Pacing Model Of Heart Failure Research Articles

Sheep for the study of the urocortins and other hormones

The use of animal models has been crucial to our understanding of the causation, progression and therapeutic management of disease. The rapid ventricular pacing model of heart failure (HF) in sheep closely replicates the haemodynamic, endocrine and metabolic characteristics of severe human HF, and h

Repolarization heterogeneity and rate dependency in a canine rapid pacing model of heart failure

BackgroundRepolarization heterogeneity and rate dependency have long been established as factors contributing to arrhythmogenic risk. However, there are conflicting observations regarding the nature and extent of ventricular repolarization heterogeneity that complicate understanding of arrhythmogenic mechanisms. To explore these disparate findings, we studied ventricular repolarization heterogeneity and rate dependency in a canine, rapid pacing model of heart failure. Methods and ResultsWe studied ventricular repolarization heterogeneity and rate dependency in 10 canine hearts (5 normal and 5 after 1 month of rapid pacing at 240 beats per minute) by analyzing 64 body surface electrocardiograms, 64 epicardial, and 190 intramural plunge electrograms. We estimated mean ventricular depolarization and repolarization times from R- and T-wave peaks of the root-mean-square electrocardiogram (body surface) and local depolarization and repolarization times using activation-recovery interval (ARI) methods from recordings obtained during a range of fixed rate pacing. In addition, we estimated local epicardial and transmural gradients of ARIs to assess cardiac locations of greatest spatial repolarization heterogeneity. We compared changes in repolarization at different rates between normal and heart failure hearts. Findings documented prolongation of repolarization, repolarization rate dependency, and increased repolarization gradients in the heart failure hearts compared with control as observed from body surface, epicardial, and transmural measurements. Maximum local epicardial and intramural ARI gradients were comparable both in heart failure and control hearts. Intramural ARI distributions tended to be more irregular in the heart failure hearts compared with the systematic epicardium to endocardium ARI increase observed in control animals. ConclusionsThis study documented prolongation of repolarization, increase in both epicardial and transmural repolarization gradients, and irregularity of transmural distribution in a rapid pacing canine model of heart failure compared with control animals. The findings support previously published results of increased repolarization heterogeneity and repolarization prolongation observed in rapid pacing models of heart failure. New findings are the irregularity of transmural heterogeneity and the ability of noninvasive root-mean-square electrocardiogram R-T intervals to estimate mean ventricular repolarization duration in the setting of rapid pacing models of heart failure. These findings suggest increased arrhythmogenic risk in this model and potentially in patients with heart failure.

Repolarization heterogeneity and rate dependency in a canine rapid pacing model of heart failure

Repolarization heterogeneity and rate dependency in a canine rapid pacing model of heart failure

Selective type 1 angiotensin II receptor blockade attenuates oxidative stress and regulates angiotensin II receptors in the canine failing heart

Angiotensin II type 1 receptor (AT(1)R) blockade reduces vascular oxidative stress but whether myocardial oxidative stress represents a mechanism for the beneficial effect of AT(1)R blockade in heart failure is unclear. Furthermore, the impact of AT(1)R blockade on the expression of angiotensin II receptors in heart failure has not been well documented. Accordingly, we examined the impact of the AT(1)R blocker candesartan on hemodynamics, left ventricular (LV) remodeling (echocardiography), oxidative stress, and tissue expression of AT(1)Rs and angiotensin II type 2 receptors (AT(2)Rs) in a canine model of pacing-induced heart failure. Animals were randomized to rapid right ventricular-pacing (250 beats/min for 3 weeks) to severe heart failure and treated with candesartan (10 mg/kg daily, n = 8) or placebo (n = 8) from day 3 onwards, or no pacing (sham, n = 7). Candesartan significantly reduced mean pulmonary arterial and LV diastolic pressure, LV end-diastolic and end-systolic volume and ascites, increased cardiac output, dP/dt, and ejection fraction, while reversing the marked increase in aldehydes, a marker of oxidative stress, observed in the placebo group. Although candesartan did not alter LV AT(1)R protein expression compared to placebo or sham, it reversed the decrease in AT(2)R protein observed in the placebo group. Our results indicate that in the pacing model of heart failure, chronic AT(1)R blockade attenuates hemodynamic deterioration and limits LV remodeling and dysfunction, in part by reversing oxidative stress and AT(2)R downregulation.

Cardiotropin-1 and Myocardial Strain Change Heterogeneously in Cardiomyopathy

The pacing model of heart failure produces heterogeneous changes in wall stress and myocyte diameter. The purpose of this study was to measure regional changes in cardiotrophin-1 (CT-1), a cytokine thought to play a role in LV remodeling, and regional changes in LV strain as measured with magnetic resonance imaging. Dilated cardiomyopathy was induced in nine mongrel dogs over 4 wk by rapid pacing using a right ventricular epicardial lead. Baseline CT-1 was measured from an apical myocardial biopsy, and regional CT-1 was measured from anterior, lateral, inferior, and septal walls after the induction of heart failure and in six control dogs. Tissue tagged images were divided into similar regions and minimal principal strain (MPS), ejection fraction, and ventricular volumes were compared after induction of heart failure. After induction of heart failure, LV ejection fraction and end-diastolic volume differed significantly from baseline (P < 0.01 and P = 0.02, respectively). Additionally, regional CT-1 and MPS were significantly different (P < 0.01 for both). Cardiotrophin-1 increased significantly in the inferior and septal walls (both P < 0.01) but not in the anterior or lateral walls (both P = NS). Minimum principal strain decreased significantly in the inferior and septal walls (both P < 0.01) but not in the anterior or lateral walls (both P = NS). The pacing model of heart failure produces heterogeneous changes in regional CT-1 and wall motion as measured by MPS. The greatest regional changes are closest to the pacemaker site: the inferior and septal walls. These differences in regional CT-1 may account for previously noted myocyte hypertrophy and preserved ventricular function in these regions.

Increased late sodium current in myocytes from a canine heart failure model and from failing human heart

Electrophysiological remodeling of ion channels in heart failure causes action potential prolongation and plays a role in arrhythmia mechanism. The importance of down-regulation of potassium currents is well-known, but a role for Na current ( I Na) in heart failure is less well established. We studied I Na in heart failure ventricular cells from a canine pacing model of heart failure and also from explanted failing human hearts. Peak I Na density was significantly decreased by 39% and 57% in the dog model and in human heart failure, respectively. The kinetics of peak I Na were not different in heart failure. Late I Na was measured 750 ms after the initial depolarization as the saxitoxin (STX)-sensitive current and also as the current remaining after contaminating currents were blocked. Late I Na as a percentage of the peak I Na was significantly increased in both conditions. In dogs, STX sensitive late I Na was 0.5 ± 0.1% n = 16 cells from eight normal hearts and 3.4 ± 1.4% n = 12 cells from seven failing hearts; in humans, it was 0.2 ± 0.1% n = 4 cells from two normal hearts and 2.4 ± 0.5% n = 10 cells from three human failing hearts (–40 mV). Quantitative measures of mRNA including RNase protection assays and real time quantitative PCR in the dog model showed no differences for different α subunit isoforms (NaV1.1, 1.3, 1.5) and for the β1 and β2 subunits. This suggests neither α subunit isoform switching nor altered β subunit expression is a mechanism for increased late I Na. We conclude that a peak I Na is decreased, and non-inactivating late I Na is increased in heart failure and this may contribute to action potential prolongation and the generation of arrhythmia.

Furosemide and the progression of left ventricular dysfunction in experimental heart failure

We tested the hypothesis that furosemide accelerates the progression of left ventricular systolic dysfunction in a tachycardia-induced porcine model of heart failure. Furosemide activates the renin-angiotensin-aldosterone system in patients with congestive heart failure (CHF). Such activation may contribute to CHF progression, but prospective data are lacking. Thirty-two Yorkshire pigs were randomized to furosemide (1 mg/kg intramuscularly daily, mean 16.1 +/- 0.9 mg) or placebo. Thereafter, a pacing model of heart failure was utilized to produce systolic dysfunction in both sets of animals (fractional shortening <0.16 by echocardiogram). The goal was to determine if furosemide would accelerate the progression of left ventricular dysfunction in the "treated" group. After sacrifice, sodium-calcium exchanger currents and their responsiveness to isoproterenol were measured during voltage clamp. All investigators were blinded to treatment assignment. Furosemide shortened the time to left ventricular dysfunction (35.1 +/- 5.1 days in placebo versus 21.4 +/- 3.2 days for furosemide animals; p = 0.038, log-rank test). By day 14, aldosterone levels were significantly higher in furosemide animals (43.0 +/- 11.8 ng/dl vs. 17.6 +/- 4.5 ng/dl; p < 0.05). Serum sodium was reduced (133.0 +/- 0.9 mmol/l furosemide vs. 135.7 +/- 0.8 mmol/l placebo; p < 0.05), but no difference in norepinephrine, potassium, magnesium, creatinine, or urea nitrogen was present. Basal sodium-calcium exchanger currents were significantly increased and isoproterenol responsiveness depressed by furosemide. Tachycardic pigs given furosemide had significant acceleration of both contractile and metabolic features of CHF, including left ventricular systolic dysfunction, elevated serum aldosterone levels, and altered calcium handling in a controlled experimental model of heart failure.

Improvement of cardiomyocyte performance in a pacing model of heart failure via adenoviral-mediated S100A1 gene delivery

Background: The calcium signaling derangements found in heart failure (HF) have been associated with a decrease in the calcium-handling protein S100A1. Overexpression of S100A1 has been shown to improve normal myocyte contractility in vitro. This study evaluates the ability of adenoviral mediated S100A1 transgene delivery to improve cardiomyocyte performance in a pacing model of porcine HF. Methods: Adult pigs were paced at a rate of 220 beats per minute. At two weeks, HF was confirmed by echocardiography.

Beneficial renal and hemodynamic effects of omapatrilat in mild and severe heart failure.

Omapatrilat is a member of the new drug class of vasopeptidase inhibitors that may offer benefit in the treatment of heart failure (HF) through simultaneous inhibition of angiotensin-converting enzyme and neutral endopeptidase. We examined the effects of omapatrilat in a placebo-controlled crossover study using a pacing model of HF. Seven sheep were paced sequentially at 180 bpm (mild HF) and then 225 bpm (severe HF) for 7 days each. Omapatrilat (0.005 mg/kg) or vehicle was administered by intravenous bolus on days 4 to 7 of each paced period. Omapatrilat lowered mean arterial and left atrial pressure and increased cardiac output acutely and chronically in both mild and severe HF (P<0.01 for all). Plasma atrial and brain natriuretic peptide and cGMP levels were stable acutely (P=NS), while brain natriuretic peptide increased after repeated dosing in severe HF (P<0.05). Plasma renin activity rose, whereas angiotensin II and aldosterone levels fell after acute and repeated dosing in both states (P<0.01 for all). Omapatrilat increased urinary sodium excretion by day 7 in both mild and severe HF (P<0.05). Effective renal plasma flow and glomerular filtration rate increased or were stable after omapatrilat in mild and severe HF after both acute and repeated dosing. Omapatrilat exhibited pronounced acute and sustained beneficial hemodynamic and renal effects in both mild and severe heart failure.

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.

Acute effect of L-arginine on hemodynamics and vascular capacitance in the canine pacing model of heart failure.

The effect of L-arginine, 250 mg/kg over 10 min, on hemodynamics and venous function was studied in nine splenectomized dogs under light pentobarbital anesthesia before and after 17 +/- 1 days of rapid right ventricular pacing (RRVP) at 250 beats/min. Chronic RRVP induced mild congestive heart failure with increased mean circulatory filling (Pmcf), right atrial (Pra) and pulmonary capillary wedge pressures (Ppcw), and reduced cardiac output (CO). During the development of heart failure, total vascular compliance assessed from Pmcf-blood volume relationships during circulatory arrest was unchanged, but total vascular capacitance was markedly reduced, with an increase in stressed and reduction in unstressed blood volumes. At baseline but not after RRVP, L-arginine increased CO and reduced pulmonary vascular resistance. There were no significant changes in Pra, Ppcw, or total peripheral resistance. L-Arginine failed to alter total vascular compliance and capacitance or central blood volume in the baseline or failure state. These results do not support the hypothesis that increased Pmcf and reduced total vascular capacitance in the early stages of pacing-induced heart failure are caused by reduced substrate availability for or an endogenous competitive antagonist of NO synthase in venous endothelial cells.

Pronounced increase in defibrillation threshold associated with pacing-induced cardiomyopathy in the dog

Progressive changes in myopathology after implantation of an automatic defibrillator could compromise device efficacy. The influence of heart failure development on the defibrillation threshold was evaluated by means of a rapid ventricular pacing model of heart failure in dogs. After transvenous pacemaker lead implantation, adult mongrel dogs were randomly assigned to either the control (n = 7) or rapidly paced group (240 beats/min, n = 6). Seventeen days after implantation, triplicate determinations of the defibrillation threshold were made with three epicardial electrodes. The average defibrillation threshold was four times higher in the rapidly paced group, 13.3 ± 2.0 joules (mean ± SEM), than in the control group, 3.3 ± 0.7 joules (p < 0.01), and was significantly correlated with ventricular weight (r = 0.70, p < 0.01). Both defibrillation threshold energy per gram of ventricle and ventricular weight corrected for body weight were significantly higher in rapidly paced dogs compared with control dogs. It was concluded that myocardial hypertrophy and heart failure may profoundly increase defibrillation energy requirements.

Ischemic myocardial injury in rapidly paced dogs: Contribution to ventricular dysfunction

Chronic rapid ventricular pacing in the dog has been shown to provide a predictable and stable model of heart failure for which the operative pathomechanism remains in question. In a group of 20 dogs with congestive failure induced by rapid ventricular pacing for a mean duration of 29.5 ± 13.1 days (range 7 to 55 days), mean left ventricular end diastolic pressure (LVEDP) was elevated as compared with unpaced controls (23.2 ± 2.7 mmHg vs. 2.0 ± 0 mmHg, p < 0.001). Gross myocardial hemorrhage was present at autopsy in 9 of 20 (45%) paced animals, and necrosis was present in 5 of 20 (25%). Histologic findings included acute ischemic myocardial injury with contraction band necrosis, wavy myofibers, and coagulation necrosis ranging from 0 to 4 lesions per paced animal (1.4 ± 1.4, mean ± SD), compared with none in unpaced animals ( p < 0.03). Healed ischemic lesions ranged from 0 to 10 per animal (mean 3.2 ± 2.9) versus none in control animals ( p < 0.0001). Total injury score (acute plus healed) for each paced animal ranged from 0 to 12 (mean 4.6 ± 2.9), compared with no injury in nonpaced controls ( p < 0.0001). Thus ischemic injury reflected by multiple foci of acute and healed myocardial injury is a prominent and common feature in the canine rapid ventricular pacing model of heart failure.