True Resistant Hypertension among Treated Hypertensive Black Patients. A Clinical-Based Cross-Sectional Study

Background and Objective: 24-h ambulatory blood pressure monitoring (ABPM) aids to precisely identify patients with true resistant hypertension (tRH). The present study was aimed to assess the frequency and correlates of tRH among patients with clinically suspected RH. Methods: Medical records of treated hypertensive patients referred in four healthcare centers for BP control evaluation by 24-h ABPM were reviewed to assess the prevalence of tRH. Inclusion criteria were age ≥ 18 years, clinical diagnosis of RH. Data on demographic, clinical, laboratory, 2D-echocardiography and 24-h ABPM parameters were retrieved from patient’s medical records. True RH (tRH) was defined as office blood pressure (BP) ≥ 140/90 mmHg and 24-h ambulatory BP ≥ 130/80 mmHg. Simple and multiple linear regression analyses were used to assess factors associated with systolic BP (SBP) as a proxy of RH among patients with tRH. P < 0.05 defined the level of statistical significance. Results: Of 636 patients referred for BP control evaluation by 24-h ABPM, 75 (11.7%) had suspected RH by office BP measurements. After 24-h ABPM, pseudo or apparent RH (aRH) and tRH were observed in 15 (2.3%) and 60 (9.4%) patients, respectively. BMI (p = 0.007) and blood glucose (p = 0.024) were positively associated with SBP whereas a negative association was observed with eGFR (p = 0.022) among tRH hypertensive patients in multiple regression analysis. Conclusion: True RH was a common finding among paHow to cite this paper: Kuntonda, D.K., Lepira, F.B., Lubenga, Y., Makulo,, J.R.R., Nkodila, A., Otshudi, N., Mvunzi, T., Mupepe, D., Ngoyi, G., Kintoki, F., Kintoki, E.V. and M’buyamba-Kabangu, J.R. (2020) True Resistant Hypertension among Treated Hypertensive Black Patients. A Clinical-Based Cross-Sectional Study. World Journal of Cardiovascular Diseases, 10, 278-293. https://doi.org/10.4236/wjcd.2020.105026 Received: March 21, 2020 Accepted: May 5, 2020 Published: May 8, 2020 Copyright © 2020 by author(s) and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access D. K. Kuntonda et al. DOI: 10.4236/wjcd.2020.105026 279 World Journal of Cardiovascular Diseases tients with clinical RH and associated with obesity and silent target organ, especially kidney dysfunction. The present study highlights the diagnostic and prognostic importance of 24-h ABPM among patients with clinical RH.


Introduction
In sub-Saharan Africa (SSA), very low rates of blood pressure (BP) control may predict an increased prevalence of resistant hypertension (RH) across the continent [1]. Indeed, RH, defined as failure to achieve BP to target despite adherence to appropriate treatment with full doses of at least 3 drug regimens including a diuretic [2], is a life-threatening medical condition associated with a fourfold increased risk for cardiovascular events compared with patients achieving BP targets [3]. Unfortunately, few studies on the epidemiology and management of RH are available in SSA [1]. A recent meta-analysis reported that out of 259 studies retrieved from the medical literature, only 4 studies from SSA (Burkina Faso, Cameroon, Lesotho and Nigeria) were included in the review [1]. Although the definition of RH was not similar across studies, the overall pooled prevalence of RH was 12.1% (95% CI 8.0% to 17.7%) [1]. Therefore, studies from other SSA countries using 24-h ambulatory blood pressure monitoring (ABPM) are awaited to better determine the burden of RH and associated risk factors across the continent for their optimal management and control [1]. The recognition and identification of individuals with RH is of particular importance, given the fact that they may require further diagnostic evaluation for specific interventions [4].
As the diagnosis of RH is based on office BP measurements, its prevalence may be influenced by the white coat phenomenon [5] [6]. In this regard, previous studies have found that about one third of subjects with clinically suspected RH have indeed "apparent or pseudo-resistant" hypertension (aRH) (office BP ≥ 140/90 mmHg and 24-h ABPM < 130/80 mmHg) when using 24-h ABPM. Thus, 24-h ABPM aids to precisely identify subjects with "true" RH (tRH) (office BP ≥ 140/90 mm Hg and 24-h ambulatory BP ≥ 130/80 mm Hg) [6]. ABPM, a technique of obtaining automated brachial BP measurements at fixed time intervals, during a 24-hour period away from a medical environment, represents a more "realistic" approach to BP assessment. It involves measurement of BP during the usual daily activities and sleep and estimates more accurately the overall hemodynamic load and BP variability [6].
In the Democratic Republic of the Congo (DRC), the prevalence of hypertension is estimated to be of 30% -40% [7] [8] [9] and associated with an increased D. K. Kuntonda et al. World Journal of Cardiovascular Diseases cardiovascular (CV) morbidity and mortality [10] due, in a substantial part, to lower BP control rates in the general population [6] [7] [8] as well as in-hospital setting [11]. Lower rates of BP control highlight the need to study RH and characterize its phenotypes to avoid the overtreatment of patients with apparent or pseudo-RH under a context of limited resources. Since the recent availability of 24-h ABPM in some health centers in Kinshasa, studies have focused only on BP patterns and dipping status among hypertensive [12] and chronic hemodialysis [13] patients; despite the increased prevalence of uncontrolled hypertension, data on RH using 24-h ABPM are not yet available. Therefore, the present study was aimed to asses, using 24-h ABPM, the frequency and clinical profile of "true" RH (tRH) among patients with clinically suspected RH.

Patients and Methods
We reviewed medical files of all treated hypertensive patients referred to four private healthcare Centers (Ngaliema Medical Center, Kinshasa Medical Center, Diamant Medical Center and "Médecins de Nuit" Center) in Kinshasa for BP control evaluation by 24-h ABPM during the period between January 1, 2019 and September 30, 2019. Inclusion criteria were age ≥ 18 years, office BP-based RH, and available data on 24-h ABPM. Patients with clinical signs of secondary hypertension, incomplete medical files, atrial fibrillation and those on drugs interfering with BP like non-steroidal anti-inflammatory drugs (NSAIDs) were excluded. The study was approved by the Internal Review Board (IRB) of the University of Kinshasa Hospital and obtained the clearance of the medical staff of participating Centers. Patient's information at the visit before ABPM was extracted from their medical records using a predetermined proforma which included the patient's past medical history (duration of hypertension, family history of hypertension, alcohol intake, smoking, physical activity, use of antihypertensive agents, co-morbidities), socio-demographic (age, gender, education level), clinical (symptoms, office blood pressure, weight, and height), biochemical profile [fasting plasma glucose (FPG), blood urea nitrogen (BUN), serum uric acid, serum creatinine, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), high-density lipoprotein-cholesterol (HDL-c), triglycerides (TG), serum sodium and potassium, serum c-reactive protein (CRP), dipstick proteinuria, 2D-echocardiography and 24-h ABPM parameters. The data was captured by a trained and experienced member of the research team at each participating center and accuracy of data entry was checked by the principal investigator herself. Alcohol intake and smoking as well as physical activity status were retrieved from patient's medical records. Patient's BP, which was measured by attending physicians as a part of daily routine care, was captured from medical records. Hypertension was defined as BP ≥ 140/90 mmHg or current use of antihypertensive agents [2]; clinically suspected RH as office BP ≥ 140/90 mmHg despite appropriate treatment with full doses of at least 3 antihypertensive drugs, including a diuretic [2]. Antihypertensive drug use was captured from medical records and classified into the following classes: renin angiotensin system inhi-World Journal of Cardiovascular Diseases bitors encompassing angiotensin converting enzyme inhibitors (ACEI) and angiotensin type 1 receptor blockers (ARB), calcium channel blockers (CCB), beta-blockers (BB), diuretics, central acting agents (CAA), and alpha-blockers. 24-h ABPM was performed using a commercially available system (Space Labs 90207 system). BP was recorded during the day for every 15 minutes (from 07:00 to 21:00) and every 30 minutes during the night (from 21:00 to 07:00). 24-h ABPM parameters of interest were daytime, nighttime and 24-h SBP and DBP. ABPM records were considered valid only if the number of BP recordings were at least 70% of the expected readings assessed as valid by the software analysis. True (tRH) and apparent (aRH) RH was defined as office BP ≥ 140/90 mmHg and 24-h ABPM ≥ 130/80 mmHg and office BP ≥ 140/90 mmHg and 24-h ABPM < 130/80 mmHg, respectively [6]. Body mass index was calculated as weight in kilogram per square meter height (Kg/m 2 ). Overweight and obesity were defined as BMI ≥ 25 Kg/m 2 and ≥30 Kg/m 2 , respectively. Increased age was defined as age ≥ 45 and ≥55 years in men and women, respectively. Diabetes was defined as fasting blood glucose ≥ 126 mg/dL, or the use of antidiabetic drugs [14]. Dyslipidemia was defined as total cholesterol ≥ 200 mg/dL, triglyceride ≥ 150 mg/dL, HDL < 40 in men and <50 mg/dL in women, or the use of statin [15]. Low estimated glomerular filtration rate (eGFR) was defined as estimated glomerular filtration rate (eGFR) calculated by modification of diet in renal disease (MDRD) equation < 60 ml/min/1.73m 2 [16] [17]. Subclinical inflammation was defined as CRP ≥ 6 mg/L. Urine dipstick test 1+ or more defined proteinuria. Echocardiographic parameters of interest were end-systolic and end-diastolic left ventricular internal diameter (LVIDd, LVIDs), interventricular septum thickness (IVST) and posterior wall thickness (PWT) calculated from 2D guided M-mode tracing. Left ventricular mass was estimated by Devereux's formula and normalized by body surface area (LVM index) [18]. Left ventricular hypertrophy (LVH) was defined as increased LVMI (≥95 g/m 2 in women and ≥115 g/m 2 in men) and classified as concentric (LVMI ≥ 115 g/m 2 and RWT ≥ 0.42) and eccentric (LVMI ≥ 115 g/m 2 and RWT < 0.42) [19]. Relative wall thickness was calculated as 2 × PWT/LVIDd [19]. A normal dipping pattern was diagnosed when the reduction in the average SBP during the nighttime period was >10% of mean SBP during the daytime; when this proportion was >20%, the patient was classified as an extreme dipper. Non-dipping pattern was diagnosed when the average nighttime SBP reduction was <10% with respect to daytime values; when the mean nighttime SBP was higher than the daytime one, the patient was classified as reverse dipper [20]. Advanced hypertensive retinopathy was defined as stage 3 -4 according to Keith and Wegener classification. Ten years global cardiovascular risk was evaluated according to the 2018 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines [21].

Statistical Analysis
The SPSS software (Statistical Package for the Social Sciences, version 22, SPSS

D. K. Kuntonda et al. World Journal of Cardiovascular Diseases
Inc., Chicago, IL, USA) was used for statistical analysis. Baseline characteristics were summarized as mean (standard deviation) or median (interquartile range) for continuous variables and as absolute (n) and relative (in %) frequencies for categorical variables. The association of parameters of interest with systolic blood pressure among patients with tRH was assessed using multiple linear regression analysis. P value ˂ 0.05 defined the level of statistical significance.

Results
• Frequency of true hypertension in patients with clinical resistant hypertension In the present study (Figure 1) Table 2    Data are expressed as mean ± standard deviation, median (interquartile range), absolute (n) and relative (in percent) frequency. Abbreviations: HT, hypertension CCB, calcium channel blockers RAS, renin angiotensin system ACEIs, angiotensin converting enzyme inhibitors ARBs, angiotensin type 1 receptor blockers.

Discussion
The main findings of the present study are as follows.  [29]. In the absence of accurate epidemiology capturing the burden of RH in Africa, a recent meta-analysis by Nanseu et al. [1] reported an overall prevalence  [1]. The observed disparity in RH prevalence study between studies could be explained by differences in the definition of RH used, the characteristics of studied populations, the availability of ABPM, the duration of hypertension and the period when the study was conducted since the burden of hypertension varies overtime [1]. With regard to the period when the studies were conducted, the study from Cameroon was conducted 25 years ago, that from Nigeria 13 years ago, the one from Burkina Faso 4 years ago and those from Lesotho and Algeria 3 and 2 years back, respectively [1]. In Cameroon, the mean duration of hypertension since diagnosis was 7 ± 5 years in men and 8 ± 6 years in women; in Burkina Faso, 11 (10.9%) patients with RH were followed-up for not more than 1 year and 15 (14.9%) for at least 10 years [1].
In the present study, the frequency of true resistant hypertension was 9.4%. Our observed frequency is lower than that reported by several studies conducted in Europe and North America [30] as well as in Asia [31] [32]. In the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints, the prevalence of true RH was 18% [30]. In a study from an Asian population, Naseem et al., [32] reported a prevalence of true RH of 12%. In SSA, only one study by Yaméogo et al. [33] from Burkina Faso undertook the ABPM to exclude white-coat-related RH and found a prevalence of true RH of 14.6% (95% CI 12.2% to 17.4%). The reasons underlying the disparity in true RH prevalence between studies have been already discussed in the section clinic RH.
Headache followed by dyspnea and precordial chest pain were symptoms most frequently reported by true RH patients in the present study. In SSA, only one study by Yaméogo [33] from Burkina Faso found headaches (11.9%), dizziness (9.9%), precordial chest pain (8.9%) and hemiplegia (4.1%) as signs and symptoms most frequently reported by true RH patients. All these signs and symptoms do translate the severity of tissue and organ failure associated with true RH.
True RH was associated in the present study with a non-dipping pattern. In a cohort prospective study comparing the prevalence of nocturnal hypertension and non-dipping among black with and without RH, Irvin et al. [34] [35] demonstrated that subjects with true RH compared to white coat RH had lower nocturnal systolic BP reductions (6.4 ± 8.8 versus 9.8 ± 7.5 mmHg, P = 0.0004), lower nocturnal DBP (10.4 ± 9.6 versus 13.6 ± 9.2 mmHg, P = 0.001), and a higher percentage of non-dippers (68.7% versus 49.6%, P = 0.001). Similarly, Friedman and Logan [36] showed that the prevalence of non-dipping among normotensive, controlled hypertensive, and resistant hypertensive subjects was 25.0%, 42.3%, and 61.5%, respectively (P = 0.006). Given the high prevalence of D. K. Kuntonda et al. nocturnal hypertension and non-dipping BP among individuals with TRH, treatment strategies directed at lowering nighttime BP and increasing BP dipping may be warranted. One prior randomized trial suggests that taking antihypertensive medication at bedtime may lower nighttime SBP to a greater extent than taking it in the morning [37]. As diuretic treatment was associated with a lower prevalence of non-dipping, pressure natriuresis may play a role in non-dipping where BP remains high during sleeping hours to counteract sodium retention during the day [38]. Diuretics may be especially beneficial in blacks, a population with a high prevalence of salt-sensitive hypertension [38].
BMI, blood glucose, uric acid and were positively correlated to SBP in true resistant hypertension patients in the present study. The pathogenetic link underlying the relationship between BMI, blood glucose, uric acid and RH is insulin resistance and subsequent hyperinsulinemia [39] [40]. Indeed, these metabolic risk in isolation or combined as metabolic syndrome are factors known to negatively interfere with BP control via endothelial dysfunction [41]. Obesity, the sixth most important predisposing factor for RH [42], elevates, solely or in interaction with blood glucose and uric acid [41], the need for increased number of antihypertensive medications and also increases tendency of never achieving required BP control [43]. Increased body weight predisposes to true RH by causing decreased sodium excretion, insulin resistance, increased activity of sympathetic nervous system and lastly renal injury by the activation of the renin-angiotensin system and subsequent oxidative stress [44] [45].
In multiple regression analysis, HDL-c and eGFR were negatively correlated with SBP among true RH patients in the present study. Low HDL-c is a well-known marker of insulin-resistance [41] and negatively interferes with BP control through above-mentioned biochemical and metabolic pathways. Most studies on the relationship between kidney function and RH were cross-sectional ones and found that the prevalence of true RH is substantially higher in patients with CKD, estimated to be 40% of hypertensive participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. Approximately 50% had BP that was not at target on three or more medications, and the other one half had BP that was at target on four or more medications [46]. In the CRIC Study, participants with CKD and treatment-rHTN had a 38% higher risk of cardiovascular events or all-cause mortality and a 28% higher risk of ESRD or 50% decline in GFR [46]. Importantly, non-dipping occurs in 49% -82% of hypertensive patients with CKD and is associated with progression of CKD [46]. In a recent prospective study on the relationship between kidney function and RH, Kaboré et al. [47] reported a mean eGFR decline using the MDRD equation during follow-up of 1.5 ± 2.9 mL/min/1.73m 2 per year. After adjusting for age, sex, obesity, diabetes, and cardiovascular history, the odds ratios (ORs) for new-onset treatment-RH associated with a mean eGFR level, per 15 mL/min/1.73m 2 drop, were 1.23 [l0.91 -1.64] vs controlled hypertension and 1.10 [0.83 -1.45] vs uncontrolled non-RH. Apart from renin angiotensin system activation and uremic toxins, water and salt retention via high salt diet has been reported as the main culprit World Journal of Cardiovascular Diseases causing resistance to antihypertensive agents by increment of BP and/or blunting the BP-lowering effect of antihypertensive agents [46].
The interpretation should take into account of some limitations. First, the study design precludes the establishment of any temporal relationship between variables of interest. Second, the small sample size did not confer sufficient power to statistical tests in detecting potential associations between variable of interest. Third, the hospital-based design of the present study did allow the generalization of our results to the whole true hypertensive patients.

Conclusion
True

Author's Contribution
DK participated in survey conception, data collection and management and reviewed the manuscript; drafted the manuscript.
FBL participated in survey conception, data analysis and drafted the manuscript.
YL participated in survey conception and reviewed the manuscript; drafted the manuscript.
JRRM participated in survey conception, data analysis and revised the manuscript.
AN conducted data management and analysis and reviewed the manuscript.
NO reviewed the manuscript.
TM reviewed the manuscript.
DM reviewed the manuscript.
GN reviewed the manuscript.
FK reviewed the manuscript.
EVK reviewed the manuscript.
JRM reviewed the manuscript.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.