Endoscopic Ultrasound Guided Liver Palpation As a Screening Tool for Advanced Fibrosis and Cirrhosis in Patients with Suspected Metabolic Dysfunction-Associated Steatotic Liver Disease: A Pilot Study.

BACKGROUND AND AIMS: Endoscopic liver "palpation" can be performed by indenting the liver surface under endoscopic ultrasound (EUS). Indentation depth is measured with sonographic calipers. We hypothesize that fibrotic livers are more difficult to indent, and indentation can accurately predict liver fibrosis staging. We compared EUS-guided liver palpation to conventional screening modalities in patients with suspected metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: This was a cross-sectional pilot study. Consecutive patients at three hospitals between 2021-2023 underwent EUS-guided palpation with liver biopsy. Liver palpation was compared to Fibrosis-4 index (FIB-4), AST to Platelet Ratio Index (APRI), NAFLD Fibrosis Score (NFS), and transient elastography in predicting fibrosis staging on histology. Area under the receiver operator characteristic (AUROC) curve analysis was performed. RESULTS: 73 patients were included. Mean age was 49.1 and 71.2% were female. Mean body mass index was 41.1. Indentation depth was negatively correlated with fibrosis stage (Kruskal-Willis test, p<0.0001). EUS palpation demonstrated c-statistic of 0.79 and 0.95 discriminating advanced fibrosis and cirrhosis respectively. EUS-liver palpation was superior to NFS in predicting advanced fibrosis (p=0.0057) and superior to APRI and NFS predicting cirrhosis (p=0.0099 and 0.045 respectively). EUS palpation was not significantly different versus FIB-4. EUS palpation was superior to transient elastography in predicting cirrhosis (p=0.045). Using optimal cut-offs, indentation measurement ≤3.5mm yielded 100% predictive value ruling in advanced fibrosis, and ≥4.0mm yielded 100% predictive value ruling out cirrhosis. CONCLUSIONS: EUS liver palpation is a novel, accurate, and easy-to-use screening tool for advanced fibrosis and cirrhosis in patients with MASLD.

Correlates of Plasma NT-proBNP/Cyclic GMP Ratio in Heart Failure With Preserved Ejection Fraction: An Analysis of the RELAX Trial.

BACKGROUND: Phosphodiesterases degrade cyclic GMP (cGMP), the second messenger that mediates the cardioprotective effects of natriuretic peptides. High natriuretic peptide/cGMP ratio may reflect, in part, phosphodiesterase activity. Correlates of natriuretic peptide/cGMP in patients with heart failure with preserved ejection fraction are not well understood. Among patients with heart failure with preserved ejection fraction in the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) trial, we examined (1) cross-sectional correlates of circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide)/cGMP ratio, (2) whether selective phosphodiesterase-5 inhibition by sildenafil changed the ratio, and (3) whether the effect of sildenafil on 24-week outcomes varied by baseline ratio. METHODS AND RESULTS: In 212 subjects, NT-proBNP/cGMP ratio was calculated at randomization and 24 weeks. Correlates of the ratio and its change were examined in multivariable proportional odds models. Whether baseline ratio modified the sildenafil effect on outcomes was examined by interaction terms. Higher NT-proBNP/cGMP ratio was associated with greater left ventricular mass and troponin, the presence of atrial fibrillation, and lower estimated glomerular filtration rate and peak oxygen consumption. Compared with placebo, sildenafil did not alter the ratio from baseline to 24 weeks (P=0.17). The effect of sildenafil on 24-week change in peak oxygen consumption, left ventricular mass, or clinical composite outcome was not modified by baseline NT-proBNP/cGMP ratio (P-interaction >0.30 for all). CONCLUSIONS: Among patients with heart failure with preserved ejection fraction, higher NT-proBNP/cGMP ratio associated with an adverse cardiorenal phenotype, which was not improved by selective phosphodiesterase-5 inhibition. Other phosphodiesterases may be greater contributors than phosphodiesterase-5 to the adverse phenotype associated with a high natriuretic peptide/cGMP ratio in HFpEF. REGISTRATION INFORMATION: clinicaltrials.gov. Identifier: NCT00763867.

EUS-guided coil injection therapy in the management of gastric varices: the first U.S. multicenter experience (with video).

BACKGROUND AND AIMS: Despite the significant morbidity associated with gastric variceal bleeding, there is a paucity of high-quality data regarding optimal management. EUS-guided coil injection therapy (EUS-COIL) has recently emerged as a promising endoscopic modality for the treatment of gastric varices (GV), particularly compared with traditional direct endoscopic glue injection. Although there are data on the feasibility and safety of EUS-COIL in the management of GV, these have been limited to select centers with particular expertise. The aim of this study was to report the first U.S. multicenter experience of EUS-COIL for the management of GV. METHODS: This retrospective analysis included patients with bleeding GV or GV at risk of bleeding who underwent EUS-COIL at 10 U.S. tertiary care centers between 2018 and 2022. Baseline patient and procedure-related information was obtained. EUS-COIL entailed the injection of .018 inch or .035 inch hemostatic coils using a 22-gauge or 19-gauge FNA needle. Primary outcomes were technical success (defined as successful deployment of coil into varix under EUS guidance with diminution of Doppler flow), clinical success (defined as cessation of bleeding if present and/or absence of bleeding at 30 days' postintervention), and intraprocedural and postprocedural adverse events. RESULTS: A total of 106 patients were included (mean age 60.4 ± 12.8 years; 41.5% female). The most common etiology of GV was cirrhosis (71.7%), with alcohol being the most common cause (43.4%). Overall, 71.7% presented with acute GV bleeding requiring intensive care unit stay and/or blood transfusion. The most common GV encountered were isolated GV type 1 (60.4%). A mean of 3.8 ± 3 coils were injected with a total mean length of 44.7 ± 46.1 cm. Adjunctive glue or absorbable gelatin sponge was injected in 82% of patients. Technical success and clinical success were 100% and 88.7%, respectively. Intraprocedural adverse events (pulmonary embolism and GV bleeding from FNA needle access) occurred in 2 patients (1.8%), and postprocedural adverse events occurred in 5 (4.7%), of which 3 were mild. Recurrent bleeding was observed in 15 patients (14.1%) at a mean of 32 days. Eighty percent of patients with recurrent bleeding were successfully re-treated with repeat EUS-COIL. No significant differences were observed in outcomes between high-volume (>15 cases) and low-volume (<7 cases) centers. CONCLUSIONS: This U.S. multicenter experience on EUS-COIL for GV confirms high technical and clinical success with low adverse events. No significant differences were seen between high- and low-volume centers. Repeat EUS-COIL seems to be an effective rescue option for patients with recurrent bleeding GV. Further prospective studies should compare this modality versus other interventions commonly used for GV.

Towards Allograft Longevity: Leveraging Omics Technologies to Improve Heart Transplant Outcomes.

PURPOSE OF REVIEW: Heart transplantation (HT) remains the optimal therapy for patients living with end-stage heart disease. Despite recent improvements in peri-transplant management, the median survival after HT has remained relatively static, and complications of HT, including infection, rejection, and allograft dysfunction, continue to impact quality of life and long-term survival. RECENT FINDINGS: Omics technologies are becoming increasingly accessible and can identify novel biomarkers for, and reveal the underlying biology of, several disease states. While some technologies, such as gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA), are routinely used in the clinical care of HT recipients, a number of emerging platforms, including pharmacogenomics, proteomics, and metabolomics, hold great potential for identifying biomarkers to aid in the diagnosis and management of post-transplant complications. Omics-based assays can improve patient and allograft longevity by facilitating a personalized and precision approach to post-HT care. The following article is a contemporary review of the current and future opportunities to leverage omics technologies, including genomics, transcriptomics, proteomics, and metabolomics in the field of HT.

Effect of Dietary Sodium on Blood Pressure: A Crossover Trial.

Importance: Dietary sodium recommendations are debated partly due to variable blood pressure (BP) response to sodium intake. Furthermore, the BP effect of dietary sodium among individuals taking antihypertensive medications is understudied. Objectives: To examine the distribution of within-individual BP response to dietary sodium, the difference in BP between individuals allocated to consume a high- or low-sodium diet first, and whether these varied according to baseline BP and antihypertensive medication use. Design, Setting, and Participants: Prospectively allocated diet order with crossover in community-based participants enrolled between April 2021 and February 2023 in 2 US cities. A total of 213 individuals aged 50 to 75 years, including those with normotension (25%), controlled hypertension (20%), uncontrolled hypertension (31%), and untreated hypertension (25%), attended a baseline visit while consuming their usual diet, then completed 1-week high- and low-sodium diets. Intervention: High-sodium (approximately 2200 mg sodium added daily to usual diet) and low-sodium (approximately 500 mg daily total) diets. Main Outcomes and Measures: Average 24-hour ambulatory systolic and diastolic BP, mean arterial pressure, and pulse pressure. Results: Among the 213 participants who completed both high- and low-sodium diet visits, the median age was 61 years, 65% were female and 64% were Black. While consuming usual, high-sodium, and low-sodium diets, participants' median systolic BP measures were 125, 126, and 119 mm Hg, respectively. The median within-individual change in mean arterial pressure between high- and low-sodium diets was 4 mm Hg (IQR, 0-8 mm Hg; P < .001), which did not significantly differ by hypertension status. Compared with the high-sodium diet, the low-sodium diet induced a decline in mean arterial pressure in 73.4% of individuals. The commonly used threshold of a 5 mm Hg or greater decline in mean arterial pressure between a high-sodium and a low-sodium diet classified 46% of individuals as "salt sensitive." At the end of the first dietary intervention week, the mean systolic BP difference between individuals allocated to a high-sodium vs a low-sodium diet was 8 mm Hg (95% CI, 4-11 mm Hg; P < .001), which was mostly similar across subgroups of age, sex, race, hypertension, baseline BP, diabetes, and body mass index. Adverse events were mild, reported by 9.9% and 8.0% of individuals while consuming the high- and low-sodium diets, respectively. Conclusions and Relevance: Dietary sodium reduction significantly lowered BP in the majority of middle-aged to elderly adults. The decline in BP from a high- to low-sodium diet was independent of hypertension status and antihypertensive medication use, was generally consistent across subgroups, and did not result in excess adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT04258332.

Metabolite Signature of Life's Essential 8 and Risk of Coronary Heart Disease Among Low-Income Black and White Americans.

BACKGROUND: Life's essential 8 (LE8) is a comprehensive construct of cardiovascular health. Yet, little is known about the LE8 score, its metabolic correlates, and their predictive implications among Black Americans and low-income individuals. METHODS: In a nested case-control study of coronary heart disease (CHD) among 299 pairs of Black and 298 pairs of White low-income Americans from the Southern Community Cohort Study, we estimated LE8 score and applied untargeted plasma metabolomics and elastic net with leave-one-out cross-validation to identify metabolite signature (MetaSig) of LE8. Associations of LE8 score and MetaSig with incident CHD were examined using conditional logistic regression. The mediation effect of MetaSig on the LE8-CHD association was also examined. The external validity of MetaSig was evaluated in another nested CHD case-control study among 299 pairs of Chinese adults. RESULTS: Higher LE8 score was associated with lower CHD risk (standardized odds ratio, 0.61 [95% CI, 0.53-0.69]). The MetaSig, consisting of 133 metabolites, showed significant correlation with LE8 score (r=0.61) and inverse association with CHD (odds ratio, 0.57 [0.49-0.65]), robust to adjustment for LE8 score and across participants with different sociodemographic and health status ([odds ratios, 0.42-0.69]; all P<0.05). MetaSig mediated a large portion of the LE8-CHD association: 53% (32%-80%). Significant associations of MetaSig with LE8 score and CHD risk were found in validation cohort (r=0.49; odds ratio, 0.57 [0.46-0.69]). CONCLUSIONS: Higher LE8 score and its MetaSig were associated with lower CHD risk among low-income Black and White Americans. Metabolomics may offer an objective measure of LE8 and its metabolic phenotype relevant to CHD prevention among diverse populations.

Gastric varices.

PURPOSE OF REVIEW: Gastric varices are a rare cause of gastrointestinal bleeding in patients with portal hypertension. There have been significantly advances within endoscopic ultrasound for treatment of gastric varices over the past 5 years in addition to the conventional endoscopic and endovascular therapies. In this review, we will review the latest literature on gastric varices with emphasis on changes to the conventional classification systems and comparisons among the different treatment options for gastric varices in terms of efficacy and safety. RECENT FINDINGS: There have been new guidelines proposed by the American Gastrointestinal Association on a simpler classification system compared to the conventional Sarin classification. In addition, endoscopic ultrasound guided coil embolization, a novel treatment pioneered over the past 5 years for gastric varices, has shown increased efficacy and reduced adverse event profile compared to cyanoacrylate glue, the more traditional therapy for gastric variceal bleeding. Options for endovascular therapy overall have not significantly changed over the recent years. SUMMARY: Based on our literature review, we recommend a step-up approach with initial medical and endoscopic management with consideration of endovascular therapies when initial therapies fail.

Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma.

Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.

Polygenic risk score in comparison with C-reactive protein for predicting incident coronary heart disease.

BACKGROUND AND AIMS: Despite interest in the use of polygenic risk scores (PRS) for predicting coronary heart disease (CHD) risk, the clinical utility of PRS compared to conventional risk factors has not been demonstrated. We compared the performance of PRS with that of high-sensitivity C-reactive protein (hsCRP) in two well-established cohorts. METHODS: The study population included individuals of European ancestry free of baseline CHD from ARIC (N = 13,113) and the Framingham Offspring Study (FHS) (N = 2,696). The primary predictors included a validated PRS consisting of >6.6 million single nucleotide polymorphisms and hsCRP. The outcome was incident CHD, defined as non-fatal or fatal myocardial infarction. We compared the performance of both predictors after adjusting for the Pooled Cohort Equations in multivariable-adjusted Cox regression models. We assessed discrimination and reclassification using c-statistics and net reclassification improvement. RESULTS: Incident CHD occurred in 565 ARIC and 153 FHS participants. In multivariable-adjusted models, both PRS and hsCRP were associated with incident CHD (p < 0.05 in both cohorts). In models incorporating both predictors, strengths of association were similar. For instance, in ARIC, the hazard ratio per SD increment was 1.38 (95% CI, 1.27-1.50, p = 2.94 × 10-14) for PRS and 1.41 (1.30-1.55, p = 3.10 × 10-15) for hsCRP. Neither predictor significantly increased model discrimination or net reclassification when compared with models containing the Pooled Cohort Equations alone. CONCLUSIONS: In two independent cohorts, PRS performed similarly to hsCRP for the prediction of CHD risk. These findings suggest PRS does not have unique clinical utility beyond this widely-available, inexpensive measure of risk in unselected middle-aged populations.

Effect of 2022 ACC/AHA/HFSA Criteria on Stages of Heart Failure in a Pooled Community Cohort.

BACKGROUND: The 2022 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) clinical practice guideline proposed an updated definition for heart failure (HF) stages. OBJECTIVES: This study aimed to compare prevalence and prognosis of HF stages according to classification/definition originally described in 2013 and 2022 ACC/AHA/HFSA definitions. METHODS: Study participants from 3 longitudinal cohorts (the MESA [Multi-Ethnic Study of Atherosclerosis], CHS [Cardiovascular Health Study], and the FHS [Framingham Heart Study]), were categorized into 4 HF stages according to the 2013 and 2022 criteria. Cox proportional hazards regression was used to assess predictors of progression to symptomatic HF and adverse clinical outcomes associated with each HF stage. RESULTS: Among 11,618 study participants, according to the 2022 staging, 1,943 (16.7%) were healthy, 4,348 (37.4%) were in stage A (at risk), 5,019 (43.2%) were in stage B (pre-HF), and 308 (2.7%) were in stage C/D (symptomatic HF). Compared to the classification/definition originally described in 2013, the 2022 ACC/AHA/HFSA approach resulted in a higher proportion of individuals with stage B HF (increase from 15.9% to 43.2%); this shift disproportionately involved women as well as Hispanic and Black individuals. Despite the 2022 criteria designating a greater proportion of individuals as stage B, the relative risk of progression to symptomatic HF remained similar (HR: 10.61; 95% CI: 9.00-12.51; P < 0.001). CONCLUSIONS: New standards for HF staging resulted in a substantial shift of community-based individuals from stage A to stage B. Those with stage B HF in the new system were at high risk for progression to symptomatic HF.

Systemic Markers of Lung Function and Forced Expiratory Volume in 1 Second Decline across Diverse Cohorts.

Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. Objectives: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population. Methods: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analysis and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC). In linear mixed effects models, we investigated the associations of baseline protein levels with rate of FEV1 decline (ml/yr) in 2,777 participants with up to 7 years of follow-up spirometry. Results: We identified 254 proteins associated with FEV1 in our discovery analyses, with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (discovery ß = 0.0561, Q = 4.05 × 10-10; ß = 0.0421, Q = 1.12 × 10-3; and ß = 0.0358, Q = 1.67 × 10-3, respectively). In longitudinal analyses within cohorts with follow-up spirometry, we identified 15 proteins associated with FEV1 decline (Q < 0.05), including elafin leukocyte elastase inhibitor and mucin-associated TFF2 (trefoil factor 2; ß = -4.3 ml/yr, Q = 0.049; ß = -6.1 ml/yr, Q = 0.032, respectively). Pathways and processes highlighted by our study include aberrant extracellular matrix remodeling, enhanced innate immune response, dysregulation of angiogenesis, and coagulation. Conclusions: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. In addition, we identify novel protein markers associated with FEV1 decline. Several protein findings are supported by previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent markers for risk stratification, as well as novel molecular targets for treatment of COPD.

Metabolite Signature of Life's Essential 8 and Risk of Coronary Heart Disease among Low-Income Black and White Americans.

Background and Aims: Life's Essential 8 (LE8) is a comprehensive construct of cardiovascular health. Yet, little is known about LE8 score, its metabolic correlates, and their predictive implications among Black Americans and low-income individuals. Methods: In a nested case-control study of coronary heart disease (CHD) among 598 Black and 596 White low-income Americans, we estimated LE8 score, conducted untargeted plasma metabolites profiling, and used elastic net with leave-one-out cross-validation to identify metabolite signature (MetaSig) of LE8. Associations of LE8 score and MetaSig with incident CHD were examined using conditional logistic regression. Mediation effect of MetaSig on the LE8-CHD association was also examined. The external validity of MetaSig was evaluated in another nested CHD case-control study among 598 Chinese adults. Results: Higher LE8 score was associated with lower CHD risk [standardized OR (95% CI)=0.61 (0.53-0.69)]. The identified MetaSig, consisting of 133 metabolites, showed strong correlation with LE8 score ( r =0.61) and inverse association with CHD risk [OR (95% CI)=0.57 (0.49-0.65)], robust to adjustment for LE8 score and across participants with different sociodemographic and health status (ORs: 0.42-0.69; all P <0.05). MetaSig mediated a large portion of the LE8-CHD association: 53% (32%-80%) ( P <0.001). Significant associations of MetaSig with LE8 score and CHD risk were found in validation cohort [ r =0.49; OR (95% CI)=0.57 (0.46-0.69)]. Conclusions: Higher LE8 score and its MetaSig were associated with lower CHD risk among low-income Black and White Americans. Metabolomics may offer an objective and comprehensive measure of LE8 score and its metabolic phenotype relevant to CHD prevention among diverse populations.

Defining the optimal technique for endoscopic ultrasound shear wave elastography: a combined benchtop and animal model study with comparison to transabdominal shear wave elastography.

BACKGROUND/AIMS: Shear wave elastography (SWE) is used for liver fibrosis staging based on stiffness measurements. It can be performed using endoscopic ultrasound (EUS) or a transabdominal approach. Transabdominal accuracy can be limited in patients with obesity because of the thick abdomen. Theoretically, EUS-SWE overcomes this limitation by internally assessing the liver. We aimed to define the optimal technique for EUS-SWE for future research and clinical use and compare its accuracy with that of transabdominal SWE. METHODS: Benchtop study: A standardized phantom model was used. The compared variables included the region of interest (ROI) size, depth, and orientation and transducer pressure. Porcine study: Phantom models with varying stiffness values were surgically implanted between the hepatic lobes. RESULTS: For EUS-SWE, a larger ROI size of 1.5 cm and a smaller ROI depth of 1 cm demonstrated a significantly higher accuracy. For transabdominal SWE, the ROI size was nonadjustable, and the optimal ROI depth ranged from 2 to 4 cm. The transducer pressure and ROI orientation did not significantly affect the accuracy. There were no significant differences in the accuracy between transabdominal SWE and EUS-SWE in the animal model. The variability among the operators was more pronounced for the higher stiffness values. Small lesion measurements were accurate only when the ROI was entirely situated within the lesion. CONCLUSION: We defined the optimal viewing windows for EUS-SWE and transabdominal SWE. The accuracy was comparable in the non-obese porcine model. EUS-SWE may have a higher utility for evaluating small lesions than transabdominal SWE.

Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization.

BACKGROUND: Brugada syndrome (BrS) is an inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac sodium channel gene SCN5A (sodium voltage-gated channel alpha subunit 5) in ≈20% of subjects. We identified a family with 4 individuals diagnosed with BrS harboring the rare G145R missense variant in the cardiac transcription factor TBX5 (T-box transcription factor 5) and no SCN5A variant. METHODS: We generated induced pluripotent stem cells (iPSCs) from 2 members of a family carrying TBX5-G145R and diagnosed with Brugada syndrome. After differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), electrophysiologic characteristics were assessed by voltage- and current-clamp experiments (n=9 to 21 cells per group) and transcriptional differences by RNA sequencing (n=3 samples per group), and compared with iPSC-CMs in which G145R was corrected by CRISPR/Cas9 approaches. The role of platelet-derived growth factor (PDGF)/phosphoinositide 3-kinase (PI3K) pathway was elucidated by small molecule perturbation. The rate-corrected QT (QTc) interval association with serum PDGF was tested in the Framingham Heart Study cohort (n=1893 individuals). RESULTS: TBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced "late" cardiac sodium current (INa), which were entirely corrected by editing G145R to wild-type. Transcriptional profiling and functional assays in genome-unedited and -edited iPSC-CMs showed direct SCN5A down-regulation caused decreased peak INa, and that reduced PDGF receptor (PDGFRA [platelet-derived growth factor receptor α]) expression and blunted signal transduction to PI3K was implicated in enhanced late INa. Tbx5 regulation of the PDGF axis increased arrhythmia risk due to disruption of PDGF signaling and was conserved in murine model systems. PDGF receptor blockade markedly prolonged normal iPSC-CM action potentials and plasma levels of PDGF in the Framingham Heart Study were inversely correlated with the QTc interval (P<0.001). CONCLUSIONS: These results not only establish decreased SCN5A transcription by the TBX5 variant as a cause of BrS, but also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor-mediated PI3K signaling.

Impact of Vitamin D3 Versus Placebo on Cardiac Structure and Function: A Randomized Clinical Trial.

Background Vitamin D supplementation leads to regression of left ventricular (LV) hypertrophy and improves LV function in animal models. However, limited data exist from prospective human studies. We examined whether vitamin D supplementation improved cardiac structure and function in midlife/older individuals in a large randomized trial. Methods and Results The VITAL (Vitamin D and OmegA-3 Trial) was a nationwide double-blind, placebo-controlled randomized trial that tested the effects of vitamin D3 (2000 IU/d) and n-3 fatty acids (1 g/d) on cardiovascular and cancer risk in 25 871 individuals aged ≥50 years. We conducted a substudy of VITAL in which participants underwent echocardiography at baseline and 2 years. Images were interpreted by a blinded investigator at a central core laboratory. The primary end point was change in LV mass. Among 1054 Greater Boston-area participants attending in-clinic visits, we enrolled 1025 into this study. Seventy-nine percent returned for follow-up and had analyzable echocardiograms at both visits. At baseline, the median age was 64 years (interquartile range, 60-69 years), 52% were men, and 43% had hypertension. After 2 years, the change in LV mass did not significantly differ between the vitamin D and placebo arms (median +1.4 g versus +2.6 g, respectively; P=0.32). Changes in systolic and diastolic LV function also did not differ significantly between arms. There were no significant changes in cardiac structure and function between the n-3 fatty acids and placebo arms. Conclusions Among adults aged ≥50 years, neither vitamin D3 nor n-3 fatty acids supplementation had significant effects on cardiac structure and function after 2 years. Registration URL: https://clinicaltrials.gov/; Unique identifiers: NCT01169259 (VITAL) and NCT01630213 (VITAL-Echo).

Plasma metabolomic signatures of obesity and risk of type 2 diabetes.

OBJECTIVE: The mechanisms linking obesity to type 2 diabetes (T2D) are not fully understood. This study aimed to identify obesity-related metabolomic signatures (MESs) and evaluated their relationships with incident T2D. METHODS: In a nested case-control study of 2076 Chinese adults, 140 plasma metabolites were measured at baseline, linear regression was applied with the least absolute shrinkage and selection operator to identify MESs for BMI and waist circumference (WC), and conditional logistic regression was applied to examine their associations with T2D risk. RESULTS: A total of 32 metabolites associated with BMI or WC were identified and validated, among which 14 showed positive associations and 3 showed inverse associations with T2D; 8 and 18 metabolites were selected to build MESs for BMI and WC, respectively. Both MESs showed strong linear associations with T2D: odds ratio (95% CI) comparing extreme quartiles was 4.26 (2.00-9.06) for BMI MES and 9.60 (4.22-21.88) for WC MES (both p-trend < 0.001). The MES-T2D associations were particularly evident among individuals with normal WC: odds ratio (95% CI) reached 6.41 (4.11-9.98) for BMI MES and 10.38 (6.36-16.94) for WC MES. Adding MESs to traditional risk factors and plasma glucose improved C statistics from 0.79 to 0.83 (p < 0.001). CONCLUSIONS: Multiple obesity-related metabolites and MESs strongly associated with T2D in Chinese adults were identified.

Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals.

Integrating genetic information with metabolomics has provided new insights into genes affecting human metabolism. However, gene-metabolite integration has been primarily studied in individuals of European Ancestry, limiting the opportunity to leverage genomic diversity for discovery. In addition, these analyses have principally involved known metabolites, with the majority of the profiled peaks left unannotated. Here, we perform a whole genome association study of 2,291 metabolite peaks (known and unknown features) in 2,466 Black individuals from the Jackson Heart Study. We identify 519 locus-metabolite associations for 427 metabolite peaks and validate our findings in two multi-ethnic cohorts. A significant proportion of these associations are in ancestry specific alleles including findings in APOE, TTR and CD36. We leverage tandem mass spectrometry to annotate unknown metabolites, providing new insight into hereditary diseases including transthyretin amyloidosis and sickle cell disease. Our integrative omics approach leverages genomic diversity to provide novel insights into diverse cardiometabolic diseases.

Genetic Architecture of Plasma Alpha-Aminoadipic Acid Reveals a Relationship With High-Density Lipoprotein Cholesterol.

Background Elevated plasma levels of alpha-aminoadipic acid (2-AAA) have been associated with the development of type 2 diabetes and atherosclerosis. However, the nature of the association remains unknown. Methods and Results We identified genetic determinants of plasma 2-AAA through meta-analysis of genome-wide association study data in 5456 individuals of European, African, and Asian ancestry from the Framingham Heart Study, Diabetes Prevention Program, Jackson Heart Study, and Shanghai Women's and Men's Health Studies. No single nucleotide polymorphisms reached genome-wide significance across all samples. However, the top associations from the meta-analysis included single-nucleotide polymorphisms in the known 2-AAA pathway gene DHTKD1, and single-nucleotide polymorphisms in genes involved in mitochondrial respiration (NDUFS4) and macrophage function (MSR1). We used a Mendelian randomization instrumental variable approach to evaluate relationships between 2-AAA and cardiometabolic phenotypes in large disease genome-wide association studies. Mendelian randomization identified a suggestive inverse association between increased 2-AAA and lower high-density lipoprotein cholesterol (P=0.005). We further characterized the genetically predicted relationship through measurement of plasma 2-AAA and high-density lipoprotein cholesterol in 2 separate samples of individuals with and without cardiometabolic disease (N=98), and confirmed a significant negative correlation between 2-AAA and high-density lipoprotein (rs=-0.53, P<0.0001). Conclusions 2-AAA levels in plasma may be regulated, in part, by common variants in genes involved in mitochondrial and macrophage function. Elevated plasma 2-AAA associates with reduced levels of high-density lipoprotein cholesterol. Further mechanistic studies are required to probe this as a possible mechanism linking 2-AAA to future cardiometabolic risk.