Scott, Christopher G.

Abstract Aims The current guidelines recommend aortic valve intervention in patients with severe aortic regurgitation (AR) with the onset of symptoms, left ventricular enlargement, or systolic dysfunction. Recent studies have suggested that we might be missing the window of early intervention in a significant number of patients by following the guidelines. Methods and results The overarching goal was to determine if machine learning (ML)-based algorithms could be trained to identify patients at risk for death from AR independent of aortic valve replacement (AVR). Models were trained with five-fold cross-validation on a dataset of 1035 patients, and performance was reported on an independent dataset of 207 patients. Optimal predictive performance was observed with a conditional random survival forest model. A subset of 19/41 variables was selected for inclusion in the final model. Variable selection was performed with 10-fold cross-validation using random survival forest model. The top variables included were age, body surface area, body mass index, diastolic blood pressure, New York Heart Association class, AVR, comorbidities, ejection fraction, end-diastolic volume, and end-systolic dimension, and the relative variable importance averaged across five splits of cross-validation in each repeat were evaluated. The concordance index for predicting survival of the best-performing model was 0.84 at 1 year, 0.86 at 2 years, and 0.87 overall, respectively. Conclusion Using common echocardiographic parameters and patient characteristics, we successfully trained multiple ML models to predict survival in patients with severe AR. This technique could be applied to identify high-risk patients who would benefit from early intervention, thereby improving patient outcomes.

ImportanceAnthracyclines increase the risk for congestive heart failure (CHF); however, long-term cumulative incidence and risk factors for CHF after anthracycline therapy are not well defined in population-based studies.ObjectiveTo compare the long-term cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracycline therapy compared with healthy controls from the same community.Design, Setting, and ParticipantsThis retrospective population-based case-control study included data from the Rochester Epidemiology Project. Participants included residents of Olmsted County, Minnesota, diagnosed with breast cancer or lymphoma from January 1985 through December 2010 matched for age, sex, and comorbidities with healthy controls, with a final ratio of 1 case to 1.5 controls. Statistical analysis was performed between July 2017 and February 2022.ExposuresCancer treatment and CHF risk factors.Main Outcomes and MeasuresThe main outcome was new-onset CHF, as defined by the modified Framingham criteria. Cox proportional hazards regression was used to estimate hazard ratios (HRs) to compare the risk of CHF in participants with cancer vs controls, adjusted for age, sex, diabetes, hypertension, hyperlipidemia, coronary artery disease, obesity, and smoking history.ResultsA total of 2196 individuals were included, with 812 patients with cancer and 1384 participants without cancer. The mean (SD) age was 52.62 (14.56) years and 1704 participants (78%) were female. Median (IQR) follow-up was 8.6 (5.2-13.4) years in the case group vs 12.5 (8.7-17.5) years in the control group. Overall, patients with cancer had higher risk of CHF compared with the control cohort even after adjusting for age, sex, diabetes, hypertension, coronary artery disease, hyperlipidemia, obesity, and smoking status (HR, 2.86 [95% CI, 1.90-4.32]; P < .001). After adjusting for the same variables, CHF risk was greater for patients with cancer receiving anthracycline (HR, 3.25 [95% CI, 2.11-5.00]; P < .001) and was attenuated and lost statistical significance for patients with cancer not receiving anthracyclines (HR, 1.78 [95% CI, 0.83-3.81]; P = .14). Higher cumulative incidence for patients treated with anthracyclines vs comparator cohort was observed at 1 year (1.81% vs 0.09%), 5 years (2.91% vs 0.79%), 10 years (5.36% vs 1.74%), 15 years (7.42% vs 3.18%), and 20 years (10.75% vs 4.98%) (P < .001). There were no significant differences in risk of CHF for patients receiving anthracycline at a dose of less than 180 mg/m2 compared with those at a dose of 180 to 250 mg/m2 (HR, 0.54 [95% CI, 0.19-1.51]) or at a dose of more than 250 mg/m2 (HR, 1.23 [95% CI, 0.52-2.91]). At diagnosis, age was an independent risk factor associated with CHF (HR per 10 years, 2.77 [95% CI, 1.99-3.86]; P < .001).Conclusions and RelevanceIn this retrospective population-based case-control study, anthracyclines were associated with an increased risk of CHF early during follow-up, and the increased risk persisted over time. The cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracyclines at 15 years was more than 2-fold that of the control group.

Abstract Introduction: Mammographic breast density is among the strongest risk factors for breast cancer. However, breast density is typically assessed subjectively by the radiologist according to the Breast Imaging Reporting and Data System (BI-RADS) based on 2 dimensional (2D) digital mammography (DM) images. Digital breast tomosynthesis (DBT) is quickly replacing DM and allows more detailed volumetric imaging of the breast. Advances in radiomics, the high-throughput extraction of radiologic features, has enabled characterization of breast parenchymal complexity beyond breast density alone. The purpose of this study was to compare the performance of volumetric parenchymal pattern analysis from DBT and DM with conventional breast density measurement with respect to breast cancer risk estimation. Methods: We performed a case control study among women with concurrent DM and DBT screening (Selenia Dimensions, Hologic Inc.) at our institution between 3/2011-12/2014. Cases were diagnosed with breast cancer within 1 year of screening; controls were confirmed negative or benign at 1 year follow-up, matched on race (Black, White, other/unknown) and age (5-year bins). After exclusions for imaging artifacts, craniocaudal (CC) and mediolateral oblique (MLO) views for 187 cases and 737 controls, in six image formats were assessed: 1) raw (“FOR PROCESSING”) DM; 2) processed (“FOR PRESENTATION”) DM; 3) raw DBT central projection; 4) processed DBT central projection; 5) DBT central reconstructed slice; and 6) DBT reconstructed stack. For cases, we analyzed the breast contralateral to cancer diagnosis; for controls the same breast as the matched case. We extracted radiomic features using a lattice-based approach with the publicly available CaPTk software, averaging features for each breast over CC and MLO views. We examined 3 lattice window sizes (6.4, 12.8, and 25.6 mm) and 23 resolutions for image resampling (0.075 - 2mm). We performed PCA on the resulting 487 features for each combination of window size and resolution and built conditional logistic regression models to assess the association of the first 7 principal components with breast cancer, with models including age, BMI, and BI-RADS density. For each image type we calculated the model C-statistic at all window sizes and resolutions, for a total of 2304 experimental conditions. Results: Features from reconstructed DBT scans had on average higher C-statistics across all experimental conditions. A model using only age, BMI, and BI-RADS density had a C-statistic of 0.61. Models using radiomic features plus age, BMI, and BI-RADS density had mean C-statistic of 0.68 (IQR 0.68, 0.69) for reconstructed DBT scans; for all other image types, the mean C-statistic ranged from 0.64 to 0.66. Conclusions: Incorporating volumetric breast parenchymal patterns from DBT improves breast cancer risk estimation beyond markers derived from DM and beyond conventional BI-RADS density. Citation Format: Eric A. Cohen, Omid Haji Maghsoudi, Raymond Acciavatti, Lauren Pantalone, Walter Mankowski, Alex A Nguyen, Christopher G. Scott, Stacey Winham, Andrew D. Maidment, Anne Marie McCarthy, Celine M Vachon, Emily F Conant, Despina Kontos. Volumetric parenchymal pattern analysis for breast cancer risk estimation. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P070.

Abstract Introduction Aortic stenosis (AS) is the most common significant valvular heart disease in developed countries. A significant portion of the AS populations have low-gradient AS (LGAS), defined as aortic valve area ≤1.0 cm2 and a trans-aortic mean systolic gradient and peak velocity <40 mmHg and <4 m/s, respectively. LGAS has been shown previously to have worse mortality compared to high-gradient AS (HGAS). Atrial fibrillation (AF) is associated with LGAS and AF has been associated with worse outcomes compared to sinus rhythm (SR) in HGAS. The prognostic impact of AF in LGAS is not well described in previous literature. Hypothesis AF will be associated with worse clinical outcomes compared to SR in patients with LGAS. Methods 3400 patients diagnosed with LGAS from 2010–2020 were retrospectively identified and analyzed. Their electrical rhythm was analyzed at the time of their echocardiographic diagnosis of LGAS and patients were split into 3 separate groups: SR (n=2036), SR with history of AF (n=519), and AF (n=845). After adjustment for age, sex, and Charlson Comorbidity Index (CCI), primary endpoints of overall mortality and cardiac mortality were assessed for patients. Results Compared to those with SR, patients with AF and history of AF had significantly higher overall mortality (HR 1.52, p<0.0001 and HR 1.22, p=0.004, respectively) and cardiac mortality (HR 2.05, p<0.0001 and HR 1.37, p=0.03, respectfully) (Figure 1). On further sub group analysis, AF seemed to be most importantly associated with mortality and cardiac mortality in patients with preserved ejection fraction (EF >50%, normal flow LGAS) compared to those patients with reduced EF (classical low-flow LGAS), where there was no statistically significant difference in outcomes between AF and SR (Figure 2). Conclusions Atrial fibrillation, compared to sinus rhythm, is associated with worse overall mortality and cardiac mortality in patients with LGAS and preserved EF. Specifically, this association was strongest in patients with preserved EF >50%. Given these findings, the presence of AF should be factored into clinical decision making regarding LGAS management given the higher risk of age, sex, and CCI adjusted overall and cardiac mortality. Further research needs to be done to see if earlier aortic valve intervention in these patients would improve mortality compared to their SR counterparts. Funding Acknowledgement Type of funding sources: None.

Abstract Background Bioprosthetic valve thrombosis is currently a well-recognized cause of bioprosthetic valve dysfunction. It was found to be associated with accelerated degeneration of the bioprosthesis with higher rates of valve re-replacement, even after treatment with anticoagulation. We hypothesized that the use of warfarin for three months after transcatheter aortic valve replacement (TAVR) protects against accelerated valve degeneration and is therefore associated with better outcomes compared to dual antiplatelet therapy (DAPT). Methods Consecutive adult patients who underwent TAVR in our clinic between 2012 and 2019 were identified retrospectively. Patients with atrial fibrillation were excluded. Subsequently, patients who received DAPT were propensity matched to up to 2 patients who received three months of warfarin as part of their anti-thrombotic regimen. Matching was performed for variables that were significantly different at baseline between the two groups and included diabetes mellitus, prior myocardial infarctions, chronic lung disease, peripheral arterial disease, hemoglobin at time of TAVR, kidney function [creatinine>2], use of angiotensin-converting enzyme inhibitors / angiotensin II receptor blockers, beta blockers, the Society of Thoracic Surgeons (STS) score [STS ≥8, STS 4–8, STS<4], and valve size. The two groups were then compared for outcomes of ischemic stroke, death, valve re-replacement/intervention, the composite endpoint of the aforementioned three outcomes, as well as the three-month outcome of hemorrhagic strokes. Kaplan Meier was used for outcome analysis, and discharge date was considered time zero. Patients who had their anti-thrombotic therapy interrupted were censored at that time point. Results A total of 1,373 patients who underwent TAVR were identified. Of these, 576 patients with atrial fibrillation were excluded. Baseline characteristics were compared between 633 patients who received three months of warfarin and 164 patients who received DAPT after TAVR. After matching the two groups, 435 patients were included in the final analysis [warfarin in 281, DAPT in 154; median time to last follow up 2.61 years], Table 1. There was no difference in matched (Figure 1) or unmatched analysis (not shown) in outcomes of ischemic stroke, death, valve re-replacement/intervention, their composite endpoint, or hemorrhagic strokes (p>0.05 for all). Conclusion Antithrombotic regimen including three months of warfarin after TAVR was not associated with better outcomes of ischemic strokes, deaths, and valve re-replacement/intervention or with increased risk of hemorrhagic strokes compared to DAPT. Funding Acknowledgement Type of funding sources: None.

ImportanceTransthyretin amyloid cardiomyopathy (ATTR-CM) is a form of heart failure (HF) with preserved ejection fraction (HFpEF). Technetium Tc 99m pyrophosphate scintigraphy (PYP) enables ATTR-CM diagnosis. It is unclear which patients with HFpEF have sufficient risk of ATTR-CM to warrant PYP.ObjectiveTo derive and validate a simple ATTR-CM score to predict increased risk of ATTR-CM in patients with HFpEF.Design, Setting, and ParticipantsRetrospective cohort study of 666 patients with HF (ejection fraction ≥ 40%) and suspected ATTR-CM referred for PYP at Mayo Clinic, Rochester, Minnesota, from May 10, 2013, through August 31, 2020. These data were analyzed September 2020 through December 2020. A logistic regression model predictive of ATTR-CM was derived and converted to a point-based ATTR-CM risk score. The score was further validated in a community ATTR-CM epidemiology study of older patients with HFpEF with increased left ventricular wall thickness ([WT] ≥ 12 mm) and in an external (Northwestern University, Chicago, Illinois) HFpEF cohort referred for PYP. Race was self-reported by the participants. In all cohorts, both case patients and control patients were definitively ascertained by PYP scanning and specialist evaluation.Main Outcomes and MeasuresPerformance of the derived ATTR-CM score in all cohorts (referral validation, community validation, and external validation) and prevalence of a high-risk ATTR-CM score in 4 multinational HFpEF clinical trials.ResultsParticipant cohorts included were referral derivation (n = 416; 13 participants [3%] were Black and 380 participants [94%] were White; ATTR-CM prevalence = 45%), referral validation (n = 250; 12 participants [5%]were Black and 228 participants [93%] were White; ATTR-CM prevalence = 48% ), community validation (n = 286; 5 participants [2%] were Black and 275 participants [96%] were White; ATTR-CM prevalence = 6% ), and external validation (n = 66; 23 participants [37%] were Black and 36 participants [58%] were White; ATTR-CM prevalence = 39%). Score variables included age, male sex, hypertension diagnosis, relative WT more than 0.57, posterior WT of 12 mm or more, and ejection fraction less than 60% (score range −1 to 10). Discrimination (area under the receiver operating characteristic curve [AUC] 0.89; 95% CI, 0.86-0.92; P < .001) and calibration (Hosmer-Lemeshow; χ2 = 4.6; P = .46) were strong. Discrimination (AUC ≥ 0.84; P < .001 for all) and calibration (Hosmer-Lemeshow χ2 = 2.8; P = .84; Hosmer-Lemeshow χ2 = 4.4; P = .35; Hosmer-Lemeshow χ2 = 2.5; P = .78 in referral, community, and external validation cohorts, respectively) were maintained in all validation cohorts. Precision-recall curves and predictive value vs prevalence plots indicated clinically useful classification performance for a score of 6 or more (positive predictive value ≥25%) in clinically relevant ATTR-CM prevalence (≥10% of patients with HFpEF) scenarios. In the HFpEF clinical trials, 11% to 35% of male and 0% to 6% of female patients had a high-risk (≥6) ATTR-CM score.Conclusions and RelevanceA simple 6 variable clinical score may be used to guide use of PYP and increase recognition of ATTR-CM among patients with HFpEF in the community. Further validation in larger and more diverse populations is needed.

Background Religiosity/spirituality is a major coping mechanism for African Americans, but no prior studies have analyzed its association with the American Heart Association Life's Simple 7 (LS7) indicators in this group. Methods and Results This cross‐sectional study using Jackson Heart Study (JHS) data examined relationships between religiosity (religious attendance, private prayer, religious coping) and spirituality (theistic, nontheistic, total) with LS7 individual components (eg, physical activity, diet, smoking, blood pressure) and composite score among African Americans. Multivariable logistic regression assessed the odds of achieving intermediate/ideal (versus poor) LS7 levels adjusted for sociodemographic, behavioral, and biomedical factors. Among the 2967 participants (mean [SD] age=54.0 [12.3] years; 65.7% women), higher religious attendance was associated with increased likelihood (reported as odds ratio [95% CI]) of achieving intermediate/ideal levels of physical activity (1.16 [1.06–1.26]), diet (1.10 [1.01–1.20]), smoking (1.50 [1.34–1.68]), blood pressure (1.12 [1.01–1.24]), and LS7 composite score (1.15 [1.06–1.26]). Private prayer was associated with increased odds of achieving intermediate/ideal levels for diet (1.12 [1.03–1.22]) and smoking (1.24 [1.12–1.39]). Religious coping was associated with increased odds of achieving intermediate/ideal levels of physical activity (1.18 [1.08–1.28]), diet (1.10 [1.01–1.20]), smoking (1.32 [1.18–1.48]), and LS7 composite score (1.14 [1.04–1.24]). Total spirituality was associated with increased odds of achieving intermediate/ideal levels of physical activity (1.11 [1.02–1.21]) and smoking (1.36 [1.21–1.53]). Conclusions Higher levels of religiosity/spirituality were associated with intermediate/ideal cardiovascular health across multiple LS7 indicators. Reinforcement of religiosity/spirituality in lifestyle interventions may decrease overall cardiovascular disease risk among African Americans.

Background A high prevalence of preclinical heart failure (HF) (Stages A and B) has previously been shown. The aim of this study was to explore factors associated with the incidence of preclinical HF in a community population. Methods and Results Retrospective review of 393 healthy community individuals aged ≥45 years from the Olmsted County Heart Function Study that returned for 2 visits, 4 years apart. At visit 2, individuals that remained normal were compared with those that developed preclinical HF. By the second visit, 191 (49%) developed preclinical HF (12.1 cases per 100 person‐years of follow‐up); 65 (34%) Stage A and 126 (66%) Stage B. Those that developed preclinical HF (n=191) were older ( P =0.004), had a higher body mass index ( P <0.001), and increased left ventricular mass index ( P =0.006). When evaluated separately, increased body mass index was seen with development of Stage A ( P <0.001) or Stage B ( P =0.009). Echocardiographic markers of diastolic function were statistically different in those that developed Stage A [higher E/e’ ( P <0.001), lower e’ ( P <0.001)] and Stage B [higher left atrial volume index ( P <0.001), higher E/e’ ( P <0.001), lower e’ ( P <0.001)]. NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) was higher at visit 2 in those that developed Stage A or B ( P <0.001 for both). Hypertension (57%), obesity (34%), and hyperlipidemia (25%) were common in the development of Stage A. Of patients who developed Stage B, 71% (n=84) had moderate or severe diastolic dysfunction. Conclusions There is a high incidence of preclinical HF in a community population. Development of Stage A was driven by hypertension and obesity, while preclinical diastolic dysfunction was seen commonly in those that developed Stage B.

Background Many patients with symptomatic severe aortic stenosis do not undergo aortic valve replacement (AVR) despite clinical guidelines. This study analyzed the association of managing provider type with cardiac specialist follow‐up, AVR, and mortality for patients with newly diagnosed severe aortic stenosis (sAS). Methods and Results We identified adults with newly diagnosed sAS per echocardiography performed between January 2017 and March 2019 using Optum electronic health record data. We then selected from those meeting all eligibility criteria patients managed by a primary care provider (n=1707 [25%]) or cardiac specialist (n=5039 [75%]). We evaluated the association of managing provider type with cardiac specialist follow‐up, AVR, and mortality, as well as the independent association of cardiac specialist follow‐up and AVR with mortality, within 1 year of echocardiography detecting sAS. A subgroup analysis was limited to patients with symptomatic sAS. Patient characteristics and comorbidities at baseline were used for covariate‐adjusted cause‐specific and multivariable Cox proportional hazard models assessing group differences in outcomes by managing provider type. An adjusted Cox proportional hazard model with additional time‐dependent covariates for follow‐up and AVR was used to assess these practices' association with mortality. Within 1 year of echocardiography detecting sAS, data revealed that primary care provider management was associated with lower rates of cardiac specialist follow‐up (hazard ratio [HR], 0.47 [95% CI, 0.43–0.50], P <0.0001) and AVR (HR, 0.58 [95% CI, 0.53–0.64], P <0.0001) and with higher 1‐year mortality (HR, 1.45 [95% CI, 1.26–1.66], P <0.0001). Cardiac specialist follow‐up and AVR were independently associated with lower mortality (follow‐up: HR, 0.55 [95% CI, 0.48–0.63], P <0.0001; AVR: HR, 0.70 [95% CI, 0.60–0.83], P <0.0001). Results were similar for patients with symptomatic sAS. All analyses were adjusted for baseline patient characteristics and comorbidities. Conclusions For patients newly diagnosed with sAS, we observed differences in rates of cardiac specialist follow‐up and AVR and risk of mortality between primary care provider‐ versus cardiologist‐managed patients with sAS. In addition, a lower likelihood of receiving follow‐up and AVR was independently associated with higher mortality.

Abstract Introduction: Incorporation of mammographic density to breast cancer risk models could improve risk stratification to tailor screening and prevention strategies according to risk. However, robust validation of such models in prospective cohort studies is needed to determine their accuracy in identifying women at different risk levels. Methods: We incorporated Breast Imaging and Reporting Data System (BI-RADS) breast density to a literature-based model with questionnaire-based risk factors and a 313-variant polygenic risk score (PRS). The Individualized Coherent Absolute Risk Estimator (iCARE) tool was used to build and validate a 5-year absolute risk model for breast cancer. The model was evaluated for calibration and discrimination in three prospective cohorts of women of European ancestry (1,468 cases, 19,104 controls): US-based Nurses’ Health Study (NHS I and II) and Mayo Mammography Health Study (MMHS); and Sweden-based Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) study. Analyses were done separately for women younger (NHS II, KARMA) and older than 50 years (NHS I, MMHS, KARMA). Improvements in risk stratification were assessed among US non-Hispanic White women aged 50-70 years. Results: For women younger than 50 years, the model with questionnaire-based risk factors, PRS and BI-RADS was well calibrated across risk deciles in NHS II, but overestimated risk at the highest risk decile in KARMA. For women 50 years or older, the model showed good calibration in all studies, with evidence of slight overestimation at the highest risk decile and underestimation at the lowest risk decile. The model with PRS and BI-RADS was well calibrated for women at high-risk in both age groups. Incorporation of BI-RADS to questionnaire-based risk factors and PRS improved risk discrimination: area under the curves (AUC) 67.0% (95% CI: 63.5-70.6%) vs. 65.6% (95% CI: 61.9-69.3%) for models with and without BI-RADS for younger women and 66.1% (95% CI 64.4-67.8%) vs. 65.5% (95% CI: 63.8-67.2%) for older women. The model with BI-RADS identified 18.4% population of non-Hispanic US women 50-70 years old above 3% 5-year risk (used for recommending risk-reducing medication in the US), with 42.4% of future cases expected to occur in this group. Addition of BI-RADS led to the reclassification of ~8.0% of US non-Hispanic White women aged 50-70 years at the high-risk threshold (3% 5-year risk), resulting in identification of 4.2% of additional future cases. Conclusion: Integrating BI-RADS with questionnaire-based risk factors and PRS resulted in improved risk stratification among women of European ancestry, with evidence of slight overestimation of risk for women at elevated risk. Additional validation of the integrated model in diverse populations is needed prior to considering clinical applications. Citation Format: Charlotta V. Mulder, Yon Ho Jee, Xin Yang, Christopher G. Scott, Chi Gao, Amber N. Hurson, Mikael Eriksson, Per Hall, Peter Kraft, Celine M. Vachon, Antonis C. Antoniou, Gretchen Gierach, Montserrat Garcia-Closas, Parichoy Pal Choudhury. Validation of an integrated breast cancer risk model with mammographic density in three prospective cohort studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2256.