Weeks Of Rapid Pacing Research Articles

Alternation of left ventricular load by a continuous-flow left ventricular assist device with a native heart load control system in a chronic heart failure model

We previously developed a native heart load control system for a continuous-flow left ventricular assist device and demonstrated that the rotational speed synchronized with the cardiac cycle can alter left ventricular preload and myocardial oxygen consumption. In the present study, we assessed this system in a conscious goat model of chronic heart failure. Chronic heart failure was induced by coronary microsphere embolization of the left ascending artery and subsequent rapid ventricular pacing in 6 goats. After 4 to 6 weeks of rapid pacing, the goats showed a decreased ejection fraction (from 89.7% ± 3.1% to 53.3% ± 5.4%) measured during sinus rhythm. The assist device was implanted by way of a left thoracotomy, and we examined the effects of the continuous, co-pulse, andcounterpulse mode on the end-diastolic volume and stroke work, determined from the left ventricular pressure-volume loops. Significant decreases were found in the end-diastolic volume and stroke work in the counterpulse mode relative to the values observed with 0% bypass (63.4% ± 15.2% and 39.1% ± 18.2%, respectively; P<.01). Furthermore, both increased in the co-pulse mode (82.1% ± 17.6% and 68.3% ± 22.2%; P<.01) compared with those in the continuous mode (69.6% ± 15.4% and 54.6% ± 21.6%) with 100% bypass. The system offers the possibility to control the left ventricular load by changing the rotational speed of a continuous-flow assist device in synchronization with the cardiac cycle. This system should provide the most favorable left ventricular loading conditions for recovery of the native heart.

Ventricular ErbB2/ErbB4 activation and downstream signaling in pacing-induced heart failure

The neuregulin-1 (NRG-1)/ErbB system has emerged as a cardioprotective system that becomes activated during myocardial stress, most convincingly shown in response to cardiotoxic chemotherapy. Direct evidence of increased ventricular ErbB receptor activity in heart failure unrelated to cardiotoxic drugs is, however, limited. We investigated changes in NRG-1 expression, ErbB receptor phosphorylation and downstream activation of intracellular ErbB targets during rapid pacing and progressive ventricular dysfunction in the dog. Heart failure was induced in dogs by 7 weeks of rapid pacing. Ventricular function was assessed by echocardiography. Messenger RNA expression was investigated in ventricular biopsies using quantitative PCR. Activation of NRG-1/ErbB signaling and of downstream targets was investigated using immunoprecipitation and/or Western blotting. Over the course of 7 weeks of pacing and ventricular dilatation, ventricular levels of NRG-1, but not of other ErbB4 ligands, and of ADAM19, a protease promoting NRG-1 release, progressively increased. In parallel, levels of activated ErbB2 and ErbB4, phosphorylated at tyrosine residues 877/1248 and 1284 respectively, became progressively higher. Similarly, levels of total and phosphorylated PI-3 kinase increased. Surprisingly, however, and in contrast with activation of downstream targets of ErbB receptors in normal hearts, Akt and ERK1/2, remained inactivated. This study shows that ventricular ErbB2 and ErbB4 receptors become activated during the development of pacing-induced heart failure, but that downstream signaling is, at least partly, abrogated. Abrogation of cardioprotective signaling after ErbB activation is an unanticipated phenomenon in the progression of heart failure with possibly major pathophysiological significance. The underlying mechanisms should be further elucidated.

Feasibility of Using an Implantable System to Measure Thoracic Congestion in an Ambulatory Chronic Heart Failure Canine Model

Noninvasive measures of impedance reflect alterations in thoracic fluid and pulmonary edema in acute animal and human studies. We evaluated the feasibility of using an implantable impedance measuring device and cardiac lead system to monitor intrathoracic congestion in a pacing-induced heart failure canine model. Three devices were implanted in each of five dogs: a modified pacemaker to measure impedance from a defibrillation lead implanted in the right ventricle; an implantable hemodynamic monitoring device to measure left ventricular end diastolic pressure (LVEDP) and a second pacemaker to deliver rapid (240 pulses per minute) ventricular pacing to induce heart failure. All five dogs developed severe heart failure after 3-4 weeks of rapid pacing and recovered following pacing termination. The LVEDP increased and impedance decreased during pacing-induced heart failure and recovered after pacing cessation. At the end of pacing, there was a mean impedance reduction of 10.6 +/- 8.3% and a mean LVEDP increase of 18.1 +/- 4.5 mmHg compared to baseline. The impedance and LVEDP were inversely correlated (r =-0.41 to -0.85, all P < 0.05). In the canine model, measurement of chronic intrathoracic impedance with an implantable system effectively revealed changes in thoracic congestion due to heart failure reflected by LVEDP. These data suggest that implantable device-based impedance measurement merits further investigation as a tool to monitor the fluid status of heart failure patients.

Mechanisms of elevated plasma endothelin-1 in CHF: congestion increases pulmonary synthesis and secretion of endothelin-1.

The pulmonary circulation may contribute to elevated plasma levels of endothelin-1 (ET-1) in congestive heart failure (CHF). The aims of the present study were to determine the mechanisms of increased secretion of ET-1 from the pulmonary circulation in CHF. Juvenile pigs were subjected to sham operation (n=9) or rapid cardiac pacing-induced CHF (215-240 bpm, n=15). Three weeks of rapid pacing led to significant left ventricular dilatation, increased cardiac filling pressures, and reduced contractility (CHF pigs). Arterial plasma ET-1 levels in the CHF pigs were increased 4-fold compared to sham pigs (P<0.001). Single-bolus multiple indicator-dilution experiments revealed that pulmonary synthesis and release of ET-1 was increased in CHF, while pulmonary clearance of plasma ET-1 remained unaltered despite significant reduction of pulmonary fractional extraction of plasma ET-1. Pulmonary ECE-1 isozyme activity (pmol.min-1.mg protein-1) was selectively increased in lower lobe segments of CHF pigs (2.0+/-0.3) compared to lower lobe segments of controls (1.1+/-0.1, P<0.02), and to upper lobe segments of CHF pigs (1.1+/-0.1, P<0.005), and correlated significantly with the wet/dry weight ratios of the pulmonary tissue samples (R=0.75, P<0.001), i.e. a marker of pulmonary congestion. Furthermore, alveolar macrophages in congested lobe segments were identified as likely sites of increased synthesis and release of ET-1. In rapid pacing-induced CHF, a complex cardiopulmonary interaction revealed by pulmonary congestion causes increased pulmonary production and secretion of ET-1 due to enhanced pulmonary ECE-1 activities. Pulmonary secretion of ET-1 during evolving CHF is an important contributor to elevated plasma ET-1 levels in the systemic circulation.

Attenuation of angiotensin II-mediated coronary vasoconstriction and vasodilatory action of angiotensin-converting enzyme inhibitor in pacing-induced heart failure in dogs

OBJECTIVESWe investigated the changes in coronary vascular resistance caused by angiotensin II, angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 or 2 receptor (AT1R and AT2R, respectively) antagonists in chronic heart failure (CHF).BACKGROUNDAngiotensin II is an intense vasoconstrictor, and increased angiotensin II in CHF might exert significant vasoconstriction.METHODSEleven dogs were studied. Before and after three and five weeks of rapid pacing, coronary flow dynamics were evaluated by the coronary pressure–flow relationship (PFR) in long diastole, before and after intracoronary injection of angiotensin II, the ACE inhibitor enalaprilat, the AT1R antagonist L158,809 or the AT2R antagonist PD123319.RESULTSBefore rapid pacing, angiotensin II reduced the slope of PFR (1.16 ± 0.08 to 0.81 ± 0.07 ml/min/100 g left ventricular mass per mm Hg; p < 0.01) and increased the perfusion pressure at which coronary flow ceased (zero-flow pressure [Pf= 0]), whereas enalaprilat did not change either of them. After rapid pacing, angiotensin II did not change the slope or Pf= 0. In contrast, enalaprilat increased the slope (three weeks: 1.20 ± 0.05 to 1.50 ± 0.03; five weeks: 1.25 ± 0.19 to 1.37 ± 0.08; both p < 0.05) and decreased Pf= 0 after three weeks of pacing, but not after five weeks. Pretreatment with the bradykinin antagonist HOE-140 attenuated the enalaprilat-induced increase in coronary blood flow. L158,809 and PD123319 had no effect both before and after rapid pacing.CONCLUSIONSThis suggests that the coronary vasoconstrictive effect of angiotensin II would disappear and the vasodilatory effect of the ACE inhibitor, partly through bradykinin, would be enhanced in the early stage of CHF.

Heart failure in the dog induced by rapid ventricular pacing using a newly designed cardiac pacemaker, MCMS-0102

Tahyccardia-induced heart failure is an ideal experimental heart-failure model. We designed a new cardiac pacemaker (MCMS-0102) for rapid ventricular pacing to induce congestive heart filure, and we then implanted and tested this pacemaker in an adult mongrel dog. The dog was paced at 250 beats/min (bpm) for 3 weeks and subsequently paced at 256 bpm for another 3 weeks. After 4 weeks of rapid pacing, the dog showed symptoms of cardiac failure (ascites and edema in the paws), and its body weight increased from 24 to 26 kg. After 6 weeks of pacing, the body weight increased to 28kg, and ascites and edema in the paws were more remarkable than after 4 weeks of pacing. Postmortem examination revealed massive ascites, pleural effusion, cardiomegaly, and liver congestion. The explanted pacemaker showed no mechanical problems. We evaluated neurohumoral changes in the dog before and after rapid pacing. Plasma renin activity increased from 3.2 to 17.9 ng/ml/h, plasma aldosterone from 100 to 2200 pg/ml, plasma norepinephrine from 60 to 861 pg/ml, and atrial natriuretic peptide from 28 to 250pg/ml. This study suggests that the MCMS-0102 has a high potential for use in heart-failure research.

Cardiac natriuretic peptides and continuously monitored atrial pressures during chronic rapid pacing in pigs.

Changes in atrial natriuretic peptide (ANP), N-terminal proatrial natriuretic peptide and brain natriuretic peptide (BNP) were evaluated in relation to continuously monitored atrial pressures in a pacing model of heart failure. Pigs were subjected to rapid atrial pacing (225 beats min-1) for 3 weeks with adjustments of pacing frequencies if the pigs showed overt signs of cardiac decompensation. Atrial pressures were monitored by a telemetry system with the animals unsedated and freely moving. Left atrial pressure responded stronger and more rapidly to the initiation of pacing and to alterations in the rate of pacing than right atrial pressure. Plasma natriuretic peptide levels were measured by radioimmunoassay and all increased during pacing with BNP exhibiting the largest relative increase (2.9-fold increase relative to sham pigs). Multiple regression analysis with dummy variables was used to evaluate the relative changes in natriuretic peptides and atrial pressures and the strongest correlation was found between BNP and left atrial pressure with R 2=0.81. Termination of pacing resulted in rapid normalization of ANP values in spite of persistent elevations in atrial pressures. This may reflect an increased metabolism or an attenuated secretory response of ANP to atrial stretch with established heart failure. In conclusion, 3 weeks of rapid pacing induced significant increases in atrial pressures and natriuretic peptide levels. All the natriuretic peptides correlated with atrial pressures with BNP appearing as a more sensitive marker of cardiac filling pressures than ANP and N-terminal proatrial natriuretic peptide.

Cardiac loading conditions modify the ventricular repolarization in conscious dogs with heart failure.

Changes in myocardial loading conditions influence the ventricular action potential via mechanoelectric feedback, a mechanism impaired in pathology. In vivo the QT interval of the electrocardiogram which reflects the action potential duration allows appropriate determination of its modifications. The effects of changes in cardiac loading conditions (load reduction with trinitrin; volume loading with Plasmion) on regional function and ventricular local electrogram were investigated in conscious dogs before (control) and after 4 weeks of rapid pacing (dilated cardiomyopathy, DCM). In controls both interventions increased heart rate. Trinitrin increased end-diastolic wall thickness (EDWth, P<0.001) and reduced absolute QT interval duration (P<0.05). Plasmion decreased EDWth (P<0.001) and increased left ventricular end diastolic pressure (LVEDP, P<0.001) without QT interval alteration. However, the corrected QT interval was unchanged in both interventions. In DCM, trinitrin did not change the QT interval. Plasmion increased LVEDP (P<0.01) and prolonged QT and corrected QT intervals (P<0.01) despite the tachycardia. In controls the changes in cardiac loading conditions did not modify the QT interval, suggesting intact endogenous regulation of repolarization. The impaired adaptation observed in DCM contributed to an increase in QT interval following volume loading. In this model, a prolonged repolarization after abrupt volume loading may result from enhanced or disclosed mechanoelectric feedback.

Relation between ligament of Marshall and adrenergic atrial tachyarrhythmia.

The mechanism of the adrenergic atrial tachyarrhythmia is unclear. We hypothesize that the ligament of Marshall (LOM) is sensitive to adrenergic stimulation and may serve as a source of the adrenergic atrial tachyarrhythmia. We performed computerized mapping studies in isolated-perfused canine left atrial tissues from normal dogs (n=9) and from dogs with chronic atrial fibrillation (AF) induced by 10 to 41 weeks of rapid pacing (n=3). Before isoproterenol, spontaneous activity occurred in only one normal tissue (cycle length, CL >1300 ms). During isoproterenol infusion, automatic rhythm was induced in both normal tissues (CL=578+/-172 ms) and AF tissues (CL=255+/-29 ms, P<0.05). The origin of spontaneous activity was mapped to the LOM. In the AF tissues, but not the normal tissues, we observed the transition from rapid automatic activity to multiple wavelet AF. Ablation of the LOM terminated the spontaneous activity and prevented AF. Immunocytochemical studies of the LOM revealed muscle tracts surrounded by tyrosine hydroxylase-positive (sympathetic) nerves. We conclude that the LOM is richly innervated by sympathetic nerves and serves as a source of isoproterenol-sensitive focal automatic activity in normal canine atrium. The sensitivity to isoproterenol is upregulated after long-term rapid pacing and may contribute to the development of AF in this model.

Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I: experimental studies.

Pacing-induced heart failure in the dog recapitulates many of the electrophysiological and hemodynamic abnormalities of the human disease; however, the mechanisms underlying altered Ca2+ handling have not been investigated in this model. We now show that left ventricular midmyocardial myocytes isolated from dogs subjected to 3 to 4 weeks of rapid pacing have prolonged action potentials and Ca2+ transients with reduced peaks, but durations approximately 3-fold longer than controls. To discriminate between action potential effects on Ca2+ kinetics and direct changes in Ca2+ regulatory processes, voltage-clamp steps were used to examine the time constant for cytosolic Ca2+ removal (tauCa). tauCa was prolonged by just 35% in myocytes from failing hearts after fixed voltage steps in physiological solutions (tauCa control, 216+/-25 ms, n=17; tauCa failing, 292+/-23 ms, n=22; P<0.05), but this difference was markedly accentuated when Na+/Ca2+ exchange was eliminated (tauCa control, 282+/-30 ms, n=13; tauCa failing, 576+/-83 ms, n=11; P<0. 005). Impaired sarcoplasmic reticular (SR) Ca2+ uptake and a greater dependence on Na+/Ca2+ exchange for cytosolic Ca2+ removal was confirmed by inhibiting SR Ca2+ ATPase with cyclopiazonic acid, which slowed Ca2+ removal more in control than in failing myocytes. beta-Adrenergic stimulation of SR Ca2+ uptake in cells from failing hearts sufficed only to accelerate tauCa to the range of unstimulated controls. Protein levels of SERCA2a, phospholamban, and Na+/Ca2+ exchanger revealed a pattern of changes qualitatively similar to the functional measurements; SERCA2a and phospholamban were both reduced in failing hearts by 28%, and Na+/Ca2+ exchange protein was increased 104% relative to controls. Thus, SR Ca2+ uptake is markedly downregulated in failing hearts, but this defect is partially compensated by enhanced Na+/Ca2+ exchange. The alterations are similar to those reported in human heart failure, which reinforces the utility of the pacing-induced dog model as a surrogate for the human disease.

The effects of prosthetic cardiac binding and adynamic cardiomyoplasty in a model of dilated cardiomyopathy

Objective: Because adynamic cardiomyoplasty, or wrapping skeletal muscle around the heart, had been shown to provide a girdling effect and delay progressive ventricular dilatation in heart failure, a similar girdling effect by the much simpler procedure of cardiac binding, using a prosthetic membrane to wrap the heart, was studied and compared with that of adynamic cardiomyoplasty. Methods: Twenty-one dogs were divided into control, adynamic cardiomyoplasty, and cardiac binding groups. Cardiac dimension and hemodynamic studies were carried out before and 4 weeks after rapid pacing at 250 beats/min. For adynamic cardiomyoplasty, the left latissimus dorsi muscle was used for the cardiac wrap; for cardiac binding, a Marlex sheet (C. R. Bard, Inc., Murray Hill, N.J.) was used. Serial two-dimensional echocardiography, right heart catheterization, and in the cardiac binding group, left heart catheterization were performed. Results: Four weeks of rapid pacing induced severe heart failure and cardiac dilatation. The magnitude of ventricular dilatation at the end of rapid pacing was less in the cardiac binding group than in the control group and least in the adynamic cardiomyoplasty group. Left ventricular end-diastolic volume, end-systolic volume, and ejection fraction were 82.1 ± 21.1 ml, 67.1 ± 16.0 ml, and 17.5% ± 5.8%, respectively, in the control group; 61.9. ± 8.1 ml, 44.1 ± 7.8 ml, and 30.1% ± 3.6%, respectively, in the cardiac binding group; and 51.8 ± 8.7 ml, 30.3 ± 10.4 ml, and 27.0% ± 4.0%, respectively, in the adynamic cardiomyoplasty group. Conclusions: Both adynamic cardiomyoplasty and cardiac binding reduced cardiac enlargement and functional deterioration after rapid pacing, with adynamic cardiomyoplasty appearing to be more effective, perhaps because of the adaptive capabilities of the skeletal muscle wrap. However, cardiac binding is a simpler and less invasive procedure, which may be useful as an adjunct to prevent or delay progressive ventricular dilatation in heart failure. (J Thorac Cardiovasc Surg 1998;116:148-53)

Mechanisms of Cardiomyoplasty: Comparative Effects of Adynamic Versus Dynamic Cardiomyoplasty

Background. The apparent paradox seen in patients who have undergone dynamic cardiomyoplasty and shown substantial clinical and functional improvements with only modest hemodynamic changes may be due to inappropriate end points chosen for study, a result of incomplete understanding of mechanisms involved. The purpose of this study was to compare the relative role of the passive “girdling effect” and the dynamic “systolic squeezing effect” of the wrapped muscle in cardiomyoplasty. Methods. The control group of 6 dogs underwent 4 weeks of rapid pacing (250 beats/min) to induce severe heart failure followed by 8 weeks of observation without rapid pacing. The trajectory of recovery in hemodynamics and cardiac dimensions was followed with echocardiography and Swan-Ganz catheters. In the “adynamic” cardiomyoplasty group (n = 4), the left latissimus dorsi muscle was wrapped around the ventricles and allowed to stabilize and mature for 4 weeks. This was followed by rapid pacing and recovery as in the control group. In the “dynamic” cardiomyoplasty group (n = 3), the same protocol for the adynamic group was followed except that a synchronizable cardiomyostimulator was attached to the thoracodorsal nerve of the muscle wrap. This allowed the latter to be transformed during the rapid-pacing phase and permitted dynamic squeezing of the muscle wrap to be generated by burst stimulation synchronized with cardiac contraction in a 1:2 ratio. Results. Baseline data were comparable in all groups prior to rapid pacing. After 4 weeks of rapid pacing, the left ventricular ejection fraction was higher in the adynamic (27.0% ± 3.9%; p < 0.05) and dynamic (33.3% ± 2.3%; p < 0.02) cardiomyoplasty groups compared with controls (18.8% ± 8.3%). Similarly, ventricular dilatation in both systole and diastole was less in the adynamic (51.8 ± 8.7 mL, [ p < 0.002] and 38.2 ± 7.2 mL [ p < 0.001], respectively) and dynamic (62.0 ± 7.2 [ p < 0.02] and 41.3 ± 3.5 mL [ p < 0.005], respectively) cardiomyoplasty groups compared with controls. In the dynamic group, on and off studies were carried out after cessation of rapid pacing while the heart was still in severe failure, and they demonstrated a systolic squeezing effect in stimulated beats. Only this group recovered fully to baseline after 8 weeks. Conclusions. By reducing myocardial stress, both the passive girdling effect and the dynamic systolic squeezing effect have complementary roles in the mechanisms of dynamic cardiomyoplasty.

Increased cardiac and pulmonary endothelin-1 mRNA expression in canine pacing-induced heart failure.

The canine model of pacing-induced heart failure (HF) simulates human dilated cardiomyopathy and is characterized by severe hemodynamic perturbations. We have previously demonstrated increased plasma endothelin-1 (ET-1) and left ventricular (LV) tissue peptide levels in this model. However, the gene expression of ET-1 has not been studied. Accordingly, we compared preproET-1 mRNA in the lungs and LV in control normal dogs, dogs with severe HF after 3 weeks of rapid pacing (pHF), and pHF dogs chronically treated with an ETA antagonist, LU135252 (pHF-LU). PreproET-1 mRNA expression was determined by ribonuclease protection assay and quantified by densitometry. In paced dogs, mean pulmonary artery pressure (PA) and LV end-diastolic pressure (LVEDP) increased markedly from 16 +/- 4 and 8 +/- 3 mm Hg, respectively, at baseline to 40 +/- 11 and 34 +/- 7 mm Hg, respectively, at 3 weeks (both p < 0.001). Treatment with LU135252 attenuated the increase in PA and LVEDP by 30% and 19%, respectively (p < 0.05 for both). Compared to controls, preproET-1 mRNA expression in the LV and lungs was markedly increased in pHF. This was not changed in the LV but was reduced in the lungs by treatment with the ETA antagonist. Increased pulmonary and LV expression of preproET-1 suggests that ET-1 plays a role in mediating the pulmonary hypertension and LV dysfunction characteristic of this model.

Hemodynamic response to in situ latissimus dorsi muscle stimulation: implications in dynamic cardiomyoplasty.

Dynamic cardiomyoplasty (DCM) involves the electrical stimulation of a pedicled latissimus dorsi muscle flap wrapped around the falling ventricle as a means of cardiac assist. To further elucidate a potential neurohumoral mechanism for improvement of cardiac output after myoplasty, we evaluated the hemodynamic effects of in situ stimulation of the latissimus dorsi muscle (in the absence of cardiomyoplasty). In seven mongrel dogs, a nerve cuff electrode (Medtronic 6901) was placed around the left thoracodorsal nerve (TDN). This was attached to a pulse generator (Medtronic, Itrel 7420), delivering a 4.0 volt, 0.19 second on, 0.81 second off, 33 Hz, 210 microsecond pulse width, cyclic bursts similar to that used in DCM. Stroke volume index (SVI) and other hemodynamic parameters as well as plasma norepinephrine (NE) levels were measured at five stages: baseline, stimulator on at 0, 2, and 5 minutes, and stimulator off at 30 minutes after. The animals were then subjected to 4 weeks of rapid pacing at 240 beats/min (Medtronic 8329) to induce heart failure, and as the rapid pacing was discontinued, measurements were repeated as above. After rapid pacing, cardiac function was significantly depressed, and NE was elevated (133 +/- 69 versus 500 +/- 353 pg/mL, p < 0.05). In the normal hearts, TDN stimulation increased SVI, heart rate, systemic pressure, and NE levels. In heart failure, however, no significant changes in cardiac function and NE levels were noted. In conclusion, our data indicate that in the normal hearts, afferent impulses from TDN stimulation alone may augment cardiac function by means of a neurohumoral effect that is not seen in severe heart failure. The implications of these findings in DCM are discussed.

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 “off” data at 10 weeks of rapid pacing demonstrated chronic effects by enhanced ventricular function (end-systolic elastance = l.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 “off” 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. (J Thorac Cardiovasc Surg 1997;114:169-78)

Direct Effects of chronic beta-adrenergic receptor blockade on left ventricular and myocyte function in a model of tachycardia-induced congestive heart failure

Background: Chronic beta-receptor blockade (beta-blockade) has been reported to improvesymptoms and increase survival in patients with congestive heart failure (CHF); however, whether the mechanisms for the effects of beta-blockade in CHF are due to modulating chronotropy, inotropy, or both remains unknown. To address this issue, left ventricular function and isolated myocyte function were examined with chronic beta-blockade in a rapid pacing model of CHF, thereby eliminating potential chronotropic effects of beta-blockade. Methods and Results: Pigs were randomly assigned to three groups of six pigs each: supraventriculartachycardia (SVT): 3 weeks of atrial pacing at 240 beats/min; SVT/beta-blockade: 3 weeks of rapid pacing and beta-blockade (25 mg atenolol twice daily on days 14–21 of pacing); control group, sham control animals. This dosage schedule for beta-blockade was chosen because catecholamines are persistently elevated by day 14 in this model of CHF. Left ventricular fractional shortening and end-diastolic dimension were measured by echocardiography in the conscious state with a resting ambient heart rate. Isolated left ventricular myocyte function was examined using high-speed videomicroscopy. Supraventricular tachycardia caused left ventricular dilation (5.4 ± 0.1 vs 3.5 ± 0.1 cm) and reduced fractional shortening (12 ± 1% vs 35 ± 1%) compared with control animals (P < .05). The SVT/beta-blockade group showed no significant effects on left ventricular size or function compared with the SVT group, but their ambient resting heart rate was reduced by 20% relative to the SVT group (P < .05). Myocyte shortening was reduced in the SVT group (2.2 ± 0.1% vs 4.5 ± 0.1%, P < .05) compared with the control group and increased from SVT only values with beta-blockade (2.7 ± 0.1%, P < .05). Similarly, myocyte shortening velocity was similarly reduced in the SVT and SVT/beta-blockade groups (31 ± 1 and 32 ± 1 μm/s) compared with the control group (51 ± 1 μm/s, P < .05). With SVT/beta-blockade myocyte contraction duration was prolonged (525 ± 5 ms) compared with SVT-only or control values (469 ± 9 and 473 ± 4 ms, P < .05). Thus, institution of beta-1-selective blockade during the development of SVT-induced CHF altered the temporal characteristics of the myocyte contraction process, which resulted in improved myocyte shortening. Conclusions: In a model of CHF due to the maintenance of a chronically elevated heart rate,institution of beta- 1-selective blockade during the progression of the CHF process minimally affected left ventricular size and function. At the level of the myocyte, chronic beta- 1-recep for blockade prolonged the contraction interval and thereby increased myocyte shortening. These unique results suggest that a contributory mechanism for the effects of beta-blockade in the setting of CHF is chronotropic modulation.

Beta-adrenoceptor desensitization during the development of canine pacing-induced heart failure.

1. The goal of this review is to emphasize four major points regarding the development of catecholamine desensitization in heart failure (HF). 2. Catecholamine desensitization occurs prior to the development of HF (i.e. after 1 day of rapid pacing, physiological responses to beta-adrenoceptor stimulation are depressed by over 50%, yet no evidence of HF is observed for 3-4 weeks of rapid pacing). 3. Multiple mechanisms in the beta-adrenoceptor cascade are involved. In HF there are decreases in beta 1-adrenoceptors, high affinity beta-adrenoceptors, adenylyl cyclase activity and messenger RNA and increases in Gi. 4. Not all mechanisms appear simultaneously (i.e. early decreases occur in high affinity beta-adrenoceptors and adenylyl cyclase; late increases in Gi and decreases in beta-adrenoceptor density evolves). 5. Mechanisms distal to cAMP generation also play a role (i.e. alterations in ryanodine receptor binding and excitation-contraction coupling also occur).

Comparative efficacy of three indexes of left ventricular performance derived from pressure-volume loops in heart failure induced by tachypacing

Objectives. The purpose of this study was to serially evaluate the response and variability of the end-systolic pressure-volume relation, the left ventricular end-diastolic volume-peak positive first derivative of left ventricular pressure (dP/dt) relation and the left ventricular end-diastolic volume-stroke work relation in the development of progressive left ventricular dysfunction.Background. Evaluation of systolic performance of the failing left ventricle may be enhanced by using relatively load-insensitive measures of left ventricular performance. The end-systolic pressure-volume, left ventricular end-diastolic volume-peak positive dP/dt and left ventricular end-diastolic volume-stroke work relations adequately define left ventricular performance under multiple leading conditions, but efficacy has not been fully assessed in the failing heart, particularly in the intact circulation.Methods. Fourteen dogs underwent instrumentation and rapid pacing to heart failure. Variably loaded pressure-volume beats were produced by inferior vena cava occlusion. The dogs were evaluated at baseline and at three progressively more severe levels of left ventricular dysfunction.Results. There was a progressive increase in left ventricular volumes at end-diastole ([mean value ± SE]60 ± 28 to 73 ± 29 ml, p < 0.001) and end-systole (39 ± 19 to 61 ± 27 ml, p < 0.001) during the 3 weeks of rapid pacing and a progressive decline in peak positive dP/dt (1,631 ± 410 to 993 ± 222 nun Hg/s, p < 0.001) and ejection fraction (37 ± 8% to 16 ± 11%, p < 0.001). There was a corresponding decline in the slope of each of the three relations: for end-systolic pressure-volume, 6.3 ± 2.2 to 2.8 ± 0.7 (p < 0.05); for left ventricular end-diastolic volume-stroke work, 61.9 ± 9,1 to 26.5 ± 2.4 (p < 0.05); and for left ventricular end-diastolic volume-peak positive dP/dt, 47.1 ± 13.6 to 20.31 ± 6.8 (p < 0.05). There was also a corresponding increase in position volumes: for end-systolic pressure-volume, 33.6 ± 3.9 to 61.2 ± 6.6 ml (p < 0.05); for left ventricular end-diastolic volume-stroke work, 46.2 ± 3.6 to 89.3 ± 7.6 ml (p < 0.05); and for left ventricular end-diastolic volume-peak positive dP/dt, 29.1 ± 19.1 to 68.6 ± 25.9 ml (p < 0.05). The relative degree of change in each of the three relations was similar as more severe heart failure developed. The coefficients of variation for position were significantly less than the variation for slopes. The response of volume intercepts was heterogeneous. For left ventricular end-diastolic volume-stroke work, the intercept increased as ventricular performance decreased. The intercept of the end-systolic pressure-volume relation was significantly more variable than the left ventricular end-diastolic volume-stroke work relation and did not change with progressive heart failure. The intercept for left ventricular end-diastolic volume-peak positive dP/dt was highly variable and showed no consistent changes as left ventricular function declined.Conclusions. All three relations consistently describe changes in left ventricular performance brought about by tachypaing. Evolution of left ventricular dysfunction causes a decline in slope and a rightward shift of these relations. The position of the relation is the most sensitive and least variable indicator of left ventricular systolic performance.