Journal of Hypertension

Background Hypertension remains one of the most challenging healthcare problems in the community. It is a common, measurable, and treatable condition that is nonetheless responsible for millions of preventable deaths each year. Hypertension affects approximately 1.28 billion adults worldwide, yet fewer than half (46%) are aware of their condition. Undiagnosed hypertension is a critical public health gap, contributing to preventable cardiovascular morbidity through silent end-organ damage. Machine learning can enable community-level screening using routinely available, non-invasive data, without the requirement of laboratory investigations. Methods We conducted a cross-sectional ML study using the National Health and Nutrition Examination Survey (NHANES) 2017-2018 cycle. Adults aged [≥]18 years were included; those with a self-reported prior hypertension diagnosis (n=1,930) were retained as negative controls. Probable undiagnosed hypertension was defined as mean blood pressure [≥]130/80 mmHg among participants reporting no prior hypertension diagnosis, consistent with the ACC/AHA 2017 threshold. Three classifiers: Logistic Regression (LR), Random Forest (RF), and Extreme Gradient Boosting (XGBoost) were trained on eight non-invasive predictor variables. Performance was assessed using AUC-ROC, sensitivity, specificity, and F1 score with bootstrap 95% confidence intervals (CIs). Stratified 5-fold cross-validation was applied. Results Of 9,254 NHANES 2017-2018 participants, 5,237 adults were included after exclusion criteria were applied; 1,072 (20.5%) had probable undiagnosed hypertension. LR achieved the highest test AUC of 0.611 (95% CI: 0.571-0.652), with sensitivity 0.535 (95% CI: 0.473-0.600) and specificity 0.594 (95% CI: 0.560-0.626). RF demonstrated near-absent sensitivity (0.047) despite adequate AUC (0.607), while XGBoost performed intermediately (AUC: 0.599; sensitivity: 0.279). Diabetes status, sex, and age were the most influential predictors by permutation feature importance. Conclusion ML classifiers trained on eight non-invasive variables demonstrated modest but consistent discrimination for identifying probable undiagnosed hypertension, supporting the feasibility of laboratory-free community screening. External validation in diverse populations is warranted before clinical implementation.

Objectives: To compare real-world cardiovascular outcomes and safety events in patients with resistant hypertension following initiation of transdermal clonidine (TC) or spironolactone. Methods: A retrospective analysis was performed using Merative MarketScan(R) Databases in the USA to identify cohorts with resistant hypertension initiating TC or spironolactone as a fourth-line agent between January 2012 and September 2024. Major Adverse Cardiovascular Events (MACE) and safety events were assessed during variable follow-up periods. Inverse probability of treatment weighting (IPTW) was applied to adjust for differences in baseline characteristics. Cox proportional hazard models were used to adjust for post-index beta-blocker utilization as a time-varying covariate for MACE outcomes. Results: The analysis included 3,113 patients in the TC cohort and 30,640 in the spironolactone cohort. After IPTW, baseline characteristics were well balanced between cohorts (standardized mean differences <0.10; mean age 60 years, 54% male). Mean follow-up was 7.1 and 10.5 months for the TC and spironolactone cohorts, respectively. After IPTW no differences in MACE outcomes were observed between the two cohorts (weighted rate ratio 1.27 [0.79-2.06]). Results were consistent after adjusting for post-index beta-blocker use. The risk of hyperkalemia was significantly lower in the TC cohort (weighted rate ratio, 0.48 [0.33-0.70]. Conclusions: In this real-world analysis, patients with resistant hypertension treated with TC have similar risk for MACE outcomes as with spironolactone, but with significantly lower risk of hyperkalemia. Thus, in patients with resistant hypertension TC appears to provide similar cardiovascular protection, with a more favorable safety profile.

We evaluated the blood pressure (BP) lowering efficacy and safety of triple vs dual therapy of antihypertensive drug (AHTD) combinations, among adults with hypertension. Seventeen randomized, double-blind trials (41 comparisons and 13,461 participants) comparing triple versus dual therapy for 3 weeks identified by multiple literature databases searches including PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) until October 2024 were included in the meta-analysis. Triple therapy achieved a greater reduction in systolic BP (SBP) compared with dual therapy (26.9 vs. 21.7 mmHg, mean difference 5.4 mmHg [95% CI, 4.7 to 6.2]). Among patients receiving dual therapy at submaximal and maximal doses, the addition of a third drug further reduced SBP by 7.5 and 3.6 mmHg, respectively. BP control was significantly better with triple therapy (60% vs. 47%, RR=1.34 [1.27 to 1.41]). Withdrawal due to adverse events was slightly higher in the triple therapy group (4% vs. 3%, RR=1.5 [1.2 to 1.8]). Triple AHTD therapy provides superior BP reduction and is well-tolerated compared to dual therapy.

This study enrolled 152 hypertensive patients with an ARR > 3.7 to assess the relationship between the traditional hypokalemia cutoff (3.5 mmol/L) and primary aldosteronism (PA) screening, and to establish a new cutoff. Under the traditional cutoff, only 35.7% of PA patients presented with hypokalemia. ROC curve analysis identified a new cutoff of 4.22 mmol/L, which increased sensitivity from 35.7% to 77.5%, with a specificity of 91.1% and an AUC of 0.897. The findings indicate that the traditional cutoff is insufficiently sensitive, while the new cutoff markedly improves screening sensitivity and facilitates early detection of PA.

Background: Pediatric hypertension (HTN) remains underdiagnosed despite established guidelines. Prior studies evaluating social drivers of health (SDOH) relied on diagnostic codes or single-visit blood pressure (BP) measurements, limiting identification of persistent BP elevation. We evaluated longitudinal BP patterns and associated SDOH among children with continuity of care. Methods: We conducted a retrospective cohort study of children aged 6-17 years with [&ge;]3 primary care visits between 2017 and 2024 within a large healthcare network. BP was classified according to guidelines. Multivariable logistic regression evaluated associations between persistent abnormal BP ([&ge;]3 abnormal readings, would meet guideline-based diagnosis for HTN) and stage 1/2 HTN with demographic, clinical, and neighborhood-level factors, including Area Deprivation Index (ADI), Child Opportunity Index (COI), and insurance instability. Results: Among 71,683 children, 2,911 (4.2%) had persistent abnormal BP, whereas only 848 (1.2%) had a documented HTN diagnosis. Obesity, age [&ge;]13 years, male sex, prematurity, and insurance instability were associated with abnormal BP and stage 1/2 HTN. Higher ADI quartiles were associated with increased odds of abnormal BP (Q3: OR 2.48) and stage 1/2 HTN (Q3: OR 4.89). Higher COI socioeconomic opportunity was associated with lower odds of abnormal BP, whereas higher educational opportunity was associated with higher odds; these associations were not observed for stage 1/2 HTN. Conclusions: Among children with continuity of care, substantial gaps in HTN recognition persist despite repeated opportunities for diagnosis. SDOH factors remained associated with BP abnormalities, supporting the need for system-level and community-based strategies to improve HTN detection.

Background: Hypertension is a leading modifiable cardiovascular risk factor prominently influenced by health-related social needs (HRSN). Whether detailed information on HRSN can improve identification of hypertension among minoritized women is unknown. Methods: Black and Latina women aged 18-65 years completed the Centers for Medicare and Medicaid Services Accountable Health Communities Screening Tool, assessing 13 HRSN domains. Hypertension was ascertained by a validated EHR-based algorithm or self-report of hypertension. Logistic regression tested associations of HRSN with hypertension. LASSO regression with 10-fold cross-validation was used to derive a poly-social risk score in the training set (random 70%) and tested in the validation set (30%) against a sociodemographic model (age, race, income, education). Results: Among 1302 participants (mean [SD] age 40.1 [11.3] years, 70.4% Black, 44.3% Latina), higher cumulative burden of HRSN was associated with increased odds of hypertension (adjusted odds ratio [aOR] for each additional domain of HRSN: 1.07 [95% CI 1.01-1.14], P=0.02). Food insecurity (aOR 2.30 [1.37-3.87], P= 0.002), lapse in utilities (aOR 1.44 [1.04-1.96], P=0.02), poor concentration (aOR 1.57 [1.13-2.17], P=0.007), and social isolation (aOR 1.77 [1.14-2.73], P=0.01) were associated with hypertension. In the validation set, the poly-social risk score did not improve discrimination for hypertension vs. the sociodemographic model (AUC 0.76 [95% CI 0.71-0.81] vs. AUC 0.80 [0.75-0.85]). Conclusion: In this cross-sectional analysis of Black and Latina women, greater cumulative social disadvantage was associated with hypertension. While inclusion of HRSN did not improve hypertension prediction beyond conventional sociodemographic indices, findings may inform targeted interventions among minorities at cardiometabolic risk.

Introduction: Diastolic pulse wave analysis provides non-invasive indices of arterial elasticity, but their associations with cardiac structure and function remain incompletely understood. Objective: To examine associations between arterial elasticity assessed by diastolic pulse wave analysis and echocardiographic measures of cardiac structure and function in a community-based cohort. Methods: A population-based cohort recruited 2816 randomly selected men and women aged 30-75 years between 2002 and 2005. A random subsample (n = 1,035) underwent echocardiography by a single senior cardiologist. Large-artery elasticity (C1) and small-artery elasticity (C2) were assessed by radial artery applanation tonometry. The analytical sample included 991 participants. Associations were examined using multivariable linear and logistic regression with sequential adjustment. The final model included sex, age, heart rate, diabetes mellitus, LDL cholesterol, body mass index, antihypertensive medication use, current smoking, alcohol intake, leisure-time physical activity, and systolic blood pressure. Results: Among 991 participants, mean age was 51 years, 488 were men, and 160 had left ventricular hypertrophy. Mean C1 was 16.0 {+/-} 5.1 mL/mmHg x 10, mean C2 was 6.9 {+/-} 3.5 mL/mmHg x 100, and mean EF was 73.4 {+/-} 8.5%. Higher C2 was associated with higher EF after systolic blood pressure adjustment ({beta} per 1-SD increase: 1.2; 95% CI: 0.5-1.9; p < 0.001). Higher C1 was associated with lower odds of left ventricular hypertrophy (OR per 1-SD increase: 0.61; 95% CI: 0.44-0.84; p = 0.003). Conclusions: Higher C2 was associated with better systolic function, whereas higher C1 was associated with lower odds of left ventricular hypertrophy.

Blood pressure (BP) is a vital sign which is measured to diagnose and manage hypertension. However, current methods to measure BP use inflatable cuffs which cause discomfort and limit the frequency at which measurements can be made, or intra-arterial catheters which are invasive and pose infection risks. Here, we propose and evaluate the use of Diffuse Speckle Pulsatile Flowmetry (DSPF) as a cuffless BP measurement method to address these limitations. DSPF is a laser speckle-based technique which simultaneously records blood flow rate and blood volume (i.e. photoplethysmography or PPG) signals from relatively deep vascular tissue. Using information from these signals, we studied DSPFs effectiveness in measuring systolic BP (SBP) and diastolic BP (DBP) through an outpatient study in which 133 patients were recruited, and in measuring beat-to-beat BP waveforms through an inpatient study in which two patients were recruited. In the outpatient study, the DSPF method was able to achieve mean absolute errors (MAEs) of 4.17 mmHg and 2.42 mmHg for SBP and DBP respectively compared to conventional cuff-based methods. It was also able to fulfil the requirements of the AAMI/ESH/ISO 81060-2:2018 standard for BP measurement devices and attain an "A" grade according to the British Hypertension Society grading scheme. For the inpatient study, it produced BP waveforms which had MAEs of 2.35 mmHg and 3.06 mmHg compared to arterial-line measurements for the two patients, respectively. Compared to PPG which has been studied more extensively as a cuffless BP measurement method, we found through ablation studies that DSPF was able to reach significantly lower MAEs and hence better accuracies. DSPF augments the performance of PPG-only methods by leveraging additional information from the blood flow rate signal, and we therefore find it to be a superior cuffless BP measurement method which can potentially be used in outpatient, inpatient, and remote settings.

Background: Hypertension is the leading modifiable cardiovascular risk factor globally, with the fastest-growing burden in low- and middle-income countries. This study aimed to estimate national hypertension prevalence, map provincial patterns, assess spatial clustering, and identify individual and community-level determinants among Zambian adults using the 2017 WHO STEPS survey. Methods: This cross-sectional study used data from the 2017 WHO STEPS survey, a nationally representative sample of 4,301 adults aged 18-69 years. Hypertension was defined as systolic BP [&ge;]140 mmHg, diastolic BP [&ge;]90 mmHg, or current antihypertensive use. Spatial autocorrelation was assessed via Moran's I and LISA. Four nested generalised linear mixed models with PSU-level random intercepts identified individual and community-level determinants. Results: Overall weighted hypertension prevalence was 24.0%. Lusaka recorded the highest prevalence (30.2%), followed by Southern (29.9%) and Muchinga (28.3%) provinces; Western Province had the lowest (12.4%). Spatial clustering was statistically significant but modest (Moran's I = 0.0247, p < 0.001). Between-cluster variation reduced from ICC = 5.9% to 1.8% in the full model, indicating geographic differences were largely explained by individual characteristics. Age was the strongest predictor; adults aged 60-69 had nearly sevenfold higher odds than those aged 18-29 (AOR 6.92, 95% CI: 4.95-9.66). Women had lower odds than men (AOR 0.64, 95% CI: 0.52-0.79). Obesity (AOR 2.34), overweight (AOR 1.65), high cholesterol (AOR 1.40), diabetes (AOR 1.35), and single marital status (AOR 1.34) were independently significant. Western Province showed consistently lower odds than Central Province (AOR 0.48). Conclusion: Hypertension affects one in four Zambian adults, driven primarily by age, sex, obesity, dyslipidaemia, and diabetes. Geographically prioritised interventions, including community health worker-led screening programmes in Lusaka and Southern Province, would maximise population-level impact. Population-level salt reduction and alcohol policies represent cost-effective complementary strategies. Longitudinal studies with finer spatial resolution are needed to clarify causal pathways underlying observed geographic clustering and inform SDG Target 3.4 progress.

Background: Metabolic syndrome (MetS) has been associated with cognitive decline. Considering its increasing prevalence worldwide, the goal of this study was to evaluate the feasibility and efficacy of a short-term, self-administered computerized cognitive training programme in individuals with metabolic syndrome and low cognitive performances. Methods: Thirty six participants, aged 40-72 years (mean age: 57.8 years), were randomly assigned to the cognitive training or the passive control group. The cognitive training component of Long Lasting Memories (LLM) Care was used as an interactive software to enhance participants' cognitive functions. Up to 24 sessions, each lasting 45 minutes, were self-administered at home twice per week for 3 months. Thorough cognitive assessments with were performed at baseline (randomization), at the end of intervention, and 12 months after baseline. The primary outcome was performance at nine neuropsychological tests, and the secondary outcome was a self-reported questionnaire assessing everyday functional abilities. Primary analyses were performed employing mixed-effect models using the intention-to-treat principle. Results: Low adherence was observed in the study, as only 9 participants (50%) completed at least 8 sessions of the cognitive training programme (range 9-24 sessions, median 15 sessions). No statistically significant effect of the cognitive training programme on performance in neuropsychological tests or everyday functioning was found. At the end of the 3-month intervention programme, effect for visual memory enhancement in immediate ({beta} = 1.58, 95% CI = -1.84 to 4.99, Cohen's d = 0.39) and delayed recall ({beta} = 2.17, 95% CI = -1.68 to 6.01, Cohen's d = 0.45) was moderate in favour of the intervention group, and at 12-month follow-up, semantic verbal fluency gains for the intervention group were detected ({beta} = 2.78, 95% CI = -0.92 to 6.49, Cohen's d = 0.70), though with wide confidence intervals. Conclusions: Despite some small effects observed in memory and verbal fluency, cognitive training did not yield statistically significant improvements. The observed low adherence and limited benefits on mild cognitive deficits in mostly middle-aged individuals with MetS are likely associated with the self-administered and short-term nature of the computerized intervention. This highlights the need for more intensive and clinician-delivered approaches to enhance engagement. Registry: ClinicalTrials.gov, TRN: NCT05658354, Registration date: 08 December 2022. Keywords: Metabolic syndrome, cognitive deficits, cognitive training, computerized, adults

Background: The fibrosis-4 index (FIB-4) is a simple noninvasive marker originally developed to assess liver fibrosis risk. Accumulating evidence suggests that FIB-4 is associated with adverse cardiovascular outcomes, but its prognostic relevance in patients with primary aldosteronism (PA) remains unclear. Methods: In this retrospective multicenter cohort study, patients with PA were stratified into low, intermediate, and high FIB-4 groups using established cutoffs: <1.3, 1.3-2.67, and >2.67. Outcomes included all-cause mortality, ischemic stroke, hemorrhagic stroke, acute myocardial infarction, and major adverse cardiovascular events (MACE). Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) across FIB-4 categories. Results: Among 2,467 patients with PA, 1,215 (49.3%) had FIB-4 <1.3, 863 (35.0%) had FIB-4 1.3-2.67, and 389 (15.8%) had FIB-4 >2.67. Patients with higher FIB-4 were older and had lower body mass index, worse renal function, lower potassium, and a higher comorbidity burden. During follow-up, all-cause mortality increased across FIB-4 categories, from 13.9% in the low FIB-4 group to 58.1% in the high FIB-4 group. After multivariable adjustment, FIB-4 >2.67 was associated with higher risks of all-cause mortality (adjusted HR, 1.98; 95% CI, 1.54-2.54) and MACE (adjusted HR, 1.78; 95% CI, 1.44?2.20), compared with FIB-4 <1.3. Adjusted linear regression analyses showed that higher FIB-4 was significantly associated with lower renin and higher aldosterone-to-renin ratio. Conclusions: In patients with PA, elevated FIB-4 identified a high-risk subgroup with increased all-cause mortality and MACE. FIB-4 may serve as a simple, noninvasive tool for prognostic stratification in patients with PA.

Background: Elevated C-Reactive Protein (CRP), interleukin-6 (IL-6) and testosterone deficiency are associated with advanced age and chronic inflammatory diseases; while normal testosterone levels have been shown to decrease inflammation through several mechanisms. Cross-sectional studies have shown an inverse relationship between CRP, IL-6 and total testosterone (TT) levels, yet mixed findings have been reported when individual components of metabolic syndrome are considered. We evaluated the relationship between CRP, IL-6 and TT levels in men from 2004-2018 using the Baltimore Longitudinal Study of Aging to determine if low testosterone status is associated with a high inflammatory profile. Methods: Participants were selected from the Baltimore Longitudinal Study of Aging. Male participants with serum TT level measured during at least three visits were included in our cohort. Common measures of inflammatory disease such as CRP, High-Density Lipoprotein (HDL) and Triglyceride levels were collected via blood specimens. Comorbidity data were documented at each visit. Panel regression was used to analyze the relationship of a series of independent variables collected in pooled cross-sectional observations over time with a dependent variable for modeling. Results: A total of 347 patients were included in this study (median age = 70, IQR = 18, average follow up time = 6.7 +/- 3.2 years). Participants had a median CRP level of 1.0 mg/dL, median IL-6 level of 3.6, a median TT level of 446 ng/dL. On univariable analysis, increasing TT and HDL levels were associated with a decline in CRP, while high Body Mass Index (BMI), congestive heart failure (CHF), Diabetes, and increased serum triglycerides were associated with increased CRP. Age was not associated with CRP. On multivariable analysis, we found that increasing TT level was associated with a decline in CRP levels, independent of comorbidities (p = 0.018; Table 1). As expected, increased BMI was associated with a significant increase in CRP (p = 0.001, Table 1). Age, CHF, Diabetes, HDL, and Triglycerides were not significant predictors of CRP on multivariable analysis. Similarly, on multivariable analysis, increasing TT levels were independently associated with lower IL-6 levels. Higher HDL cholesterol levels were also associated with lower IL-6 levels, whereas increasing age was associated with higher IL-6 levels. BMI, CHF, diabetes, and triglycerides were not significant predictors of IL-6. Conclusions: Lower levels of serum total testosterone are associated with an increase in CRP in older men over time, independent of chronic inflammatory disease. Given the importance of CRP in pathogenesis of chronic disease, we highlight the potential benefits of using total testosterone as a biomarker of chronic inflammatory states.

Background: Despite the common use of local heating and intradermal microdialysis perfusion of acetylcholine (ACh) to probe cutaneous endothelium and nitric oxide (NO)-dependent dilation, sex differences in microvascular responsiveness to these stimuli in healthy young adults remain incompletely understood. Methods: Cutaneous vasodilation was assessed in response to local heating to 39{degrees}C and 42{degrees}C and graded perfusion of ACh (10-10 to 10-1 mol/L) alone or concurrently with 15 mM NG-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor) using laser-Doppler flowmetry coupled with intradermal microdialysis in 80 young adults (40 females). Results: Local heating to 42{degrees}C elicited greater endothelium- and NO-dependent dilation than heating to 39{degrees}C in both groups (p<0.001), but no sex differences were observed at either temperature (p=0.65). ACh-induced endothelium-dependent dilation also was not different between sexes (p=0.08), but the NO-dependent component was greater in females than in males (p=0.01). In young females, menstrual cycle day (range: day 2-33) was not associated with endothelium- or NO-dependent dilation in response to any stimulus (all p[&ge;]0.19), regardless of hormonal contraceptive use. Conclusions: Taken together, these findings suggest that sex differences in microvascular NO bioavailability in healthy young adults depend on the stimulus used to elicit cutaneous vasodilation and, in females, microvascular endothelium- and NO-dependent dilation are not meaningfully influenced by menstrual cycle phase.

Background and aims: Longitudinal data and tracking of serum lipoprotein(a) (Lp(a)) concentrations through childhood?s development from infancy to adolescence are lacking. We aimed to establish the strength of the tracking phenomenon from early infancy to adolescence and to examine whether a heart-healthy dietary intervention and individual dietary components influence serum concentrations of Lp(a). Methods: 1062 healthy children aged 7 months were recruited and randomized into control (N=522) and intervention (N=540) groups in the Special Turku Coronary Risk Factor Intervention Project (STRIP). Serum Lp(a) concentration was measured at 10 age points (0.7, 1.3, 2, 3, 4, 5, 9, 11, 13, and 15 years) and median serum Lp(a) levels were studied longitudinally. Tracking across age points was studied using Spearman's rank-order correlation. Sex differences and the effects of the dietary intervention and individual dietary components were analyzed with linear mixed-effects models for repeated measures. Results: A total of 7018 Lp(a) measurements were analyzed. Median serum Lp(a) concentrations increased from infancy until approximately age 13 years. After age 13, median Lp(a) declined in boys (-15.1%) but was largely unchanged in girls. Girls had higher Lp(a) concentrations at all age points (P=0.01). Spearman's correlation analysis indicated a strong tracking between age points in both sexes (r=0.854-0.956). Achievement of at least one dietary fat quality goal of the intervention corresponded to a 2.5% increase in serum Lp(a) concentration (P=0.0004). Higher sucrose intake was associated with modestly higher Lp(a), whereas fiber intake showed no association. At age 15 years, 16.2% of all participants with available measurements had elevated Lp(a) ([&ge;] 30mg/dL). Conclusions: A rising trend was observed in median serum Lp(a) concentrations from infancy to adolescence. Due to strong tracking, these findings suggest that early-life measurements may provide valuable insight for longitudinal cardiovascular risk assessment. Heart-healthy diet does not meaningfully influence serum Lp(a).

Background: Although diabetes is a potent risk factor for the development of peripheral artery disease (PAD), the effect of cumulative metabolic exposure to hyperglycemia on risk of cardiovascular or limb events in patients with PAD remains unclear. Methods: The Peripheral Artery Disease: Long-term Survival (PEARLS) is a longitudinal registry of Veterans with newly diagnosed PAD identified using a natural language processing approach. Included patients had ankle brachial index [&le;]0.9 or toe brachial index [&le;]0.7, and no history of lower extremity revascularization or major amputation. Among patients with diabetes in this cohort, we assessed cumulative exposure to hyperglycema based on a 24-month rolling average of hemoglobin (Hgb) A1c values, categorized as [&le;]7%, >7% to [&le;]8%, and >8%. Multivariable Cox regression models evaluated the association between categories of HgbA1c, modeled as a time-varying exposure, and risk of cardiovascular (CV: myocardial infarction or stroke) and limb (chronic limb threatening ischemia [CLTI] or major amputation) events. Results: Among 45,109 patients with new diagnosis of PAD and pre-existing diabetes, the mean HgbA1c at baseline was 7.5%, with nearly one-third (30.4%) having HgbA1c >8%. The mean age was 70.4 years, 19.8% were Black and 4% were Hispanic. Patients with baseline HgbA1c >8% were younger and compared to those with HgbA1c [&le;]7%, more likely to have coronary disease, kidney disease, and obesity. Over a median follow up of 4.2 years, 8,306 (18.4%) patients experienced a CV event, and 8,199 (18.2%) experienced a limb event. The adjusted association between HgbA1c and hazard of CV events was 12% higher in patients exposed to HgbA1c >7% to [&le;]8% (HR 1.12; 95%CI: 1.05-1.18) and 38% higher in those exposed to HgbA1c >8% (HR 1.38; 95%CI: 1.30-1.46), compared to HgbA1c <7%. The association with limb events was even stronger, with 20% and 60% higher hazard in those exposed to >7% to [&le;]8% (HR 1.20; 95%CI: 1.13-1.28) and HgbA1c >8% (HR 1.60; 95%CI: 1.51-1.70), respectively when compared to HgbA1c [&le;]7%. These findings were consistent in subgroups based on age and severity of PAD. Conclusions: Among diabetic patients with PAD, cumulatiave metabolic exposure to hyperglycemia is associated with a markedly increased risk of clinical events, especially limb events.

Elastin haploinsufficiency is a primary determinant of arteriopathy and hypertension that hallmark Williams syndrome (WS), a rare genetic disorder resulting from microdeletion of genes on human chromosome 7, including the elastin gene (ELN). Accumulating evidence suggests renal dysfunction, including enhanced sodium and water retention as an underlying cause of blood pressure elevation resulting from heterozygous deletion of Eln (Eln+/-) in mice that recapitulates the cardiovascular phenotype of WS. However, the underlying pathophysiological mechanisms are poorly understood. Here, we determined whether the activity of neuraminidase-1 (NEU1) of the elastin receptor complex (ERC) contributes to abnormal handling of water and electrolytes by the kidney in Eln haploinsufficiency. Adult male and female Eln+/+ and Eln+/- mice were subjected to acute extracellular fluid volume expansion with normal saline, combined with pharmacological intervention targeting vasopressin V2 receptor (V2R), NEU1, ENaC, and NKCC2. In male Eln+/+ mice, V2R blockade induced a dose-dependent increase in urine flow rate without affecting sodium excretion. Conversely, V2R stimulation with desmopressin markedly increased urinary sodium excretion in male Eln+/+ but not Eln+/- mice, while both sexes of Eln+/- mice exhibited marked suppression of urine flow rate. Abrogation of ERC signaling through NEU1 inhibition produced a modest increase in urinary sodium excretion in male mice of both genotypes but augmented urine flow rate only in male Eln+/+mice. NEU1 blockade strikingly enhanced the natriuretic effect of furosemide and amiloride in male Eln+/+ and modestly in Eln+/-mice. Taken together, we conclude that Eln haploinsufficiency disrupts vasopressin-dependent modulation of sodium and water reabsorption by sex-dependently altering ERC-mediated modulation of NKCC2 and ENaC. These findings reveal a novel mechanism by which abnormal ERC activity due to Eln haploinsufficiency potentially contributes to renal dysfunction and hypertension. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/731713v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1870e8org.highwire.dtl.DTLVardef@9cbd8dorg.highwire.dtl.DTLVardef@60b2deorg.highwire.dtl.DTLVardef@7f31f1_HPS_FORMAT_FIGEXP M_FIG C_FIG AC, adenylyl cyclase; AQP2, aquaporin 2; CD, collecting duct; CNT, connecting tubule; DCT, distal convoluted tubule; EBP, elastin binding protein; Eln, elastin allele; ENaC, epithelial sodium channel; ERC, elastin receptor complex; Gs, stimulatory G subunit; NEU1, neuroaminidase1; NKCC2, sodium-potassium-chloride cotransporter; PPCA, protective protein/ cathepsin A; TAL, loop of Henle thick ascending limb; V2R, vasopressin receptor type 2

ABSTRACT Importance: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE), due to both traditional CVD risk factors and SLE specific factors. Although statins are first-line therapy for primary prevention of CVD in the general population, it is unclear whether statins protect against first time cardiovascular events (CVEs) in patients with SLE. Objective: Determine whether statins are protective in primary prevention of CVEs among patients with SLE. Design, setting, and participants: This cohort study is a retrospective analysis of a well-characterized, prospective cohort of patients with SLE with patient follow-up beginning in 2013. Main outcome and measures: CVEs were defined as the occurrence of myocardial infarction, thrombotic stroke, onset of angina, or coronary bypass procedure. Statin use in the prior year was quantified based on standardized defined daily doses (DDD). Rates of occurrence were compared using pooled logistic regression. A multivariable model was performed to adjust for possible confounders. Results: The analysis was based on 8708 person-years of follow-up from 1396 cohort participants: 1283 (92%) were women, 567 (41%) Black, and 665 (48%) White. Patients were stratified by use of statin within the last year: none, < standard DDD, or [&ge;] standard DDD. The rate of events per 1000 person-years was respectively 5.3, 8.5, and 8.0 (p=0.31) within these 3 groups, suggesting potential lack of protective effect of statin treatment. The rates of CVEs among statin versus non-statin users remained the same after adjusting for and stratifying by total cholesterol level (p=0.18). Significantly higher rates of CVEs occurred among those with body mass index (BMI) 25-30 kg/m^2 (p=0.0066) and those prescribed [&ge;] 10 mg/day of prednisone (p=0.0003). Multivariable analysis also suggested a potential lack of protective effect of statins against CVEs (OR 1.48; 95% CI, 0.79-2.75; p=0.21883) and diabetes mellitus was found to be independently associated with an increased risk for development of CVEs (OR 4.48; 95% CI 1.99-10.08; p=0.00029). Conclusion and Relevance: Among patients with SLE, statin use may not be protective in primary prevention of CVEs, regardless of statin exposure. Prednisone use, history of diabetes mellitus, and elevated BMI were drivers of increased cardiovascular risk in univariate analysis. Diabetes mellitus persisted as an independent risk factor for CVEs in a multivariable model. Our work reinforces findings from clinical trials which have shown no reduction in subclinical measures of atherosclerosis with statin use among patients with SLE, as well as a mechanistic substudy which demonstrated that statins are ineffective in normalizing the pro-atherogenic changes induced by SLE.

Abstract Background: Immune-mediated inflammatory diseases (IMIDs) are associated with increased risk of cardiometabolic diseases. Investigating genetic overlap among these conditions can provide insights into their clinical management. Methods: Genetic correlation was assessed using linkage disequilibrium score regression (LDSC). Then, a meta-analysis was conducted using Association Analysis Based on SubSETs (ASSET) to pinpoint independent single nucleotide polymorphisms (SNPs) shared across the diseases. Each independent SNP was then used to define a genomic window (+/-500KB) for colocalisation analysis and Local Analysis of [co]Variant Association (LAVA) to offer multiple layers of regional pleiotropic evidence. Over-representation analysis was then run to identify enriched biological pathways, which then were used for drug target analysis. Results: The LDSC analysis showed a significant global genetic correlation for rheumatoid arthritis (RA) and cardiometabolic diseases including hypertension, coronary artery disease (CAD), heart failure (HF), stroke, atrial fibrillation (AF), and type two diabetes mellitus (T2DM) ranging from rg = 0.09 to 0.24. ASSET meta-analysis identified 164 independent SNPs shared across RA and the cardiometabolic diseases with P < 5 x 10- in the overall one-sided meta-analysis P-value, FDR < 0.05 in both individual GWASs, and TRUE phenotype matrix. Colocalisation analysis revealed multiple loci with strong evidence (Posterior probabilities [&ge;] 80) of single causal SNPs between the trait pairs. LAVA analysis was then used as an additional layer of confirmation for the findings generated by ASSET and colocalisation and thus several loci were highlighted. Over-representation analysis showed significant enriched immune-related pathways across RA-hypertension, RA-CAD, RA-AF, and RA-T2DM trait pairs. Drug target analysis highlighted several drugs which could be further tested for their effectiveness in RA and its common comorbidities. Conclusion: The findings revealed a shared genetic architecture and key immune-related biological pathways underlying RA and its associated cardiometabolic comorbidities. The identified genes and drugs provide opportunities for further therapeutic assessment which could improve clinical management strategies.

Background: Familial hypercholesterolemia (FH) is a semi-dominant genetic disorder characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C) and a markedly increased risk of premature atherosclerotic cardiovascular disease (CVD). Despite this elevated risk, some individuals with FH survive beyond 70 years of age without developing clinical CVD. This study aimed to identify genetic variants associated with protection against cardiovascular events and to uncover mechanisms contributing to this resilience phenotype. Methods: Whole-exome sequencing (WES) was performed in 243 French-Canadian heterozygous FH individuals carrying the pathogenic LDLR c.259T>G (p.Trp87Gly) variant. After stratification by age and cardiovascular event (CVE) status, 35 individuals with premature CVE and 20 individuals aged [&ge;]70 years who remained free of CVE despite spending several decades in the pre-statin era were selected for comparative analysis. Results: Variant annotation and quality-control validation using Firth logistic regression identified 12 genetic variants potentially associated with cardiovascular resilience. Among these, a stop-gain variant resulting from the single-nucleotide polymorphism rs4985556 in IL34 demonstrated the strongest association with event-free survival (allele frequency in CVE- = 0.25 vs. CVE+ = 0.00; {chi}2 = 19.25; P = 1.15 x 10-5). The IL34 stop-gain variant (c.639C>A [p.Tyr213*]) was associated with a markedly increased likelihood of cardiovascular event-free survival (OR = 20.9; 95% CI, 2.7-2841.7; P = 3.45 x 10-4). Conclusion: These findings identify IL34 as a potential cardiovascular resilience gene and highlight novel genetic determinants that may protect against cardiovascular events despite lifelong exposure to elevated LDL-C levels. In addition to IL34, eleven variants showed strong associations with a CVE-free phenotype and warrant further investigation to elucidate their biological mechanisms and potential relevance for cardiovascular disease prevention.

Background: Elevated low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Guidelines recommend reducing saturated fat intake to lower LDL-C. However, LDL-C responses to saturated fat vary substantially from person to person. Genetic factors may contribute to individual differences in response to saturated fat. Objectives: We aimed to examine whether genetic propensity for higher LDL-C modifies the association of saturated fat intake with LDL-C and incident ASCVD. Methods: We studied 20,940 genotyped postmenopausal women from the Women's Health Initiative. Exposures included saturated fat intake (percentage of total calories) derived from food frequency questionnaires and a genome-wide polygenic score for LDL-C (PGS-LDL). The primary outcome was LDL-C. The secondary outcome was incident ASCVD. Associations were assessed using multivariable linear and Cox regressions. Effect modification was evaluated using interaction terms and restricted cubic spline analyses. Results: The median LDL-C at baseline for participants with PGS-LDL below and above the median was 135 mg/dL [Q1: 114, Q3: 160] and 162 mg/dL [137, 188], respectively. Saturated fat intake was positively associated with LDL-C in the high PGS-LDL group, but the association attenuated in the low PGS-LDL group (P-interaction=0.01). Spline analysis revealed a non-linear interaction between PGS-LDL and saturated fat, with modifying effects emerging at higher PGS-LDL. Compared to individuals with low PGS-LDL and low saturated fat intake, only those with both high PGS-LDL and high saturated fat intake had increased risk for ASCVD in an adjusted analysis (HR 1.30, 95% CI 1.13-1.51). This association remained significant after further adjustment for baseline LDL-C (HR 1.17, 95% CI 1.01-1.37). Spline analyses of ASCVD risk revealed a similar interaction pattern to that observed for LDL-C. Conclusions: These findings suggest that the association between saturated fat intake and LDL-C and subsequent ASCVD risk may be stronger for individuals with a genetic propensity towards high LDL-C.