Resistant hypertension refers to patients with difficult-to-treat hypertension, generally defined as needing 3 or more blood pressure medications. It is a common medical disorder, affecting approximately 7-10 million Americans. Within this group of patients with resistant hypertension is a proportion of patients failing antihypertensive treatment in spite of maximum therapy. We propose referring to this antihypertensive treatment failure as refractory hypertension. In a preliminary analysis of our clinical experience over the last several years, we found that the prevalence of refractory hypertension was approximately 10% of patients initially referred for resistant hypertension. If generally true, this would translate int about 1 million Americans. Refractory hypertension has not been previously described. The current application is designed to test hypothesized mechanisms of antihypertensive treatment failure. In our initial analysis of this group of patients, we found evidence of increased sympathetic activity as an important contributing cause antihypertensive treatment failure. This hypothesized excess in adrenergic activity is suggested by higher resting heart rates and by higher levels of urinary norepinephrine levels compared to patients with controlled resistant hypertension. We will test for heightened sympathetic tone in this group of patients by prospectively comparing plasma norepinephrine levels in patients with refractory hypertension to patients with controlled resistant hypertension. We will also determine the antihypertensive benefit of blocking the effects of sympathetic activity with an agent that provides both alpha and beta adrenergic receptor blockade. Persistent intravascular fluid retention has been shown by us and other investigators to be a common cause of resistant hypertension. To what extent refractory hypertension is volume dependent is unknown. In a second series of experiments, we will test the hypothesis that persistent fluid retention contributes importantly to the development of refractory hypertension by comparing cardiac volumes, as measured by magnetic resonance imaging, in patients with refractory versus controlled resistant hypertension. In a second experiment, will compare the antihypertensive benefit of dietary salt restriction in patients with refractory hypertension versus control patients, to determine to what extent salt sensitivity contributes to antihypertensive treatment failure. Lastly, obstructive sleep apnea is extremely common in patients with resistant hypertension and is thought to contribute to difficulty controlling blood pressure. The role that untreated sleep apnea plays in causing refractory hypertension is unknown. The third objective of this application is to determine the prevalence of moderate/severe obstructive sleep apnea in patients with refractory hypertension compared to patients with controlled resistant hypertension. If poorly treated obstructive sleep apnea is common in patients with refractory hypertension, it will indicate an important and potentially reversible cause of antihypertensive treatment failure.

Public Health Relevance

Refractory hypertension, defined as patients whose blood pressure cannot be controlled in spite of maximum medical therapy, may affect some 1 million Americans. Causes of refractory hypertension have not been previously identified. If underlying causes of refractory hypertension could be identified, it may allow for development of more effective prevention and treatment strategies for this extremely high-risk group.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZRG1-CVRS-E (02))
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Mcdonald, Cheryl
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University of Alabama Birmingham
Internal Medicine/Medicine
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United States
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Siddiqui, Mohammed; Phillips, Robert A; Bursztyn, Michael et al. (2018) Case of Refractory Hypertension Controlled After Aortic and Mitral Valve Replacement and Coronary Artery Bypass Grafting. Hypertension 72:3-9
Velasco, Alejandro; Siddiqui, Mohammed; Kreps, Eric et al. (2018) Refractory Hypertension Is not Attributable to Intravascular Fluid Retention as Determined by Intracardiac Volumes. Hypertension 72:343-349
Calhoun, David A (2018) Medical Versus Surgical Treatment of Primary Aldosteronism. Hypertension 71:566-568
Dudenbostel, Tanja; Siddiqui, Mohammed; Gharpure, Nitin et al. (2017) Refractory versus resistant hypertension: Novel distinctive phenotypes. J Nat Sci 3:
Cai, Anping; Calhoun, David A (2017) Resistant Hypertension: An Update of Experimental and Clinical Findings. Hypertension 70:5-9
Calhoun, D A (2017) Sleep disorders and hypertension risk. J Hum Hypertens 31:371-372
Ghazi, Lama; Oparil, Suzanne; Calhoun, David A et al. (2017) Distinctive Risk Factors and Phenotype of Younger Patients With Resistant Hypertension: Age Is Relevant. Hypertension 69:827-835
Siddiqui, Mohammed; Calhoun, David A (2017) Refractory versus resistant hypertension. Curr Opin Nephrol Hypertens 26:14-19
Ghazi, Lama; Dudenbostel, Tanja; Hachem, Maria El et al. (2017) 11-Beta Dehydrogenase Type 2 Activity Is Not Reduced in Treatment Resistant Hypertension. Am J Hypertens 30:518-523
Siddiqui, Mohammed; Judd, Eric K; Oparil, Suzanne et al. (2017) White-Coat Effect Is Uncommon in Patients With Refractory Hypertension. Hypertension 70:645-651

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