Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks.

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable.

Plasma Proteomics of Exercise Blood Pressure and Incident Hypertension.

Importance: Blood pressure response during acute exercise (exercise blood pressure [EBP]) is associated with the future risk of hypertension and cardiovascular disease (CVD). Biochemical characterization of EBP could inform disease biology and identify novel biomarkers of future hypertension. Objective: To identify protein markers associated with EBP and test their association with incident hypertension. Design, Setting, and Participants: This study assayed 4977 plasma proteins in 681 healthy participants (from 763 assessed) of the Health, Risk Factors, Exercise Training and Genetics (HERITAGE; data collection from January 1993 to December 1997 and plasma proteomics from January 2019 to January 2020) Family Study at rest who underwent 2 cardiopulmonary exercise tests. Individuals were free of CVD at the time of recruitment. Individuals with resting SBP ≥160 mm Hg or DBP ≥100 mm Hg or taking antihypertensive drug therapy were excluded from the study. The association between resting plasma protein levels to both resting BP and EBP was evaluated. Proteins associated with EBP were analyzed for their association with incident hypertension in the Framingham Heart Study (FHS; n = 1177) and validated in the Jackson Heart Study (JHS; n = 772) and Multi-Ethnic Study of Atherosclerosis (MESA; n = 1367). Proteins associated with incident hypertension were tested for putative causal links in approximately 700 000 individuals using cis-protein quantitative loci mendelian randomization (cis-MR). Data were analyzed from January 2023 to January 2024. Exposures: Plasma proteins. Main Outcomes and Measures: EBP was defined as the BP response during a fixed workload (50 W) on a cycle ergometer. Hypertension was defined as BP ≥140/90 mm Hg or taking antihypertensive medication. Results: Among the 681 participants in the HERITAGE Family Study, the mean (SD) age was 34 (13) years; 366 participants (54%) were female; 238 (35%) were self-reported Black and 443 (65%) were self-reported White. Proteomic profiling of EBP revealed 34 proteins that would not have otherwise been identified through profiling of resting BP alone. Transforming growth factor ß receptor 3 (TGFBR3) and prostaglandin D2 synthase (PTGDS) had the strongest association with exercise systolic BP (SBP) and diastolic BP (DBP), respectively (TGFBR3: exercise SBP, ß estimate, -3.39; 95% CI, -4.79 to -2.00; P = 2.33 × 10-6; PTGDS: exercise DBP ß estimate, -2.50; 95% CI, -3.29 to -1.70; P = 1.18 × 10-9). In fully adjusted models, TGFBR3 was inversely associated with incident hypertension in FHS, JHS, and MESA (hazard ratio [HR]: FHS, 0.86; 95% CI, 0.75-0.97; P = .01; JHS, 0.87; 95% CI, 0.77-0.97; P = .02; MESA, 0.84; 95% CI, 0.71-0.98; P = .03; pooled cohort, 0.86; 95% CI, 0.79-0.92; P = 6 × 10-5). Using cis-MR, genetically predicted levels of TGFBR3 were associated with SBP, hypertension, and CVD events (SBP: ß, -0.38; 95% CI, -0.64 to -0.11; P = .006; hypertension: odds ratio [OR], 0.99; 95% CI, 0.98-0.99; P < .001; heart failure with hypertension: OR, 0.86; 95% CI, 0.77-0.97; P = .01; CVD: OR, 0.84; 95% CI, 0.77-0.92; P = 8 × 10-5; cerebrovascular events: OR, 0.77; 95% CI, 0.70-0.85; P = 5 × 10-7). Conclusions and Relevance: Plasma proteomic profiling of EBP identified a novel protein, TGFBR3, which may protect against elevated BP and long-term CVD outcomes.

Omics-driven investigation of the biology underlying intrinsic submaximal working capacity and its trainability.

Submaximal exercise capacity is an indicator of cardiorespiratory fitness with clinical and public health implications. Submaximal exercise capacity and its response to exercise programs are characterized by heritability levels of about 40%. Using physical working capacity (power output) at a heart rate of 150 beats/min (PWC150) as an indicator of submaximal exercise capacity in subjects of the HERITAGE Family Study, we have undertaken multi-omics and in silico explorations of the underlying biology of PWC150 and its response to 20 wk of endurance training. Our goal was to illuminate the biological processes and identify panels of genes associated with human variability in intrinsic PWC150 (iPWC150) and its trainability (dPWC150). Our bioinformatics approach was based on a combination of genome-wide association, skeletal muscle gene expression, and plasma proteomics and metabolomics experiments. Genes, proteins, and metabolites showing significant associations with iPWC150 or dPWC150 were further queried for the enrichment of biological pathways. We compared genotype-phenotype associations of emerging candidate genes with reported functional consequences of gene knockouts in mouse models. We investigated the associations between DNA variants and multiple muscle and cardiovascular phenotypes measured in HERITAGE subjects. Two panels of prioritized genes of biological relevance to iPWC150 (13 genes) and dPWC150 (6 genes) were identified, supporting the hypothesis that genes and pathways associated with iPWC150 are different from those underlying dPWC150. Finally, the functions of these genes and pathways suggested that human variation in submaximal exercise capacity is mainly driven by skeletal muscle morphology and metabolism and red blood cell oxygen-carrying capacity.NEW & NOTEWORTHY Multi-omics and in silico explorations of the genes and underlying biology of submaximal exercise capacity and its response to 20 wk of endurance training were undertaken. Prioritized genes were identified: 13 genes for variation in submaximal exercise capacity in the sedentary state and 5 genes for the response level to endurance training, with no overlap between them. Genes and pathways associated with submaximal exercise capacity in the sedentary state are different from those underlying trainability.

Associations between Metabolomic Biomarkers of Avocado Intake and Glycemia in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Avocado consumption is linked to better glucose homeostasis, but small associations suggest potential population heterogeneity. Metabolomic data capture the effects of food intake after digestion and metabolism, thus accounting for individual differences in these processes. OBJECTIVES: To identify metabolomic biomarkers of avocado intake and to examine their associations with glycemia. METHODS: Baseline data from 6224 multi-ethnic older adults (62% female) included self-reported avocado intake, fasting glucose and insulin, and untargeted plasma proton nuclear magnetic resonance metabolomic features (metabolomic data were available for a randomly selected subset; N = 3438). Subsequently, incident type 2 diabetes (T2D) was assessed over an ∼18 y follow-up period. A metabolome-wide association study of avocado consumption status (consumer compared with nonconsumer) was conducted, and the relationship of these features with glycemia via cross-sectional associations with fasting insulin and glucose and longitudinal associations with incident T2D was examined. RESULTS: Three highly-correlated spectral features were associated with avocado intake at metabolome-wide significance levels (P < 5.3 ∗ 10-7) and combined into a single biomarker. We did not find evidence that these features were additionally associated with overall dietary quality, nor with any of 47 other food groups (all P > 0.001), supporting their suitability as a biomarker of avocado intake. Avocado intake showed a modest association only with lower fasting insulin (ß = -0.07 +/- 0.03, P = 0.03), an association that was attenuated to nonsignificance when additionally controlling for body mass index (kg/m2). However, our biomarker of avocado intake was strongly associated with lower fasting glucose (ß = -0.22 +/- 0.02, P < 2.0 ∗ 10-16), lower fasting insulin (ß = -0.17 +/- 0.02, P < 2.0 ∗ 10-16), and a lower incidence of T2D (hazard ratio: 0.68; 0.63-074, P < 2.0 ∗ 10-16), even when adjusting for BMI. CONCLUSIONS: Highly significant associations between glycemia and avocado-related metabolomic features, which serve as biomarkers of the physiological impact of dietary intake after digestion and absorption, compared to modest relationships between glycemia and avocado consumption, highlights the importance of considering individual differences in metabolism when considering diet-health relationships.

Plasma Proteomic Kinetics in Response to Acute Exercise.

Regular exercise has many favorable effects on human health, which may be mediated in part by the release of circulating bioactive factors during each bout of exercise. Limited data exist regarding the kinetic responses of plasma proteins during and after acute exercise. Proteomic profiling of 4163 proteins was performed using a large-scale, affinity-based platform in 75 middle-aged adults who were referred for treadmill exercise stress testing. Plasma proteins were quantified at baseline, peak exercise, and 1-h postexercise, and those with significant changes at both exercise timepoints were further examined for their associations with cardiometabolic traits and change with aerobic exercise training in the Health, Risk Factors, Exercise Training and Genetics Family Study, a 20-week exercise intervention study. A total of 765 proteins changed (false discovery rate < 0.05) at peak exercise compared to baseline, and 128 proteins changed (false discovery rate < 0.05) at 1-h postexercise. The 56 proteins that changed at both timepoints included midkine, brain-derived neurotrophic factor, metalloproteinase inhibitor 4, and coiled-coil domain-containing protein 126 and were enriched for secreted proteins. The majority had concordant direction of change at both timepoints. Across all proteins assayed, gene set enrichment analysis showed increased abundance of coagulation-related proteins at 1-h postexercise. Forty-five proteins were associated with at least one measure of adiposity, lipids, glucose homeostasis, or cardiorespiratory fitness in Health, Risk Factors, Exercise Training and Genetics Family Study, and 20 proteins changed with aerobic exercise training. We identified hundreds of novel proteins that change during acute exercise, most of which resolved by 1 h into recovery. Proteins with sustained changes during exercise and recovery may be of particular interest as circulating biomarkers and pathways for further investigation in cardiometabolic diseases. These data will contribute to a biochemical roadmap of acute exercise that will be publicly available for the entire scientific community.

Association of healthy dietary patterns and cardiorespiratory fitness in the community.

AIMS: To evaluate the associations of dietary indices and quantitative cardiorespiratory fitness (CRF) measures in a large, community-based sample harnessing metabolomic profiling to interrogate shared biology. METHODS AND RESULTS: Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise tests for CRF quantification (via peak VO2) and completed semi-quantitative food frequency questionnaires. Dietary quality was assessed by the Alternative Healthy Eating Index (AHEI) and Mediterranean-style Diet Score (MDS), and fasting blood concentrations of 201 metabolites were quantified. In 2380 FHS participants (54 ± 9 years, 54% female, body mass index 28 ± 5 kg/m2), 1 SD higher AHEI and MDS were associated with 5.2% (1.2 mL/kg/min, 95% CI 4.3-6.0%, P < 0.0001) and 4.5% (1.0 mL/kg/min, 95% CI 3.6-5.3%, P < 0.0001) greater peak VO2 in linear models adjusted for age, sex, total daily energy intake, cardiovascular risk factors, and physical activity. In participants with metabolite profiling (N = 1154), 24 metabolites were concordantly associated with both dietary indices and peak VO2 in multivariable-adjusted linear models (FDR < 5%). Metabolites that were associated with lower CRF and poorer dietary quality included C6 and C7 carnitines, C16:0 ceramide, and dimethylguanidino valeric acid, and metabolites that were positively associated with higher CRF and favourable dietary quality included C38:7 phosphatidylcholine plasmalogen and C38:7 and C40:7 phosphatidylethanolamine plasmalogens. CONCLUSION: Higher diet quality is associated with greater CRF cross-sectionally in a middle-aged community-dwelling sample, and metabolites highlight potential shared favourable effects on cardiometabolic health.

This study seeks to address whether healthy dietary patterns relate to gold-standard measures of physical fitness in community-dwelling adults and how circulating metabolites can demonstrate biological relationships between diet and fitness. Healthy diet is associated with greater physical fitness in middle-aged adults. The beneficial relationship between diet and fitness may be partly explained by favourable metabolic health.

Bias-Compensated Integral Regression for Human Pose Estimation.

In human and hand pose estimation, heatmaps are a crucial intermediate representation for a body or hand keypoint. Two popular methods to decode the heatmap into a final joint coordinate are via an argmax, as done in heatmap detection, or via softmax and expectation, as done in integral regression. Integral regression is learnable end-to-end, but has lower accuracy than detection. This paper uncovers an induced bias from integral regression that results from combining the softmax and the expectation operation. This bias often forces the network to learn degenerately localized heatmaps, obscuring the keypoint's true underlying distribution and leads to lower accuracies. Training-wise, by investigating the gradients of integral regression, we show that the implicit guidance of integral regression to update the heatmap makes it slower to converge than detection. To counter the above two limitations, we propose Bias Compensated Integral Regression (BCIR), an integral regression-based framework that compensates for the bias. BCIR also incorporates a Gaussian prior loss to speed up training and improve prediction accuracy. Experimental results on both the human body and hand benchmarks show that BCIR is faster to train and more accurate than the original integral regression, making it competitive with state-of-the-art detection methods.

Mixed meal tolerance testing highlights in diabetes altered branched-chain ketoacid metabolism and pathways associated with all-cause mortality.

BACKGROUND: Elevated BCAA levels are strongly associated with diabetes, but how diabetes affects BCAA, branched-chain ketoacids (BCKAs), and the broader metabolome after a meal is not well known. OBJECTIVE: To compare quantitative BCAA and BCKA levels in a multiracial cohort with and without diabetes after a mixed meal tolerance test (MMTT) as well as to explore the kinetics of additional metabolites and their associations with mortality in self-identified African Americans. METHODS: We administered an MMTT to 11 participants without obesity or diabetes and 13 participants with diabetes (treated with metformin only) and measured the levels of BCKAs, BCAAs, and 194 other metabolites at 8 time points across 5 h. We used mixed models for repeated measurements to compare between group metabolite differences at each timepoint with adjustment for baseline. We then evaluated the association of top metabolites with different kinetics with all-cause mortality in the Jackson Heart Study (JHS) (N = 2441). RESULTS: BCAA levels, after adjustment for baseline, were similar at all timepoints between groups, but adjusted BCKA kinetics were different between groups for α-ketoisocaproate (P = 0.022) and α-ketoisovalerate (P = 0.021), most notably diverging at 120 min post-MMTT. An additional 20 metabolites had significantly different kinetics across timepoints between groups, and 9 of these metabolites-including several acylcarnitines-were significantly associated with mortality in JHS, irrespective of diabetes status. The highest quartile of a composite metabolite risk score was associated with higher mortality (HR:1.57; 1.20, 2.05, P = 0.00094) than the lowest quartile. CONCLUSIONS: BCKA levels remained elevated after an MMTT among participants with diabetes, suggesting that BCKA catabolism may be a key dysregulated process in the interaction of BCAA and diabetes. Metabolites with different kinetics after an MMTT may be markers of dysmetabolism and associated with increased mortality in self-identified African Americans.

Association of Healthy Dietary Patterns and Cardiorespiratory Fitness in the Community.

Aims: To evaluate the associations of dietary indices and quantitative CRF measures in a large, community-based sample harnessing metabolomic profiling to interrogate shared biology. Methods: Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise tests for CRF quantification (via peak VO 2 ) and completed semi-quantitative FFQs. Dietary quality was assessed by the Alternative Healthy Eating Index (AHEI) and Mediterranean-style Diet Score (MDS), and fasting blood concentrations of 201 metabolites were quantified. Results: In 2380 FHS participants (54±9 years, 54% female, BMI 28±5 kg/m 2 ), 1-SD higher AHEI and MDS were associated with 5.1% (1.2 ml/kg/min, p<0.0001) and 4.4% (1.0 ml/kg/min, p<0.0001) greater peak VO 2 in linear models adjusted for age, sex, total energy intake, cardiovascular risk factors, and physical activity. In participants with metabolite profiling (N=1154), 24 metabolites were concordantly associated with both dietary indices and peak VO 2 in multivariable-adjusted linear models (FDR<5%). These metabolites included C6 and C7 carnitines, C16:0 ceramide, and dimethylguanidino valeric acid, which were higher with lower CRF and poorer dietary quality and are known markers of insulin resistance and cardiovascular risk. Conversely, C38:7 phosphatidylcholine plasmalogen and C38:7 and C40:7 phosphatidylethanolamine plasmalogens were associated with higher CRF and favorable dietary quality and may link to lower cardiometabolic risk. Conclusion: Higher diet quality is associated with greater CRF cross-sectionally in a middle-aged community-dwelling sample, and metabolites highlight potential shared favorable effects on health.

Plasma Proteomic Risk Markers of Incident Type 2 Diabetes Reflect Physiologically Distinct Components of Glucose-Insulin Homeostasis.

High-throughput proteomics allows researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (N = 2,631) and IVGTT-derived measures in participants from the HERITAGE Family Study (N = 752). We characterize 51 proteins that were associated with longitudinal diabetes risk, using their respective 39, 9, and 8 concurrent associations with insulin sensitivity index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations appear to be novel, including ß-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative pathway to insulin for glucose disposal; and plexin-B2, which also was associated with increased diabetes risk, but with lower AIRG, and not with SI, indicating a mechanism related instead to pancreatic dysfunction. Other novel protein associations included alcohol dehydrogenase-1C, fructose-bisphosphate aldolase-B, sorbitol dehydrogenase with elevated type 2 diabetes risk, and a leucine-rich repeat containing protein-15 and myocilin with decreased risk. ARTICLE HIGHLIGHTS: Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response.

Protein Markers of Diabetes Discovered in an African American Cohort.

Proteomics has been used to study type 2 diabetes, but the majority of available data are from White participants. Here, we extend prior work by analyzing a large cohort of self-identified African Americans in the Jackson Heart Study (n = 1,313). We found 325 proteins associated with incident diabetes after adjusting for age, sex, and sample batch (false discovery rate q < 0.05) measured using a single-stranded DNA aptamer affinity-based method on fasting plasma samples. A subset was independent of established markers of diabetes development pathways, such as adiposity, glycemia, and/or insulin resistance, suggesting potential novel biological processes associated with disease development. Thirty-six associations remained significant after additional adjustments for BMI, fasting plasma glucose, cholesterol levels, hypertension, statin use, and renal function. Twelve associations, including the top associations of complement factor H, formimidoyltransferase cyclodeaminase, serine/threonine-protein kinase 17B, and high-mobility group protein B1, were replicated in a meta-analysis of two self-identified White cohorts-the Framingham Heart Study and the Malmö Diet and Cancer Study-supporting the generalizability of these biomarkers. A selection of these diabetes-associated proteins also improved risk prediction. Thus, we uncovered both novel and broadly generalizable associations by studying a diverse population, providing a more complete understanding of the diabetes-associated proteome.

An Unusual Cause of Functional Mitral Stenosis: A Left Atrial Intimal Sarcoma.

Primary cardiac tumors are rare, with an incidence of <0.1% in postmortem series; sarcomas comprise 75% of these. Cardiac sarcomas may be life-threatening at the time of presentation. We describe a left atrial intimal sarcoma presenting with constitutional symptoms, obstructive shock, and systemic emboli, and treated with proton beam therapy. (Level of Difficulty: Intermediate.).

Usefulness of Rivaroxaban for Secondary Prevention of Acute Coronary Syndrome in Patients With History of Congestive Heart Failure (from the ATLAS-ACS-2 TIMI-51 Trial).

Patients with both acute coronary syndromes (ACS) and congestive heart failure are at an increased risk of recurrent cardiovascular (CV) events attributed in part to both excess thrombin generation and impaired fibrinolysis. We hypothesized that patients with the overlap of ACS and CHF would thus derive particular benefit from antithrombotic therapy with rivaroxaban. ATLAS-ACS-2 Thrombolysis in Myocardial Infarction-51 was a double-blind, multicenter, phase 3 clinical trial that randomized patients within 7 days of an ACS event to standard of care plus either rivaroxaban 2.5 mg BID, 5 mg BID, or placebo (n = 15,526). In this post hoc subgroup analysis, subjects with a history of CHF at randomization (n = 1,694) were evaluated. Among subjects with a history of CHF, both rivaroxaban doses reduced the primary composite end point of CV death, myocardial infarction, or stroke (2.5 mg BID vs placebo: hazard ratio [HR] 0.59, 95% confidence interval [CI] (0.42, 0.81), p = 0.001; 5 mg BID vs placebo: HR 0.61, 95% CI (0.44, 0.84), p = 0.002; p interaction = 0.006). Both doses of rivaroxaban reduced CV mortality (rivaroxaban 2.5 mg BID vs placebo: 4.1% vs 9.0%, HR 0.45, 95% CI [0.27, 0.74], p = 0.002; rivaroxaban 5 mg BID vs placebo: 5.8% vs 9.0%, HR 0.62, 95% CI [0.40, 0.96], p = 0.031) as well as all-cause mortality. There was no significant increase in noncoronary artery bypass graft-related Thrombolysis in Myocardial Infarction major bleeding with either dose of rivaroxaban as compared with placebo (rivaroxaban 2.5 mg BID = 0.4% vs rivaroxaban 5 mg BID = 1.1% vs placebo = 0.5%). Rivaroxaban also did not increase either intracranial hemorrhage or fatal bleeding. In conclusion, in ACS subjects with a history of CHF, secondary prevention with rivaroxaban reduced the composite of CV death, myocardial infarction, or stroke without an increase in noncoronary artery bypass graft-related major bleeding. These findings require further prospective evaluation in an adequately powered phase 3 study.

Effect of Educational Intervention on the Rate of Rarely Appropriate Outpatient Echocardiograms Ordered by Attending Academic Cardiologists: A Randomized Clinical Trial.

Importance: Appropriate use criteria-based educational initiatives have been shown to improve transthoracic echocardiography (TTE) ordering practices of physicians in training. Whether such an intervention is successful with attending cardiologists remains unknown. Objective: To prospectively investigate the effect of an appropriate use criteria-based educational intervention on ordering of outpatient TTEs by attending academic cardiologists. Design, Setting, and Participants: We conducted a prospective, randomized clinical trial of an educational intervention designed to reduce the number of outpatient TTEs that were deemed to be rarely appropriate by published appropriate use criteria. Investigators classifying TTEs were blinded to participant groupings. The study was conducted within the cardiology division at the Massachusetts General Hospital, an academic quaternary care hospital. Staff members of the cardiology division were included; 66 cardiologists were randomized. The study was conducted from November 19, 2013, to June 1, 2014. An analysis of the evaluable population was performed. Interventions: The appropriate use criteria-based educational intervention consisted of a review lecture and electronic information card, as well as monthly individual physician feedback via email. The email described the percentage of rarely appropriate TTEs as well as the appropriate use criteria rationale for classifying studies as rarely appropriate. Main Outcomes and Measures: We hypothesized a priori that the educational intervention would reduce the number of rarely appropriate TTEs. The primary outcome was the rate of rarely appropriate TTEs. Results: Of the 66 cardiologists enrolled in the study, 65 were included in the analysis (1 intervention cardiologist retired from practice during the study). The participants' mean (SD) age was 50.6 (10.5) years; 48 (73%) were men. Following intervention, the proportion of rarely appropriate TTEs was significantly lower in the intervention vs control group (143 of 1359 [10.5%] vs 285 of 1728 [16.5%]; odds ratio [OR], 0.59 [95% CI, 0.39-0.88]; P = .01), and there was a nonsignificant increase in the proportion of appropriate TTEs in the intervention vs control group (1054 [77.6%] vs 1244 [72.0%]; OR, 1.38 [95% CI, 0.93-2.05]; P = .11). The most common of the 428 rarely appropriate indications were routine surveillance within 3 years after prosthetic valve insertion (73 [17.1%]), routine surveillance within 1 year for moderate or severe valvular stenosis (64 [15.0%]), and routine surveillance of cardiomyopathy (45 [10.5%]) or ventricular function (36 [8.4%]). Conclusions and Relevance: An appropriate use criteria-based educational and feedback intervention reduced the number of rarely appropriate TTEs ordered by attending academic cardiologists. This strategy may be feasible to improve TTE utilization among cardiologists, and this type of intervention warrants study in other practice environments. Trial Registration: clinicalrials.gov Identifier: NCT01968642.

Clinical and Echocardiographic Factors Associated With In-Hospital Mortality in Patients With Infective Endocarditis Affecting the Native Tricuspid Valve.

Infective endocarditis (IE) is a highly morbid disease, for which most outcomes data come from patients with left-sided valvular lesions. Echocardiographic findings such as vegetation size and prosthetic valve involvement have been identified as important predictors of mortality in left-sided IE, but predictors of outcomes in right-sided IE are less well characterized. Therefore, the aim of this study was to identify clinical and echocardiographic findings predictive of mortality in tricuspid valve (TV) IE. We retrospectively reviewed all echocardiograms showing TV vegetations that were performed at the Massachusetts General Hospital from January 1, 2003, to December 31, 2013. We identified 105 patients who had echocardiographic evidence of TV vegetations and a definite clinical diagnosis of IE based on the modified Duke's criteria but did not have intracardiac device-associated vegetations. Of the 105 patients, 88 survived until discharge. Clinical and echocardiographic factors that positively correlated with in-hospital mortality included age (p = 0.002), immunosuppression status (p = 0.016), blood urea nitrogen level (p = 0.029), Candida causative organism (p = 0.025), left ventricular ejection fraction <40% (p = 0.027), right ventricular (RV) systolic dysfunction (p = 0.009), and estimated RV systolic pressure >40 mm Hg (p = 0.040). Of these factors, immunosuppression status, blood urea nitrogen level, and RV systolic dysfunction were independently associated with increased in-hospital mortality. In conclusion, RV systolic dysfunction may serve as an echocardiographic marker to aid clinicians in identifying high-risk patients with right-sided IE for more aggressive therapy.

Reliability of medical record abstraction by non-physicians for orthopedic research.

BACKGROUND: Medical record review (MRR) is one of the most commonly used research methods in clinical studies because it provides rich clinical detail. However, because MRR involves subjective interpretation of information found in the medical record, it is critically important to understand the reproducibility of data obtained from MRR. Furthermore, because medical record review is both technically demanding and time intensive, it is important to establish whether trained research staff with no clinical training can abstract medical records reliably. METHODS: We assessed the reliability of abstraction of medical record information in a sample of patients who underwent total knee replacement (TKR) at a referral center. An orthopedic surgeon instructed two research coordinators (RCs) in the abstraction of inpatient medical records and operative notes for patients undergoing primary TKR. The two RCs and the surgeon each independently reviewed 75 patients' records and one RC reviewed the records twice. Agreement was assessed using the proportion of items on which reviewers agreed and the kappa statistic. RESULTS: The kappa for agreement between the surgeon and each RC ranged from 0.59 to 1 for one RC and 0.49 to 1 for the other; the percent agreement ranged from 82% to 100% for one RC and 70% to 100% for the other. The repeated abstractions by the same RC showed high intra-rater agreement, with kappas ranging from 0.66 to 1 and percent agreement ranging from 97% to 100%. Inter-rater agreement between the two RCs was moderate with kappa ranging from 0.49 to 1 and percent agreement ranging from 76% to 100%. CONCLUSION: The MRR method used in this study showed excellent reliability for abstraction of information that had low technical complexity and moderate to good reliability for information that had greater complexity. Overall, these findings support the use of non-surgeons to abstract surgical data from operative notes.