Abstract

Congestive heart failure continues to be a leading health concern in Western society. This syndrome is caused by a variety of different diseases with ischemic heart disease being the most common. The prognosis for heart failure patients remains very poor even though some beneficial treatments have recently been developed. The purpose of this research is to identify defective processes that contribute to the initiation and progression of human heart failure in the hope that they can be targeted for improved heart failure therapies The specific aims are to: 1) Determine the in-vivo """"""""contractility reserve"""""""" of nonfailing, failing and LVAD-supported human hearts by measuring the changes in cardiac performance caused by increases in heart rate (pacing stress) and adrenergic agonists (dobutamine stress). The most important aspect of these descriptive studies is that we will also obtain tissue samples before and during pacing and during adrenergic stress (and subsequently obtain tissues and myocytes from these hearts when they are explanted) to define the cellular and molecular bases of defective rate and adrenergic responses (Aims 2 and 3). These studies will allow us to translate biochemical, molecular and biophysical abnormalities within single myocytes to impaired function of the intact heart. 2): Determine why SR Ca load does not increase normally (negative versus positive force frequency relationship) when the pacing rate is increased in failing human myocytes (depressed """"""""rate reserve""""""""). The respective roles of the SR (uptake, release and leak), the NCX, the action potential duration and the L-type Ca channel will be studied. 3): Determine why adrenergic agonists do not produce the normal increase in SR Ca loading in failing human myocytes. The respective roles of the SERCA, PLB, RYR and the L-type Ca channel in the inability of adrenergic agonists to increase SR Ca loading and release (""""""""adrenergic reserve"""""""") will be studied. These experiments will be performed in nonfailing and failing human hearts to more clearly define the mechanism responsible for abnormal """"""""contractility reserve.""""""""

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL061495-06
Application #
6686121
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Reinlib, Leslie
Project Start
1998-09-30
Project End
2007-07-31
Budget Start
2003-08-08
Budget End
2004-07-31
Support Year
6
Fiscal Year
2003
Total Cost
$376,250
Indirect Cost

  Institution

Name
Temple University
Department
Physiology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122

  Publications

Harper, Shavonn C; Johnson, Jaslyn; Borghetti, Giulia et al. (2018) GDF11 Decreases Pressure Overload-Induced Hypertrophy, but Can Cause Severe Cachexia and Premature Death. Circ Res 123:1220-1231
Troupes, Constantine D; Wallner, Markus; Borghetti, Giulia et al. (2017) Role of STIM1 (Stromal Interaction Molecule 1) in Hypertrophy-Related Contractile Dysfunction. Circ Res 121:125-136
Makarewich, Catherine A; Troupes, Constantine D; Schumacher, Sarah M et al. (2015) Comparative effects of urocortins and stresscopin on cardiac myocyte contractility. J Mol Cell Cardiol 86:179-86
Harris, David M; Chen, Xiongwen; Pesant, Stéphanie et al. (2009) Inhibition of angiotensin II Gq signaling augments beta-adrenergic receptor mediated effects in a renal artery stenosis model of high blood pressure. J Mol Cell Cardiol 46:100-7
MacDonnell, Scott M; Garcia-Rivas, Gerardo; Scherman, Joseph A et al. (2008) Adrenergic regulation of cardiac contractility does not involve phosphorylation of the cardiac ryanodine receptor at serine 2808. Circ Res 102:e65-72
Chen, Xiongwen; Wilson, Rachel M; Kubo, Hajime et al. (2007) Adolescent feline heart contains a population of small, proliferative ventricular myocytes with immature physiological properties. Circ Res 100:536-44
Mills, Geoffrey D; Harris, David M; Chen, Xiongwen et al. (2007) Intracellular sodium determines frequency-dependent alterations in contractility in hypertrophied feline ventricular myocytes. Am J Physiol Heart Circ Physiol 292:H1129-38
Quaile, Michael P; Rossman, Eric I; Berretta, Remus M et al. (2007) Reduced sarcoplasmic reticulum Ca(2+) load mediates impaired contractile reserve in right ventricular pressure overload. J Mol Cell Cardiol 43:552-63
Mills, Geoffrey D; Kubo, Hajime; Harris, David M et al. (2006) Phosphorylation of phospholamban at threonine-17 reduces cardiac adrenergic contractile responsiveness in chronic pressure overload-induced hypertrophy. Am J Physiol Heart Circ Physiol 291:H61-70
Altamirano, Julio; Li, Yanxia; DeSantiago, Jaime et al. (2006) The inotropic effect of cardioactive glycosides in ventricular myocytes requires Na+-Ca2+ exchanger function. J Physiol 575:845-54

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