4 | 0.022 |
| Triglycerides (mmol/L) | 1.9 ± 0.9 | 1.5 ± 0.6 | 1.7 ± 0.7 | <0.05 |
| HT (years) | 13.8 (0.6–33.3) | 5.3 (0.1–23.5) * | 12.1 (0.2–26.7) * | <0.05 |
| Smoking (%) | 17.3 | 8.1 * | 15.2 | <0.05 |
| Drinking (%) | 9.9 | 6.4 | 20.1 * | <0.05 |
| Diabetes (%) | 22.2 | 6.4 * | 12.68 | <0.05 |
| Carotid plaque (%) | 28.5 | 30.1 | 26.8 | 0.886 |
| Snoring (%) | 66.8 | 58.8 | 63.7 | 0.732 |
Indicates statistical significance, with p < 0.05.
3.2. Resistant Hypertension and Indices of Target Organ Damage
The association between RH and TOD was examined by comparing uncontrolled RH, controlled RH, and controlled hypertension. As shown in Table 2, uncontrolled RH was associated with significantly higher urinary ACR, cf‐PWV, and ba‐PWV compared to both controlled RH and controlled hypertension.
TABLE 2.
Resistant hypertension and indices of target organ damage.
| Index | Uncontrolled resistant HT | Controlled resistant HT | Controlled HT |
|---|---|---|---|
| Men | n = 23 | n = 6 | n = 50 |
| ACR (mg/mmol) | 1.53 (0.62–18.5) | 0.74 (0.53–2.1) * | 1.26 (0.58–2.9) |
| Creatinine (mmol/L) | 91.3 ± 17.5 | 85.8 ± 14.6 | 81.3 ± 13.2 * |
| GFR (mL/min/1.73 m2) | 79.1 ± 17.3 | 80.2 ± 15.0 | 87.5 ± 17.5 |
| cf‐PWV (m/s) | 8.6 ± 1.5 | 8.4 ± 1.9 | 7.5 ± 1.2 * |
| Ba‐PWV (m/s) | 16.1 ± 2.2 | 15.1 ± 2.2 | 14.3 ± 1.8 * |
| Central AI (%) | 24.5 ± 11.1 | 28.3 ± 6.5 | 25.3 ± 10.8 |
| Women | n = 20 | n = 16 | n = 23 |
| ACR (mg/mmol) | 2.44 (1.01–12.1) | 1.91 (0.69–5.0) | 1.63 (1.16–3.89) * |
| Creatinine (mmol/L) | 62.9 ± 11.6 | 64.8 ± 10.5 | 62.6 ± 11.7 |
| GFR (mL/min/1.73 m2) | 93.2 ± 18.3 | 88.3 ± 16.3 | 93.1 ± 19.3 |
| cf‐PWV (m/s) | 9.5 ± 1.9 | 8.6 ± 1.2 | 7.9 ± 1.1 * |
| Ba‐PWV (m/s) | 15.8 ± 3.2 | 14.5 ± 2.4 | 15.1 ± 2.4 |
| Central AI (%) | 31.6 ± 10.2 | 30.4 ± 6.5 | 33.6 ± 9.3 |
| Total | n = 43 | n = 22 | n = 163 |
| ACR (mg/mmol) | 2.19 (0.86–17.4) | 1.41 (0.62–1.7) * | 1.75 (0.80–3.8) * |
| Creatinine (mmol/L) | 77.7 ± 20.7 | 72.1 ± 15.6 | 68.1 ± 15.2 * |
| GFR (mL/min/1.73 m2) | 86.0 ± 18.8 | 85.5 ± 16.1 | 91.4 ± 18.9 |
| cf‐PWV (m/s) | 9.0 ± 1.6 | 8.6 ± 1.4 | 8.0 ± 1.0 * |
| Ba‐PWV (m/s) | 15.9 ± 2.8 | 15.1 ± 2.3 | 14.2 ± 2.3 * |
| Central AI (%) | 27.8 ± 11.3 | 29.5 ± 6.5 | 31.0 ± 10.3 |
Notes: Compared to uncontrolled resistant hypertension,
p < 0.05. For controlled resistant hypertension versus controlled hypertension, all p > 0.05.
Abbreviations: ACR, albumin‐creatinine ratio; ba‐PWV, brachial‐ankle pulse wave velocity, an indicator of peripheral arterial stiffness; cf‐PWV, carotid‐femoral pulse wave velocity, an indicator of central arterial stiffness; eGFR, estimated glomerular filtration rate.
In the male subgroup, uncontrolled RH showed higher levels of serum creatinine and arterial stiffness (cf‐PWV and ba‐PWV) compared to controlled RH and controlled hypertension. ACR was significantly higher in uncontrolled RH compared to controlled RH, but no other TOD indices demonstrated statistical significance between these two groups.
In the female subgroup, similar trends were observed, with uncontrolled RH showing significantly higher ACR and cf‐PWV compared to controlled RH. The overall analysis indicated that uncontrolled RH was associated with worse renal and vascular TOD indices than controlled RH and controlled hypertension.
3.3. Multivariate Analysis of Resistant Hypertension and Target Organ Damage
The multivariate analysis revealed that uncontrolled RH was associated with more severe TOD compared to controlled RH and controlled HT. In men, the uncontrolled RH group had significantly higher urinary ACR, serum creatinine levels, and arterial stiffness (cf‐PWV and ba‐PWV) compared to the controlled RH and controlled HT groups. Similarly, in women, uncontrolled RH showed significantly higher ACR, serum creatinine, and cf‐PWV compared to controlled RH. When considering the total population, uncontrolled RH exhibited significantly higher ACR, serum creatinine levels, and arterial stiffness compared to controlled RH and controlled HT. No significant differences in GFR were observed between the groups. These results highlight that uncontrolled RH is associated with greater renal and vascular damage, emphasizing the importance of better BP control to prevent further TOD.
3.4. Clinical Features and Target Organ Damage Associated with Resistant Hypertension Versus Controlled Hypertension
Logistic regression analysis revealed several clinical features distinguishing RH from controlled hypertension (Table 3). Significant predictors included male sex, smoking, diabetes, higher BMI, longer hypertension duration, and higher levels of serum uric acid and creatinine (p < 0.05). Additionally, cf‐PWV and ba‐PWV were significantly higher in RH, indicating greater arterial stiffness. Multivariate models confirmed that elevated cf‐PWV, serum uric acid, and serum creatinine were independent predictors of RH (p < 0.05).
TABLE 3.
Clinical features and target organ damage associated with resistant hypertension versus controlled hypertension.
| Indices | Unadjusted odds ratio (95% CI) | Regression p value | Multi‐variate adjusted odds ratio (95% CI) | Regression p value |
|---|---|---|---|---|
| Age (years) | 0.98 (0.95–1.01) | 0.07 | ||
| BMI (kg/m2) | 1.13 (1.04–1.24) | 0.0065 | 0.95 (0.92–0.98) | <0.001 |
| Duration of HT (years) | 1.05 (1.03–1.08) | 0.001 | 1.03 (1.00–1.05) | 0.0005 |
| Age of diagnosis (years) | 0.94 (0.92–0.97) | <0.001 | 1.08 (1.00–1.16) | 0.047 |
| LDL cholesterol (mmol/L) | 0.93 (0.69–1.26) | 0.65 | 3.86 (1.41–10.6) | 0.0085 |
| Triglycerides (mmol/L) | 1.40 (1.05–1.87) | 0.02 | 1.73 (1.31–2.26) | <0.001 |
| HDL cholesterol (mmol/L) | 0.40 (0.18–0.88) | 0.02 | ||
| Total cholesterol (mmol/L) | 0.96 (0.74–1.23) | 0.67 | ||
| Uric acid (µmol/L) | 1.01 (1.00–1.06) | <0.001 | ||
| Serum creatinine (mmol/L) | 1.08 (1.01–1.18) | 0.0029 | ||
| Male vs. Female | 1.95 (1.13–3.35) | 0.016 | ||
| Current smokers (yes/no | 2.20 (1.01–4.83) | 0.04 | ||
| Current drinkers (yes/no) | 1.63 (0.62–4.18) | 0.32 | ||
| Diabetes mellitus (yes/no) | 4.21 (1.88–9.45) | 0.0005 | ||
| Chronic kidney disease (yes/no) | 1.36 (0.43–4.29) | 0.60 | ||
| ACR (mg/mmol) | 1.05 (0.99–1.07) | 0.18 | ||
| CfPWV (m/s) | 1.66 (1.29–2.01) | <0.001 | ||
| BaPWV (+10 cm/s) | 1.18 (1.03–1.28) | 0.01 | ||
| Central AI (%) | 0.98 (0.95–1.06) | 0.06 |
Notes: The multivariate regression model was adjusted for hypertension duration, age at hypertension diagnosis, smoking, diabetes, BMI, serum triglycerides, high‐density lipoprotein cholesterol, serum uric acid, serum creatinine, cf‐PWV, and ba‐PWV.
Abbreviations: ACR, urinary albumin‐creatinine ratio; BMI, body mass index; CI, confidence interval; HDL, high‐density lipoprotein cholesterol; HT, hypertension; LDL, low‐density lipoprotein cholesterol.
3.5. Association of 24‐Hour BP and Heart Rate Variability with Target Organ Damage
The association between 24‐h systolic and diastolic BP, HRV, and TOD indices is summarized in Table 4. ACR was significantly correlated with both systolic BP (β = 0.002 ± 0.0005, p < 0.001) and diastolic BP (β = 0.002 ± 0.0006, p < 0.001). Serum creatinine levels showed a significant relationship with systolic BP (β = 0.43 ± 0.11, p < 0.001) but not with diastolic BP or heart rate. Arterial stiffness indices (cf‐PWV and ba‐PWV) were strongly associated with systolic BP, diastolic BP, and heart rate (p < 0.001). Central AI was significantly associated with heart rate (p < 0.001) but not with BP. These results highlight the importance of BP variability and heart rate in predicting TOD in RH patients.
TABLE 4.
Association of 24‐h systolic and diastolic blood pressure and heart rate with target organ damage indices in the 386 patients.
| Indices of target organ damage | Systolic blood pressure | Diastolic blood pressure | Heart rate | |||
|---|---|---|---|---|---|---|
| β ± SE | p value | β ± SE | p value | β ± SE | p value | |
| Log2 (ACR) (mg/mmol) | 0.002 ± 0.0005 | <0.001 | 0.002 ± 0.0006 | <0.001 | 0.0004 ± 0.0006 | 0.53 |
| Creatinine (mmol/L) | 0.43 ± 0.11 | <0.001 | 0.19 ± 0.16 | 0.28 | −0.32 ± 0.18 | 0.08 |
| GFR (mL/min/1.73 m2) | −0.126 ± 0.05 | 0.048 | −0.16 ± 0.11 | 0.13 | 0.27 ± 0.13 | 0.02 |
| cf‐PWV (m/s) | 0.05 ± 0.003 | <0.001 | 0.05 ± 0.006 | <0.001 | 0.04 ± 0.008 | <0.001 |
| Ba‐PWV (cm/s) | 8.43 ± 0.72 | <0.001 | 11.05 ± 1.26 | <0.001 | 6.23 ± 1.46 | <0.001 |
| Central AI (%) | 0.03 ± 0.05 | 0.29 | 0.03 ± 0.05 | 0.65 | −0.38 ± 0.05 | <0.001 |
Note: β represents the regression coefficient, indicating the change in the target organ damage index for each unit change in the independent variable. SE represents the standard error. Covariates include age, sex, body mass index, smoking and drinking habits, blood glucose, serum triglycerides, total cholesterol, and low‐density lipoprotein cholesterol. ACR was log‐transformed before inclusion in the model for analysis.
3.6. Impact of BP and HR Variability Indices on Target Organ Damage
To further explore the role of variability in TOD, regression models incorporating standard variability indices were constructed (Table 5). Higher 24‐h SD, ARV, and CV of systolic BP were significantly associated with increased ACR, cf‐PWV, ba‐PWV, and serum creatinine levels. In contrast, lower SDNN, an HRV metric reflecting autonomic function, was significantly associated with higher ACR and greater arterial stiffness. These findings indicate that increased BP variability and impaired autonomic regulation contribute to vascular and renal damage in RH.
TABLE 5.
Association of blood pressure and heart rate variability parameters with target organ damage in patients with resistant hypertension.
| TOD Index | Uncontrolled resistant HT | p value | ARV SBP (β ± SE) | p value | ARV SBP (β ± SE) | p value |
|---|---|---|---|---|---|---|
| Log₂(ACR) (mg/mmol) | 0.013 ± 0.003 | <0.001 | 0.009 ± 0.002 | <0.001 | 0.009 ± 0.002 | <0.001 |
| Creatinine (mmol/L) | 0.32 ± 0.09 | <0.001 | 0.27 ± 0.08 | <0.001 | 0.27 ± 0.08 | <0.001 |
| GFR (mL/min/1.73 m2) | −0.42 ± 0.15 | 0.006 | −0.39 ± 0.13 | 0.004 | −0.39 ± 0.13 | 0.004 |
| cf‐PWV (m/s) | 0.06 ± 0.009 | <0.001 | 0.05 ± 0.008 | <0.001 | 0.05 ± 0.008 | <0.001 |
| Ba‐PWV (m/s) | 10.4 ± 2.3 | <0.001 | 8.9 ± 2.0 | <0.001 | 8.9 ± 2.0 | <0.001 |
| Central AI (%) | 0.15 ± 0.06 | 0.011 | 0.13 ± 0.05 | 0.008 | 0.13 ± 0.05 | 0.008 |
Notes: All models were adjusted for age, sex, BMI, smoking, diabetes, uric acid, and total cholesterol. ACR was log₂‐transformed prior to analysis.
Abbreviations: V 24h‐SD, standard deviation of 24‐h systolic BP; ARV, average real variability of SBP; CV, coefficient of variation of SBP (%); SDNN, standard deviation of all NN intervals (HRV marker).
4. Discussion
This study highlights significant differences in TOD among patients with uncontrolled RH, controlled RH, and controlled hypertension. Uncontrolled RH was associated with the most severe TOD, as evidenced by higher urinary ACR and greater arterial stiffness, measured by cf‐PWV and ba‐PWV. In contrast, controlled RH demonstrated less pronounced TOD, and no significant differences were observed between controlled RH and controlled hypertension for several indices. The analysis revealed a strong association between BP variability, HRV, and TOD indices. Elevated BP variability was significantly correlated with increased ACR and arterial stiffness, while HRV was particularly linked to arterial stiffness and central AI, indicating its role in vascular health. Multivariate analysis identified several independent predictors of RH and its complications. Younger age at hypertension diagnosis, elevated serum uric acid, higher serum creatinine levels, and increased cf‐PWV were robust predictors of RH, reflecting the interplay between renal function, vascular health, and disease progression. These findings underscore the complex pathophysiology of RH and the critical importance of effective BP control and risk factor management in mitigating TOD.
4.1. Interpretation of Results
Uncontrolled RH leads to disproportionately severe renal and vascular damage through a convergence of interrelated pathophysiological mechanisms. Persistent elevation of BP despite optimal multidrug therapy imposes chronic mechanical stress on target organs, directly damaging vascular and renal structures. Elevated aldosterone levels contribute to vascular remodeling, increased sympathetic nervous system activity, insulin resistance, and reduced responsiveness to antihypertensive agents, all of which aggravate BP dysregulation [17, 18]. Sympathetic overactivity—often accompanied by a high prevalence of obstructive sleep apnea (OSA) in RH patients—further promotes nocturnal hypertension and subclinical organ injury [19]. Meanwhile, impaired renal function exacerbates volume retention and neurohormonal activation, creating a self‐reinforcing cycle that accelerates both kidney and vascular damage [20]. Arterial stiffness, frequently observed in aging, is markedly intensified in RH, causing microvascular injury in high‐perfusion organs such as the kidneys, brain, and retina.
In this context, BPV and HRV emerge as critical modulators of TOD. Elevated BPV results in intermittent surges in intravascular pressure, which amplify endothelial shear stress, trigger inflammatory cascades, and lead to microvascular injury and fibrosis, especially in renal and large conduit arteries [21]. In addition, BPV has been associated with impaired autoregulatory function and endothelial dysfunction, which collectively impair organ perfusion and compromise vascular integrity. Reduced HRV, a marker of autonomic imbalance, reflects diminished baroreflex sensitivity and impaired vascular tone control, and has been independently linked to increased arterial stiffness and TOD [22]. These hemodynamic instabilities synergistically drive the structural and functional deterioration of target organs in RH patients.
Our analysis also identified several independent predictors of RH, offering mechanistic insights into disease progression. Elevated serum uric acid levels are known to induce oxidative stress and inflammatory responses, which impair endothelial function and promote vascular remodeling [23]. Increased cf‐PWV, an established indicator of arterial stiffness, represents both a cause and consequence of chronic hypertension, perpetuating a vicious cycle of pressure overload and vessel wall damage [24]. Notably, younger age at hypertension diagnosis may signal a more aggressive disease phenotype, potentially underpinned by genetic predisposition or early vascular dysfunction. Collectively, these findings emphasize the multifactorial nature of RH and underscore the necessity of targeted interventions addressing both hemodynamic variability and structural vascular abnormalities.
Our additional analysis incorporating quantitative BPV and HRV parameters further reinforces the relationship between hemodynamic instability and TOD in RH. Specifically, we observed that increased 24‐h standard deviation (24h‐SD), ARV, and CV of systolic BP were strongly associated with elevated urinary ACR, higher cf‐PWV, and increased serum creatinine levels. These findings underscore the role of BPV as a surrogate marker of vascular and renal stress, likely mediated through intermittent surges in arterial pressure that promote glomerular hypertension, endothelial damage, and arterial wall remodeling. In contrast, reduced HRV, as reflected by lower SDNN values, was significantly associated with increased arterial stiffness and central AI. This suggests that autonomic dysregulation may contribute to vascular dysfunction in RH patients, possibly through impaired baroreflex sensitivity and sympathetic overactivation. Prior studies have demonstrated that decreased HRV is an early marker of cardiovascular autonomic neuropathy and is associated with adverse cardiovascular outcomes. The clinical implications of these findings are substantial. BPV and HRV measurements obtained via 24‐h ambulatory monitoring offer non‐invasive and quantifiable markers for identifying RH patients at higher risk for TOD. These parameters, especially when integrated with arterial stiffness assessments, may enhance risk stratification and guide more aggressive or tailored therapeutic strategies. Furthermore, future interventional studies targeting BPV and autonomic regulation may provide new avenues for reducing the TOD burden in this high‐risk population.
4.2. Comparison with Previous Studies
The findings of this study are consistent with existing literature demonstrating that uncontrolled RH is associated with significantly greater TOD compared to controlled RH and controlled hypertension. Prior studies have shown that elevated BP in RH patients exacerbates renal impairment and accelerates arterial stiffness, supporting the observed associations between uncontrolled RH, increased urinary ACR, and higher cf‐PWV and ba‐PWV levels in this study [25]. These results reinforce the understanding that TOD is directly linked to the inability to achieve adequate BP control in RH patients. A notable contribution of this study is the strong link identified between BP variability and renal damage. While previous research has established BP variability as a predictor of cardiovascular events, its direct association with renal outcomes in RH patients has been less thoroughly explored. This study highlights BP variability as a key driver of renal damage, likely through mechanisms involving episodic glomerular hypertension and progressive microvascular injury. Another significant insight is the role of cf‐PWV as a robust predictor of TOD in RH patients. While cf‐PWV has been widely recognized as a marker of arterial stiffness, this study emphasizes its predictive value in identifying patients at higher risk of TOD, particularly those with uncontrolled RH. This finding aligns with prior evidence linking cf‐PWV to increased cardiovascular and renal risk but further underscores its clinical utility in the context of RH. These results not only corroborate prior research but also expand the current understanding of the complex relationships between BP control, variability, arterial stiffness, and TOD in RH patients.
4.3. Clinical Implications
The findings of this study have important clinical implications for the management of RH. The significant association between uncontrolled RH and increased TOD highlights the urgent need for early identification and aggressive intervention in patients with uncontrolled RH. Early recognition and treatment can potentially slow the progression of TOD, reduce the burden of renal and vascular complications, and improve overall cardiovascular outcomes. Incorporating advanced diagnostic tools into routine assessments for RH patients can enhance risk stratification and management. Specifically, 24‐h ABPM provides detailed insights into BP variability and control, which are critical for identifying patients at risk of TOD. Similarly, non‐invasive arterial stiffness measurements, such as cf‐PWV and ba‐PWV, should be routinely considered. These assessments can serve as early indicators of vascular damage and guide treatment adjustments to address underlying pathophysiological changes. Addressing modifiable risk factors is another key aspect of managing RH. Elevated serum uric acid, a strong predictor of TOD, should be actively managed through lifestyle modifications and pharmacological interventions when indicated. Smoking cessation programs should also be prioritized, as smoking exacerbates vascular damage and reduces treatment efficacy in RH patients. Comprehensive lifestyle counseling, coupled with personalized pharmacotherapy, can target these modifiable factors and enhance BP control. By integrating these strategies into clinical practice, healthcare providers can improve the long‐term management of RH, reduce the risk of TOD, and achieve better outcomes for this high‐risk patient population.
4.4. Strengths of the Study
This study has several notable strengths that enhance its validity and relevance. The comprehensive evaluation of TOD indices, including advanced arterial stiffness measurements such as cf‐PWV and ba‐PWV, provides a robust assessment of vascular health. These indices are well‐established markers of arterial damage and were measured using validated non‐invasive techniques, adding reliability to the findings. The use of multivariate analysis allowed for the control of confounding factors such as age, BMI, duration of hypertension, and biochemical markers. This statistical approach strengthened the study's ability to identify independent predictors of RH and its associated complications. Additionally, the inclusion of real‐world data from a diverse patient population enhances the generalizability of the findings to clinical practice, providing practical insights into RH management (Table 6).
TABLE 6.
Multivariate analysis of resistant hypertension and target organ damage.
| Index | Uncontrolled resistant HT | Controlled resistant HT | Controlled HT |
|---|---|---|---|
| Men | n = 23 | n = 6 | n = 50 |
| ACR (mg/mmol) | 3.6 (1.7–7.4) | 1.1 (0.4–2.5) * | 2.6 (1.2–5.5) * |
| Creatinine (mmol/L) | 102.5 ± 4.8 | 103.1 ± 7.1 | 98.1 ± 5.0 |
| GFR (mL/min/1.73 m2) | 67.5 ± 5.6 | 67.3 ± 8.6 | 72.7 ± 6.1 |
| cf‐PWV (m/s) | 8.7 ± 0.5 | 7.7 ± 0.7 | 7.2 ± 0.5 * |
| Ba‐PWV (m/s) | 16.4 ± 0.7 | 14.1 ± 1.0 * | 14.0 ± 0.7 * |
| Central AI (%) | 24.7 ± 3.4 | 20.5 ± 5.0 | 19.9 ± 3.6 |
| Women | n = 20 | n = 16 | n = 23 |
| ACR (mg/mmol) | 3.6 (1.7–7.9) | 1.8 (0.8–4.4) * | 2.3 (1.0–4.9) * |
| Creatinine (mmol/L) | 79.7 ± 4.5 | 81.8 ± 5.0 | 80.4 ± 4.6 |
| GFR (mL/min/1.73 m2) | 72.6 ± 8.4 | 68.5 ± 9.4 | 71.6 ± 8.6 |
| cf‐PWV (m/s) | 8.6 ± 0.7 | 7.5 ± 0.8 * | 7.9 ± 1.1 * |
| Ba‐PWV (m/s) | 13.4 ± 1.15 | 11.9 ± 1.3 | 12.1 ± 1.2 * |
| Central AI (%) | 22.1 ± 5.0 | 19.1 ± 5.5 | 23.2 ± 5.1 |
| Total | n = 43 | n = 22 | n = 163 |
| ACR (mg/mmol) | 4.0 (2.7–5.9) | 1.6 (1.0–2.7) * | 2.5 (1.7–3.6) * |
| Creatinine (mmol/L) | 87.1 ± 2.4 | 86.5 ± 3.0 | 84.9 ± 2.4 |
| GFR (mL/min/1.73 m2) | 76.3 ± 3.8 | 75.9 ± 4.7 | 78.4 ± 3.7 |
| cf‐PWV (m/s) | 9.5 ± 0.3 | 8.5 ± 0.3 * | 8.2 ± 0.3 * |
| Ba‐PWV (m/s) | 16.7 ± 0.5 | 14.3 ± 0.6 * | 14.5 ± 0.5 * |
| Central AI (%) | 27.5 ± 2.3 | 25.3 ± 2.9 | 27.2 ± 2.3 |
Notes: Values in the table are presented as mean ± standard error. The multivariate model was adjusted for age, duration of hypertension, smoking, alcohol consumption, diabetes, chronic kidney disease, BMI, blood glucose, serum uric acid, total cholesterol, low‐density lipoprotein cholesterol, and the presence of carotid plaques. Gender was also included in the analysis model for the total population. Compared to uncontrolled resistant hypertension,
p < 0.05. For controlled resistant hypertension versus controlled hypertension, all p > 0.05.
4.5. Limitations
Despite its strengths, this study has several limitations. Most importantly, its cross‐sectional design limits the ability to infer causality between RH, BPV, HRV, and TOD. Although significant associations were identified, the directionality of these relationships remains uncertain. Pre‐existing organ damage may affect hemodynamic variability, just as increased variability may worsen organ injury. Longitudinal studies are needed to clarify these bidirectional mechanisms and monitor TOD progression in RH patients over time.
The relatively small sample size, especially in subgroup analyses, may have reduced statistical power to detect subtle or rare effects. The single‐center nature of the study may also limit generalizability to populations with different clinical characteristics or care practices. Additionally, although medication use and adherence were recorded and partially adjusted for, residual confounding from variability in compliance and treatment regimens cannot be excluded. Future prospective, multicenter studies with standardized adherence tracking are warranted to confirm and expand upon these findings.
5. Conclusion
This study demonstrates that uncontrolled RH is closely associated with a higher burden of TOD, with BPV, HRV, and arterial stiffness playing key roles in disease progression. Predictors such as serum uric acid and cf‐PWV highlight the need for targeted risk assessment and intervention. Routine use of 24‐h BP monitoring and arterial stiffness evaluation may improve clinical management and risk stratification in RH. Future research should clarify the mechanisms linking BPV to TOD, particularly the roles of endothelial dysfunction, vascular remodeling, and autonomic imbalance. Longitudinal studies are needed to determine whether modulating BPV can slow renal and vascular deterioration and whether treatment strategies tailored to hemodynamic variability can improve long‐term outcomes in RH patients.
Author Contributions
Conceptualization: Xiaoxia He. Methodology: Lingyan Chen, Lv Huang, and Xianhu Luo. Software: Xiaoxia He. Validation: Lingyan Chen and Lv Huang. Formal analysis: Xiaoxia He and Lingyan Chen. Investigation: Xiaoxia He. Resources: Lingyan Chen. Data curation: Xiaoxia He. Writing–original draft preparation: Xiaoxia He. Writing–review and editing: Huiwen Tan. Visualization: Xiaoxia He. Supervision: Xiahong Chen. Project administration: Xiahong Chen. All authors have read and agreed to the published version of the manuscript.
Ethics Statement
The authors have nothing to report.
Consent
The need for consent to participate was waived by the ethics committee, and the authors have no disclosures regarding consent for publication.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1. Antihypertensive Medication Use Among Study Participants.
Acknowledgments
This study was supported by the Chongqing Three Gorges Medical College 2023 School‐Level Natural Science Research Project (Project No. XJ2023001102).
Funding: This study was supported by the following funding sources: the 2023 School‐Level Natural Science Research Project of Chongqing Three Gorges Medical College (Project No. XJ2023001102); the 2024 Youth Science and Technology Research Program of the Chongqing Municipal Education Commission (Project No. KJQN202402714); and the 2024 General Medical Research Project jointly funded by the Wanzhou District Science and Health Committee (Project No. wzwjw‐kw2024032).
Data Availability Statement
All data generated or analyzed during the present study are included in this published article.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Antihypertensive Medication Use Among Study Participants.
Data Availability Statement
All data generated or analyzed during the present study are included in this published article.