Scott, Christopher G.

Abstract Purpose: Volumetric breast density and body mass index (BMI) are increasingly used for breast cancer risk stratification. We examine if the effect of volumetric breast density on breast cancer risk increases with increasing BMI. Methods: Participants were from two case-control studies within mammography practices, the San Francisco Mammography Registry and the Mayo Clinic Rochester, Breast Screening Practice. Breast cancers were included if diagnosed between January 2007 and 2015 and with a screening full-field digital mammogram at least 6 months prior to diagnosis; the earliest mammogram within 5 years of diagnosis was selected. Up to three controls were matched to each case on age, race, date, mammography machine, and state of residence. Volumetric percent density (VPD), dense volume (DV) and non-dense volume (NDV) were measured using VolparaTM software. Breast cancer risk was assessed using logistic regression stratified by menopause status and adjusted for matching factors, family history of breast cancer, parity/age at first birth, and postmenopausal hormone therapy. Models for DV were additionally adjusted for NDV, and NDV models for DV. Multiplicative interactions were fit between BMI categories [<25 (underweight), 25-30 (normal weight) and >30 (overweight/obese) kg/m2] and VPD, DV, and NDV, and trend tests assessed for increasing odds ratios (OR) with increasing BMI. Results: A total of 781 premenopausal and 1850 postmenopausal breast cancers and 3535 controls were included in the analysis. Median age of premenopausal women was 45 years (IQR: 6.1) and 63.3 years (IQR: 14) for postmenopausal women. Cases vs. controls had greater VPD and DV for both premenopausal (VPD: 14.9% vs. 12.0%, DV: 74.1 cm3 vs. 64.4 cm3) and postmenopausal women (VPD: 6.8% vs. 6.1%, DV: 53.4 cm3 vs. 48.0 cm3)(all p's<0.001). Trends between increasing BMI and VPD were evident for both pre (ptrend=0.0007) and postmenopausal (ptrend=0.0005) women. Among premenopausal women, the odds ratio (OR) for breast cancer associated with a 10% increase in VPD was of 1.39, 2.19 and 2.88 for BMI <25, 25-30 and >30 kg/m2 (p-trend=0.0007), respectively. For DV, OR's were 1.39, 1.33 and 1.51 for a 1 SD increase in DV, respectively, though the interaction with DV was not significant (ptrend=0.68). Among postmenopausal women, a 10% increase in VPD was associated with OR's of 1.35, 2.03, 3.6 for BMI <25, 25-29, >30-kg/m2 (ptrend =0.0001), respectively, and 1.31, 1.34 and 1.65 for a 1 SD increase in DV (ptrend =0.01), respectively. Associations between NDV and breast cancer risk did not differ by BMI category for premenopausal (ptrend =0.52) or postmenopausal (ptrend =0.07) women. Conclusions: The effect of VPD on breast cancer risk is strongest in overweight/obese women. As volumetric breast density and BMI are commonly used in clinical risk stratification, these differences in risk have high clinical relevance for informing prevention decisions. Citation Format: Natalie J. Engmann, Christopher G. Scott, Matthew R. Jensen, Stacey J. Winham, Lin Ma, Kathleen R. Brandt, Amir Mahmoudzadeh, Serghei Malkov, Dana Whaley, Carrie Hruska, Fang Fang Wu, Diana L. Miglioretti, Aaron D. Norman, John Heine, John Shepherd, Vernon S. Pankratz, Celine M. Vachon, Karla Kerlikowske. Overweight and obese women with high volumetric breast density at high breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3226.

Background Ideal cardiovascular health metrics (defined by the American Heart Association Life's Simple 7 [LS7]) are suboptimal among blacks, which results in high risk of cardiovascular disease. We examined the association of multiple stressors with LS7 components among blacks. Methods and Results Using a community‐based cohort of blacks (N=4383), we examined associations of chronic stress, minor stressors, major life events, and a cumulative stress score with LS7 components (smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting plasma glucose) and an LS7 composite score. Multivariable logistic regression assessed the odds of achieving intermediate/ideal levels of cardiovascular health adjusted for demographic, socioeconomic, behavioral, and biomedical factors. The LS7 components with the lowest percentages of intermediate/ideal cardiovascular health levels were diet (39%), body mass index (47%), and physical activity (51%). Higher chronic, minor, and cumulative stress scores were associated with decreased odds (odds ratio [OR]) of achieving intermediate/ideal levels for smoking (OR [95% confidence interval], 0.80 [0.73–0.88], 0.84 [0.75–0.94], and 0.81 [0.74–0.90], respectively). Participants with more major life events had decreased odds of achieving intermediate/ideal levels for smoking (OR, 0.84; 95% confidence interval, 0.76–0.92) and fasting plasma glucose (OR, 0.90; 95% confidence interval, 0.82–0.98). Those with higher scores for minor stressors and major life events were less likely to achieve intermediate or ideal LS7 composite scores (OR [95% confidence interval], 0.89 [0.81–0.97] and 0.91 [0.84–0.98], respectively). Conclusions Blacks with higher levels of multiple stress measures are less likely to achieve intermediate or ideal levels of overall cardiovascular health (LS7 composite score), specific behaviors (smoking), and biological factors (fasting plasma glucose).

AbstractBackgroundQRS fragmentation (fQRS) during baseline ventricular conduction, a myocardial fibrosis marker, is associated with increased risk of ventricular tachyarrhythmias but may not manifest unless ventricular activation change is provoked. We examined the association of fQRS during right ventricular (RV) pacing with death and ventricular tachyarrhythmia in patients with left ventricular (LV) dysfunction undergoing electrophysiology study (EPS).Methods and resultsStudy participants had LV dysfunction (ejection fraction < 50%) undergoing EPS from January 2002 to May 2014 at Mayo Clinic in Rochester, Minnesota. fQRS during RV stimulation involved >2 notches on R/S waves identified in ≥2 contiguous standard electrocardiographic leads representing anterior, inferior, or lateral ventricular segments. Primary outcomes were ventricular tachyarrhythmias that were symptomatic or required intervention and total and cardiac deaths. In all, 528 patients participated (mean age, 65 years; male sex, 80%). Of them, 312 (59%) had ischemic cardiomyopathy and mean (SD) left ventricular ejection fraction (LVEF) of 33.2% (9.5%); 457 (87%) had implantable cardiac devices (implanted defibrillator, n = 380). Mean (SD) follow‐up was 3.2 (3.0) years. fQRS during RV pacing was observed in 292 patients (60%) in any ventricular segment. Patients with fQRS during RV pacing had 2.5 higher rate of ventricular tachyarrhythmia events than patients with no fQRS (hazard ratio [95% CI], 2.45 [1.5–4.2]; P < 0.01), after correcting for baseline ventricular conduction defect and QRS duration, LVEF, inducible sustained ventricular tachycardia, diabetes mellitus, chronic kidney disease, and ischemic cardiomyopathy.ConclusionsRV stimulation can unmask fQRS, and it is associated with increased risk of ventricular tachyarrhythmia in LV dysfunction.

Background: Heart involvement is the most important prognostic determinant in AL amyloidosis patients. Echocardiography is a cornerstone for the diagnosis and provides important prognostic information. Methods and Results: We studied 754 patients with AL amyloidosis who underwent echocardiographic assessment at the Mayo Clinic, including a Doppler-derived measurement of stroke volume (SV) within 30 days of their diagnosis to explore the prognostic role of echocardiographic variables in the context of a well-established soluble cardiac biomarker staging system. Reproducibility of SV, myocardial contraction fraction, and left ventricular strain was assessed in a separate, yet comparable, study cohort of 150 patients from the Pavia Amyloidosis Center. The echocardiographic measures most predictive for overall survival were SV index <33 mL/min, myocardial contraction fraction <34%, and cardiac index <2.4 L/min/m 2 with respective hazard ratios (95% confidence intervals) of 2.95 (2.37–3.66), 2.36 (1.96–2.85), and 2.32 (1.91–2.80). For the subset that had left ventricular strain performed, the prognostic cut point was −14% (hazard ratios, 2.70; 95% confidence intervals, 1.84–3.96). Each parameter was independent of systolic blood pressure, Mayo staging system (NT-proBNP [N-terminal pro-B-type natriuretic peptide] and troponin), and ejection fraction on multivariable analysis. Simple predictive models for survival, including biomarker staging along with SV index or left ventricular strain, were generated. Conclusions: SV index prognostic performance was similar to left ventricular strain in predicting survival in AL amyloidosis, independently of biomarker staging. Because SV index is routinely calculated and widely available, it could serve as the preferred echocardiographic measure to predict outcomes in AL amyloidosis patients.

In a prospective cohort study of the health effects associated with prenatal Diethylstilbestrol (DES) exposure, DES was associated with an increased breast cancer risk after 40 years of age. It is unknown whether it is associated with greater mammographic density, which strongly predicts breast cancer risk. A cohort of DES‐exposed and unexposed women was assembled at the Mayo Clinic in 1975, and followed through 2012 as part of the National Cancer Institute's DES follow‐up study. Mammographic density from 3,637 mammograms for 332 (222 DES‐exposed, 110 unexposed) women in this cohort screened at the Mayo Clinic, Rochester between 1996 and 2015 was determined clinically using the Breast Imaging Reporting and Data System (BI‐RADS). Any effect of prenatal DES exposure on mammographic density was estimated using repeated measures logistic regression. There was no association between prenatal DES exposure and high mammographic density for either premenopausal [Odds ratios (OR) = 0.92 (95% Confidence Interval (CI): 0.50, 1.7] or postmenopausal women (OR = 0.90; 95% CI: 0.54, 1.5). Among premenopausal women, associations differed by body mass index (BMI), with ORs of 1.47 (0.70, 3.1) for women with BMI above the median and 0.53 (0.23, 1.3) for those with BMI below the median (pinteraction = 0.05). Overall, however, prenatal DES exposure was not associated with high mammographic density in this sample of DES Study participants. Consequently, this study does not provide evidence that high mammographic density is involved with the influence of DES on breast cancer risk.

Cenderitide is a novel designer natriuretic peptide (NP) composed of C‐type natriuretic peptide (CNP) fused to the C‐terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to coactivate the two NP receptors, particulate guanylyl cyclase (pGC)‐A and ‐B. The rationale for its design was to achieve the renal‐enhancing and antifibrotic properties of dual receptor activation, but without clinically significant hypotension. Here we report the first clinical trial on the safety, tolerability, and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable heart failure (HF). Four‐hour infusion of Cenderitide was safe, well‐tolerated, and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP‐enhancing therapeutic strategy.

Background: Although the hallmark of long-QT syndrome (LQTS) is abnormal cardiac repolarization, there are varying degrees of phenotypic expression and arrhythmic risk. Our aim was to evaluate the performance of a morphological T-wave analysis program in defining breakthrough LQTS arrhythmic risk beyond the QTc value. Methods and Results: We analyzed 407 genetically confirmed patients with LQT1 (n=246; 43% men) and LQT2 (n=161; 41% men) over the mean follow-up period of 6.4±3.9 years. ECG analysis was conducted using a novel, proprietary T-wave analysis program. Time to a LQTS-associated cardiac event was analyzed using Cox proportional hazards regression methods. Twenty-three patients experienced ≥1 defined breakthrough cardiac arrhythmic events with 5- and 10-year event rates of 4% and 7%. Two independent predictors of future LQTS-associated cardiac events from the surface ECG were identified: left slope of T wave in lead V6 (hazard ratio=0.40 [0.24–0.69]; P <0.001) and T-wave center of gravity x axis (last 25% of wave) in lead I (hazard ratio=1.90 [1.21–2.99]; P =0.005), C statistic of 0.77 (0.65–0.89). When added to the QTc (C statistic 0.68 for QTc alone), discrimination improved to 0.78. Genotype analysis showed weaker association between these T-wave variables and LQT1-triggered events while these features were stronger in patients with LQT2 and significantly outperformed the QTc (C statistic, 0.82 [0.71–0.93]). Conclusion: Detailed morphological analysis of the T wave provides novel insights into risk of breakthrough arrhythmic events in LQTS, particularly LQT2. This observation has the potential to guide clinical decision making and further refine risk stratification.

The burden and predictors of hospitalization over time in community-based patients with peripheral artery disease (PAD) have not been established. This study evaluates the frequency, reasons and predictors of hospitalization over time in community-based patients with PAD. We assembled an inception cohort of 1798 PAD cases from Olmsted County, MN, USA (mean age 71.2 years, 44% female) from 1 January 1998 through 31 December 2011 who were followed until 2014. Two age- and sex-matched controls ( n = 3596) were identified for each case. ICD-9 codes were used to ascertain the primary reasons for hospitalization. Patients were censored at death or last follow-up. The most frequent reasons for hospitalization were non-cardiovascular: 68% of 8706 hospitalizations in cases and 78% of 8005 hospitalizations in controls. A total of 1533 (85%) cases and 2286 (64%) controls ( p < 0.001) were hospitalized at least once; 1262 (70%) cases and 1588 (44%) controls ( p < 0.001) ≥ two times. In adjusted models, age, prior hospitalization and comorbid conditions were independently associated with increased risk of recurrent hospitalizations in both groups. In cases, severe PAD (ankle–brachial index < 0.5) (HR: 1.25; 95% CI: 1.15, 1.36) and poorly compressible arteries (HR: 1.26; 95% CI: 1.16, 1.38) were each associated with increased risk for recurrent hospitalization. We demonstrate an increased rate of hospitalization in community-based patients with PAD and identify predictors of recurrent hospitalizations. These observations may inform strategies to reduce the burden of hospitalization of PAD patients.