Downregulation of cardiac guanosine 5'-triphosphate-binding proteins in right atrium and left ventricle in pacing-induced congestive heart failure.

The extent to which congestive heart failure (CHF) is dependent upon increased levels of the cardiac inhibitory GTP-binding protein (Gi), and the impact of CHF on the cardiac stimulatory GTP-binding protein (Gs) and mechanisms by which Gs may change remain unexplored. We have addressed these unsettled issues using pacing-induced CHF in pigs to examine physiological, biochemical, and molecular features of the right atrium (RA) and left ventricle (LV). CHF was associated with an 85 +/- 20% decrease in LV segment shortening (P < 0.001) and a 3.5-fold increase (P = 0.006) in the ED50 for isoproterenol-stimulated heart rate responsiveness. Myocardial beta-adrenergic receptor number was decreased 54% in RA (P = 0.004) and 57% in LV (P < 0.001), and multiple measures of adenylyl cyclase activity were depressed 49 +/- 8% in RA (P < 0.005), and 44 +/- 9% in LV (P < 0.001). Quantitative immunoblotting established that Gi and Gs were decreased in RA (Gi: 59% reduction; P < 0.0001; Gs: 28% reduction; P < 0.007) and LV (Gi: 35% reduction; P < 0.008; Gs: 28% reduction; P < 0.01) after onset of CHF. Reduced levels of Gi and Gs were confirmed by ADP ribosylation studies, and diminished function of Gs was established in reconstitution studies. Steady state levels for Gs alpha mRNA were increased in RA and unchanged in LV, and significantly more GS alpha was found in the supernatant (presumably cytosolic) fraction in RA and LV membrane homogenates after CHF, suggesting that increased Gs degradation, rather than decreased Gs synthesis, is the mechanism by which Gs is downregulated. We conclude that cardiac Gi content poorly predicts adrenergic responsiveness or contractile function, that decreased Gs is caused by increased degradation rather than decreased synthesis, and that alterations in beta-adrenergic receptors, adenylyl cyclase, and GTP-binding proteins are uniform in RA and LV in this model of congestive heart failure.

Force-frequency relations during heart failure in pigs.

In isolated cardiac muscle from patients with severe heart failure (HF) the force-frequency relation (FFR) is often negative, but the characteristics of the FFR under basal conditions and its responsiveness to adrenergic stimulation have not been studied in the intact, failing heart. Severe HF was produced in pigs (n = 6) by continuous rapid left ventricular (LV) pacing (225 beats/min). In the conscious resting state, high-fidelity LV pressure and its maximum first derivative (LV dP/dtmax) were obtained over a range of atrial pacing rates (100-225 beats/min) before (control) and after HF. Before HF, the relationship between increased heart rate and LV dP/dtmax (a measure of the FFR) was flat, but during dobutamine infusion the FFR showed a significant positive slope (P < 0.003). After HF, the basal FFR was depressed, but the slope of the FFR was not increased by dobutamine. After HF, responses of dP/dtmax to slowing of HR by a specific sinus node inhibitor confirmed the absence of a negative basal FFR. In conclusion, the basal LV FFR in conscious pigs with severe HF was not negative. Unlike the normal heart, in HF beta-adrenergic receptor stimulation did not amplify the FFR, a phenomenon that could play an important role in the impaired response to exercise in patients with HF.

Detection of regional left ventricular dysfunction in early pacing-induced heart failure using ultrasonic integrated backscatter.

BACKGROUND: It has been demonstrated that cyclic variation of ultrasonic integrated backscatter (CVIBS) may be useful in detecting altered physical conditions in the heart. However, no previous study has examined serial changes of CVIBS in the myocardium during the development of left ventricular dysfunction. METHODS AND RESULTS: We examined alterations of CVIBS in pacing-induced cardiac dysfunction. Eight pigs (36 +/- 2 kg) were studied before and sequentially during sustained rapid ventricular pacing (225 +/- 9 beats per minute). CVIBS was measured in the IVS and left ventricular PLW before pacing and daily for 4 days after onset of pacing. Five additional pigs (35 +/- 10 kg) were examined after 14 days of pacing. Regional function and CVIBS were assessed with pacemakers inactivated. A quantitative integrated backscatter imaging system (two-dimensional format) was used. Over 4 days of pacing, the magnitude of CVIBS progressively decreased in the PLW but was unchanged in the IVS, findings that persisted at 14 days. Percent wall thickening in the PLW progressively decreased to a greater degree than percent wall thickening in the IVS. A linear relation between the magnitude of CVIBS and percent wall thickening was found. At 14 days, blood flow to the two regions was similar but regional differences in CVIBS persisted. CONCLUSIONS: Rapid left ventricular pacing produces abnormalities of regional myocardial function within 48 hours of pacing. Regional myocardial dysfunction is accompanied by a reduction in CVIBS in the same region.

Regional deficits of myocardial blood flow and function in left ventricular pacing-induced heart failure.

BACKGROUND: Pacing-induced congestive hear, failure has become a preferred model for the study of the pathogenesis of dilated cardiomyopathy. However, little is known regarding regional myocardial blood flow and function during the development of heart failure in this model. METHODS AND RESULTS: To determine whether regional differences in myocardial blood flow are associated with regional dysfunction in ventricular pacing-induced heart failure, regional myocardial blood flow (radioactive microspheres) and regional wall thickening (transthoracic echocardiography) were measured in pigs studied at weekly intervals during the progression of heart failure induced by rapid pacing from the lateral wall of the left ventricle (220 +/- 9 bpm for 26 +/- 4 days). Echocardiography and hemodynamic measurements with the pacemaker off showed progressive, severe global left ventricular dysfunction. During pacing over the 3- to 4-week period, a progressive decrease in systolic wall thickening in the lateral wall occurred compared with the interventricular septum (IVS; P = .001); at 21 to 28 days, the difference was 50% (lateral wall, 14 +/- 6%; IVS, 28 +/- 6%; P = .0001). A difference in subendocardial blood flow per beat between the left ventricular lateral wall (the site of stimulation) and the IVS was found immediately on the initiation of pacing (IVS, 0.009 +/- 0.002 mL.min-1.g-1.beat-1; lateral wall, 0.005 +/- 0.001 mL.min-1.g-1.beat-1; P = .001), a difference that was sustained during pacing throughout the study. Subendocardial blood flow per beat was normal in both regions with the pacemaker off throughout the study. CONCLUSIONS: These data indicate that regional myocardial ischemia is associated with the development of contractile dysfunction of the paced wall during prolonged rapid left ventricular pacing and that regional stunning contributes to persistent global left ventricular dysfunction when pacing is discontinued.