The goal of this research is to understand the significance and mechanism of left ventricular (LV) restoring forces (RFs) and mitral inflow by suction. A RF is present and suction occurs when end-systolic volume (ESV) is less than equilibrium volume. The investigators will employ a servomotor system in open chest dogs which rapidly clamps left atrial pressure (LAP) at a desired value. With LAP less than LV diastolic pressure, filling is prevented and the LV fully relaxes at ESV. A negative fully relaxed pressure (FRP) indicates presence of a RF. With LAP = 0 mmHg (quasi-zero source pressure), filling occurs exclusively by suction. The system allows the investigators to relate ESV to RFs (neg FRP) an suction flow by manipulating loading conditions. The applicant indicates that the investigators have previously delineated the magnitude of RF present over """"""""physiologic"""""""" range of filling and the effect of acute coronary occlusion on FRP. Preliminary data indicate that 1) both systemic and intra-coronary (left anterior descending artery) dobutamine increase RFs and suction flow; 2) anterior wall transmural deformation patterns are especially important as a mechanism of RFs; and 3) RFs are markedly impaired in pacing tachycardia heart failure. The investigators now propose to more completely delineate the relationship between anterior wall deformation linked to LV torsion (""""""""twist"""""""") and RFs and suction. In addition, the investigators will test the hypothesis that negative intra-thoracic pressure, pericardial restraint and intra-cardiac hydrostatic gradients do not have a major effect on RFs or suction. Last, the investigators will begin to determine the role and mechanism of changes in RFs and suction as a component of the pathophysiology of diastolic filling abnormalities in several overload states.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051201-06
Application #
6183412
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1994-01-14
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
6
Fiscal Year
2000
Total Cost
$349,742
Indirect Cost
Name
University of Vermont & St Agric College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Wu, Yiming; Bell, Stephen P; Trombitas, Karoly et al. (2002) Changes in titin isoform expression in pacing-induced cardiac failure give rise to increased passive muscle stiffness. Circulation 106:1384-9
Wu, Yiming; Labeit, Siegfried; Lewinter, Martin M et al. (2002) Titin: an endosarcomeric protein that modulates myocardial stiffness in DCM. J Card Fail 8:S276-86
Bell, S P; Nyland, L; Tischler, M D et al. (2000) Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res 87:235-40
Bell, S P; Fabian, J; LeWinter, M M (1998) Effects of dobutamine on left ventricular restoring forces. Am J Physiol 275:H190-4
LeWinter, M M; Fabian, J; Bell, S P (1998) Left ventricular restoring forces: modulation by heart rate and contractility. Basic Res Cardiol 93 Suppl 1:143-7
Bell, S P; Fabian, J; Watkins, M W et al. (1997) Decrease in forces responsible for diastolic suction during acute coronary occlusion. Circulation 96:2348-52
Watkins, M W; Higashiyama, A; Chen, Z et al. (1996) Rapid shortening during relaxation increases activation and improves systolic performance. Circulation 94:1475-82