Use of machine learning and Poincaré density grid in the diagnosis of sinus node dysfunction caused by sinoatrial conduction block in dogs.

BACKGROUND: Sinus node dysfunction because of abnormal impulse generation or sinoatrial conduction block causes bradycardia that can be difficult to differentiate from high parasympathetic/low sympathetic modulation (HP/LSM). HYPOTHESIS: Beat-to-beat relationships of sinus node dysfunction are quantifiably distinguishable by Poincaré plots, machine learning, and 3-dimensional density grid analysis. Moreover, computer modeling establishes sinoatrial conduction block as a mechanism. ANIMALS: Three groups of dogs were studied with a diagnosis of: (1) balanced autonomic modulation (n = 26), (2) HP/LSM (n = 26), and (3) sinus node dysfunction (n = 21). METHODS: Heart rate parameters and Poincaré plot data were determined [median (25%-75%)]. Recordings were randomly assigned to training or testing. Supervised machine learning of the training data was evaluated with the testing data. The computer model included impulse rate, exit block probability, and HP/LSM. RESULTS: Confusion matrices illustrated the effectiveness in diagnosing by both machine learning and Poincaré density grid. Sinus pauses >2 s differentiated (P < .0001) HP/LSM (2340; 583-3947 s) from sinus node dysfunction (8503; 7078-10 050 s), but average heart rate did not. The shortest linear intervals were longer with sinus node dysfunction (315; 278-323 ms) vs HP/LSM (260; 251-292 ms; P = .008), but the longest linear intervals were shorter with sinus node dysfunction (620; 565-698 ms) vs HP/LSM (843; 799-888 ms; P < .0001). CONCLUSIONS: Number and duration of pauses, not heart rate, differentiated sinus node dysfunction from HP/LSM. Machine learning and Poincaré density grid can accurately identify sinus node dysfunction. Computer modeling supports sinoatrial conduction block as a mechanism of sinus node dysfunction.

Electrocardiographic patterns of ventricular pre-excitation in dogs with right-sided accessory pathways.

INTRODUCTION: The aim of the study was to describe the electrocardiographic features of ventricular pre-excitation (VPE) patterns characterized by the presence of delta (δ) wave, short P-δQRS interval, wide δQRS complexes in dogs with right-sided accessory pathways. ANIMALS, MATERIALS AND METHODS: Twenty-six dogs with a confirmed accessory pathways (AP) via electrophysiological mapping were included. All dogs underwent a complete physical examination, 12-lead ECG, thoracic radiography, echocardiographic examination and electrophysiologic mapping. The AP were located in the following regions: right anterior, right posteroseptal, right posterior. The following parameters were determined: P-δQRS interval, δQRS duration, δQRS axis, δQRS morphology, δ-wave polarity, Q-wave, R-wave, R'-wave, S-wave amplitude, and R/S ratio. RESULTS: In lead II, the median δQRS complex duration was 82.4 (IQR 7.2) and the median P-δQRS interval duration was 54.6 (IQR 4.2) msec. The median δQRS complex axis in the frontal plane was: + 68° (IQR 52.5) for right anterior APs, - 24 ° (IQR 24) for right postero-septal APs, - 43.5 ° (IQR 27.25) for right posterior APs (P = 0.007). In lead II, the polarity of the δ wave was positive in 5/5 right anterior APs and negative in 7/11 postero-septal APs and 8/10 in right posterior APs. In precordial leads of all dogs, R/S was ≤ 1 in V1 and > 1 in all leads from V2 to V6. CONCLUSION: Surface electrocardiogram can be used to distinguish right anterior APs from right posterior and right postero-septal ahead of an invasive electrophysiological study.

Physiological consequences of transient outward K+ current activation during heart failure in the canine left ventricle.

BACKGROUND: Remodeling of ion channel expression is well established in heart failure (HF). We determined the extent to which I(to) is reduced in tachypacing-induced HF and assessed the ability of an I(to) activator (NS5806) to recover this current. METHOD AND RESULTS: Whole-cell patch clamp was used to record I(to) in epicardial (Epi) ventricular myocytes. Epi- and endocardial action potentials were recorded from left ventricular wedge preparations. Right ventricular tachypacing-induced heart failure reduced I(to) density in Epi myocytes (Control=22.1±1.9pA/pF vs 16.1±1.4 after 2weeks and 10.7±1.4pA/pF after 5 weeks, +50mV). Current decay as well as recovery of I(to) from inactivation progressively slowed with the development of heart failure. Reduction of I(to) density was paralleled by a reduction in phase 1 magnitude, epicardial action potential notch and J wave amplitude recorded from coronary-perfused left ventricular wedge preparations. NS5806 increased I(to) (at +50mV) from 16.1±1.4 to 23.9±2.1pA/pF (p<0.05) at 2weeks and from 10.7±1.4 to 14.4±1.9pA/pF (p<0.05) in 5 weeks tachypaced dogs. NS5806 increased both fast and slow phases of I(to) recovery in 2 and 5-week HF cells and restored the action potential notch and J wave in wedge preparations from HF dogs. CONCLUSIONS: The I(to) agonist NS5806 increases the rate of recovery and density of I(to), thus reversing the HF-induced reduction in these parameters. In wedge preparations from HF dogs, NS5806 restored the spike-and-dome morphology of the Epi action potential providing proof of principal that some aspects of electrical remodelling during HF can be pharmacologically reversed.

Fast, exact linkage analysis for categorical traits on arbitrary pedigree designs.

Multi-symptom diseases without a consistent continuous measurement of severity may be best understood with a categorical interpretation. In this paper, we present LOCate v.2, a fast, exact algorithm for linkage analysis of all types of categorical traits, both ordinal and nominal. Our method is able to incorporate missing data and analyze complex genealogical structure, including inbreeding loops. LOCate v.2 computes exact likelihoods efficiently through an elimination algorithm, similar to that used by Superlink for binary traits. We compare LOCate v.2 to LOT and QTLlink, two existing methods of linkage analysis for ordinal traits. We find that LOCate v.2 outperforms both methods when used to analyze simulated nominal traits. In addition, LOCate v.2 performs as well as QTLlink on simulated ordinal traits, and better than LOT due to the necessity of cutting large pedigrees for analysis in LOT. To demonstrate the versatility of LOCate v.2, we conduct an ordinal and nominal linkage analysis of ventricular arrhythmias in a large, inbred pedigree of German Shepherd dogs. We find that a trichotomous ordinal or nominal interpretation strengthens the evidence in favor of linkage to a region on chromosome 6, and provides new evidence of linkage to a region on chromosome 11. LOCate v.2 is a unified, fast, and robust method for linkage analysis of ordinal and nominal traits which will be valuable to researchers interested in investigating any type of categorical trait.

Optimizing single-chamber pacing in dogs Part 1: Rate determinations, rate interventions and hysteresis.

Determining ideal pacing rates to meet physiological needs and optimizing programming to prevent unnecessary right ventricular pacing in dogs requires an understanding of heart rate profiles and applicable pacing technology. The heart rate and rhythm of the dog is complex necessitating investigation of rate requirements of activity and circadian influences. Overlaying this information are a multiplicity of other factors such as age, breed, temperament, cardiovascular disease and underlining rhythm disorders that contribute to the difficulty in making general conclusions. However, all such information permits better implementation of programming options with the goal of better outcomes. In this review (Part 1 of a two-part review) instantaneous heart rate, rolling average heart rate, simple average heart rate, heart rate tachograms, RR interval tachograms (2D, 3D and dynamic), and Poincaré plots (2D, 3D and dynamic) are discussed as they apply to decisions in the determination and examination of pacing rates for dogs programmed in the VVI pacing mode (Ventricular paced, Ventricular sensed, Inhibited pacing). The applicable pacing operations available for three pacemaker companies are reviewed (Abbott, Biotronik/Dextronix, and Medtronic). The programmable options considered include: slowest pacing rate without additional features to extend the pacing interval, sleep/rest rate preferences, hysteresis to lengthen pacing interval following intrinsic beats, and intermittent increases in pacing following abrupt loss of intrinsic rhythm. Recommendations are suggested for follow-up of individual dogs with examination of pacing statistics and Holter monitoring.

Optimizing single-chamber pacing in dogs. Part 2: Rate adaptive pacing.

Proper programming of pacemakers for dogs in the rate adaptive mode requires an understanding of the rate requirements for each individual and the interplay of programmable features. The specific advantages and disadvantages of the rate adaptive mode should be considered on a case by case basis. Fundamentally, two components are linked in the implementation of rate adaptive pacing: (1) sensing the need for a change in rate and (2) responding with the appropriate alteration in pacing rate. The programming interaction of these two components are interdependent and affected by the rates programmed. These features may be adjusted manually or automatically. In this review (Part 2 of a two-part review) the considerations required to program each aspect that optimizes the pacing rate profile are reviewed. These include the lower rate, upper sensor rate, activities of daily life rate, sensor threshold, acceleration and deceleration, slope, activities of daily life zone, exertion zone, automatic versus manual adjustments and closed loop stimulation. The programming features of pacemakers manufactured by three companies are summarized (Abbott, formerly St. Jude; Biotronik/Dextronix; Medtronic). Means of assessing the success of pacemaker programing is examined through examples of pacemaker data, Holter analysis, Poincaré plots and tachograms. Finally, the questions and considerations for rate adaptive pacing in dogs that demand investigation are proposed.

Temporal changes in clinical and radiographic variables in dogs with preclinical myxomatous mitral valve disease: The EPIC study.

BACKGROUND: The Evaluation of pimobendan in dogs with cardiomegaly caused by preclinical myxomatous mitral valve disease (EPIC) study monitored dogs with myxomatous mitral valve disease (MMVD) as they developed congestive heart failure (CHF). OBJECTIVES: To describe the changes in clinical and radiographic variables occurring as dogs with MMVD and cardiomegaly develop CHF, compared to similar dogs that do not develop CHF. ANIMALS: One hundred and thirty-five, and 73 dogs that did or did not develop CHF, respectively. MATERIALS AND METHODS: The following variables were evaluated in 2 groups of dogs (dogs that did or did not develop CHF): Heart rate (HR), clinic respiratory rate (RR), home-measured resting respiratory rate (RRR), rectal temperature (RT), body weight (BW), and vertebral heart sum (VHS). Absolute value and rate of change of each variable were calculated for each day a dog was in study. Daily means were calculated and plotted against time. The onset of CHF or last visit before leaving the study were set as reference time points. RESULTS: The most extreme values and rate of change occurred in variables immediately before onset of CHF. Vertebral heart sum increased earliest. Heart rate, RR, and RRR also increased. Rectal temperature and BW decreased. Increases in RR and RRR were most extreme and occurred immediately before CHF. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with MMVD and cardiomegaly experience increases in HR, RR, RRR, and VHS, and decreases in BW and RT as they develop CHF. The variables with highest absolute change and rate of change were RR and RRR. These findings reinforce the value of RR and RRR as indicators of impending or incipient CHF.

Estimation of heritabilities, genetic correlations, and breeding values of four traits that collectively define hip dysplasia in dogs.

OBJECTIVE-To estimate heritabilities and genetic correlations among 4 traits of hip joints (distraction index [DI], dorsolateral subluxation [DLS] score, Norberg angle [NA], and extended-hip joint radiograph [EHR] score) and to derive the breeding values for these traits in dogs. ANIMALS-2,716 dogs of 17 breeds (1,551 dogs in which at least 1 hip joint trait was measured). PROCEDURES-The NA was measured, and an EHR score was assigned. Hip joint radiographs were obtained from some dogs to allow calculation of the DI and DLS score. Heritabilities, genetic correlations, and breeding values among the DI, DLS score, NA, and EHR score were calculated by use of a set of multiple-trait, derivative-free, restricted maximum likelihood computer programs. RESULTS-Among 2,716 dogs, 1,411 (52%) had an estimated inbreeding coefficient of 0%; the remaining dogs had a mean inbreeding coefficient of 6.21%. Estimated heritabilities were 0.61, 0.54, 0.73, and 0.76 for the DI, DLS score, NA, and EHR score, respectively. The EHR score was highly genetically correlated with the NA (r = -0.89) and was moderately genetically correlated with the DI (r = 0.69) and DLS score (r = -0.70). The NA was moderately genetically correlated with the DI (r = -0.69) and DLS score (r = 0.58). Genetic correlation between the DI and DLS score was high (r = -0.91). CONCLUSIONS AND CLINICAL RELEVANCE-Establishment of a selection index that makes use of breeding values jointly estimated from the DI, DLS score, NA, and EHR score should enhance breeding programs to reduce the incidence of hip dysplasia in dogs.

Beat-to-Beat Patterning of Sinus Rhythm Reveals Non-linear Rhythm in the Dog Compared to the Human.

The human and dog have sinus arrhythmia; however, the beat-to-beat interval changes were hypothesized to be different. Geometric analyses (R-R interval tachograms, dynamic Poincaré plots) to examine rate changes on a beat-to-beat basis were analyzed along with time and frequency domain heart rate variability from 40 human and 130 canine 24-h electrocardiographic recordings. Humans had bell-shaped beat-interval distributions, narrow interval bands across time with continuous interval change and linear changes in rate. In contrast, dogs had skewed non-singular beat distributions, wide interval bands {despite faster average heart rate of dogs [mean (range); 81 (64-119)] bpm compared to humans [74.5 (59-103) p = 0.005]} with regions displaying a paucity of intervals (zone of avoidance) and linear plus non-linear rate changes. In the dog, dynamic Poincaré plots showed linear rate changes as intervals prolonged until a point of divergence from the line of identity at a mean interval of 598.5 (95% CI: 583.5-613.5) ms (bifurcation interval). The dog had bimodal beat distribution during sleep with slower rates and greater variability than during active hours that showed singular interval distributions, higher rates and less variability. During sleep, Poincaré plots of the dog had clustered or branched patterns of intervals. A slower rate supported greater parasympathetic modulation with a branched compared to the clustered distribution. Treatment with atropine eliminated the non-linear patterns, while hydromorphone shifted the bifurcated branching and beat clustering to longer intervals. These results demonstrate the unique non-linear nature of beat-to-beat variability in the dog compared to humans with increases in interval duration (decrease heart rate). These results provoke the possibility that changes are linear with a dominant sympathetic modulation and non-linear with a dominant parasympathetic modulation. The abrupt bifurcation, zone of avoidance and beat-to-beat patterning are concordant with other studies demonstrating the development of exit block from the sinus node with parasympathetic modulation influencing not only the oscillation of the pacing cells, but conduction to the atria. Studies are required to associate the in vivo sinus node beat patterns identified in this study to the mapping of sinus impulse origin and exit from the sinus node.

Long-term incidence and risk of noncardiovascular and all-cause mortality in apparently healthy cats and cats with preclinical hypertrophic cardiomyopathy.

BACKGROUND: Epidemiologic knowledge regarding noncardiovascular and all-cause mortality in apparently healthy cats (AH) and cats with preclinical hypertrophic cardiomyopathy (pHCM) is limited, hindering development of evidence-based healthcare guidelines. OBJECTIVES: To characterize/compare incidence rates, risk, and survival associated with noncardiovascular and all-cause mortality in AH and pHCM cats. ANIMALS: A total of 1730 client-owned cats (722 AH, 1008 pHCM) from 21 countries. METHODS: Retrospective, multicenter, longitudinal, cohort study. Long-term health data were extracted by medical record review and owner/referring veterinarian interviews. RESULTS: Noncardiovascular death occurred in 534 (30.9%) of 1730 cats observed up to 15.2 years. Proportion of noncardiovascular death did not differ significantly between cats that at study enrollment were AH or had pHCM (P = .48). Cancer, chronic kidney disease, and conditions characterized by chronic weight-loss-vomiting-diarrhea-anorexia were the most frequently recorded noncardiovascular causes of death. Incidence rates/risk of noncardiac death increased with age in AH and pHCM. All-cause death proportions were greater in pHCM than AH (65% versus 40%, respectively; P < .001) because of higher cardiovascular mortality in pHCM cats. Comparing AH with pHCM, median survival (study entry to noncardiovascular death) did not differ (AH, 9.8 years; pHCM, 8.6 years; P = .10), but all-cause survival was significantly shorter in pHCM (P = .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: All-cause mortality was significantly greater in pHCM cats due to disease burden contributed by increased cardiovascular death superimposed upon noncardiovascular death.

Evaluation of atrial fibrillation induced during anesthesia with fentanyl and pentobarbital in German Shepherd Dogs with inherited arrhythmias.

OBJECTIVE: To determine the type of atrial fibrillation induced by use of 2 pacing protocols during fentanyl and pentobarbital anesthesia before and after administration of atropine and to determine the organization of electrical activity in the left and right atria during atrial fibrillation in German Shepherd Dogs. ANIMALS: 7 German Shepherd Dogs. PROCEDURES: Extrastimulus and pacedown protocols were performed before and after atropine administration. Monophasic action potential spectral entropy and mean dominant frequency were calculated during atrial fibrillation. RESULTS: Atrial fibrillation occurred spontaneously in 6 of 7 dogs. All 7 dogs had atrial fibrillation induced. Sustained atrial fibrillation occurred in 13 of 25 (52%) episodes induced by the extrastimulus protocol and in 2 of 12 episodes of atrial fibrillation induced by pacedown. After atropine administration, sustained atrial fibrillation did not occur, and the duration of the nonsustained atrial fibrillation (6 episodes in 2 dogs of 1 to 26 seconds) was significantly shorter than before atropine administration (25 episodes in 7 dogs of 1 to 474 seconds). The left atrium (3.67 +/- 0.08) had lower spectral entropy than the right atrium (3.81 +/- 0.03), indicating more electrical organization in the left atrium. The mean dominant frequency was higher in the left atrium in 3 dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Atrial fibrillation developed spontaneously and was induced in German Shepherd Dogs under fentanyl and pentobarbital anesthesia. Electrical activity was more organized in the left atrium than in the right atrium as judged by use of spectral entropy.

Clinical and electrocardiographic presentations of transient trifascicular block in three cats.

This report describes transient trifascicular block in three cats presented with lethargy and inappetence, and elevated cardiac troponin I concentrations. The electrocardiogram (ECG) of cat 1 showed a sinus rhythm with pronounced first-degree atrioventricular (AV) block, right bundle branch block, and left anterior fascicular block. The ECG of cat 2 showed truncular left bundle branch block alternating with left anterior fascicular block coupled with prolonged PR intervals, second-degree heart block, and paroxysmal third-degree AV block. The ECG of cat 3 showed first-degree AV block with concomitant right bundle branch block. The diagnosis of trifascicular block was made when paroxysmal third-degree AV block was documented. All cats recovered with medical management within weeks. Each cat resumed a sinus rhythm. Elevated cardiac troponin I concentrations suggested myocarditis that improved.

International collaborative study to assess cardiovascular risk and evaluate long-term health in cats with preclinical hypertrophic cardiomyopathy and apparently healthy cats: The REVEAL Study.

BACKGROUND: Hypertrophic cardiomyopathy is the most prevalent heart disorder in cats and principal cause of cardiovascular morbidity and mortality. Yet, the impact of preclinical disease is unresolved. HYPOTHESIS/OBJECTIVES: Observational study to characterize cardiovascular morbidity and survival in cats with preclinical nonobstructive (HCM) and obstructive (HOCM) hypertrophic cardiomyopathy and in apparently healthy cats (AH). ANIMALS: One thousand seven hundred and thirty client-owned cats (430 preclinical HCM; 578 preclinical HOCM; 722 AH). METHODS: Retrospective multicenter, longitudinal, cohort study. Cats from 21 countries were followed through medical record review and owner or referring veterinarian interviews. Data were analyzed to compare long-term outcomes, incidence, and risk for congestive heart failure (CHF), arterial thromboembolism (ATE), and cardiovascular death. RESULTS: During the study period, CHF, ATE, or both occurred in 30.5% and cardiovascular death in 27.9% of 1008 HCM/HOCM cats. Risk assessed at 1, 5, and 10 years after study entry was 7.0%/3.5%, 19.9%/9.7%, and 23.9%/11.3% for CHF/ATE, and 6.7%, 22.8%, and 28.3% for cardiovascular death, respectively. There were no statistically significant differences between HOCM compared with HCM for cardiovascular morbidity or mortality, time from diagnosis to development of morbidity, or cardiovascular survival. Cats that developed cardiovascular morbidity had short survival (mean ± standard deviation, 1.3 ± 1.7 years). Overall, prolonged longevity was recorded in a minority of preclinical HCM/HOCM cats with 10% reaching 9-15 years. CONCLUSIONS AND CLINICAL IMPORTANCE: Preclinical HCM/HOCM is a global health problem of cats that carries substantial risk for CHF, ATE, and cardiovascular death. This finding underscores the need to identify therapies and monitoring strategies that decrease morbidity and mortality.

Molecular composition of the intercalated disc in a spontaneous canine animal model of arrhythmogenic right ventricular dysplasia/cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by ventricular arrhythmias, sudden death, and fatty or fibrofatty replacement of right ventricular myocytes. Recent studies have noted an association between human ARVD/C and molecular remodeling of intercalated disc structures. However, progress has been constrained by limitations inherent to human studies. OBJECTIVE: We studied the molecular composition of the intercalated disc structure in a naturally occurring animal model of ARVD/C (Boxer dogs). METHODS: We studied hearts from 12 Boxers with confirmed ARVD/C and 2 controls. Ventricular sections from 4 animals were examined by immunofluorescent microscopy. Frozen tissue samples were used for Western blot analysis. Proteins investigated were N-cadherin, plakophilin 2, desmoplakin, plakoglobin, desmin, and connexin 43 (Cx43). RESULTS: In control dogs, all proteins tested by immunofluorescence analysis yielded intense localized signals at sites of end-to-end cell apposition. In contrast, myocardial tissues from ARVD/C-afflicted Boxers showed preservation of N-cadherin staining but loss of detectable signal for Cx43 at the intercalated disc location. Western blots indicated that the Cx43 protein was still present in the samples. Gene sequencing analysis showed no mutations in desmoplakin, plakoglobin, Cx43, or plakophilin 2. CONCLUSION: Mutation(s) responsible for ARVD/C in Boxers lead, directly or indirectly, to severe modifications of mechanical and electrical cell-cell interactions. Furthermore, significant reduction in gap junction formation may promote a substrate for malignant ventricular arrhythmias. This model may help to advance our understanding of the molecular basis, pathophysiology, and potential therapeutic approach to patients with ARVD/C.

Prospective evaluation of the balloon-to-annulus ratio for valvuloplasty in the treatment of pulmonic stenosis in the dog.

BACKGROUND: In dogs, treatment of pulmonic valve stenosis (PS) with pulmonary balloon valvuloplasty (PBV) is a viable method to decrease the pressure gradient across the valve. However, to the authors' knowledge, the variables that influence the selection of the correct balloon size for the procedure have not been explored. Moreover, the lesions caused by the procedure have not been detailed. HYPOTHESIS: Variables that influence the measurement of the annulus could affect selection of the balloon size. We sought to determine the effects of treatment when the balloon-to-annulus ratio (BAR) was or > 1.3, but within the recommended range of 1.2-1.5, regardless of whether dilation was performed with single or double balloon technique. ANIMALS: Twenty-five Beagles with PS were studied. METHODS: Inter- and intra-observer variability, echocardiography versus angiocardiography, and systolic versus diastolic timing were evaluated for the BAR. Assessment of right ventricular (RV) pressure, Doppler gradient, stenotic valve area, and RV wall thickness were compared before and 1, 90, and 180 days after treatment. Postmortem examination of the heart was done. RESULTS: Significant correlations existed in measurement of the annulus; however, variation existed that would change balloon size. Improvement in the degree of PS was significant regardless of the BAR or single or double ballooning. In the most severely affected dogs, continued improvement was noted on day 90. Postmortem examination revealed tears in the commissures and the valve leaflets. CONCLUSIONS: Multiple factors influenced determination of the BAR and a range of 1.2-1.5 was effective without detrimental consequences. Dogs with severe PS had continued decrease in RV pressure 3 months after treatment.

Heterogeneous ventricular repolarization provides a substrate for arrhythmias in a German shepherd model of spontaneous arrhythmic death.

BACKGROUND: German shepherd dogs with inherited arrhythmias and sudden death appear to be a model for catecholamine-dependent ventricular tachycardias in human subjects. We tested the hypothesis that heterogeneity of left ventricular repolarization creates an arrhythmogenic substrate for pause-dependent ventricular tachycardia in these animals. METHODS AND RESULTS: We used microelectrode techniques to record action potentials (AP) from midmyocardial sections of anteroseptal, anterobasal, and posterobasal left ventricular (LV) wall of unafflicted and afflicted dogs. There were no differences in AP duration to 90% repolarization (APD) among LV regions in unafflicted dogs. In contrast, in afflicted dogs, there was significant heterogeneity, with the longest APD in anterobasal and shortest in anteroseptal regions. Isoproterenol did not affect repolarization in unafflicted dogs, whereas in afflicted dogs, it shortened APD anterobasally and prolonged APD anteroseptally. We studied the repolarizing currents, IKr and IKs, in single anteroseptal and anterobasal LV myocytes with the use of a whole-cell voltage clamp. There were no differences in IKr and IKs between anteroseptal and anterobasal regions in unafflicted dogs, whereas in afflicted dogs, IKr was smaller anterobasally (P<0.05). Isoproterenol produced a more prominent leftward shift in IKs voltage-dependent activation in anterobasal regions of afflicted than unafflicted dogs. CONCLUSIONS: Spatial heterogeneity in expression and catecholamine responsiveness of IKr and IKs results in heterogeneous LV repolarization in afflicted German shepherd dogs, contributing importantly to the arrhythmogenic substrate.

Regional dispersion of L-type calcium current in ventricular myocytes of German shepherd dogs with lethal cardiac arrhythmias.

OBJECTIVES: The purpose of this study was to determine if regional differences in L-type Ca(2+) current (I(Ca,L)) are altered in a German shepherd model of sudden death. BACKGROUND: German shepherd dogs with inherited sudden cardiac death have reduced sympathetic innervation in the anteroseptal left ventricle that may contribute to arrhythmias in afflicted animals compared to control unafflicted animals. Differences in a number of repolarizing K(+) currents have been identified in this model, but I(Ca,L) has not been studied. METHODS: We measured action potentials in intact tissue and I(Ca,L) in isolated myocytes from anteroseptal and anterobasal left ventricle. RESULTS: Action potential plateau level and I(Ca,L) density were significantly lower in unafflicted anteroseptal than in afflicted anteroseptal, afflicted anterobasal, or unafflicted anterobasal. Isoproterenol increased I(Ca,L) density more in the unafflicted anteroseptal group than in the other groups. CONCLUSIONS: Differences in I(Ca,L) between afflicted and control animals, combined with our earlier finding of regional reductions in I(Kr), provide a likely substrate for the occurrence of pause-dependent arrhythmias in afflicted animals and for the T-wave abnormalities characterizing them.

Mechanisms of alpha-adrenergic potentiation of ventricular arrhythmias in dogs with inherited arrhythmic sudden death.

OBJECTIVE: In German shepherd dogs having inherited arrhythmias and sudden death, pause-dependent arrhythmias are triggered by early afterdepolarizations (EADs) originating from left ventricular (LV) Purkinje fibers (PF). Heterogeneity of LV repolarization provides the arrhythmogenic substrate. To elucidate the mechanisms whereby alpha-adrenergic stimulation exacerbates these arrhythmias we tested the effects of phenylephrine on both arrhythmogenic trigger and substrate. METHODS AND RESULTS: We used microelectrode techniques to record action potentials from LV and right ventricular (RV) PF and from midmyocardial sections of anteroseptal, anterobasal and posterobasal LV wall of unafflicted and afflicted dogs. EADs occurred spontaneously in 8 of 12 LV PF and in no RV PF from afflicted dogs and in no PF from unafflicted dogs. In LV PF from afflicted dogs, phenylephrine (10(-9)-10(-5) M) concentration-dependently decreased membrane potential, induced abnormal automaticity at membrane potentials from -65 to -45 mV in 6 LV PF and potentiated EADs in another 6. To determine the mechanisms of membrane depolarization we studied phenylephrine effects on IK1 in voltage-clamped single LV and RV PF cells from afflicted dogs. In LV PF, phenylephrine (10(-5) M) reduced IK1 over the range of -120 to -40 mV and had no effects on RV PF. Regional heterogeneity of LV repolarization was observed in afflicted dogs only. Phenylephrine had no effects on repolarization in either group. CONCLUSION(S): Alpha-adrenergic stimulation exacerbates arrhythmias in afflicted dogs by increasing the arrhythmogenic trigger while leaving the substrate unchanged. Decrease in IK1 contributes importantly to alpha-adrenergic effects on LV PF.

Cardiovascular-renal axis disorders in the domestic dog and cat: a veterinary consensus statement.

OBJECTIVES: There is a growing understanding of the complexity of interplay between renal and cardiovascular systems in both health and disease. The medical profession has adopted the term "cardiorenal syndrome" (CRS) to describe the pathophysiological relationship between the kidney and heart in disease. CRS has yet to be formally defined and described by the veterinary profession and its existence and importance in dogs and cats warrant investigation. The CRS Consensus Group, comprising nine veterinary cardiologists and seven nephrologists from Europe and North America, sought to achieve consensus around the definition, pathophysiology, diagnosis and management of dogs and cats with "cardiovascular-renal disorders" (CvRD). To this end, the Delphi formal methodology for defining/building consensus and defining guidelines was utilised. METHODS: Following a literature review, 13 candidate statements regarding CvRD in dogs and cats were tested for consensus, using a modified Delphi method. As a new area of interest, well-designed studies, specific to CRS/CvRD, are lacking, particularly in dogs and cats. Hence, while scientific justification of all the recommendations was sought and used when available, recommendations were largely reliant on theory, expert opinion, small clinical studies and extrapolation from data derived from other species. RESULTS: Of the 13 statements, 11 achieved consensus and 2 did not. The modified Delphi approach worked well to achieve consensus in an objective manner and to develop initial guidelines for CvRD. DISCUSSION: The resultant manuscript describes consensus statements for the definition, classification, diagnosis and management strategies for veterinary patients with CvRD, with an emphasis on the pathological interplay between the two organ systems. By formulating consensus statements regarding CvRD in veterinary medicine, the authors hope to stimulate interest in and advancement of the understanding and management of CvRD in dogs and cats. The use of a formalised method for consensus and guideline development should be considered for other topics in veterinary medicine.

Morphology of ventricular arrhythmias in the boxer as measured by 12-lead electrocardiography with pace-mapping comparison.

The QRS amplitude and polarity were determined in 12-lead electrocardiograms recorded from 22 Boxers with ventricular arrhythmias. Eighty-one percent (18/22) of dogs displayed a positive QRS morphology in the caudoventral leads (II, III, and aVF) and 77% (17/22) of dogs displayed a positive QRS morphology in the left precordial leads (V2-V6). In leads I and V1, the polarity of the QRS complex was variable (positive or negative). To determine if these morphologic features were suggestive of ventricular complexes arising from the right or left ventricle, a comparison was made to the QRS complexes in a pace-mapping study performed in 7 healthy mixed-breed dogs. A total of 3 right and 4 left ventricular sites were paced. None of the left ventricular paced sites resulted in a QRS morphology similar to the most common spontaneous ventricular arrhythmia in the Boxers. In contrast, QRS morphology in each of the 3 right ventricular sites was similar to that observed in the Boxers (P < .033). Each of these produced positive deflections in the caudoventral and left precordial leads, but both positive and negative QRS complexes were observed in leads I and V1 only when the right ventricular septum was paced. This finding suggested that the right ventricular septum might be a site of origin for the ventricular rhythm observed in the Boxers because in the Boxers the polarity of leads I and V1 also varied. Pacing the right ventricular outflow tract always resulted in a negative QRS complex in lead 1, whereas pacing the right ventricular apex always resulted in a positive QRS complex in lead I and a negative QRS complex in V1. However, these locations cannot be excluded as possible sites of origin for the spontaneous ventricular arrhythmias in the Boxers because the arrhythmias could be originating from both of these locations. The spontaneous ventricular arrhythmia of the Boxer is most similar to that of paced ventricular rhythms arising from the right ventricle. More precise localization to a region of the right ventricle such as outflow tract, septal, or apical could not be made.