Publications by authors named "Jeffrey Brandimarto"

17 Publications

  • Page 1 of 1

Noncanonical WNT Activation in Human Right Ventricular Heart Failure.

Front Cardiovasc Med 2020 7;7:582407. Epub 2020 Oct 7.

Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

No medical therapies exist to treat right ventricular (RV) remodeling and RV failure (RVF), in large part because molecular pathways that are specifically activated in pathologic human RV remodeling remain poorly defined. Murine models have suggested involvement of Wnt signaling, but this has not been well-defined in human RVF. Using a candidate gene approach, we sought to identify genes specifically expressed in human pathologic RV remodeling by assessing the expression of 28 WNT-related genes in the RVs of three groups: explanted nonfailing donors (NF, = 29), explanted dilated and ischemic cardiomyopathy, obtained at the time of cardiac transplantation, either with preserved RV function (pRV, = 78) or with RVF ( = 35). We identified the noncanonical WNT receptor ROR2 as transcriptionally strongly upregulated in RVF compared to pRV and NF (Benjamini-Hochberg adjusted < 0.05). ROR2 protein expression correlated linearly to mRNA expression ( = 0.41, = 8.1 × 10) among all RVs, and to higher right atrial to pulmonary capillary wedge ratio in RVF ( = 0.40 = 3.0 × 10). Utilizing Masson's trichrome and ROR2 immunohistochemistry, we identified preferential ROR2 protein expression in fibrotic regions by both cardiomyocytes and noncardiomyocytes. We compared RVF with high and low ROR2 expression, and found that high ROR2 expression was associated with increased expression of the WNT5A/ROR2/Ca responsive protease calpain-μ, cleavage of its target FLNA, and FLNA phosphorylation, another marker of activation downstream of ROR2. ROR2 protein expression as a continuous variable, correlated strongly to expression of calpain-μ ( = 0.25), total FLNA ( = 0.67), calpain cleaved FLNA ( = 0.32) and FLNA phosphorylation ( = 0.62, < 0.05 for all). We demonstrate robust reactivation of a fetal WNT gene program, specifically its noncanonical arm, in human RVF characterized by activation of ROR2/calpain mediated cytoskeleton protein cleavage.
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http://dx.doi.org/10.3389/fcvm.2020.582407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575695PMC
October 2020

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Nat Commun 2020 01 9;11(1):163. Epub 2020 Jan 9.

Department of Biostatistics, University of Liverpool, Liverpool, UK.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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http://dx.doi.org/10.1038/s41467-019-13690-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952380PMC
January 2020

Tunable and Reversible Substrate Stiffness Reveals a Dynamic Mechanosensitivity of Cardiomyocytes.

ACS Appl Mater Interfaces 2019 Jun 30;11(23):20603-20614. Epub 2019 May 30.

Department of Physics , Bryn Mawr College , Bryn Mawr , Pennsylvania 19010 , United States.

New directions in material applications have allowed for the fresh insight into the coordination of biophysical cues and regulators. Although the role of the mechanical microenvironment on cell responses and mechanics is often studied, most analyses only consider static environments and behavior, however, cells and tissues are themselves dynamic materials that adapt in myriad ways to alterations in their environment. Here, we introduce an approach, through the addition of magnetic inclusions into a soft poly(dimethylsiloxane) elastomer, to fabricate a substrate that can be stiffened nearly instantaneously in the presence of cells through the use of a magnetic gradient to investigate short-term cellular responses to dynamic stiffening or softening. This substrate allows us to observe time-dependent changes, such as spreading, stress fiber formation, Yes-associated protein translocation, and sarcomere organization. The identification of temporal dynamic changes on a short time scale suggests that this technology can be more broadly applied to study targeted mechanisms of diverse biologic processes, including cell division, differentiation, tissue repair, pathological adaptations, and cell-death pathways. Our method provides a unique in vitro platform for studying the dynamic cell behavior by better mimicking more complex and realistic microenvironments. This platform will be amenable to future studies aimed at elucidating the mechanisms underlying mechanical sensing and signaling that influence cellular behaviors and interactions.
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http://dx.doi.org/10.1021/acsami.9b02446DOI Listing
June 2019

Cardioprotective Effects of MTSS1 Enhancer Variants.

Circulation 2019 04;139(17):2073-2076

Division of Cardiovascular Medicine and Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (M.P.P., X.W., R.H., J.B., K.B.M., K.M., T.P.C.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.037939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510256PMC
April 2019

Thyroid Dysfunction in Heart Failure and Cardiovascular Outcomes.

Circ Heart Fail 2018 12;11(12):e005266

Division of Endocrinology, Diabetes, and Metabolism (L.K., A.R.C.) at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

Background: The effects of thyroid dysfunction in patients with preexisting heart failure have not been adequately studied. We examined the prevalence of thyroid dysfunction and associations with cardiovascular outcomes in a large, prospective cohort of outpatients with preexisting heart failure.

Methods And Results: We examined associations between thyroid dysfunction and New York Heart Association class, atrial fibrillation, and a composite end point of ventricular assist device placement, heart transplantation, or death in 1365 participants with heart failure enrolled in the Penn Heart Failure Study. Mean age was 57 years, 35% were women, and the majority had New York Heart Association class II (45%) or III (32%) symptoms. More severe heart failure was associated with higher thyroid-stimulating hormone (TSH), higher free thyroxine (FT4), and lower total triiodothyronine (TT3) concentrations ( P<0.001 all models). Atrial fibrillation was positively associated with higher levels of FT4 alone ( P≤0.01 all models). There were 462 composite end points over a median 4.2 years of follow-up. In adjusted models, compared with euthyroidism, subclinical hypothyroidism (TSH 4.51-19.99 mIU/L with normal FT4) was associated with an increased risk of the composite end point overall (hazard ratio, 1.82; 95% CI, 1.27-2.61; P=0.001) and in the subgroup with TSH ≥7.00 mIU/L (hazard ratio, 3.25; 95% CI, 1.96-5.39; P<0.001), but not in the subgroup with TSH 4.51-6.99 mIU/L (hazard ratio, 1.26; 95% CI, 0.78-2.06; P=0.34). Isolated low T3 was also associated with the composite end point (hazard ratio, 2.12; 95% CI, 1.65-2.72; P<0.001).

Conclusions: In patients with preexisting heart failure, subclinical hypothyroidism with TSH ≥7 mIU/L and isolated low T3 levels are associated with poor prognosis. Clinical trials are needed to explore therapeutic effects of T4 and T3 administration in heart failure.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.118.005266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352308PMC
December 2018

Increased Afterload Augments Sunitinib-Induced Cardiotoxicity in an Engineered Cardiac Microtissue Model.

JACC Basic Transl Sci 2018 Apr 30;3(2):265-276. Epub 2018 May 30.

Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Sunitinib, a multitargeted oral tyrosine kinase inhibitor, used widely to treat solid tumors, results in hypertension in up to 47% and left ventricular dysfunction in up to 19% of treated individuals. The relative contribution of afterload toward inducing cardiac dysfunction with sunitinib treatment remains unknown. We created a preclinical model of sunitinib cardiotoxicity using engineered microtissues that exhibited cardiomyocyte death, decreases in force generation, and spontaneous beating at clinically relevant doses. Simulated increases in afterload augmented sunitinib cardiotoxicity in both rat and human microtissues, which suggest that antihypertensive therapy may be a strategy to prevent left ventricular dysfunction in patients treated with sunitinib.
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http://dx.doi.org/10.1016/j.jacbts.2017.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059907PMC
April 2018

Genetic Reduction in Left Ventricular Protein Kinase C-α and Adverse Ventricular Remodeling in Human Subjects.

Circ Genom Precis Med 2018 03;11(3):e001901

From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana-Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Germany (F.R., M.S.); INSERM UMRS1166-IACN, Hôpital Pitié-Salpêtrière, Paris, France (E.V., F.C.); Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, MA (H.L.); Department of Epidemiology, University of Washington, Seattle (N.L.S.); Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands (J.F.F.); Boston University School of Medicine, MA (R.S.V.); Department of Cardiology, University of Groningen, University Medical Center Groningen, the Netherlands (P.v.d.H.); Medical and Population Genetics Program, Broad Institute, Cambridge, MA (C.N.-C.); Center for Applied Genomics, Children's Hospital of Philadelphia, PA (J.L., C.E.K., H.H.); Center for Bioinformatics and Computational Biology, University of Maryland, College Park (S.H.); Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, CA (E.A.A.); Department of Cardiovascular Medicine, Cleveland Clinic, OH (C.S.M., W.H.W.T.); and Howard Hughes Medical Institute and Cincinnati Children's Hospital Medical Center, OH (M.M., J.D.M.).

Background: Inhibition of PKC-α (protein kinase C-α) enhances contractility and cardioprotection in animal models, but effects in humans are unknown. Genotypes at rs9912468 strongly associate with expression in the left ventricle, enabling genetic approaches to measure effects of reduced PKC-α in human populations.

Methods And Results: We analyzed the expression quantitative trait locus for marked by rs9912468 using 313 left ventricular specimens from European Ancestry patients. The forward strand minor allele (G) at rs9912468 is associated with reduced PKC-α transcript abundance (1.7-fold reduction in minor allele homozygotes, =1×10). This association was cardiac specific in expression quantitative trait locus data sets that span 16 human tissues. Cardiac epigenomic data revealed a predicted enhancer in complete (=1.0) linkage disequilibrium with rs9912468 within intron 2 of We cloned this region and used reporter constructs to verify cardiac-specific enhancer activity in vitro in cardiac and noncardiac cells and in vivo in zebrafish. The enhancer contains 2 common genetic variants and 4 haplotypes; the haplotype correlated with the rs9912468 PKC-α-lowering allele (G) showed lowest activity. In contrast to previous reports in animal models, the PKC-α-lowering allele is associated with adverse left ventricular remodeling (higher mass, larger diastolic dimension), reduced fractional shortening, and higher risk of dilated cardiomyopathy in human populations.

Conclusions: These findings support PKC-α as a regulator of the human heart but suggest that PKC-α inhibition may adversely affect the left ventricle depending on timing and duration. Pharmacological studies in human subjects are required to discern potential benefits and harms of PKC-α inhibitors as an approach to treat heart disease.
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http://dx.doi.org/10.1161/CIRCGEN.117.001901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858599PMC
March 2018

Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction.

Circ Res 2017 Mar 7;120(7):1151-1161. Epub 2016 Dec 7.

From the Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia (P.Z., V.T., H.S.-C., M.B., J.A.B., S.V., K.B.M., T.P.C., J.A.C.); Rowan University School of Osteopathic Medicine, Stratford, NJ (L.T.); Children's Hospital of Philadelphia Research Institute, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); Office of Nursing Research, School of Nursing, University of Pennsylvania, Philadelphia (J.C.); Departments of Kinesiology, Anatomy, and Physiology, Kansas State University, Manhattan (D.C.P.).

Rationale: Nitrate-rich beetroot juice has been shown to improve exercise capacity in heart failure with preserved ejection fraction, but studies using pharmacological preparations of inorganic nitrate are lacking.

Objectives: To determine (1) the dose-response effect of potassium nitrate (KNO) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO in heart failure with preserved ejection fraction.

Methods And Results: We randomized 12 subjects with heart failure with preserved ejection fraction to oral KNO (n=9) or potassium chloride (n=3). Subjects received 6 mmol twice daily during week 1, followed by 6 mmol thrice daily during week 2. Supine cycle ergometry was performed at baseline (visit 1) and after each week (visits 2 and 3). Quality of life was assessed with the Kansas City Cardiomyopathy Questionnaire. The primary efficacy outcome, peak O-uptake, did not significantly improve (=0.13). Exploratory outcomes included exercise duration and quality of life. Exercise duration increased significantly with KNO (visit 1: 9.87, 95% confidence interval [CI] 9.31-10.43 minutes; visit 2: 10.73, 95% CI 10.13-11.33 minute; visit 3: 11.61, 95% CI 11.05-12.17 minutes; =0.002). Improvements in the Kansas City Cardiomyopathy Questionnaire total symptom (visit 1: 58.0, 95% CI 52.5-63.5; visit 2: 66.8, 95% CI 61.3-72.3; visit 3: 70.8, 95% CI 65.3-76.3; =0.016) and functional status scores (visit 1: 62.2, 95% CI 58.5-66.0; visit 2: 68.6, 95% CI 64.9-72.3; visit 3: 71.1, 95% CI 67.3-74.8; =0.01) were seen after KNO. Pronounced elevations in trough levels of nitric oxide metabolites occurred with KNO (visit 2: 199.5, 95% CI 98.7-300.2 μmol/L; visit 3: 471.8, 95% CI 377.8-565.8 μmol/L) versus baseline (visit 1: 38.0, 95% CI 0.00-132.0 μmol/L; <0.001). KNO did not lead to clinically significant hypotension or methemoglobinemia. After 6 mmol of KNO, systolic blood pressure was reduced by a maximum of 17.9 (95% CI -28.3 to -7.6) mm Hg 3.75 hours later. Peak nitric oxide metabolites concentrations were 259.3 (95% CI 176.2-342.4) μmol/L 3.5 hours after ingestion, and the median half-life was 73.0 (interquartile range 33.4-232.0) minutes.

Conclusions: KNO is potentially well tolerated and improves exercise duration and quality of life in heart failure with preserved ejection fraction. This study reinforces the efficacy of KNO and suggests that larger randomized trials are warranted.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02256345.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.309832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376233PMC
March 2017

Effect of Heart Failure With Preserved Ejection Fraction on Nitric Oxide Metabolites.

Am J Cardiol 2016 Dec 15;118(12):1855-1860. Epub 2016 Sep 15.

Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

Endothelial function may be deranged in heart failure with preserved ejection fraction (HFpEF). Serum NO-derived metabolites (NO) might provide a biochemical surrogate of endothelial function in patients with heart failure (HF). We measured serum NO in 415 participants in the Penn HF Study. Participants with HFpEF (n = 82) and those whose EF had recovered (Recovered-HF, n = 125) were matched 1:1 to heart failure with reduced ejection fraction (HFrEF) participants based on age, gender, race, tobacco use, and eGFR. Serum NO levels were quantified after chemical reduction coupled with gas-phase chemiluminescence detection. After adjustment for matching covariates and BMI, HFpEF (34.5 μM; interquartile range [IQR] 25.0, 51.5) participants had lower NO levels than HFrEF (41.0 μM; IQR 28.3, 58.0; ratio of HFpEF:HFrEF 0.82, 95% confidence interval [CI] 0.67 to 0.99; p = 0.04), which further decreased when adjusted for covariates that affect endothelial function (ratio 0.79, 95% CI 0.65 to 0.98; p = 0.03). There were no differences between HFrEF (34.0; IQR 25.3, 49.0) and matched Recovered-HF (36.0 μM; IQR 25.0, 55.0) or HFpEF and Recovered-HF. Age (+21%/10-year increase, p <0.001) and black race (-28%, p = 0.03) associated with NO in HFpEF, whereas age (+11%/10-year increase, p = 0.03), current tobacco use (+67%, p = 0.01), and eGFR (p = 0.01) associated with NO in Recovered-HF. In conclusion, HFpEF participants have reduced NO compared with HFrEF in this matched cohort. This might suggest either compromised endothelial function or poor dietary intake. Black race was associated with lower NO in HFpEF.
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http://dx.doi.org/10.1016/j.amjcard.2016.08.077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127733PMC
December 2016

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

PLoS Genet 2016 05 5;12(5):e1006034. Epub 2016 May 5.

The Framingham Heart Study, Framingham, Massachusetts, United States of America.

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.
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http://dx.doi.org/10.1371/journal.pgen.1006034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858216PMC
May 2016

Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure.

Circulation 2016 Feb 27;133(8):706-16. Epub 2016 Jan 27.

From Cardiovascular Institute University of Pennsylvania Perelman School of Medicine, Smilow Translational Research Center, Philadelphia, PA (K.C.B., J.B., A.J., K.B.M., J.E.R.); A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA (N.W.S.); and Center of Cancer Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (M.A., C.M., A.J.W., L.L.W., I.A.B.).

Background: The failing human heart is characterized by metabolic abnormalities, but these defects remains incompletely understood. In animal models of heart failure there is a switch from a predominance of fatty acid utilization to the more oxygen-sparing carbohydrate metabolism. Recent studies have reported decreases in myocardial lipid content, but the inclusion of diabetic and nondiabetic patients obscures the distinction of adaptations to metabolic derangements from adaptations to heart failure per se.

Methods And Results: We performed both unbiased and targeted myocardial lipid surveys using liquid chromatography-mass spectroscopy in nondiabetic, lean, predominantly nonischemic, advanced heart failure patients at the time of heart transplantation or left ventricular assist device implantation. We identified significantly decreased concentrations of the majority of myocardial lipid intermediates, including long-chain acylcarnitines, the primary subset of energetic lipid substrate for mitochondrial fatty acid oxidation. We report for the first time significantly reduced levels of intermediate and anaplerotic acyl-coenzyme A (CoA) species incorporated into the Krebs cycle, whereas the myocardial concentration of acetyl-CoA was significantly increased in end-stage heart failure. In contrast, we observed an increased abundance of ketogenic β-hydroxybutyryl-CoA, in association with increased myocardial utilization of β-hydroxybutyrate. We observed a significant increase in the expression of the gene encoding succinyl-CoA:3-oxoacid-CoA transferase, the rate-limiting enzyme for myocardial oxidation of β-hydroxybutyrate and acetoacetate.

Conclusions: These findings indicate increased ketone utilization in the severely failing human heart independent of diabetes mellitus, and they support the role of ketone bodies as an alternative fuel and myocardial ketone oxidation as a key metabolic adaptation in the failing human heart.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.017545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779339PMC
February 2016

Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure.

J Am Coll Cardiol 2015 Dec;66(22):2522-33

Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California. Electronic address:

Background: The genetic determinants of heart failure (HF) and response to medical therapy remain unknown. We hypothesized that identifying genetic variants of HF that associate with response to medical therapy would elucidate the genetic basis of cardiac function.

Objectives: This study sought to identify genetic variations associated with response to HF therapy.

Methods: This study compared extremes of response to medical therapy in 866 HF patients using a genome-wide approach that informed the systems-based design of a customized single nucleotide variant array. The effect of genotype on gene expression was measured using allele-specific luciferase reporter assays. Candidate gene transcription-deficient mice underwent echocardiography and treadmill exercise. The ability of the target gene agonist to rescue mice from chemically-induced HF was assessed with echocardiography.

Results: Of 866 HF patients, 136 had an ejection fraction improvement of 20% attributed to resynchronization (n = 83), revascularization (n = 7), tachycardia resolution (n = 2), alcohol cessation (n = 1), or medications (n = 43). Those with the minor allele for rs7767652, upstream of hypocretin (orexin) receptor-2 (HCRTR2), were less likely to have improved left ventricular function (odds ratio: 0.40 per minor allele; p = 3.29 × 10(-5)). In a replication cohort of 798 patients, those with a minor allele for rs7767652 had a lower prevalence of ejection fraction >35% (odds ratio: 0.769 per minor allele; p = 0.021). In an HF model, HCRTR2-deficient mice exhibited poorer cardiac function, worse treadmill exercise capacity, and greater myocardial scarring. Orexin, an HCRTR2 agonist, rescued function in this HF mouse model.

Conclusions: A systems approach identified a novel genetic contribution to human HF and a promising therapeutic agent efficacious in an HF model.
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http://dx.doi.org/10.1016/j.jacc.2015.09.061DOI Listing
December 2015

Prognostic Value of Galectin-3 for Adverse Outcomes in Chronic Heart Failure.

J Card Fail 2016 Apr 10;22(4):256-62. Epub 2015 Nov 10.

Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Background: Clinical studies have suggested the prognostic value of galectin-3, a marker of fibrosis, in chronic heart failure. However, the specific role of galectin-3, compared with established biomarkers, remains uncertain.

Methods And Results: The Penn Heart Failure Study was an ambulatory heart failure cohort that included 1385 participants with reduced (1141), preserved (106), and recovered (138) left ventricular ejection fraction (LVEF). Cox regression models determined the association between galectin-3 and risk of all-cause mortality, cardiac transplantation, or placement of a ventricular assist device. Receiver operating characteristic curves compared the prognostic accuracy of galectin-3, high-sensitivity soluble Toll-like receptor 2 (ST2), troponin I, and B-type natriuretic peptide (BNP) at 1 and 5 years. Higher galectin-3 levels were associated with an increased risk of adverse events (adjusted hazard ratio of 1.96 for each doubling in galectin-3; P < .001). This association was most pronounced among participants with preserved LVEF (adjusted hazard ratio 3.30; P < .001). At 5 years, galectin-3 was the most accurate discriminator of risk among participants with preserved LVEF (area under the curve 0.782; P = .81 vs high-sensitivity ST2; P = .029 vs troponin I; P = .35 vs BNP). BNP was most accurate among participants with reduced and recovered LVEF (areas under the curves 0.716 and 0.728, respectively).

Conclusions: Galectin-3 could have prognostic value for long-term events among patients with heart failure and preserved ejection fraction.
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http://dx.doi.org/10.1016/j.cardfail.2015.10.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818189PMC
April 2016

RNA-Seq identifies novel myocardial gene expression signatures of heart failure.

Genomics 2015 Feb 17;105(2):83-9. Epub 2014 Dec 17.

Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States. Electronic address:

Heart failure is a complex clinical syndrome and has become the most common reason for adult hospitalization in developed countries. Two subtypes of heart failure, ischemic heart disease (ISCH) and dilated cardiomyopathy (DCM), have been studied using microarray platforms. However, microarray has limited resolution. Here we applied RNA sequencing (RNA-Seq) to identify gene signatures for heart failure from six individuals, including three controls, one ISCH and two DCM patients. Using genes identified from this small RNA-Seq dataset, we were able to accurately classify heart failure status in a much larger set of 313 individuals. The identified genes significantly overlapped with genes identified via genome-wide association studies for cardiometabolic traits and the promoters of those genes were enriched for binding sites for transcriptions factors. Our results indicate that it is possible to use RNA-Seq to classify disease status for complex diseases such as heart failure using an extremely small training dataset.
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http://dx.doi.org/10.1016/j.ygeno.2014.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684258PMC
February 2015

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

Nat Genet 2014 Aug 22;46(8):826-36. Epub 2014 Jun 22.

Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy (affiliated institute of the University of Lübeck, Lübeck, Germany).

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
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http://dx.doi.org/10.1038/ng.3014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124521PMC
August 2014

An enhancer polymorphism at the cardiomyocyte intercalated disc protein NOS1AP locus is a major regulator of the QT interval.

Am J Hum Genet 2014 Jun 22;94(6):854-69. Epub 2014 May 22.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

QT interval variation is assumed to arise from variation in repolarization as evidenced from rare Na- and K-channel mutations in Mendelian QT prolongation syndromes. However, in the general population, common noncoding variants at a chromosome 1q locus are the most common genetic regulators of QT interval variation. In this study, we use multiple human genetic, molecular genetic, and cellular assays to identify a functional variant underlying trait association: a noncoding polymorphism (rs7539120) that maps within an enhancer of NOS1AP and affects cardiac function by increasing NOS1AP transcript expression. We further localized NOS1AP to cardiomyocyte intercalated discs (IDs) and demonstrate that overexpression of NOS1AP in cardiomyocytes leads to altered cellular electrophysiology. We advance the hypothesis that NOS1AP affects cardiac electrical conductance and coupling and thereby regulates the QT interval through propagation defects. As further evidence of an important role for propagation variation affecting QT interval in humans, we show that common polymorphisms mapping near a specific set of 170 genes encoding ID proteins are significantly enriched for association with the QT interval, as compared to genome-wide markers. These results suggest that focused studies of proteins within the cardiomyocyte ID are likely to provide insights into QT prolongation and its associated disorders.
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http://dx.doi.org/10.1016/j.ajhg.2014.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121472PMC
June 2014

The mitogen-activated protein kinase pathway tonically inhibits both basal and IGF-I-stimulated IGF-binding protein-5 production in mammary epithelial cells.

J Endocrinol 2007 Aug;194(2):349-59

Rutgers, The State University of New Jersey, 59 Dudley Road, New Brunswick, NJ 08901-8520, USA.

The IGF system plays a key role in mammary gland growth and development. Our lab previously reported that IGF-I primarily regulates IGF-binding protein (BP)-3 in bovine mammary epithelial cells (MEC) and IGFBP-5 in mammary fibroblasts (MF). Presently, we examined the signaling pathways used by IGF-I to elicit this distinct, cell-type specific regulation. The phosphatidylinositol-3 kinase pathway was required for IGF-I to increase IGFBP-3 and -5 in MF and IGFBP-3 in MEC. Surprisingly, inhibiting the mitogen-activated protein kinase (MAPK) pathway in MEC increased IGFBP-5 mRNA levels 2- to 4-fold under basal conditions and 8- to 12-fold in cells treated with IGF-I within 4 h. Similar patterns of IGFBP-3 and -5 regulation were observed in murine MEC. Cells treated with IGF-I in the presence of MAPK inhibitors secreted more IGFBP-5 protein into conditioned media relative to cells treated with IGF-I alone; however, IGFBP-5 protein was not detected in conditioned media of cells treated with only a MAPK inhibitor. The IGFBP-5 mRNA response to MAPK inhibitors was specific for MEC, as blocking MAPK activity decreased the ability of IGF-I to induce IGFBP-5 in MF. In addition, no other IGFBP was increased in either cell type when MAPK activity was inhibited. These increases in IGFBP-5 expression in response to inhibition of the MAPK pathway corresponded with the induction of apoptosis. In conclusion, we report the novel observation that the MAPK/extracellular signal regulated kinase (ERK) pathway specifically represses IGFBP-5 expression in MEC. The corresponding changes in apoptosis and IGFBP-5 expression support a role for this specific IGFBP in mammary gland involution.
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http://dx.doi.org/10.1677/JOE-06-0121DOI Listing
August 2007