Treatment of Resistant and Refractory Hypertension Acelajado, Maria Czarina; Hughes, Zachary H; Oparil, Suzanne ...
Circulation research,
2019-March-29, 2019-03-29, 20190329, Volume:
124, Issue:
7
Journal Article
Peer reviewed
Open access
Resistant hypertension (RHTN) is defined as uncontrolled blood pressure despite the use of ≥3 antihypertensive agents of different classes, including a diuretic, usually thiazide-like, a long-acting ...calcium channel blocker, and a blocker of the renin- angiotensin system, either an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin receptor blocker), at maximal or maximally tolerated doses. Antihypertensive medication nonadherence and the white coat effect, defined as elevated blood pressure when measured in clinic but controlled when measured outside of clinic, must be excluded to make the diagnosis. RHTN is a high-risk phenotype, leading to increased all-cause mortality and cardiovascular disease outcomes. Healthy lifestyle habits are associated with reduced cardiovascular risk in patients with RHTN. Aldosterone excess is common in patients with RHTN, and addition of spironolactone or amiloride to the standard 3-drug antihypertensive regimen is effective at getting the blood pressure to goal in most of these patients. Refractory hypertension is defined as uncontrolled blood pressure despite use of ≥5 antihypertensive agents of different classes, including a long-acting thiazide-like diuretic and an MR (mineralocorticoid receptor) antagonist, at maximal or maximally tolerated doses. Fluid retention, mediated largely by aldosterone excess, is the predominant mechanism underlying RHTN, while patients with refractory hypertension typically exhibit increased sympathetic nervous system activity.
The brain must dynamically integrate, coordinate, and respond to internal and external stimuli across multiple time scales. Non-invasive measurements of brain activity with fMRI have greatly advanced ...our understanding of the large-scale functional organization supporting these fundamental features of brain function. Conclusions from previous resting-state fMRI investigations were based upon static descriptions of functional connectivity (FC), and only recently studies have begun to capitalize on the wealth of information contained within the temporal features of spontaneous BOLD FC. Emerging evidence suggests that dynamic FC metrics may index changes in macroscopic neural activity patterns underlying critical aspects of cognition and behavior, though limitations with regard to analysis and interpretation remain. Here, we review recent findings, methodological considerations, neural and behavioral correlates, and future directions in the emerging field of dynamic FC investigations.
•Imaging studies have recently begun to examine dynamic properties of FC.•Dynamic FC may yield novel insights into brain function and dysfunction.•We review results, methods, interpretations, and limitations in this emerging field.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Resistant hypertension affects an estimated 10-15 million American adults and is increasing in prevalence. The etiology of resistant hypertension is almost always multifactorial, including obesity, ...older age, high dietary salt, chronic kidney disease, and aldosterone excess. Classical primary aldosteronism and lesser degrees of aldosterone excess, possibly originating from visceral adipocytes, contribute broadly to antihypertensive treatment resistance. Treatment of resistant hypertension is predicated on appropriate lifestyle changes and use of effective combinations of antihypertensive agents from different classes. Blockade of aldosterone with spironolactone has been shown to be particularly effective for treatment of resistant hypertension. The antihypertensive benefit of spironolactone is not limited to patients with demonstrable hyperaldosteronism but instead can be effective in resistant hypertensive patients regardless of aldosterone levels. Chlorthalidone is a potent, long-acting thiazide-like diuretic and should be used preferentially to treat resistant hypertension as it is superior to normally used doses of hydrochlorothiazide.
Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium ...channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. The antihypertensive drugs should be administered at maximum or maximally tolerated daily doses. RH also includes patients whose BP achieves target values on ≥4 antihypertensive medications. The diagnosis of RH requires assurance of antihypertensive medication adherence and exclusion of the “white-coat effect” (office BP above goal but out-of-office BP at or below target). The importance of RH is underscored by the associated risk of adverse outcomes compared with non-RH. This article is an updated American Heart Association scientific statement on the detection, evaluation, and management of RH. Once antihypertensive medication adherence is confirmed and out-of-office BP recordings exclude a white-coat effect, evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. Management of RH includes maximization of lifestyle interventions, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP. If BP remains uncontrolled, referral to a hypertension specialist is advised.
Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease.
To characterize the prevalence of nonsuppressible ...renin-independent aldosterone production, as well as biochemically overt primary aldosteronism, in relation to blood pressure.
Cross-sectional study.
4 U.S. academic medical centers.
Participants with normotension (
= 289), stage 1 hypertension (
= 115), stage 2 hypertension (
= 203), and resistant hypertension (
= 408).
Participants completed an oral sodium suppression test, regardless of aldosterone or renin levels, as a confirmatory diagnostic for primary aldosteronism and to quantify the magnitude of renin-independent aldosterone production. Urinary aldosterone was measured in participants in high sodium balance with suppressed renin activity. Biochemically overt primary aldosteronism was diagnosed when urinary aldosterone levels were higher than 12 μg/24 h.
Every blood pressure category had a continuum of renin-independent aldosterone production, where greater severity of production was associated with higher blood pressure, kaliuresis, and lower serum potassium levels. Mean adjusted levels of urinary aldosterone were 6.5 μg/24 h (95% CI, 5.2 to 7.7 μg/24 h) in normotension, 7.3 μg/24 h (CI, 5.6 to 8.9 μg/24 h) in stage 1 hypertension, 9.5 μg/24 h (CI, 8.2 to 10.8 μg/24 h) in stage 2 hypertension, and 14.6 μg/24 h (CI, 12.9 to 16.2 μg/24 h) in resistant hypertension; corresponding adjusted prevalence estimates for biochemically overt primary aldosteronism were 11.3% (CI, 5.9% to 16.8%), 15.7% (CI, 8.6% to 22.9%), 21.6% (CI, 16.1% to 27.0%), and 22.0% (CI, 17.2% to 26.8%). The aldosterone-renin ratio had poor sensitivity and negative predictive value for detecting biochemically overt primary aldosteronism.
Prevalence estimates rely on arbitrary and conventional thresholds, and the study population may not represent nationwide demographics.
The prevalence of primary aldosteronism is high and largely unrecognized. Beyond this categorical definition of primary aldosteronism, there is a prevalent continuum of renin-independent aldosterone production that parallels the severity of hypertension. These findings redefine the primary aldosteronism syndrome and implicate it in the pathogenesis of "essential" hypertension.
National Institutes of Health.
Multiple studies indicate that primary aldosteronism (PA) is common in patients with resistant hypertension, with an estimated prevalence of approximately 20%. Additional studies suggest that beyond ...this 20% of patients with classical PA, there is a larger proportion of patients with lesser degrees of hyperaldosteronism which contributes even more broadly to antihypertensive treatment resistance. Given these observations, it is intuitive that use of aldosterone antagonists will provide antihypertensive benefit in patients with resistant hypertension and evidence of aldosterone excess. Intriguingly, however, are clinical findings demonstrating substantive benefit of aldosterone antagonists in patients with resistant hypertension, but without demonstrative evidence of hyperaldosteronism, that is, with seemingly normal or even low aldosterone levels.
Spironolactone is clearly established as the most effective fourth agent for treatment of uncontrolled resistant hypertension. Emerging observations suggest a further role of spironolactone for counteracting the effects of diet high in sodium, particularly in obese, hypertensive patients.
In 2018, the American Heart Association published a Scientific Statement on resistant hypertension. We compared the prevalence of apparent treatment-resistant hypertension (aTRH) among US adults as ...defined in the 2018 and 2008 American Heart Association Scientific Statements using data from 4158 participants with hypertension, taking antihypertensive medication in the 2009 to 2014 National Health and Nutrition Examination Survey. Blood pressure (BP) was measured 3 times, and antihypertensive medication classes were identified through a pill bottle review. In both Scientific Statements, aTRH was defined as uncontrolled BP while taking ≥3 classes of antihypertensive medication or taking ≥4 classes of antihypertensive medication regardless of BP level. Uncontrolled BP was defined as systolic/diastolic BP ≥140/90 mm Hg (≥130/80 mm Hg for those with diabetes mellitus or chronic kidney disease) in the 2008 Scientific Statement and systolic/diastolic BP ≥130/80 mm Hg (systolic BP ≥130 mm Hg only for low-risk adults ≥65 years of age) in the 2018 Scientific Statement. The prevalence of aTRH was 17.7% and 19.7% according to the 2008 and 2018 Scientific Statement definitions, respectively (Δ=2.0%; 95% CI, 1.5%–2.7%). Overall, 10.3 million US adults had aTRH according to the 2018 Scientific Statement. The most common 3-drug combination taken included an angiotensin-converting enzyme inhibitor, β-blocker, and thiazide diuretic. Using the 2018 definition, 3.2% of US adults with aTRH were taking a thiazide-like diuretic (chlorthalidone or indapamide), and 9.0% were taking a mineralocorticoid receptor blocker (spironolactone or eplerenone). In conclusion, the prevalence of aTRH is only modestly higher using the definition in the 2018 versus 2008 resistant hypertension Scientific Statement.
Hypertension (HTN) and CKD are closely associated with an intermingled cause and effect relationship. Blood pressure (BP) typically rises with declines in kidney function, and sustained elevations in ...BP hasten progression of kidney disease. This review addresses current management issues in HTN in patients with CKD including altered circadian rhythm of BP, timing of antihypertensive medication dosing, BP targets, diagnostic challenges in evaluating secondary forms of HTN, and the role of salt restriction in CKD. HTN in patients with CKD is often accompanied by a decrease in the kidney's ability to remove salt. Addressing this salt sensitivity is critical for the management of HTN in CKD. In addition to the well-established use of an ACEI or angiotensin receptor blocker, dietary salt restriction and appropriate diuretic therapy make up the mainstay of HTN treatment in patients with CKD. Bedtime dosing of antihypertensive medications can restore nocturnal dips in BP, and future clinical practice guidelines may recommend bedtime dosing of 1 or more antihypertensive medications in patients with CKD.
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