Nonpharmacological Management of Resistant Hypertension

Abstract

Purpose of Review

In the United States (US), 46% of adults have hypertension (systolic blood pressure ≥ 130 mmHg, diastolic blood pressure ≥ 80 mmHg). Approximately, 16% of patients with hypertension have apparent treatment-resistant hypertension (aTRH) and the incidence of true resistant hypertension (RHT) is thought to be much lower (~ 2%). These patients with RHT are at a higher risk for adverse events and worse clinical outcomes.

Recent Findings

Although lifestyle interventions have proven to be effective as the first line of defense in treating hypertension, their role in the management of patients with RHT is not well established. Despite fewer in number, available studies examining lifestyle interventions in patients with RHT do indeed show promising results.

Summary

In this review, we aim to discuss the role of common lifestyle interventions such as physical activity, exercise, weight loss, and dietary modifications on blood pressure control in patients with RHT.

Introduction

High blood pressure (BP) is the leading risk factor for attributable death worldwide [1]. When using the Joint National Committee Seven (JNC 7) BP thresholds of ≥ 140/90 mmHg, one in three adults in the United States (US) are estimated to have hypertension (HTN) [2]. This rate increases to 46% (105.3 million) of US adults when using BP thresholds recommended by the 2017 American College of Cardiology/American Heart Association (ACC/AHA) clinical practice guidelines (≥ 130/80) [3, 4]. HTN stands out among all modifiable cardiovascular disease (CVD) risk factors and amounts to most CVD-related deaths in the US [3] and worldwide [5]. Despite significant medical and pharmacological advances, only 21.6% of patients with HTN are thought to have their BP values under control [4].

Resistant hypertension (RHT) is a subtype of HTN and defined as BP values that remain above treatment goals despite the use of three antihypertensive medications of different classes, 1 of them a diuretic, while at the maximal tolerated dose and frequency [6]. This definition also includes patients that require ≥ four antihypertensive medications to reach said treatment goals [6]. If medication dose, adherence to treatment, or out-of-office BP readings are missing or cannot be determined, true RHT cannot be confirmed, and patients may be presenting with pseudo resistance. In this case, the term apparent treatment RHT (aTRH) should be used.

Achieving lower BP values in patients with RHT has been shown to improve CVD risk. Patients with uncontrolled RHT had a twofold increase in the risk of coronary heart disease when compared to patients with controlled RHT [6]. However, BP control appears to provide less benefit in patients with aTRH than in patients without aTRH [7].

Patients with RHT are at a 50% higher risk for CVD-related events compared to patients with controlled HTN [8], have higher rates of target organ damage [6], and generally have worse outcomes when compared to patients without RHT [6]. The prevalence of RHT among patients with treated HTN in the Spanish Ambulatory Blood Pressure Monitoring Registry (N = 70,997) was found to be 17% [9]. In patients with chronic kidney disease, the prevalence of aTRH was found to be 40% [4, 10]. When compared to patients without RHT, patients with RHT had a 32% greater risk for end-stage renal disease (ESRD), 24% greater risk for ischemic heart events, 46% greater risk for congestive heart failure, 14% greater risk for cerebral vascular accidents, and 6% greater risk for all-cause mortality [11]. Furthermore, RHT is usually associated with multiple comorbidities such as obesity, obstructive sleep apnea (OSA), diabetes mellitus, and others [6]. Practicing healthy lifestyle behaviors such as maintaining healthy body weight, exercise, and physical activity, following the Dietary Approaches to Stop Hypertension (DASH diet), and smoking cessation have shown to be effective for patients with HTN, with emerging evidence indicating similar benefit in those with RHT (Fig. 1) [12, 13, 14•]. Notably, the benefits received from lifestyle modifications appear to be additive. Those individuals who practice multiple healthy lifestyle behaviors are more likely to confer a lower risk of CV events [12]. In this review, we aim to review the benefits of primary lifestyle interventions used in the management of patients with RHT.

Fig. 1.

Nonpharmacological management of hypertension. ^aBP reductions listed are based on impact found in patients with HTN [54]. ^bOne standard drink contains approximately 14 g of pure alcohol which is found in 12 oz. of regular beer (5% alcohol), 5 oz. of wine (12% alcohol) and 1.5 oz. of distilled spirits (40% alcohol) [12]. HRR, heart rate reserve; 1RM, 1-repetition maximum; DASH, dietary approaches to stop hypertension. Image created with Bioredner.com

Exercise and Physical Activity

There are several effective exercise-based interventions available to help treat RHT. Similar to the mechanisms contributing to RHT, there are also multiple hypothesized mechanisms responsible for the beneficial therapeutic effects of exercise training on BP control and other important surrogate outcomes.

The most widely accepted and utilized mode of exercise training for treating various cardiovascular conditions, including RHT, is continuous aerobic exercise training (AET). The available evidence supports that AET is safe and improves BP control in patients with RHT [6, 12, 13, 15, 16••, 17, 18]. The BP-lowering effects of AET in patients with RHT have been similar to those of individuals with nonresistant HTN [16••]. A randomized clinical trial by Dimeo et al. reported that following an 8–12 week AET protocol of moderate-intensity treadmill walking, there was a reduction of 6 mmHg in systolic BP (SBP) and 3 mmHg in diastolic BP (DBP) in patients with RHT assessed via ambulatory BP [16••]. The mechanisms most likely involved in the BP-lowering effects of AET are improvements in endothelial function, vascular compliance, body composition, and sympathetic tone [12, 13, 15, 16••, 17–19].

Due to the time constraints required of AET, high-intensity interval training (HIIT) has gained recent popularity as a mode of exercise training for patients with various cardiovascular diseases. While HIIT requires the individual to exercise at a high work rate, the length of the training session is much shorter than a typical AET session, potentially making it more convenient [20]. The available evidence suggests that the BP-lowering effects of HIIT compared to moderate continuous AET are similar and potentially favoring HIIT [20, 21].

To date, there have been no published studies that have investigated the effects of HIIT in patients with RHT specifically. Additionally, evidence suggests that a single session of lower intensity exercise may elicit a more prolonged BP-lowering effect in patients with RHT [17]. The reasons for this potentially paradoxical inverse relationship between exercise intensity and BP control in patients with RHT are not well understood. The authors suggest that this paradox may be due to the complex nature of RHT and the multitude of different pathological contributors [6]. For example, HIIT results in more significant improvements in endothelial function and nitric oxide availability than AET [20], likely due to greater endothelial shear stress occurring during HIIT and stronger stimulation of endothelial nitric oxide synthase. Therefore, perhaps in individuals with RHT with relatively preserved endothelial function or other primary pathological mechanisms, significant differences in BP control outcomes between HIIT and lower exercise training intensities may not be observed.

Historically, resistance training (RT) was considered contraindicated for individuals with any cardiovascular condition due to the pronounced hemodynamic response that it elicits, especially at higher loads or intensities [22]. However, more recently, RT has gained greater acceptance as a primary therapeutic intervention for cardiovascular diseases, including RHT [6]. The most recent American Heart Association (AHA) Scientific Statement on RHT recommends that light RT be included as part of the exercise regimen for these patients [6]. For individuals who cannot sustain the exercise durations involved in AET, RT may also serve as a good initial training mode [6, 23].

Only a limited number of studies with relatively small sample sizes have investigated the use of RT as a standalone intervention for improving BP control in patients with RHT. de Carvalho et al. compared the effects of 12 weeks of either AET or RT in 11 patients with RHT [15]. They reported that while the AET group demonstrated significant SBP, DBP, and MAP reductions, no significant reductions were observed in the RT group. However, the RT group in that study had a lower BP at baseline (121 ± 5 mmHg) compared to the AET group (129 ± 7 mmHg) [15]. It does appear that a combined (RT and AET) program may be a more effective approach. A small study by Pires demonstrated that a combined exercise program resulted in a more prolonged and significant acute reduction in ambulatory BP outcomes in patients with RHT than RT and AET only [18]. While the statistical power of these studies is limited due to sample size, the combination of these findings suggests a potential and additive effect on BP control by including both modes into an exercise training program. This additive effect would be consistent with previous literature investigating combined exercise protocols in patients with various cardiovascular conditions [24].

Inspiratory muscle training (IMT) has gained recent interest as an intervention for improving cardiovascular outcomes such as BP. This form of training requires the patient to breathe through a device with a valve set to a predetermined pressure threshold. Once the patient generates enough pressure, the valve opens, and air flows through the device. IMT protocols typically utilize training loads ranging between 30 and 80% of the patient’s maximal inspiratory pressure and are done in relatively shorter training sessions (30 breaths) performed twice daily. While there are no studies today that had investigated the role of IMT in patients with RHT, there are now several studies demonstrating improved BP outcomes following IMT [25–27] in protocols ranging from 6 to 8 weeks [25–28]. The proposed mechanisms of IMT contributing to improved BP include baroreflex sensitivity, vagal tone, and endothelial function [25–28]. Interestingly the BP-lowering effects of IMT have been reported to occur independently of changes in body weight, body composition, blood lipids, blood glucose, or carotid vascular function (β-stiffness and arterial pulse wave velocity) [27].

While there are no studies that have specifically investigated the effects of IMT on BP outcomes in patients with RHT, it has been investigated in patients with obstructive sleep apnea (OSA), which is a known contributor to RHT. Vranish et al. reported that 5 min of IMT performed daily for 6 weeks resulted in significant improvements in sleep quality, BP, and plasma catecholamines in patients with OSA [25]. Therefore, in individuals with RHT and especially concurrent OSA, IMT may be considered in the clinical management plan.

The variety of safe and effective modes of exercise training provides clinicians and patients a wide array of options to improve BP. Like pharmacological agents, each of the different modes of exercise training can be incorporated into a patient’s BP management plan according to their unique characteristics, lifestyle, interests, and factors contributing to RHT. It is thus imperative that clinical exercise physiologists, physical therapists, and other qualified health care professionals be actively engaged in exercise prescription to achieve BP control in patients with HTN.

Dietary Modifications

Causes of RHT are multifactorial and include excessive dietary salt intake, obesity, CKD, and OSA [6, 29, 30]. Among these factors, excess body fat is purported as being an independent risk factor of RHT, with evidence from multiple population-based registries indicating a body mass index (BMI) ≥ 30 kg/m² confers approximately a twofold increased risk of RHT [31–33], and an even greater risk observed in those with co-existing comorbidity (i.e., CKD) [10, 34]. Mounting evidence further suggests that visceral adiposity is fundamentally responsible for the development and rising prevalence of RHT [6, 35], manifesting in greater salt sensitivity, vascular dysfunction, and sympathetic nervous system activation, renin-angiotensin system, and mineralocorticoid receptor activity [6, 36]. Understanding the co-existence of comorbidities and HTN complications associated with the pathogenesis and progression of RHT is highly relevant to establishing individual BP goals and appropriate antihypertensive treatment.

Lifestyle interventions promoting weight reduction and weight loss maintenance are regarded as critical and practical approaches to managing elevated BP, with diet modification, including calorie restriction, being a necessary component [37]. Current guidelines indicate that achieving weight reduction of > 5 to 10% body weight will help lower BP in individuals who are overweight or obese [3, 37]. Various reviews have similarly shown that short-term weight reduction through diet modification leads to significant and meaningful reductions in systolic BP by 5.7 mmHg. Longer-term randomized control trials of patients with primary HTN followed for a minimum of 24 weeks follow-up have reported modest reductions in body weight (~ 4 kg) that are necessary to achieve BP reductions of ~ 4.5/3.2 mm Hg [38]. Given the well-described link between obesity and RHT, dietary weight loss interventions are a plausible strategy to concomitantly target excess body weight and high BP in patients with RHT. However, evidence demonstrating the efficacy of dietary weight loss on BP in RHT patients is currently lacking, and long-term effects of sustained weight loss on BP warrants further investigation. Despite the paucity of research, it is presumed that weight loss of similar magnitude observed in patients with primary HTN will provide similar BP-lowering benefits in those with RHT [38]. Importantly, weight loss may reduce antihypertensive medication dependency or facilitate medication withdrawal [37]. Weight loss can help to reassure that adequate BP control may be achieved by maintaining weight loss alongside minimal pharmacological intervention.

Reducing sodium intake through dietary behavior modification has accumulated the strongest support for reducing BP and HTN risk across all age, gender, and ethnic groups [37, 39–41]. In a recent pooled analysis of 133,118 individuals (63,559 with HTN), Mente et al. [42] reported an estimated 1-g reduction in daily sodium intake was associated with a 2.1 mmHg decrease in SBP among those with HTN (n = 63,559) and lower but clinically significant reductions observed among those without HTN. Another meta-analysis of 103 studies found strong evidence for a linear dose–response effect on BP. Each reduction of sodium intake by 2,300 mg/day equates to a reduction of 3.82 mmHg systolic BP [40]. Notably, larger effects of sodium restriction on BP in more high-risk populations are expected in older adults and those with obesity [41], and CKD [43], consistent with decreasing vascular compliance and renal filtration [40], and in black individuals or African Americans, given their differences in renal handling of sodium [41, 44]. Although data remains limited, evidence from 2 small but well-controlled studies has convincingly shown that reduced sodium intake effectively lowers BP in patients with RHT [43, 45]. Among 12 patients with RHT, Pimenta et al. [45] found that a low (1150 mg/day) versus high (5750 mg/day) sodium diet followed for 7 days was associated with profound reductions in office BP (−22.7/−9.1 mmHg) as well as daytime, nocturnal, and 24-h BP levels (−20.1/−9.8 mmHg).

Similarly, in a double-blind, randomized controlled crossover trial in 20 stage 3–4 CKD patients with HTN, of whom RHT was highly prevalent, patients following a sodium-restricted diet (4140 to 4600 mg/day) over 2 weeks, demonstrated significant reductions in 24-h ambulatory BP (−9.7/−3.9 mmHg), compared to those on a high sodium diet (4140 to 4600 mg/day) [43]. Despite the preliminary nature of these findings, dietary modification emphasizing salt restriction shows promise as adjunctive therapy to improve BP control in patients with RHT. In this regard, current guidelines by national advisory councils recommend sodium intakes of 1500 mg/day or less, particularly among high-risk populations [3, 41]. However, optimal sodium intakes for BP control and management in patients with RHT have yet to be established, and controversy exists regarding the potential harms associated with very low sodium intakes in high-risk populations, such as those with RHT [6]. Thus, data from more rigorously designed trials are needed to support and recommend sodium reduction strategies for concomitant BP lowering in patients with RHT before definitive recommendations for this patient population can be made.

In addition to modifying salt or sodium intakes, improving overall diet quality has emerged as a critical strategy to improve and manage BP. Adoption of The Dietary Approaches to Stop Hypertension (DASH) diet has produced the most salient results for reducing BP with average reductions by 6.7/3.5 mmHg [37, 46], a magnitude that is similar to earlier pharmacological therapeutic trials for mild HTN [39]. With the DASH diet, consumption of potassium-rich foods is recommended, which, together with low-sodium content (< 1500 mg/day), can significantly contribute to BP reduction [47]. However, caution should be exercised in adopting a high-potassium DASH diet in patients with advanced CKD (stages 4 and 5) who have an increased risk of developing severe hyperkalemia and related complications [6]. Notwithstanding, a DASH-like diet emphasizes greater intakes of fruits, vegetables, fiber, and low-fat dairy products, thereby encouraging individuals to modify their entire eating pattern (and thus, dietary behaviors) versus select nutrient(s), which may translate to additional cardiovascular benefit [48, 49].

While the evidence base supporting adopting a DASH-like eating pattern for BP control in the general population remains robust and persuasive, findings in patients with RHT suggest otherwise [30]. Alternative, DASH-style diets that resemble a Mediterranean diet, including a 10% substitution of carbohydrates with unsaturated (primarily monounsaturated) fat, or lean protein and fish, have also yielded appreciable improvements in BP [39], a phenomenon believed to be partly explained by the hypotensive effects of oleic acid (OA) found in extra-virgin olive oil [50]. However, the BP-lowering effects associated with the Mediterranean in patients with RHT remain to be elucidated. Further studies are needed to clarify the implications of poor diet in the pathogenesis of RHT and potential mechanisms by which improving diet quality, whether through the adoption of a DASH- or Mediterranean-like lifestyle, might facilitate BP control for patients with RHT, particularly those with comorbidities such as CKD, obesity, and diabetes.

Limiting alcohol intake has also been found to provide beneficial effects for BP management and control. Current ACC/AHA clinical guidelines recommend reducing alcohol intake for the management of HTN [3]. In a meta-analysis that included 361,254 participants, any level of alcohol consumption was associated with an increased risk of HTN in men [51]. In women, the increased risk of HTN was only present with intake levels beyond 2 drinks per day (12 g ethanol per drink) [51]. The magnitude of BP reduction associated with limiting alcohol consumption was found to be higher in those consuming ≥ 6 drinks per day (5.5 mmHg decrease in SBP and 4 mmHg decrease in DBP) [52]. These results show that reducing alcohol intake can be beneficial for BP management and control [14•].

Summary and Conclusions

Current practice guidelines recommend nonpharmacological management in lifestyle modifications as the initial treatment option for most patients with high BP [3]. If lifestyle modifications alone are not successful in achieving BP control, the current guidelines suggest a combination of lifestyle interventions and antihypertensive medications. Thus, it should be realized that all patients with HTN, including those with RHT, should be continuously encouraged to adopt healthy lifestyle behaviors regardless of their state of BP control, assuming medical appropriateness. Research shows that men with stage 1 HTN (SBP = 140–159 mmHg) who were highly physically active had a 30% lower risk for CVD mortality compared to physically inactive patients with lower BP values (120–129 mmHg) [51, 52]. The benefits of healthy lifestyle behaviors encompass improved BP control and go beyond and significantly impact morbidity rates, mortality rates, and quality of life [53].

Nonetheless, the current state of the literature investigating the effects of different lifestyle interventions on BP control in patients with RHT is lacking [53]. Increasing physical activity, reducing sedentary time, weight loss, and dietary modifications show promising potential to help achieve clinically significant outcomes in this patient population. Further studies are required to determine the clinical impact of these interventions in this patient population.