Refractory Hypertension

Abstract

Refractory hypertension is an extreme phenotype of treatment failure defined as uncontrolled blood pressure (BP) in spite of ≥5 classes of antihypertensive agents, including chlorthalidone and a mineralocorticoid receptor antagonist. A prospective evaluation of possible mechanisms of refractory hypertension has not been done. The goal of this study was to test for evidence of heightened sympathetic tone as indicated by 24-hr urinary (U-) normetanephrine levels, clinic and ambulatory heart rate (HR), HR variability (HRV), arterial stiffness as indexed by pulse wave velocity (PWV), and systemic vascular resistance (SVR) compared to patients with controlled resistant hypertension. Forty-four consecutive patients, 15 with refractory and 29 with controlled resistant hypertension, were evaluated prospectively. Refractory hypertensive patients were younger (48±13.3 vs. 56.5±14.1 years, p=0.038) and more likely female (80.0 vs 51.9 %, p=0.047) compared to patients with controlled resistant hypertension. They also had higher U-normetanephrine levels (464.4±250.2 vs. 309.8±147.6 μg/24h, p=0.03), higher clinic HR (77.8±7.7 vs. 68.8±7.6 bpm, p=0.001) and 24-hr ambulatory HR (77.8±7.7 vs 68.8±7.6, p=0.0018), higher PWV (11.8±2.2 vs. 9.4±1.5 m/s, p=0.009), reduced HRV (4.48 vs. 6.11, p=0.03), and higher SVR (3795±1753 vs. 2382±349 dyne·sec·cm5·m2, p=0.008). These findings are consistent with heightened sympathetic tone being a major contributor to antihypertensive treatment failure and highlight the need for effective sympatholytic therapies in patients with refractory hypertension.

Prevalence and Clinical Characteristics of Refractory Hypertension

“…In the present study, 7.9% of RH had RfH. Dudenbostel et al9, 17 reported that the prevalence of RfH in a referral hypertension unit was ≈5%, and Calhoun et al8 estimated a prevalence of RfH of 3.6% of subjects with controlled or uncontrolled RH. The slightly higher prevalence observed in our study could be explained by 2 reasons: first, because low BP control is one of the main indications for ABPM, it is possible that the Spanish Registry was selecting more subjects with difficult‐to‐treat hypertension than other population‐based studies.…”

Emerging concepts for patients with treatment-resistant hypertension

“…Furthermore, sympathetic activation is higher in patients with TRH than in individuals with elevated BP who respond to antihypertensive drug administration. In a recent study, Dudenbostel and colleagues found increased 24-hour urinary normetanephrine levels in patients with uncontrolled TRH, suggesting that heightened sympathetic tone might be partly responsible for antihypertensive treatment failure [10]. Importantly, these findings support expanded efforts to design denervation device-based interventions to treat TRH.…”

“…In a retrospective analysis of 304 patients with TRH, Acelajado et al identified that 29 (9.5%) remained refractory to treatment, despite maximal antihypertensive therapy [21]. Likewise, a prospective analysis of 559 patients with TRH revealed that 15 (2.6%) of patients sustained uncontrolled BP, in spite of treatment with more than 5 classes of antihypertensive agents [10]. …”

Resistant Hypertension

“…In addition, there is evidence for excessive aldosterone secretion, including high plasma aldosterone levels, albeit not as high as in patients with primary aldosteronism, and BP responsiveness to mineralocorticoid receptor antagonists (1,3,4). A small subset (2.7%) of RH, requiring ≥ 5 classes of antihypertensive agents for BP control, has recently been termed “refractory hypertension” (7). These patients may have different pathophysiologic mechanisms for treatment failure, especially excessive sympathetic output as evidenced by greater urinary 24h normetanephrine levels, greater arterial stiffness, higher heart rate, lower heart rate variability, and higher systemic vascular resistance than patients with controlled RH (7).…”

“…A small subset (2.7%) of RH, requiring ≥ 5 classes of antihypertensive agents for BP control, has recently been termed “refractory hypertension” (7). These patients may have different pathophysiologic mechanisms for treatment failure, especially excessive sympathetic output as evidenced by greater urinary 24h normetanephrine levels, greater arterial stiffness, higher heart rate, lower heart rate variability, and higher systemic vascular resistance than patients with controlled RH (7). …”