Jenifer M. Brown

Background: Dietary sodium intake is a modifiable determinant of blood pressure, and impaired renal sodium handling is implicated in the pathogenesis of hypertension. Whether dietary sodium intake modulates renal tubular sodium transporter abundance among normotensive adults at risk for hypertension is unknown. Methods: Forty-six normotensive adults with normal kidney function at risk of developing hypertension were prospectively enrolled to complete a very low sodium (LS) diet followed by a high sodium (HS) diet. Urinary extracellular vesicle (uEV) proteins were quantified from a 24-hour urine collection at the end of each diet. We compared normalized uEV protein concentrations between diets and tested whether diet modified uEV protein associations with serum aldosterone, urinary aldosterone, and serum cortisol-cortisone ratio under either diet using Wilcoxon rank sums and linear mixed effects models, respectively. Results: Participants achieved median [IQR] urine sodium 13.2 [7.7-19.9] mEq/24h on the LS diet and 244.0 [197.1-297.0] mEq/24h on the HS diet. LS intake induced greater renin activity, greater plasma and urinary aldosterone, and lower urinary cortisol, when compared to HS intake. In parallel, NCC, ENaC, SGLT2, OXSR1, and Pendrin uEV concentrations were significantly higher during LS intake than HS intake ( p p in vivo renal sodium, water, and electrolyte handling.

Background: Accumulating evidence suggests that the prevalence of hypercortisolism in patients with cardiometabolic risk factors is much higher than previously thought. This study aimed to evaluate the prevalence of ACTH-independent hypercortisolism across the spectrum of cardiometabolic risk. Methods: Participants were prospectively recruited into three cohorts to undergo protocolized assessment of adrenal physiology:1) normotensive participants; 2) participants with hypertension and obesity, but without diabetes; 3) participants with diabetes and overweight/obesity. All participants (n=216) underwent overnight 1 mg dexamethasone suppression testing followed by cosyntropin stimulation test, and 24-hour urine free cortisol (UFC) testing. ACTH-independent hypercortisolism was defined as post-dexamethasone serum cortisol >1.8 μg/dL (50 nmol/L) with a concomitant post-dexamethasone ACTH ≤10 pg/mL (2.2 pmol/L). Result: 16 of 216 (7.4%) participants were found to have ACTH-independent hypercortisolism, including 5.6% (4/71) in the normotensive cohort, 6.2% (5/81) in the hypertension-obesity cohort and 10.9% (7/64) in the diabetes-obesity cohort. Age, body mass index, hemoglobin A1c, blood pressure, renal function, morning ACTH, and 24-hour UFC were similar among those with and without ACTH-independent hypercortisolism. Following cosyntropin stimulation, those with ACTH-independent hypercortisolism had higher stimulated cortisol levels (greater ACTH-dependent responses) when compared to those without ACTH-independent hypercortisolism: 25.8 +/- 4.5 versus 20.6 +/- 4.1 μg/dL (711 +/- 124 v. 568 +/- 113 nmol/L) (P<0.001). Conclusions: In this prospective study, the prevalence of ACTH-independent hypercortisolism paralleled the burden of cardiometabolic risk features. ACTH-independent hypercortisolism was associated with greater ACTH-stimulable cortisol production, identifying a unique biochemical phenotype. These findings reveal new insights into cortisol pathophysiology as a function of ACTH and cardiometabolic risk profiles.

Background: Pathologic aldosteronism induces oxidative stress, tissue injury, and increases in hemoglobin. Conversely, aldosterone antagonist therapy decreases hemoglobin. Whether these effects are attributable to aldosterone-mediated changes in iron and oxygen metabolism is unknown. Methods: The plasma proteome of participants with overt primary aldosteronism (PA) (n=50) was compared with participants without overt PA (n=61). To isolate aldosterone-dependent effects, participants without overt PA underwent oral sodium suppression testing to quantify the magnitude of renin-independent aldosterone production, enabling monotonic dose-response analyses across the continuum of renin-independent aldosteronism (subclinical to overt PA). Differential abundance testing was performed using empirical Bayes linear modeling, followed by Reactome pathway enrichment analysis and covariate-adjusted sensitivity analyses. To validate clinical relevance, aldosterone dose-response trends with blood count parameters were examined in this cohort, and an independent population-based cohort of 5,713 people with hypertension. Results: 903 proteins in the peripheral circulation were differentially abundant in overt PA versus participants without PA. The most significantly increased protein in overt PA was CYBRD1, involved in iron reduction and absorption. Pathway enrichment identified 16 iron- and heme-related pathways, including erythropoietin signaling, heme biosynthesis and mitochondrial iron-sulfur cluster biogenesis, with increases in heme and erythroid proteins and decreases in mitochondrial iron-sulfur proteins. Linear aldosterone dose-dependent trend analyses across the PA continuum further supported this signature, identifying progressive increases in hemoglobin subunits (HBA1/HBB), heme-related proteins (HMBS, UROS, AMBP, HPX, GLO1) and erythrocyte oxygen handling enzymes (CA1/CA3), alongside progressive reductions in mitochondrial electron transport chain subunits (CYCS, ETFA). These proteomic changes corresponded with aldosterone dose-dependent increases in red blood cell count, hemoglobin, and hematocrit, in this cohort and another population-based cohort. Conclusion: The continuum of PA is characterized by a progressive shift away from mitochondrial oxidative phosphorylation and toward increased intestinal iron absorption, preferential iron transport over storage, and enhanced heme synthesis and recycling, possibly reflecting cellular pseudohypoxia and systemic adaptations to increase oxygen delivery. These findings provide a novel mechanistic basis for aldosterone-mediated tissue injury and the benefits of aldosterone-directed therapy.

BACKGROUND: Although the prognostic utility of positron emission tomography (PET) myocardial flow reserve (MFR) is well established, emerging data suggest that reduced subendocardial flows also predict adverse outcomes. However, the incremental value of subendocardial MFR (MFR _SE ) beyond transmural MFR (MFR _TM ) remains unclear. METHODS: We studied patients in a multicenter PET registry with normal perfusion on stress/rest Rb-82 PET, excluding those with a previous history of coronary artery bypass surgery, heart transplantation, or left ventricular ejection fraction SE cutoff for predicting major adverse cardiovascular events (MACEs; death, myocardial infarction [MI], revascularization, or heart failure [HF] hospitalization) was determined using Youden’s index. Patients were stratified into 3 groups: concordant-normal (MFR _TM ≥2.0; MFR _SE ≥2.1), discordant (low-MFR _SE , normal MFR _TM ), and abnormal MFR _TM . Clinical outcomes were compared by MFR groups. RESULTS: Among 6603 patients (normal N=4103; discordant N=885; abnormal N=1615) the mean age was 66.3±12.4 years, and 54% were women. Compared with the concordant-normal group, patients with discordant low-MFR _SE were older and more likely to have hypertension, diabetes, peripheral artery disease, and previous percutaneous coronary intervention. The median MFR _TM for normal, discordant, and abnormal groups were 2.86, 2.15, and 1.72, respectively. Over a m edian follow-up of 4.9 years, 1661 MACE events occurred. Discordant low-MFR _SE patients had a higher risk of MACE (hazard ratio [HR], 1.41; 95% CI, 1.22–1.64) and all-cause mortality (HR, 1.36; 95% CI, 1.14–1.61) compared with concordant-normal patients. The discordant group had an intermediate absolute risk of MACE, with an adjusted annualized event rate of 5.79% (95% CI, 5.10–6.49) compared with 3.99% (95% CI, 3.67–4.30; P P TM group. CONCLUSIONS: Subendocardial MFR reveals clinically meaningful risk heterogeneity among patients with preserved transmural flow reserve, helping refine risk stratification beyond traditional PET metrics.

Background: Recent primary aldosteronism (PA) guidelines proposed probability-based stratifications, and use of aldosterone suppression testing, to predict lateralizing PA subtype. This guideline framework was based on very low-quality evidence. Methods: The discriminatory capacity of guideline-endorsed probability frameworks for PA subtyping were evaluated in this retrospective study of 319 PA patients, from two large tertiary centers in Bangkok, Thailand, who underwent subtyping assessments regardless of probability status. PA subtypes were determined by adrenal venous sampling (AVS) and/or post-adrenalectomy outcomes using PASO criteria. The main objectives were to evaluate the accuracy of predicting PA subtype using: 1) guideline-endorsed classification to “high,” “intermediate,” and “low” probabilities of lateralization; and 2) the seated saline suppression test (SST). Results: The majority of PA patients were characterized as having “intermediate” probability for lateralizing PA (75%); however, lateralizing PA was ultimately confirmed in 61-78% of all patients, regardless of guideline-based probability classification. The vast majority of SST results were positive using guideline-derived criteria, regardless of probability stratification or ultimate subtype: 89.3% of patients with lateralizing PA and 80.6% of those with bilateral PA had a positive SST. Among patients with “intermediate” probability of lateralizing PA, where guidelines specifically endorse the value of SST, the SST had a sensitivity of 89.4% and specificity of 22.0% for detecting lateralizing PA, with 78.0% false-positive and 10.6% false-negative rates. Consistently, post-SST aldosterone concentrations exhibited near-complete overlap between those with and without lateralizing PA. Conclusion: Guideline-endorsed probability frameworks, and the use of SST, lacked discriminatory capacity to predict PA subtype.

Background: Primary aldosteronism (PA) testing is recommended for patients with resistant hypertension but remains underused, and evidence linking aldosterone-targeted therapy to improved cardiovascular and renal outcomes is limited. Methods: In a nationwide cohort of patients with resistant hypertension between 2001 and 2022, we assessed PA testing and subsequent mineralocorticoid receptor antagonist (MRA) use and adrenalectomy. Among tested patients, time-dependent Cox models were used to assess associations between treatment exposure and mortality, major adverse cardiovascular events (MACE) and renal outcomes. Results: Among 254,338 patients, only 2.0% were tested for PA. Tested patients had a higher prevalence of hypokalemia and cardiometabolic comorbidities. In the overall tested population, MRA use was not associated with lower risks of cardiovascular or renal outcomes. However, when testing resulted in an established PA diagnosis, the use of both MRA (hazard ratio [HR] 0.60, 95% CI 0.42–0.86) and adrenalectomy (HR 0.33, 95% CI 0.20–0.54) were associated with a reduced risk of MACE compared with no aldosterone-targeted therapy. Similar results were observed regarding mortality. Adrenalectomy was associated with lower risk of MACE (HR 0.55, 95% CI 0.30–0.99), all-cause mortality (HR 0.52, 95% CI 0.29–0.93) and renal outcomes (HR 0.37, 95% CI 0.17–0.80) compared with MRA in patients with a diagnosis of PA. Conclusions: PA remains markedly underrecognized in resistant hypertension. Among patients with resistant hypertension who did undergo PA testing with establishment of a PA diagnosis, aldosterone-targeted therapy resulted in lower risk of adverse cardiorenal outcomes and death when compared to conventional antihypertensive therapy.

Background: Risk stratification in hypertension remains challenging. The prognostic value of plasma renin in guiding therapy for hypertension is not well established. Methods: In this multicenter retrospective cohort of 16,600 people with hypertension, we evaluated the association between plasma renin activity and major adverse cardiovascular events (MACE) defined as stroke, myocardial infarction, and all-cause death. Plasma renin was analyzed as a continuous variable using restricted cubic splines. A 6-month landmark analysis assessed treatment effects of mineralocorticoid receptor antagonists (MRA) as opposed to baseline renin-angiotensin system inhibitors. Results: Continuous renin level showed a U-shaped association with MACE, with the lowest risk at 1.17ng/mL/h. In categorical analyses, low renin (3.0ng/mL/h; HR=1.19, 95% CI 1.06-1.33) were both associated with higher MACE risk. Initiation of MRA therapy after renin measurement was associated with a graded reduction in MACE risk where patients with low renin had the lowest risk (HR=0.75, 95%CI 0.60-0.92), and patients with high-renin had the highest risk (HR=1.41, 95%CI 1.03-1.94). In contrast, baseline use of renin-angiotensin system inhibitors was associated with a graded reduction in MACE risk where patients with high-renin had the lowest risk (HR=0.76, 95%CI 0.63-0.92) but those with low renin did not benefit (HR=0.87, 95%CI 0.72-1.04). Conclusions: Plasma renin is a prognostic biomarker for MACE and may serve as a guide for treatment selection. A renin-guided strategy that favors MRAs in patients with low renin may reduce MACE and support individualized hypertension care.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) affect up to 15% of pregnancies and are linked to adverse maternal and fetal outcomes. Primary aldosteronism (PA) affects up to 25% of patients with hypertension. In women with prior HDP and PA risk factors, we examined PA prevalence and its relationship to hypertension trajectory. METHODS: Adults across the US meeting guideline-recommended screening criteria for PA were prospectively tested. Women with a self-reported history of HDP completed a questionnaire examining the relationship between PA and hypertension trajectory. RESULTS: Of 330 hypertensive parous women (62.4±9.8 years; 32.1% non-White), 83 (25.2%) reported a history of HDP. Women with HDP were younger at hypertension diagnosis (38.8 versus 47.9 years; P P =0.35). Among women with HDP, 63 completed the follow-up questionnaire, of whom 15 (23.8%) tested positive for PA. Compared with PA-negative women, those with PA reported a higher proportion of pregnancies complicated by hypertension (76.5% versus 60.9%; P =0.11) and fetal complications (55.6% versus 27.9%; P P =0.047). CONCLUSIONS: Over 25% of women with hypertension, ≥1 PA risk factor, and prior pregnancy tested positive for PA, highlighting its high prevalence, irrespective of a history of HDP. Women with HDP face elevated cardiovascular risk, and PA may represent a targetable contributor.

BACKGROUND: New guidelines recommend testing for primary aldosteronism (PA) in all people with hypertension. Interpreting population-based results for PA will require understanding the influence of demographic characteristics. METHODS: 858 adults from across the US meeting traditional guideline criteria for PA testing underwent testing. The influence of demographic factors on test result interpretations was assessed after multivariable adjustment. RESULTS: Mean age was 62±11 years, with 54.6% women, 14% Black, and 22.9% Hispanic. Independent of antihypertensive medications and clinical comorbidities, participants aged ≥70 years had 24% lower aldosterone ( P P P =0.14), compared with those P P P =0.002), and Black participants had 22% higher odds of a positive test than White participants ( P <0.001). CONCLUSIONS: In this large, diverse, nationwide sample, older and Black participants had higher aldosterone-to-renin ratio and higher odds of testing positive for PA, and women had higher aldosterone levels than men across the lifespan. With newly expanded indications for PA testing, a greater appreciation of the influence of demographic characteristics on PA test results will be required.