Resistant hypertension—complex mix of secondary causes and comorbidities

Abstract

Resistant hypertension (RHTN) is an increasingly common clinical problem1, 2 that studies have suggested is almost always heterogeneous in terms of etiology, risk factors and comorbidities. There has been a growing interest in defining epidemiology and pathophysiology in hope of identifying treatment targets. Cross-sectional assessments of subjects with RHTN compared with subjects without RHTN have consistently found the former to have an increased frequency of cardiovascular complications, including prior myocardial infarction, stroke, congestive heart failure and chronic kidney disease (CKD).3, 4 A recent 5-year longitudinal assessment of cardiovascular outcomes in a large cohort of subjects with rigorously defined RHTN demonstrated a 50% increase in cardiovascular events in RHTN subjects compared with patients whose blood pressure (BP) had been controlled on ≤3 medications.5 The study further documented that compared with all subjects being newly treated for hypertension (HTN), the risk of cardiovascular events in patients diagnosed with RHTN was increased by twofold. These demonstrated differences in complication rates suggest possibly unique underlying factors as important mediators of accelerated cardiovascular disease progression in patients with RHTN. Early identification and effective clinical management of comorbidities and concomitant secondary causes of RHTN is imperative in patients with RHTN in order to facilitate BP control and reduce long-term cardiovascular risk. Matching appropriate therapies to important comorbidities and secondary causes of RHTN remains elusive, however, as such factors often remain undiagnosed and unappreciated in terms of the role they have in promoting resistance to antihypertensive treatment. Accordingly, all too often, current treatment of RHTN is often based on a onesize fits all approach as opposed to tailoring therapy based on accurate identification of underlying contributing factors. Therefore, the first step in reversing this generalized treatment approach is to know the likelihood of underlying secondary causes of RHTN as well as the prevalence of important comorbidities in patients with RHTN. However, until this edition of the Journal of Human Hypertension, a systematic evaluation of a large cohort of patients with RHTN that rigorously defines these prevalence rates has been lacking. In the current edition of the Journal of Human Hypertension, Florczak et al.6 report the results of a prospective evaluation of 204 subjects with RHTN. The study was designed to determine the prevalence of secondary causes in patients with confirmed RHTN by ambulatory blood pressure monitoring (ABPM). Appropriate biochemical analysis, radiologic imaging and polysomnographic assessment was systematically done to test for secondary causes of HTN and/or comorbid conditions. Older age (≥65 years), CKD stage ≥3 and the presence of diabetes were exclusion criteria. Florczak et al. found that obstructive sleep apnea (OSA), primary aldosteronism (PA) and metabolic syndrome (MS) were the most frequently identified comorbid conditions, with the large majority of evaluated subjects having at least one or more of these three comorbidities. Perhaps one of the most important findings was the extremely high prevalence of OSA, having been diagnosed in 72% of all subjects with RHTN. The high prevalence of OSA in subjects with RHTN is consistent with previous clinical studies, which have shown similar results.7 However, these earlier studies were limited by being generally smaller and having not confirmed true treatment resistance by ABPM.8 Like OSA, Florczak et al. also found the presence of MS to be extraordinarily high in patients with RHTN, with a prevalence of over 65%. MS, OSA and PA commonly coexisted, with 43% of the cohort having been diagnosed with two of the three and 11% having all the three disorders. This high degree of concordance between RHTN and PA, OSA and MS suggests a possible common causality that warrants further exploration. Early observations by Conn9 involving small series of patients indicated glucose intolerance and reduced insulin sensitivity to be common in the setting of PA. Many years later, an increased association of MS and PA was described in an Italian cohort of patients with PA.10 In this study, patients with PA had a significantly higher prevalence of MS than a control group of generalized hypertensive patients (41% vs 29%, respectively). In addition, the subjects with PA had other indications of altered glucose metabolism, such as higher fasting glucose levels.10 It has been suggested, based on experimental and clinical studies, that aldosterone excess may induce insulin resistance by acting on insulin-target tissues through alteration of insulin receptors and insulin signaling, reduced insulin secretion, inflammatory cytokine production, induction of fibrosis, fat accumulation or dysregulation of glucose uptake/release and gluconeogenesis.11 However, the possible direct and indirect effects of aldosterone on glucose metabolism in humans, particularly in the setting of RHTN, lack full explanation.11 In addition to a high rate of OSA, PA and MS, the investigators also found a high prevalence of visceral obesity in their cohort of patients with RHTN. Visceral obesity, which has been identified as an important contributor to the development of MS, was present in 53% of all patients with RHTN and was even more frequent in patients with OSA (81%).12 Interestingly, Florczak et al. observed a slightly higher rate of abdominal obesity in subjects with PA as compared with subjects without PA (78% vs 72.3%). Subjects with PA had a higher prevalence of impaired glucose tolerance (34% vs 18%) and a higher rate of newly recognized diabetes (31% vs 11.6%). As there was no overall difference in body mass index between patients with and without PA, the findings suggest that aldosterone excess may represent an important intermediate link between visceral obesity and glucose intolerance. Several lines of evidence have shown an association of increased aldosterone levels and obesity,13 especially visceral obesity,14 and it has been suggested that one possible mechanism relating HTN to visceral obesity is stimulation of aldosterone release through direct and indirect factors.15 Consistent with studies linking aldosterone to obesity, weight loss studies support a mechanistic link between obesity and aldosterone release by showing significant decreases in aldosterone levels.16 Prior studies of patients with RHTN have reported that OSA severity increases with increasing aldosterone levels, suggesting that aldosterone excess may be an important mediator of OSA.17 This positive relation suggests two causal but opposing possibilities: either untreated OSA is stimulating aldosterone release or aldosterone excess is worsening OSA. The former possibility is supported by experimental data that intermittent hypoxemia promotes a generalized stimulation of the reninangiotensin–aldosterone system. Human studies, however, have generally not shown treatment of OSA with continuous positive airway pressure to have a substantive effect on aldosterone levels.18 This lack of a demonstrative effect of continuous positive airway pressure on aldosterone levels seems to argue against OSA causing excess aldosterone release, but definitive testing is still needed. Clinical data, however, does support the opposite effect, that is, aldosterone excess worsens OSA severity in patients with RHTN. Our laboratory has shown that aldosterone blockade with spironolactone lessens the severity of OSA in patients with RHTN, supporting the possibility that aldosterone excess contributes importantly to the severity of OSA.18 This effect is hypothesized to be through aldosterone-induced increase in airway edema and associated increases in upper airway resistance. Overall, a growing body of literature links aldosterone excess to RHTN, OSA and MS. The findings of Florczak and colleagues importantly support these earlier findings in clearly demonstrating that patients with RHTN are characterized by a high degree of aldosterone excess, OSA, MS and visceral obesity. Although admittedly speculative, it is tempting, based on the current and prior findings, to suggest that visceral adiposity serves as a stimulus of aldosterone excess, which in turn contributes importantly to antihypertensive treatment resistance, OSA severity and glucose intolerance. The current evaluation has a number of important strengths. First, it is a large prospective, systematic evaluation of patients with true RHTN, having been confirmed by ABPM. Second, the investigators tested for multiple comorbidities in the same patients as opposed to testing for single comorbidity. Lastly, the authors included only patients younger than 65 years with normal renal function and without a history of diabetes, thus reducing potentially the confounding effects of older age and CKD. However, such exclusions may preclude generalizing the results to broader cohorts of RHTN. Florczak et al.6 show in this very thorough study that the RHTN is almost always characterized by multiple comorbidities and/or secondary causes of HTN. These findings highlight the importance of systematically screening for these risk factors, both to identify potentially reversible causes of treatment resistance and to allow for use of targeted therapies to reduce cardiovascular risk.