(Applicant?s Abstract) The candidate is a 42-year-old tenured Associate Professor who is in his 11th year after fellowship training. He is an established independent investigator who is completely committed to a life-long career in research and the mentoring of trainees. His outstanding institutional environment is supportive of high quality collaboration and ongoing research. This Midcareer Investigator Award in Patient-Oriented Research proposal will enable the expansion of two principal areas of hypotheses-driven human research: 1) Effects of cytokines on left ventricular (LV) performance in patients undergoing cardiac surgery and 2) Assessment of contractile reserve to predict prognosis in heart failure patients. The American Heart Association has recently awarded a National Grant-In-Aid entitled """"""""Effects of Inflammatory Mediators on Left Ventricular Performance Following Cardiac Surgery"""""""" to the applicant as PI. This 3-year grant will support the infrastructure that is a requirement of this K24 application.
A specific aim i s to test the hypothesis that inflammatory mediators play an important role in cardiac depression following coronary bypass surgery. In particular, expression of the cytokine TNF- alpha will be studied both systemically and locally in coronary sinus samples. Seventy-two patients will be studied before and after bypass using transesophageal echo automated border detection and high fidelity pressure catheters to quantify LV performance in a predominant load-independent manner using pressure-volume relations. The anti-cytokine role of adenosine will be explored by randomizing patients to receive either routine cardioplegeia or an adenosine cardiopledgia. This K24 award will allow the applicant to expand this research work and mentor research fellows by directly involving them in this and related projects. The second arm of this proposal will test the hypothesis that contractile reserve is an important prognostic determinant in patients with severe heart failure. Dobutamine echocardiography will noninvasively assess the functionality of the myocardial beta-adrenergic receptor complex in 100 heart failure patients with ejection fraction less than 35%. Quantitative automated border detection and tissue Doppler will be used. Contractile reserve will be tested as a marker for patient?s prognosis using: preload-adjusted maximal power, tissue Doppler measures of longitudinal shortening velocity, and right ventricular fractional area change. The inability to augment ventricular contractility in response to dobutamine will be tested as a marker predictive of cardiac morbidity or mortality within one year. Patients will be followed for adverse events defined as requirements for hospitalization for heart failure, continuous intravenous inotropic or mechanical circulatory support. This information has promise to dramatically impact on the clinical management of these patients, including priority status for transplantation or mechanical circulatory assist device implantation. These ongoing studies provide ample opportunities for mentoring of fellows in patient-oriented research.
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