1) Pathogenesis of Cardiac Dysfunction of Obstructive Sleep Apnea
Obstructive sleep apnea/hypopnea syndrome (OSA) affects about 4-6% of males and 2-4% of females in mid-aged population. OSA increases cardiovascular morbidity and mortality due to hypertension, ischemic heart disease, heart failure and stroke. Chronic intermittent hypoxia (CIH), which results from the repetitive episodes of upper airway occlusion during sleep, is important for the cardiovascular sequelae of OSA. Indeed, rats exposed to CIH develop hypertension, ventricular hypertrophy and dysfunction. Recently, we observed an upregulation of myocardial Na+/H+ exchanger-1 (NHE1) in CIH rats and mice. NHE1 regulates cellular pH and Na+ in physiological condition and may be involved in cardiac injury during ischemia and reperfusion injury. We are currently examining the role of NHE1 in cardiac dysfunction following CIH. Multidisciplinary approaches are used, including conscious blood pressure and cardiac output, echocardiography, contractile function of isolated cells, molecular imaging, and genetic modified mice. If NHE1 plays a role in the pathogenesis of cardiac dysfunction, further study on effort of NHE1 inhibition may lead to a novel adjunct therapy for OSA.
2) Mechanisms of Cardiac Dysfunction Following Brain Death
The lifetime risk of developing heart failure is 1 in 5 for men and women. Only heart transplantation offers a meaningful long-term survival for late-stage heart failure, about 50% at 10 years. While estimated 100,000 patients in the United States might benefit from the surgery, however, the procedures are limited to 2,200 annually because of lack of viable hearts donated by brain-dead patients. As clinicians observed a long time ago, hearts can remain viable for only a short period of time following brain death. Using the rat model of brain death, we explore several putative mechanisms, such as NHE1, in initiation of cardiac dysfunction following brain death. Our long-term goal is to develop novel strategies for treatment of the organ donors and/or the donor hearts, in order to improve the availability and quality of donor hearts for transplantation.
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Cohen RI, Chen L, Scharf SM. The effects of high dose NG-nitro-L-arginine-methyl ester on myocardial blood flow and left ventricular function in dogs. J Crit Care. 1996;11(4):206-13.
Chen L, Scharf SM. Comparative hemodynamic effects of periodic obstructive and simulated central apneas in sedated pigs. J Appl Physiol. 1997;83(2):485-94.
Tarasiuk A, Chen L, Scharf SM. Effects of periodic obstructive apnoeas on superior and inferior venous return in dogs. Acta Physiol Scand. 1997;161(2):187-94.
Sofer S, Cohen R, Shapir Y, Chen L, Colon A, Scharf SM. Scorpion venom leads to gastrointestinal ischemia despite increased oxygen delivery in pigs. Crit Care Med. 1997;25(5):834-40.
Chen L, Sica AL, Greenberg H, Scharf SM. Role of hypoxemia and hypercapnia in acute cardiovascular response to periodic apneas in sedated pigs. Respir Physiol. 1998;111(3):257-69.
Chen L, Scharf SM. Systemic and myocardial hemodynamics during periodic obstructive apneas in sedated pigs. J Appl Physiol. 1998;84(4):1289-98.
Cohen RI, Shapir Y, Chen L, Scharf SM. Right ventricular overload causes the decrease in cardiac output after nitric oxide synthesis inhibition in endotoxemia. Crit Care Med. 1998;26(4):738-47.
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Chen L, Sica AL, Scharf SM. Mechanisms of acute cardiovascular response to periodic apneas in sedated pigs. J Appl Physiol. 1999;86(4):1236-46.
Chen L, Shi Q, Scharf SM. Hemodynamic effects of periodic obstructive apneas in sedated pigs with congestive heart failure. J Appl Physiol. 2000;88(3):1051-60.
Chen L, Scharf SM. Effects of aortic nerve on hemodynamic response to obstructive apnea in sedated pigs. J Appl Physiol. 2000;89(4):1455-61.
Chen L, Gan XT, Haist JV, Feng Q, Lu X, Chakrabarti S, Karmazyn M. Attenuation of compensatory right ventricular hypertrophy and heart failure following monocrotaline-induced pulmonary vascular injury by the Na+-H+ exchange inhibitor cariporide. J Pharmacol Exp Ther. 2001;298(2):469-76.
Rojas A, Chen L, Bartlett RH, Arenas JD. Assessment of liver function during extracorporeal membrane oxygenation in the non-heart beating donor swine. Transplant Proc 2004;36 (5):1268-70
Chen L, Chen CX, Gan XT, Beier N, Scholz W, Karmazyn M. Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition. Am J Physiol Heart Circ Physiol. 2004;286(1):H381-7.
Chen L, Einbinder E, Zhang Q, Balke CW, Hasday J, Scharf SM. Oxidative Stress and Left Ventricular Function with Chronic Intermittent Hypoxia in Rats. Am J Respir Crit Care Med 2005 (in press), published on-line on June 23, 2005
Zhang J, Lee MY, Cavalli M, Chen L, Berra-Romani R, Balke CW, Bianchi G, Ferrari P, Iwamoto T, Lingrel JB, Matteson DR, Philipson KD, Wier WG, Blaustein MP. Sodium pump alpha2 subunits control arterial myogenic tone and blood pressure in mice. J Physiol. 2005; 569: 243-56.
Blaustein MP, Zhang J, Chen L, and Hamilton BP. How does salt retention raise blood pressure? Am J Physiol Regul Intergr Comp Physiol (invited review) 2006; 290(3):R514-23.
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