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In this retrospective cross-sectional study, we assessed sex differences in in-basket messages generated by outpatient workflows among internal medicine specialists as compared to relative value units; we found that female physicians had a greater burden of in-basket work for each unit of paid clinical care.

IntroductionPropionic acid (PA) is a common food preservative generally recognized as safe by the US Food and Drug Administration; however, exogenous PA has effects on glucose metabolism that are not fully understood. Our preclinical studies demonstrated exogenous PA increases glucagon, norepinephrine, and endogenous glucose production (EGP).Research design and methodsWe performed a randomized, placebo-controlled, crossover study in 28 healthy men and women to determine the effect of PA (1500 mg calcium propionate) on these factors. Subjects had two study visits, each preceded by a 1 week, PA-free diet. During each visit, glucose, insulin, glucagon, norepinephrine, epinephrine, and EGP were assessed for 2 hours after oral administration of PA/placebo under resting conditions (protocol 1) and during either a euglycemic (~85–90 mg/dL) or hypoglycemic (~65–70 mg/dL) hyperinsulinemic clamp (protocol 2).ResultsPA, as compared with placebo, significantly increased: (1) glucagon and norepinephrine during protocol 1; (2) glucagon, norepinephrine, and epinephrine under euglycemic conditions in protocol 2; and (3) norepinephrine, epinephrine, and EGP under hypoglycemic conditions in protocol 2.ConclusionOral consumption of PA leads to inappropriate activation of the insulin counterregulatory hormonal network. This inappropriate stimulation highlights PA as a potential metabolic disruptor.

Among persons presenting to the emergency department with suspected acute myocardial infarction (MI), cardiac troponin (cTn) testing is commonly used to detect acute myocardial injury. Accelerated diagnostic protocols (ADPs) guide clinicians to integrate cTn results with other clinical information to decide whether to order further diagnostic testing. To determine the change in the rate and yield of stress test or coronary CT angiogram following cTn measurement in patients with chest pain presenting to the emergency department pre- and post-transition to a high-sensitivity (hs-cTn) assay in an updated ADP. Using electronic health records, we examined visits for chest pain at five emergency departments affiliated with an integrated academic health system 1-year pre- and post-hs-cTn assay transition. Outcomes included stress test or coronary imaging frequency, ADP compliance among those with additional testing, and diagnostic yield (ratio of positive tests to total tests). There were 7564 patient-visits for chest pain, including 3665 in the pre- and 3899 in the post-period. Following the updated ADP using hs-cTn, 862 (23.5 per 100 patient visits) visits led to subsequent testing versus 1085 (27.8 per 100 patient visits) in the pre-hs-cTn period, (P < 0.001). Among those who were tested, the protocol-compliant rate fell from 80.9% to 46.5% (P < 0.001), but the yield of those tests rose from 24.5% to 29.2% (P = 0.07). Among tests that were noncompliant with ADP guidance, yield was similar pre- and post-updated hs-cTn ADP implementation (pre 13.0%, post 15.4% (P = 0.43). Implementation of hs-cTn supported by an updated ADP was associated with a lower rate of stress testing and coronary CT angiogram.

Adiponectin, a secretagogue exclusively produced by adipocytes, has been associated with metabolic features, but its role in the development of the metabolic syndrome remains unclear. We investigated the association between serum adiponectin level and metabolic traits, using both observational and genetic epidemiologic approaches in a multiethnic population assembled in Canada. Clinical data and serum adiponectin level were collected in 1,157 participants of the SHARE/SHARE-AP studies. Participants were genotyped for the functional rs266729 and rs1260326 SNPs in ADIPOQ and GCKR genes. Adiponectin level was positively associated with HDL cholesterol and negatively associated with body mass index, waist-to-hip ratio, triglycerides, fasting glucose, fasting insulin, systolic and diastolic pressure (all P<0.002). The rs266729 minor G allele was associated with lower adiponectin and higher HOMA-IR (P = 0.004 and 0.003, respectively). The association between rs266729 SNP and HOMA-IR was no longer significant after adjustment for adiponectin concentration (P = 0.10). The rs266729 SNP was associated with HOMA-IR to an extent that exceeded its effect on adiponectin level (0.15 SD 95% C.I. [0.06, 0.24], P<0.001). There was no significant interaction between rs266729 SNP and ethnicity on adiponectin or HOMA-IR. In contrast, the SNP rs1260326 in GCKR was associated with HOMA-IR (P<0.001), but not with adiponectin level (P = 0.67). The association of the functional promoter polymorphism rs266729 with lower serum adiponectin and increased insulin resistance in diverse ethnic groups may suggest a causal relationship between adiponectin level and insulin resistance.

Background Both ambulatory atrial fibrillation (AF) and post-operative AF (poAF) are associated with substantial morbidity and mortality. Analyzing the tissue-specific gene expression in the left atrium (LA) can identify novel genes associated with AF and further the understanding of the mechanism by which previously identified genetic variants associated with AF mediate their effects. Methods LA free wall samples were obtained intraoperatively immediately prior to mitral valve surgery in 62 Caucasian individuals. Gene expression was quantified on mRNA harvested from these samples using RNA sequencing. An expression quantitative trait loci (eQTL) analysis was performed, comparing gene expression between different genotypes of 1.0 million genetic markers, emphasizing genomic regions and genes associated with AF. Results Comparison of whole-genome expression between patients who later developed poAF and those who did not identified 23 differentially expressed genes. These included genes associated with the resting membrane potential modified by potassium currents, as well as genes within Wnt signaling and cyclic GMP metabolism. The eQTL analysis identified 16,139 cis eQTL relationships in the LA, including several involving genes and single nucleotide polymorphisms (SNPs) linked to AF. A previous relationship between rs3744029 and MYOZ1 expression was confirmed, and a novel relationship between rs6795970 and the expression of the SCN10A gene was identified. Conclusions The current study is the first analysis of the human LA expression landscape using high-throughput RNA sequencing. Several novel genes and variants likely involved in AF pathogenesis were identified, thus furthering the understanding of how variants associated with AF mediate their effects via altered gene expression. Trial registration ClinicalTrials.gov ID: NCT00833313 , registered 5. January 2009

Abstract Context Hypertension, a prevalent cardiovascular risk, often involves dysregulated aldosterone and its interaction with the mineralocorticoid receptor (MR). Experimental designs in animal models and human cohorts have demonstrated a sex and age dependency of aldosterone secretion that expands our pathophysiologic understanding. Objective This study explores the genetic variation of NR3C2, which encodes MR, in relation to aldosterone, considering age, sex, and race. Methods Incorporating 720 Caucasians and 145 Africans from the HyperPATH cohort, we investigated the impact of rs4835490, a single nucleotide risk allele variant, on aldosterone levels and vasculature. Results Notably, a significant association between rs4835490 and plasma aldosterone under liberal salt conditions emerged in individuals of European ancestry (P = .0002). Homozygous carriers of the risk A allele exhibited elevated plasma aldosterone levels (AA = 8.1 ± .9 vs GG = 4.9 ± .5 ng/dL). Additionally, aldosterone activation through posture (P = .025) and urinary excretion (P = .0122) showed notable associations. Moreover, genetic interactions with race, sex, and age were observed. Caucasian females under 50 years displayed higher plasma aldosterone, urine aldosterone, and posture aldosterone with the AA genotype compared to females over 50 years, suggesting a potential connection with menopausal or estrogen influences. Interestingly, such age-dependent interactions were absent in the African cohort. Conclusion Our study highlights the significance of the NR3C2 genetic variation and its interplay with age, sex, and race in aldosterone activation. The findings point toward an estrogen-modulating effect on MR activation, particularly in women, underlining the role of aldosterone dysregulation in hypertension development. This insight advances our comprehension of hypertension's complexities and opens avenues for personalized interventions. Clinical Trial Registration Number: NCT03029806 (registered January 24, 2017).

Background Germline mutations of BRCA1/2 are associated with hereditary breast and ovarian cancer. Recent data suggests excess mortality in mutation carriers beyond that conferred by neoplasia, and recent in vivo and in vitro studies suggest a modulatory role for BRCA proteins in endothelial and cardiomyocyte function. We therefore tested the association of BRCA2 variants with clinical cardiovascular disease (CVD). Methods Using data from 1,170 individuals included in two multi-ethnic population-based studies (SHARE and SHARE-AP), the association between BRCA2 variants and CVD was evaluated. 15 SNPs in BRCA2 with minor allele frequencies (MAF) > 0.01 had been previously genotyped using the cardiovascular gene-centric 50 k SNP array. 115 individuals (9.8%) reported a CVD event, defined as myocardial infarction (MI), angina, silent MI, stroke, and angioplasty or coronary artery bypass surgery. Analyses were adjusted for age and sex. The SNPs rs11571836 and rs1799943 were subsequently genotyped using the MassARRAY platform in 1,045 cases of incident MI and 1,135 controls from the South Asian subset of an international case-control study of acute MI (INTERHEART), and rs11571836 was imputed in 4,686 cases and 4500 controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS). Results Two BRCA2 SNPs, rs11571836 and rs1799943, both located in untranslated regions, were associated with lower risk of CVD (OR 0.47 p = 0.01 and OR 0.56 p = 0.03 respectively) in the SHARE studies. Analysis by specific ethnicities demonstrated an association with CVD for both SNPs in Aboriginal People, and for rs11571836 only in South Asians. No association was observed in the European and Chinese subgroups. A non-significant trend towards an association between rs11571836 and lower risk of MI was observed in South Asians from INTERHEART [OR = 0.87 (95% CI: 0.75-1.01) p = 0.068], but was not evident in PROMIS [OR = 0.96 (95% CI: 0.90-1.03) p = 0.230]. Meta-analysis of both case-control studies resulted in a combined OR of 0.94 (95% CI: 0.89-1.004, p = 0.06). Conclusions Although there was an association between two SNPs in BRCA2 and CVD in a multi-ethnic population, these results were not replicated in two South Asian case-control studies of incident MI. Future studies exploring the association between BRCA variants and cardiovascular disorders are needed to clarify the role, if any, for BRCA variants in CVD pathogenesis.

Abstract Disclosure: E. Caliskan Guzelce: None. M. heydarpour: None. L. Pojoga: None. G.H. Williams: None. Background: Genetic variation in the β2-Adrenergic Receptor (ADRB2) may influence blood pressure regulation, aldosterone secretion, and renal hemodynamics. This study investigated the impact of ADRB2 diplotype on salt-sensitive blood pressure (SSBP), aldosterone (ALDO), and renal blood flow (RBF) in a diverse cohort of 517 individuals, stratified by age, sex, and disease status. Methods: Participants from HyperPath study cohort were grouped into homozygous risk, heterozygous risk, and homozygous non-risk diplotype groups. We assessed SSBP, ALDO levels, and RBF under liberal and restricted salt diets. Subgroup analyses were performed in younger (<51 years) and older (≥51 years) individuals, as well as by hypertensive and normotensive status. Results: Across the full cohort, SSBP was associated with age, sex, and disease status (p < 0.001 for each), but not with diplotype alone. In participants younger than 51 years (N = 333), SSBP was significantly higher in homozygous risk individuals than heterozygous risk, and homozygous non-risk diplotype groups (p = 0.01, and p=0.007, res.), particularly among hypertensives (p=0.025). In contrast, SSBP did not differ among diplotype groups in older individuals or normotensives. Baseline aldosterone on a liberal salt diet was elevated in the risk diplotype group in both hypertensive and normotensive young individuals (p = 0.02, p=0.03, res.), but not on a restricted salt diet. RBF was significantly higher in the homozygous risk diplotype group under both salt conditions in the young cohort (p = 0.02, p=0.01, res.). However, when stratified by disease state, RBF was significantly higher in the homozygous risk diplotype group in young normotensives (p = 0.03), but not in young hypertensives. No significant differences were observed in plasma renin activity or urinary aldosterone excretion across diplotype groups. Sex did not modify SSBP response within the young cohort. Conclusions: ADRB2 diplotype influences aldosterone secretion and renal blood flow, particularly in younger individuals. While genotype-related differences in SSBP were evident only in young hypertensives, elevated aldosterone levels and increased renal blood flow were also observed in normotensives. This suggests that enhanced renal perfusion may buffer the pressor effects of aldosterone in young normotensives, but not in hypertensives, pointing to early genotype-driven physiological adaptations that may precede the development of overt hypertension. Presentation: Saturday, July 12, 2025

Abstract Context There are well-established interactions between the thyroid and the kidney. Thyroid hypofunction is associated with reduced renal plasma flow (RPF), and hypothyroidism is highly prevalent in chronic kidney disease; however, less is known about the thyroid-kidney axis in the euthyroid state. Objective This work aimed to study the association of thyroid function with renovascular parameters in a well-phenotyped cohort of euthyroid normotensive and hypertensive individuals. Methods This cross-sectional, multicenter study of the HyperPATH Consortium took place in 5 US and European academic institutions. A total of 789 individuals, aged 18 to 65 years, with serum thyrotropin (TSH) 0.4 to 5.5 mIU/L, participated; individuals with uncontrolled or secondary hypertension or on medication affecting the hypothalamus-pituitary-thyroid axis were excluded. Hemodynamic parameters including RPF, thyroid function testing, and the Thr92Ala deiodinase 2 (D2) polymorphism were assessed in the setting of a liberal and restricted salt diet. We searched for associations between thyroid function and renovascular parameters and accounted for confounding factors, such as older age, hypertension, and diabetes. Results Serum TSH was inversely associated with RPF assessed in the setting both of liberal and restricted salt diets. This association remained significant and independent when accounting for confounding factors, whereas free thyroxine index (fTI) and the Thr92Ala polymorphism, associated with lower D2 catalytic activity and disrupted thyroid hormone tissue availability, were not independently associated with RPF. Serum TSH remained an independent predictor of RPF on a liberal salt diet when the analysis was restricted to healthy young individuals. Conclusion Serum TSH levels, but not fTI nor the Thr92Ala D2 polymorphism, were independently inversely associated with RPF in individuals of the HyperPATH Consortium. These findings suggest a direct interconnection between TSH and renovascular dynamics even with TSH within reference range, warranting further investigation.

Abstract Disclosure: H. Ngu: None. R. Uddin: None. A.V. Haas: None. M. heydarpour: None. G.H. Williams: None. J.S. Williams: None. The Amplified Salt Sensitivity of Blood Pressure of Striatin and LSD1 Risk Alleles in Black Individuals Background: Salt sensitivity of blood pressure (SSBP) is an important predictor of cardiovascular disease and renal morbidity. Genetic factors are increasingly becoming recognized as risk factors for the development of SSBP. Specifically, risk alleles in lysine specific demethylase 1 (LSD1) and striatin are independently associated with greater SSBP. LSD1 protein is an epigenetic regulator of gene transcription and is associated with increased mineralocorticoid receptor activity while striatin protein is a scaffolding/signaling protein and is associated with increased aldosterone levels. Objective: Given that LSD1 and striatin are both involved in the volume homeostatic pathway (striatin by enhancing aldosterone production and LSD1 by activating the mineralocorticoid receptor), we tested the hypothesis that Black individuals who carry risk alleles in both LSD1 and striatin would have a more severe form of SSBP than those carrying a single risk allele from either gene alone. Methods: Data was obtained from the international HyperPATH cohort. Hypertensive individuals studied in HyperPATH stopped antihypertensive medication for at least 2 weeks prior to entering the study. Individuals completed assessments for blood pressure and hormone levels after 7 days of a restricted sodium diet (< 10 mEq sodium/day) and again after 7 days of a liberal sodium diet (> 200 mEq sodium/day). Individuals who self-identified as Black with genotype data for both LSD1 gene (rs587168) and Striatin diplotype (rs888083 and rs6744560) were included. SSBP was defined as the change in systolic blood pressure on liberal sodium diet compared to restricted sodium diet. Results: 131 Black individuals were included in the analysis; 65 individuals carried a risk allele from both LSD1 and striatin genes (double risk) and 66 individuals lacked a risk allele from both genes (non-double risk). In multivariate analysis (correcting for site, hypertensive status, sex, age), SSBP was significantly higher among double risk compared to non-double risk individuals (17.9 +/- 13.4 mmHg vs 10.4 +/- 11.1 mmHg, p-value < 0.0001). Among hypertensive individuals (n=89), SSBP was 22.2 +/- 13.8 mmHg vs 11.9 +/- 11.3 mmHg for double risk vs non-double risk groups, respectively (p-value 0.0001). Conclusion: We demonstrated that individuals with risk alleles from both LSD1 and striatin exhibited a more severe form of SSBP. Given that striatin and LSD1 protein are involved in the same volume homeostatic pathway, our findings suggest there may be important interactions between these proteins. Further, a mineralocorticoid receptor blocker may be particularly effective in treating elevated blood pressure in these individuals. Presentation: 6/3/2024