Harvey S. Hahn

Kettering Medical Center

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Gerald W. Dorn

Washington University in St. Louis

Yehia Marreez

University of Cincinnati

Nathaniel Dittoe

Loma Linda University Medical Center

Evangelia G. Kranias

Biomedical Research Foundation of the Academy of Athens

Amy Odley

University of Cincinnati

Sula Mazimba

University of Virginia

Stephen B. Liggett

University of South Florida

Jeffrey Robbins

Cincinnati Children's Hospital Medical Center

Brian Schwartz

Wright State University

Faisal Syed

Dubbo Hospital

Cooperative Institutions

University of Cincinnati

Association Clinique et Thérapeutique Infantile du Val de Marne

University of Cincinnati Medical Center

University of Pittsburgh

Harvard University

Cincinnati Children's Hospital Medical Center

National Institutes of Health

Brigham and Women's Hospital

National Heart Lung and Blood Institute

University of Illinois Chicago

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Mediating ERK1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome

Journal of Clinical Investigation (2007)

Tomoki Nakamura Melissa C. Colbert Maike Krenz Jeffery D. Molkentin Harvey S. Hahn

Noonan syndrome (NS) is an autosomal dominant disorder characterized by a wide spectrum of defects, which most frequently include proportionate short stature, craniofacial anomalies, and congenital heart disease (CHD). NS is the most common nonchromosomal cause of CHD, and 80%-90% of NS patients have cardiac involvement. Mutations within the protein tyrosine phosphatase Src homology region 2, phosphatase 2 (SHP2) are responsible for approximately 50% of the cases of NS with cardiac involvement. To understand the developmental stage- and cell type-specific consequences of the NS SHP2 gain-of-function mutation, Q79R, we generated transgenic mice in which the mutated protein was expressed during gestation or following birth in cardiomyocytes. Q79R SHP2 embryonic hearts showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects, while, in the postnatal cardiomyocyte, Q79R SHP2 expression was completely benign. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway, and breeding of the Q79R transgenics into ERK1/2-null backgrounds confirmed the pathway's necessity and sufficiency in mediating mutant SHP2's effects. Our data establish the developmental stage-specific effects of Q79R cardiac expression in NS; show that ablation of subsequent ERK1/2 activation prevents the development of cardiac abnormalities; and suggest that ERK1/2 modulation could have important implications for developing therapeutic strategies in CHD.

Noonan Syndrome

PTPN11

10.1172/jci30756

Cite

Citations (114)

Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy

Journal of Clinical Investigation (2003)

Qiujing Song Albrecht Schmidt Harvey S. Hahn Andrew N. Carr Beate Frank

Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca2+ cycling. Normalization of Ca2+ cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Gαq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-CMUT) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca2+ transients and enhanced unloaded fractional shortening with no change in SR Ca2+ pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Gαq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Gαq pathway or MyBP-C mutations.

Phospholamban

Contractility

Dilated Cardiomyopathy

Pressure overload

10.1172/jci200316738

Cite

Citations (118)

Cardiac Myosin-Binding Protein-C Phosphorylation and Cardiac Function

Circulation Research (2005)

Sakthivel Sadayappan James Gulick Hanna Osińska Lisa Martin Harvey S. Hahn

The role of cardiac myosin binding protein-C (cMyBP-C) phosphorylation in cardiac physiology or pathophysiology is unclear. To investigate the status of cMyBP-C phosphorylation in vivo, we determined its phosphorylation state in stressed and unstressed mouse hearts. cMyBP-C phosphorylation is significantly decreased during the development of heart failure or pathologic hypertrophy. We then generated transgenic (TG) mice in which the phosphorylation sites of cMyBP-C were changed to nonphosphorylatable alanines (MyBP-C(AllP-)). A TG line showing &40% replacement with MyBP-C(AllP-) showed no changes in morbidity or mortality but displayed depressed cardiac contractility, altered sarcomeric structure and upregulation of transcripts associated with a hypertrophic response. To explore the effect of complete replacement of endogenous cMyBP-C with MyBP-C(AllP-), the mice were bred into the MyBP-C(t/t) background, in which less than 10% of normal levels of a truncated MyBP-C are present. Although MyBP-C(AllP-) was incorporated into the sarcomere and expressed at normal levels, the mutant protein could not rescue the MyBP-C(t/t) phenotype. The mice developed significant cardiac hypertrophy with myofibrillar disarray and fibrosis, similar to what was observed in the MyBP-C(t/t) animals. In contrast, when the MyBP-C(t/t) mice were bred to a TG line expressing normal MyBP-C (MyBP-CWT), the MyBP-C(t/t) phenotype was rescued. These data suggest that cMyBP-C phosphorylation is essential for normal cardiac function.

Contractility

10.1161/01.res.0000190605.79013.4d

Cite

Citations (228)

Pharmacological- and Gene Therapy-Based Inhibition of Protein Kinase Cα/β Enhances Cardiac Contractility and Attenuates Heart Failure

Circulation (2006)

Michael Hambleton Harvey S. Hahn Sven T. Pleger Matthew Kuhn Raisa Klevitsky

The conventional protein kinase C (PKC) isoform alpha functions as a proximal regulator of Ca2+ handling in cardiac myocytes. Deletion of PKCalpha in the mouse results in augmented sarcoplasmic reticulum Ca2+ loading, enhanced Ca2+ transients, and augmented contractility, whereas overexpression of PKCalpha in the heart blunts contractility. Mechanistically, PKCalpha directly regulates Ca2+ handling by altering the phosphorylation status of inhibitor-1, which in turn suppresses protein phosphatase-1 activity, thus modulating phospholamban activity and secondarily, the sarcoplasmic reticulum Ca2+ ATPase.In the present study, we show that short-term inhibition of the conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 significantly augmented cardiac contractility in vivo or in an isolated work-performing heart preparation in wild-type mice but not in PKCalpha-deficient mice. Ro-32-0432 also increased cardiac contractility in 2 different models of heart failure in vivo. Short-term or long-term treatment with Ro-31-8220 in a mouse model of heart failure due to deletion of the muscle lim protein gene significantly augmented cardiac contractility and restored pump function. Moreover, adenovirus-mediated gene therapy with a dominant-negative PKCalpha cDNA rescued heart failure in a rat model of postinfarction cardiomyopathy. PKCalpha was also determined to be the dominant conventional PKC isoform expressed in the adult human heart, providing potential relevance of these findings to human pathophysiology.Pharmacological inhibition of PKCalpha, or the conventional isoforms in general, may serve as a novel therapeutic strategy for enhancing cardiac contractility in certain stages of heart failure.

Contractility

10.1161/circulationaha.105.592550

Cite

Citations (149)

A GRK5 polymorphism that inhibits β-adrenergic receptor signaling is protective in heart failure

Nature Medicine (2008)

Stephen B. Liggett Sharon Cresci Reagan Kelly Faisal Syed Scot J. Matkovich

10.1038/nm1750

Cite

Citations (313)

Abstract P320: Congestive Heart Failure Readmissions: Relationship Between Preadmission Patient Determinants and 30 Day Rehospitalization

Circulation Cardiovascular Quality and Outcomes (2011)

Sula Mazimba Jessica Tan Nakash Grant Lata Parvathaneni Vikas Kalra

Introduction Congestive heart failure (CHF) is the most costly disease in the US. Readmission costs contribute significantly to this healthcare expenditure. While adherence to published guidelines has increased, readmission rates have not improved. There is an urgent need to identify clinical and process measures that improve care for CHF patients. Thirty day readmission rates have often been used by third party payers as a surrogate index for quality of care in the inpatients settings. This study looked at the relationship between preadmission patient characteristics and 30 day readmissions. Methods: This was a single center retrospective case-control study that evaluated 6063 consecutive patients admitted with a diagnosis of CHF from December 2001 through December 2008. Data was abstracted for independent and dependent variables, including heart failure performance measures at discharge. This Ad hoc analysis focused on the relationship between patient determinants on 30 day readmissions. Statistical comparison was made between readmitted and non readmitted cohorts. Results: There were 6063 total patients admitted with the principal diagnosis of CHF. A total of 19.6% (1191 of 6063) of the patients were readmitted within 30 days of discharge. Another 19.9% (1211 of 6063) served as control cohort. The mean age for readmitted and non readmitted patients was 77.8(+/- 11.6) and 75.7 (+/- 11.8) years respectively. Mean duration of initial hospital stay for readmitted patients was 5.7 (+/- 4) days and 6.0 (+/-4) days for the control group. Readmitted patients were more likely to be smokers than their counterparts. (O.R= 1.5, 95% CI 1.2-1.9 p=0.002).Non usage of ACEI medication prior to hospitalization was associated with higher rates of readmission (O.R 1.30, 95% CI 1.1-1.6, p=0.003).However beta blocker therapy did not correlate with 30 day readmissions. (O.R 1.0, 95% CI 0.89- 1.19, p=0.970). Conclusions: In patients admitted with CHF, non usage of ACEI prior to hospitalization and smoking history may serve as indicators for early readmissions. Preadmission beta blocker use was not associated with reduced early readmissions. More studies need to be done to stratify determinants that identify patients at risk for early readmissions.

Post-hoc analysis

Hospital Readmission

10.1161/circoutcomes.4.suppl_1.ap320

Cite

Citations (0)

PERICARDIAL MESOTHELIOMA

Journal of the American College of Cardiology (2022)

Juan D Linares Velandia Damian Valencia Rebekah Lantz Krudy Zoltan Raja Amir Nazir

10.1016/s0735-1097(22)04062-1

Cite

Citations (0)

Impact of Preoperative 64-Slice CT Scanning on Mini-Maze Atrial Fibrillation Surgery

Innovations Technology and Techniques in Cardiothoracic and Vascular Surgery (2007)

Cristopher A. Meyer J. Edward Hall John R. Mehall Randall K. Wolf Eric W. Schneeberger

10.1177/155698450700200401

Cite

Citations (0)

Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy

Journal of Clinical Investigation (2003)

Qiujing Song Albrecht Schmidt Harvey S. Hahn Andrew N. Carr Beate Frank

Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca(2+) cycling. Normalization of Ca(2+) cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Galphaq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-C(MUT)) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca(2+) transients and enhanced unloaded fractional shortening with no change in SR Ca(2+) pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Galphaq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Galphaq pathway or MyBP-C mutations.

Phospholamban

Contractility

10.1172/jci16738

Cite

Citations (113)

Suicide attempts and borderline personality disorder symptomatology in a cardiac stress test population.

PubMed (2011)

Randy A. Sansone Nathaniel Dittoe Harvey S. Hahn Michael W. Wiederman

Source

Cite

Citations (5)