(LVH) or congestive heart failure (CHF). To address this issue, we studied pressure overload-induced LV hypertrophy (POLVH) and myocardial infarction-elicited congestive heart failure (MICHF) in rats. LV myocytes were isolated from control, POLVH, and MICHF hearts by mechanical homogenization, skinned with Triton, and attached to micropipettes that projected from a sensitive force transducer and high-speed motor. sensitivity toward levels observed in control cells. In contrast, integration of cTn purified from failing ventricles into control myocytes increased EC50 to levels observed in failing myocytes. The Fmax parameter was not markedly affected by troponin exchange. cTnI phosphorylation was increased in both POLVH and MICHF left ventricles. We conclude that depressed myofilament Ca 2ϩ sensitivity in experimental LVH and CHF is due, in part, to a decreased functional role of cTn that likely involves augmented phosphorylation of cTnI. left ventricle; troponin; phosphorylation; cardiac disease CONGESTIVE HEART FAILURE (CHF) is characterized by reduced ventricular pump function, which is due, in part, to cardiac myocyte dysfunction. It has been widely reported that Ca 2ϩ homeostasis is impaired in CHF (14). However, whether depressed myofilament function contributes to reduced ventricular myocyte contractility in CHF is less clear (5). Studies probing myofilament activation in failing human myocardium must be interpreted with caution because tissue quality, pharmacological treatment, and brain death of donors may confound experimental findings (15,30,44). For these reasons, investigators have employed animal models that allow for the study of myofilament function under more carefully controlled circumstances. For instance, studies in the pacing-induced canine model of CHF indicate that the myofilaments generate more force for a given level of activator Ca 2ϩ (increased Ca 2ϩ sensitivity) compared with controls (45). Examination of myofilament activity in the spontaneously hypertensive heart failure prone (SHHF) rat demonstrates that myofilament function is either augmented or unchanged depending on when studies are performed during the disease progression (32). In contrast, Pérez and coworkers (31) found reduced myofilament function in right ventricular (RV) trabeculae of the SHHF rat. Similarly, de Tombe et al. (7) have also shown reduced myofilament function in RV trabeculae obtained from rats with large left ventricular (LV) infarcts and in skinned RV myocytes isolated from rats with chronic RV hypertrophy induced by pulmonary artery banding (9). However, the impact of experimental LV hypertrophy (LVH) or CHF on myofilament function in the more clinically relevant left ventricle has not been carefully studied. The molecular basis for altered myofilament function in LVH and CHF likely involves changes in thick and thin filament proteins. It has been reported that protein kinase C (PKC) is upregulated in cardiac disease (6,13,43). In addition, recent work from our group indicates that PKC-mediated phosphoryla...

Aneurysm plication abruptly decreases left ventricular volume and diastolic compliance, increases end-systolic elastance and PRSW, but decreases the Starling relationship. The net effect on left ventricular function is mixed. Furthermore, left ventricular remodeling 6 weeks after aneurysm plication causes left ventricular volume, end-systolic elastance, diastolic compliance, PRSW, and the Starling relationship to return to preplication values.

The inotropic and toxic effects of cardiac glycosides are thought to be related to their ability to inhibit the Na,K-ATPase. We examined the effects of ouabain and its analogs on sarcoplasmic reticulum (SR) Ca 2ϩ release in intact cat ventricular myocytes under Na ϩ -free conditions and in myocytes in which the sarcolemma was permeabilized using saponin so that cytoplasmic ionic composition was fixed by the bath solutions. We also compared ouabain actions in cat myocytes to those in rat myocytes because the latter is considered to be a glycoside-insensitive species. In intact cat myocytes (Na ϩ -free conditions), spontaneous Ca 2ϩ sparks were prolonged and frequency, amplitude and width were reduced by exposure to ouabain (3 M). Nearly identical results were obtained with its analogs dihydroouabain or ouabagenin (10 M). The frequency of spontaneous Ca 2ϩ waves was also reduced by ouabain. In contrast, ouabain (100 M) had negligible effects on sparks and waves in rat myocytes in Na ϩ -free conditions, consistent with the decreased sensitivity to cardiac glycosides observed in this species. In cat myocytes permeabilized with saponin (0.01%), ouabain (Ն50 nM) decreased spark frequency and increased background SR Ca 2ϩ leak only when the SR was well loaded (free [Ca 2ϩ ] ϭ 275 nM) and not when SR load was low (free [Ca 2ϩ ] ϭ 50 nM). Similar effects were observed in rat myocytes only when ouabain concentration was 1 M. These results suggest that the cellular actions of cardiac glycosides may include a direct effect on SR Ca 2ϩ release, possibly through activation of SR Ca 2ϩ release channels (ryanodine receptors). In addition, these results are consistent with the idea that direct activation of SR Ca 2ϩ release is dependent on the extent of SR Ca 2ϩ load, with elevated load increasing sensitivity of the channel release mechanism to activation by glycoside.

Ventricular volume reduction surgery shifts end-systolic elastance and diastolic compliance to the left on the pressure-volume diagram. The net effect on ventricular function is mixed. Volume reduction surgery increases the slope of preload recruitable stroke work, but increased diastolic compliance causes a small decrease in the Starling relationship (3 mm Hg difference between dilated cardiomyopathy and volume reduction surgery at stroke work = 0.5 J).