BACKGROUND
The mechanism of the alterations in the pattern of left ventricular (LV) filling during the development of congestive heart failure (CHF) is not fully understood.
METHODS AND RESULTS
We studied six conscious dogs instrumented to measure LV and left atrial (LA) pressures and LV volume as CHF was induced by rapid pacing. Diastolic filling dynamics were serially measured over 4 weeks during normal sinus rhythm. Four days after we initiated pacing, the peak early diastolic filing rate decreased from 108 +/- 24 to 88 +/- 27 mL/s (P < .05) as the maximal early diastolic LA-LV pressure gradient decreased associated with a slowing of the rate of LV relaxation. Subsequently, the peak early filling rate progressively increased, returning to control at 1 week, and by the fourth week, it had increased to 168 +/- 39 mL/s (P < .05). These changes in early filling rates occurred as the maximal early diastolic LA-LV pressure gradient increased in association with a progressive increase in LV pressure despite further progressive slowing of the rate of LV relaxation. Throughout the development of CHF, peak early filling rate and the maximal LA-LV pressure gradient correlated (r = .99, P < .001). The early filling deceleration rate increased and deceleration time progressively decreased over the 4 weeks as LV stiffness and net LA plus LV stiffness increased (P < .05). As predicted by a theoretical analysis, the deceleration time was linearly related to the reciprocal of the square root of LV stiffness (r = .94, P < .01).
CONCLUSIONS
Early in CHF, slowing of LV relaxation reduces the maximal early diastolic LA-LV pressure gradient, decreasing the peak early filling rate. As CHF progresses, this is overcome by an increase in LA pressure that augments the early diastolic LA-LV pressure gradient, increasing peak early filling rate. Increasing LV stiffness during the development of CHF progressively shortens the early filling deceleration time and augments the early filling deceleration rate. These observations suggest that the early filling deceleration time reflects LV stiffness.
Abstract-Altered expression and functional responses to cardiac  3 -adrenergic receptors (ARs) may contribute to progressive cardiac dysfunction in heart failure (CHF). We compared myocyte  3 -AR mRNA and protein levels and myocyte contractile, [Ca 2ϩ ] i transient, and Ca 2ϩ current (I Ca,L ) responses to BRL-37344 (BRL, 10 Ϫ8 mol/L), a selective  3 -AR agonist, in 9 instrumented dogs before and after pacing-induced CHF. Myocytes were isolated from left ventricular myocardium biopsy tissues. Using reverse transcription-polymerase chain reaction, we detected  3 -AR mRNA from myocyte total RNA in each animal. Using a cloned canine  3 -AR cDNA probe and myocyte poly A ϩ RNA, we detected a single band about 3.4 kb in normal and CHF myocytes.  3 -AR protein was detected by Western blot.  3 -AR mRNA and protein levels were significantly greater in CHF myocytes than in normal myocytes. Importantly, these changes were associated with enhanced  3 -AR-mediated negative modulation on myocyte contractile response and [Ca 2ϩ ] i regulation. Compared with normal myocytes, CHF myocytes had much greater decreases in the velocity of shortening and relengthening with BRL accompanied by larger reductions in the peak systolic [Ca 2ϩ ] i transient and I Ca,L . These responses were not modified by pretreating myocytes with metoprolol (a  1 -AR antagonist) or nadolol (a  1 -and  2 -AR antagonist), but were nearly prevented by bupranolol or L-748,337 ( 3 -AR antagonists). We conclude that in dogs with pacing-induced CHF,  3 -AR gene expression and protein levels are upregulated, and the functional response to  3 -AR stimulation is increased. This may contribute to progression of cardiac dysfunction in CHF.
With slowed relaxation during the development of HF, E(M) is reduced and delayed so that it occurs after early, rapid filling. Thus, with slowed relaxation, E(M) does not respond to the early diastolic LA to LV pressure gradient, because it occurs when LV pressure is greater than or equal to LA pressure.
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