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Weight regain occurs after medical weight loss via mechanisms of post-weight-loss "metabolic adaptation." The relationship of inflammatory proteins with weight loss/regain was studied to determine a role for inflammation in metabolic adaptation.Seventy-four proteins central to inflammation and immune regulation (Olink) were analyzed in plasma from up to 490 participants in a trial of medical weight-loss maintenance. Cross-sectional and longitudinal associations of proteins with weight were measured using linear and mixed effects regression models and t testing, with replication in the Framingham Heart Study.Broad changes in the inflammatory proteome were observed among the study cohort (60% women, 35% African American) with initial weight loss of ≈8 kg from a median 94 kg at study entry (33/74 proteins; 7 increased; 26 decreased), many of which tracked with weight regain of median ≈2 kg over the next 30 months. Ten proteins were associated with different rates of weight regain, some specifying pathways of chemotaxis and innate immune responses. Several of the observed protein associations were also linked to prevalent obesity in the Framingham Heart Study.Broad changes in the inflammatory proteome track with changes in weight and may identify specific pathways that modify patterns of weight regain.

Post-transplant diabetes mellitus (PTDM) is common following heart transplant, impacting greater than 20% of patients with most cases occurring in the first year after transplant. PTDM is associated with multiple negative sequelae including increased post-operative infections, a higher rate of renal failure, and increased mortality. Compared with pre-transplant diabetes mellitus, PTDM has several unique risk factors and immunosuppressive medications play an important role in disease pathophysiology. Newer treatments for hyperglycemia, including glucagon like peptide-1 receptor agonists and sodium glucose cotransporter-2 inhibitors, may counter the mechanisms of immunosuppression-related hyperglycemia making them an appealing treatment option for patients with PTDM. Here, we review the definitions, incidence, risk factors, pathophysiology, clinical outcomes, treatment options, pharmacologic considerations, and future directions in PTDM.

BackgroundHuman genetic studies suggest that the branched chain amino acids (BCAA) valine, leucine and isoleucine have a causal association with type 2 diabetes. However, inferences are based on analyses of a limited number of genetic loci associated with BCAAs. Whether these conclusions are supported when using instrumental variables for BCAAs that capture a broad set of genetic mechanisms is not known.MethodsWe constructed and validated instrumental variables for each BCAA using large well-powered datasets and tested their association with type 2 diabetes using the two-sample inverse variance weighted (IWV) Mendelian randomization (MR) approach. Sensitivity analyses were performed to ensure the accuracy of the findings. Instrumental variables for type 2 diabetes, fasting insulin and body mass index (BMI) were also tested for associations with BCAA levels.ResultsThere were no significant associations with diabetes for valine (beta=0.17 change in log-odds per standard deviation change in valine, [95% CI, −0.28 - 0.62], p=0.45), leucine (beta=0.19 [−0.30 - 0.68] p=0.45) or isoleucine (beta=0.02 [−0.54 - 0.59], p=0.94). In contrast, type 2 diabetes was associated with each BCAA (valine: beta=0.08 per standard deviation change in levels per log-odds change in type 2 diabetes, [0.05 - 0.10], p=1.8×10−9), (leucine: beta= 0.06 [0.04 - 0.09], p=4.5×10−8) and isoleucine (beta= 0.06 [0.04 - 0.08], p=2.8×10−8). The type 2 diabetes associations were replicated in an independent population, but not in a second population where type 2 diabetes cases were removed, highlighting the consistency and specificity of the association. Similar positive associations were seen for fasting insulin and BMI with the BCAAs. In multivariable MR analyses, type 2 diabetes and fasting insulin had consistent independent associations with each BCAA.ConclusionsThese data suggest that the BCAAs are not mediators of type 2 diabetes risk but are biomarkers of diabetes and higher insulin.

OBJECTIVE The effects of the Renin Angiotensin Aldosterone System in cardiovascular system has been described based on small studies. The aim of this study was to evaluate the relationship between aldosterone and plasma renin activity and cardiovascular structure and function. METHODS We studied a random sample of Multi-Ethnic Study of Atherosclerosis participants who had aldosterone and plasma renin activity blood assays at 2003-2005 and underwent cardiac magnetic resonance at 2010. Participants taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were excluded. RESULTS The aldosterone group was composed by 615 participants, mean age 61.6 ± 8.9 years, while the renin group was 580 participants, mean age 61.5 ± 8.8 years and both groups had roughly 50% females. In multivariable analysis, 1 SD increment of log-transformed aldosterone level was associated with 0.07 g/m 2 higher left ventricle mass index (p=0.04) and 0.11 ml/m 2 higher left atrium minimal volume index (p < 0.01). Additionally, higher log-transformed aldosterone was associated with lower left atrium maximum strain and left atrium emptying fraction (βstandardized = -0.12, p < 0.01 and - 0.15, p < 0.01, respectively). Aldosterone levels were not significantly associated with aortic measures. Log-transformed plasma renin activity was associated with lower left ventricle end diastolic volume index (βstandardized = 0.08, p=0.05). Plasma renin activity levels were not significantly associated with left atrium and aortic structural or functional differences. CONCLUSIONS Higher levels of aldosterone and plasma renin activity are associated with concentric left ventricle remodeling changes. Moreover, aldosterone was related to deleterious left atrium remodeling changes.

This study aimed to evaluate hemodynamic correlates of inducible blood pressure (BP) pulsatility with exercise in heart failure with preserved ejection fraction (HFpEF), to identify relationships to outcomes, and to compare this with heart failure with reduced ejection fraction (HFrEF).In HFpEF, determinants and consequences of exercise BP pulsatility are not well understood.We measured exercise BP in 146 patients with HFpEF who underwent invasive cardiopulmonary exercise testing. Pulsatile BP was evaluated as proportionate pulse pressure (PrPP), the ratio of pulse pressure to systolic pressure. We measured pulmonary arterial catheter pressures, Fick cardiac output, respiratory gas exchange, and arterial stiffness. We correlated BP changes to central hemodynamics and cardiovascular outcome (nonelective cardiovascular hospitalization) and compared findings with 57 patients with HFrEF from the same referral population.In HFpEF, only age (standardized beta = 0.593; P 0.001), exercise stroke volume (standardized beta = 0.349; P 0.001), and baseline arterial stiffness (standardized beta = 0.182; P = 0.02) were significant predictors of peak exercise PrPP in multivariable analysis (R = 0.661). In HFpEF, lower PrPP was associated with lower risk of cardiovascular events, despite adjustment for confounders (HR:0.53 for PrPP below median; 95% CI: 0.28-0.98; P = 0.043). In HFrEF, lower exercise PrPP was not associated with arterial stiffness but was associated with lower peak exercise stroke volume (P = 0.013) and higher risk of adverse cardiovascular outcomes (P = 0.004).In HFpEF, greater inducible BP pulsatility measured using exercise PrPP reflects greater arterial stiffness and higher risk of adverse cardiovascular outcomes, in contrast to HFrEF where inducible exercise BP pulsatility relates to stroke volume reserve and favorable outcome.

Introduction: Circulating branched chain amino acid (BCAA) levels are associated with the development of diabetes mellitus (DM) and downstream ASCVD in middle-aged women. It is unknown if BCAAs in young adult men and women are associated with ASCVD events. BCAA levels may be dynamic in middle-aged adults prior to the development of DM or ASCVD events, thus cumulative BCAA measures in early life may better quantify exposure risk than a single measure at mid-life. Methods: We measured plasma BCAA levels in 3110 Coronary Artery Risk Development in Young Adults study participants using nuclear magnetic resonance (NMR) at Years (y) 2, 7, 15, and 20. To minimize missingness bias, BCAA levels were imputed for the residual 1835 participants without NMR measures. Cumulative BCAA exposure from 19-40y of age was calculated as the area under the curve using a spline-based mixed-effects model to estimate subject-specific BCAA trajectories from 19-40y. Sex-specific associations between cumulative BCAA exposure and incident ASCVD events after 40y of age were assessed by multivariable (Table) Cox proportional hazards regression models including BCAA levels and fasting blood glucose (FBG) at age 40y and further stratified by DM status. Results: Among 4945 participants (55.3% female), there were 255 ASCVD events and 675 DM cases over a median of 18.8 years of follow-up after age 40y. In adjusted models, cumulative BCAA exposure from 19-40y was associated with ASCVD events after 40y of age in women, but not men (Table). The associations in women were robust to adjustment for BCAAs and FBG at age 40y. There was no significant difference in the cumulative BCAA-ASCVD association among men or women who developed DM before ASCVD versus those who did not. Conclusions: Cumulative BCAA exposure in early adulthood is associated with ASCVD in women independent of mid-life BCAA levels. Elevated BCAA levels in women during early adulthood may reflect behaviors and/or metabolic pathways that increase risks for ASCVD independent of the development of hyperglycemia.

Introduction: HDL particles vary in size and concentration. Indices of overall HDL particle concentration (HDL-P) and the concentrations of different HDL size subspecies (small: H1-H3, medium: H4, H5, and large: H6, H7) have differential associations with near-term CVD events in middle-aged adults. It is unclear if measures of HDL particle concentration predict long-term ASCVD risk in young adults. Methods: Among CARDIA participants (ppts), NMR was used to measure HDL-P and HDL particle size subgroup H1-H7 concentrations. HDL cholesterol (HDL-C) was measured using standard assays. We stratified the ppts into 2 age windows: 20-30y (n= 1645) and 30-40y (n=2922). We used adjusted Cox proportional hazards models to assess the associations between a 1SD higher HDL-C, HDL-P, and HDL1-7 subgroups with incident ASCVD events. We added HDL-P, HDL H1-H7, and HDL-C separately to a modified Pooled Cohort Equation (PCE) model; model performance (discrimination and reclassification) was evaluated. Results: 81 and 163 ASCVD events occurred over (median (IQR)) 31.8y (31.1-32.0y) for the 20-30y age window and over 26.8y (19.1-27.1y) for the 30-40y age window, respectively. In ppts age 20-30y, a higher HDL-P and HDL-C were not associated with ASCVD events, however a higher HDL H6 subgroup level was associated with lower risk for ASCVD in demographic adjusted models. In the age 30-40y group, higher HDL-P, HDL-C, and H6 subgroup were significantly associated with lower ASCVD risks in all models. There were no significant differences in c-statistics across PCE models. However, there were improvements in reclassification for all HDL measures when added to the PCE model in the 20-30y age window, and significant improvements in reclassification when HDL H1-7 were added to the PCE for the 30-40y age window. Conclusion: At younger ages (

Introduction: Measures of atherogenic particle number (apoB and LDL particle number [LDL-P]) are stronger predictors of atherosclerotic cardiovascular disease (ASCVD) risk than measures of cholesterol concentration (LDL-C, non-HDL-C, total cholesterol [TC]) in middle-aged adults. It is unclear if this is true for younger adults. Methods: Among CARDIA participants (ppts), NMR was used to measure apoB and LDL-P. Non-HDL-C and TC were measured using standard assays; LDL-C was calculated using the Friedewald equation. We stratified the ppts into two age windows: age 20-30y (n=1645) and age 30-40y (n=2922). We used adjusted Cox proportional hazards models to assess the associations of 1SD higher apoB, LDL-P, non-HDL-C, LDL-C, or TC with incident ASCVD events. We substituted each measure of atherogenic lipid burden for TC in a modified Pooled Cohort Equation (PCE) model (with and without HDL-C); and model performance (discrimination and reclassification) was evaluated. Results: There were 81 and 163 ASCVD events over (median [IQR]) 31.8y (31.1-32.0y) for the age 20-30 age window and over 26.8y (19.1-27.1y) for the 30-40y age window, respectively. In ppts age 20-30y, a 1SD higher apoB, LDL-P, non-HDL-C, and LDL-C were significantly associated with incident ASCVD in demographic adjusted models. The strengths of associations with ASCVD were not significantly different across these measures. For the 30-40y age window, all measures of atherogenic lipoproteins were significantly associated with ASCVD; the strengths of association were not significantly different across atherogenic lipid measures in all models. There were no significant differences in the C-statistic and no improvement in reclassification when each measure was used to replace TC in the PCE model. Conclusions: ApoB, LDL-P, LDL-C or non-HDL-C may be slightly better markers of long-term ASCVD risk than TC in adults < 30y. However, in adults between 30-40y all measures of atherogenic lipid burden appeared to be equivalent predictors of long-term risk.

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.

Cardiac allograft vasculopathy (CAV) is the leading cause of late allograft failure and mortality after heart transplantation. As current standards of diagnosis and treatment of CAV have significant limitations, understanding cell-specific responses may prove critical for developing improved detection strategies and novel therapeutics. This study is the first to successfully utilize human endomyocardial biopsy (EMB) samples to isolate large numbers of intact nuclei for single-nuclear transcriptomics. These data also lay the groundwork for ongoing experiments to study serial, routinely-collected EMB specimens after heart transplantation to identify novel biomarkers and pathways through which early CAV pathogenesis can be interrupted, thereby prolonging allograft survival.

Aims While greater physical activity (PA) is associated with improved health outcomes, the direct links between distinct components of PA, their changes over time, and cardiorespiratory fitness are incompletely understood. Methods and results Maximum effort cardiopulmonary exercise testing (CPET) and objective PA measures [sedentary time (SED), steps/day, and moderate-vigorous PA (MVPA)] via accelerometers worn for 1 week concurrent with CPET and 7.8 years prior were obtained in 2070 Framingham Heart Study participants [age 54 ± 9 years, 51% women, SED 810 ± 83 min/day, steps/day 7737 ± 3520, MVPA 22.3 ± 20.3 min/day, peak oxygen uptake (VO2) 23.6 ± 6.9 mL/kg/min]. Adjusted for clinical risk factors, increases in steps/day and MVPA and reduced SED between the two assessments were associated with distinct aspects of cardiorespiratory fitness (measured by VO2) during initiation, early-moderate level, peak exercise, and recovery, with the highest effect estimates for MVPA (false discovery rate Conclusions Our findings provide a detailed assessment of relations of different types of PA with multidimensional cardiorespiratory fitness measures and suggest favourable longitudinal changes in PA (and MVPA in particular) are associated with greater objective fitness.

Diabetes is characterized as an integrated condition of dysregulated metabolism across multiple tissues, with well-established consequences on the cardiovascular system. Recent advances in precision phenotyping in biofluids and tissues in large human observational and interventional studies have afforded a unique opportunity to translate seminal findings in models and cellular systems to patients at risk for diabetes and its complications. Specifically, techniques to assay metabolites, proteins, and transcripts, alongside more recent assessment of the gut microbiome, underscore the complexity of diabetes in patients, suggesting avenues for precision phenotyping of risk, response to intervention, and potentially novel therapies. In addition, the influence of external factors and inputs (eg, activity, diet, medical therapies) on each domain of molecular characterization has gained prominence toward better understanding their role in prevention. Here, the authors provide a broad overview of the role of several of these molecular domains in human translational investigation in diabetes.

Objective: Adiposity is associated with oxidative stress, inflammation, and glucose intolerance. Previous data suggest that platelet gene expression is associated with key cardiometabolic phenotypes, including body mass index but stable in healthy individuals over time. However, modulation of gene expression in platelets in response to metabolic shifts (eg, weight reduction) is unknown and may be important to defining mechanism. Approach and Results: Platelet RNA sequencing and aggregation were performed from 21 individuals with massive weight loss (>45 kg) following bariatric surgery. Based on RNA sequencing data, we measured the expression of 67 genes from isolated platelet RNA using high-throughput quantitative reverse transcription quantitative PCR in 1864 FHS (Framingham Heart Study) participants. Many transcripts not previously studied in platelets were differentially expressed with bariatric surgical weight loss, appeared specific to platelets (eg, not differentially expressed in leukocytes), and were enriched for a nonalcoholic fatty liver disease pathway. Platelet aggregation studies did not detect alteration in platelet function after significant weight loss. Linear regression models demonstrated several platelet genes modestly associated with cross-sectional cardiometabolic phenotypes, including body mass index. There were no associations between studied transcripts and incident diabetes or cardiovascular end points. Conclusions: In summary, while there is no change in platelet aggregation function after significant weight loss, the human platelet experiences a dramatic transcriptional shift that implicates pathways potentially relevant to improved cardiometabolic risk postweight loss (eg, nonalcoholic fatty liver disease). Further studies are needed to determine the mechanistic importance of these observations.

Background: Whereas cardiovascular disease (CVD) metrics define risk in individuals >40 years of age, the earliest lesions of CVD appear well before this age. Despite the role of metabolism in CVD antecedents, studies in younger, biracial populations to define precise metabolic risk phenotypes are lacking. Methods: We studied 2330 White and Black young adults (mean age, 32 years; 45% Black) in the CARDIA study (Coronary Artery Risk Development in Young Adults) to identify metabolite profiles associated with an adverse CVD phenome (myocardial structure/function, fitness, vascular calcification), mechanisms, and outcomes over 2 decades. Statistical learning methods (elastic nets/principal components analysis) and Cox regression generated parsimonious, metabolite-based risk scores validated in >1800 individuals in the Framingham Heart Study. Results: In the CARDIA study, metabolite profiles quantified in early adulthood were associated with subclinical CVD development over 20 years, specifying known and novel pathways of CVD (eg, transcriptional regulation, brain-derived neurotrophic factor, nitric oxide, renin–angiotensin). We found 2 multiparametric, metabolite-based scores linked independently to vascular and myocardial health, with metabolites included in each score specifying microbial metabolism, hepatic steatosis, oxidative stress, nitric oxide modulation, and collagen metabolism. The metabolite-based vascular scores were lower in men, and myocardial scores were lower in Black participants. Over a nearly 25-year median follow-up in CARDIA, the metabolite-based vascular score (hazard ratio, 0.68 per SD [95% CI, 0.50–0.92]; P =0.01) and myocardial score (hazard ratio, 0.60 per SD [95% CI, 0.45–0.80]; P =0.0005) in the third and fourth decades of life were associated with clinical CVD with a synergistic association with outcome ( P interaction =0.009). We replicated these findings in 1898 individuals in the Framingham Heart Study over 2 decades, with a similar association with outcome (including interaction), reclassification, and discrimination. In the Framingham Heart Study, the metabolite scores exhibited an age interaction ( P =0.0004 for a combined myocardial–vascular score with incident CVD), such that young adults with poorer metabolite-based health scores had highest hazard of future CVD. Conclusions: Metabolic signatures of myocardial and vascular health in young adulthood specify known/novel pathways of metabolic dysfunction relevant to CVD, associated with outcome in 2 independent cohorts. Efforts to include precision measures of metabolic health in risk stratification to interrupt CVD at its earliest stage are warranted.

Objective: Data from animal models supports a role for metabolites in the choline pathway in glycemic control and diabetes. Cross-sectional and case-control studies have documented positive associations between trimethylamine N-oxide (TMAO) and prevalent diabetes, but these findings have not been replicated in prospective analysis. Circulating choline has been positively, and betaine negatively, associated with diabetes in some, but not all, prospective data. We tested associations between three metabolites in the choline pathway (TMAO, choline, betaine) and 15-year incident diabetes in a diverse cohort of early-middle-aged adults. Methods: Study participants were from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a multicenter cohort of Black and White Americans established in 1985/86 (baseline n=5,115; ages 18-30). Plasma concentrations of TMAO, choline, and betaine were measured from Year 15 (2000-01) stored plasma (-70°C) with liquid chromatography mass spectrometry (LC-MS). Logistic regression was used to quantify associations between plasma metabolites and diabetes, adjusting for sociodemographic, behavioral, and clinical covariates. Results: Among 3,317 participants without diabetes at Year 15, n=373 developed diabetes over 15 years of follow-up (2000-2016). Plasma TMAO and choline were not significantly associated with incident diabetes in all multivariable-adjusted models, while betaine was negatively associated with incident diabetes in all models (Table). Conclusion: In this population-based cohort of early-middle-aged US adults, plasma TMAO and choline were not associated with incident diabetes over 15 years of follow-up, while plasma betaine was negatively associated with incident diabetes.

Recent evidence links long-term (visit-to-visit) blood pressure (BP) variability to the risk of cardiovascular disease, independent of mean BP levels. Potential associations between long-term BP variability and cardiovascular disease risk may be reflected in early life course alterations in coronary artery calcium (CAC) and carotid intima-media thickness. We evaluated 2482 CARDIA study (Coronary Artery Risk Development in Young Adults) participants (mean [SD] age at the year 20 exam [2005–2006] was 45.4 [3.6] years, 43.2% men, and 41.3% black). We included participants with BP assessments across 20-years (year 0, 2, 5, 7, 10, 15, 20 exams) and carotid intima-media thickness and CAC data at the year 20 exam. BP variability was assessed using variability independent of the mean and SD. Adjusted multivariable linear or logistic regression models (as appropriate) were used to assess associations between long-term BP variability measures and carotid intima-media thickness. and CAC (ln [CAC+1] and prevalent CAC). Long-term systolic BP variability independent of the mean (per 1 SD) was positively associated with carotid intima-media thickness (β=10 μm, SE=3, P =0.002). Similarly, long-term diastolic BP variability independent of the mean was associated with carotid intima-media thickness (β=10 μm, SE (3), P =0.001). Long-term BP variability was not associated with either ln [CAC+1] or prevalent CAC. Long-term systolic and diastolic BP variability across early adulthood was positively associated with modest adverse midlife alterations in carotid intima-media thickness but not to CAC. Our findings provide further insights into pathophysiologic mechanisms that link long-term BP variability to cardiovascular disease.

Exercise intolerance is a principal feature of heart failure with preserved ejection fraction (HFpEF), whether or not there is evidence of congestion at rest. The degree of functional limitation observed in HFpEF is comparable to patients with advanced heart failure and reduced ejection fraction. Exercise intolerance in HFpEF is characterized by impairments in the physiological reserve capacity of multiple organ systems, but the relative cardiac and extracardiac deficits vary among individuals. Detailed measurements made during exercise are necessary to identify and rank-order the multiorgan system limitations in reserve capacity that culminate in exertional intolerance in a given person. We use a case-based approach to comprehensively review mechanisms of exercise intolerance and optimal approaches to evaluate exercise capacity in HFpEF. We also summarize recent and ongoing trials of novel devices, drugs, and behavioral interventions that aim to improve specific exercise measures such as peak oxygen uptake, 6-min walk distance, heart rate, and hemodynamic profiles in HFpEF. Evaluation during the clinically relevant physiological perturbation of exercise holds promise to improve the precision with which HFpEF is defined and therapeutically targeted.

Aims Cumulative blood pressure (BP) is a measure that incorporates the severity and duration of BP exposure. The prognostic significance of cumulative BP in young adults for cardiovascular diseases (CVDs) in comparison to BP severity alone is, however, unclear. Methods and results We investigated 3667 Coronary Artery Risk Development in Young Adults participants who attended six visits over 15 years (year-0 (1985–1986), year-2, year-5, year-7, year-l0, and year-15 exams). Cumulative BP was calculated as the area under the curve (mmHg × years) from year 0 through year 15. Cox models assessed the association between cumulative BP (year 0 through year 15), current BP (year 15), and BP change (year 0 and year 15) and CVD outcomes. Mean (standard deviation) age at year 15 was 40.2 (3.6) years, 44.1% were men, and 44.1% were African-American. Over a median follow-up of 16 years, there were 47 heart failure (HF), 103 coronary heart disease (CHD), 71 stroke, and 191 CVD events. Cumulative systolic BP (SBP) was associated with HF (hazard ratio (HR) = 2.14 (1.58–2.90)), CHD (HR = 1.49 (1.19–1.87)), stroke (HR = 1.81 (1.38–2.37)), and CVD (HR = 1.73 (1.47–2.05)). For CVD, the C-statistic for SBP (year 15) was 0.69 (0.65–0.73) and change in C-statistic with the inclusion of SBP change and cumulative SBP was 0.60 (0.56–0.65) and 0.72 (0.69–0.76), respectively. For CVD, using year-15 SBP as a reference, the net reclassification index (NRI) for cumulative SBP was 0.40 (p Conclusions Cumulative BP in young adults was associated with the subsequent risk of HF, CHD, stroke, and CVD. Cumulative BP provided incremental prognostic value and improved risk reclassification for CVD, when compared to single BP assessments or changes in BP.

Borderline personality disorder (BPD) is a serious psychiatric illness, and it is often associated with dissociative symptoms. The purpose of this study was to assess the course of depersonalization and derealization symptoms in recovered and non-recovered borderline patients over 20 years of prospective follow-up. The Dysphoric Affect Scale (DAS) - a 50-item self-report measure was administered to 290 borderline inpatients at baseline, and the remaining participants (85%) at 10 follow-up interviews conducted over 20 years. The level of depersonalization and derealization experienced by borderline patients was assessed using three items (feeling unreal, feeling completely numb, and feeling like people and things aren't real) from the DAS. The patients who recovered from BPD reported significantly lower scores in all three inner states (62 - 63%) at baseline compared to those patients who did not recover. Furthermore, scores of recovered and non-recovered groups decreased significantly in all three inner states studied over 20 years of prospective follow-up. Overall, these results suggest that the severity of depersonalization and derealization symptoms decreased significantly over 20 years of prospective follow-up and had a strong association with BPD recovery status.

Objectives This study evaluated whether plasma miRNAs were specifically associated with sudden cardiac and/or arrhythmic death (SCD) in a cohort of patients with coronary heart disease (CHD), most of whom were without primary prevention implantable cardioverter-defibrillators. Background Novel biomarkers for sudden death risk stratification are needed in patients with CHD to more precisely target preventive therapies, such as implantable cardioverter-defibrillators. miRNAs have been implicated in regulating inflammation and cardiac fibrosis in cells, and plasma miRNAs have been shown to predict cardiovascular death in patients with CHD. Methods We performed a nested case control study within a multicenter cohort of 5,956 patients with CHD followed prospectively for SCD. Plasma levels of 18 candidate miRNAs previously associated with cardiac remodeling were measured in 129 SCD cases and 258 control subjects matched on age, sex, race, and left ventricular ejection fraction. Results miR-150-5p, miR-29a-3p, and miR-30a-5p were associated with increased SCD risk (odds ratios and 95% confidence intervals: 2.03 [1.12 to 3.67]; p = 0.02; 1.93 [1.07 to 3.50]; p = 0.02; 0.55 [0.31 to 0.97]; p = 0.04, respectively, for third vs. first tertile miRNA level). Unfavorable levels of all 3 miRNAs was associated with a 4.8-fold increased SCD risk (1.59 to 14.51; p = 0.006). A bioinformatics-based approach predicted miR-150-5p, miR-29a-3p, and miR-30a-5p to be involved in apoptosis, fibrosis, and inflammation. Conclusions These findings suggest that plasma miRNAs may regulate pathways important for remodeling and may be useful in identifying patients with CHD at increased risk of SCD.

Background Abnormal pulmonary arterial pressure (PAP) responses to exercise have been described in select individuals; however, clinical and prognostic implications of exercise pulmonary hypertension (exPH) among broader samples remains unclear. Objectives This study sought to investigate the association of exPH with clinical determinants and outcomes. Methods The authors studied individuals with chronic exertional dyspnea and preserved ejection fraction who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring. Exercise pulmonary hypertension was ascertained using minute-by-minute PAP and cardiac output (CO) measurements to calculate a PAP/CO slope, and exPH defined as a PAP/CO slope >3 mm Hg/l/min. The primary outcome was cardiovascular (CV) hospitalization or all-cause mortality. Results Among 714 individuals (age 57 years, 59% women), 296 (41%) had abnormal PAP/CO slopes. Over a mean follow-up of 3.7 ± 2.9 years, there were 208 CV or death events. Individuals with abnormal PAP/CO slope had a 2-fold increased hazard of future CV or death event (multivariable-adjusted hazard ratio: 2.03; 95% confidence interval: 1.48 to 2.78; p Conclusions Exercise pulmonary hypertension is independently associated with CV event-free survival among individuals undergoing evaluation of chronic dyspnea. These findings suggest incremental value of exercise hemodynamic assessment to resting measurements alone in characterizing the burden of PH in individuals with dyspnea. Whether PH and PH subtypes unmasked by exercise can be used to guide targeted therapeutic interventions requires further investigation.

Aims Observational studies of diet in cardiometabolic-cardiovascular disease (CM-CVD) focus on self-reported consumption of food or dietary pattern, with limited information on individual metabolic responses to dietary intake linked to CM-CVD. Here, machine learning approaches were used to identify individual metabolic patterns related to diet and relation to long-term CM-CVD in early adulthood. Methods and results In 2259 White and Black adults (age 32.1 ± 3.6 years, 45% women, 44% Black) in the Coronary Artery Risk Development in Young Adults (CARDIA) study, multivariate models were employed to identify metabolite signatures of food group and composite dietary intake across 17 food groups, 2 nutrient groups, and healthy eating index-2015 (HEI2015) diet quality score. A broad array of metabolites associated with diet were uncovered, reflecting food-related components/catabolites (e.g. fish and long-chain unsaturated triacylglycerols), interactions with host features (microbiome), or pathways broadly implicated in CM-CVD (e.g. ceramide/sphingomyelin lipid metabolism). To integrate diet with metabolism, penalized machine learning models were used to define a metabolite signature linked to a putative CM-CVD-adverse diet (e.g. high in red/processed meat, refined grains), which was subsequently associated with long-term diabetes and CVD risk numerically more strongly than HEI2015 in CARDIA [e.g. diabetes: standardized hazard ratio (HR): 1.62, 95% confidence interval (CI): 1.32–1.97, P < 0.0001; CVD: HR: 1.55, 95% CI: 1.12–2.14, P = 0.008], with associations replicated for diabetes (P < 0.0001) in the Framingham Heart Study. Conclusion Metabolic signatures of diet are associated with long-term CM-CVD independent of lifestyle and traditional risk factors. Metabolomics improves precision to identify adverse consequences and pathways of diet-related CM-CVD.

AIMS/HYPOTHESIS: The aim of this work was to define metabolic correlates and pathways of diabetes pathogenesis in young adults during a subclinical latent phase of diabetes development. METHODS: We studied 2083 young adults of Black and White ethnicity in the prospective observational cohort Coronary Artery Risk Development in Young Adults (CARDIA) study (mean ± SD age 32.1 ± 3.6 years; 43.9% women; 42.7% Black; mean ± SD BMI 25.6 ± 4.9 kg/m(2)) and 1797 Framingham Heart Study (FHS) participants (mean ± SD age 54.7 ± 9.7 years; 52.1% women; mean ± SD BMI 27.4 ± 4.8 kg/m(2)), examining the association of comprehensive metabolite profiles with endophenotypes of diabetes susceptibility (adipose and muscle tissue phenotypes and systemic inflammation). Statistical learning techniques and Cox regression were used to identify metabolite signatures of incident diabetes over a median of nearly two decades of follow-up across both cohorts. RESULTS: We identified known and novel metabolites associated with endophenotypes that delineate the complex pathophysiological architecture of diabetes, spanning mechanisms of muscle insulin resistance, inflammatory lipid signalling and beta cell metabolism (e.g. bioactive lipids, amino acids and microbe- and diet-derived metabolites). Integrating endophenotypes of diabetes susceptibility with the metabolome generated two multi-parametric metabolite scores, one of which (a proinflammatory adiposity score) was associated with incident diabetes across the life course in participants from both the CARDIA study (young adults; HR in a fully adjusted model 2.10 [95% CI 1.72, 2.55], p

Myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) is widely used for coronary artery disease (CAD) evaluation. Although attenuation correction is recommended to diminish image artifacts and improve diagnostic accuracy, approximately 3/4ths of clinical MPI worldwide remains non-attenuation-corrected (NAC). In this work, we propose a novel deep learning (DL) algorithm to provide "virtual" DL attenuation-corrected (DLAC) perfusion polar maps solely from NAC data without concurrent computed tomography (CT) imaging or additional scans.SPECT MPI studies (N = 11,532) with paired NAC and CTAC images were retrospectively identified. A convolutional neural network-based DL algorithm was developed and trained on half of the population to predict DLAC polar maps from NAC polar maps. Total perfusion deficit (TPD) was evaluated for all polar maps. TPDs from NAC and DLAC polar maps were compared to CTAC TPDs in linear regression analysis. Moreover, receiver-operating characteristic analysis was performed on NAC, CTAC, and DLAC TPDs to predict obstructive CAD as diagnosed from invasive coronary angiography.DLAC TPDs exhibited significantly improved linear correlation (p 0.001) with CTAC (RThe proposed DL algorithm provided attenuation correction comparable to CTAC without the need for additional scans. Compared to conventional NAC perfusion imaging, DLAC significantly improved diagnostic accuracy.

Cardiorespiratory fitness (CRF) is intricately related to health status. The optimal approach for CRF quantification is through assessment of peak oxygen uptake (VO(2)), but such measurements have been largely confined to small referral populations. Here we describe protocols and methodological considerations for peak VO(2) assessment and determination of volitional effort in a large community-based sample. Maximum incremental ramp cycle ergometry cardiopulmonary exercise testing (CPET) was performed by Framingham Heart Study participants at a routine study visit (2016–2019). Of 3486 individuals presenting for a multi-component study visit, 3116 (89%) completed CPET. The sample was middle-aged (54±9 years), with 53% women, body mass index 28.3±5.6 kg/m(2), 48% with hypertension, 6% smokers, and 8% with diabetes. Exercise duration was 12.0±2.1 minutes (limits 3.7–20.5). No major cardiovascular events occurred. A total of 98%, 96%, 90%, 76%, and 57% of the sample reached peak respiratory exchange ratio (RER) values of ≥1.0, ≥1.05, ≥1.10, ≥1.15, and ≥1.20, respectively (mean peak RER=1.22±0.10). With rising peak RER values up to ≈1.10, steep changes were observed for percent predicted peak VO(2), VO(2) at the ventilatory threshold/peak VO(2), heart rate response, and Borg (subjective dyspnea) scores. More shallow changes for effort dependent CPET variables were observed with higher achieved RER values. In conclusion, measurement of peak VO(2) is feasible and safe in a large sample of middle-aged, community-dwelling individuals with heterogeneous cardiovascular risk profiles. Peak RER ≥1.10 was achievable by the majority of middle-aged adults and RER values beyond this threshold did not necessarily correspond to higher peak VO(2) values.

Background Obesity may be associated with a range of cardiometabolic manifestations. We hypothesized that proteomic profiling may provide insights into the biological pathways that contribute to various obesity‐associated cardiometabolic traits. We sought to identify proteomic signatures of obesity and examine overlap with related cardiometabolic traits, including abdominal adiposity, insulin resistance, and adipose depots. Methods and Results We measured 71 circulating cardiovascular disease protein biomarkers in 6981 participants (54% women; mean age, 49 years). We examined the associations of obesity, computed tomography measures of adiposity, cardiometabolic traits, and incident metabolic syndrome with biomarkers using multivariable regression models. Of the 71 biomarkers examined, 45 were significantly associated with obesity, of which 32 were positively associated and 13 were negatively associated with obesity (false discovery rate q q Conclusions We found that the proteomic architecture of obesity overlaps considerably with associated cardiometabolic traits, implying shared pathways. Despite overlap, hierarchical clustering of proteomic profiles identified 3 distinct clusters of cardiometabolic traits: adipose, metabolic, and lipid. Further exploration of these novel protein targets and associated pathways may provide insight into the mechanisms responsible for the progression from obesity to cardiometabolic disease.

Patients with borderline personality disorder have high rates of comorbid mood, anxiety, substance use, and eating disorders. The longitudinal studies conducted on borderline patients over 10 years of prospective follow-up suggest that patients with borderline personality disorder experienced declining rates of Axis I disorders over time, but the rates of these disorders remained high compared with those with other personality disorders. In addition, patients whose borderline personality disorder remitted over time experienced a substantial decline in all comorbid Axis I disorders, but those whose borderline personality disorder did not remit over time, reported stable rates of comorbid disorders.

Introduction: Tetralogy of Fallot (TOF) and Ventricular Septal Defect (VSD) patients have non-diagnostic Q-waves within inferior (II, III, aVF) or septal (V1-V2) leads on ECG, perhaps due to incomplete conduction through septal defects. Non-diagnostic Q-waves tend to either be wide within a single lead, or deep (3-4mm) in contiguous leads, but do not meet diagnostic criteria for infarct. Hypothesis: Non-Adult Congenital Heart Disease (ACHD) physicians may inaccurately characterize non-diagnostic Q-waves as pathologic opposed to expert interpretation by ACHD-trained physicians in VSD and TOF patients. Thus, misinterpreting ECGs to suggest prior infarct and decreasing their positive predictive value (PPV). Methods: With application of pre-specified inclusion and exclusion criteria, we retrospectively reviewed 72 ECGs from TOF or VSD patients at Penn State Hershey Medical Center from 2002-2020 that were separately read by ACHD and non-ACHD specialists. Primary outcomes were ECGs with diagnosed Q-waves in two separate distributions, inferior or septal leads, by both groups using standard criteria for Q-wave infarct. Reported measures were sensitivity, specificity, PPV, and negative predictive value (NPV). Results: The 72 subjects with isolated TOF or VSD had a mean age of 39 years and 63% were male. Total disease prevalence (presence of Q-waves) was 4.6%. Q-wave infarct diagnosed by non-ACHD physicians had a sensitivity and specificity of 33% and 74% respectively. Their PPV was 5.87% and NPV was 95.85%. Conclusions: This retrospective cohort analysis of TOF and VSD patient ECGs showed the low PPV of non-ACHD physician diagnosis of Q-waves in this respective population. Misinterpretation and misdiagnosis of infarct based off ECG, has ramifications for both the patient and medical system as a whole. Sequelae include, but are not limited to, increasing patient risk for unwarranted medical treatment and affecting hospital billing and insurance coverage.

Introduction: Exercise intolerance is common in cardiovascular disease and is a cardinal manifestation of heart failure with preserved ejection fraction (HFpEF). Decreased exercise capacity is often attributed to cardiac limitations, though HFpEF is increasingly recognized to be both a metabolic and a cardiovascular disorder. Hypothesis: Patients with HFpEF will have exaggerated metabolic cost of exercise initiation with associated high expenditure of hemodynamic reserve capacity. Methods: We quantified the workload-equivalent cost of initiating exercise using cardiopulmonary exercise testing in patients with HFpEF (N=184, age 62±13, 47% women, peak VO2 13.8±3.3 ml/kg/min). Individualized VO2-work rate relationships during loaded exercise were used to derive the work-equivalents required to move extremities with zero external resistance (0 watts)—termed “internal work” (IW). Standard linear regression techniques were used for comparisons. Results: In individuals with HFpEF, the internal work (42±28 W) was often a large portion of the total workload achieved. BMI accounted for the greatest variance in IW (23%), suggesting a metabolic basis for IW. Resting measures of myocardial function and biventricular filling pressures did not measurably contribute to explanatory variance in IW, suggesting a non-cardiac origin. Individuals with HFpEF in the fourth quartile of IW (76±28W) had a dramatic hemodynamic response to exercise in pulmonary capillary wedge and mean pulmonary arterial pressures. Changes in hemodynamic measurements were more modest between quartiles of IW in the submaximal ramp period following unloaded exercise. Conclusions: Internal work is a new measure that captures the metabolic cost of initiating movement. Internal work is associated with limitations in achievable external workload as well as steep early increases in cardiac filling pressures in HFpEF. Further investigation into the pathophysiology of elevated IW is needed.

Diabetes is characterized as an integrated condition of dysregulated metabolism across multiple tissues, with well-established consequences on the cardiovascular system. Recent advances in precision phenotyping in biofluids and tissues in large human observational and interventional studies have afforded a unique opportunity to translate seminal findings in models and cellular systems to patients at risk for diabetes and its complications. Specifically, techniques to assay metabolites, proteins, and transcripts, alongside more recent assessment of the gut microbiome, underscore the complexity of diabetes in patients, suggesting avenues for precision phenotyping of risk, response to intervention, and potentially novel therapies. In addition, the influence of external factors and inputs (eg, activity, diet, medical therapies) on each domain of molecular characterization has gained prominence toward better understanding their role in prevention. Here, the authors provide a broad overview of the role of several of these molecular domains in human translational investigation in diabetes.

Rationale: Previous translational studies implicate plasma extracellular microRNA-30d (miR-30d) as a biomarker in left ventricular remodeling and clinical outcome in heart failure (HF) patients, although precise mechanisms remain obscure. Objective: To investigate the mechanism of miR-30d–mediated cardioprotection in HF. Methods and Results: In rat and mouse models of ischemic HF, we show that miR-30d gain of function (genetic, lentivirus, or agomiR-mediated) improves cardiac function, decreases myocardial fibrosis, and attenuates cardiomyocyte (CM) apoptosis. Genetic or locked nucleic acid–based knock-down of miR-30d expression potentiates pathological left ventricular remodeling, with increased dysfunction, fibrosis, and cardiomyocyte death. RNA sequencing of in vitro miR-30d gain and loss of function, together with bioinformatic prediction and experimental validation in cardiac myocytes and fibroblasts, were used to identify and validate direct targets of miR-30d. miR-30d expression is selectively enriched in cardiomyocytes, induced by hypoxic stress and is acutely protective, targeting MAP4K4 (mitogen-associate protein kinase 4) to ameliorate apoptosis. Moreover, miR-30d is secreted primarily in extracellular vesicles by cardiomyocytes and inhibits fibroblast proliferation and activation by directly targeting integrin α5 in the acute phase via paracrine signaling to cardiac fibroblasts. In the chronic phase of ischemic remodeling, lower expression of miR-30d in the heart and plasma extracellular vesicles is associated with adverse remodeling in rodent models and human subjects and is linked to whole-blood expression of genes implicated in fibrosis and inflammation, consistent with observations in model systems. Conclusions: These findings provide the mechanistic underpinning for the cardioprotective association of miR-30d in human HF. More broadly, our findings support an emerging paradigm involving intercellular communication of extracellular vesicle–contained miRNAs (microRNAs) to transregulate distinct signaling pathways across cell types. Functionally validated RNA biomarkers and their signaling networks may warrant further investigation as novel therapeutic targets in HF.