We evaluated kidney fibrosis in renovascular disease (RVD) using quantitative (q) and semi-quantitative magnetization-transfer (MT) magnetic resonance imaging (MRI). Ten RVD patients and 22 healthy volunteers (HVs) were prospectively enrolled. Of HVs, 10 (HV-1) underwent imaging studies whereas plasma samples were collected from 12 others (HV-2). The qMT-derived bound-pool fraction (f) was compared to MRI-based MT imaging (MTI)-derived MT ratio (MTR), blood oxygenation-level-dependent (BOLD) R2*, and diffusion-weighted imaging (DWI) apparent diffusion coefficient (ADC). MTR was assessed at offset frequencies of 600 Hz and 1000 Hz, and RVD qMT and MTI on both 1.5T and 3.0T MRI. Additionally, we measured plasma and urinary levels of fibrogenic cytokines and micro-RNAs, and stenotic kidney (STK) perfusion and volume with multidetector computed-tomography (MDCT). At 3.0T-MRI, STK cortex and medulla qMT-f were higher in RVD vs. HV-1 (p = 0.01, p = 0.05, respectively), as was MTR-600 Hz, whereas BOLD-R2* and the DWI ADC were not different. MTR and f measured at 1.5T were comparable to those obtained at 3.0T. STK blood flow was decreased vs. the contralateral kidney (CLK) (p = 0.033) but plasma and urinary fibrogenic indices were unchanged in RVD vs. HV-2. Both f and MTI at 3.0T-MRI may be useful for noninvasive assessment of STK fibrosis, independent of magnetic-field strength. MTI is potentially more sensitive than fibrogenic cytokine levels for detecting mild RVD-related fibrosis changes.

OBJECTIVE:To determine long-term trends in the incidence of hypertension. PATIENTS AND METHODS:Healthy adults in Olmsted County, Minnesota, from 1962 to 2012 were identified and studied with follow-up through 2024. One blood pressure (BP) reading for each calendar year (as available) through follow-up was identified. Hypertension was defined by BP ≥130/80 mm Hg or ≥140/90 mm Hg in 2 different calendar years or by use of antihypertensive medication. Analyses were adjusted for calendar period, age, sex, race, tobacco smoking, nontobacco substance use, depression/anxiety, dyslipidemia; family history of diabetes mellitus or hypertension, body mass index, systolic and diastolic BP, and fasting blood glucose level. Cumulative incidence estimates of hypertension accounted for death as a competing risk and were adjusted to characteristics of the 2000-2012 subcohort. RESULTS:There were 8323 healthy adults studied (mean age, 39 years). Risk factors for hypertension were older age, male sex, Black race, past and current tobacco smoking, current substance use, depression/anxiety, family history of diabetes or hypertension, higher systolic and diastolic BP, higher blood glucose level, higher body mass index, and period. For the baseline periods of 1963-1969, 1970-1979, 1980-1989, 1990-1999, and 2000-2012, the adjusted 20-year cumulative incidence of hypertension defined by BP ≥130/80 mm Hg was 45%, 47%, 54%, 70%, and 67%; by BP ≥140/90 mm Hg was 22%, 24%, 26%, 35%, and 33%; and by medication use alone was 13%, 12%, 13%, 17%, and 19%, respectively. CONCLUSION:A large increase in the incidence of hypertension among healthy adults occurred in the 1990s, with subsequent stabilization.

Background/Objective: Hypertension is the most prevalent chronic disease in primary care and a leading cause of cardiovascular morbidity and mortality. Despite existing guidelines, therapeutic inertia and suboptimal control persist. Large language models (LLMs) offer a potential valuable addition to augment clinical decision-making, yet their reliability for guideline-driven tasks remains unverified. This study evaluated the accuracy and safety of hypertension management recommendations generated by three LLMs compared to expert responses. Methods: Fifty-one clinical vignettes representing 17 core hypertension management concepts were constructed by hypertension experts. Each case was submitted to three LLMs (GPT-4, Gemini, MedLM) and a hypertension expert also wrote the “gold standard” answers. Three blinded expert reviewers rated each response on a 4-point accuracy scale, a binary safety (safe/unsafe) scale, and attempted to identify the source (LLM vs. expert) providing the response. Ratings were analyzed using mean scores, percentages of accurate and safe responses, and inter-rater agreement. Results: GPT-4 had the highest accuracy (83%) and safety (86%) scores among LLMs but remained inferior to expert responses (92% accuracy, 93% safety). Gemini and MedLM performed significantly worse (accuracy: 64% and 35%; safety: 73% and 39%, respectively). GPT-4 generated the most guideline-concordant responses (46%) among the three LLMs (Gemini 35%, MedLM 14%), but remains lower than experts’ responses (68%). Evaluators misidentified LLM responses as expert-written in 10 to 25% of cases, particularly with GPT-4. Inter-rater reliability for accuracy ratings was highest for expert-generated responses (ICC 0.81), with progressively lower agreement for GPT-4 (0.76), Gemini (0.70), and MedLM (0.68). A similar pattern was observed for safety and source discrimination ratings. The agreement was strongest for safety assessments and weakest for source discrimination. Conclusion: Among three tested LLMs, GPT-4 demonstrated closer agreement to expert decisions thereby showing greater potential for supporting hypertension management. However, current LLMs’ versions frequently produce inaccurate or unsafe recommendations and remain inferior to expert judgment. Human-in-the-loop supervision remains essential when deploying LLMs for clinical decision-making.

Obesity is a chronic complex disease with deleterious effects on multiple organs and systems through a process called lipotoxicity. Obesity is commonly associated with a range of systemic comorbidities, including cardiovascular diseases, obstructive sleep apnea, type 2 diabetes mellitus, dyslipidemia, osteoarthritis, and depression. Unfortunately, these conditions can be overlooked in the clinical setting, yet early detection and intervention of obesity-related comorbidities can lead to significantly improved health outcomes and well-being. An important consideration for clinicians is that obesity is the root cause and its associated comorbidities are downstream conditions. This perspective may help prioritize the management of obesity in the clinical setting. Adopting this clinical approach to treating obesity may help to improve or resolve several related conditions simultaneously rather than treating each condition as an isolated unassociated disease. This comprehensive review is based on the published literature on PubMed and Google Scholar and summarizes the latest recommendations and guidelines from international associations when diagnosing multimorbidity associated with adiposity and can be a valuable resource for diagnosing and managing obesity in the primary care setting.

BACKGROUND:Hypertension, the leading cause of cardiovascular mortality, remains suboptimally controlled. Large language models (LLMs) could improve hypertension control by augmenting clinical decision-making, but their reliability for guideline-driven tasks is unverified. This study evaluated the accuracy and safety of hypertension management recommendations generated by 3 LLMs. METHODS:Fifty-one vignettes were constructed and submitted to the LLMs (GPT-4, Gemini, Medical Large Language Model [by Google; MedLM]) and a hypertension expert to generate the responses. Three blinded reviewers rated each response on a 4-point accuracy scale, a binary safety (safe/unsafe) scale, and attempted to identify the source (LLM versus expert) providing the response. RESULTS:GPT-4 had the highest accuracy (83%) and safety (86%) scores among LLMs but remained inferior to expert responses (92% accuracy, 93% safety). Gemini and MedLM performed significantly worse (accuracy: 64% and 35%; safety: 73% and 39%, respectively). GPT-4 generated the most guideline-concordant responses (46%) among the 3 LLMs (Gemini 35%, MedLM 14%) but was lower than expert responses (68%). Interrater reliability for accuracy ratings was higher for LLM-generated responses (GPT-4 [intraclass correlation coefficient, 0.30], Gemini [intraclass correlation coefficient, 0.61], and MedLM [intraclass correlation coefficient, 0.58]), with lower agreement for expert responses (intraclass correlation coefficient, 0.23). A similar pattern was observed for safety and source discrimination ratings. The agreement was strongest for safety assessments and weakest for source discrimination. CONCLUSIONS:Among the 3 tested LLMs, GPT-4 demonstrated closer agreement to expert decisions, thereby showing greater potential for supporting hypertension management. Despite their potential, current LLM versions are inferior to expert recommendations. Human-in-the-loop supervision remains essential when deploying LLMs for clinical decision-making.

BACKGROUND:Among hypertensive patients, plasma renin activity is lower and the response to diuretic monotherapy greater in volume responsive hypertensive patients. We hypothesized that hormones influencing extracellular volume such as vasopressin / antidiuretic hormone (ADH) might permit the development of a simple test to identify those with volume-related hypertension. Such a test might be of particular benefit to the Black population which is purported to have a higher incidence of volume-related and responsive hypertension. Thus, using copeptin, a surrogate marker for ADH, we studied if there were differences in this hormone between those with and without volume responsive hypertension. METHODS:Serum copeptin was measured in biobanked blood samples from the Genetic Epidemiology of Responses to Antihypertensives (GERA) I study and analyzed with other variables from the study dataset. RESULTS:There was no relationship between PRA and copeptin values nor could the response in blood pressure be predicted by the copeptin values. However, baseline copeptin levels were higher in Black than in White subjects (7.5 pmol/L vs 5.4 pmol/L, P < 0.001) while plasma sodium and calculated plasma osmolality were slightly lower in keeping with the concept that Black subjects have more volume-related hypertension. In addition, after hydrochlorothiazide (HCTZ), copeptin was significantly lower in Black (6.2 pmol/L, P = 0.004) but unchanged in White subjects (5.2 pmol/L, P = 0.901) and there were also changes in sodium. CONCLUSION:The current study suggests differences in ADH physiology between hypertensive Black and White patients. However, the use of copeptin to identify volume responsive patients could not be confirmed.

Background: Hypertension (HTN) affects almost half of the adults in the US, and most do not have their blood pressure (BP) under control. Minorities and individuals living in rural areas experience health disparities. The goal of this study was to assess the rate of BP control among adults in a large health system that included minorities and adults living in rural areas. Methods: Clinical cohort study of adults with HTN who live in Southeast Minnesota and had at least one outpatient clinic encounter within the Mayo Clinic Health System in the last 12 months (5/2021-5/2022). Data was extracted through the HTN registry of the electronic health record and included age, race, ethnicity, last office BP and any active anti-hypertensives drug use. Results: The overall rate of HTN control among 127,644 individuals with HTN, defined as an office BP < 130/80 mmHg, was 25.7%. The rates of BP control between HTN subjects living in rural (64527, 67.3%) versus urban areas (41285, 32.3 %), were significantly lower at 24.9% vs. 27% respectively, p< 0.001. A total of 8,722 (6.8%) were non-white, including 2640 Black, 1919 Asian, and 2867 Hispanics A total of 5,734 (45%) had a SBP ≥ 140 or DBP ≥ 90 mmHg and 7178 (12.5%) did not have any anti-hypertensives in their medication list. The percentage of White and Asian persons who were not on anti-hypertensives was 12.4% and 12.5%, respectively, while a larger percentage of Black (13.8%) and Hispanic (14%) persons were not (p<0.001). The corresponding percentage was 16.7% among individuals who did not disclose their race (p<0.001). Conclusion: Among hypertensive adults, BP was not at goal in most patients based on their most recent office BP measurement with a higher rate among those living in rural areas. About 12.5% were not on anti-hypertensives with a disproportionate larger percentage of Black and Hispanic compared to White and Asian persons.

Background: Although the role of radon gas in lung carcinogenesis is well-known, relatively little is known about radon’s role in the pathogenesis or epidemiology of cerebrovascular disease. Methods: We therefore identified postmenopausal women without a history of stroke at the 1993-1998 screening visit of the Women’s Health Initiative Clinical Trials and Observational Study (WHI CT and OS). We linked their geocoded addresses to U.S. Environmental Protection Agency (EPA)-predicted, county-level, indoor, screening radon gas concentrations classified as follows: Zone 3 (<2 pCi/L), Zone 2 (2-4 pCi/L), and Zone 1 (>4 pCi/L). We identified incident strokes based on physician-reviewed, classified, and adjudicated medical records. We measured time from screening to the earliest stroke or censoring date (02/28/20). We used Cox proportional hazards models to estimate radon-related risk of stroke on an attained-age scale as a hazard ratio (HR) and 95% confidence interval (CI), adjusting for WHI design, race/ethnicity, education, homemaker status, U.S. Census region, neighborhood socioeconomic status, smoking, alcohol intake, sodium intake (g/day), 2005 Healthy Eating Index, recreational physical activity (MET-hr/wk), body mass index (kg/m 2 ), systolic blood pressure (mm Hg), as well as history of diabetes, hypercholesterolemia, atrial fibrillation, and deep vein thrombosis/pulmonary embolism. Results: Among 158,906 women (mean, standard deviation [SD] age = 63.1 [7.2] years; 83% white; 9% black; 4% Hispanic; 4% other), we identified 6,979 incident strokes over a mean [SD] follow-up period of 9.3 [5.6] person-years, i.e. 3.41 strokes / 1,000 person-years. The proportion of women with incident stroke was 1.38%, 1.72%, and 1.30% in EPA Radon Zones 3, 2, and 1, respectively. Corresponding incidence rates by EPA Radon Zone were 3.33, 3.43 and 3.49 per 1,000 person-years. Relative to women in Zone 3, those in Zones 2 and 1 had higher adjusted risks of incident stroke: HR (95% CI) = 1.07 (1.00, 1.14) and 1.15 (1.07 , 1.24). Conclusion: Radon gas is a pervasive carcinogen that also may increase susceptibility to a societally burdensome form of cerebrovascular disease, thereby highlighting the potential value of targeted testing, radon-safe construction, and mitigation in stroke prevention.

A 73-year-old man with a history of hypertension, type 2 diabetes, atrial fibrillation, and gastroesophageal reflux disease was evaluated for recent episodes of “spells” of aphasia. He was taking metoprolol succinate, diltiazem, apixaban, atorvastatin, and omeprazole. Physical examination and a detailed neurological examination were normal. He underwent magnetic resonance angiogram of the brain and neck, which was unremarkable. Awake and sleep electroencephalogram was also normal. Echocardiogram revealed a normal ejection fraction (63%) without atrial mass or clot. Following evaluation, he was involved in a motor vehicle accident, presumably due to loss of consciousness while driving, resulting in a fractured L1 vertebra. When seen in the Emergency Department, he was noted to be in a postictal state. A diagnosis of probable focal seizure disorder was made. He received a loading dose of levetiracetam and was placed on a maintenance dose at dismissal.

Objective: Vasopressin increases water permeability and activity of the epithelial sodium channel ENaC in the distal nephron of the kidney, favoring increased water and sodium retention. We hypothesized that genetically mediated differences in circulating vasopressin concentrations could contribute to features of hypertension that vary between non-Hispanic blacks and whites. To test this hypothesis we measured copeptin, a fragment of pre-pro arginine vasopressin with a prolonged half-life that is more easily quantified. Methods: The Genetic Epidemiology of Responses to Antihypertensives (GERA) I study was designed to identify predictors of response to diuretic therapy in non-Hispanic black and non-Hispanic white adults with essential hypertension. Blood samples were obtained after a 4 week washout of anti-hypertensive medication while on a sodium intake of 2 mmol/kg. Copeptin was measured from thawed EDTA plasma samples using the copeptin proAVP homogeneous automated immunofluorescent assay on the BRAHMS Kryptor Compact PLUS (Thermo Fisher). Results: Copeptin was significantly higher in blacks (median: 7.4 pmol/L, IQR: 4.4-10.2 pmol/L) than in whites (median: 5.4 pmol/L, IQR: 3.6-8.0 pmol/L) (p <0.001), while renin was lower (Table 1). Racial differences remained significant (p = 0.001) in multivariate models that included 24 hour urine sodium excretion and calculated plasma osmolality. Conclusions: Higher copeptin (vasopressin) concentrations in non-Hispanic blacks compared to whites may contribute to the distinct differences in the hypertensive phenotypes between these racial groups. The underlying mechanism(s) require further study.

HomeHypertensionVol. 76, No. 6Uncontrolled Hypertension in an Elderly Man on Multiple Antihypertensive Drugs Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessResearch ArticlePDF/EPUBUncontrolled Hypertension in an Elderly Man on Multiple Antihypertensive Drugs Matthew R. D'Costa, Sandra J. Taler, Anna F. Dominiczak, Rhian M. Touyz, Robert M. Carey, Jan N. Basile, Michael Bursztyn, Vivek Bhalla and Gary L. Schwartz Matthew R. D'CostaMatthew R. D'Costa Correspondence to Matthew R. D'Costa, Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Email E-mail Address: [email protected] From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (M.R.D., S.J.T., G.L.S.), Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom , Sandra J. TalerSandra J. Taler From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (M.R.D., S.J.T., G.L.S.), Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom , Anna F. DominiczakAnna F. Dominiczak College of Medical, Veterinary and Life Sciences (A.F.D.), Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom , Rhian M. TouyzRhian M. Touyz BHF Glasgow Cardiovascular Research Centre (R.M.T.), Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom , Robert M. CareyRobert M. Carey Division of Endocrinology and Metabolism, University of Virginia School of Medicine, Charlottesville (R.M.C.) , Jan N. BasileJan N. Basile https://orcid.org/0000-0002-2302-7084 Division of Cardiology, Medical University of South Carolina, Ralph H Johnson VA Medical Center, Charleston (J.N.B.) , Michael BursztynMichael Bursztyn https://orcid.org/0000-0001-7239-0501 Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, IL (M.B.) , Vivek BhallaVivek Bhalla Division of Nephrology, Department of Medicine (V.B.), Stanford University School of Medicine, CA. Stanford Hypertension Center (V.B.), Stanford University School of Medicine, CA. and Gary L. SchwartzGary L. Schwartz From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (M.R.D., S.J.T., G.L.S.), Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom Originally published26 Oct 2020https://doi.org/10.1161/HYPERTENSIONAHA.120.15310Hypertension. 2020;76:1658–1663Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 26, 2020: Ahead of Print We present a case of uncontrolled hypertension in an 80-year-old White male and retired family medicine physician despite being on multiple antihypertensive drugs. The patient was a nonsmoker, nondiabetic, and had a past medical history of hypertension for 25 years, coronary artery disease with stenting 2 years before presentation, bioprosthetic aortic valve replacement for aortic stenosis, paroxysmal atrial fibrillation with a history of transient ischemic attack on clopidogrel and aspirin, chronic lymphocytic leukemia with bulky lymphadenopathy and normal leukocyte count on ibrutinib, benign prostatic hypertrophy, hyperlipidemia, and chronic kidney disease, stage 3 with a baseline creatinine of 1.3 mg/dL.His blood pressure (BP) was previously well controlled for many years on monotherapy, initially with atenolol and later with amlodipine. In 2015, he developed acute kidney injury with a peak creatinine of 2.5 mg/dL in the setting of sepsis due to aspergillosis. Amlodipine was stopped during that episode. His kidney function eventually recovered to baseline. He was then placed on lifelong posaconazole prophylaxis.BP was controlled with lifestyle factors only over the next 2 years until 2017 after which home and clinic readings began ranging from 130 to 180/60 to 80 mm Hg with headaches associated with higher readings. For the worsening hypertension, he was treated with an escalating antihypertensive drug regimen. He was initiated on losartan 50 mg daily, and then metoprolol tartrate 25 mg twice daily was added. Initially, BP control improved, and then 3 months before our evaluation the hypertension worsened with more frequent headaches. HCTZ (hydrochlorothiazide) 25 mg daily and amlodipine 2.5 mg daily were added. Subsequently, the patient developed lower extremity edema. He was prescribed furosemide 40 mg daily as needed, and he reported taking it twice weekly. BP remained uncontrolled, and we were consulted for further management.Upon evaluation in our clinic, the patient had no new concerns other than what was previously mentioned. Home BP readings were reviewed and were consistent with prior reports of suboptimal control. Average office BP using the BPTru device was 144/77 mm Hg. BPs were equal in both arms. A standing BP was also elevated at 142/74 mm Hg. Pulse was 62 beats per minute, and body mass index was 28 kg/m2 with a weight of 70 kg, which had been stable over the previous 2 years. On physical exam, he was alert and appeared younger than stated age. He had a benign funduscopic exam. His cardiac exam revealed a low-grade systolic murmur over the aortic area, and he had a significant amount of pitting edema in both lower extremities as well as the right upper extremity some of which was chronic in the setting of chronic lymphocytic leukemia and associated bulky lymphadenopathy and lymphedema. His lungs were clear except for chronic changes in the right lung base from the prior pneumonia from aspergillosis. His abdomen was soft with no bruits, masses, or organomegaly, and his pulses were normal.After being presented with this information, what are the initial thoughts and considerations in this patient with uncontrolled hypertension?DiscussionProfessor Touyz: Are there any comments in terms of the uncontrolled hypertension? And if I just recall, this has been over the previous two years, correct? During this time, was he given any other medication other than the changes in antihypertensive?Dr D'Costa: That is correct, and no other changes to his medications were made.Dr Carey: The definition of resistant hypertension requires optimal dosing; that is, maximal or maximally tolerated dosing. I think this gentleman was under-treated at least as presented up to this time. In addition, it would have been appropriate to use a thiazide-like diuretic such as chlorthalidone or indapamide instead of hydrochlorothiazide in the regimen.Dr D'Costa: Agreed. Does this patient on multiple antihypertensive drugs with uncontrolled hypertension, meet the definition of resistant hypertension?Resistant HypertensionAs previously stated, there are specific criteria that must be met to reach the threshold of resistant hypertension (Figure 2). These criteria include (1) BP above 130/80 mm Hg in most cases,1 despite the use of 3 antihypertensive drug classes, which typically includes a combination of various first-line agents for hypertension including a long-acting diuretic, calcium channel blocker, and ACE (angiotensin-converting enzyme) inhibitor or ARB (angiotensin receptor blocker); (2) BP is at goal on ≥4 antihypertensive medications.2,3 In either case, the antihypertensive agents should be prescribed at the highest tolerated daily doses. The diagnosis of resistant hypertension requires exclusion of pseudoresistance which includes accurate BP measurement, medication adherence, and exclusion of white-coat hypertension with assessment and comparison of in-office and ambulatory readings.3Download figureDownload PowerPointFigure 2. The evaluation of resistant hypertension. NSAIDs indicates nonsteroidal anti-inflammatory drugs; and VEGF, vascular endothelial growth factor. Adapted from Calhoun et al2 Copyright ©2008, Wolters Kluwer Health, Inc. Adapted from Carey et al3 with permission. Copyright ©2018, Wolters Kluwer Health, Inc.With these factors in mind, we reviewed the patient's antihypertensive regimen. In summary, the patient was prescribed losartan 50 mg daily, metoprolol tartrate 25 mg twice daily, hydrochlorothiazide 25 mg daily, amlodipine 2.5 mg daily, and furosemide 40 mg daily as needed for lower extremity edema. Losartan and amlodipine were prescribed at submaximal doses, and hydrochlorothiazide is not the preferred thiazide-type diuretic in uncontrolled hypertension. While he is on a low dose of metoprolol tartrate, he may not tolerate a higher dose due to bradycardia given his resting heart rate of 62 beats per minute in the clinic. Furosemide was only prescribed as needed. Given these factors alone, he would not meet the definition of resistant hypertension. However, using the guidelines for the evaluation of resistant hypertension as a template would allow us to better determine the cause of the patient's uncontrolled hypertension. To assess the possibility of pseudoresistance, we reviewed the accuracy of the home BP measurement technique. The patient measured his BP 1 to 3 times per day. He used an automated, upper arm cuff of appropriate size with accuracy verified manually by his wife, a registered nurse, within 5 mm Hg on multiple readings. We then assessed the patient's adherence and determined that the patient was not taking hydrochlorothiazide or amlodipine. Upon further questioning, he reported taking hydrochlorothiazide until furosemide was prescribed for lower extremity edema after which he stopped taking hydrochlorothiazide and was taking furosemide 40 mg daily twice per week. The patient was not taking amlodipine due to concern for drug interaction with posaconazole and was only using it as needed when BPs exceeded 170/90 mm Hg.The patient's in-office, home, and 24-hour ambulatory BP (Figure 1) readings were then reviewed. As noted previously, BP was uncontrolled in-office and at home. The 24-hour ambulatory monitor revealed sustained hypertension with average daytime readings 159/80 mm Hg and nondipping with elevated nocturnal BP of 152/75 mm Hg. Average heart rate was 57 beats per minute.Download figureDownload PowerPointFigure 1. Twenty-four-hour ambulatory blood pressure monitor. The ambulatory monitor reveals elevated daytime (orange boxes) and nocturnal (green box) readings with average blood pressures of 159/80 and 152/75 mm Hg, respectively. Insufficient dipping at night is also noted.DiscussionDr Basile: Did you directly give him this regimen? I think losartan once a day is not as effective and the preferred regimen would be 50 mg twice daily. I note that he is on HCTZ with a creatinine of 1.3 but we do not know his glomerular filtration rate as of yet, and he has significant edema, which seems out of proportion for amlodipine 2.5 mg daily. It may not be ideal that his antihypertensive regimen is taken all in the morning, and I would have had the patient undergo directly supervised therapy with my nurse. Directly observed therapy (DOT) I think is key, even before primary care physicians refer these patients as resistant because we have to rule out nonadherence before patients can be considered resistant. We love our patients and they are good people, but they sometimes do not take their medicine as written. And, as Dr Schwartz noted, our own patient decided not to take amlodipine and he stopped HCTZ with furosemide being taken only twice a week.Dr Schwartz: Maybe I could just make a comment. We routinely evaluate patients with resistant hypertension on multiple medications, and it seems pretty obvious to us that despite patients telling us they are adherent, they often are not taking their medications as prescribed. For these patients, we do have a protocol utilizing a 48-hour ambulatory monitor. In the first 24 hours, the patient takes their medications at home, and during the second 24-hour period, we supervise medication administration in the clinic with the assistance of our specialized nurses. I must say that some of the patients we evaluate in this setting are on unbelievable regimens, with seven or eight antihypertensive drugs prescribed at full doses all taken in the morning in one fell swoop. In some instances, we have seen significant hypotension occur when administering their prescribed regimen. Given this potential risk, we often give their medications in a stepwise manner including half doses and only some of their prescribed medications in the morning while monitoring their response.Dr Basile: Yes, and when administering supervised, I would not let patients come to the office without someone that can drive them home because of the possibility of hypotension now that they are taking their antihypertensives.Assessment of Associated Conditions and Causes of HypertensionAfter discovering medication nonadherence as a main contributor to the patient's uncontrolled hypertension, we were still concerned due to the presence of worsening hypertension over the past 2 years when it was previously well controlled on monotherapy. Therefore, we assessed potential associated conditions and identifiable causes of hypertension. Regarding lifestyle factors, the patient is physically active going to the gym 3 to 4 times per week at least 30 minutes per session, including use of a treadmill and light weights. He maintains a low-sodium diet and has not >1 to 2 alcoholic beverages per week. The patient reported not taking any over the counter medications including avoidance of nonsteroidal anti-inflammatory drugs and herbal supplements. His wife was not concerned regarding the possibility of sleep apnea including no witnessed apneic episodes or loud snoring.The patient has a history of chronic kidney disease with serum creatinine of 1.3 mg/dL. By the Modification of Diet in Renal Disease equation, the estimated glomerular filtration rate (eGFR) would be 52 mL/min. Given that this gentleman is 80 years old, and he has multiple comorbidities, we obtained a serum Cystatin C measurement to provide an additional marker of kidney function that is not dependent on muscle mass. eGFR by cystatin C was 27 mL/min, which is much lower than what was predicted by serum creatinine. In this patient, we ultimately used eGFR by Chronic Kidney Disease Epidemiology Collaboration 2012 equation, and his glomerular filtration rate was 36 mL/min. Given these findings, the patient has chronic kidney disease stage 3B to 4. Urinalysis and albumin/creatinine ratio were within normal limits. Serum electrolytes were normal including normal serum potassium levels, and he had no prior history of recurrent metabolic acidosis or alkalosis.In further evaluation of secondary causes for hypertension, we obtained a renal ultrasound with renal artery dopplers, which revealed mildly echogenic kidneys but no evidence of renal artery stenosis. Plasma renin activity and serum aldosterone levels were suppressed at <0.6 ng/mL per hour and <4.0 ng/dL, respectively. Given the findings of edema and suppressed renin and aldosterone, we suspected volume expansion was contributing to his uncontrolled hypertension. The patient had normal serum glucose so we did not assess for Cushing syndrome, and the history was not consistent with pheochromocytoma/paraganglioma thus further workup was not obtained for those conditions.At this point, we would like further discussion from the audience regarding the workup we obtained as well as thoughts regarding other potential interfering substances including posaconazole and ibrutinib as possible contributors to his hypertension.DiscussionDr Bursztyn: While I am not particularly familiar with this specific medication, -azole medications in general are strong inhibitors of the cytochrome P450 system so they can affect the variety of other drugs and also potentially endogenous metabolism of endogenous substances. I would like to comment about the previous workup. I think that in someone with low renin and no response to losartan, seeking renal artery stenosis is a futile maneuver.Dr D'Costa: Thank you for your comments.Dr Bhalla: As you know, posaconazole is associated with low renin and low aldosterone-mediated hypertension. Given this patient's suppressed renin and aldosterone levels, posaconazole could certainly be contributing to uncontrolled hypertension. Two factors argue against this. One is the lack of concominant hypokalemia and metabolic alkalosis. However, these metabolic derangements may be masked by the depressed glomerular filtration rate or the use of losartan. Two, in the case series that have been published on posaconazole-mediated hypertension, the level of serum posaconazole is an important factor. I do not recall when this gentleman was first prescribed posaconazole, but a newer formulation by Merck that was released in approximately 2015. This new formulation has a higher bioavailability, and consequently, higher serum levels, and thus, posaconazole-mediated hypertension has been more frequently reported since then.Dr D'Costa: We agree with your statements and will be discussing the possibility of hypertension associated with posaconazole in this patient. To clarify, he was placed on posaconazole in 2015 after he developed aspergillosis thus, it is likely he is on the newer formulation.Dr Dudenbostel: Most of my questions are addressed, but could you comment on the interaction of posaconazole with the mineralocorticoid receptor.Dr D'Costa: Yes, Thank you. We will be discussing that.Dr Lee: I am concerned about Ibrutinib. It has been reported to increase the incidence of BP in 40% of the patients.Dr D'Costa: Thank you and we agree that ibrutinib is also a potential contributor to his hypertension.Potential Causes of Drug-Induced Hypertension: Posaconazole and IbrutinibTo review, posaconazole is a triazole antifungal agent used to treat invasive fungal infections in immunocompromised hosts. Posaconazole is a strong inhibitor of the cytochrome P450 system and drug-drug interactions should be assessed when patients are on this medication.4,5 As an example, the effect of amlodipine would significantly increase in the setting of posaconazole which was of significant concern for our patient. Posaconazole is associated with potentially serious side effects including a syndrome of mineralocorticoid excess manifested by worsening hypertension and hypokalemia along with low renin and aldosterone. This likely occurs by inhibition of 11β hydroxylase leading to the accumulation of the mineralocorticoid hormone 11-deoxycorticosterone as well as inhibition of 11β hydroxysteroid dehydrogenase type 2.6 This side effect may be more common at higher drug levels. The patient was noted to have stable, therapeutic levels while on treatment.The other possible contributor to this patient's hypertension is ibrutinib. Ibrutinib is an oral inhibitor of Bruton's tyrosine kinase, which is also known as agammaglobulinemia tyrosine kinase. This enzyme was originally identified in patients with X-linked agammaglobulinemia and is predominantly expressed in B-lymphocytes but also expressed in other cells, such as macrophages. It is involved in cell receptor signaling, B-cell proliferation, survival differentiation, and motility as well as cytokine production and angiogenesis.7 Ibrutinib has shown significant efficacy in clinical trials leading to increased use over time.7 Ibrutinib is commonly associated with cardiac side effects including atrial fibrillation, as well as worsening hypertension and edema. The incidence of new-onset hypertension ranges from 5% to 14% in the first 1 to 2 years of therapy and up to a third of patients at 5 years especially in those with associated risk factors, including older age, male sex, and duration of drug administration.7 The mechanisms of why this agent is associated with hypertension is not entirely clear. VEGF (Vascular endothelial growth factor) inhibitors are commonly associated with hypertension and worsening edema, and while ibrutinib is not directly involved in these pathways, it may lead to decreased vascular endothelial growth factor expression and worsening hypertension.8 Ibrutinib has been shown to impair nitric oxide production, which may lead to peripheral vasoconstriction and worsening hypertension.9 Finally, ibrutinib has also been implicated in renal dysfunction. Manohar et al10 published a case series of 2 patients that develop increasing creatinine on ibrutnib with biopsy-proven acute tubular injury and fibrosis. Posaconazole is also known to increase levels of ibrutinib, and the patient was on a reduced dose-frequency with preserved efficacy. It is unclear if posaconazole would potentiate the potential side effects of ibrutinib as well.Hypertension ManagementIn this elderly gentleman with uncontrolled hypertension and edema, the main culprits were nonadherence, suboptimal drug regimens, volume excess, chronic kidney disease, and potentially ibrutinib and less likely posaconazole.To address the patient's nonadherence, we focused on patient education. This was a very well educated and reasonable gentleman, and we had a long discussion about the pharmacokinetics of the medications and the ineffectiveness of taking amlodipine as needed, for example. In addition, we discussed the importance of mutual decision making and open communication with adjustments of medications. We discussed the potential benefits of initiating a regimen, including daily amlodipine, but he was not willing to do this initially because of the potential significant drug interaction with posaconazole. Given the fact that the patient had volume excess on exam as well as suppressed renin and aldosterone, we elected to reinstitute a diuretic. The patient was willing to resume hydrochlorothiazide at 25 mg daily. Due to the sustained, nondipping nocturnal hypertension, we changed losartan to be taken at night.Follow-up BPs in the clinic ranged from 130 to 142/60 to 70 mm Hg with one standing BP of 120/62 mm Hg with similar readings reported at home. At this point, we would like to open up discussion regarding the management and outcomes in this patient.DiscussionDr Bursztyn: I would say generally speaking, losartan and beta-blockade is an ineffective combination. Some other type of combination should have been tried. It seems fortunate that standard dose of hydrochlorothiazide was helpful in the setting of reduced glomerular filtration rate level, but one does not argue with the reality.Professor Dominiczak: Could I add to this? I think going back to add a diuretic in this situation seems strange. It might work for a few months, but there will be a problem the underlying etiology of this patient's hypertension and edema may progress.Dr Hamrahian: I argue against the drug interactions. I think this patient was not well managed initially, and we heard that the definition of resistant hypertension was not met. The regimen was inappropriate. The patient adherence was poor. In summary, this patient was on a suboptimal losartan dose, which in my opinion is the weakest ARB as well as hydrochlorothiazide 25 mg and short-acting metoprolol which very few of the nephrologists in the room would use in controlling BP. This does not seem to be a case of resistant hypertension, and there was concern for a specific drug interaction.Dr Byrd: It certainly seems as though this patient was volume overloaded, but I did just want to make the following point. I think it is underappreciated that data from radiolabeled albumin studies of patients with essential hypertension, revealed that essential hypertension is often a volume-depleted state when assessed in that way. This is something to bear in mind.Dr Jennings: I have a question. Is his edema better or worse now that you have changed his medication? I ask because we attributed the edema to amlodipine, and he was not actually taking that. In addition, as he needed intermittent loop diuretic therapy this seems to be setting him up for cyclical edema and a sodium avid state.Dr D'Costa: We agree with the audience that this was not a case of resistant hypertension as we had mentioned earlier, and it is unlikely that posaconazole is playing a role. These were mainly talking points for discussion. We also agree that various regimens could have been attempted including increasing losartan, changing hydrochlorothiazide to chlorthalidone, changing metoprolol to another agent, among others. Finally, we did not resume as needed furosemide.Dr Jennings: And just in terms of my original question did the edema go away when you resumed hydrochlorothiazide?Dr D'Costa: Not at this point in time, no.Dr Basile: In patients that I have treated like this, I have called the infectious disease specialist and the oncologist and inquired about the patient's prognosis and how long the patient needs to be in these agents. Also, with the posaconazole would he benefit from a little spironolactone? I think I could be happy with these BP for the rest of his life, but I do not know if we are addressing the posaconazole side effect or if ibrutinib is the best option for him.Dr D'Costa: We do not know exactly the mechanisms as to why it causes hypertension, but it is possible that diuretics and calcium channel blockers and other vasodilators may be beneficial. As previously stated, the patient was not interested in amlodipine or an equivalent but we considered them. As for the treatment of his chronic lymphocytic leukemia, ibrutinib seemed to be the most efficacious and seemingly well-tolerated option for him at this point so he continued on that agent. Certainly, spironolactone may be an option for this patient as well, but we wanted to initiate a diuretic first and monitor his response.Dr Carey: I agree with Dr Basile that this is a problem of multiple interacting disorders requiring physician judgment, patient discussion and shared decision making in terms of which is the most important. From a strict hypertension standpoint, according to our recent guideline, the BP remains out of control. And we have reasonably good evidence in ambulatory, free-living older adults with eGFR in this range and absence of major comorbidities that the systolic BP target should be <130 mm Hg.1Dr Schwartz: There has been a lot of discussion. We tend to talk about BP as a dichotomous variable. It is either controlled or it is not controlled, and I completely disagree with that sort of thinking at the individual patient level. There is a range of control levels in my view. As an example, if BP is taken down from 180/110 to 140/90 in an individual, you have reduced that individual's risk from hypertension remarkably. Is there still a little risk for that individual left on the table? Perhaps, but you have done a lot of good for that patient, and this is where a conversation with the patient and shared decision making comes into play especially in a patient that is 80 years old with multiple comorbidities. As you can tell by the presentation, he was very nervous about these medicines and how he took them. Therefore, he might be very comfortable with a BP of 136/74, and although it does not meet the guidelines for control, it is reasonably well controlled when these other factors are accounted for. The risk that is left on the table for this patient is quite small, and his other comorbidities are arguably more significant than mildly uncontrolled hypertension. Thus, I would say his BP is controlled to a certain level. I prefer that phraseology.Dr Carey: Yes. I totally agree. I do think there is residual risk related to multiple different entities in this patient.Professor Touyz: At this point, we will wrap-up this conference. I would like to thank our two speakers, the participation by the audience, and this closes the session, thank you.SummaryThe evaluation of uncontrolled hypertension includes the determination of whether the criteria for resistant hypertension are met which includes ruling out pseudoresistant hypertension. This may uncover significant nonadherence which is a common cause of uncontrolled hypertension. Even when resistant hypertension is not present, the principles of evaluation of this disorder are helpful in many cases of uncontrolled hypertension and will assist with management. The evaluation may identify potential contributing factors of uncontrolled hypertension including newer medications for which hypertension is a common side effect. Posaconazole may cause a mineralocorticoid-excess syndrome with hypertension and hypokalemia. Ibrutinib may also lead to worsening hypertension through various mechanisms.AcknowledgmentsWe are grateful to the following session audience members for contributing to the discussion: Tanja Dudenbostel, Michael Wing-Khiang Lee, Seyed Hamrahian, J. Brian Byrd, and Garry Jennings.Sources of FundingNone.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.The following case was presented on September 7, 2019, as part of the Clinical-Pathological Conference chaired by Anna F. Dominiczak and Rhian M. Touyz at the Hypertension 2019 Scientific Sessions in New Orleans, LA. Matthew R. D'Costa and Gary L. Schwartz presented the case and led the discussion.Correspondence to Matthew R. D'Costa, Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Email [email protected]comReferences1. Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, et al.. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.Hypertension. 2018; 71:e13–e115. doi: 10.1161/HYP.0000000000000065LinkGoogle Scholar2. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, et al.; American Heart Association Professional Education Committee. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.Circulation. 2008; 117:e510–e526. doi: 10.1161/CIRCULATIONAHA.108.189141LinkGoogle Scholar3. Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison-Himmelfarb CR, Egan BM, Flack JM, Gidding SS, Judd E, et al.; American Heart Association Professional/Public Education and Publications Committee of the Council on Hypertension; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Genomic and Precision Medicine; Council on Peripheral Vascular Disease; Council on Quality of Care and Outcomes Research; and Stroke Council. Resistant hypertension: detection, evaluation, and man-agement: a scientific statement from the American Heart Association.Hypertension. 2018; 72:e53–e90. doi: 10.1161/HYP.0000000000000084LinkGoogle Scholar4. Andes D, Azie N, Yang H, Harrington R, Kelley C, Tan RD, Wu EQ, Franks B, Kristy R, Lee E, et al.. Drug-drug interaction associated with mold-active triazoles among hospitalized patients.Antimicrob Agents Chemother. 2016; 60:3398–3406. doi: 10.1128/AAC.00054-16CrossrefMedlineGoogle Scholar5. Moore JN, Healy JR, Kraft WK. Pharmacologic and clinical evaluation of posaconazole.Expert Rev Clin Pharmacol. 2015; 8:321–334. doi: 10.1586/17512433.2015.1034689CrossrefMedlineGoogle Scholar6. Boughton C, Taylor D, Ghataore L, Taylor N, Whitelaw BC. Mineralocorticoid hypertension and hypokalaemia induced by posaconazole.Endocrinol Diabetes Metab Case Rep. 2018; 2018:17-0157. doi: 10.1530/EDM-17-0157MedlineGoogle Scholar7. Brown JR. How I treat CLL patients with ibrutinib.Blood. 2018; 131:379–386. doi: 10.1182/blood-2017-08-764712CrossrefMedlineGoogle Scholar8. Wasserstrum Y, Kornowski R, Raanani P, Leader A, Pasvolsky O, Iakobishvili Z. Hypertension in cancer patients treated with anti-angiogenic based regimens.Cardio-Oncology. 2015; 1:6CrossrefMedlineGoogle Scholar9. Stiff A, Trikha P, Wesolowski R, Kendra K, Hsu V, Uppati S, McMichael E, Duggan M, Campbell A, Keller K, et al.. Myeloid-derived suppressor cells express Bruton's tyrosine kinase and can be depleted in tumor-bearing hosts by ibrutinib treatment.Cancer Res. 2016; 76:2125–2136. doi: 10.1158/0008-5472.CAN-15-1490CrossrefMedlineGoogle Scholar10. Manohar S, Bansal A, Wanchoo R, Sakhiya V, Lucia S, Jhaveri KD. Ibrutinib induced acute tubular injury: a case series and review of the literature.Am J Hematol. 2019; 94:e223–e225. doi: 10.1002/ajh.25546CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByDominiczak A and Meyer T (2020) Hypertension, Hypertension, 77:1, (4-5), Online publication date: 1-Jan-2021. December 2020Vol 76, Issue 6Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.120.15310PMID: 33100046 Originally publishedOctober 26, 2020 PDF download Advertisement

Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D-5 receptor (D5R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1(-/-) mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT(1)R), NADPH oxidase (NOX) subunits, D5R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1(-/-) mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D5R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D5R agonist-induced increase in cAMP production and decrease in Na+ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.

BACKGROUND Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood. METHODS Using systematic-phased approach, PRA's clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed. RESULTS EAs with PRA < 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by -15.9 mm Hg, adjusted P < 0.0001), whereas those with PRA >= 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA >= 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%. CONCLUSIONS PRA at the previously established 0.60-0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs.

Despite the availability of many antihypertensive drug classes, half of patients with hypertension have uncontrolled blood pressure ( BP ). The authors sought to assess the effect of age on BP response in European American and African American patients with hypertension. Clinic BP from the PEAR 2 (Pharmacogenomics Evaluation of Antihypertensive Responses 2) study was used to estimate BP responses from baseline following sequential treatment with metoprolol 100 mg twice daily and chlorthalidone 25 mg daily for 8 to 9 weeks each, with a minimum 4‐week washout between treatments. BP responses to both drugs were compared in 159 European Americans and 119 African Americans by age with adjustment for baseline BP and sex. European Americans younger than 50 years responded better to metoprolol than chlorthalidone (diastolic BP : −9.6 ± 8.0 vs −5.9 ± 6.8 mm Hg, adjusted P = .003), whereas patients 50 years and older responded better to chlorthalidone than metoprolol (systolic BP : −18.7 ± 13.8 vs −13.6 ± 14.8 mm Hg, adjusted P = .008). African Americans younger than 50 years responded similarly to both drugs, whereas those 50 years and older responded better to chlorthalidone than metoprolol (−17.0 ± 13.2/−9.6 ± 7.5 vs −7.0 ± 18.6/−6.7 ± 9.3 mm Hg, adjusted P <.0001/.008). Therefore, age should be considered when selecting antihypertensive therapy in European and African American populations with hypertension.