The clinical importance of the diastolic properties of the left ventricle (LV) have been increasingly recognized. Patients with common cardiac diseases such as hypertension, LV hypertrophy, or ischemia may have congestive heart failure (CHF), despite normal LV systolic function, due to impaired diastolic LV filling. This has led to investigation of the determinants of normal LV diastolic filling. However, the mechanisms of the effects of exercise or the development of heart failure on LV diastolic performance have not been investigated. During exercise, cardiac output rises primarily due to a marked increase in heart rate. The tachycardia decreases the duration of diastole, providing less time for diastolic filling of the LV. Thus, the velocity of mitral valve flow (and rate of LV filling) must markedly increase during exercise to maintain or increase the stroke volume. The mechanism by which rapid diastolic filling of the LV is produced during vigorous exercise is not known. Further, the effect of heart failure on the early diastolic filling during exercise has not been investigated. This project will quantitatively evaluate the mechanism of LV diastolic filling in conscious dogs during exercise, during the development of heart failure (CHF), and during exercise after CHF. We will test four hypotheses. Hypothesis 1. During exercise, the rate of LV early diastolic filling is augmented by an increased rate of myocardial relaxation and a fall in end-systolic volume. This results in a reduction of early diastolic LV pressure (P), increasing the early diastolic mitral valve gradient without an increase in left atrial (LA) P. The LV end-diastolic pressure-volume relation is unaltered. Hypothesis 2. In chronic, tachycardia-induced CHF, the rate of myocardial relaxation is reduced and there is an upward shift of the LV end-diastolic pressure-volume relationship. The early diastolic mitral valve gradient for LV diastolic filling is produced by an elevation of LAP. Hypothesis 3. The dynamics of diastolic filing during exercise are altered after CHF. With CHF, myocardial relaxation and LV emptying are not enhanced during exercise and early diastolic LV pressure is elevated. Any increase in the rate of LV diastolic filing with exercise after CHF results from an increase in LAP. Hypothesis 4. The exercise induced increase in left atrial pressure occurring in CHF can be diminished by treatment with a positive inotrope or an angiotensin converting enzyme inhibitor. These studies will be performed in conscious dogs, chronically instrumented to measure LVP, LAP, and LV volume. These studies will provide important new information concerning the mechanism of LV diastolic filing during normal exercise and exercise after CHF. These studies are necessary to extend our knowledge of the diastolic LV filing in normal animals at rest to common physiologic stress and pathologic conditions. This may lead to new strategies to improve exercise tolerance in CHF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29HL045258-01
Application #
3473276
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1991-01-01
Project End
1995-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Fukuta, Hidekatsu; Little, William C (2008) The cardiac cycle and the physiologic basis of left ventricular contraction, ejection, relaxation, and filling. Heart Fail Clin 4:1-11
Zhang, Zhu-Shan; Cheng, Heng-Jie; Onishi, Katsuya et al. (2005) Enhanced inhibition of L-type Ca2+ current by beta3-adrenergic stimulation in failing rat heart. J Pharmacol Exp Ther 315:1203-11
Little, W C; Cheng, C P (1994) Coupling of the left ventricular and arterial system. Med Biol Eng Comput 32:205-9
Nozawa, T; Cheng, C P; Noda, T et al. (1994) Effect of exercise on left ventricular mechanical efficiency in conscious dogs. Circulation 90:3047-54
De Tombe, P P; Little, W C (1994) Inotropic effects of ejection are myocardial properties. Am J Physiol 266:H1202-13
Cheng, C P; Noda, T; Nordlander, M et al. (1994) Comparison of effects of dihydropyridine calcium antagonists on left ventricular systolic and diastolic performance. J Pharmacol Exp Ther 268:1232-41
Nozawa, T; Cheng, C P; Noda, T et al. (1994) Relation between left ventricular oxygen consumption and pressure-volume area in conscious dogs. Circulation 89:810-7
Cheng, C P; Pettersson, K; Little, W C (1994) Effects of felodipine on left ventricular systolic and diastolic performance in congestive heart failure. J Pharmacol Exp Ther 271:1409-17
Cheng, C P; Noda, T; Nozawa, T et al. (1993) Effect of heart failure on the mechanism of exercise-induced augmentation of mitral valve flow. Circ Res 72:795-806
Cheng, C P; Igarashi, Y; Klopfenstein, H S et al. (1993) Effect of vasopressin on left ventricular performance. Am J Physiol 264:H53-60

Showing the most recent 10 out of 15 publications