Ten weeks of rapid ventricular pacing creates a long-term model of left ventricular dysfunction.

OBJECTIVE: Rapid ventricular pacing produces a reliable model of heart failure. Cessation after 4 weeks of rapid ventricular pacing results in rapid normalization of left ventricular function, but the left ventricle remains persistently dilated. We present novel data that show that prolonged rapid ventricular pacing (10 weeks) creates a model of chronic left ventricular dysfunction. METHODS: In 9 dogs undergoing 10 weeks of rapid ventricular pacing, left ventricular function and volumes were serially assessed by using 2-dimensional echocardiography and pressure-volume analysis for 12 weeks after cessation of pacing. RESULTS: Increased end-diastolic volume and decreased systolic and diastolic function were seen at the end of pacing. By 2 weeks of recovery from rapid ventricular pacing, end-diastolic volume and ejection fraction were partially recovered but did not improve further thereafter. Load-independent and load-sensitive indices of function obtained by pressure-volume analysis at 8 and 12 weeks of recovery confirmed a persistence of both systolic and diastolic dysfunction. In addition, left ventricular mass increased with pacing and remained elevated at 8 and 12 weeks of recovery. Four of these dogs studied at 6 months of recovery showed similar left ventricular abnormalities. CONCLUSION: Ten weeks of rapid ventricular pacing creates a long-term model of left ventricular dysfunction.

Cardiovascular effects of inhaled nitric oxide in a canine model of cardiomyopathy.

BACKGROUND: The inhalation of nitric oxide (NO) in patients with heart failure decreases pulmonary vascular resistance (PVR) and is associated with an increase in pulmonary artery wedge pressure (PAWP). The mechanism for this effect remains unclear. METHODS: In dogs rapid-paced for 8 weeks to induce cardiac dysfunction, we performed left ventricular pressure-volume analysis of unpaced hearts in situ to determine whether during NO inhalation (80 ppm), the mechanism for the rise in PAWP is due to: 1) primary pulmonary vasodilation; 2) a direct negative inotropic effect; or 3) impairment of ventricular relaxation. RESULTS: Inhalation of NO decreased PVR by 51%+/-3.8% (257+/-25 vs 127+/-18 dynes x sec x cm(-5) [NO 80 ppm]; p < 0.001) and increased PAWP (15.4+/-2.4 vs 18.1+/-2.6 mm Hg [NO 80 ppm]; p < 0.001). Calculated systemic vascular resistance remained unchanged. Left ventricular (LV) end-diastolic pressure rose (16.4+/-1.9 vs 19.1+/-1.8 mm Hg [NO 80 ppm]; p < 0.001), as did LV end-diastolic volume (83.5+/-4.0 vs 77.0+/-3.4 mL [NO 80 ppm]; p = 0.006). LV peak +dP/dt was unchanged by NO (1,082+/-105 vs 1,142+/-111 mm Hg/sec [NO 80 ppm]; p = NS). There was a trend toward a stroke volume increase (17.4+/-1.2 vs 18.8+/-1.3 mL; p = NS), but the relaxation time constant and end-diastolic pressure-volume relation were both unchanged. CONCLUSIONS: In this canine model of cardiomyopathy, inhaled NO decreases pulmonary vascular resistance. The associated increase in left ventricular filling pressure appears to be secondary to a primary pulmonary vasodilator effect of NO without primary effects on the contractile or relaxation properties of the left ventricle.

Long-term dynamic cardiomyoplasty improves chronic and acute myocardial energetics in a model of left ventricular dysfunction.

BACKGROUND: We present the first long-term evaluation of myocardial energetics after dynamic cardiomyoplasty (CMP) in a model of left ventricular (LV) dysfunction. METHODS AND RESULTS: Seventeen dogs underwent rapid ventricular pacing (RVP) to create heart failure. Eight dogs were randomly selected to undergo cardiomyoplasty. All dogs continued RVP for 6 additional weeks, whereas the CMP dogs underwent a simultaneously delivered synchronized muscle wrap conditioning protocol. After termination of RVP at 10 weeks in all dogs, myoplasty dogs continued to receive muscle wrap stimulation until the terminal study. Pressure-volume analysis to assess LV energetics was conducted at baseline and 4 weeks and 3 months after termination of RVP (6 months after baseline). At 6 months, CMP dogs displayed enhanced contractility, lower volumes, and more optimal energetics compared with control animals. Acute muscle wrap stimulation further increased effective contractility and myocardial efficiency compared with unassisted beats. CONCLUSIONS: The decrease in NYHA functional class that occurs in patients after dynamic cardiomyoplasty may be secondary to its beneficial effects on long-term myocardial function, volume, and energetics.

Stabilization of chronic remodeling by asynchronous cardiomyoplasty in dilated cardiomyopathy: effects of a conditioned muscle wrap.

BACKGROUND: Dynamic cardiomyoplasty is a promising new therapy for dilated cardiomyopathy. The girdling effects of a conditioned muscle wrap alone have recently been postulated to partly explain its mechanism. We investigated this effect in a canine model of chronic dilated cardiomyopathy. METHODS AND RESULTS: Twenty dogs underwent rapid ventricular pacing (RVP) for 4 weeks to create a model of dilated cardiomyopathy. Seven dogs were then randomly selected to undergo subsequent cardiomyoplasty, and all dogs had 6 weeks of additional RVP. The cardiomyoplasty group also received 6 weeks of concurrent skeletal muscle stimulation consisting of single twitches delivered asynchronously at 2 Hz to transform the wrap without active assistance. All dogs were studied by pressure-volume analysis and echocardiography at baseline and after 4 and 10 weeks of pacing. Systolic indices, including ejection fraction (EF), end-systolic elastance (Ees), and preload-recruitable stroke work (PRSW) were all increased at 10 weeks in the wrap versus controls (EF, 34.0 versus 27.1, P=.008; Ees, 1.65 versus 1.26, P=.09; PRSW, 35.9 versus 25.5, P=.001). Ventricular volumes, diastolic relaxation, and left ventricular end-diastolic pressures stabilized in the cardiomyoplasty group but continued to deteriorate in controls. Both the end-systolic and end-diastolic pressure-volume relationships shifted farther rightward in controls but remained stable in the cardiomyoplasty group. CONCLUSIONS: In addition to potential benefits from active systolic assistance, benefits from dynamic cardiomyoplasty appear to be partially accounted for by the presence of a conditioned muscle wrap alone. This conditioned wrap stabilizes the remodeling process of heart failure, arresting progressive deterioration of systolic and diastolic function.

Dynamic cardiomyoplasty: its chronic and acute effects on the failing heart.

OBJECTIVES: Dynamic cardiomyoplasty is an alternative therapy for end-stage heart failure. We investigated the mechanisms, both acute and chronic, by which a synchronously stimulated conditioned muscle wrap affects left ventricular function in a chronic canine model of dilated cardiomyopathy. METHODS: Nineteen dogs underwent rapid ventricular pacing at a rate of 215 beats/min for 4 weeks to create a model of heart failure. Eight dogs were then randomly selected to undergo cardiomyoplasty, and all dogs received 6 additional weeks of rapid ventricular pacing. The cardiomyoplasty group also received a graded muscle conditioning protocol of synchronized burst stimulation to transform the muscle wrap. All dogs were studied with pressure-volume analysis and echocardiography at baseline and after 4 and 10 weeks of rapid ventricular pacing. Data in the cardiomyoplasty group were analyzed with the stimulator off, with it augmenting every beat (1:1), and with it augmenting only every other beat (1:2). RESULTS: Stimulator "of" data at 10 weeks of rapid pacing demonstrated chronic effects by enhanced ventricular function (end-systolic elastance = 1.80 after myoplasty vs 1.17 for controls, p = 0.005) and a stabilization of volumes and composite end-systolic and end-diastolic pressure-volume relations in the cardiomyoplasty group when compared with controls. Myoplasty stimulation increased apparent contractility (preload recruitable stroke work = 31.3 for stimulator "of" vs 40.6 for stimulator 1:2 assisted beats [p < 0.05] and vs 45.4 for stimulator 1:1 [p < 0.05]). CONCLUSIONS: Benefits from dynamic cardiomyoplasty are by at least two mechanisms: (1) the girdling effects of a conditioned muscle wrap, which halts the chronic remodeling of heart failure, and (2) active systolic assistance, which augments the apparent contractility of the failing heart.

Triiodothyronine optimizes sheep ventriculoarterial coupling for work efficiency.

BACKGROUND: Triiodothyronine (T3) administration after cardiopulmonary bypass has been shown to significantly improve cardiac performance. The present study was undertaken to elucidate the effects of T3, when administered as an intravenous bolus, on both cardiac energetics and stroke work-oxygen utilization (EW/LVVO2) efficiency. METHODS: In both unstressed and stressed hearts, energetics were evaluated at baseline and 2 hours after intervention in an in vivo sheep preparation. In the first group (n = 5) sheep received saline vehicle. In the second group (n = 9) sheep received an intravenous bolus of 1.2 micrograms/kg of T3. In the third group (n = 7) sheep received a 2-hour intravenous infusion of dobutamine at a rate of 5 micrograms/kg/min. RESULTS: In the unstressed heart, T3 improved cardiac function at no cost in oxygen consumption by decreasing afterload and hence improved EW/LVVO2 efficiency. In contrast, dobutamine improved unstressed cardiac function by increasing contractility at the cost of increased oxygen consumption and thus decreased EW/LVVO2 efficiency. Triiodothyronine optimized ventriculoarterial coupling for efficiency, but dobutamine optimized coupling for maximal work. In the stressed heart, T3 again improved EW/LVVO2 efficiency, but dobutamine had the opposite effect. CONCLUSIONS: The bolus administration of T3 improves unstressed cardiac performance through optimization of ventriculoarterial coupling for EW/LVVO2 efficiency, primarily through vasodilation. Triiodothyronine also increases efficiency in the stressed heart. This study supports the use of T3 in cardiac operations to improve cardiac performance with no cost in oxygen consumption characteristic of inotropic agents.

Acute systolic and diastolic indices of left ventricular function after cardiomyoplasty in a chronic model of heart failure.

Recent experimental studies have suggested that the initial nonstimulated stage of dynamic cardiomyoplasty acutely impairs ventricular function. Those investigations were performed on normal hearts and primarily examined diastolic alterations as a result of the passive muscle wrap. The purpose of this study was to assess the acute systolic and diastolic effects of a nonstimulated muscle wrap in chronic heart failure induced by rapid ventricular pacing in canines. Pressure-volume analysis of ventricular function based on conductance catheter volume and micromanometer pressure data was used. Each animal was studied before rapid pacing, before cardiomyoplasty, and immediately after wrap. By the end of the pacing period and before wrap, left ventricular dysfunction developed in all dogs, manifested by significant deterioration of both systolic and diastolic indices of ventricular function, as well as progressive increases in left ventricular volumes. However, no further deterioration with load insensitive indices of systolic or diastolic indicators of ventricular function was found as a result of the passive muscle wrap. These results suggest that the cardiomyoplasty procedure can be safely performed on failing hearts without prohibitive acute impairment of ventricular function.