Impact of a combination of pimobendan, furosemide, and enalapril on heart rate variability in naturally occurring, symptomatic, myxomatous mitral valve degeneration dogs.

BACKGROUND: Pimobendan, diuretics, and an angiotensin-converting enzyme inhibitor (ACEi) are widely used for the management of chronic valvular heart disease in dogs; however, the effects of that combination on heart rate variability (HRV) are unknown. The purpose of this study was to assess the HRV of symptomatic myxomatous mitral valve degeneration (MMVD) dogs in response to therapy with a combination of pimobendan, diuretics, and ACEi. RESULTS: MMVD stage C (n = 17) dogs were enrolled and a 1-hour Holter recording together with echocardiography, blood pressure measurement, and blood chemistry profiles were obtained before and 1, 3, and 6 months after oral treatment with pimobendan (0.25 mg/kg), enalapril (0.5 mg/kg), and furosemide (2 mg/kg) twice daily. The results revealed that MMVD stage C dogs at the baseline had lower values of time-domain indices, low frequency (LF), high frequency (HF), and total power, as well as higher value of LF/HF. Triple therapy significantly increases these parameters in MMVD stage C dogs (P < 0.05). A positive moderate correlation was observed between time domain parameters and a left ventricular internal diastole diameter normalized to body weight (P < 0.05). CONCLUSIONS: It can be concluded that MMVD stage C dogs possess low HRV due to either the withdrawal of parasympathetic tone or enhanced sympathetic activation, and a combination therapy was shown to enhance cardiac autonomic modulation inferred from the increased heart rate variability. Therefore, a combination therapy may be useful for restoring normal autonomic nervous system activity in dogs with MMVD stage C.

Relationship between muscle sympathetic nerve activity and aortic wave reflection characteristics in aerobic- and resistance-trained subjects.

PURPOSE: Increased arterial stiffness is associated with an impairment of ventricular-vascular coupling efficiency and increased risk of cardiovascular mortality. Recently, it has been suggested that an increase in arterial stiffness is associated with resistance exercise training. Therefore, the aims of this study were to compare augmentation index (AIx) and left ventricular wasted pressure energy (LVEW) as markers of arterial stiffness and ventricular-vascular coupling efficiency in young aerobic-trained (AT) and resistance (RT)-trained subjects. We also investigated the relationship of muscle sympathetic nerve activity (MSNA) and flow-mediated dilation (FMD) to AIx in both sets of subjects to determine if endothelial function or sympathetic outflow could explain any differences in arterial stiffness. METHOD: To achieve our aims, we measured MSNA in 15 male subjects (8 RT, 7 AT) using microneurography. We also used applanation tonometry of the radial pressure waveform to noninvasively synthesize aortic pressure waveforms. FMD was calculated as percent dilation of the radial artery from baseline following a 5 min occlusion. RESULT: RT subjects had an increased AIx (12 ± 3 vs. -7 ± 2; P < 0.01), LVEW (429 ± 111 vs. -360 ± 77; P < 0.01) and MSNA burst incidence (34 ± 4 vs. 26 ± 4; P < 0.01) when compared with AT subjects. There was no difference in FMD between groups. MSNA burst incidence was also significantly related to AIx in subjects (R (2) = 0.61; P < 0.01) with a distinct demarcation between RT and AT subjects. CONCLUSION: These results confirm previous reports of a positive association between MSNA and AIx in young male resistance-trained subjects. Furthermore, RT is associated with increased arterial stiffness and elevated sympathetic outflow.

Ibandronate and ventricular arrhythmia risk.

INTRODUCTION: Bisphosphonates, including ibandronate, are used in the prevention and treatment of osteoporosis. METHODS AND RESULTS: We report a case of suspected ibandronate-associated arrhythmia, following a single dose of ibandronate in a 55-year-old female. ECG at presentation revealed frequent ectopy and QT/QTc interval prolongation; at follow-up 9 months later the QT/QTc intervals were normalized. Proarrhythmic potential of ibandronate was assessed with a combination of in vivo and in vitro approaches in canines and canine ventricular myocytes. We observed late onset in vivo repolarization instability after ibandronate treatment. Myocytes superfused with ibandronate exhibited action potential duration (APD) prolongation and variability, increased early afterdepolarizations (EADs) and reduced Ito (P < 0.05), with no change in IKr . Ibandronate-induced APD changes and EADs were prevented by inhibition of intracellular calcium cycling. Ibandronate increased sarcoplasmic reticulum calcium load; during washout there was an increase in calcium spark frequency and spontaneous calcium waves. Computational modeling was used to examine the observed effects of ibandronate. While reductions in Ito alone had modest effects on APD, when combined with altered RyR inactivation kinetics, the model predicted effects on APD and SR Ca(2+) load consistent with observed experimental results. CONCLUSION: Ibandronate may increase the susceptibility to ventricular ectopy and arrhythmias. Collectively these data suggest that reduced Ito combined with abnormal RyR calcium handling may result in a previously unrecognized form of drug-induced proarrhythmia.

At-risk but viable myocardium in a large animal model of non ST-segment elevation acute coronary syndrome: cardiovascular magnetic resonance with ex vivo validation.

BACKGROUND: Patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) have varying degrees of salvageable myocardium at risk of irreversible injury. We hypothesized that a novel model of NSTE-ACS produces acute myocardial injury, measured by increased T2 cardiovascular magnetic resonance (CMR), without significant necrosis by late gadolinium enhancement (LGE). METHODS: In a canine model, partial coronary stenosis was created and electrodes placed on the epicardium. Myocardial T2, an indicator of at-risk myocardium, was measured pre- and post-tachycardic pacing. RESULTS: Serum troponin-I (TnI) was not detectable in unoperated sham animals but averaged 1.97 ± 0.72 ng/mL in model animals. Coronary stenosis and pacing produced significantly higher T2 in the affected vs. the remote myocardium (53.2 ± 4.9 vs. 43.6 ± 2.8 ms, p < 0.01) with no evident injury by LGE. Microscopy revealed no significant irreversible cellular injury. Relative respiration rate (RRR) of affected vs. remote myocardial tissue was significantly lower in model vs. sham animals (0.72 ± 0.07 vs. 1.04 ± 0.07, p < 0.001). Lower RRR corresponded to higher final TnI levels (R(2) = 0.83, p = 0.004) and changes in CaMKIID and mitochondrial gene expression. CONCLUSIONS: A large animal NSTE-ACS model with mild TnI elevation and without ST elevation, similar to the human syndrome, demonstrates signs of acute myocardial injury by T2-CMR without significant irreversible damage. Reduced tissue respiration and associated adaptations of critical metabolic pathways correspond to increased myocardial injury by serum biomarkers in this model. T2-CMR as a biomarker of at-risk but salvageable myocardium warrants further consideration in preclinical and clinical studies of NSTE-ACS.

Dynamic detection and reversal of myocardial ischemia using an artificially intelligent bioelectronic medicine.

Myocardial ischemia is spontaneous, frequently asymptomatic, and contributes to fatal cardiovascular consequences. Importantly, myocardial sensory networks cannot reliably detect and correct myocardial ischemia on their own. Here, we demonstrate an artificially intelligent and responsive bioelectronic medicine, where an artificial neural network (ANN) supplements myocardial sensory networks, enabling reliable detection and correction of myocardial ischemia. ANNs were first trained to decode spontaneous cardiovascular stress and myocardial ischemia with an overall accuracy of ~92%. ANN-controlled vagus nerve stimulation (VNS) significantly mitigated major physiological features of myocardial ischemia, including ST depression and arrhythmias. In contrast, open-loop VNS or ANN-controlled VNS following a caudal vagotomy essentially failed to reverse cardiovascular pathophysiology. Last, variants of ANNs were used to meet clinically relevant needs, including interpretable visualizations and unsupervised detection of emerging cardiovascular stress. Overall, these preclinical results suggest that ANNs can potentially supplement deficient myocardial sensory networks via an artificially intelligent bioelectronic medicine system.

Myocardial Contractility: Historical and Contemporary Considerations.

The term myocardial contractility is thought to have originated more than 125 years ago and has remained and enigma ever since. Although the term is frequently used in textbooks, editorials and contemporary manuscripts its definition remains illusive often being conflated with cardiac performance or inotropy. The absence of a universally accepted definition has led to confusion, disagreement and misconceptions among physiologists, cardiologists and safety pharmacologists regarding its definition particularly in light of new discoveries regarding the load dependent kinetics of cardiac contraction and their translation to cardiac force-velocity and ventricular pressure-volume measurements. Importantly, the Starling interpretation of force development is length-dependent while contractility is length independent. Most historical definitions employ an operational approach and define cardiac contractility in terms of the hearts mechanical properties independent of loading conditions. Literally defined the term contract infers that something has become smaller, shrunk or shortened. The addition of the suffix "ility" implies the quality of this process. The discovery and clinical investigation of small molecules that bind to sarcomeric proteins independently altering force or velocity requires that a modern definition of the term myocardial contractility be developed if the term is to persist. This review reconsiders the historical and contemporary interpretations of the terms cardiac performance and inotropy and recommends a modern definition of myocardial contractility as the preload, afterload and length-independent intrinsic kinetically controlled, chemo-mechanical processes responsible for the development of force and velocity.

Hyperbaric oxygenation enhances transplanted cell graft and functional recovery in the infarct heart.

A major limitation to the application of stem-cell therapy to repair ischemic heart damage is the low survival of transplanted cells in the heart, possibly due to poor oxygenation. We hypothesized that hyperbaric oxygenation (HBO) can be used as an adjuvant treatment to augment stem-cell therapy. Therefore, the goal of this study was to evaluate the effect of HBO on the engraftment of rat bone marrow-derived mesenchymal stem cells (MSCs) transplanted in infarct rat hearts. Myocardial infarction (MI) was induced in Fisher-344 rats by permanently ligating the left-anterior-descending coronary artery. MSCs, labeled with fluorescent superparamagnetic iron oxide (SPIO) particles, were transplanted in the infarct and peri-infarct regions of the MI hearts. HBO (100% oxygen at 2 ATA for 90 min) was administered daily for 2 weeks. Four MI groups were used: untreated (MI); HBO; MSC; MSC+HBO. Echocardiography, electro-vectorcardiography, and magnetic resonance imaging were used for functional evaluations. The engraftment of transplanted MSCs in the heart was confirmed by SPIO fluorescence and Prussian-blue staining. Immunohistochemical staining was used to identify key cellular and molecular markers including CD29, troponin-T, connexin-43, VEGF, alpha-smooth-muscle actin, and von Willebrand factor in the tissue. Compared to MI and MSC groups, the MSC+HBO group showed a significantly increased recovery of cardiac function including left-ventricular (LV) ejection fraction, fraction shortening, LV wall thickness, and QRS vector. Further, HBO treatment significantly increased the engraftment of CD29-positive cells, expression of connexin-43, troponin-T and VEGF, and angiogenesis in the infarct tissue. Thus, HBO appears to be a potential and clinically-viable adjuvant treatment for myocardial stem-cell therapy.

Use of the rabbit with a failing heart to test for torsadogenicity.

Torsades de pointes is a potentially lethal arrhythmia that occurs infrequently but may be drug-induced particularly in patients with pathological substrates. However drugs are usually evaluated for torsadogenicity in normal subjects, thus potentially limiting the sensitivity of studies to predict liability in man. Heart failure is a pathological substrate permissive to drug-induced torsades de pointes. Failing hearts may be produced with a high yield in rabbits with ligation of coronary arteries. Failing myocardium may be documented by reduced left ventricular ejection fraction and elevation of NTproBNP. QTc in failing hearts prolonged only slightly more in failing hearts than in normals in response to torsadogens, but incidence of torsades de pointes increased dramatically. Abnormal calcium cycling resulting in early afterdepolarizations appeared to develop more in hypertrophic myocardial cells located in the border between normal myocardium and infarct. In failing hearts, torsades de pointes appeared to develop more prevalently without greater lengthening of QT than in hearts from normal rabbits. Thus this model appears to be a facile and useful preparation for identifying torsadogenic potential of test articles, and it probably possesses anatomical and physiological substrates that mimic closely the torsadogenic substrates in the many millions of persons possessing failing hearts.

Animal models of ventricular arrhythmias.

Limitations in understanding of arrhythmias stem from lack of animal models which serve as surrogates for man. The purpose of this review is to discuss iatrogenic and naturally occurring animal models that are useful in our understanding of the mechanisms of ventricular arrhythmia and of antiarrhythmic and proarrhythmic agents. It is not surprising however that some information obtained from studies on infrahuman mammals may not be extrapolated to man. Need for anesthesia affects profoundly the electrophysiology of the heart, including autonomic affects. Most of the animal are modification of the Harris' 2-stage model. A model proposed by Schwartz, Billman and Stone has evolved as one that produces arguably the most information on the pathophysiology of arrhythmia production, including the role of the autonomic nervous system and the interaction with pharmacological agents. Intoxication with digitalis and escalating doses of epinephrine are commonly used models for production of ventricular arrhythmias. No matter what model of ventricular arrhythmias is used, programmed electrical stimulation can be useful to uncover increased tendency for arrhythmia, even if no arrhythmia occurs spontaneously. Models of spontaneous ventricular arrhythmia occur in German shepherd puppies, Boxer dogs, Doberman pinchers with dilated cardiomyopathy, and in large dogs with gastric dilatation or splenic torsion. Models are necessary because they allow for controlled studies and methods of exploration impossible, for legal and ethical reasons, in humans. Nonetheless, ethical considerations in using animal models are still important, and there is a continual search for non-animal models to explore ventricular arrhythmias.

How many ECG leads are required for in vivo studies in safety pharmacology?

This article explains the principles of electrocardiography, and explains how it is used by Safety Pharmacology, with a focus on the requirement for multiple leads in Safety Pharmacology assessment. Electrocardiography as used in different disciplines (e.g., medicine, anesthesiology, physiology, and pharmacology/toxicology/safety pharmacology) has different requirements for the number of electrodes applied. Electrodes may be placed at an infinite number of points on the body, and voltages (electrocardiograms) may be registered between/among them. However in safety pharmacology there is little evidence that more than 1--or at most 3--lead(s) is (are) required to provide all of the information that might be present using an infinite number. This is based upon (1) the biophysics of the heart as a generator of electrical potential/voltage, (2) the fact that most properties of electrophysiology affected adversely by drugs are expressed as changes in durations, and (3) experience. A single, unipolar lead (V(3)) recorded from the left sternal border at the 5th intercostal space possesses minimal artifact and large, stable deflections. This lead allows for accurate measurement of heart rate and rhythm, durations of component deflections (e.g., PQ, QRS, QT), and J-point deviation. A greater number of leads seldom or never yield additional information that detects liabilities. Commonly voltages recorded between the right thoracic and left pelvic limbs (lead II) provides information similar to lead V(3), and lead II is easier to apply, and produces voltages with less artifact and similar to those in lead V(3). A lead measuring the voltage between the left and right thoracic limbs (lead I) along with lead II allows for estimating orientation of vectors in the frontal plane, but knowledge of these vectors seldom or never indicates liability of a test article.

Chronic xanthine oxidase inhibition following myocardial infarction in rabbits: effects of early versus delayed treatment.

Xanthine oxidase (XO) expression is increased in the failing heart, and animal studies in rodents and dogs showed that XO inhibition with allopurinol can improve left ventricular (LV) function and myocardial oxygen efficiency in the failing heart. The purpose of this study was to determine whether chronic XO inhibition by allopurinol or febuxostat, an investigational, potent non-purine, selective inhibitor of XO, could prevent or treat the progression of congestive heart failure (CHF) induced by coronary artery ligation in rabbits, a species that exhibits low intrinsic XO activity similar to humans. One day after coronary ligation, rabbits were assigned to one of four groups (n = 7-8/group): control group (vehicle for 49 days), early treatment (prevention) group (febuxostat for 49 days), and two delayed-treatment groups (vehicle for 21 days followed by either febuxostat or allopurinol for 28 days). An echocardiogram of the LV was obtained on Days 0 (prior to surgery), 21, and 49. Control rabbits developed CHF by Day 21 (significant reduction in LV shortening fraction and ejection fraction, thinning of the LV posterior wall, and increases in LV internal dimensions and end-diastolic volume). Early preventive treatment with febuxostat significantly lessened the reduction of LV function when compared to vehicle on both Days 21 and 49. These cardiac functional improvements were accompanied by moderately less severe changes in LV dimensional parameters relative to vehicle controls. In contrast, when treatments with XO inhibitors were started after the establishment of CHF, no significant relative improvements in cardiac functional or dimensional parameters were observed. These results suggest that chronic preventive treatment with an XO inhibitor initiated shortly after myocardial infarction can delay or prevent the onset of CHF, and that XO inhibition initiated after establishment of the disease does not offer cardiac protection. In contrast to previous rodent studies which do suggest a cardiovascular (CV) benefit of delayed XO inhibition, the results of this rabbit study are in keeping with those of recently completed studies in severe CHF patients treated with oxypurinol, the active metabolite of allopurinol, in which no clinical benefit was observed. This may be due to the fact that rodents have relatively high levels of XO activity, while the levels in rabbits and humans are intrinsically low, suggesting that the rabbit may be the preferred model for investigating the role of XO in CV diseases.

A canine model of sustained atrial fibrillation induced by rapid atrial pacing and phenylephrine.

Atrial fibrillation is a common arrhythmia with considerable morbidity and mortality. Limitations in studying both the mechanisms and therapy of atrial fibrillation arise due to the paucity of models that yield sufficiently high-quality data, are not costly, and in which atrial fibrillation is sustained long enough to make the necessary observations. The canine model we present is based on the hypothesis that atrial fibrillation requires heterogeneity of repolarization, that distribution of vagal fibers is heterogeneous in the atria, and that atrial fibrillation will persist after reflex stimulation of vagal efferents by increased systemic arterial pressure. Dogs were anesthetized with morphine-chloralose because this combination maintains nearly intact autonomic control. Systemic arterial pressure was elevated approximately 75 mm Hg during infusion of phenylephrine (2 microg/kg x min(-1)). The right atrium was paced for 20 min at 40 Hz. Atrial fibrillation was sustained after cessation of atrial pacing in dogs receiving phenylephrine, but terminated within seconds in normotensive animals. In conclusion, atrial fibrillation can be maintained for at least 40 min after cessation of rapid atrial pacing in dogs with phenylephrine-induced hypertension.

An increasing electromechanical window is a predictive marker of ventricular fibrillation in anesthetized rabbit with ischemic heart.

The QTc interval is widely used in Safety Pharmacological studies to predict arrhythmia risk, and the electromechanical window (EMW) and short-term variability of QT intervals (STVQT) have been studied as new biomarkers for drug-induced Torsades de Pointes (TdP). However, the use of EMW and STVQT to predict ventricular fibrillation (VF) has not been elucidated. This study aimed to evaluate EMW and STVQT to predict VF in anesthetized rabbit model of VF. VF was induced by ligation of the left anterior descending and a descending branch of the left circumflex coronary arteries in a sample population of rabbits (n=18). VF was developed 55.6% (10/18). In rabbit with VF, the EMW was significantly higher than in rabbits without VF (96.3 ± 15.6 ms and 49.5 ± 5.6 ms, respectively, P<0.05). STVQT had significantly increased before the onset of VF in rabbits that experienced VF, but not in rabbits that did not experience VF (11.7 ± 1.8 ms and 3.7 ± 0.4 ms, respectively, P<0.05). The EMW and STVQT had better predictive power for VF with higher sensitivity and specificity than the QTc measure. The result suggested that the increasing of EMW, as well as the elevation of STVQT, can potentially be used as biomarkers for predicting of VF.

Enhanced ryanodine receptor-mediated calcium leak determines reduced sarcoplasmic reticulum calcium content in chronic canine heart failure.

In this study, we investigated the role of elevated sarcoplasmic reticulum (SR) Ca(2+) leak through ryanodine receptors (RyR2s) in heart failure (HF)-related abnormalities of intracellular Ca(2+) handling, using a canine model of chronic HF. The cytosolic Ca(2+) transients were reduced in amplitude and slowed in duration in HF myocytes compared with control, changes paralleled by a dramatic reduction in the total SR Ca(2+) content. Direct measurements of [Ca(2+)](SR) in both intact and permeabilized cardiac myocytes demonstrated that SR luminal [Ca(2+)] is markedly lowered in HF, suggesting that alterations in Ca(2+) transport rather than fractional SR volume reduction accounts for the diminished Ca(2+) release capacity of SR in HF. SR Ca(2+) ATPase (SERCA2)-mediated SR Ca(2+) uptake rate was not significantly altered, and Na(+)/Ca(2+) exchange activity was accelerated in HF myocytes. At the same time, SR Ca(2+) leak, measured directly as a loss of [Ca(2+)](SR) after inhibition of SERCA2 by thapsigargin, was markedly enhanced in HF myocytes. Moreover, the reduced [Ca(2+)](SR) in HF myocytes could be nearly completely restored by the RyR2 channel blocker ruthenium red. The effects of HF on cytosolic and SR luminal Ca(2+) signals could be reasonably well mimicked by the RyR2 channel agonist caffeine. Taken together, these results suggest that RyR2-mediated SR Ca(2+) leak is a major factor in the abnormal intracellular Ca(2+) handling that critically contributes to the reduced SR Ca(2+) content of failing cardiomyocytes.

Increased myosin heavy chain-beta with atrial expression of ventricular light chain-2 in canine cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy is a naturally occurring disease in humans and dogs. Human studies have shown increased levels of myosin heavy chain (MHC)-beta in failing ventricles and the left atria (LA) and of ventricular light chain (VLC)-2 in the right atria in dilated cardiomyopathy. METHODS AND RESULTS: This study evaluates the levels of MHC-beta in all heart chambers in prolonged canine right ventricular pacing. In addition, we determined whether levels of VLC2 were altered in these hearts. Failing hearts demonstrated significantly increased levels of MHC-beta in the right atria, right atrial appendage, LA, left atrial appendage (LAA), and right ventricle compared with controls. Significant levels of VLC2 were detected in the right atria of paced hearts. Differences in MHC-beta expression were observed between the LA and the LAA of paced and control dogs. MHC-beta expression was significantly greater in the LA of paced and control dogs compared with their respective LAA. CONCLUSIONS: The cardiac myosin isoform shifts in this study were similar to those observed in end-stage human heart failure and more severe than those reported in less prolonged pacing models, supporting the use of this model for further study of end-stage human heart failure. The observation of consistent differences between sampling sites, especially LA versus LAA, indicates the need for rigorous sampling consistency in future studies.

Chronic cardiac resynchronization therapy and reverse ventricular remodeling in a model of nonischemic cardiomyopathy.

While cardiac resynchronization therapy (CRT) has been shown to reduce morbidity and mortality in heart failure (HF) patients, the fundamental mechanisms for the efficacy of CRT are poorly understood. The lack of understanding of these basic mechanisms represents a significant barrier to our understanding of the pathogenesis of HF and potential recovery mechanisms. Our purpose was to determine cellular mechanisms for the observed improvement in chronic HF after CRT. We used a canine model of chronic nonischemic cardiomyopathy. After 15 months, dogs were randomized to continued RV tachypacing (untreated HF) or CRT for an additional 9 months. Six minute walk tests, echocardiograms, and electrocardiograms were done to assess the functional response to therapy. Left ventricular (LV) midmyocardial myocytes were isolated to study electrophysiology and intracellular calcium regulation. Compared to untreated HF, CRT improved HF-induced increases in LV volumes, diameters and mass (p<0.05). CRT reversed HF-induced prolongations in LV myocyte repolarization (p<0.05) and normalized HF-induced depolarization (p<0.03) of the resting membrane potential. CRT improved HF-induced reductions in calcium (p<0.05). CRT did not attenuate the HF-induced increases in LV interstitial fibrosis. Using a translational approach in a chronic HF model, CRT significantly improved LV structure; this was accompanied by improved LV myocyte electrophysiology and calcium regulation. The beneficial effects of CRT may be attributable, in part, to improved LV myocyte function.

Effects of 4 classes of cardiovascular drugs on ventricular function in dogs with mitral regurgitation.

BACKGROUND: There have been few trials in which dogs with mitral regurgitation (MR) have been treated with various cardioactive drugs to determine effects on left ventricular (LV) function. HYPOTHESIS: Four classes of cardiovascular drugs may improve LV function in dogs with MR without increasing MR. ANIMALS: Nine mature dogs were included in the study. METHODS: MR was produced in 9 dogs. Five months later under butorphanol narcosis, parameters of LV function and left atrial dimension (LAD) were monitored by LV micromanometry and echocardiography/Doppler. Dogs were given (in random order) enalaprilat, nitroglycerine, ouabain, milrinone, and placebo. RESULTS: Nitroglycerin produced no significant change; milrinone and ouabain increased contractility; ouabain decreased heart rate; and there was evidence that enalaprilat and milrinone decreased LAD. Milrinone and ouabain decreased isovolumetric contraction time and therefore the time available for MR. There was no evidence that a positive inotrope increased MR despite increasing LV contractility and stroke volume. CONCLUSION AND CLINICAL IMPORTANCE: This study contradicts the hypotheses that (1) strengthening the left ventricle may increase MR and (2) treatment of MR (even before symptoms of heart failure develop) may decrease LAD. It is reasonable that strengthening the force of LV contraction should increase the driving pressure for MR; however, this effect did not appear to increase MR. Although some investigators believe that treating dogs with MR with afterload reducers and decreasing hindrance to ejection of blood from the LV to aorta may lengthen life by decreasing MR, there did not appear to be a reduction in MR, at least in response to the angiotensin-converting enzyme (ACE) inhibitor.

Atrial, SA nodal, and AV nodal electrophysiology in standing horses: normal findings and electrophysiologic effects of quinidine and diltiazem.

BACKGROUND: Although atrial arrhythmias are clinically important in horses, atrial electrophysiology has been incompletely studied. HYPOTHESES: Standard electrophysiologic methods can be used to study drug effects in horses. Specifically, the effects of diltiazem on atrioventricular (AV) nodal conduction are rate-dependent and allow control of ventricular response rate during rapid atrial pacing in horses undergoing quinidine treatment. ANIMALS: Fourteen healthy horses. METHODS: Arterial blood pressure, surface electrocardiogram, and right atrial electrogram were recorded during sinus rhythm and during programmed electrical stimulation at baseline, after administration of quinidine gluconate (10 mg/kg IV over 30 minutes, n = 7; and 12 mg/kg IV over 5 minutes followed by 5 mg/kg/h constant rate infusion for the remaining duration of the study, n = 7), and after coadministration of diltiazem (0.125 mg/kg IV over 2 minutes repeated every 12 minutes to effect). RESULTS: Quinidine significantly prolonged the atrial effective refractory period, shortened the functional refractory period (FRP) of the AV node, and increased the ventricular response rate during atrial pacing. Diltiazem increased the FRP, controlled ventricular rate in a rate-dependent manner, caused dose-dependent suppression of the sinoatrial node and produced a significant, but well tolerated decrease in blood pressure. Effective doses of diltiazem ranged from 0.125 to 1.125 mg/kg. CONCLUSIONS AND CLINICAL IMPORTANCE: Standard electrophysiologic techniques allow characterization of drug effects in standing horses. Diltiazem is effective for ventricular rate control in this pacing model of supraventricular tachycardia. The use of diltiazem for rate control in horses with atrial fibrillation merits further investigation.

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes.

The current regulatory guidelines recommend the use of QT interval to assess the risk of arrhythmogenic potential of new chemical entities. Recently, the electromechanical window (EMW), the difference in duration between electrical and mechanical systole, has been proposed as markers for drug-induced torsades de pointes (TdP); however, data of EMW in short QT model are not available. This study aimed to characterize the EMW as a marker for drug-induced ventricular arrhythmias in anesthetized rabbit model of long QT syndrome type 2 (LQT2) and short QT syndrome (SQTS) infused with reference compounds known to lengthen or shorten QT intervals. After rabbits were anesthetized with isoflurane, body surface electrocardiograms and left ventricular pressure were recorded. The LQT2 was produced by intravenous infusion with dofetilide (n = 6), quinidine (n = 6) and sotalol (n = 6) whereas the SQTS was induced by intravenous escalating concentrations of nicorandil (n = 7), pinacidil (n = 5) and cromakalim (n = 5). The EMW in anesthetized rabbits ranged from 1.3 to 53.3 msec. All three drugs known to lengthen QT intervals prolonged QT and QTcF interval while the EMW was markedly decreased to negative values. Pinacidil significantly produced QT and QTcF shortening and significantly abbreviated the EMW (p < 0.05). This study demonstrated that the EMW is associated with QT intervals (p < 0.001). It is negative in the presence of QT-prolonging drugs while it is more positive in the presence of QT-shortening drugs. The results suggest that the EMW in anesthetized rabbits can be used in drug safety evaluation in addition to the QT interval.

Dronedarone attenuates the duration of atrial fibrillation in a dog model of sustained atrial fibrillation.

Atrial fibrillation (AF) is a supraventricular arrhythmia that leads to a decrease in cardiac output and impairs cardiac function and quality of life. Dronedarone has an atrial-selective property and has been used for management of AF in humans, but limited information is available in dogs. This study was designed to evaluate efficacy of dronedarone in attenuating the duration of AF in dog model of sustained AF. Six beagle dogs were anesthetized with isoflurane and instrumented to measure atrial action potential duration (aAPD) and atrial effective refractory period (AERP). Then AF was induced by rapid right atrial pacing (20 V, 40 Hz) simultaneously with infusion of phenylephrine (2 µg/kg/min, intravenously) for 20 min. The duration of sustained AF was recorded, and the animals were allowed to recover. Dronedarone was given at a dose of 20 mg/kg, BID, orally for 7 days. On the last day, the dogs were anesthetized again to record aAPD and AERP, and AF was induced with the same procedure as described above. The results showed that after dronedarone administration the aAPD was lengthened significantly from 76.4 ± 4.2 ms to 91.2 ± 3.9 ms (P<0.05) and AERP was prolonged significantly from 97.5 ± 2.8 ms to 120 ± 4.8 ms (P<0.05). The duration of sustained AF was also significantly attenuated after receipt of dronedarone (P<0.05). It can be suggested that oral dronedarone attenuates the duration of sustained AF in a dog model of AF by extending the AERP more than the aAPD, causing post-repolarization refractoriness. Hence, dronedarone may be useful for management of AF in dogs.