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.

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.

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.

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 .

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.

The effects of urate lowering therapy on inflammation, endothelial function, and blood pressure (SURPHER) study design and rationale.

BACKGROUND: The association between hyperuricemia and hypertension is controversial. Animal models, epidemiological data, and small clinical trials have favored a causative role for hyperuricemia in hypertension but more studies are necessary to elucidate putative mechanisms, population susceptibility, and potential for urate-lowering therapies (ULT) to decrease blood pressure (BP). PURPOSE: To describe the background and design of the Serum Urate Reduction to Prevent Hypertension (SURPHER) study. METHODS: SURPHER is a single center, double-blinded, crossover trial in which participants are randomly assigned to allopurinol (300mg) or placebo. Enrollment focused on adults 18-40years old with baseline systolic blood pressure≥120 and <160mmHg or diastolic blood pressure≥80 and <100mmHg, and serum urate ≥5.0mg/dL or ≥4.0mg/dL for men or women, respectively. SURPHER recruitment targets participants without chronic kidney disease (estimated glomerular filtration rate>60mL/min/1.73m2), and without prior diagnosis of gout or use of ULT to treat gout. The primary outcome is change from baseline in blood pressure assessed by 24hour ambulatory blood pressure monitoring and mechanistic outcomes include changes in endothelial function as measured by flow-mediated dilation, as well as C-reactive protein levels. RESULTS: Since June 16, 2014 until present, SURPHER is recruiting participants in the city of Birmingham, Alabama. LIMITATIONS: The study aims to enroll otherwise healthy young adults for a pharmacological intervention study with multiple study-related procedures. Challenges related to recruitment are anticipated and multiple strategies for increasing recruitment and retention are planned if necessary.