Scott, Christopher G.

Abstract Background Most breast biopsies are diagnosed as benign breast disease, with 1.5- to 4-fold increased breast cancer risk. Apart from pathologic diagnoses of atypical hyperplasia, few factors aid in breast cancer risk assessment of these patients. We assessed whether a 313–single nucleotide variation (formerly single-nucleotide polymorphism) polygenic risk score stratifies risk of benign breast disease patients. Methods We pooled data from 5 Breast Cancer Association Consortium case-control studies (mean age = 59.9 years), including 6706 participants with breast cancer and 8488 participants without breast cancer. Using logistic regression, we estimated breast cancer risk associations by self-reported benign breast disease history and strata of polygenic risk score, with median polygenic risk score category among women without benign breast disease as the referent. We assessed interactions and mediation of benign breast disease and polygenic risk score with breast cancer risk. Results Benign breast disease history was associated with increased breast cancer risk (odds ratio [OR] = 1.48, 95% confidence interval [CI] = 1.37 to 1.60; P < .001). Polygenic risk score increased breast cancer risk, irrespective of benign breast disease history (Pinteraction = .48), with minimal evidence of mediation of either factor by the other. Women with benign breast disease and polygenic risk score in the highest tertile had more than twofold increased odds of breast cancer (OR = 2.73, 95% CI = 2.41 to 3.09), and those with benign breast disease and polygenic risk score in the lowest tertile experienced reduced breast cancer risk (OR = 0.79, 95% CI = 0.70 to 0.91) compared with the referent group. Women with benign breast disease and polygenic risk score in the highest decile had a 3.7-fold increase (95% CI = 3.00 to 4.61) compared with those with median polygenic risk score without benign breast disease. Conclusion Breast cancer risks are elevated among women with benign breast disease and increase progressively with polygenic risk score, suggesting that optimal combinations of these factors may improve risk stratification.

Abstract Aims Aortic valve calcification (AVC) is prognostic in patients with aortic stenosis (AS). We assessed the AVC prognostic value in non-severe AS patients. Methods and results We conducted a retrospective study of 395 patients with non-severe AS, LVEF ≥ 50%. The Agatston method was used for CT AVC assessment. The log-rank test determined the best AVC cut-offs for survival under medical surveillance: 1185 arbitrary unit (AU) in men and 850 AU in women, lower than the established cut-offs for severe AS (2064 AU in men and 1274 AU in women). Patients were divided into 3 AVC groups based on these cut-offs: low (<1185 AU in men and <850 AU in women), sub-severe (1185–2064 AU in men and 850–1274 AU in women), and severe (>2064 AU in men and >1274 AU in women). Of 395 patients (mean age 73 ± 12 years, 60.5% men, aortic valve area 1.23 ± 0.30 cm2, mean pressure gradient 28 ± 8 mmHg), 218 underwent aortic valve intervention (AVI) and 158 deaths occurred during follow-up, 82 before AVI. Median survival time under medical surveillance was 2.1 (0.7–4.9) years. Compared with the low AVC group, both sub-severe and severe AVC groups had higher risk for all-cause death under medical surveillance after comprehensive adjustment including echocardiographic AS severity and coronary artery calcium score (all P ≤ 0.006); while mortality risk was similar between sub-severe and severe AVC groups (all P ≥ 0.2). This mortality risk pattern persisted in the overall survival analysis after adjustment for AVI. AVI was protective of all-cause death in the sub-severe and severe AVC (all P ≤ 0.01), but not in the low AVC groups. Conclusion Sub-severe AVC is a robust risk stratification parameter in patients with non-severe AS and may inform AVI timing.

Abstract Background and Aims Incidence and types of secondary tricuspid regurgitation (TR) are not well defined in atrial fibrillation (AFib) and sinus rhythm (SR). Atrial secondary TR (A-STR) is associated with pre-existing AFib; however, close to 50% of patients with A-STR do not have AFib. The aim of this study was to assess incidence, types, and outcomes of ≥ moderate TR in AFib vs. SR. Methods Adults with and without new-onset AFib without structural heart disease or ≥ moderate TR at baseline were followed for the development of ≥ moderate TR. Tricuspid regurgitation types were pacemaker, left-sided valve disease, left ventricular (LV) dysfunction, pulmonary hypertension (PH), isolated ventricular, and A-STR. Results Among 1359 patients with AFib and 20 438 in SR, 109 and 378 patients developed ≥ moderate TR, respectively. The individual types of TR occurred more frequently in AFib related to the higher pacemaker implantation rates (1.12 vs. 0.19 per 100 person-years, P < .001), larger right atrial size (median 78 vs. 53 mL, P < .001), and higher pulmonary pressures (median 30 vs. 28 mmHg, P < .001). The most common TR types irrespective of rhythm were LV dysfunction-TR and A-STR. Among patients in SR, those with A-STR were older, predominantly women with more diastolic abnormalities and higher pulmonary pressures. All types of secondary TR were associated with all-cause mortality, highest in PH-TR and LV dysfunction-TR. Conclusions New-onset AFib vs. SR conferred a higher risk of the individual TR types related to sequelae of AFib and higher pacemaker implantation rates, although the distribution of TR types was similar. Secondary TR was universally associated with increased mortality.

AbstractIntroductionAlthough prior studies indicate that a QTc > 500 ms on a single baseline 12‐lead electrocardiogram (ECG) is associated with significantly increased risk of arrhythmic events in long QT syndrome (LQTS), less is known about the risk of persistent QT prolongation. We sought to determine QTc persistence and its prognostic effect on breakthrough cardiac events (BCEs) among pediatric patients treated for LQTS.MethodsWe performed a retrospective analysis of 433 patients with LQTS evaluated, risk‐stratified, and undergoing active guideline‐based LQTS treatment between 1999 and 2019. BCEs were defined as arrhythmogenic syncope/seizure, sudden cardiac arrest (SCA), appropriate VF‐terminating ICD shock, and sudden cardiac death (SCD).ResultsDuring the median follow‐up of 5.5 years (interquartile range [IQR] = 3–9), 32 (7%) patients experienced a total of 129 BCEs. A maximum QTc threshold of 520 ms and median QTc threshold of 490 ms were determined to be strong predictors for BCEs. A landmark analysis controlling for age, sex, genotype, and symptomatic status demonstrated models utilizing both the median QTc and maximum QTc demonstrated the highest discriminatory value (c‐statistic = 0.93–0.95). Patients in the high‐risk group (median QTc > 490 ms and maximum QTc > 520 ms) had a significantly lower BCE free survival (70%–81%) when compared to patients in both medium‐risk (93%–97%) and low‐risk (98%–99%) groups.ConclusionsThe risk of BCE among patients treated for LQTS increases not only based upon their maximum QTc, but also their median QTc (persistence of QTc prolongation). Patients with a maximum QTc > 520 ms and median QTc > 490 ms over serial 12‐lead ECGs are at the highest risk of BCE while on guideline‐directed medical therapy.

Abstract Artificial intelligence (AI) models based on deep learning of mammogram images have been developed for lesion detection and diagnosis as well as breast cancer (BC) risk. We and others have shown that these AI models, coupled with breast density, predict long-term breast cancer risk. Common germline genetic variation, in particular a polygenic risk score (PRS) that captures the cumulative impact of hundreds of common risk variants, has been shown associated with 3-fold increased BC risk. The BC-PRS may complement imaging risk factors to improve identification of women at high BC risk and better target prevention strategies. We evaluated the contribution of a BC-PRS to two imaging-based AI models (Transpara AI cancer detection system and Mirai 5-year risk) and breast density measures to long-term BC risk. We hypothesized that the BC-PRS will improve long-term risk prediction above AI and density measures. We examined this hypothesis within a cohort of 10,271 women enrolled to the Mayo Clinic Biobank between 2009 and 2015. Eligible women had no prior cancer, were ages 35 to 85, had a full-field digital screening mammogram within two years of enrollment and genotyping by Regeneron. Incident invasive and DCIS BC was identified through the Mayo tumor registry and follow-up questionnaires, and person years were calculated from date of mammogram through date of BC, last mammogram at Mayo or last questionnaire. We estimated Transpara AI malignancy score (1-10), 5-year Mirai risk and Volpara volumetric density measures (volumetric percent density, dense volume) on screening mammograms at enrollment and obtained clinical BI-RADS density. We calculated the BC-PRS using 268 SNPs (of the 313-SNP score) and the weighted sum of the SNPs using odds ratios from the largest BC GWAS of European ancestry to date. We performed cox proportional hazards regression adjusting for age and BMI to estimate hazard ratios (HRs), 95% confidence intervals (CI), and C-statistics (AUC) to describe the contribution of BC-PRS (per standard deviation (SD)) to the association of AI scores and breast density with BC risk. Likelihood ratio tests (LRT) and bootstrapping were used to compare model performance with vs. without inclusion of BC-PRS, at 10-years follow-up. Comparisons to the Tyrer-Cuzick model are ongoing. Over a median of 9.1 years (Interquartile range, 6.8 to 10.6), 446 incident BC were identified of which 285 invasive and 103 DCIS were confirmed by pathology report (60 were self-reported); 399 (256 invasive) occurred within 10 years and were used in primary analyses. Transpara score [HR per 1 unit=1.18 (1.14, 1.23), AUC=0.655 (0.628, 0.682)] and Mirai risk [HR per SD log risk=1.54 (1.43, 1.65), AUC=0.681 (0.655, 0.706)] were both associated with BC. All three breast density measures were also significantly associated with BC, including in models with AI scores (Table). Addition of the BC-PRS to models with AI scores and breast density improved both model fit (All PLRT < 0.001; Table) and discrimination, with increases in AUC ranging from 0.033 to 0.034 for models with Transpara and density and 0.025 to 0.026 for models with Mirai and density (all P-values < 0.001; Table). Analyses restricted to invasive BC showed identical results. But, the BC-PRS contribution at 5-year follow-up was attenuated. In this cohort study, we found BC-PRS contributed to long-term risk prediction of BC above imaging AI models and breast density. Imaging and genetic risk factors are complementary and may outperform existing risk models and provide more accurate risk assessment to aid in precision prevention strategies. Citation Format: Celine Vachon, Christopher Scott, Imon Banerjee, Ramon Correa Moderno, Dan Hursh, Matthew Jensen, Yvonne Wang, Kathleen Brandt, Karla Kerlikowske, Sandhya Pruthi, Fergus Couch, Stacey Winham. Contribution of a breast cancer polygenic risk score to mammography artificial intelligence models and breast density for long term breast cancer risk prediction [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS10-06.

Background Symptomatic limitations in apical hypertrophic cardiomyopathy may occur because of diastolic dysfunction with resultant elevated left ventricular filling pressures, cardiac output limitation to exercise, pulmonary hypertension (PH), valvular abnormalities, and/or arrhythmias. In this study, the authors aimed to describe invasive cardiac hemodynamics in a cohort of patients with apical hypertrophic cardiomyopathy. Methods and Results Patients presenting to a comprehensive hypertrophic cardiomyopathy center with apical hypertrophic cardiomyopathy were identified (n=542) and those who underwent invasive hemodynamic catheterization (n=47) were included in the study. Of these, 10 were excluded due to postmyectomy status or incomplete hemodynamic data. The mean age was 56±18 years, 16 (43%) were women, and ejection fraction was preserved (≥50%) in 32 (91%) patients. The most common indication for catheterization was dyspnea (48%) followed by suspected PH (13%), and preheart transplant evaluation (10%). Elevated left ventricular filling pressures at rest or exercise were present in 32 (86%) patients. PH was present in 30 (81%) patients, with 6 (20%) also having right‐sided heart failure. Cardiac index was available in 25 (86%) patients with elevated resting filling pressures. Of these, 19 (76%) had reduced cardiac index and all 6 with right‐sided heart failure had reduced cardiac index. Resting hemodynamics were normal in 8 of 37 (22%) patients, with 5 during exercise; 3 of 5 (60%) patients had exercise‐induced elevation in left ventricular filling pressures. Conclusions In patients with apical hypertrophic cardiomyopathy undergoing invasive hemodynamic cardiac catheterization, 86% had elevated left ventricular filling pressures at rest or with exercise, 81% had PH, and 20% of those with PH had concomitant right‐sided heart failure.

Introduction: A significant portion of patients with aortic stenosis (AS) have low-gradient AS (LGAS) defined as aortic valve area ≤ 1.0 cm 2 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). Etiologies for LGAS include diastolic dysfunction, heart failure, other significant valvular disease, and atrial fibrillation (AF). AF is associated with worse outcomes compared to sinus rhythm (SR) in HGAS. AF is common in LGAS, but whether AF is associated with worse outcomes versus SR in LGAS has not been elucidated. Hypothesis: We hypothesize that AF is associated with higher mortality compared to SR in patients with LGAS. Methods: We retrospectively identified and reviewed charts of patients who were diagnosed with LGAS on transthoracic echocardiogram (TTE) from 2010-2020 at Mayo Clinic. Patient were classified according to rhythm at the time of TTE and history of AF was ascertained among those in SR. Patents were divided into 3 groups; SR without history of AF (group 1), SR with history of AF (group 2), and AF during TTE (group 3). Primary endpoints of overall mortality and cardiac mortality were ascertained. Results: A total of 3400 patients were included: n=2036 in group 1, n=519 in group 2, and n=845 in group 3. After adjusting for age, sex, and the Charlson index, group 2 and group 3 patient had significantly higher overall mortality (HR 1.22 and HR 1.52, respectively, p<0.0001 for both) and cardiac mortality (HR 1.37 and HR 2.05, respectively, p<0.0001 for both), Figure . Conclusions: In LGAS, AF is a significant prognostic indicator of overall mortality and cardiac mortality. LAGS associated with AF may need different management strategies given the higher mortality associated with the presence of AF.

Introduction: Aldosterone (Aldo) increases sodium and water reabsorption and mediates inflammatory processes. Its relationship to co-morbidities has not been well defined in the general population. Hypothesis: We addressed the hypothesis that plasma aldosterone concentration (PAC) is associated with metabolic and cardiorenal diseases in the general community. Methods: We determined PAC in a general community-based cohort from Olmsted County, MN (n=1,674), and defined correlations with cardiorenal, metabolic diseases and myocardial function and structure. Results: PAC was detected in all subjects and ranged from 2.5 to 91 ng/dl (mean value 6.7 ng/dl, +/- SD 6.6). Multivariate analysis adjusted for age, gender, BMI, ANP and BNP showed highly significant correlations between PAC and hypertension (HTN) (p<.0001, OR=2.28, CI:1.91-2.71), atrial fibrillation (p<.01), chronic kidney disease (CKD) (p<.0001, OR=1.64, CI:1.33-2.02), central obesity (p<.0001, OR=1.61, CI:1.27-2.05), hypertriglyceridemia (p<.003), prevalence of metabolic syndrome (MetS) (p<.0007, OR=1.40, CI=1.15-1.71), obesity (p<.0001, OR=1.48, CI:1.27-1.73), and concentric left ventricular hypertrophy (cLVH) (p=.01). Recognizing that ANP and BNP are known inhibitors of Aldo, we defined the relationship between these cardiac hormones (NTpro-ANP and NT-proBNP) and PAC and observed highly significant inverse relationships with NTpro-ANP (p=0.0009), NTpro-BNP (p=0.0003) in the general population. Conclusions: In conclusion, in the general community, PAC is strongly correlated with renal, metabolic and cardiovascular diseases as well as cardiac remodeling. Specifically, increasing PAC is strongly associated with HTN, CKD, obesity, MetS, cLVH, and lower levels of natriuretic peptides. Our data suggest a key role of Aldo as a possible biomarker and/or mediator of human cardiorenal and metabolic diseases even in the general adult population, prior to overt disease. This study also supports a possible counter regulatory relationship between cardiac natriuretic peptides and PAC. Further studies are warranted to evaluate possible therapeutic interventions targeting Aldo as a strategy to delay disease progression.

Background: Non-cardiac surgery (NCS) in patients with severe aortic stenosis has traditionally been associated with high perioperative mortality. Aortic valve replacement is recommended prior to elective NCS, but the impact of this strategy has not been systematically assessed. Methods: A retrospective review was performed of all patients with severe aortic stenosis undergoing major NCS at Mayo Clinic between 2000 and 2013. Patients undergoing aortic valve intervention (AVI) prior to NCS were compared to those undergoing surgery without prior AVI (control). Patients undergoing emergency surgery were excluded. Primary endpoint was occurrence of major adverse cardiac events (MACE; combination of death, stroke, myocardial infarction, new/worsening heart failure, ventricular arrhythmia) within 30 days of NCS; secondary endpoints were mortality at 30 days and 1 year after NCS. Results: 180 patients (age 74.5 ± 10.5 years, 64% male) who underwent NCS within 12 months after AVI, were compared to 232 patients (age 76.6 ± 10.7 years, 56% male) in the control group. Patients undergoing AVI were more often symptomatic than controls (41% vs 26%, p = 0.002). MACE was significantly higher in the control group (21.6% vs 5.6%, p < 0.001), mainly due to the increased risk of heart failure in the postoperative period in this group (18.5% vs 2.2%, p < 0.001). There was no significant difference in the rate of myocardial infarction (1.7% vs 0.6%, p = 0.39), ventricular arrhythmia (0.9 % vs 0 %, p = 0.51) or stroke (0.9 % vs 0 %, p = 0.51). Kaplan-Meier assessment demonstrated no significant difference at 30 days but a reduction in 1 year mortality in the AVI group compared to the control group (Figure). Conclusions: Pre-operative AVI for severe aortic stenosis results in reduced heart failure and improved 1 year survival. However, other MACE and 30 day mortality appears unchanged. Pre-operative AVI should be considered in symptomatic patients, where the benefit of AVI is demonstrated to be greatest.