National Heart, Lung, and Blood Institute (NHLBI) Strategy for Addressing Health Disparities

Throughout its history, the NHLBI has been a leader in conducting and supporting research to alleviate the health disparities that exist between various segments of the U.S. population, and its outstanding efforts in this area have been publicly recognized in Congressional hearings. Projects with a strong minority component have been initiated so that comparisons may be made between various populations. These projects have produced a wealth of information that enable identification of health disparities and provide clues about their causes

Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10⁻⁹. We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10⁻⁴⁰) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10⁻⁴). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.National Heart, Lung, and Blood Institute (HHSN268201100005C)National Heart, Lung, and Blood Institute (HHSN268201100006C)National Heart, Lung, and Blood Institute (HHSN268201100007C)National Heart, Lung, and Blood Institute (HHSN268201100008C)National Heart, Lung, and Blood Institute (HHSN268201100009C)National Heart, Lung, and Blood Institute (HHSN268201100010C)National Heart, Lung, and Blood Institute (HHSN268201100011C)National Heart, Lung, and Blood Institute (HHSN268201100012C)National Heart, Lung, and Blood Institute (N01-HC-55015)National Heart, Lung, and Blood Institute (N01-HC-55016)National Heart, Lung, and Blood Institute (N01-HC-55018)National Heart, Lung, and Blood Institute (N01-HC-55019)National Heart, Lung, and Blood Institute (N01-HC-55020)National Heart, Lung, and Blood Institute (N01-HC-55021)National Heart, Lung, and Blood Institute (N01-HC-55022)National Heart, Lung, and Blood Institute (R01HL087641)National Heart, Lung, and Blood Institute (R01HL59367)National Heart, Lung, and Blood Institute (R01HL086694)National Human Genome Research Institute (U.S.) (U01HG004402)United States. National Institutes of Health (HHSN268200625226C)United States. National Institutes of Health (UL1RR025005)National Heart, Lung, and Blood Institute (HHSN268201200036C)National Heart, Lung, and Blood Institute (N01HC55222)National Heart, Lung, and Blood Institute (HHSN268200800007C)National Heart, Lung, and Blood Institute (N01HC85079)National Heart, Lung, and Blood Institute (N01HC85080)National Heart, Lung, and Blood Institute (N01HC85081)National Heart, Lung, and Blood Institute (N01HC85082)National Heart, Lung, and Blood Institute (N01HC85083)National Heart, Lung, and Blood Institute (N01HC85086)National Heart, Lung, and Blood Institute (U01HL080295)National Science Foundation (U.S.) (R01HL087652)National Heart, Lung, and Blood Institute (R01HL105756)National Heart, Lung, and Blood Institute (R01HL103612)National Heart, Lung, and Blood Institute (R01HL120393)National Institute on Aging (R01AG023629)National Center for Advancing Translational Sciences (U.S.) (UL1TR000124)National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (DK063491)National Heart, Lung, and Blood Institute (N01-HC-25195)National Heart, Lung, and Blood Institute (2K24HL04334)National Heart, Lung, and Blood Institute (R01HL077477)National Heart, Lung, and Blood Institute (R01HL093328)National Heart, Lung, and Blood Institute (NIH R01HL105993)National Institute on Aging (N01AG62101)National Heart, Lung, and Blood Institute (N01AG62103)National Heart, Lung, and Blood Institute (N01AG62106)National Institute on Aging (1R01AG032098-01A1)United States. National Institutes of Health (HHSN268200782096C)National Cancer Institute (U.S.) (CA-34944)National Cancer Institute (U.S.) (CA-40360)National Cancer Institute (U.S.) (CA-097193)National Heart, Lung, and Blood Institute (HL-26490)National Heart, Lung, and Blood Institute (HL-34595

JACC Cardiovasc Imaging

OBJECTIVESThe study evaluated whether lipoprotein apheresis produces immediate changes in resting perfusion in subjects with severe hypercholesterolemia, and whether there is a difference in the response between peripheral and coronary microcirculations.BACKGROUNDLipoprotein apheresis is used in patients with severe hypercholesterolemia to reduce plasma levels of low-density lipoprotein cholesterol.METHODSQuantitative contrast-enhanced ultrasound perfusion imaging of the myocardium at rest and skeletal muscle at rest and during calibrated contractile exercise was performed before and immediately after lipoprotein apheresis in 8 subjects with severe hypercholesterolemia, 7 of whom had a diagnosis of familial hypercholesterolemia. Myocardial perfusion imaging was also performed in 14 normal control subjects. Changes in myocardial work and left ventricular function were assessed by echocardiography. Ex vivo ovine coronary and femoral artery ring tension assays were assessed in the presence of pre- and post-apheresis plasma.RESULTSApheresis acutely decreased low-density lipoprotein cholesterol (234.9 \ub1 103.2 mg/dl vs. 67.1 \ub1 49.5 mg/dl; p < 0.01) and oxidized phospholipid on apolipoprotein B-100 (60.2 \ub1 55.2 nmol/l vs. 47.0 \ub1 24.5 nmol/l; p = 0.01), and acutely increased resting myocardial perfusion (55.1 [95% confidence interval: 77.2 to 73.1] vs. 135 [95% confidence interval: 81.2 to 189.6] IU/s; p = 0.01), without changes in myocardial work. Myocardial longitudinal strain improved in those subjects with reduced pre-apheresis function. Skeletal muscle perfusion at rest and during contractile exercise was unchanged by apheresis. Acetylcholine-mediated dilation of ex vivo ovine coronary but not femoral arteries was impaired in pre-apheresis plasma and was completely reversed in post-apheresis plasma.CONCLUSIONSLipoprotein apheresis produces an immediate improvement in coronary microvascular function, which increases myocardial perfusion and normalizes endothelial-dependent vasodilation. These changes are not observed in the periphery. (Acute Microvascular Changes With LDL Apheresis; NCT02388633).P51 OD011092/ODCDC CDC HHS/Office of the Director/United StatesR35 HL135737/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL106579/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesP01 HL136275/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL111969/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesT32 HL094294/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL128550/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL078610/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL136098/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL130046/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL119828/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL120046/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesK08 HL133493/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States2020-08-01T00:00:00Z29909101PMC64580986559vault:3367

Thorax

BackgroundTraditional metrics of lung disease such as those derived from spirometry and static single-volume CT images are used to explain respiratory morbidity in patients with chronic obstructive pulmonary disease (COPD), but are insufficient. We hypothesized that the mean Jacobian determinant, a measure of local lung expansion and contraction with respiration, would contribute independently to clinically relevant functional outcomes.MethodsWe applied image registration techniques to paired inspiratory-expiratory CT scans and derived the Jacobian determinant of the deformation field between the two lung volumes to map local volume change with respiration. We analyzed 490 participants with COPD with multivariable regression models to assess strengths of association between traditional CT metrics of disease and the Jacobian determinant with respiratory morbidity including dyspnea (mMRC), St Georges Respiratory Questionnaire (SGRQ) score, six-minute walk distance (6MWD), and the BODE index, as well as all-cause mortality.ResultsThe Jacobian determinant was significantly associated with SGRQ (adjusted regression co-efficient \u3b2 = 1211.75,95%CI 1221.6 to 121.7;p=0.020), and with 6MWD (\u3b2=321.15, 95%CI 134.1 to 508.1;p<0.001), independent of age, sex, race, body-mass-index, FEV1, smoking pack-years, CT emphysema, CT gas trapping, airway wall thickness, and CT scanner protocol. The mean Jacobian determinant was also independently associated with the BODE index (\u3b2= 120.41, 95%CI 120.80 to 120.02; p = 0.039), and mortality on follow-up (adjusted hazards ratio = 4.26, 95%CI = 0.93 to 19.23; p = 0.064).ConclusionBiomechanical metrics representing local lung expansion and contraction improve prediction of respiratory morbidity and mortality and offer additional prognostic information beyond traditional measures of lung function and static single-volume CT metrics.R01 HL079406/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesT32 HL007749/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL089897/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesS10 OD018526/ODCDC CDC HHS/Office of the Director/United StatesR01 HL112986/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesP30 ES005605/NIEHS NIH HHS/National Institute of Environmental Health Sciences/United StatesK23 HL128936/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesU01 HL089897/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesK23 HL133438/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL089856/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesU01 HL089856/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesP30 DK054759/NIDDK NIH HHS/National Institute of Diabetes and Digestive and Kidney Diseases/United States2018-05-01T00:00:00Z28044005PMC5526353654

Propionate functions as a feeding state-dependent regulatory metabolite to counter proinflammatory signaling linked to nutrient load and obesity.

The authors thank Drs. Antonio Murgia and Ben McNally of the University of Cambridge Biochemistry Department for their contributions to metabolomics and lipidomic data processing. They thank and acknowledge the assistance of the National Heart, Lung, and Blood Institute DNA Sequencing and Genomics Core in performing the RNA library sequencing and the National Heart, Lung, and Blood Institute Flow Cytometry Core for performing the flow cytometry.Peer reviewe

J Physiol

Cardiac electrophysiology and Ca| handling change rapidly during the fight-or-flight response to meet physiological demands. Despite dramatic differences in cardiac electrophysiology, the cardiac fight-or-flight response is highly conserved across species. In this study, we performed physiological sympathetic nerve stimulation (SNS) while optically mapping cardiac action potentials and intracellular Ca| transients in innervated mouse and rabbit hearts. Despite similar heart rate and Ca| handling responses between mouse and rabbit hearts, we found notable species differences in spatio-temporal repolarization dynamics during SNS. Species-specific computational models revealed that these electrophysiological differences allowed for enhanced Ca| handling (i.e. enhanced inotropy) in each species, suggesting that electrophysiological responses are fine-tuned across species to produce optimal cardiac fight-or-flight responses.|Sympathetic activation of the heart results in positive chronotropy and inotropy, which together rapidly increase cardiac output. The precise mechanisms that produce the electrophysiological and Ca| handling changes underlying chronotropic and inotropic responses have been studied in detail in isolated cardiac myocytes. However, few studies have examined the dynamic effects of physiological sympathetic nerve activation on cardiac action potentials (APs) and intracellular Ca| transients (CaTs) in the intact heart. Here, we performed bilateral sympathetic nerve stimulation (SNS) in fully innervated, Langendorff-perfused rabbit and mouse hearts. Dual optical mapping with voltage- and Ca| -sensitive dyes allowed for analysis of spatio-temporal AP and CaT dynamics. The rabbit heart responded to SNS with a monotonic increase in heart rate (HR), monotonic decreases in AP and CaT duration (APD, CaTD), and a monotonic increase in CaT amplitude. The mouse heart had similar HR and CaT responses; however, a pronounced biphasic APD response occurred, with initial prolongation (50.9\ua0\ub1\ua05.1\ua0ms at t\ua0=\ua00\ua0s vs. 60.6\ua0\ub1\ua04.1\ua0ms at t\ua0=\ua015\ua0s, P\ua0<\ua00.05) followed by shortening (46.5\ua0\ub1\ua09.1\ua0ms at t\ua0=\ua060\ua0s, P\ua0=\ua0NS vs. t\ua0=\ua00). We determined the biphasic APD response in mouse was partly due to dynamic changes in HR during SNS and was exacerbated by \u3b2-adrenergic activation. Simulations with species-specific cardiac models revealed that transient APD prolongation in mouse allowed for greater and more rapid CaT responses, suggesting more rapid increases in contractility; conversely, the rabbit heart requires APD shortening to produce optimal inotropic responses. Thus, while the cardiac fight-or-flight response is highly conserved between species, the underlying mechanisms orchestrating these effects differ significantly.16GRNT30960054/American Heart Association/K99 HL138160/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL111600/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesUC Davis Academic Federation Professional Development Award (LW)/OT2 OD026580/ODCDC CDC HHS/Office of the Director/United StatesOT2 OD026580/ODCDC CDC HHS/Office of the Director/United StatesR01HL131517/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL131517/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States1OT2OD026580/NIH HHS/National Institutes of Health/United States15SDG24910015/American Heart Association/R01 HL131517/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States1OT2OD023848-01/NIH HHS/National Institutes of Health/United StatesOT2 OD023848/ODCDC CDC HHS/Office of the Director/United States1OT2OD026580-01/NIH HHS/National Institutes of Health/United StatesR01HL141214/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesRG/17/3/32774/British Heart Foundation/United KingdomK99 HL138160/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01HL111600/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL111600/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesK99HL138160/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL141214/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States2020-08-01T00:00:00Z31215643PMC66756326525vault:3359

Cell Metab

Obesity induces lipotoxic cardiomyopathy, a condition in which lipid accumulation in cardiomyocytes causes cardiac dysfunction. Here, we show that glycogen synthase kinase-3\u3b1 (GSK-3\u3b1) mediates lipid accumulation in the heart. Fatty acids (FAs) upregulate GSK-3\u3b1, which phosphorylates PPAR\u3b1 at Ser280 in the ligand-binding domain (LBD). This modification ligand independently enhances transcription of a subset of PPAR\u3b1 targets, selectively stimulating FA uptake and storage, but not oxidation, thereby promoting lipid accumulation. Constitutively active GSK-3\u3b1, but not GSK-3\u3b2, was sufficient to drive PPAR\u3b1 signaling, while cardiac-specific knockdown of GSK-3\u3b1, but not GSK-3\u3b2, or replacement of\ua0PPAR\u3b1 Ser280 with Ala conferred resistance to lipotoxicity in the heart. Fibrates, PPAR\u3b1 ligands, inhibited phosphorylation of PPAR\u3b1 at Ser280 by inhibiting the interaction of GSK-3\u3b1 with the LBD of PPAR\u3b1, thereby reversing lipotoxic cardiomyopathy. These results suggest that GSK-3\u3b1 promotes lipid anabolism through PPAR\u3b1-Ser280 phosphorylation, which underlies the development of lipotoxic cardiomyopathy in the context of obesity.R01 HL102738/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL091469/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL138720/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL067724/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesR01 HL112330/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United StatesS10 OD021505/ODCDC CDC HHS/Office of the Director/United StatesR01 AG023039/NIA NIH HHS/National Institute on Aging/United States2020-05-07T00:00:00Z30745182PMC66772696525vault:3360

The Association of Hemoglobin A1c With Incident Heart Failure Among People Without Diabetes: The Atherosclerosis Risk in Communities Study

OBJECTIVE-This study sought to investigate an association of HbA1c (A1C) with incident heart failure among individuals without diabetes and compare it to fasting glucose. RESEARCH DESIGN AND METHODS-We studied 11,057 participants of the Atherosclerosis Risk in Communities (ARIC) Study without heart failure or diabetes at baseline and estimated hazard ratios of incident heart failure by categories of A1C (<5.0, 5.0-5.4 [reference], 5 5-59, and 6.0-6.4%) and fasting glucose (<90, 90-99 [reference], 100-109, and 110-125 mg/dl) using Cox proportional hazards models. RESULTS-A total of 841 cases of incident heart failure hospitalization or deaths (International Classification of Disease, 9th/10th Revision, 428/150) occurred during a median follow-up of 14.1 years (incidence rate 5.7 per 1,000 person-years). After the adjustment for covariates including fasting glucose, the hazard ratio of incident heart failure was higher in individuals with A1C 6.0-6.4% (1.40 [95% CI, 1 09-1.79]) and 5.5-6.0% (1.16 [0.98-1 37]) as compared with the reference group. Similar results were observed when adjusting for insulin level or limiting to heart failure cases without preceding coronary events or developed diabetes during follow-up. In contrast, elevated fasting glucose was not associated with heart failure after adjustment for covariates and A1C. Similar findings were observed when the top quartile (A1C, 5.7-6.4%, and fasting glucose, 108-125 mg/dl) was compared with the lowest quartile (<5 2% and <95 mg/dl, respectively). CONCLUSIONS-Elevated A1C (>= 5.5-6 0%) was associated with incident heart failure in a middle-aged population without diabetes, suggesting that chronic hyperglycemia prior to the development of diabetes contributes to development of heart failure. Diabetes 59:2020-2026, 2010National Heart, Lung, and Blood Institute (NHLBI/NIH)[N01-HC-55015]National Heart, Lung, and Blood Institute (NHLBI/NIH)[N01-HC-55016]National Heart, Lung, and Blood Institute (NHLBI/NIH)[N01-HC-55018]National Heart, Lung, and Blood Institute (NHLBI/NIH)[N01-HC-55019]National Heart, Lung, and Blood Institute (NHLBI/NIH)[N01-HC-55020]National Heart, Lung, and Blood Institute (NHLBI/NIH)[N01-HC-55021]National Heart, Lung, and Blood Institute (NHLBI/NIH)[N01-HC-55022]NIH/NIDDK[R21-DK-080294]NIH/NIDDK[K01-DK-076595]NIH/NIDDK[R01-DK-076770]NIH/NHLBI[5T32-HL-007024

Adversarial consistency for single domain generalization in medical image segmentation

7R01HL141813-06 - NIH/National Heart, Lung, and Blood Institute; NIH/National Institutes of HealthFirst author draf

Dividing and conquering a BlackBox to a mixture of interpretable models: route, interpret, repeat

7R01HL141813-06 - NIH/National Heart, Lung, and Blood Institute; Optum Labs, Inc.; NIH/National Institutes of HealthAccepted manuscrip