Scott, Christopher G.

Abstract Aims Cardiac power is a measure of cardiac performance that incorporates both pressure and flow components. Prior studies have shown that cardiac power predicts outcomes in patients with reduced left ventricular (LV) ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise cardiac power and power reserve in patients with normal EF. Methods and results We performed a retrospective analysis in 24 885 patients (age 59 ± 13 years, 45% females) with EF ≥50% and no significant valve disease or right ventricular dysfunction, undergoing exercise stress echocardiography between 2004 and 2018. Cardiac power and power reserve (developed power with stress) were normalized to LV mass and expressed in W/100 g of LV myocardium. Endpoints at follow-up were all-cause mortality and diagnosis of heart failure (HF). Patients in the higher quartiles of power/mass (rest, peak stress, and power reserve) were younger and had higher peak blood pressure and heart rate, lower LV mass, and lower prevalence of comorbidities. During follow-up [median 3.9 (0.6–8.3) years], 929 patients died. After adjusting for age, sex, metabolic equivalents (METs) achieved, ischaemia/infarction on stress test results, medication, and comorbidities, peak stress power/mass was independently associated with mortality [adjusted hazard ratio (HR), highest vs. lowest quartile, 0.5, 95% confidence interval (CI) 0.4–0.6, P < 0.001] and HF at follow-up [adjusted HR, highest vs. lowest quartile, 0.4, 95% CI (0.3, 0.5), P < 0.001]. Power reserve showed similar results. Conclusion The assessment of cardiac power during exercise stress echocardiography in patients with normal EF provides valuable prognostic information, in addition to stress test findings on inducible myocardial ischaemia and exercise capacity.

Objective To comprehensively explore contemporary differences between bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) patients with chronic haemodynamically significant aortic regurgitation (AR). Methods Consecutive patients with chronic ≥moderate-severe AR from a tertiary referral centre (2006–2017) were included. All-cause mortality, surgical indications and aortic valve surgery (AVS) were analysed. Results Of 798 patients (296 BAV-AR, age 46±14 years; 502 TAV-AR, age 67±14 years, p<0.0001) followed for 5.5 (IQR: 2.9–9.2) years, 403 underwent AVS (repair in 96) and 154 died during follow-up. The 8-year AVS incidence was 60%±3% versus 53%±3% for BAV-AR and TAV-AR, respectively (p=0.014). The unadjusted (real-life) 8-year total survival was 93%±7% versus 71%±2% for BAV-AR and TAV-AR, respectively (p<0.0001), and became statistically insignificant after sole adjustment for age (p=0.14). The within-group relative risk of death in BAV-AR patients demonstrated a large age-dependent increase (two fold at 50–55 years, up to 10-fold at 70 years). The presence of baseline symptoms was significantly associated with death for both BAV-AR (p=0.039) and TAV-AR (p<0.0001), but the strength of the association decreased with age adjustment for BAV-AR (age-adjusted HR 2.43 (0.92–6.39), p=0.07) and not for TAV-AR (age-adjusted HR, 2.3 (1.6–3.3), p<0.0001). As compared with general population, TAV-AR exhibited baseline excess risk which further increased at left ventricular ejection fraction (LVEF) <60% and left ventricular end-systolic dimension index (LVESDi) >20 mm/m2; similar thresholds were observed for BAV-AR patients. Conclusion BAV-AR patients were two decades younger than TAV-AR and underwent AVS more frequently, resulting in a considerable real-life survival advantage for BAV-AR that was determined primarily by age and not valve anatomy. Pragmatically, regardless of valve anatomy, patients with haemodynamically significant AR and age >50–55 years require a low-threshold for surgical referral to prevent symptom development where LVEF <60% and LVESDi >20 mm/m2 seem appropriate referral thresholds.

Abstract Aims Right atrial pressure (RAP) provides a composite measure of right ventricular diastolic dysfunction, right atrial compliance, and volume status, and these three variables are typically abnormal in adults with repaired tetralogy of Fallot (TOF). RAP is a well-established prognostic metric in patients with pulmonary hypertension, and recent data suggest that RAP is associated with clinical outcomes in TOF. The purpose of this study was to determine the role of inferior vena cava (IVC) haemodynamics (size and collapsibility) for the assessment of RAP and its potential application for risk stratification and prognostication in the TOF population. Methods and results Adult TOF patients with echocardiographic assessment of IVC haemodynamics were divided into patients with (derivation cohort, n = 256) and without (validation cohort, n = 492) cardiac catheterization data. We assessed the correlation between IVC haemodynamics, RAP, and disease severity indices [arrhythmias, peak oxygen consumption (VO2), and heart failure hospitalization] in derivation cohort and compared it with the correlations in the validation cohort. IVC haemodynamics correlated with RAP (r = 0.52, P &lt; 0.001), with disease severity indices {atrial arrhythmias [area under the curve (AUC) 0.81], ventricular arrhythmias [AUC 0.67], heart failure hospitalizations [AUC 0.78], and peak VO2 [r = 0.53]}, and with transplant-free survival in the derivation cohort. Similar correlations between IVC haemodynamics, disease severity indices, and transplant-free survival were also observed in the validation cohort. Conclusions These findings suggest that IVC haemodynamics can potentially be used for risk stratification and prognostication in TOF patients and can complement the current risk models that are based predominately on right ventricular volumes and systolic function.

Abstract We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Abstract Background: Alcohol intake and breast density are established risk factors for breast cancer (BC). A few studies suggest breast density is on the causal pathway between alcohol and BC but the literature is not consistent. We examine the interrelationship between alcohol, volumetric breast density and BC risk, specifically whether there is a stronger alcohol and BC association among women with dense breasts and/or whether breast density mediates the alcohol and BC association. Methods: We conducted a nested case-control study within the San Francisco Mammography Registry consisting of four breast screening centers. From 2006-2013, through linkages with the California cancer registry, we identified 2572 women diagnosed with BC who had screening mammograms performed at least six months prior to diagnosis. Controls (5119) were matched to cases on age, date of earliest mammogram, race/ethnicity, facility, and mammography machine. We obtained the raw format of digital mammograms on average 3.1 (standard deviation (SD) =1.7) years prior to diagnosis or corresponding date for controls. We ascertained usual daily alcohol intake and other risk factors from a clinical questionnaire at time of mammography. We obtained BI-RADS density from clinical records and used VolparaTM to assess volumetric percent density, dense volume and non-dense volume from the mammogram. We examined the associations of daily alcohol intake (none, one or less, two or more drinks per day) and volumetric density phenotypes (per 1 SD) with BC risk using logistic regression (odds ratios, OR; 95% confidence intervals, CI; and trend tests). We examined deviation from multiplicative interaction using chi-squared tests. We evaluated mediation of the alcohol and BC association by volumetric density measures using logistic regression to estimate the association between alcohol use and BC with and without adjustment for density measures. Percent mediation was estimated using the differences in the log OR estimates from the two models. All models were adjusted for age, 1/BMI and menopause and matching factors. Analyses were also stratified by menopausal status. Results: Alcohol intake was available on 2233 cases and 4562 controls, 88% of those eligible. BC cases and controls had similar age (57.2 years (SD=11.5) vs. 57.1 years (SD=11.5)), BMI (25.3 kg/m2 (SD=5.3) vs. 24.9 kg/ m2 (SD=5.1)) and race (69.0% vs. 68.2% Caucasian). Cases were more likely to drink alcohol daily than controls (52.1% vs. 49.0%), in particular two or more drinks per day (14.8% vs. 13.2%). Alcohol was associated with increased BC risk (OR=1.14, 95% CI:1.02-1.27, for one or less drinks per day and OR=1.22, 95% CI:1.05-1.42 for 2 or more drinks per day) compared to non-drinkers (p-trend=0.004). Percent volumetric density (OR=1.45 per SD, 95%CI: 1.36-1.56,) and dense volume (OR=1.30, 95% CI: 1.24-1.37) were also positively associated with BC risk; non-dense volume was inversely associated (OR=0.93, 95%CI: 0.86-1.01). Associations were similar by menopausal subgroup. There was no evidence for a differential association of alcohol and breast cancer risk by dense breasts assessed using any of the density phenotypes examined (all P’s&gt;0.1). However, the association between alcohol and overall risk of BC was partially mediated by dense volume among all women (percent mediated=25%, P=0.01) and postmenopausal women (percent mediated=19%, P=0.03). Conclusions: The association of daily alcohol intake and breast cancer risk was similar among women with dense and non-dense breasts. However, dense volume partially mediated the association between alcohol and risk of breast cancer, particularly among postmenopausal women, suggesting that alcohol partially influences breast cancer risk through changes in breast tissue composition. Citation Format: Celine Marie Vachon, Christopher G. Scott, Stacey J Winham, John A Shepherd, Kathleen R Brandt, Matthew R Jensen, Carrie B Hruska, John J Heine, V. Shane Pankratz, Karla Kerlikowske. Association of daily alcohol intake, volumetric density and breast cancer risk [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-02.

Abstract Background: Polygenic risk scores (PRS) based on a large number of SNPs associated with breast cancer have recently been made available in combination with multigene panel testing for clinical management of breast cancer risk. Breast cancer risk assessment has historically been performed using various non-genetic risk models, which predict lifetime risk of breast cancer in unaffected women based on personal and family history information. While clinical use of PRS in combination with these models continues to increase, the predictive performance of a PRS combined with clinical information in real-world patient populations has not been thoroughly investigated. Methods: We assessed a 100-SNP breast cancer PRS in combination with the Tyrer-Cuzick model-estimated lifetime breast cancer risk in 5,374 Caucasian women from the case-control Mayo Clinic Breast Cancer Study (MCBCS), comprised of 3,373 breast cancer cases and 2,001 unaffected controls seen at Mayo Clinic from 2004 to 2016. Clinical, family history, and demographic information was collected on all MCBCS participants via questionnaires and medical record review. SNPs were selected for the PRS if they exceeded genome-wide significance in ≥2 large-scale breast cancer genome wide association studies (GWAS) in women of European descent. Selected SNPs were then used to construct a population standardized PRS, accounting for per-allele odds ratios reported in the largest GWAS to date and population-specific allele frequencies. PRS and Tyrer-Cuzick model associations with breast cancer and related clinical features were tested using multivariate logistic regression. Results: Among cases and controls, mean±SD age at diagnosis and study enrollment was 56.4±12.4 and 56.2±14.1, respectively. Approximately 36.9% of cases and 16.9% of controls had ≥1 first- or second-degree relative with breast or ovarian cancer, respectively. Among unaffected women, the median (IQR) estimated lifetime risk of breast cancer to age 85 based on Tyrer-Cuzick alone was 8.3% (6.9%), and 2.6% had a clinically actionable lifetime risk of ≥20%. The mean±SD sum of the risk alleles across 100 SNPs was significantly higher for cases vs. controls (94.8±6.3 vs. 92.7±6.2, p&lt;0.001). Compared to women in the lowest quartile of PRS, those in the 2nd, 3rd and 4th quartiles were 1.47 (95% CI: 1.26-1.72), 1.87 (95% CI: 1.60-2.19), and 2.22 (95% CI: 1.89-2.61) times more likely to have breast cancer after adjustment for age and family history. The AUC was 0.59 (95% CI: 0.58-0.61) for PRS and 0.60 (95% CI: 0.58-0.61) for Tyrer-Cuzick model estimated risk alone; but when combined, the model achieved an AUC of 0.63 (95% CI: 0.62-0.65). Among unaffected women, 6.7% had ≥20% lifetime risk of breast cancer based on the combined PRS-clinical model. Conclusions: These findings suggest that the 100-SNP PRS significantly improves estimation of breast cancer risk based on non-genetic models, and can be used to further identify women at increased lifetime risk who would otherwise not be identified by clinical assessment alone. Citation Format: Mary Helen Black, Shuwei Li, Holly LaDuca, Sebastian Armasu, Eric C. Polley, Patrick Fitz-Gibbon, Chris G. Scott, Stacey J. Winham, Janet E. Olson, Kathryn J. Ruddy, Celine M. Vachon, Fergus J. Couch. Performance of a polygenic risk score combined with clinical assessment for breast cancer risk [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-06.

Objective To determine whether echocardiography-derived left ventricular filling pressure influences survival in patients with severe aortic stenosis (AS) undergoing aortic valve replacement (AVR). Methods We retrospectively reviewed 1383 consecutive patients with severe AS, normal ejection fraction and interpretable filling pressure undergoing AVR. Left ventricular filling pressure was determined according to current guidelines using mitral inflow, mitral annular tissue Doppler, estimated right ventricular systolic pressure and left atrial volume index. Cox proportional hazards regression was used to assess the influence of various parameters on mortality. Results Age was 75±10 years and 552 (40%) were female. Left ventricular filling pressure was normal in 325 (23%), indeterminate in 463 (33%) and increased in 595 (43%). Mean follow-up was 7.3±3.7 years, and mortality was 1.2%, 4.2% and 18.9% at 30 days and 1 and 5 years, respectively. Compared with patients with normal filling pressure, patients with increased filling pressure were older (78±9 vs 70±12, p<0.001), more often female (45% vs 35%, p=0.002) and were more likely to have New York Heart Association class III–IV symptoms (35% vs 24%, p=0.004), coronary artery disease (55% vs 42%, p<0.001) and concentric left ventricular hypertrophy (63% vs 37%, p<0.001). After correction for other factors, increased left ventricular filling pressure remained an independent predictor of mortality after successful AVR (adjusted HR 1.45 (95% CI 1.16 to 1.81), p=0.005). Conclusions Preoperative increased left ventricular filling pressure is common in patients with AS undergoing AVR and has important prognostic implications, regardless of symptom status. Future prospective studies should consider whether patients with increased filling pressure would benefit from earlier operation.