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This is the final peer-reviewed accepted manuscript of: Diagnostic and prognostic utility of surface electrocardiography in cats with left ventricular hypertrophy HYPERLINK "" \l "!" G.Romito, HYPERLINK "" \l "!" C.Guglielmini, HYPERLINK "" \l "!" M.O.Mazzarella, HYPERLINK "" \l "!" M.Cipone, HYPERLINK "" \l "!" A.Diana, B.Contiero, HYPERLINK "" \l "!" M.Baron ToaldoJournal of Veterinary Cardiology,Volume 20, Issue 5, 2018, Pages 364-375The final published version is available online at: . This manuscript version is made available under the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) 4.0 International License ()Diagnostic and prognostic utility of surface electrocardiography in cats with left ventricular hypertrophyGiovanni Romito DVM, PhD,a Carlo Guglielmini DVM, PhD,b Marco Orazio Mazzarella DVM,a Mario Cipone DVM,a Alessia Diana DVM, PhD,a Barbara Contiero MScS,b Marco Baron Toaldo DVM, PhD, Dipl. ECVIM-CA (Cardiology)aa Department of Veterinary Medical Sciences, Alma Mater Studiorum - University of Bologna, Italy; b Department of Animal Medicine, Production and Health, University of Padua, Italy.This work was done at the Department of Veterinary Medical Sciences, Alma Mater Studiorum - University of Bologna, Via Tolara di Sopra 50, 40064 Ozzano Emilia, Italy.Corresponding author: M Baron Toaldo, E-mail marco.barontoaldo@unibo.itPresented as an oral abstract at the 27th Congress of the European Society of Veterinary Internal Medicine – Companion Animals, St. Julian's, Malta, 14th-16th September 2017.Corresponding author address: Department of Veterinary Medical Sciences, Alma Mater Studiorum - University of Bologna, Via Tolara di Sopra 50, 40064 Ozzano Emilia, Italy. Phone (+39) 051 2097878; Fax (+39) 051 2097593.Short title: Electrocardiography in cats with cardiomyopathyAbstractObjectives - To assess the ability of electrocardiography (ECG) to predict left ventricular hypertrophy (LVH) in the cat and to investigate the prognostic value of selected ECG variables in cats with LVH.Animals - Fifty-seven privately owned cats: 22 clinically healthy cats and 35 cats with LVH. Material and methods – Clinical cohort study. Echocardiographic diagnosis and surface ECG were available. ECG analysis included rhythm diagnosis and specific electrocardiographic measurements. In cats with LVH, cause of death and outcome data were recorded and analyzed using Kaplan-Meier curves.Results - The presence of arrhythmia had sensitivity and specificity of 29% and 100%, respectively, for identifying LVH. Among ECG measurements, duration of QT interval (QT) and QT interval corrected for heart rate (QTc) were statistically different between healthy cats and cats with LVH (P = .007). Overall, the most accurate cut-offs to identify LVH were QT > 170 ms (sensitivity and specificity 48.3% and 91%, respectively) and QTc > 188 ms (sensitivity and specificity 62% and 77%, respectively). In healthy cats, the highest QT and QTc values were 180 ms and 200 ms, respectively. Mean survival time was 58 days and indeterminable for cats with QT > 180 ms and QT ≤ 180 ms, respectively (P = .042), and 125 days and indeterminable for cats with QTc > 200 ms and QTc ≤ 200 ms, respectively (P = .017).Conclusions - Arrhythmias as well as prolonged QT and QTc are useful ECG parameters in identifying LVH and predicting survival in affected cats.ATEarterial thromboembolismAVBatrioventricular blockCHFcongestive heart failureECGelectrocardiographyHCMhypertrophic cardiomyopathyHRheart rateHThyperthyroidismLAleft atriumLVleft ventricleLVHleft ventricular hypertrophyQTQT interval QTcQT interval corrected for heart rateROCreceiver operating characteristicSAHsystemic arterial hypertensionSAMsystolic anterior motion of the mitral valveSBPsystemic arterial blood pressureVPCventricular premature complexVTventricular tachycardiaAbbreviation TableKeywordsFeline; survival; QT interval; hypertrophic cardiomyopathy.IntroductionFeline hypertrophic cardiomyopathy (HCM), which by convention is morphologically defined by concentric hypertrophy of a non-dilated left ventricle (LV), represents the most common heart disease in the cat [1,2]. This condition exhibits a broad spectrum of severity and a heterogeneous outcome, with some cats having a subclinical disease course and long survival time while others experience severe complications, such as congestive heart failure (CHF), arterial thromboembolism (ATE) and cardiac arrhythmias [1-4]. Many authors have previously described the association between feline HCM and different types of cardiac rhythm disturbances. A large retrospective study of 282 cats with HCM identified arrhythmias in 31% of cats, and ventricular premature complexes (VPC) were overrepresented compared to supraventricular tachyarrhythmias and bradyarrhythmias [3]. A recent 24-hour Holter analysis in 17 cats with asymptomatic HCM revealed VPCs in all cats studied, with 14 cats exhibiting complex arrhythmias (couplets, triplets, or ventricular tachycardia [VT]). Additionally, 15/17 cats with HCM had supraventricular arrhythmias, with only 4 cats exhibiting complexity [5]. Although generally less common than ventricular arrhythmias, supraventricular arrhythmias tend to be more frequent in cats with structural heart disease associated with atrial enlargement, as demonstrated by a retrospective study of 50 cats with atrial fibrillation and underlying cardiomyopathies including left ventricular hypertrophy (LVH)[6]. Various types of conduction disturbances have been also identified in cats with HCM, including bundle branch blocks and different degrees of atrioventricular block (AVB) [1,7,8]. Additionally, a retrospective analysis of electrocardiographic tracings from 61 cats with HCM demonstrated changes of waveform morphology in 49% of subjects, with LV enlargement pattern (QRS complexes >40 ms and R waves >0.9 mV) being overrepresented (25% of population) [1]. In human cardiomyopathies, surface electrocardiography (ECG) is known to have predictive utility and is frequently used to stratify the risk of the affected individuals, especially in the case of HCM [9-19]. Despite the abundance of descriptive data on rhythm abnormalities in cats with cardiomyopathy, no prior study has specifically addressed the predictive utility of ECG in identifying feline LVH or its possible prognostic use. The aim of this study was to determine the ability of 2-min ECG analysis to distinguish healthy cats from cats with LVH, and to evaluate the ability of selected ECG variables to predict survival in the affected population.Animals, materials and methodsStudy PopulationThe clinical archive of the Veterinary Teaching Hospital of the University of Bologna was retrospectively reviewed to identify cats diagnosed with LVH on the basis of two-dimensional echocardiography, as subsequently described, between January 2008 and September 2016. To be included, cats had to have a complete case record, including signalment, history, clinical findings and cardiac investigation, and a definitive diagnosis of LVH based on echocardiography. Cardiovascular investigation included systemic arterial blood pressure (SBP) assessment, thoracic radiography, 6-lead surface ECG and transthoracic echocardiography. The oscillometric technique was used to assess SBP as recommended by the American College of Veterinary Internal Medicine guidelines [20] using two dedicated devices.c,d When SBP was > 160 mmHg on serial repeated measurements in an apparently calm cat, the subject was classified as affected by systemic arterial hypertension (SAH) [20]. Laboratory data were also annotated when available, including serum biochemistry profile and total thyroxine concentration T4 (reference range: 5-40 nmol/L) (the latter measured in cats ≥ 7 years). Thoracic radiography in two orthogonal projections was performed to exclude or confirm the presence of CHF (pulmonary edema and/or pleural effusion) in all cats with echocardiographic evidence of a dilated left atrium (LA) or clinical signs of dyspnea, unless pleural effusion had already been noted during transthoracic echocardiography. Limb ATE was defined as sudden onset of lower motor neuron de?cits in one or more limbs coupled to tissue pallor, cool extremity, and loss of peripheral pulse in the presence of LA dilatation [3]. Clinically healthy cats were also selected to act as the control group. These animals were owned by students and staff of the University of Bologna. Cats were enrolled in the control group if no abnormalities were identified on medical history, if they had normal SBP values, if no clinical signs of hyperthyroidism (HT) or other systemic diseases were present on physical examination, and if echocardiographic examination was within normal limits. After enrollment, each healthy cat underwent a standardized 6-lead ECG analysis.Echocardiographic examination Standard transthoracic two-dimensional measurements were performed using an ultrasound unite equipped with phased-array probes of various frequency (S8-3; S12-4) and continuous ECG. Cats were unsedated and gently restrained in right and left lateral recumbency during the examination. A mean of three measurements was obtained for each echocardiographic parameter on three consecutive cardiac cycles on the same frame. The LV wall thickness in diastole and systole, LV internal diameter in diastole and systole, and LA diameter in systole were recorded. Echocardiographic evidence of LVH was obtained from two-dimensional recorded cine-loops in the right parasternal short and long axis views, with LVH confirmed by at least one segment of the LV walls showing a thickness ≥ 5.5 mm at end-diastole [21]. The presence of systolic anterior motion of the mitral valve (SAM), assessed from the right parasternal long axis view with visualization of the LV outflow tract, was also recorded. Primary HCM was diagnosed in cats with concentric LVH in the absence of any other cardiac or systemic illness that might produce the same echocardiographic phenotype, whereas cats with LVH and T4 and/or SBP above the reference values were classified as secondary LVH [22,23]. Cats with subjectively normal assessment of cardiac morphology and LV wall thickness < 5.5 mm were considered echocardiographically normal [24] and then selected for the control group. Cats were excluded if their echocardiographic studies were incomplete or of poor quality.Electrocardiographic examination All cats were positioned and manually restrained in right laterxal recumbency, with the front legs placed parallel to each other and perpendicular to the long axis of the body, and the hind limbs in a neutral semiflexed position [25]. The animals were unsedated and were allowed time to acclimatize so that the ECG could be taken from relaxed cats. All ECGs were recorded using two commercially available ECG machines.f,g The ECG leads were attached to the skin by flattened alligator clips at the level of the olecranon on the caudal aspect of the forelimb, and over the patellar ligaments on the cranial aspect of the hind limbs [26]. Isopropyl alcohol was applied to maintain electrical contact with the skin. Standard 6-lead ECGs (leads I, II, III, aVR, aVL, and aVF) were recorded for 2 minutes in all cats at a paper speed of 50 mm/s and paper sensitivity of 20 mm/mV. For each animal, an effort was made to obtain an ECG tracing showing a clean isoelectric line with easily recognizable waveforms. Systematic ECG measurements were performed only for the traces recorded with one ECG machine,g while rhythm diagnosis was carried out for all the tracings, regardless of the machine used. One operator (MBT), blinded to the group assignment of the cats, reviewed the ECG tracings and manually measured intervals and amplitudes using a caliper and a ruler with 0.5 mm graduations. The ECG settings for the machine used for the measurements were as follows: low-pass filter, 35 Hz; high pass filter, 0.05 Hz; notch filter, 50 Hz; sampling frequency, 500 Hz. Three representative consecutive beats were used to measure various ECG variables and the results were averaged for each variable. Variables analyzed included cardiac rhythm (i.e., normal sinus rhythm, sinus arrhythmia, and pathological arrhythmias); heart rate (HR) in bpm calculated by determining the number of QRS complexes in a three-second interval and multiplying this number by twenty; amplitude and duration of the P wave; PQ-interval duration; amplitude and duration of the QRS complex; presence of ST-segment elevation or depression; amplitude of the T wave; duration of the QT interval (QT) and QT interval corrected for the heart rate (QTc) according to the logarithmic formula (QTc= log600 x QT/logRR) [27]; mean electrical axis of the P wave, the QRS complex and the T wave. Amplitudes and durations were expressed in mV and ms, respectively. The mean electrical axis was calculated using the following equation: mean electrical axis = arctan (Iamp, aVFamp) x 180/π [26]. Rhythm analysis was based on the following criteria [26,28]: normal sinus rhythm, sinus rhythm with a normal HR (120-220 bpm) with less than 10% variation in R-R intervals; sinus arrhythmia, sinus rhythm with normal HR (120-220 bpm) and more than 10% variation in R-R intervals; sinus tachycardia, more than 3 consecutive sinus complexes at a HR above the upper normal limit; sinus bradycardia, more than 3 consecutive sinus complexes at a HR below the lower normal limit; atrial premature complex, premature narrow QRS complex conducted by a P wave with an abnormal morphology; supraventricular tachycardia, more than 3 consecutive atrial premature complexes at a HR above upper normal limit; VPC, premature wide and bizarre QRS complex without an associated P wave; accelerated idioventricular rhythm, more than 3 VPCs at a normal HR; VT, more than 3 VPCs at a HR above the upper normal limit; second-degree AVB, one or more P waves not followed by a QRS complex, while others conducted with an associated QRS complex; third-degree AVB, complete dissociation between atria and ventricles, with an atrial rate independent of a junctional or ventricular escape rhythm.Survival analysis Among cats with LVH, survival data were obtained by reviewing an internal database or through telephonic questionnaires. Date of death, whether the cat died naturally or because of euthanasia, and whether death was related to cardiac disease (i.e., CHF, ATE, or sudden death) or non-cardiac causes were recorded. Congestive heart failure death was defined as dying with dyspnea, crackles, cyanosis, expectoration of fluid from the respiratory tract and/or euthanasia due to becoming refractory to CHF medication [4]. Arterial thromboembolism death was defined as death or euthanasia following a new episode of ATE or worsening of a current ATE [4]. Sudden cardiac death was defined as being found dead without an obvious cause at home or as a witnessed event where the cat had been apparently well in the preceding 24 h [4]. Time in days from the cardiologic examination to the phone call for cats still alive (follow-up time) or to death (survival time) was recorded.Statistical analysis Initial descriptive statistics included mean ± standard deviation for normally distributed data and median and range (minimum – maximum) for data that were not normally distributed. All data were tested for their distribution with a D’Agostino-Pearson normality test. Continuous variables were compared between groups with a Student’s T-test or a Mann-Whitney U test, while categorical data were compared using a Fisher’s exact test. A correlation analysis between the maximal degree of LVH, expressed as the absolute maximal thickness of one segment of the LV walls at end-diastole (considering both the interventricular septum and the left ventricular free wall), and duration of QT and QTc was performed with a Spearman correlation test. The sensitivity and specificity for identification of LVH on the basis of presence or absence of any type of arrhythmia were calculated using standard formulas. Additionally, receiver operating characteristic (ROC) curves were obtained by plotting sensitivity versus 100-specificity to determine the ability of ECG parameters to identify cats with LVH. The area under the curve of the ROC curves for each parameter was compared. Moreover, for each ECG parameter the optimal cut-off corresponding to the value closest to the upper left corner of the graph was identified (Youden criterion). Sensitivity, specificity, and positive and negative likelihood ratios were calculated by use of the cut-offs determined with the ROC curves. For the survival analysis, Kaplan-Meier curves were generated, survival times reported as median and range, and di?erences between groups analysed by the log-rank (Mantel-Cox) test. Non-cardiac deaths (with survival included up to the point of death) and cats still alive at the time of analysis were right-censored. A composite end-point of all cardiac-related deaths (CHF, ATE, and sudden death) was analysed. Data analysis was performed with statistical software packagesh,i and a value of P < 0.05 was considered significant.ResultsGeneral characteristics of the study population and echocardiographic dataThe study population included 22 healthy cats used as control group, and 35 cats with echocardiographic evidence of LVH. Population characteristics and echocardiographic data are summarized in Tables 1 and 2. Affected cats were older (12 years [1-17]) than healthy subjects (6.5 years [4-15]) (P = 0.026), while body weight and sex distribution were not statistically different between groups (P = 0.222 and P = 0.354, respectively). Among healthy subjects, European Shorthair cats represented the most common breed (n = 14; 64%), followed by Maine Coon (n = 4; 18%), and Norwegian Forest and Persian cats (each n = 2; 18%). In the LVH group, European Shorthair was the most common breed (n = 26; 74%), followed by Persian (n = 7; 20%), and Exotic Shorthair and Siamese (each n = 1; 3%). Cats in the control group had lower values of LV wall thickness and smaller LA compared to cats with LVH (P < 0.001). Of the 35 cats with LVH, 9 had SAH (of these, 2 had also elevated serum T4 concentration), and 3 were diagnosed with HT. The remaining 23 cats had no comorbidities and were diagnosed with primary HCM. Systolic anterior motion of the mitral valve was identified in 10 cats with LVH (of which 6 had primary HCM, 3 had SAH and 1 had HT). Regarding serum biochemistry results, serum potassium and calcium levels were always within reference ranges in all cats, with the exception of one cat showing mild hypercalcemia (11.7 mg/dL, reference range 6.0-10.5 mg/dL). At study inclusion, isolated CHF was identified in 9 cats with LVH (of which only 1 had SAH and the remaining 8 had primary HCM), isolated ATE in 5 cats (all with primary HCM), and a combination of CHF and ATE in 2 cats (1 each with primary HCM and SAH). Regarding cardiac drugs employed in cats with LVH, the 9 subjects with CHF received furosemide (n = 9; 0.5-2 mg/kg q12h), benazepril (n = 8; dose, 0.25-0.6 mg/kg q24h), and acetylsalicylic acid (n = 7;12.5-25mg/cat q24h); the 5 subjects with ATE received acetylsalicylic acid (n = 4;5-25mg/cat q48h), clopidogrel (n = 3; 18.75 mg/cat q24h), and unfractioned heparin (n = 1; 200 UI/kg q8h); and the 2 subjects with CHF associated with ATE received furosemide (n = 2; 0.5-1 mg/kg q12h), clopidogrel (n = 2; 18.75 mg/cat q24h), acetylsalicylic acid (n = 1; 12.5mg/cat q24h), benazepril (n = 1; 0.3 mg/kg q24h), and pimobendan (n = 1; 0.2 mg/kg q12h). Additionally, the 10 subjects with SAM also received atenolol (n = 9; 6.25 mg/cat q24h) and carvedilol (n = 1; 0.8 mg/kg q12h).ECG data Normal sinus rhythm was diagnosed in all control cats and in 25/35 (71%) cats with LVH. Cats with LVH associated with cardiac arrhythmia (10/35, 29%) showed several types of rhythm disturbances, including third degree AVB (2/35, 6%), sinus rhythm associated with isolated atrial premature complexes (2/35, 6%) as well as isolated VPCs (2/35, 6%), sinus bradycardia (1/35, 3%), sinus rhythm with second degree AVB (1/35, 3%), accelerated idioventricular rhythm (1/35, 3%), and VT (1/35, 3%). The presence of any type of arrhythmia had sensitivity and specificity of 29% and 100%, respectively, for identifying LVH. Systematic ECG measurements were performed in all control cats and in 29/35 (83%) cats with LVH. Measurements were not performed for the remaining 6 cats with LVH due to the use of an ECG machine not suitable for measurements or the presence of sustained cardiac arrhythmias. The duration of QT and QTc were the only ECG variables that differed statistically between the two groups (P = 0.007) (Table 3). When considering data from all 22 control cats and the 29 cats with LVH and ECG measurements available, there was a weak statistically significant correlation between the maximal degree of LVH and duration of the QT and QTc (r = 0.388, P = 0.005; and r = 0.380, P = 0.006, respectively). Areas under the ROC curve for QT and QTc as predictors of LVH were 0.674 (standard error = 0.075, 95% confidence interval = 0.5286–0.799) and 0.679 (standard error = 0.076, 95% confidence interval = 0.534–0.803), respectively (Fig. 1). Optimal cut-off values to identify LVH were QT > 170 ms (sensitivity and specificity of 48.3% and 91%, respectively) and QTc > 188 ms (sensitivity and specificity of 62% and 77%, respectively) (Tab. 4). The upper limit values of QT and QTc in the control group were 180 ms and 200 ms, respectively. In the study group, a QT > 180 ms and QTc > 200 ms was diagnosed in 11/29 (38%) and 12/29 (41%) cats, respectively. When present, QT and QTc prolongation occurred simultaneously in all cats except one, where QT was 180 ms and QTc was 202 ms. Only two cats with LVH and none in the control group had a R wave amplitude >0.9 mV. Of these two cats with increased R wave amplitude, only one had QT and QTc values above 180 ms and 200 ms, respectively. Underlying disease in the 11 cats with both prolonged QT and QTc included primary HCM (n = 8), SAH (n = 2), and HT (n = 1). Additionally, SAM was identified in 3 cats (1 each with primary HCM, SAH, and HT). Clinical presentation at study inclusion of these 11 cats included isolated CHF (n = 4), isolated ATE (n = 1), and CHF with ATE (n = 2), while 4 cats were asymptomatic. Cardiac drugs employed in these 11 cats included furosemide (n = 6; 0.5-2 mg/kg q12h), acetylsalicylic acid (n = 4; 12.5-25mg/cat q48h), benazepril (n = 4; 0.25-0.3 mg/kg q24h), clopidogrel (n = 3; 18.75 mg/cat q24h), atenolol (n = 2; 6.25 mg/cat q24h), carvedilol (n = 1; 0.8 mg/kg q12h), and pimobendan (n = 1; 0.2 mg/kg q12h). The cat with isolated prolongation of QTc had primary compensated HCM, under treatment with acetylsalicylic acid (25mg/cat q48h). Survival analysisSurvival data were available for 23 of the 29 cats with echocardiographic evidence of LVH and all ECG measurements available. Thirteen out 23 cats (57%) died during the follow-up period. In particular, the cause of death was considered to be of cardiac and non-cardiac (chronic kidney disease) origin in 10 (77%) and 3 (23%) cats, respectively. Cardiac deaths (either spontaneous death or euthanasia due to worsening of underlying heart condition) included CHF (4/13, 31%), ATE (3/13, 23%), and sudden cardiac death (3/13, 23%). Mean follow-up time and survival time were 287 (1-1075) days and 1218 (272-2366) days for cardiac and non-cardiac death, respectively. Cats were stratified on the basis of the two variables that differed significantly between groups (i.e., duration of QT and QTc). Considering cats with LVH and all ECG measurements available with a prolongation of QT measurements, survival data were available for 8 subjects (of which one cat had a prolonged QTc only). Among them, 6/8 (75%) cats died during the study period (all cases of cardiac death [ATE, n = 3; CHF, n = 2; sudden death, n = 1]) while only 2/8 (25%) cats were still alive at the end of the study. Among cats with LVH and all ECG measurements available with both QT and QTc of normal duration, survival data were available for 15 subjects. Among them, 7/15 (47%) cats died during the study period (4 cases of cardiac death [sudden death, n = 2; CHF, n = 2] and 3 cases of non-cardiac death [chronic kidney disease]) while the remaining 8/15 (53%) cats were still alive at the end of the study. There was a statistically significant difference in survival time between cats with QT and QTc above and below the upper limit values derived from the control group. In detail, mean survival time was 58 (1-528) days and not measureable (96-973 days) for cats with QT > 180 ms (7 cats) and QT ≤ 180 ms (16 cats), respectively (P = 0.042), and 125 (1-528) days and not measureable (96-973 days) for cats with QTc > 200 ms (8 cats) and QTc ≤ 200 ms (15 cats), respectively (P = 0.017) (Fig. 2). There was no difference in the maximal degree of LVH and LA diameter between cats who died for cardiac death with QT > 180 ms and QT ≤ 180 ms (P = 1.000, and P = 0.841, respectively). Similarly, there was no difference in the maximal degree of LVH and LA diameter between cats who died for cardiac death with QTc > 200 ms and QTc ≤ 200 ms (P = 0.352, and P = 0.762, respectively). Of the 6 cats that were lost to follow-up, 2 had QT and QTc ≤ 180 and ≤ 200 ms, respectively, while the other 4 cats had QT and QTc above the limit.DiscussionThe main findings of the present study were that: (1) the documentation of any type of arrhythmia during a 2-minute ECG was a rather insensitive but highly specific method for detecting LVH in cats; (2) duration of QT and QTc were statistically longer in cats with LVH compared to healthy cats; and (3) prolonged QT and QTc represented negative prognostic factors in cats with LVH. In the present study, no rhythm abnormalities were found in healthy cats, while almost a third of cats with LVH showed some changes of cardiac excitability or electrical conduction, with 4 subjects showing ventricular arrhythmias. Similar data were previously reported in a retrospective analysis of 282 HCM cats, in which 31% of subjects demonstrated various rhythm abnormalities, with a predominant proportion of VPCs [3]. The relationship between LVH and rhythm disturbances has a rational biological basis. Indeed, multiple pathological changes occur in the myocardium of cats with HCM, including LV myocardial fiber disarray, arteriosclerosis of intramural coronary arteries with thickened media and narrowed lumen, and expanded areas of interstitial and myocardial fibrosis [29,30]. These anatomical abnormalities appear to provide substrate for cardiac conduction disturbances, particularly those of ventricular origin [8,31]. In the present study, the occurrence of any type of arrhythmia over 2 minutes of ECG recording had high specificity (100%) in identifying LVH in cats. One important clinical implication of this finding could be the strong justification to perform an echocardiogram when rhythm disturbances are incidentally identified in an overtly normal cat. At the same time, the low sensitivity (31%) of ECG excludes its potential use as an alternative reliable screening test for feline LVH. Increased sensitivity for detection of sporadic arrhythmia could be achieved through the use of 24-hour Holter monitoring, especially considering that arrhythmias may not be equally distributed over a 24-hour time period [5]. However, Holter monitoring requires relatively expensive recorders that are not readily available to many veterinary centers and time-consuming analysis. An additional intriguing finding of this study was the observed longer QT and QTc in cats with LVH cats compared to healthy subjects. A mild correlation was also found between the degree of LVH and the duration of the QT and QTc. Prolonged QT and QTc have also been described in people affected by HCM compared with healthy subjects and the increased duration was correlated to the degree of LVH [9,32]. The link between QT prolongation and LVH is complex. One explanation relies on an abnormal response to autonomic changes mediated by altered function of cardiac beta-adrenergic receptors in hypertrophied ventricles [33-35]. An additional explanation can be found in clinical studies on human SAH [36,37] and experimental murine models [38], where myocyte hypertrophy and an increase in collagen interstitial matrix have been linked to lengthening of action potential duration and reduction of its amplitude. These features could result in a prolongation and dispersion of repolarization, especially if the changes in different parts of the LV are inhomogeneous [36,37]. Lastly, thyroxine excess increases the level of cardiac sodium/potassium-ATPase, resulting in an increased intracellular potassium concentration. This leads to a membrane hyperpolarization and prolongation of the QT, which may further explain such ECG abnormalities in patients with LVH and HT [39,40]. In the present study, some cats with primary HCM, SAH, and HT showed increased QT measurements, suggesting that the above mechanisms may also occur in cats with LVH. Furthermore, prolongation of QT and QTc appears to have potential prognostic use in cats with LVH, as also demonstrated in humans with HCM [9,10,12,14,15-19]. As previously described, multiple pathological changes develop in the hypertrophied myocardium, inevitably leading to cell-to-cell coupling. This causes action potential prolongation, early afterdepolarizations, and increased transmural dispersion of refractoriness which favor the development of polymorphic reentrant VT and sudden cardiac death [14,15]. Furthermore, strain analysis has recently allowed identification of more severe mechanical dyssynchrony in people with HCM associated with long QT compared to those with a normal QT, supporting the hypothesis that electrical dispersion of repolarization is associated with a heterogeneity of mechanical contraction [14]. Additionally, such mechanical abnormality seems associated to more aggressive clinical phenotypes (e.g., higher prevalence of syncope), further highlighting the value of QT prolongation in risk stratification of human HCM [14]. Unfortunately, whether similar complications were responsible for worse outcomes of some cats from this study remains unresolved. Indeed, we did not investigate ventricular mechanical dysfunction by combining traditional echocardiography with more accurate techniques, such as tissue Doppler imaging or speckle tracking echocardiography [41]. Similarly, enrolled subjects did not undergo continuous ECG monitoring immediately before the death, making it impossible to demonstrate the development of malignant VT as the cause of clinical deterioration. Nevertheless, it is intriguing to note that in a retrospective study evaluating risk factors associated with different types of cardiac death in 255 cats with HCM, the hazard of sudden death was increased among subjects with syncope and cardiac arrhythmias [4].When evaluating the relationship between LVH and abnormalities of ventricular repolarization and their clinical impact, cardiac and extra-cardiac factors influencing QT measurements, including HR and electrolytes fluctuations, should be considered. The QT is known to be strongly dependent on the R-R interval, exhibiting an inverse relationship to HR [42]. Therefore, correction of the QT for the HR is crucial to obtain reproducible results in the single individual and to compare subjects with different HR [42]. Accordingly, QT and QTc were recorded in cats of the present study similarly to human studies with the same aim and study design [9,32]. Regarding the potential effect of serum potassium and calcium concentrations on the repolarization phase, only one cat showed mild hypercalcemia. Thus, the influence of electrolyte fluctuations on QT measurements was likely unremarkable in our cats with LVH. In people, presence of LVH can be recognized on surface ECG by increased R wave amplitude, and this parameter has its own prognostic relevance [17]. Whether this finding could be relevant in cats could not be evaluated in the present study, due to the paucity of patients (two cats) showing R wave amplitudes above 0.9 mV.Results of the present study should be read in the context of certain limitations. First of all the retrospective design, so that not all the ECGs were performed with the same machine, thus limiting the possibility of performing standardized measurements in all traces. Secondly, the number of cats in each group was small, and studies using larger number of animals are required to validate and expand upon our findings. Indeed, the limited study population prevented further analysis on possible correlations, such as prolonged QT and/or QTc and ATE. Third, a possible effect of medications on ECG findings could not be accurately evaluated due to differences in drug combinations and dosages employed. However, it is important to underline that the majority of the employed drugs have no direct effect on ECG variables. Fourth, we used fixed cut-off values to define LVH (LV wall thickness at end-diastole ≥ 5.5 mm). Although this method is generally accepted [21], a positive correlation between body weight and several echocardiographic measurements (including LV wall thicknesses) has been recently demonstrated in cats [24] suggesting the risk of underdiagnosing or overdiagnosing LVH in extremely small cats or larger cats, respectively. However, the majority of cats from our study had a typical body weight (2.5-6 kg) [24], with only three cats being heavier. Our results could be partially affected by the formula we used to calculate the QTc, namely the logarithmic equation. To the best of our knowledge, no validated equation has been reported to calculate the QTc in cats, but the logarithmic equation showed the greatest accuracy in calculating the canine QTc compared to other methods [27,43,44]. For the survival analysis, we used cardiac death as a single end-point, censoring those cats that died for non-cardiac causes. Although only a few cats experienced a non-cardiac related death, the latter might represent a competing risk that could have biased the survival estimates. Finally, although we conducted telephone interviews to identify causes of death, some of the reported events may be inaccurately categorized due to improper perception of the owners.ConclusionsThe results of this study suggest that ECG analysis may have predictive and prognostic value in cats with LVH. Specifically, standard waveform analysis of sinus rhythm during a 2-minute ECG is a rather insensitive method for detecting feline LVH. However, the occurrence of an arrhythmia during a 2-minute ECG as well as the prolongation of QT and QTc during phases of sinus rhythm strongly warrant further examination, because specificity for LVH appears to be high in this setting. Moreover, QT > 180 ms and QTc > 200 ms may represent important variables to predict cardiac death in cats with LVH.Conflict of interest The authors do not have any conflicts of interest to declare.Funding This research received no grant from any funding agency in the public, commercial or not-for-profit sectors.Footnotesc petMAP? graphic System, Ramsey Medical Inc., Tampa (FL), USA.d SunTech Vet20, SunTech Medical Inc., Morrisville (NC), USA.e iE33 ultrasound system, Philips Healthcare, Monza, Italy.f Archiwin, Esaote S.p.A., Firenze, Italy. g Cube ECG, Cardioline S.p.A., Caverano, Italy.h Prism 5?, GraphPad Software Inc., San Diego, CA.i SAS version 9.3, SAS Institute Inc., Cary, NC, USA.References[1] Ferasin L, Sturgess CP, Cannon MJ, Caney SM, Gruffydd-Jones TJ, Wotton PR. Feline idiopathic cardiomyopathy: a retrospective study of 106 cats (1994-2001). J Feline Med Surg 2003;5:151-9.[2] Ferasin L. 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Assessment of left ventricular longitudinal function in cats with subclinical hypertrophic cardiomyopathy using tissue Doppler imaging and speckle tracking echocardiography. J Vet Med Sci 2015;77:1101-8.[42] Funck-Brentano C, Jaillon P. Rate-corrected QT interval: techniques and limitations. Am J Cardiol 1993;72:17B-22B.[43] Miyazaki H, Tagawa M. Rate-correction technique for QT interval in long-term telemetry ECG recording in Beagle dogs. Exp Anim 2002;51:465-75.[44] Takahara A, Sugiyama A, Satoh Y, Hashimoto K. Comparison of four rate-correction algorisms for the ventricular repolarization period in assessing net effect of Ikr blockers in dogs. J Pharmacol Sci 2006;102:396-404.Figure legendsFig. 1. Receiver operating characteristic (ROC) curve for QT (A) and QTc (B) duration for the diagnosis of left ventricular hypertrophy in 51 cats. (A) The area under the ROC curve represented by the thicker line is 0.674 (95% confidence interval = 0.528–0.799). The overall most accurate cut‐point identified on the curve was QT > 170 ms, which had sensitivity and specificity of 48.3 and 91%, respectively. (B) The area under the ROC curve represented by the thicker line is 0.679 (95% confidence interval = 0.534–0.803). The overall most accurate cut‐point identified on the curve was QTc > 188 ms, which had a sensitivity and a specificity of 62 and 77%, respectively.Fig. 2. Kaplan-Meyer curve showing the differences in survival associated with QT (A) and QTc (B) duration in 23 cats with left ventricular hypertrophy. (A) Mean survival time was 58 days and not measureable in cats with QT > 180 ms (7 cats) and QT ≤ 180 ms (16 cats), respectively. (B) Mean survival time was 125 days and not measureable in cats with QTc > 200 ms (8 cats) and QTc ≤ 200 ms (15 cats), respectively. ................
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