Richard A Kronmal's research while affiliated with University of Washington Seattle and other places

Background In infants with complete atrioventricular canal (CAVC) defects, post‐operative left atrioventricular valve regurgitation (LAVVR) is a known major cause of morbidity and mortality and a common indication for re‐operation. However, there is scarce data to identify risk factors for poor outcomes. Our study aims to find echocardiographic characteristics that predict post‐operative LAVVR at discharge and 1‐year follow‐up. Methods Retrospective cohort study of patients with initial CAVC repair at our hospital who were followed for 1 year between 2013 and 2022. Patients with major co‐morbid conditions were excluded. Serial echocardiograms were reviewed. Anatomic details, quantitative and qualitative measure of LAVVR including the number of regurgitant jets, regurgitant jet length and vena contracta width, and ventricular function were collected. The time points measured include pre‐operative transthoracic echocardiogram (TTE), post‐operative transesophageal echocardiogram (PO‐TEE), routine protocol based post‐operative day 1 (POD1) TTE, discharge TTE and 1‐year post‐operative (1yPO) TTE. Paired t ‐tests, chi‐square analysis, and linear regression analysis were performed comparing measured variables to LAVVR outcomes. Results Fifty‐two patients were included; 92% had Trisomy 21. The majority were classified as Rastelli A (71%), others Rastelli C (29%). Only two patients had moderate or greater LAVVR pre‐operatively. The mean age at repair was 125 ± 44 days. Pre‐operative LAVVR was the only significant predictor of LAVVR severity at 1 year after backward stepwise regression. Of those with < moderate LAVVR on PO‐TEE, 20% had worsening to ≥ moderate at discharge, but only 9% remained that way at 1 year. Of those with ≥ moderate LAVVR on PO‐TEE, 40% improved to < moderate by 1 year. Two patients who worsened at 1 year, both secondary to likely cleft suture dehiscence. Only one patient required reoperation in the immediate post‐operative period secondary to severe LAVVR due to suture dehiscence. Routine protocol‐based POD1 echo did not have any association with altered outcomes. Conclusion Pre‐operative LAVVR was the only significant predictor of LAVVR severity at 1 year. A significant percentage (40%) of patient with ≥ moderate LAVVR on PO‐TEE improved to < moderate by 1 year. Furthermore, routine protocol‐based POD1 echo did not have any association with altered outcomes.

Objective: Growing evidence indicates that exposure to metals are risk factors for cardiovascular disease (CVD). We hypothesized that higher urinary levels of metals with prior evidence of an association with CVD, including non-essential (cadmium , tungsten, and uranium) and essential (cobalt, copper, and zinc) metals are associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of atherosclerotic CVD. Methods: We analyzed data from 6,418 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with spot urinary metal levels at baseline (2000-2002) and 1-4 repeated measures of spatially weighted coronary calcium score (SWCS) over a ten-year period. SWCS is a unitless measure of CAC highly correlated to the Agatston score but with numerical values assigned to individuals with Agatston score=0. We used linear mixed effect models to assess the association of baseline urinary metal levels with baseline SWCS, annual change in SWCS, and SWCS over ten years of follow-up. Urinary metals (adjusted to μg/g creatinine) and SWCS were log transformed. Models were progressively adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors. Results: At baseline, the median and interquartile range (25th, 75th) of SWCS was 6.3 (0.7, 58.2). For urinary cadmium, the fully adjusted geometric mean ratio (GMR) (95%Cl) of SWCS comparing the highest to the lowest quartile was 1.51 (1.32, 1.74) at baseline and 1.75 (1.47, 2.07) at ten years of follow-up. For urinary tungsten, uranium, and cobalt the corresponding GMRs at ten years of follow-up were 1.45 (1.23, 1.71), 1.39 (1.17, 1.64), and 1.47 (1.25, 1.74), respectively. For copper and zinc, the association was attenuated with adjustment for clinical risk factors; GMRs at ten years of follow-up before and after adjustment for clinical risk factors were 1.55 (1.30, 1.84) and 1.33 (1.12, 1.58), respectively, for copper and 1.85 (1.56, 2.19) and 1.57 (1.33, 1.85) for zinc. Conclusion: Higher levels of cadmium, tungsten, uranium, cobalt, copper, and zinc, as measured in urine, were associated with subclinical CVD at baseline and at follow-up. These findings support the hypothesis that metals are pro-atherogenic factors.

Importance Atrial cardiopathy is associated with stroke in the absence of clinically apparent atrial fibrillation. It is unknown whether anticoagulation, which has proven benefit in atrial fibrillation, prevents stroke in patients with atrial cardiopathy and no atrial fibrillation. Objective To compare anticoagulation vs antiplatelet therapy for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy. Design, Setting, and Participants Multicenter, double-blind, phase 3 randomized clinical trial of 1015 participants with cryptogenic stroke and evidence of atrial cardiopathy, defined as P-wave terminal force greater than 5000 μV × ms in electrocardiogram lead V 1 , serum N-terminal pro-B-type natriuretic peptide level greater than 250 pg/mL, or left atrial diameter index of 3 cm/m ² or greater on echocardiogram. Participants had no evidence of atrial fibrillation at the time of randomization. Enrollment and follow-up occurred from February 1, 2018, through February 28, 2023, at 185 sites in the National Institutes of Health StrokeNet and the Canadian Stroke Consortium. Interventions Apixaban, 5 mg or 2.5 mg, twice daily (n = 507) vs aspirin, 81 mg, once daily (n = 508). Main Outcomes and Measures The primary efficacy outcome in a time-to-event analysis was recurrent stroke. All participants, including those diagnosed with atrial fibrillation after randomization, were analyzed according to the groups to which they were randomized. The primary safety outcomes were symptomatic intracranial hemorrhage and other major hemorrhage. Results With 1015 of the target 1100 participants enrolled and mean follow-up of 1.8 years, the trial was stopped for futility after a planned interim analysis. The mean (SD) age of participants was 68.0 (11.0) years, 54.3% were female, and 87.5% completed the full duration of follow-up. Recurrent stroke occurred in 40 patients in the apixaban group (annualized rate, 4.4%) and 40 patients in the aspirin group (annualized rate, 4.4%) (hazard ratio, 1.00 [95% CI, 0.64-1.55]). Symptomatic intracranial hemorrhage occurred in 0 patients taking apixaban and 7 patients taking aspirin (annualized rate, 1.1%). Other major hemorrhages occurred in 5 patients taking apixaban (annualized rate, 0.7%) and 5 patients taking aspirin (annualized rate, 0.8%) (hazard ratio, 1.02 [95% CI, 0.29-3.52]). Conclusions and Relevance In patients with cryptogenic stroke and evidence of atrial cardiopathy without atrial fibrillation, apixaban did not significantly reduce recurrent stroke risk compared with aspirin. Trial Registration ClinicalTrials.gov Identifier: NCT03192215

Introduction Kidney disease is common after pediatric heart transplantation. Serum creatinine‐based glomerular filtration rate is the most frequently reported measure of kidney function. Albuminuria is an additional marker of kidney dysfunction and is not well described in this population. In this study, we evaluate the prevalence and degree of albuminuria and describe clinical factors associated with albuminuria in a cohort of pediatric heart transplant recipients. Methods This was a cross‐sectional study of pediatric heart transplant recipients. Albuminuria was assessed using spot urine albumin‐to‐creatinine ratio collected at the most recent annual screening cardiac catheterization through August 2019. Results In 115 patients at a median duration of 10.2 years post‐transplant, 39% had albuminuria. Stage 3 or greater chronic kidney disease was present in 6%. The immunosuppressive regimen at the time of measurement contained a calcineurin inhibitor (CNI) in 88% and a proliferation signal inhibitor (PSI) in 62%. In multivariable modeling, lower eGFR, PSI use, and younger age at transplant were associated with higher levels of albuminuria, whereas CNI use was associated with lower levels of albuminuria. Conclusion Albuminuria is a prevalent finding in medium‐term follow up of pediatric heart transplant recipients, reflecting kidney injury, and is associated with other markers of kidney dysfunction, such as low eGFR. Younger age at transplant, lower eGFR, and PSI use were among the associations with albuminuria.

Background: Atrial cardiopathy is associated with incident ischemic stroke in the absence of clinical atrial fibrillation in prospective cohorts. Whether biomarkers of atrial cardiopathy predict recurrent stroke is less clear. Methods: In the ARCADIA trial, a multicenter randomized trial of apixaban versus aspirin in patients with cryptogenic stroke and evidence of atrial cardiopathy, we explored whether the biomarkers P-wave terminal force in ECG lead V 1 (PTFV1), N-terminal pro-Brain natriuretic peptide (NT-proBNP), or left atrial diameter index (LADI) predicted primary and secondary trial outcomes: (1) recurrent stroke of any type; (2) recurrent ischemic stroke or systemic embolism; and (3) recurrent stroke of any type or death. We analyzed the full cohort using Cox proportional hazard models , sequentially adjusting for treatment effect, demographic factors, and clinical risk factors. NT-proBNP concentrations were log-transformed. Results: With 1,015 of the target 1,100 participants enrolled (mean age 68 years, 54.3% female, 21.1% Black, and 8.1% Hispanic) and mean follow-up of 1.8 years, the trial was stopped for futility. Recurrent stroke occurred in 80 patients (annualized rate, 4.4%) and death in 54 patients. NT-proBNP significantly predicted recurrent stroke; recurrent ischemic stroke or systemic embolism; and recurrent stroke or death after adjusting for other risk factors, while PTFV1 and LADI did not (Table). NT-proBNP predicted recurrent stroke and death most strongly and with little change after adjusting for other risk factors. Treatment effect was not significant in any of the models. Conclusions: In this population of patients with cryptogenic stroke and evidence of atrial cardiopathy, NT-proBNP is a predictor of recurrent stroke and, with greater magnitude, of a composite of stroke or death. The role of NT-proBNP measurement in management after stroke deserves further study.

Introduction: The associations of body composition components, including muscle and adipose tissue, and markers of subclinical coronary artery disease are unclear. We examined the relationship between abdominal CT-derived measures of the area and density of fat and muscle with coronary artery calcification (CAC), using data from the Multi-Ethnic Study of Atherosclerosis (MESA). Methods: A randomly selected total of 1,974 MESA participants free of coronary heart disease underwent abdominal CT scans at exams 2 or 3, with the resulting images interrogated for abdominal body composition. Using six cross-sectional slices spanning L2-L5, Medical Imaging Processing Analysis and Visualization (MIPAV) software was used to determine abdominal muscle and fat composition by utilizing appropriate Hounsfield units (HU) ranges. CT chest scans obtained during the exam 1 were used to obtain CAC scores, calculated using the Agatston method and spatially weighted calcium score (SWCS). Multivariable linear regression analysis was performed to assess the relationship between both abdominal visceral fat and muscle area and density to prevalent CAC. Results: A total of 1,089 participants had a CAC>0, with an average CAC score of 310. In the fully adjusted model, for every 10 cm ² increase in visceral fat area, the likelihood of having a CAC >0 increased by 0.60% (p<0.001). In the minimally adjusted model, abdominal muscle area was significantly associated with CAC>0, which became non-significant in the fully adjusted model. For density of visceral fat , every 1 HU increase (less lipid dense fat tissue), the likelihood of having a CAC score>0 decreased by 0.29% (p<0.05). No significant relationship was observed between density of abdominal muscle and CAC>0. Conclusion: Greater area and higher lipid density of abdominal visceral fat was associated with an increased likelihood of having CAC, while there was no significant relationship between abdominal muscle area or density and CAC. Both the quantity and the quality of fat have associations with an important marker of subclinical atherosclerosis, CAC, and their significance with respect to cardiovascular outcomes requires further evaluation.

Objective: Growing evidence indicates that exposure to metals are risk factors for cardiovascular disease (CVD). We hypothesized that higher urinary levels of metals with prior evidence of an association with CVD, including non-essential (cadmium , tungsten, and uranium) and essential (cobalt, copper, and zinc) metals are associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of atherosclerotic CVD. Methods: We analyzed data from 6,418 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with spot urinary metal levels at baseline (2000-2002) and 1-4 repeated measures of spatially weighted coronary calcium score (SWCS) over a ten-year period. SWCS is a unitless measure of CAC highly correlated to the Agatston score but with numerical values assigned to individuals with Agatston score=0. We used linear mixed effect models to assess the association of baseline urinary metal levels with baseline SWCS, annual change in SWCS, and SWCS over ten years of follow-up. Urinary metals (adjusted to μg/g creatinine) and SWCS were log transformed. Models were progressively adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors. Results: At baseline, the median and interquartile range (25th, 75th) of SWCS was 6.3 (0.7, 58.2). For urinary cadmium, the fully adjusted geometric mean ratio (GMR) (95%Cl) of SWCS comparing the highest to the lowest quartile was 1.51 (1.32, 1.74) at baseline and 1.75 (1.47, 2.07) at ten years of follow-up. For urinary tungsten, uranium, and cobalt the corresponding GMRs at ten years of follow-up were 1.45 (1.23, 1.71), 1.39 (1.17, 1.64), and 1.47 (1.25, 1.74), respectively. For copper and zinc, the association was attenuated with adjustment for clinical risk factors; GMRs at ten years of follow-up before and after adjustment for clinical risk factors were 1.55 (1.30, 1.84) and 1.33 (1.12, 1.58), respectively, for copper and 1.85 (1.56, 2.19) and 1.57 (1.33, 1.85) for zinc. Conclusion: Higher levels of cadmium, tungsten, uranium, cobalt, copper, and zinc, as measured in urine, were associated with subclinical CVD at baseline and at follow-up. These findings support the hypothesis that metals are pro-atherogenic factors.