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Inhibition of the angiotensin-converting enzyme (ACE) in developing left ventricular (LV) hypertrophy has been demonstrated to have inhibitory effects on myocardial growth. An important mechanism of action of ACE inhibition is modulation of myocardial AT1 Ang II-receptor activity. However, whether and to what extent AT1 Ang II-receptor blockade may influence LV and myocyte function during the hypertrophic process remains unclear. Accordingly, our project examined the relation between changes in LV and myocyte function during the LV hypertrophic process that occurs after recovery from long-term rapid pacing. Dogs were randomly assigned to the following treatment groups: (a) Pace and Recovery, long-term rapid pacing (4 weeks; 216 +/- 2 beats/min) followed by a 4-week recovery period (n = 6); (b) Recovery/AT1 Block, concomitant AT1 Ang II-receptor blockade [irbesartan (SR 47436; BMS-186295) 30 mg/kg b.i.d.] administered during the 4-week recovery period (n = 5); and (c) Control, sham controls (n = 6). There was no difference in mean arterial pressure in any of the three groups. With pacing and recovery, LV end-diastolic volume and mass were increased by >50% from control values. The significant LV remodeling that occurred with recovery from long-term rapid pacing was associated with a decline in LV ejection fraction (59 +/- 3% vs. 68 +/- 4%) and myocyte velocity of shortening (43 +/- 3 microm/s vs. 63 +/- 3 microm/s) when compared with controls (p < 0.05). With recovery from long-term rapid pacing, LV myocyte length (176 +/- 6 microm vs. 150 +/- 1 microm) and cross-sectional area were increased (292 +/- 7 microm2 vs. 227 +/- 6 microm2) compared with controls (p < 0.05). With AT1 Ang II block during recovery from rapid pacing, LV end-diastolic volume was similar to untreated recovery values, but LV mass was normalized. LV ejection fraction was not different from control values with AT1 Ang II-receptor block. Steady-state myocyte velocity of shortening with AT1 Ang II block was similar to control values (55 +/- 5 microm/s), but percentage shortening remained reduced from control (3.55 +/- 0.37% vs. 4.71 +/- 0.12%, respectively, p < 0.05) and was similar to untreated recovery (3.59 +/- 0.23%). With AT1 Ang II block, myocyte length was similar to untreated recovery values, but cross-sectional area was reduced (260 +/- 5 microm2, p < 0.05). Thus AT1 Ang II-receptor blockade instituted in this model of developing LV hypertrophy, significantly reduced LV mass but did not reduce the degree of LV dilation. The cellular basis for these effects of AT1 Ang II-receptor blockade included persistent abnormalities in LV myocyte geometry. AT1 Ang II-receptor blockade improved certain indices of myocyte contractile function from untreated hypertrophy values. These findings suggest that in this pacing-recovery model, the development of LV hypertrophy and myocyte contractile dysfunction may be caused, at least in part, by AT1 Ang II-receptor activation.

LV and myocyte function and angiotensin converting enzyme (ACE) activity with ACE inhibitor (ACEI) treatment were examined in four groups of dogs (n = 6 each): (1) control; (2) with 4 weeks of recovery from chronic rapid pacing (REC: 216 beats/min), (3) ACEI for the first 14 days of REC (ACEI--14), and (4) ACEI for 28 days of REC (ACEI--28). Three additional control dogs were administered ACEI for 28 days. LV mass increased with REC compared to control (146 +/- 6 v 92 +/- 3 g, P < 0.05), was unaffected with ACEI--14, and was decreased with ACEI--28 compared to REC (111 +/- 8 g, P < 0.05). Myocyte function was decreased in REC compared to controls (43 +/- 3 v 63 +/- 3 microns/s, P < 0.05) and was similarly reduced with ACEI--14. However, with ACEI--28, myocyte shortening velocity was increased compared to REC (56 +/- 1 microns/s, P < 0.05). Myocyte beta-adrenergic response was decreased with REC and ACEI--14 compared to controls (53 +/- 9 and 57 +/- 14, respectively v 127 +/- 14 microns/s, P < 0.05). ACEI--28 resulted in a normalization of myocyte beta-adrenergic responsiveness (108 +/- 3 microns/s). LV myocardial ACE activity increased in REC compared to control (5.82 +/- 0.21 v 3.51 +/- 0.15 nmol/mg/min, P < 0.05). With ACEI--14 or ACEI--28, myocardial ACE activity was decreased compared to REC (4.16 +/- 0.06 and 4.08 +/- 0.23 nmol/mg/min; P < 0.05). In control dogs administered ACEI, there were no differences in any of these parameters compared to controls. The unique findings in this study were: (1) effects of ACEI treatment in this model of LV hypertrophy were time dependent with respect to LV mass and LV and myocyte function; and (2) the effect of ACEI treatment on the degree of LV hypertrophy appears to not be solely due modulation of myocardial ACE activity.

Objectives: The present study examined left ventricular (LV) and myocyte contractile performance and electrophysiologic variables after long-term digoxin treatment in a model of LV failure., Background: A fundamental therapeutic agent for patients with chronic LV dysfunction is the cardiac glycoside digoxin. However, whether digoxin has direct effects on myocyte contractile function and electrophysiologic properties in the setting of chronic LV dysfunction remains unexplored., Methods: Left ventricular and isolated myocyte function and electrophysiologic variables were examined in five control dogs, five dogs after the development of long-term rapid pacing (rapid pacing, 220 beats/min, 4 weeks) and five dogs with rapid pacing given digoxin (0.25 mg/day) during the pacing period (rapid pacing and digoxin)., Results: Left ventricular ejection fraction decreased in the dogs with rapid pacing compared with that in control dogs (30 +/- 2% vs. 68 +/- 3%, p < 0.05) and was higher with digoxin than that in the rapid pacing group (38 +/- 3%, p = 0.038). Left ventricular end-diastolic volume increased in the rapid pacing group compared with the control group (84 +/- 6 ml vs. 59 +/- 7 ml, p < 0.05) and remained increased with digoxin (79 +/- 6 ml). Isolated myocyte shortening velocity decreased in the rapid pacing group compared with the control group (37 +/- 1 microns/s vs. 59 +/- 1 microns/s, p < 0.05) and increased with digoxin compared with rapid pacing (46 +/- 1 microns/s, p < 0.05). Action potential maximal upstroke velocity was diminished in the rapid pacing group compared with the control group (135 +/- 6 V/s vs. 163 +/- 9 V/s, p < 0.05) and increased with digoxin compared with rapid pacing (155 +/- 12 V/s, p < 0.05). Action potential duration increased in the rapid pacing group compared with the control group (247 +/- 10 vs. 216 +/- 6 ms, p < 0.05) and decreased with digoxin compared with rapid pacing (219 +/- 12 ms, p < 0.05)., Conclusions: In this model of rapid pacing-induced LV failure, digoxin treatment improved LV pump function, enhanced isolated myocyte contractile performance and normalized myocyte action potential characteristics. This study provides unique evidence to suggest that the cellular basis for improved LV pump function with digoxin treatment in the setting of LV failure has a direct and beneficial effect on myocyte contractile function and electrophysiologic measures.

Background: Clinical trials have demonstrated that angiotensin-converting enzyme inhibition (ACEI) improves survival in patients with long-term left ventricular (LV) dysfunction. However, it remained unclear from these clinical reports whether the beneficial effects of ACEI were due to direct improvements in LV myocardial structure and function. Accordingly, the overall objective of the present study was to examine the direct effects of ACEI on both LV and myocyte structure and function in the setting of cardiomyopathic disease., Methods and Results: LV and isolated myocyte function and structure were examined in control dogs (n = 6), in dogs after the development of dilated cardiomyopathy caused by rapid ventricular pacing (RVP, 216 beats per minute, 4 weeks, n = 6), and in dogs with RVP and concomitant ACEI (RVP/ACEI, fosinopril 30 mg/kg BID, n = 6). LV ejection fraction fell with RVP compared with control values (35 +/- 3 versus 73 +/- 2%, P < .05) and was higher with RVP/ACEI compared with RVP values (41 +/- 4%, P = .048). LV end-diastolic volume increased with RVP compared with control values (78 +/- 7 versus 101 +/- 7 cm3, P < .05) and was lower with RVP/ACEI (82 +/- 3 cm3, P < .05). Isolated myocyte length increased with RVP (182 +- 1 versus 149 +/- 1 micron), and the velocity of shortening decreased (36 +/- 1 versus 57 +/- 1 micron/s) compared with control values (P < .05). With RVP/ACEI, myocyte length was reduced (169 +/- 1 micron) and velocity of shortening was increased (45 +/- 1 micron/s) compared with RVP values (P < .05). Myocyte velocity of shortening after beta-adrenergic receptor stimulation with 25 nmol/L isoproterenol was reduced with RVP compared with control values (142 +/- 5 versus 193 +/- 8 micron/s, P < .05) and significantly improved with RVP/ACEI (166 +/- 6 micron/s, P < .05). In the RVP group, beta-adrenergic receptor density fell 26%, and cAMP production with beta-adrenergic receptor stimulation was reduced 48% from control values. RVP/ACEI resulted in a normalization of beta-adrenergic receptor density and cAMP production. LV myosin heavy-chain content when normalized to dry weight of myocardium was unchanged with RVP (149 +/- 11 mg per gram dry weight of myocardium [gdwt]) and RVP/ACEI (150 +/- 4 mg/gdwt) compared with control values (165 +/- 4 mg/gdwt). LV collagen content decreased with RVP compared with control values (7.6 +/- 0.4 versus 9.6 +/- 0.8 mg per gram wet weight of myocardium [gwwt], P < .05) but was increased with RVP/ACEI (14.4 +/- 1.3 mg/gwwt, P < .05)., Conclusions: Concomitant ACEI with chronic tachycardia reduced LV chamber dilation and improved myocyte contractile function and beta-adrenergic responsiveness. Contributory cellular and extracellular mechanisms for the beneficial effects of ACEI in this model of dilated cardiomyopathy included a normalization of beta-adrenergic receptor function and enhanced myocardial collagen support. The results from this study provide evidence that ACEI during the development of cardiomyopathic disease provided beneficial effects on LV myocyte contractile processes and myocardial structure.

Left ventricular (LV) function and mass were measured in six conscious dogs at weekly intervals during the progression of tachycardia-induced dilated cardiomyopathy (DCM) and during a 1-mo recovery period from DCM (post-DCM). LV end-diastolic volume and LV wall stress increased and LV ejection fraction decreased with each week of pacing. Despite the increased LV wall stress, LV mass did not change during the progression of tachycardia DCM. One week post-DCM resulted in an improved LV ejection fraction and normalization of neurohormonal profiles. However, 1 wk post-DCM was accompanied by a 26% increase in LV mass and persistent LV chamber dilation. Isolated myocyte function was examined and compared with that in six normal control dogs. Myocyte percent and myocyte velocity of shortening were 19 and 32% lower, respectively, in the post-DCM group compared with controls. Thus termination of the tachycardia subsequent to the development of DCM resulted in persistent LV chamber dilation and abnormalities in myocyte contractile function. The improved LV pump function with early recovery from tachycardia-induced DCM was mediated by LV hypertrophy and a subsequent reduction in LV wall stress rather than a normalization of LV geometry and myocyte contractile function.