BACKGROUND:Diuretics are widely used alone or in combination with other medications to lower blood pressure (BP). The dosing ratio between hydrochlorothiazide and chlorthalidone for lowering BP, as well as the effects of different amiloride doses on BP and their ability to counteract thiazide's adverse metabolic effects, remain unclear. METHODS:In a factorial superiority randomized clinical trial with blinded participants and investigators, we compared the effects of chlorthalidone 25 mg with hydrochlorothiazide 50 mg and amiloride 5 mg with 10 mg on BP measured by office and ambulatory BP monitoring and laboratory parameters. Patients were followed for 12 weeks. RESULTS:The treatments showed no statistically significant interaction; comparisons were evaluated separately. Hydrochlorothiazide and chlorthalidone had similar effects on systolic and diastolic BP measured at the office and by ambulatory BP monitoring. The between-group δs (hydrochlorothiazide minus chlorthalidone) for systolic 24-hour and nighttime BP were -1.1 (95% CI, -8.0 to 5.9; P=0.8), and -2.3 (95% CI, -10.3 to 5.7; P=0.6), respectively. The effects of amiloride 5 mg and 10 mg on BP were similar. Laboratory parameters did not differ between hydrochlorothiazide and chlorthalidone. Comparing amiloride doses, serum sodium decreased more with 10 mg, while the remaining parameters were similar between doses. CONCLUSIONS:Chlorthalidone and hydrochlorothiazide, administered at a 1:2 dosing ratio, show similar effects on BP and laboratory parameters. Amiloride 5 and 10 mg show similar effects on BP and most metabolic parameters, with no clear dose-response relationship, suggesting that any independent BP-lowering effect of amiloride is, at best, weak. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03928145.
BACKGROUND:Tensor-valued diffusion magnetic resonance imaging enables the separation of total kurtosis into isotropic and anisotropic components, offering improved specificity over conventional diffusion kurtosis imaging. In this study, we introduce a novel framework for detecting anisotropic-isotropic kurtosis mismatch and evaluate its relevance in experimental ischemic stroke. METHODS:Tensor-valued diffusion magnetic resonance imaging was performed in a rat model of middle cerebral artery occlusion. Metrics, including anisotropic mean kurtosis and isotropic mean kurtosis, were quantified to assess microstructural tissue heterogeneity. Histologic validation was conducted using coregistered tissue sections. RESULTS:We observed significant mismatches between mean diffusivity, mean kurtosis, as well as specifically in anisotropic mean kurtosis and isotropic mean kurtosis in ischemic regions. Notably, anisotropic mean kurtosis and isotropic mean kurtosis exhibited statistically significant alterations compared with contralateral regions. Moreover, these metrics strongly correlated with pathologic findings. The observed mismatch highlighted microstructurally distinct subregions within the lesion. CONCLUSIONS:This study establishes an in vivo framework for characterizing anisotropic-isotropic kurtosis mismatch in an experimental stroke model. By quantifying the isotropic mean kurtosis/anisotropic mean kurtosis mismatch, tensor-valued diffusion magnetic resonance imaging provides a more specific mechanistic characterization of diffusion heterogeneity than conventional diffusion tensor imaging and diffusion kurtosis imaging metrics, supporting its use as a preclinical tool for investigating microstructural alterations in ischemic brain tissue.
BACKGROUND:Diastolic dysfunction is common in patients with aortic stenosis and may influence outcomes following surgical aortic valve replacement. We aimed to examine the association of preoperative artificial intelligence (AI)-generated diastolic function grades with early and late outcomes following aortic valve replacement and how postoperative progression influence prognosis. METHODS:We identified 5503 patients undergoing aortic valve replacement between 2000 and 2023. Diastolic function was assessed using a validated deep-learning AI model applied to 12-lead ECGs done preoperatively and on postoperative follow-up. Diastolic grades were classified by AI into Grades 1 to 3. Longitudinal trend analyses and multivariable regression models were used to assess study end points. RESULTS:Among 5503 patients (mean age 72.4±10.8 years; 39% female), higher AI ECG diastolic grades were associated with greater comorbidity burden, including diabetes, renal disease, and heart failure. AI ECG diastolic Grade 3 was independently associated with higher in-hospital mortality (odds ratio, 2.5; P=0.007) and other complications. At 5-year follow-up, patients with Grade 3 showed the least improvement in diastolic function by both ECG and echocardiography. Grades 2 and 3 diastolic function at baseline were independently associated with increased late mortality (hazard ratio, 1.3 and 2.45, respectively; both P<0.001). Additionally, lack of improvement in AI ECG diastolic grade by 1 year was also independently associated with late mortality. CONCLUSIONS:AI ECG-derived diastolic function grades strongly correlates with early complications and long-term mortality and diastolic progression after aortic valve replacement. AI ECG provides a powerful, noninvasive tool for risk stratification and longitudinal monitoring of patients with aortic stenosis.
BACKGROUND:Transthyretin amyloid cardiomyopathy (ATTR-CM) carries high risk for all-cause mortality (ACM), cardiovascular mortality (CVM), and cardiovascular hospitalization (CVH). NT-proBNP (N-terminal pro-B-type natriuretic peptide) and serum TTR (sTTR) are prognostic biomarkers in transthyretin amyloid cardiomyopathy, but their combined value for integrated risk stratification remains unknown. We evaluated the relationship between baseline NT-proBNP and sTTR and their prognostic value in ATTRIBUTE-CM (Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy). METHODS:ATTRIBUTE-CM was a phase 3, randomized, double-blind, placebo-controlled trial. Among 632 participants randomized to acoramidis or placebo, baseline NT-proBNP and sTTR concentrations were evaluated post hoc for associations with baseline characteristics, Kansas City Cardiomyopathy Questionnaire overall scores, 6-minute walk distance, National Amyloidosis Center stage, Geriatric Nutritional Risk Index score, and subsequent time to ACM/first CVH and CVM/first CVH through Month 30. RESULTS:Higher baseline NT-proBNP and lower sTTR were associated with greater disease severity and were inversely correlated. Using multivariable linear regression, sTTR remained inversely correlated with NT-proBNP. Using multivariable Cox analyses, baseline NT-proBNP and sTTR were each independently associated with ACM/first CVH and CVM/first CVH. Higher baseline NT-proBNP combined with lower sTTR conferred higher risk and shorter time to event. Acoramidis reduced risk of ACM/first CVH and CVM/first CVH regardless of baseline NT-proBNP/sTTR, National Amyloidosis Center stage, or Geriatric Nutritional Risk Index. CONCLUSIONS:Baseline NT-proBNP and sTTR were additively prognostic for ACM/first CVH and CVM/first CVH in patients with transthyretin amyloid cardiomyopathy. Their joint measurement may be useful for enhanced staging, risk stratification, and prognostication in transthyretin amyloid cardiomyopathy. Acoramidis demonstrated consistent clinical efficacy regardless of baseline NT-proBNP/sTTR status. REGISTRATION:URL: https://clinicaltrials.gov/study/NCT03860935; Unique Identifier: NCT03860935. Registered: February 2019.
BACKGROUND:Nonsyndromic ascending aortic aneurysm (AsAA) may remain clinically silent until dissection or rupture. The contributions of multidomain social determinants of health (SDOH) and polygenic susceptibility to AsAA risk are not well defined. METHODS:In a cross-sectional analysis of 124 180 participants in the National Institutes of Health All of Us Research Program, 14 SDOH measures were summarized as a standardized composite score, and an ascending aortic diameter polygenic risk score (PRS; polygenic score, 004927) was standardized within ancestry strata. Associations were tested using Firth-penalized logistic regression adjusted for clinical risk factors; discrimination was assessed by area under the receiver operating characteristic curve. RESULTS:Among 124 180 participants, 346 had AsAA. Compared with controls, cases were older (mean age, 70.7±9.0 versus 57.1±16.4 years) and more often men (60.4% versus 37.1%). Each 1-SD increase in the SDOH composite was associated with AsAA after clinical adjustment (odds ratio, 1.21 [95% CI, 1.04-1.40]) and in joint models including PRS (odds ratio, 1.28 [95% CI, 1.11-1.48]). The PRS was associated with AsAA after clinical adjustment (odds ratio per SD, 1.94 [95% CI, 1.74-2.16]); AsAA prevalence increased from 0.08% (lowest PRS decile) to 0.77% (highest). SDOH and PRS were minimally correlated (r=-0.002), with no evidence of interaction (interaction odds ratio, 1.03; P=0.62). Discrimination improved from basic covariates (area under the receiver operating characteristic curve, 0.774) to clinical covariates (area under the receiver operating characteristic curve, 0.841) and to the full model including SDOH and PRS (area under the receiver operating characteristic curve, 0.870 [95% CI, 0.851-0.889]). CONCLUSIONS:Social adversity and higher polygenic susceptibility were associated with nonsyndromic AsAA, supporting further study of integrated social and genetic risk stratification.
BACKGROUND:Despite the growing use of catheter ablation for atrial fibrillation, large-scale studies assessing the efficacy and safety of oral anticoagulation (OAC) after ablation, particularly in patients with high stroke risk, remain limited. METHODS:This prospective study enrolled consecutive patients from the China-AF (China Atrial Fibrillation) registry between August 2011 and June 2022. Stroke risk was stratified by CHA2DS2-VA score as low (0-1), intermediate (2), or high (≥3). The study end points were thromboembolism (ischemic stroke or systemic embolism), and bleeding (International Society on Thrombosis and Hemostasis major bleeding and clinically relevant non-major bleeding). A 6-month landmark analysis was applied to evaluate the association of OAC with end points using incidence rates and Cox models. RESULTS:Among 13 669 patients (median follow-up, 4.0 years), 2637 continued and 11 032 discontinued OAC at the 6-month landmark. OAC was not associated with reduced thromboembolism risk across low- (adjusted hazard ratio [aHR], 1.11 [95% CI, 0.70-1.77]; P=0.649), intermediate- (aHR, 0.64 [95% CI, 0.36-1.16]; P=0.141) or high-stroke risk patients (aHR, 1.05 [95% CI, 0.74-1.48]; P=0.801). In contrast, continued OAC was associated with higher bleeding risk, including clinically relevant non-major bleeding across stroke risk strata, and International Society on Thrombosis and Hemostasis major bleeding among high-risk patients (aHR, 2.32 [95% CI, 1.19-4.50]; P=0.013). These results were consistent across subgroups and sensitivity analyses. CONCLUSIONS:In this large, real-world cohort of patients with atrial fibrillation undergoing catheter ablation, continued OAC was not associated with lower thromboembolic risk, but with higher major bleeding risk among patients with CHA2DS2-VA scores ≥3. These findings support individualized post-ablation anticoagulation strategies and warrant future investigation. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique Identifier: NCT06987825.
BACKGROUND:The relationship between institutional volume and transcatheter aortic valve replacement outcomes is complex but vital for optimizing patient triage and developing effective care strategies. METHODS:The authors analyzed outcomes of patients undergoing transcatheter aortic valve replacement between January 2021 and February 2023 in the STS/ACC TVT (Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy) Registry at hospitals affiliated with the CommonSpirit Health network. Centers were categorized by annual TAVR volume as low (<100 cases per year), intermediate (100-300 cases per year), or high (>300 cases per year). Baseline risk assessment included the Society of Thoracic Surgeons score, an estimate of operative mortality risk. The primary outcome was major adverse cardiac and cerebrovascular events. Inverse probability of treatment weighting adjusted for baseline differences. RESULTS:Among 6663 patients, 58.6% were treated at high-volume centers. Patients treated at high-volume centers were older than those at intermediate- or low-volume centers (P<0.001). STS risk scores were highest at high-volume centers than at intermediate- and low-volume centers (P=0.005). After inverse probability of treatment weighting adjustment, high-volume centers remained associated with a reduced risk of major adverse cardiac and cerebrovascular events compared with both low-volume centers (adjusted hazard ratio [aHR], 0.40 [95% CI, 0.16-0.98]; P=0.047) and intermediate-volume centers (aHR, 0.56 [95% CI, 0.34-0.92]; P=0.021). Receiver operating characteristic analysis identified an annual procedural volume threshold of 314 cases as the empirical discriminator of MACCE (area under the curve, 0.77 [95% CI, 0.74-0.80]; P<0.001). CONCLUSIONS:Within this integrated health system, high-volume centers had better risk-adjusted outcomes despite treating higher-risk patients. The empiric volume threshold identified in this cohort should be validated in other settings.
BACKGROUND:Sudden cardiac death (SCD) is an important contributor to the global burden of cardiovascular disease. Previous studies have reported an association with extremes in temperature in the hours and days leading up to SCD, but there has been little investigation focusing on the months and year before an SCD event. Therefore, the objective of this study was to investigate the relationship between short-, medium-, and long-term temperature and SCD. METHODS:Temperature predictions using 800-m Parameter-Elevation Regressions on Independent Slopes Model data were used to estimate monthly moving average temperature. Data on temperature were appended to each Nurses' Health Study participant's geocoded residential addresses. SCD cases were determined on the basis of medical record review and next-of-kin reports. Time-varying Cox proportional hazards models were used to assess the association between exposure 1- and 12-month moving averages of temperature and SCD. Individual risk factors, socioeconomic status, and cardiovascular comorbidities were considered as confounders in the final models. RESULTS:Over the follow-up period, there was a total of 428 definite and 36 probable SCD cases among the 118 636 participants. One- and 12-month moving average temperatures were inversely associated with SCD in the basic, risk factor, and fully adjusted models. For example, in the parsimonious individual risk factor model with definite cases only, per interquartile range (15.27 °C for the 1-month moving average temperature, 4.72 °C 12-month moving average temperature) increase in temperature, the hazard ratios for definite SCD were 0.58 (95% CI, 0.44-0.77) for the 1-month and 0.76 (95% CI, 0.66-0.88) for the 12-month moving average. CONCLUSIONS:After controlling for risk factors and cardiovascular morbidities, lower temperatures were associated with SCD. This study demonstrates that short-, medium-, and long-term cold temperature also play an important role in SCD.
BACKGROUND:Spot sign is the strongest imaging marker of hematoma expansion (HE). We describe spot sign evolution patterns on multiphase computed tomographic angiography in acute intracerebral hemorrhage and assess their association and predictive performance for HE. METHODS:Acute patients with intracerebral hemorrhage undergoing noncontrast computed tomography and multiphase computed tomographic angiography were included from Foothills Medical Center, Calgary, Alberta, Canada (development cohort) and Vall d'Hebron Hospital, Barcelona, Spain (validation cohort). Expert readers assessed the spot sign on axial maximum intensity projection across 3 multiphase computed tomographic angiography phases. Patterns were no spot sign (pattern 0), spot sign with no expansion (pattern I), circular expansion (pattern II), and linear/chaotic expansion (pattern III). Logistic regression, adjusted for baseline covariates, assessed associations with HE (≥6 mL or a 33% volume increase). Predictive performance (c-statistic) was compared between spot sign patterns and simple spot sign presence. RESULTS:In the development cohort (n=217), 67 (30.9%) patients were spot sign positive, and 51 (23.5%) experienced HE: pattern 0, 8.7%; pattern I, 38.8%; pattern II, 50%; and pattern III, 71.1% (adjusted odds ratio, 3.40 [95% CI, 2.35-4.93] per each pattern increase). The predictive performance of spot sign pattern was not superior to simple spot sign presence (c-statistic, 0.810 versus 0.772; P=0.059). In the validation cohort (n=274), 76 (27.7%) patients were spot sign positive, and 67 (24.5%) experienced HE: pattern 0, 14.5%, pattern I, 50%; pattern II, 23.5%; and pattern III, 63.4% (adjusted odds ratio, 1.92 [95% CI, 1.48-2.49] per each pattern increase). The predictive performance of spot sign pattern was not superior to simple spot sign presence (c-statistic, 0.707 versus 0.712; P=0.727). CONCLUSIONS:Spot sign evolution patterns were significantly associated with HE, yet they did not outperform spot sign presence alone in predicting HE.
BACKGROUND:Patients with severe aortic stenosis with very low resting aortic valve mean gradient (MG) are underrepresented in transcatheter aortic valve replacement (TAVR) studies. We investigated the association of resting aortic valve MG with post-TAVR outcomes in a large nationwide cohort. METHODS:We included patients from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry with a self-expanding Evolut TAVR (until December 2022) and eligible for 1-year follow-up without prior balloon aortic valvuloplasty, TAVR, or surgical aortic valve replacement. RESULTS:Among 80 429 patients (mean age, 80.7±7.9; women, 53.9%; high/extreme surgery risk, 51.2%) stratified into 6 echocardiographic resting aortic valve MG groups (10-<20, 20-<25, 25-<30, 30-<35, 35-<40, ≥40 mmHg), 1 year, all-cause mortality increased progressively across decreasing MG subgroups (from 9.3%, ≥40 mmHg to 20.9%, 10-<20 mmHg; P<0.001; 10.8% entire cohort), as did hospital readmission. Kansas City Cardiomyopathy Questionnaire scores increased progressively across increasing MG subgroups (P<0.001 at all time points). The Valve Academic Research Consortium 3 Kansas City Cardiomyopathy Questionnaire ordinal outcome improved substantially/moderately for all subgroups (1 year ≥52% patients). After multiple imputation for missing covariate data, Cox regression adjusting for clinically relevant baseline factors demonstrated a significant association between baseline MG and 1-year mortality (hazard ratio, 0.93 [95% CI, 0.91-0.94]; P<0.001). CONCLUSIONS:Baseline aortic valve MG is an important predictor of 1-year all-cause mortality in patients with severe aortic stenosis undergoing TAVR. Most patients undergoing TAVR had considerably improved quality-of-life assessments regardless of resting MG. Additional studies should elucidate mechanisms associated with MG-mortality risk and whether improved patient selection can further improve outcomes.
BACKGROUND:Atrial fibrillation (AF) is common in patients with aortic stenosis (AS), but its independent long-term prognostic impact on outcomes remains uncertain. We examined the association between AF and mortality risk across the full spectrum of AS. METHOD:In this retrospective cohort study, we included 1592 patients with at least mild AS and preserved left ventricular ejection fraction (≥50%). Patients were stratified by AF status. Primary and secondary end points were all-cause and cardiovascular mortality, respectively. RESULTS:Of 1592 patients, including the full spectrum of AS severity, 254 (16%) had AF. AF was more prevalent in patients with severe paradoxical low-flow low-gradient (36%) compared with severe normal-flow (12%), severe high-gradient (10%), and mild-to-moderate (16%) AS (P<0.001). During a median follow-up of 7.2 (interquartile range, 3.6-11.0) years, 885 deaths occurred (49% cardiovascular-related). AF was associated with an increased risk of all-cause and cardiovascular mortality (both P<0.001). In multivariable Cox models, AF independently predicted a higher risk of all-cause (hazard ratio [HR], 1.78 [95% CI, 1.34-2.36], P<0.001) and cardiovascular (HR, 1.77 [95% CI, 1.20-2.62], P=0.004) mortality. The prognostic impact was greatest for permanent/persistent AF (HR, 2.04) and significant for paroxysmal AF (HR, 1.69). The association of AF with outcomes remained consistent across various subgroups, including AS flow-gradient patterns (all interaction P>0.05). CONCLUSION:In this large cohort with AS, AF was independently associated with an increased risk of both all-cause and cardiovascular mortality, regardless of treatment strategy or AS flow-gradient pattern. AF should be integrated into risk stratification algorithms in AS, beyond parameters of AS severity.
BACKGROUND:Hypertension is prevalent among communities with exposure to gun violence. However, it remains unknown whether acoustic exposure to gunfire is associated with changes in blood pressure (BP). METHODS:We performed a retrospective cohort study of 27 765 adult patients who completed ≥2 clinic visits between 2017 and 2023 at an academic medical center on the South Side of Chicago. Our primary outcome was change in clinic-measured BP. We measured acoustic exposure to gunfire using ShotSpotter, an acoustic technology that records the time and location of gunfire. We used multivariable linear regression to examine change in BP as a function of acoustic exposure to gunfire, adjusting for age, sex, season, baseline BP, and neighborhood type. RESULTS:Acoustic exposure to gunfire was associated with an increase in systolic BP ranging from 0.2 mm Hg per incident at 1 week to 0.01 mm Hg per incident at 6 months. Results were similar for diastolic BP. Patients living in areas with low baseline levels of gunfire experienced a larger rise in BP per incident (up to 10-fold higher) than those living in areas with high baseline levels of gunfire. During periods of high gunfire (90th percentile), patients in neighborhoods with high baseline levels of gunfire may experience a rise in BP up to 2.52 mm Hg, whereas those living in neighborhoods with low baseline levels may experience a larger rise up to 5.32 mm Hg. CONCLUSIONS:In a cohort of adults from an urban academic medical center, acoustic exposure to gunfire was associated with a temporal increase in BP.
BACKGROUND:Whether adjunct intra-arterial urokinase has differential effectiveness and safety by sex among patients with acute ischemic stroke who achieve near-complete to complete reperfusion after endovascular thrombectomy (EVT) remains unknown. METHODS:This post hoc analysis of the POST-UK (Adjunctive Intra-Arterial Urokinase After Successful Endovascular Thrombectomy in Patients With Large-Vessel Occlusion Stroke) multicenter randomized clinical trial included 534 patients with proximal intracranial large-vessel occlusion who achieved near-complete to complete reperfusion after endovascular thrombectomy. Participants were assigned to intra-arterial urokinase or no adjunct intra-arterial thrombolysis. The primary effectiveness outcome was 90-day survival without disability, defined as a modified Rankin Scale score of 0 to 1. Primary safety outcomes were 90-day all-cause death and symptomatic intracranial hemorrhage within 48 hours. RESULTS:Among 534 participants, 223 were female and 311 were male. The treatment-by-sex interaction for the primary outcome was not statistically significant (P for interaction=0.06). In sex-stratified analyses, intra-arterial urokinase showed a potential benefit signal for 90-day survival without disability among female participants (46.7% versus 32.2%; adjusted risk ratio [RR], 1.47 [95% CI, 1.07-2.02]; P=0.02), whereas no statistically significant difference was observed among male participants (44.1% versus 46.6%; adjusted RR, 0.97 [95% CI, 0.77-1.22]; P=0.79). No statistically significant differences in safety outcomes were observed between treatment groups in either sex, including 90-day mortality and symptomatic intracranial hemorrhage. CONCLUSIONS:Adjunct intra-arterial urokinase after endovascular thrombectomy showed a potential benefit signal for 90-day disability-free survival among female participants, without statistically significant differences in male participants or hemorrhagic outcomes across sex subgroups. These findings should be considered hypothesis generating and warrant confirmation in future prospective studies. REGISTRATION:URL: www.chictr.org.cn; Unique Identifier: ChiCTR2200065617.
