Left atrial strain is reduced following trastuzumab in breast cancer patients.

BACKGROUND: The effect of trastuzumab therapy on left atrial (LA) function remains largely unknown. Our aim was to assess the changes in LA strain parameters longitudinally in patients treated with trastuzumab. METHODS: We retrospectively studied 170 patients with stage I-IV HER2+ breast cancer. All patients had baseline echocardiograms and repeat echocardiograms at 3 months and after 1 year. We measured LA strain at all three time points. Changes in LA strain and strain rate (sr) parameters were evaluated using repeated-measures mixed-effects models. The cohort was stratified according to development of cancer therapeutics-related cardiac dysfunction (CTRCD) during follow-up. RESULTS: The mean age was 52.7 ± 13.8 years, 25.3% had hypertension and 16.0% had metastatic disease. Multiple LA strain parameters (predicted delta value, [95%CI]) showed statistically significant declines in patients who developed CTRCD from baseline to the 3-month follow-up after multivariable adjustment; LA reservoir strain (LAεres ): -4.7%; [-8.1% to -1.3%], p = .007; LA conduit strain (LAεcon ): -2.8%; [-5.3% to -.4%], p = .021); and LAεres sr: -.2/s; [-.3/s to -.09/s], p < .001). In patients who did not develop CTRCD, LA strain parameters declined significantly but to a smaller degree than in the CTRCD group (LAεres : -1.7%; [-3.1% to -.3%], p = .020, LAεcon : -2.2%; [-3.3% to -1.1%], p < .001, and LA booster pump strain : -2.4%; [-3.5% to -1.4%], p < .001). LA strain rates did not decline significantly in the non-CTRCD group. CONCLUSION: Trastuzumab treatment was associated with declines in LA strain parameters in patients with breast cancer. The largest declines were observed in patients who developed CTRCD during treatment.

The effect of kidney transplantation on left ventricular remodeling and global diastolic strain rate in end-stage renal disease.

BACKGROUND: Diastolic dysfunction is an early marker of cardiac pathology in end-stage kidney disease (ESKD) patients. The ratio of transmitral filling velocity (E) to early diastolic strain rate (E/e'sr) is a novel non-invasive marker of early left ventricular (LV) filling pressure obtained using two-dimensional speckle tracking echocardiography (2DSTE). METHODS: In a prospective cohort of kidney transplant (KTX) recipients with echocardiograms performed pre-transplant we obtained repeat echocardiograms at 6 months following transplant. All echocardiograms were analyzed using 2DSTE where E/e'sr and global longitudinal strain were obtained. Paired tests were used to assess changes to cardiac structure and function following KTX. RESULTS: A total of 33 patients were included in the study (mean age was 46.6 ± 13.7 years and 42% were males). The primary causes of ESKD in the cohort were glomerular disease (33%), hypertension (30%), and polycystic kidney disease (12%). The median (IQR) time spent on dialysis was 5.4 years [2.9, 7.7 years]. A reverse remodeling of the LV was observed following KTX as LV mass decreased (189.2 ± 57.5 g vs 171.1 ± 56.8 g, P = 0.014). LV filling pressure decreased as assessed by E/e'sr (103.7 ± 51.1 cm vs 72.6 ± 35.5 cm, P = 0.009). E to early diastolic mitral annular tissue velocity (E/e') did not change following KTX (9.9 ± 4.5 vs 10.3 ± 4.1, P = 0.54). Additionally, both LV internal diastolic and systolic diameter decreased significantly. CONCLUSION: Reverse cardiac remodeling following KTX was observed as improvements in LV mass and LV dimensions. LV filling pressure improved as assessed by E/e'sr decreased following KTX, whereas E/e' did not change.

One-Year Outcomes After MitraClip for Functional Mitral Regurgitation.

BACKGROUND: Secondary mitral regurgitation (SMR) occurs in the absence of organic mitral valve disease and may develop as the left ventricle dilates or remodels or as a result of leaflet tethering with impaired coaptation, most commonly from apical and lateral distraction of the subvalvular apparatus, with late annular dilatation. The optimal therapy for SMR is unclear. This study sought to evaluate the 1-year adjudicated outcomes of all patients with SMR undergoing the MitraClip procedure in the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study) Investigational Device Exemption program, which is comprised of the randomized clinical trial, the prospective High-Risk Registry, and the REALISM Continued Access Registry (Multicenter Study of the MitraClip System). METHODS: Patients with 3+/4+ SMR enrolled in EVEREST II were stratified by non-high surgical risk (non-HR) and high surgical risk (HR) status (defined as Society of Thoracic Surgeons risk of mortality ≥12% or predefined risk factors). Clinical, echocardiographic, and functional outcomes at 1 year were evaluated. RESULTS: A total of 616 patients (482 HR, 134 non-HR; mean age, 73.3±10.5 years; Society of Thoracic Surgeons risk, 10.2±6.9%) with SMR underwent the MitraClip procedure. At baseline, 80.5% of patients were in New York Heart Association class III/IV. Major adverse events at 30 days included death (3.6%), stroke (2.3%), and renal failure (1.5%). At discharge, 88.8% had MR ≤2+. At 1 year, there were 139 deaths, and the Kaplan-Meier estimate of freedom from mortality was 76.8%. The majority of surviving patients (84.7%) remained with MR ≤2+ and New York Heart Association class I/II (83.0%). Kaplan-Meier survival at 1 year was 74.1% in HR patients and 86.4% in non-HR patients ( P=0.0175). At 1 year, both groups achieved comparable MR reduction (MR ≤2+, 84.0% versus 87.0%) and improvement in left ventricular end-diastolic volume (-8.0 mL versus -12.7 mL), whereas New York Heart Association class I/II was found in 80.1% versus 91.8% ( P=0.008) of HR and non-HR patients, respectively. In HR patients, the annualized rate of heart failure hospitalizations decreased from 0.68 to 0.46 in the 12 months before to 12 months after the procedure ( P<0.0001). CONCLUSIONS: Transcatheter mitral valve repair with the MitraClip in patients with secondary MR is associated with acceptable safety, reduction of MR severity, symptom improvement, and positive ventricular remodeling. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov . Unique identifiers: NCT00209274, NCT01940120, and NCT01931956.

Ratio of transmitral early filling velocity to early diastolic strain rate predicts long-term risk of cardiovascular morbidity and mortality in the general population.

Aims: It has previously been demonstrated that the ratio of early mitral inflow velocity to global diastolic strain rate (E/e'sr) is a significant predictor of cardiac events in specific patient populations. The utility of this measurement to predict cardiovascular events in a general population has not been evaluated. Methods and results: A total of 1238 participants in a general population study underwent a health examination including echocardiography where global longitudinal strain (GLS) and E/e'sr were determined. The primary endpoint was the composite of incident heart failure (HF), acute myocardial infarction (AMI) or cardiovascular death (CVD). During follow-up (median 11 years), 140 (11.3%) participants reached the composite endpoint. E/e'sr was associated with adverse outcome [HR 1.17 95% CI (1.13-1.21); P < 0.001, per 10 cm increase]. After multivariable adjustment for echocardiographic and clinical parameters, E/e'sr remained an independent predictor of the composite endpoint [HR 1.08, 95% CI (1.02-1.13); P = 0.003] as opposed to E/e' [HR 1.03, 95% CI (0.99-1.06); P = 0.11 per 1 unit increase]. Global longitudinal strain modified the relationship between E/e'sr and outcome (P for interaction = 0.015). E/e'sr was a stronger predictor in participants with good systolic function as determined by GLS (GLS > 18%) after multivariable adjustment, when compared to participants with reduced systolic function (GLS < 18%) [HR 1.28 95% CI (1.06-1.54); P = 0.011, and HR 1.08 95% CI (1.02-1.14); P = 0.012, respectively). E/e'sr provided incremental information [Harrell's C-index: 0.839 (0.81-0.87) vs. 0.844 (0.82-0.87); P = 0.045] beyond the SCORE risk chart. Conclusion: In the general population, E/e'sr provides independent and incremental prognostic information regarding cardiovascular morbidity and mortality. Additionally, E/e'sr is a stronger predictor of cardiac events than E/e'.

Fully Automated Echocardiogram Interpretation in Clinical Practice.

BACKGROUND: Automated cardiac image interpretation has the potential to transform clinical practice in multiple ways, including enabling serial assessment of cardiac function by nonexperts in primary care and rural settings. We hypothesized that advances in computer vision could enable building a fully automated, scalable analysis pipeline for echocardiogram interpretation, including (1) view identification, (2) image segmentation, (3) quantification of structure and function, and (4) disease detection. METHODS: Using 14 035 echocardiograms spanning a 10-year period, we trained and evaluated convolutional neural network models for multiple tasks, including automated identification of 23 viewpoints and segmentation of cardiac chambers across 5 common views. The segmentation output was used to quantify chamber volumes and left ventricular mass, determine ejection fraction, and facilitate automated determination of longitudinal strain through speckle tracking. Results were evaluated through comparison to manual segmentation and measurements from 8666 echocardiograms obtained during the routine clinical workflow. Finally, we developed models to detect 3 diseases: hypertrophic cardiomyopathy, cardiac amyloid, and pulmonary arterial hypertension. RESULTS: Convolutional neural networks accurately identified views (eg, 96% for parasternal long axis), including flagging partially obscured cardiac chambers, and enabled the segmentation of individual cardiac chambers. The resulting cardiac structure measurements agreed with study report values (eg, median absolute deviations of 15% to 17% of observed values for left ventricular mass, left ventricular diastolic volume, and left atrial volume). In terms of function, we computed automated ejection fraction and longitudinal strain measurements (within 2 cohorts), which agreed with commercial software-derived values (for ejection fraction, median absolute deviation=9.7% of observed, N=6407 studies; for strain, median absolute deviation=7.5%, n=419, and 9.0%, n=110) and demonstrated applicability to serial monitoring of patients with breast cancer for trastuzumab cardiotoxicity. Overall, we found automated measurements to be comparable or superior to manual measurements across 11 internal consistency metrics (eg, the correlation of left atrial and ventricular volumes). Finally, we trained convolutional neural networks to detect hypertrophic cardiomyopathy, cardiac amyloidosis, and pulmonary arterial hypertension with C statistics of 0.93, 0.87, and 0.85, respectively. CONCLUSIONS: Our pipeline lays the groundwork for using automated interpretation to support serial patient tracking and scalable analysis of millions of echocardiograms archived within healthcare systems.

Ratio of Transmitral Early Filling Velocity to Early Diastolic Strain Rate Predicts All-Cause Mortality in Heart Failure with Reduced Ejection Fraction.

AIMS: The ratio of early mitral inflow velocity to global diastolic strain rate (E/e'sr) has recently emerged as a novel measure of left ventricular (LV) filling pressure. This new measure has demonstrated to have prognostic value superior to E/e'. This study aimed to investigate the prognostic value of E/e'sr in a large cohort of patients with heart failure with reduced ejection fraction (HFrEF) in relation to all-cause mortality. METHODS: We retrospectively studied 897 HFrEF (mean age 66 ± 12 years, 73% male, 59% ischemic cardiomyopathy) patients who underwent speckle tracking echocardiography where E/e'sr along with novel and conventional echocardiographic parameters were obtained. The primary endpoint was defined as all-cause mortality. RESULTS: During follow-up (median: 40 months IQR: 22-57), 137 (15.3%) patients died. Both E/e'sr and E/e' were significantly associated with mortality (E/e'sr: HR 1.03 95%CI [1.02-1.04], p<0.001, per 0.10m increase) and (E/e': HR 1.04 95%CI [1.02-1.06], p = 0.001, per 1unit increase). E/e'sr remained an independent predictor in a multivariable model after adjusting for age, gender, mean arterial pressure, heart rate, BMI, total cholesterol, diabetes mellitus, ischemic cardiomyopathy, LVEF, LVIDd, LVMI, LAVI, TAPSE and LV-GLS (HR 1.02 95%CI [1.01-1.03], p = 0.007) whereas E/e' did not (HR 1.01 95%CI [0.98-1.04], p = 0.57). Furthermore, E/e'sr provided incremental prognostic information beyond a model including known risk factors: age, gender, total cholesterol, mean arterial pressure, heart rate, BMI, smoking status and E/e' (Harrell's C-statistics: 0.72 (0.68-0.77) vs 0.70 (0.66-0.75), p = 0.047). CONCLUSIONS: In HFrEF patients, E/e'sr provides independent and incremental prognostic information regarding all-cause mortality superior to E/e'.

Cardiac function assessed by myocardial deformation in adult polycystic kidney disease patients.

BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) have an increased risk of cardiovascular morbidity and mortality. Impaired left ventricular (LV) global longitudinal strain (GLS) can be a sign of subclinical cardiac dysfunction even in patients with otherwise preserved ejection fraction (EF). Transmitral early filling velocity to early diastolic strain rate (E/SRe) is a novel measure of LV filling pressure, which is often affected early in cardiac disease. METHODS: A total of 110 ADPKD patients not on dialysis were included in this prospective study. All patients underwent an extensive echocardiographic examination including two-dimensional speckle tracking. GLS and strain rates were measured. The distribution of GLS and E/SRe was determined and patient characteristics were compared by median levels of GLS (- 17.8%) and E/SRe (91.4 cm). Twenty healthy participants were included as control group. RESULTS: There was a significantly worse GLS in the ADPKD patients (mean: - 17.8 ± 2.5%) compared to the healthy controls (mean: - 21.9 ± 1.9%), p < 0.001. The same was true for E/SRe (mean: 10.0 ± 0.3 cm) compared to the control group (mean: 6.5 ± 0.3 cm), p < 0.001. In simple logistic regression, male gender (OR: 4.74 [2.10-10.71], p < 0.001), fasting glucose (odds ratio (OR) 1.05 [1.01-1.10], p = 0.024), htTKV (OR: 1.07 [1.01-1.13], p = 0.013), HDL cholesterol (OR: 0.97 [0.94, 0.996], p = 0.025), triglycerides (OR: 1.01 [1.00-1.02], p = 0.039), hemoglobin (OR: 1.50 [1.11-2.04], p = 0.009), and ß-blocker use (OR: 1.07 [1.01, 1.13], p = 0.013) were all associated with higher GLS. After multivariate logistic regression with backward model selection, only male gender (OR: 5.78 [2.27-14.71], p < 0.001) and ß-blocker use (OR: 14.00 [1.60, 122.51], p = 0.017) remained significant. In simple logistic regression models, BMI (OR: 1.11 [1.02-1.20], p = 0.015), systolic blood pressure (OR: 1.03 [1.00-1.06], p = 0.027) and ß-blocker use (OR: 17.12 [2.15-136.20], p = 0.007) were associated with higher E/SRe - a novel measure of left ventricular filling pressure. After backward elimination, only ß-blocker use (OR: 17.22 [2.16, 137.14], p = 0.007) remained significant. CONCLUSION: Higher GLS and E/SRe are common in ADPKD patients, even in patients with preserved eGFR and normal left ventricular EF. GLS and E/SRe may aid in cardiovascular risk stratification in patients with ADPKD as they represent early markers of cardiac dysfunction.

Cardiovascular events and hospital resource utilization pre- and post-transcatheter mitral valve repair in high-surgical risk patients.

MitraClip is an approved therapy for mitral regurgitation (MR); however, health care resource utilization pre- and post-MitraClip remains understudied. METHODS: Patients with functional and degenerative MR at high surgical risk in the EVEREST II High-Risk Registry and REALISM Continued-Access Study were linked to Medicare data. Pre- and post-MitraClip all-cause death, stroke, myocardial infarction, heart failure (HF), and bleeding hospitalizations were identified. Inpatient costs, adjusted to 2010 US dollars, were calculated, and event rate ratios and cost ratios were estimated with multivariable modeling. RESULTS: Among 403 linked patients, the mean age was 80 years, 60% were male, mean baseline left ventricular ejection fraction was 49.6%, 83.3% were New York Heart Association class III/IV, 78.2% were MR grade 3+/4+, and 63.3% had functional MR. All-cause hospitalization decreased from 1,854 to 1,435/1,000 person-years (P<.001). HF hospitalization decreased following MitraClip (749 vs 332/1000 person-years, P<.001), but bleeding increased (199 vs 298/1000 person-years, P<.001). Changes in stroke and myocardial infarction were not statistically significant. Overall mean Medicare costs per patient were similar pre- and post-MitraClip, although there was a significant decrease in mean costs among those that survived a full year after MitraClip ($18,131 [SD $25,130] vs $11,679 [SD $22,486], P=.02). CONCLUSIONS: MitraClip was associated with a reduced rate of all-cause and HF hospitalizations and an increased rate of bleeding hospitalizations. One-year Medicare costs were reduced in those who survived a full year after the MitraClip procedure. Payors and providers seeking to reduce HF hospitalizations and associated Medicare costs may consider MitraClip among appropriate patients likely to survive 1 year.

AVJ-514 Trial　- Baseline Characteristics and 30-Day Outcomes Following MitraClip® Treatment in a Japanese Cohort.

BACKGROUND: The MitraClip®system is a transcatheter-based therapeutic option for patients with chronic mitral regurgitation (MR) who are at high risk for surgery. A prospective, multicenter, single-arm study was initiated to confirm the transferability of this system to Japan.Methods and Results:Patients with symptomatic chronic moderate-to-severe (3+) or severe (4+) functional or degenerative MR with a Society of Thoracic Surgery (STS) score ≥8%, or the presence of 1 predefined risk factor were enrolled. Patients with left ventricular (LV) ejection fraction (EF) <30% were excluded. MR severity and LV function were assessed by an independent echocardiography core lab. Primary outcome included major adverse events (MAE) at 30 days and acute procedural success (APS). A total of 30 patients (age: 80±7 years; STS score: 10.3%±6.6%) were treated with the MitraClip®. At baseline, all patients had MR 3+/4+ with 53%/47% patients with degenerative/functional etiology with mean LVEF of 50.2±12.8%, and 37% of patients were NYHA class III/IV. APS was achieved in 86.7% with no occurrence of MAE. At 30 days, 86.7% of patients had MR ≤2+ and 96.7% were NYHA class I/II. CONCLUSIONS: The MitraClip®procedure resulted in clinically meaningful improvements in MR severity, function and quality of life measures, and low MAE rates. These early results suggest the transferability of this therapy to appropriately selected Japanese patients. (Trial Registration: clinicaltrials.gov Identifier NCT02520310.).

Selective association of electrocardiographic abnormalities with insulin sensitivity and beta-cell function in type 2 diabetes mellitus: a cross-sectional analysis.

BACKGROUND: We investigated the association of electrocardiographic (ECG) abnormalities with markers of insulin resistance and pancreatic beta-cell dysfunction in a cross-sectional study of type 2 diabetes patients. METHODS: Electrocardiographic criteria were evaluated in the Penn Diabetes Heart Study participants (n = 1671; 64% male; 61% Caucasian), including a sub-sample (n = 710) that underwent oral glucose tolerance testing. The Matsuda Insulin Sensitivity Index and homeostasis model assessment of insulin resistance (HOMA-IR) estimated insulin sensitivity; Insulinogenic Index and homeostasis model assessment of beta-cell function assessed beta-cell function. Multivariable regression modelling was used to analyse associations of ECG changes with these indices. RESULTS: In unadjusted analyses, subjects in the highest quartile of Matsuda index had the lowest prevalence of Q-waves (6.3% versus 15.3%, p = 0.005). In adjusted models, an inverse association was seen between Q-waves and log Matsuda index [one standard deviation increase; OR = 0.59 (95% CI 0.43-0.87 p = 0.001)]. In the full Penn Diabetes Heart Study, there was a direct association between Q-waves and HOMA-IR [one standard deviation increase; OR = 1.43 (95% CI 1.13-1.81, p = 0.003)]. In adjusted models, left ventricular hypertrophy also was inversely associated with Matsuda index and directly with HOMA-IR. Higher Insulinogenic Index scores were associated with a lower prevalence of nonspecific ST changes [OR = 0.78 (95% CI 0.62-0.98, p = 0.032)]. CONCLUSIONS: In type 2 diabetic patients, both oral glucose tolerance testing-derived and HOMA-derived measures of insulin resistance were associated with pathologic Q-waves and left ventricular hypertrophy on ECGs. Copyright © 2016 John Wiley & Sons, Ltd.

Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics.

OBJECTIVE: Triglyceride-rich lipoproteins have emerged as causal risk factors for developing coronary heart disease independent of low-density lipoprotein cholesterol levels. Apolipoprotein C-III (ApoC-III) modulates triglyceride-rich lipoprotein metabolism through inhibition of lipoprotein lipase and hepatic uptake of triglyceride-rich lipoproteins. Mutations causing loss-of-function of ApoC-III lower triglycerides and reduce coronary heart disease risk, suggestive of a causal role for ApoC-III. Little data exist about the relationship of ApoC-III, triglycerides, and atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Here, we examined the relationships between plasma ApoC-III, triglycerides, and coronary artery calcification in patients with T2DM. APPROACH AND RESULTS: Plasma ApoC-III levels were measured in a cross-sectional study of 1422 subjects with T2DM but without clinically manifest coronary heart disease. ApoC-III levels were positively associated with total cholesterol (Spearman r=0.36), triglycerides (r=0.59), low-density lipoprotein cholesterol (r=0.16), fasting glucose (r=0.16), and glycosylated hemoglobin (r=0.12; P<0.0001 for all). In age, sex, and race-adjusted analysis, ApoC-III levels were positively associated with coronary artery calcification (Tobit regression ratio, 1.78; 95% confidence interval, 1.27-2.50 per SD increase in ApoC-III; P<0.001). As expected for an intermediate mediator, these findings were attenuated when adjusted for both triglycerides (Tobit regression ratio, 1.43; 95% confidence interval, 0.94-2.18; P=0.086) and separately for very low-density lipoprotein cholesterol (Tobit regression ratio, 1.14; 95% confidence interval, 0.75-1.71; P=0.53). CONCLUSIONS: In persons with T2DM, increased plasma ApoC-III is associated with higher triglycerides, less favorable cardiometabolic phenotypes, and higher coronary artery calcification, a measure of subclinical atherosclerosis. Therapeutic inhibition of ApoC-III may thus be a novel strategy for reducing plasma triglyceride-rich lipoproteins and cardiovascular risk in T2DM.

Differential association of plasma angiopoietin-like proteins 3 and 4 with lipid and metabolic traits.

OBJECTIVE: Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) are secreted proteins that inhibit lipoprotein lipase in vitro. Genetic variants at the ANGPTL3 and ANGPTL4 gene loci are significantly associated with plasma lipid traits. The aim of this study was to evaluate the association of plasma ANGPTL3 and ANGPTL4 concentrations with lipid and metabolic traits in a large community-based sample. APPROACH AND RESULTS: Plasma ANGPTL3 and ANGPTL4 levels were measured in 1770 subjects using a validated ELISA assay. A Pearson unadjusted correlation analysis and a linear regression analysis adjusting for age, sex, and race were performed. ANGPTL3 levels were significantly positively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels (both P<2×10(-5)) but not triglycerides. In contrast, ANGPTL4 levels were significantly negatively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (both P<2×10(-5)) and positively associated with triglycerides (P=0.003). In addition, ANGPTL4, but not ANGPTL3, levels were significantly positively associated with fasting blood glucose and metabolic syndrome. CONCLUSIONS: Despite having similar biochemical effects in vitro, plasma ANGPTL3 and ANGPTL4 concentrations have nearly opposite relationships with plasma lipids. ANGPTL4 is strongly negatively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and positively with multiple features of the metabolic syndrome including triglycerides, whereas ANGPTL3 is positively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and not with metabolic syndrome traits including triglycerides. Although ANGPTL3 and ANGPTL4 both inhibit lipoprotein lipase in vitro and influence lipoprotein metabolism in vivo, the physiology of these related proteins and their effects on lipoproteins is clearly divergent and complex.

Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project.

Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.

Beyond the Task: Developing a Tool to Measure Workplace Characteristics That Affect Cognitive Load and Learning.

PURPOSE: Educators lack tools to measure the workplace characteristics that learners perceive to affect learning. Without a tool that encompasses the social, organizational, and physical components of workplace learning environments (WLEs), it is challenging to identify and improve problematic workplace characteristics. Using echocardiography WLE, this study developed a tool to measure workplace characteristics that cardiology fellows perceive to affect learning. METHOD: The Workplace-Cognitive Load Tool (W-CLT) was developed, which encompasses 17 items to measure workplace characteristics that could affect perceived cognitive load and learning. Exploratory factor analysis was used to identify the most parsimonious structure. A total of 646 cardiology subspeciality fellows were recruited from 60 cardiology fellowship programs to complete the survey between November 2020 and February 2021. Validity evidence was collected, guided by the unified model of validity. RESULTS: A total of 308 fellows (response rate, 49%) participated in the survey. The most parsimonious structure included 4 factors: (1) workplace-task, (2) workplace-environment, (3) workplace-orientation, and (4) workplace-teaching and feedback. All factors had high reliability (Cronbach α = 0.92, 0.92, 0.96, and 0.94, respectively). Social, organizational, and physical components of WLEs were represented in the items. Workplace-teaching and feedback had moderate negative correlations with workplace-environment (r = -0.41, P < .001) and workplace-orientation (r = -0.36, P < .001). A moderate positive correlation was found between workplace-task and workplace-teaching and feedback (r = 0.42, P < .001). Workplace-task had weak negative correlations with workplace-environment (r = -0.22, P < .001) and workplace-orientation (r = -0.23, P < .001). CONCLUSIONS: The W-CLT measures workplace characteristics that cardiology fellows perceive to affect their learning. The presence of social, organizational, and physical components emphasizes how workplace characteristics can enhance or impede learning. The W-CLT provides a foundation to explore how learning can be optimized in other WLEs.

Normal Values and Reference Ranges for the Ratio of Transmitral Early Filling Velocity to Early Diastolic Strain Rate: The Copenhagen City Heart Study.

BACKGROUND: The ratio of transmitral early filling velocity to early diastolic strain rate (E/e'sr) has recently emerged as a measure of left ventricular filling pressure. Reference values are needed for this new parameter for it to be used clinically. METHODS: Healthy participants from a prospective general population study, the Fifth Copenhagen City Heart Study, were assessed to establish reference values for E/e'sr derived from two-dimensional speckle-tracking echocardiography. The prevalence of abnormal E/e'sr was assessed in participants with cardiovascular risk factors or specific diseases. RESULTS: The population comprised 1,623 healthy participants (median age, 45; interquartile range, 32-56; 61% female). The upper reference limit for E/e'sr in the population was 79.6 cm. Following multivariable adjustment, male participants exhibited significantly higher E/e'sr than female participants (upper reference limit for male participants, 83.7 cm; for female participants, 76.5 cm). For both sexes, E/e'sr increased in a curvilinear fashion with age such that the largest increases in E/e'sr were observed in participants >45 years. In the entire CCHS5 population with E/e'sr available (n = 3,902), increasing age, body mass index, systolic blood pressure, male sex, estimated glomerular filtration rate, and diabetes were associated with E/e'sr (all P < .05). Total cholesterol was associated with a less steep increase in E/e'sr. Abnormal E/e'sr was seldomly observed in participants with normal diastolic function but became more frequent in participants with increasing grades of diastolic dysfunction (normal, mild, moderate, severe [abnormal E/e'sr for each grade: 4.4% vs 20.0% vs 16.2% vs 55.6%, respectively]). CONCLUSION: The E/e'sr differs between sexes and is age dependent such that E/e'sr increases with advancing age. Therefore, we established sex- and age-stratified reference values for E/e'sr.

Transcatheter Edge-to-Edge Repair of Systemic Tricuspid Valve in Extracardiac Fontan Circulation: First in Human.

Transcatheter edge-to-edge valve repair can improve clinical outcomes in otherwise high-risk surgical patients. This is a first-in-human procedure outlining transcatheter edge-to-edge valve repair of a systemic tricuspid valve in an extracardiac Fontan patient born with hypoplastic left heart syndrome with prohibitive surgical risk. (Level of Difficulty: Advanced.).

Gender differences in the association of C-reactive protein with coronary artery calcium in type-2 diabetes.

OBJECTIVES: Plasma C-reactive protein (CRP) is associated with cardiovascular disease (CVD), but effects may vary by gender and degree of CVD risk. Whether CRP has value as a CVD risk marker in type-2 diabetes (T2DM) is unclear. We examined whether CRP has gender differences in association with coronary artery calcium (CAC) in diabetic and nondiabetic samples without clinical CVD. METHODS: We performed cross-sectional analyses of gender influence on CRP association with CAC in the Penn Diabetes Heart Study (N = 1299 with T2DM), the Study of Inherited Risk of Coronary Atherosclerosis (N = 860 nondiabetic subjects) and a combined sample. RESULTS: Female gender was associated with higher plasma CRP in diabetic and nondiabetic samples after adjustment for covariates. There was a strong interaction by gender in the association of CRP with CAC (interaction P < 0·001). In diabetic women, CRP was associated with higher CAC even after further adjustment for age, race, medications, metabolic syndrome, Framingham risk score and body mass index [Tobit ratio 1·60, 95% CI (1·03-2·47)]. Although this relationship was attenuated in nondiabetic women, the combined sample maintained this association in fully adjusted models [1·44, 95% CI (1·13-1·83)]. There was no association of CRP with CAC in either diabetic or nondiabetic men. CONCLUSIONS: CRP may be a useful marker of cardiovascular risk in women, particularly in diabetic women who otherwise have no known CVD. Prospective studies are needed to better assess the gender differences in CRP utility and the use of CRP in T2DM.

Race and Gender Bias in Internal Medicine Program Director Letters of Recommendation.

BACKGROUND: While program director (PD) letters of recommendation (LOR) are subject to bias, especially against those underrepresented in medicine, these letters are one of the most important factors in fellowship selection. Bias manifests in LOR in a number of ways, including biased use of agentic and communal terms, doubt raising language, and description of career trajectory. To reduce bias, specialty organizations have recommended standardized PD LOR. OBJECTIVE: This study examined PD LOR for applicants to a cardiology fellowship program to determine the mechanism of how bias is expressed and whether the 2017 Alliance for Academic Internal Medicine (AAIM) guidelines reduce bias. METHODS: Fifty-six LOR from applicants selected to interview at a cardiology fellowship during the 2019 and 2020 application cycles were selected using convenience sampling. LOR for underrepresented (Black, Latinx, women) and non-underrepresented applicants were analyzed using directed qualitative content analysis. Two coders used an iteratively refined codebook to code the transcripts. Data were analyzed using outputs from these codes, analytical memos were maintained, and themes summarized. RESULTS: With AAIM guidelines, there appeared to be reduced use of communal language for underrepresented applicants, which may represent less bias. However, in both LOR adherent and not adherent to the guidelines, underrepresented applicants were still more likely to be described using communal language, doubt raising language, and career trajectory bias. CONCLUSIONS: PDs used language in a biased way to describe underrepresented applicants in LOR. The AAIM guidelines reduced but did not eliminate this bias. We provide recommendations to PDs and the AAIM on how to continue to work to reduce this bias.

Differences in echocardiography interpretation techniques among trainees and expert readers.

BACKGROUND: Trainees learn transthoracic echocardiogram (TTE) interpretation through independently completing and reviewing selected portions of the study with experts. The diagnostic accuracy of novice TTE interpretation is known to be low and schema for reading TTEs systematically are lacking. The purpose of our study is to identify techniques experts use while reading TTEs which could be used to more effectively teach novice readers. METHODS: We performed a prospective qualitative case study to observe how experts and trainees interpret TTEs in an academic institution using a concurrent think aloud (CTA) method. Three TTEs of intermediate complexity were given to 3 advanced imaging fellows, 3 first year fellows and 3 expert TTE readers Participants filled out a report while reading and described aloud their thought processes. Sessions were video and audiotaped for analysis. RESULTS: Experts and advanced fellows used specific techniques that novices did not including: previewing studies, reviewing multiple images simultaneously, having flexibility in image review order and disease coding, and saving hardest elements to code for the end. Direct observation of TTE reading informed trainee inefficiencies and was a well-received educational tool. CONCLUSIONS: In this single centered study we identified several unique approaches experts use to interpret TTEs which may be teachable to novices. Although limited in generalizability the findings of this study suggests that a more systematic approach to TTE interpretation, using techniques found in experts, might be of significant value for trainees. Further study is needed to evaluate teaching practices at other institutions and to assess whether implementation of these techniques by novices improves can improve their diagnostic accuracy and efficiency of reading at an earlier stage in their training.