Exposure to Stress Alters Cardiac Gene Expression and Exacerbates Myocardial Ischemic Injury in the Female Murine Heart.

Mental stress is a risk factor for myocardial infarction in women. The central hypothesis of this study is that restraint stress induces sex-specific changes in gene expression in the heart, which leads to an intensified response to ischemia/reperfusion injury due to the development of a pro-oxidative environment in female hearts. We challenged male and female C57BL/6 mice in a restraint stress model to mimic the effects of mental stress. Exposure to restraint stress led to sex differences in the expression of genes involved in cardiac hypertrophy, inflammation, and iron-dependent cell death (ferroptosis). Among those genes, we identified tumor protein p53 and cyclin-dependent kinase inhibitor 1A (p21), which have established controversial roles in ferroptosis. The exacerbated response to I/R injury in restraint-stressed females correlated with downregulation of p53 and nuclear factor erythroid 2-related factor 2 (Nrf2, a master regulator of the antioxidant response system-ARE). S-female hearts also showed increased superoxide levels, lipid peroxidation, and prostaglandin-endoperoxide synthase 2 (Ptgs2) expression (a hallmark of ferroptosis) compared with those of their male counterparts. Our study is the first to test the sex-specific impact of restraint stress on the heart in the setting of I/R and its outcome.

An Update on Refractory Hypertension.

PURPOSE OF REVIEW: To update on definition, diagnosis, prevalence, patient characteristics, pathophysiology, and treatment of refractory hypertension (RfHTN). RECENT FINDINGS: Refractory hypertension (RfHTN) is defined as blood pressure (BP) that is uncontrolled despite using ≥ 5 antihypertensive medications of different classes, including a long-acting thiazide diuretic and a mineralocorticoid receptor antagonist (MRA) at maximal or maximally tolerated doses. This new phenotype is different from resistant hypertension (RHTN), defined as BP that is uncontrolled despite using ≥ 3 medications, commonly a long-acting calcium channel blocker (CCB), a blocker of the renin-angiotensin system (angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB]), and a diuretic. The RHTN phenotype includes controlled RHTN, BP that is controlled on 4 or more medications. RfHTN is largely attributable to increased sympathetic activity, unlike RHTN, which is mainly due to increased intravascular fluid volume frequently caused by hyperaldosteronism and chronic excessive sodium ingestion. Compared to those with controlled RHTN, patients with RfHTN have a higher prevalence of target organ damage and do not have elevated aldosterone levels. Ongoing clinical trials are assessing the safety and efficacy of using devices to aid with BP control in patients with RfHTN. RfHTN is a separate entity from RHTN and is generally attributable to increased sympathetic activity.

Daily 100% watermelon juice consumption and vascular function among postmenopausal women: A randomized controlled trial.

BACKGROUND AND AIMS: Watermelon juice is a rich food source of cardioprotective compounds such as arginine, citrulline, and lycopene. Preventative interventions are warranted as risk of cardiovascular disease increases among women after menopause, and age alone is an independent risk factor for vascular dysfunction. Thus, this study evaluated the effects of 100% watermelon juice on measures of vascular function. METHODS AND RESULTS: In this randomized, double-blind, placebo-controlled, crossover trial, 21 healthy postmenopausal women were randomized to consume two 360 mL servings of 100% watermelon juice per day or an isocaloric placebo for four weeks. Following a two-week washout period, they consumed the other beverage for an additional four weeks. Before and after each treatment arm, a fasting blood sample was taken for measurement of serum arginine, citrulline, lycopene, glucose, and insulin. Assessments of vascular function included pulse pressure, pulse wave velocity, 24-h ambulatory blood pressure, and flow-mediated dilation. General linear mixed models with intent-to-treat analyses were used to examine the effects of the intervention. Despite a significant treatment effect for circulating lycopene (p = 0.002), no changes in arginine, citrulline, or any vascular measures were observed. Although the juice intervention resulted in a slight but significant increase in fasting serum glucose (p = 0.001), changes in glucose homeostasis were not clinically significant. CONCLUSION: In contrast to findings from previous studies in younger adults and those with pre-existing hypertension, measures of vascular function in this cohort of healthy postmenopausal women were not impacted by supplemental watermelon juice. CLINICALTRIALS. GOV IDENTIFIER: NCT03626168.

Watermelon Juice: a Novel Functional Food to Increase Circulating Lycopene in Older Adult Women.

Because of accruing oxidative stress with advancing age, older adults may benefit from increased dietary intake of lycopene, a lipophilic carotenoid with potent antioxidant properties. Yet, intake of dietary lycopene as well as circulating lycopene levels are known to decrease with aging. Watermelon is one of the few food sources of dietary lycopene. Because heat treatment increases lycopene bioavailability, ingestion of watermelon in pasteurized juice form may be an optimal delivery vehicle to increase lycopene levels in older adults. However, due to its lipophilic nature, there are concerns that co-ingestion of dietary fat may be necessary for efficient intestinal absorption of lycopene. Thus, this feasibility study aimed to examine the effects of a one-time dose of 100% pasteurized watermelon juice on circulating lycopene concentrations of postmenopausal women after a 10-h overnight fast. Blood was sampled from eight women before and 2 h after ingestion of 360 ml of juice, and serum lycopene was measured by ultra-high performance liquid chromatography. Circulating lycopene levels increased by three-fold (p < 0.001) with increases observed for every participant. Results demonstrate that 100% watermelon juice is a palatable, effective means of increasing serum lycopene in older adult women, a group at risk for low carotenoid intake. Trial registration: Clinicaltrials.gov identifier: NCT03608254 .

Adverse cardiac remodeling is absent in patients with true controlled resistant hypertension.

Resistant hypertension (RHTN), defined as blood pressure (BP) that is uncontrolled with ≥3 medications, including a long-acting thiazide diuretic, also includes a subset with BP that is controlled with ≥4 medications, so-called controlled RHTN. This resistance is attributed to intravascular volume excess. Patients with RHTN overall have a higher prevalence of left ventricular hypertrophy (LVH) and diastolic dysfunction compared to patients with non-RHTN. We tested the hypothesis that patients with controlled RHTN due to the intravascular volume excess have higher left ventricular mass index (LVMI), higher prevalence of LVH, larger intracardiac volumes, and more diastolic dysfunction compared to patients with controlled non-resistant hypertension (CHTN), defined as BP controlled with ≤3 anti-hypertensive medications. Patients with controlled RHTN (n = 69) or CHTN (n = 63) who were treated at the University of Alabama at Birmingham were offered enrollment and underwent cardiac magnetic resonance imaging. Diastolic function was assessed by peak filling rate, time needed in diastole to recover 80% of stroke volume, E:A ratios and left atrial volume. LVMI was higher in patients with controlled RHTN (64.4 ± 22.5 vs 56.9 ± 11.5; P = .017). Intracardiac volumes were similar in both groups. Diastolic function parameters were not significantly different between groups. There were no significant differences in age, gender, race, body mass index, dyslipidemia between the two groups. The findings show that patients with controlled RHTN have higher LVMI, but comparable diastolic function to those of patients with CHTN.

Paradoxical Increase of 24-Hour Urinary Aldosterone Levels in Obese Patients With Resistant Hypertension on a High Salt Diet.

BACKGROUND: Having previously reported that aldosterone levels increase progressively with body mass index (BMI), the current analysis was done to determine to what extent this association is related to dietary high salt intake. We anticipated that aldosterone levels would decrease with higher sodium status consistent with classical suppression of aldosterone release secondary to progressive fluid retention induced by high dietary sodium intake. METHODS: Cross-sectional analysis of a large diverse cohort of 2,705 patients with resistant hypertension (HTN) seen in a referral HTN Clinic. Dietary sodium intake was indexed by 24-hour (h) urinary sodium (UNa), aldosterone status was determined by plasma aldosterone concentration, plasma renin activity, and 24 h urinary aldosterone (UAldo). Patients with normal weight served as control. RESULTS: In this study, 1,572 individuals with complete 24 h urine collections were analyzed. Mean BMI was 32.5 ± 7.1 kg/m2 and ranged from 24.6 ± 2.4 kg/m2 (first quartile) to 41.0 ± 4.2 kg/m2 (fourth quartile). BMI was positively associated with 24 h UNa and UAldo levels (P < 0.0001), 24 h UNa and UAldo. There was a positively stronger correlation in obese (r = 0.273, P < 0.0001) compared with normal weight individuals (r = 0.108, P = 0.0342) independent of number and classes of antihypertensive medications. CONCLUSIONS: Our analysis shows that there is an altered regulation of aldosterone in obese patients in the setting of high dietary salt intake.

100% Watermelon Juice as a Food-First Intervention to Improve Cognitive Function: Ancillary Findings from a Randomized Controlled Trial.

Lycopene exhibits neuroprotective properties due to its antioxidant and anti-inflammatory functionality. As watermelon is a rich source of lycopene, pasteurized watermelon juice provides lycopene in its most bioavailable form. This study examined relationships between circulating lycopene, cognitive performance, and biomarkers of oxidative stress and inflammation in response to pasteurized 100% watermelon juice supplementation. A placebo-controlled, randomized, double-blind, crossover trial was conducted with postmenopausal women (n = 16, 60 + 4.1 years). Participants consumed two 360 mL servings of pasteurized 100% watermelon juice or a placebo beverage for 4 weeks. Fasting blood samples were collected, and cognitive tests were administered to assess various neurocognitive domains. Statistical analyses included mixed models and Spearman correlations. Serum lycopene exhibited a significant treatment effect (p = 0.002) with a mean increase of 81%. However, this increase was not associated with changes in oxidative stress, inflammation, or cognitive function. Additional research is warranted to determine dose-durational effects for promoting cognition.

Masked Uncontrolled Hypertension Is Accompanied by Increased Out-of-Clinic Aldosterone Secretion.

Masked uncontrolled hypertension (MUCH) in treated patients is defined as controlled office blood pressure (BP) but uncontrolled out-of-clinic ambulatory BP. Previously, we have shown that patients with MUCH have evidence of heightened out-of-clinic sympathetic nervous system activity. The aim is to test the hypothesis that MUCH patients have higher aldosterone secretion compared with patients with true controlled hypertension. Two hundred twenty-two patients were recruited after having controlled office BP readings at ≥3 clinic visits. Patients taking MR (mineralocorticoid receptor) antagonists and epithelial sodium channel blockers were excluded. All patients were evaluated by clinic automated office BP and morning serum aldosterone and plasma renin activity. Out-of-clinic ambulatory BP monitoring and 24-hour urinary aldosterone, catecholamines, and metanephrines were also measured. Sixty-four patients had MUCH, and the remaining 48 patients had true controlled hypertension. MUCH patients had significantly higher out-of-clinic levels of 24-hour urinary aldosterone, catecholamines, and metanephrines compared with true controlled hypertension. The 2 groups did not differ in serum aldosterone, plasma renin activity, or aldosterone-renin ratio collected in clinic. In addition, 32.8% of MUCH patients had high out-of-clinic 24-hour urinary aldosterone (≥12 µg) but normal clinic serum aldosterone (<15 ng/dL) and aldosterone-renin ratio (<20). Further, in correlation matrix analysis, higher 24-hour urinary catecholamines and metanephrines were associated with higher 24-hour urinary aldosterone and plasma renin activity levels in MUCH patients. Patients with MUCH have higher out-of-clinic urinary aldosterone levels compared with patients with true controlled hypertension. This study suggests that patients with MUCH likely have higher out-of-clinic sympathetic nervous system tone increases aldosterone secretion mediated by increased renin release that may contribute to their higher out-of-clinic BP.

Effect of Serum Urate Lowering With Allopurinol on Blood Pressure in Young Adults: A Randomized, Controlled, Crossover Trial.

OBJECTIVE: To determine whether serum urate reduction with allopurinol lowers blood pressure (BP) in young adults and the mechanisms mediating this hypothesized effect. METHODS: We conducted a single-center, randomized, double-blind, crossover clinical trial. Adults ages 18-40 years with baseline systolic BP ≥120 and <160 mm Hg or diastolic BP ≥80 and <100 mm Hg, and serum urate ≥5.0 mg/dl for men or ≥4.0 mg/dl for women were enrolled. Main exclusion criteria included chronic kidney disease, gout, or past use of urate-lowering therapies. Participants received oral allopurinol (300 mg daily) or placebo for 1 month followed by a 2-4 week washout and then were crossed over. Study outcome measures were change in systolic BP from baseline, endothelial function estimated as flow-mediated dilation (FMD), and high-sensitivity C-reactive protein (hsCRP) levels. Adverse events were assessed. RESULTS: Ninety-nine participants were randomized, and 82 completed all visits. The mean ± SD age was 28.0 ± 7.0 years, 62.6% were men, and 40.4% were African American. In the primary intent-to-treat analysis, systolic BP did not change during the allopurinol treatment phase (mean ± SEM -1.39 ± 1.16 mm Hg) or placebo treatment phase (-1.06 ± 1.08 mm Hg). FMD increased during allopurinol treatment periods compared to placebo treatment periods (mean ± SEM 2.5 ± 0.55% versus -0.1 ± 0.42%; P < 0.001). There were no changes in hsCRP level and no serious adverse events. CONCLUSION: Our findings indicate that urate-lowering therapy with allopurinol does not lower systolic BP or hsCRP level in young adults when compared with placebo, despite improvements in FMD. These findings do not support urate lowering as a treatment for hypertension in young adults.

Variation of Serum Lycopene in Response to 100% Watermelon Juice: An Exploratory Analysis of Genetic Variants in a Randomized Controlled Crossover Study.

BACKGROUND: Watermelon, a rich source of lycopene, has garnered attention for cardioprotective effects including cholesterol reduction and promotion of redox balance. It is unknown whether 100% watermelon juice may represent a food-first approach to confer cardioprotective benefits of lycopene. OBJECTIVES: This study examined influences of 100% watermelon juice on serum lycopene, lipids, and antioxidant capacity. Secondly, the study explored genetic influences on lycopene metabolism and bioavailability. METHODS: A placebo-controlled, randomized, double-blind, crossover trial with postmenopausal women (n = 16, mean ± SD age: 60 ± 4.1 y) assessed effects of 100% watermelon juice on mechanistic and clinical outcomes influencing vascular function. Participants maintained low-lycopene diets for a 1-wk run-in period and throughout the study. Morning and evening consumption of 100% watermelon juice provided a daily dose of 14.4 ± 0.34 mg lycopene. Study arms of 4 wk were separated by a 2-wk washout period. Saliva was collected for genetic analysis of single nucleotide polymorphisms, and fasting blood samples were taken pre- and post-study arms. Statistical analyses included mixed models, linear regression, and nonparametric tests. RESULTS: Serum lycopene exhibited a significant treatment effect (P = 0.002) along with notable interindividual responses; however, significant improvements in serum lipids or antioxidant capacity were not observed. Genetic variant rs6564851 in the ß-carotene 15,15'-oxygenase-1 (BCO1) gene was associated with changes in lycopene such that TT homozygotes exhibited a significantly greater increase (ß ± SE: 13.4 ± 1.6, P = 1.4 × 10-06). CONCLUSIONS: Watermelon juice supplementation did not result in improvements in serum lipids or antioxidant capacity; however, results support findings in which watermelon juice significantly, yet differentially, increased circulating lycopene. Genetics appears to explain some of the variability. Given that dose has been shown to overcome individual responsiveness to lycopene interventions, future investigations with varying doses of lycopene-rich foods would be strengthened by genotyping so as to establish personalized nutrition recommendations.This trial was registered at clinicaltrials.gov as NCT03626168.

Race-based and sex-based differences in bioactive lipid mediators after myocardial infarction.

AIMS: Leucocyte-directed specialized pro-resolving mediators (SPMs) are essential for cardiac repair, and their biosynthesis coincides with the expression of pro-inflammatory mediators; however, the precise quantitation during an acute myocardial infarction (MI) event is poorly understood in race-specific and sex-specific manner. Coronary heart disease is the leading cause of death and disability in the USA. Although the prevalence of coronary heart disease is similar between Black and White patients, cardiovascular events (including MI), rehospitalization, and mortality are disproportionately higher in Black patients. Therefore, understanding differences in inflammation and resolution can enable the development of predictive, personalized, and precise treatment and attenuate sex/racial disparities. Thus, herein, we assess differences in bioactive lipids and SPMs, between Black and White patients experiencing an acute MI. METHODS AND RESULTS: From the PRiME-GGAT cohort, we collected plasma after MI within 24-48 h from 22 Black (15 male and 7 female) and 31 White (23 male and 8 female) subjects for a comparative race-based and sex-based analyses. MI was confirmed using a biochemical measurement of plasma troponin and ST elevation. Plasma levels of three essential polyunsaturated fatty acids [arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA)] and a set of 40 bioactive lipid mediators with major emphasis on SPMs were quantified by liquid chromatography-mass spectrometry. AA and DHA were higher in White male and female patients, and EPA was noted higher only in White male patients compared with White female and Black male and female patients. Lipoxygenase-mediated AA-derived 12-hydroxyeicosatetraenoic acid (29-63%) and 15-hydroxyeicosatetraenoic acid (3-9%) and DHA-derived 17-hydroxydocosahexaenoic acid (3-22%) and 14-hydroxydocosahexaenoic acid (7-10%) were major bioactive lipid mediators in plasma. The SPM signature resolvin E1 was significantly lower in Black patients compared with White male and female patients, whereas protectin D1 was lower in White male patients compared with White female and Black male and female patients. CONCLUSION: Our comparative analyses of fatty acids and respective cyclooxygenase-derived and lipoxygenase-derived SPM signatures capture the heterogeneity of disease pathology and elucidate potential mechanisms underlying sex-based and race-based differences following MI.

Antihypertensive Medication Adherence and Confirmation of True Refractory Hypertension.

Refractory hypertension (RfHTN) is a phenotype of antihypertensive treatment failure defined as uncontrolled BP despite the use of effective doses of ≥5 antihypertensive medications including a long-acting thiazide-like diuretic (chlorthalidone) and a mineralocorticoid receptor antagonist. The degree of medication nonadherence is unknown among patients with RfHTN. In this prospective evaluation, 54 patients with apparent RfHTN were recruited from the University of Alabama at Birmingham Hypertension Clinic after having uncontrolled BP at 3 or more clinic visits. All patients' BP was evaluated by automated office BP and 24-hour ambulatory BP monitoring (n=49). Antihypertensive medication adherence was determined by measuring 24-hour urine specimens for antihypertensive medications and their metabolites by high-performance liquid chromatography-tandem mass spectrometry (n=45). Of the 45 patients who completed 24-hour ambulatory BP monitoring, 40 (88.9%) had confirmed RfHTN based on an elevated automated office BP (≥130/80 mm Hg), mean 24-hour ABP (≥125/75 mm Hg), and mean awake (day-time) ABP (≥130/80 mm Hg). Out of the 40 fully evaluated patients with RfHTN, 16 (40.0%) were fully adherent with all prescribed medications. Eighteen (45.0%) patients were partially adherent and 6 (15.0%) had none of the prescribed agents detected in their urine. Of 18 patients who were partially adherent, 5 (12.5%) were adherent with at least 5 medications, including chlorthalidone and the mineralocorticoid receptor antagonist, consistent with true RfHTN. Of patients identified as having apparent RfHTN, 52.5% were adherent with at least 5 antihypertensive medications, including chlorthalidone and a mineralocorticoid receptor antagonist, confirming true RfTHN. These findings validate RfHTN as a rare, but true phenotype of antihypertensive treatment failure.

Masked Uncontrolled Hypertension Is Not Attributable to Medication Nonadherence.

Masked uncontrolled hypertension (MUCH) in treated hypertensive patients is defined as controlled automated office blood pressure (BP; <135/85 mm Hg) in-clinic but uncontrolled out-of-clinic BP by ambulatory BP monitoring (awake [daytime] readings ≥135/85 mm Hg or 24-hour readings ≥130/80 mm Hg). To determine whether MUCH is attributable to antihypertensive medication nonadherence. One hundred eighty-four enrolled patients were confirmed to have controlled office BP; of these, 167 patients were with adequate 24-hour ambulatory BP recordings. Of 167 patients, 86 were controlled by in-clinic BP assessment but had uncontrolled ambulatory awake BP, indicative of MUCH. The remaining 81 had controlled in-clinic and ambulatory awake BP, consistent with true controlled hypertension. After exclusion of 9 patients with missing 24-hour urine collections, antihypertensive medication adherence was determined based on the detection of urinary drugs or drug metabolites by high-performance liquid chromatography-tandem mass spectrometry. Of the 81 patients with MUCH, 69 (85.2%) were fully adherent and 12 (14.8%) were partially adherent (fewer medications detected than prescribed). Of the 77 patients with true controlled hypertension, 69 (89.6%) were fully adherent with prescribed antihypertensive medications and 8 (10.4%) were partially adherent. None of the patients in either group were fully nonadherent. There was no statistically significant difference in complete or partial adherence between the MUCH and true controlled groups (P=0.403). Measurement of urinary drug and drug metabolite levels demonstrates a similarly high level of antihypertensive medication adherence in both MUCH and truly controlled hypertensive patients. These findings indicate that MUCH is not attributable to antihypertensive medication nonadherence.

Out-of-Clinic Sympathetic Activity Is Increased in Patients With Masked Uncontrolled Hypertension.

Masked uncontrolled hypertension (MUCH) is defined as controlled automated office blood pressure (BP; AOBP <135/85 mm Hg) in-clinic in patients receiving antihypertensive medication(s) but uncontrolled BP out-of-clinic by 24-hour ambulatory BP monitoring (ABPM; awake ≥135/85 mm Hg). We hypothesized that MUCH patients have greater out-of-clinic sympathetic activity compared with true controlled hypertensives. Patients being treated for hypertension were prospectively recruited after 3 or more consecutive clinic visits. All patients were evaluated by in-clinic automated office BP, plasma catecholamines, and spot-urine/plasma metanephrines. In addition, out-of-clinic 24-hour ABPM, 24-hour urinary for catecholamines and metanephrines was done. Out of 237 patients recruited, 169 patients had controlled in-clinic BP of which 156 patients had completed ABPM. Seventy-four were true controlled hypertensives, that is controlled by clinic automated office BP and by out-of-clinic ABPM. The remaining 82 were controlled by clinic automated office BP, but uncontrolled during out-of-clinic ABPM, indicative of MUCH. After exclusion of 4 patients because of inadequate or lack of 24-hour urinary collections, 72 true controlled hypertensive and 80 MUCH patients were analyzed. MUCH patients had significantly higher out-of-clinic BP variability and lower heart rate variability compared with true controlled hypertensives, as well as higher levels of out-of-clinic urinary catecholamines and metanephrines levels consistent with higher out-of-clinic sympathetic activity. In contrast, there was no difference in in-clinic plasma catecholamines and spot-urine/plasma levels of metanephrines between the 2 groups, consistent with similar levels of sympathetic activity while in clinic. MUCH patients have evidence of heightened out-of-clinic sympathetic activity compared with true controlled hypertensives, which may contribute to the development of MUCH.

Refractory Hypertension Is not Attributable to Intravascular Fluid Retention as Determined by Intracardiac Volumes.

Refractory hypertension (RfHTN) is an extreme phenotype of antihypertensive treatment failure defined as lack of blood pressure control with ≥5 medications, including a long-acting thiazide and a mineralocorticoid receptor antagonist. RfHTN is a subgroup of resistant hypertension (RHTN), which is defined as blood pressure >135/85 mm Hg with ≥3 antihypertensive medications, including a diuretic. RHTN is generally attributed to persistent intravascular fluid retention. It is unknown whether alternative mechanisms are operative in RfHTN. Our objective was to determine whether RfHTN is characterized by persistent fluid retention, indexed by greater intracardiac volumes determined by cardiac magnetic resonance when compared with controlled RHTN patients. Consecutive patients evaluated in our institution with RfHTN and controlled RHTN were prospectively enrolled. Exclusion criteria included advanced chronic kidney disease and masked or white coat hypertension. All enrolled patients underwent biochemical testing and cardiac magnetic resonance. The RfHTN group (n=24) was younger (mean age, 51.7±8.9 versus 60.6±11.5 years; P=0.003) and had a greater proportion of women (75.0% versus 43%; P=0.02) compared with the controlled RHTN group (n=30). RfHTN patients had a greater left ventricular mass index (88.3±35.0 versus 54.6±12.5 g/m2; P<0.001), posterior wall thickness (10.1±3.1 versus 7.7±1.5 mm; P=0.001), and septal wall thickness (14.5±3.8 versus 10.0±2.2 mm; P<0.001). There was no difference in B-type natriuretic peptide levels and left atrial or ventricular volumes. Diastolic dysfunction was noted in RfHTN. Our findings demonstrate greater left ventricular hypertrophy without chamber enlargement in RfHTN, suggesting that antihypertensive treatment failure is not attributable to intravascular volume retention.

Use of Aldosterone Antagonists for Treatment of Uncontrolled Resistant Hypertension.

BACKGROUND: 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. CONCLUSION: 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.

Refractory versus resistant hypertension: Novel distinctive phenotypes.

Resistant hypertension (RHTN) is relatively common with an estimated prevalence of 10-20% of treated hypertensive patients. It is defined as blood pressure (BP) >140/90 mmHg treated with ≥3 antihypertensive medications, including a diuretic, if tolerated. Refractory hypertension is a novel phenotype of severe antihypertensive treatment failure. The proposed definition for refractory hypertension, i.e. BP >140/90 mmHg with use of ≥5 different antihypertensive medications, including a diuretic and a mineralocorticoid receptor antagonist (MRA) has been applied inconsistently. In comparison to RHTN, refractory hypertension seems to be less prevalent than RHTN. This review focuses on current knowledge about this novel phenotype compared with RHTN including definition, prevalence, mechanisms, characteristics and comorbidities, including cardiovascular risk. In patients with RHTN excess fluid retention is thought to be a common mechanism for the development of RHTN. Recently, evidence has emerged suggesting that refractory hypertension may be more of neurogenic etiology due to increased sympathetic activity as opposed to excess fluid retention. Treatment recommendations for RHTN are generally based on use and intensification of diuretic therapy, especially with the combination of a long-acting thiazide-like diuretic and an MRA. Based on findings from available studies, such an approach does not seem to be a successful strategy to control BP in patients with refractory hypertension and effective sympathetic inhibition in such patients, either with medications and/or device based approaches may be needed.

Distinctive Risk Factors and Phenotype of Younger Patients With Resistant Hypertension: Age Is Relevant.

Resistant hypertension, defined as blood pressure >140/90 mm Hg despite using ≥3 antihypertensive medications, is a well-recognized clinical entity. Patients with resistant hypertension are at an increased risk of cardiovascular disease compared with those with more easily controlled hypertension. Coronary heart disease mortality rates of younger adults are stagnating or on the rise. The purpose of our study was to characterize the phenotype and risk factors of younger patients with resistant hypertension, given the dearth of data on cardiovascular risk profile in this cohort. We conducted a cross-sectional analysis with predefined age groups of a large, ethnically diverse cohort of 2170 patients referred to the Hypertension Clinic at the University of Alabama at Birmingham. Patients (n=2068) met the inclusion criteria and were classified by age groups, that is, ≤40 years (12.7% of total cohort), 41 to 55 years (32.1%), 56 to 70 years (36.1%), and ≥71 years (19.1%). Patients aged ≤40 years compared with those aged ≥71 years had significantly earlier onset of hypertension (24.7±7.4 versus 55.0±14.1 years; P<0.0001), higher rates of obesity (53.4% versus 26.9%; P<0.0001), and significantly higher levels of plasma aldosterone (11.3±9.8 versus 8.9±7.4 ng/dL; P=0.005), plasma renin activity (4.9±10.2 versus 2.5±5.0 ng/mL per hour; P=0.001), 24-hour urinary aldosterone (13.4±10.0 versus 8.2±6.2 µg/24 h; P<0.0001), and sodium excretion (195.9±92.0 versus 146.8±67.1 mEq/24 h; P<0.0001). Among patients with resistant hypertension, younger individuals have a distinct phenotype characterized by overlapping risk factors and comorbidities, including obesity, high aldosterone, and high dietary sodium intake compared with elderly.

11-Beta Dehydrogenase Type 2 Activity Is Not Reduced in Treatment Resistant Hypertension.

BACKGROUND AND OBJECTIVE: Decreased renal 11-beta dehydrogenase type 2 (11ß-HSD2) activity, as reflected by an increased urinary free cortisol to cortisone ratio (UFF/UFE), is associated with having hypertension (HTN). The current study was conducted to determine if reduced 11ß-HSD2 activity is also associated with having resistant HTN. METHOD: We evaluated 55 consecutive patients with RHTN, defined as blood pressure (BP) ≥140/90 mm Hg despite using ≥3 antihypertensive medications including a diuretic, and 38 patients whose BP was controlled on ≤3 medications to serve as a non-RHTN comparator group. All patients underwent biochemical evaluation, including measurement of 24-hour urinary UFF/UFE. RESULTS: The 2 study groups had similar demographic characteristics. Systolic, diastolic BP, and number of antihypertensive medications were greater in patients with uncontrolled RHTN vs. the control group (167.5 ± 28.2/91.2 ± 18.8 vs. 126.6 ± 11.4/77.8 ± 8.65 mm Hg and 4.31 ± 1.23 vs. 2.74 ± 0.6, respectively). The 24-hour UFF was 13.6 ± 11.8 vs. 14.3 ± 10.7 µg/24 h and UFE was 64.9 ± 36.3 vs. 76.1 ± 44 µg/24 h such that the UFF/UFE was 0.22 ± 0.16 vs. 0.19 ± 0.09 in RHTN vs. the control group. This ratio was not associated to age, race, gender, and body mass index. CONCLUSION: An elevated UFF/UFE was not present in this large cohort of patients with uncontrolled RHTN. This suggests that reduced conversion of cortisol to cortisone does not contribute to the development of RHTN.

Prevalence and Clinical Characteristics of Refractory Hypertension.

BACKGROUND: We aimed to estimate the prevalence of refractory hypertension (RfH) and to determine the clinical differences between these patients and resistant hypertensives (RH). Secondly, we assessed the prevalence of white-coat RfH and clinical differences between true- and white-coat RfH patients. METHODS AND RESULTS: The present analysis was conducted on the Spanish Ambulatory Blood Pressure Monitoring Registry database containing 70 997 treated hypertensive patients. RH and RfH were defined by the presence of elevated office blood pressure (≥140 and/or 90 mm Hg) in patients treated with at least 3 (RH) and 5 (RfH) antihypertensive drugs. White-coat RfH was defined by RfH with normal (<130/80 mm Hg) 24-hour blood pressure. A total of 11.972 (16.9%) patients fulfilled the standard criteria of RH, and 955 (1.4%) were considered as having RfH. Compared with RH patients, those with RfH were younger, more frequently male, and after adjusting for age and sex, had increased prevalence of target organ damage, and previous cardiovascular disease. The prevalence of white coat RfH was lower than white-coat RH (26.7% versus 37.1%, P<0.001). White-coat RfH, in comparison with those with true RfH, showed a lower prevalence of both left ventricular hypertrophy (22% versus 29.7%; P=0.018) and microalbuminuria (28.3% versus 42.9%; P=0.047). CONCLUSIONS: The prevalence of RfH was low and these patients had a greater cardiovascular risk profile compared with RH. One out of 4 patients with RfH have normal 24-hour blood pressure and less target organ damage, thus indicating the important role of ambulatory blood pressure monitoring in guiding antihypertensive therapy in difficult-to-treat patients.