Abstract
Hypercortisolism is one of the most common endocrine diseases in dogs. In humans, it is clearly associated with a higher risk of cardiovascular events, but studies in dogs are scarce. To investigate the arrhythmogenic risk of dogs with naturally-occurring hypercortisolism (NOHC), indices of variability and instability of the QT interval were retrospectively studied in 38 dogs with NOHC and prospectively studied in 12 healthy dogs: variance (QTv), total instability (TI), short-term (STI) and long-term (LTI), and mean (QTm). Except for QTm, all parameters studied were higher in the NOHC group than in the control group. In addition, STI and QTv showed moderate positive correlation with left ventricle wall thickness. The NOHC group was subdivided according to cortisol suppression pattern in the low-dose dexamethasone suppression test. All electrocardiographic indices of partial and absent suppression patterns were numerically higher than healthy dogs. QTv and TI were lower in the control group than in both NOHC subgroups. LTI and STI were lower in the CG than in the group with the partial suppression pattern. There was no statistical difference between sex groups in any of the electrocardiographic parameters studied. This result might indicate that the etiology of NOHC, and its consequent influence on hypothalamus–pituitary–adrenal axis could interfere on the heterogeneity of ventricular repolarization parameters in different ways, especially in the short-term and the long-term stability; however further studies are necessary to understand the role of cortisol on electrical instability in dogs.
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ECG-PC, Teb, São Paulo, São Paulo, Brazil.
References
Ahmad K, Dorian P (2007) Drug-induced QT prolongation and proarrhythmia: an inevitable link? Europace 9:iv16–iv22. https://doi.org/10.1093/europace/eum167
Armstrong HF, Lovasi GS, Soliman EZ, Heckbert SR, Psaty BM, Austin JHM, Krishnan JA, Hoffman EA, Johnson C, Budoff MJ, Watson KE, Barr RG (2017) Lung function, percent emphysema, and QT duration: The Multi-Ethnic Study of Atherosclerosis (MESA) lung study. Respir Med 123:1–7. https://doi.org/10.1016/j.rmed.2016.12.003
Bancos I, Alahdab F, Crowley RK, Chortis V, Delivanis DA, Erickson D, Natt N, Terzolo M, Arlt W, Young WFJ, Murad MH (2016) THERAPY OF ENDOCRINE DISEASE: Improvement of cardiovascular risk factors after adrenalectomy in patients with adrenal tumors and subclinical Cushing’s syndrome: a systematic review and meta-analysis. Eur J Endocrinol 175:R283–R295. https://doi.org/10.1530/EJE-16-0465
Baumert M, Porta A, Vos MA, Malik M, Couderc J-P, Laguna P, Piccirillo G, Smith GL, Tereshchenko LG, Volders PGA (2016) QT interval variability in body surface ECG: measurement, physiological basis, and clinical value: position statement and consensus guidance endorsed by the European Heart Rhythm Association jointly with the ESC Working Group on Cardiac Cellular Electrop. Europace 18:925–944. https://doi.org/10.1093/europace/euv405
Bennaim M, Shiel RE, Forde C, Mooney CT (2018) Evaluation of individual low-dose dexamethasone suppression test patterns in naturally occurring hyperadrenocorticism in dogs. J Vet Intern Med 32:967–977. https://doi.org/10.1111/jvim.15079
Bonnemeier H, Wiegand UKH, Braasch W, Brandes A, Richardt G, Potratz J (2003) Circadian profile of QT interval and QT interval variability in 172 healthy volunteers. Pacing Clin Electrophysiol 26:377–382. https://doi.org/10.1046/j.1460-9592.2003.00053.x
Boulaksil M, Jungschleger JG, Antoons G, Houtman MJC, De Boer TP, Wilders R, Beekman JD, Maessen JG, Van Der Hulst FF, Van Der Heyden MAG, Van Veen TAB, Van Rijen HVM, De Bakker JMT, Vos MA (2011) Drug-Induced torsade de pointes arrhythmias in the chronic AV block dog are perpetuated by Focal Activity. Circ Arrhythmia Electrophysiol 4:566–576. https://doi.org/10.1161/CIRCEP.110.958991
Brendorp B, Pedersen O, Torp-Pedersen C, Sahebzadah N, Køber L (2002) A benefit-risk assessment of class III antiarrhythmic agents. Drug Saf 25:847–865. https://doi.org/10.2165/00002018-200225120-00003
Brüler BC, Jojima FS, Dittrich G, Giannico AT, Sousa MG (2018) QT instability, an indicator of augmented arrhythmogenesis, increases with the progression of myxomatous mitral valve disease in dogs. J Vet Cardiol 20:254–266. https://doi.org/10.1016/j.jvc.2018.06.002
Carotenuto G, Malerba E, Dolfini C, Brugnoli F, Giannuzzi P, Semprini G, Tosolini P, Fracassi F (2019) Cushing’s syndrome—an epidemiological study based on a canine population of 21,281 dogs. Open Vet J 9:27–32. https://doi.org/10.4314/ovj.v9i1.5
Chatterjee S, Bavishi C, Sardar P, Agarwal V, Krishnamoorthy P, Grodzicki T, Messerli FH (2014) Meta-analysis of left ventricular hypertrophy and sustained arrhythmias. Am J Cardiol 114:1049–1052. https://doi.org/10.1016/j.amjcard.2014.07.015
Chen H-Y, Lien Y-H, Huang H-P (2016) Association of Renal Resistive Index, Renal Pulsatility Index, Systemic Hypertension, and Albuminuria with Survival in Dogs with Pituitary-Dependent Hyperadrenocorticism. Int J Endocrinol 2016:1–7. https://doi.org/10.1155/2016/3814034
Chen H-Y, Lien Y-H, Huang H-P (2014) Assessment of left ventricular function by two-dimensional speckle-tracking echocardiography in small breed dogs with hyperadrenocorticism. Acta Vet Scand 56:88. https://doi.org/10.1186/s13028-014-0088-5
Colao A, Pivonello R, Spiezia S, Faggiano A, Ferone D, Filippella M, Marzullo P, Cerbone G, Siciliani M, Lombardi G (1999) Persistence of increased cardiovascular risk in patients with cushing’s disease after five years of successful cure. J Clin Endocrinol Metab 84:2664–2672. https://doi.org/10.1210/jcem.84.8.5896
Cornell CC, Kittleson MD, Della Torre P, Häggström J, Lombard CW, Pedersen HD, Vollmar A, Wey A (2004) Allometric scaling of M-mode cardiac measurements in normal adult dogs. J Vet Intern Med 18:311–321. https://doi.org/10.1892/0891-6640(2004)18%3c311:asomcm%3e2.0.co;2
De Caterina R, Ruigómez A, Rodríguez LAG (2010) Long-term use of anti-inflammatory drugs and risk of atrial fibrillation. Arch Intern Med 170:1450–1455. https://doi.org/10.1001/archinternmed.2010.305
Dekkers OM, Horváth-Puhó E, Jørgensen JOL, Cannegieter SC, Ehrenstein V, Vandenbroucke JP, Pereira AM, Sørensen HT (2013) Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab 98:2277–2284. https://doi.org/10.1210/jc.2012-3582
Di Dalmazi G, Berr CM, Fassnacht M, Beuschlein F, Reincke M (2014) Adrenal function after adrenalectomy for subclinical hypercortisolism and Cushing’s syndrome: a systematic review of the literature. J Clin Endocrinol Metab 99:2637–2645. https://doi.org/10.1210/jc.2014-1401
Fridericia LS (1920) Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken. Acta Med Scand 53:469–486
García San José P, Arenas Bermejo C, Alonso-Miguel D, Clares Moral I, Cuesta-Alvaro P, Pérez Alenza MD (2021) Changes in systolic blood pressure in dogs with pituitary dependent hyperadrenocorticism during the first year of trilostane treatment. J Vet Intern Med 35:130–141. https://doi.org/10.1111/jvim.15978
García San José P, Arenas Bermejo C, Clares Moral I, Cuesta Alvaro P, Pérez Alenza MD (2020) Prevalence and risk factors associated with systemic hypertension in dogs with spontaneous hyperadrenocorticism. J Vet Intern Med 34:1768–1778. https://doi.org/10.1111/jvim.15841
Gonçalves AC, Orton EC, Boon JA, Salman MD (2002) Linear, logarithmic, and polynomial models of M-mode echocardiographic measurements in dogs. Am J Vet Res 63:994–999. https://doi.org/10.2460/ajvr.2002.63.994
Hess RS, Kass PH, Van Winkle TJ (2003) Association between diabetes mellitus, hypothyroidism or hyperadrenocorticism, and atherosclerosis in dogs. J Vet Intern Med 17:489–494. https://doi.org/10.1892/0891-6640(2003)017%3c0489:ABDMHO%3e2.3.CO;2
Hoffman JM, Lourenço BN, Promislow DEL, Creevy KE (2018) Canine hyperadrenocorticism associations with signalment, selected comorbidities and mortality within North American veterinary teaching hospitals. J Small Anim Pract 59:681–690. https://doi.org/10.1111/jsap.12904
Hondeghem LM (2008a) QT and TdP. QT: an unreliable predictor of proarrhythmia. Acta Cardiol 63:1–7. https://doi.org/10.2143/AC.63.1.2025324
Hondeghem LM (2008b) QT prolongation is an unreliable predictor of ventricular arrhythmia. Heart Rhythm 5:1210–1212. https://doi.org/10.1016/j.hrthm.2008.05.006
Hondeghem LM (2011) QTc prolongation as a surrogate for drug-induced arrhythmias: fact or fallacy? Acta Cardiol 66:685–689
Hsue W, Visser LC (2020) Reproducibility of echocardiographic indices of left atrial size in dogs with subclinical myxomatous mitral valve disease. J Vet Intern Med 34:1779–1786. https://doi.org/10.1111/jvim.15850
Huerta C, Lanes SF, García Rodríguez LA (2005) Respiratory medications and the risk of cardiac arrhythmias. Epidemiology 16:360–366. https://doi.org/10.1097/01.ede.0000158743.90664.a7
Itoh H, Crotti L, Aiba T, Spazzolini C, Denjoy I, Fressart V, Hayashi K, Nakajima T, Ohno S, Makiyama T, Wu J, Hasegawa K, Mastantuono E, Dagradi F, Pedrazzini M, Yamagishi M, Berthet M, Murakami Y, Shimizu W et al (2016) The genetics underlying acquired long QT syndrome: Impact for genetic screening. Eur Heart J 37:1456–1464. https://doi.org/10.1093/eurheartj/ehv695
Kim PY, Irizarry-Caro JA, Ramesh T, Iliescu C, Lopez-Mattei JC (2021) How to diagnose and manage QT prolongation in cancer patients. JACC CardioOncology 3:145–149. https://doi.org/10.1016/j.jaccao.2021.01.002
Koracevic G, Micíc S, Stojanovic M, Zdravkovic M, Kostic T, Koracévic M, Kutlešic M, Pavlovic M, Dakic S (2020) High likelihood for atrial fibrillation in Cushing’s syndrome. Eur Rev Med Pharmacol Sci 24:1391–1397. https://doi.org/10.26355/eurrev_202002_20196
Koyama H, Yoshii H, Yabu H, Kumada H, Fukuda K, Mitani S, Rousselot JF, Hirose H, Uchino T (2004) Evaluation of QT interval prolongation in dogs with heart failure. J Vet Med Sci 66:1107–1111. https://doi.org/10.1292/jvms.66.1107
Krauss TT, Mäuser W, Reppel M, Schunkert H, Bonnemeier H (2009) Gender effects on novel time domain parameters of ventricular repolarization inhomogeneity. Pacing Clin Electrophysiol 32(Suppl 1):S167–S172. https://doi.org/10.1111/j.1540-8159.2008.02278.x
Leonard CE, Freeman CP, Newcomb CW, Bilker WB, Kimmel SE, Strom BL, Hennessy S (2013) Antipsychotics and the risks of sudden cardiac death and all-cause death: cohort studies in medicaid and dually-eligible medicaid-medicare beneficiaries of five states. J Clin Exp Cardiolog Suppl 10:1–9. https://doi.org/10.4172/2155-9880.S10-006
Limprasutr V, Pirintr P, Kijtawornrat A, Hamlin RL (2018) An increasing electromechanical window is a predictive marker of ventricular fibrillation in anesthetized rabbit with ischemic heart. Exp Anim 67:175–183. https://doi.org/10.1538/expanim.17-0100
Linde C, Bongiorni MG, Birgersdotter-Green U, Curtis AB, Deisenhofer I, Furokawa T, Gillis AM, Haugaa KH, Lip GYH, Van Gelder I, Malik M, Poole J, Potpara T, Savelieva I, Sarkozy A, Fauchier L, Kutyifa V, Ernst S, Gandjbakhch E et al (2018) Sex differences in cardiac arrhythmia: a consensus document of the European Heart Rhythm Association, endorsed by the Heart Rhythm Society and Asia Pacific Heart Rhythm Society. Europace 20:1565–1565ao. https://doi.org/10.1093/europace/euy067
Mancini T, Kola B, Mantero F, Boscaro M, Arnaldi G (2004) High cardiovascular risk in patients with Cushing’s syndrome according to 1999 WHO/ISH guidelines. Clin Endocrinol (oxf) 61:768–777. https://doi.org/10.1111/j.1365-2265.2004.02168.x
Niemeijer MN, van den Berg ME, Deckers JW, Franco OH, Hofman A, Kors JA, Stricker BH, Rijnbeek PR, Eijgelsheim M (2015) Consistency of heart rate-QTc prolongation consistency and sudden cardiac death: The Rotterdam Study. Heart Rhythm 12:2078–2085. https://doi.org/10.1016/j.hrthm.2015.07.011
Nigro G, Russo V, Di Salvo G, De Crescenzo I, Rago A, Perrone L, Golino P, Russo MG, Calabrò R (2010) Increased Heterogenity of ventricular repolarization in obese nonhypertensive children. Pacing Clin Electrophysiol 33:1533–1539. https://doi.org/10.1111/j.1540-8159.2010.02889.x
O’Neill DG, Scudder C, Faire JM, Church DB, McGreevy PD, Thomson PC, Brodbelt DC (2016) Epidemiology of hyperadrenocorticism among 210,824 dogs attending primary-care veterinary practices in the UK from 2009 to 2014. J Small Anim Pract 57:365–373. https://doi.org/10.1111/jsap.12523
Orosz A, Baczkó I, Nagy V, Gavallér H, Csanády M, Forster T, Papp JG, Varró A, Lengyel C, Sepp R (2015) Short-term beat-to-beat variability of the QT interval is increased and correlates with parameters of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy. Can J Physiol Pharmacol 93:765–772. https://doi.org/10.1139/cjpp-2014-0526
Pecori Giraldi F, Toja PM, Michailidis G, Metinidou A, De Martin M, Scacchi M, Stramba-Badiale M, Cavagnini F (2011) High prevalence of prolonged qt interval duration in male patients with Cushing’s disease. Exp Clin Endocrinol Diabetes 119:221–224. https://doi.org/10.1055/s-0031-1271628
Piccirillo G, Moscucci F, Pascucci M, Pappadà MA, D’Alessandro G, Rossi P, Quaglione R, Di Barba D, Barillà F, Magrì D (2013) Influence of aging and chronic heart failure on temporal dispersion of myocardial repolarization. Clin Interv Aging 8:293–300. https://doi.org/10.2147/CIA.S41879
Santilli RA, Moïse NS, Pariaut R, Perego M (2019) Electrocardiography of the dog and cat: diagnosis of arrhythmias. Edra, Trento
Sarusi A, Rárosi F, Szűcs M, Csík N, Farkas AS, Papp JG, Varró A, Forster T, Curtis MJ, Farkas A (2014) Absolute beat-to-beat variability and instability parameters of ECG intervals: biomarkers for predicting ischaemia-induced ventricular fibrillation. Br J Pharmacol 171:1772–1782. https://doi.org/10.1111/bph.12579
Schneider J, Hauser R, Andreas J-O, Linz K, Jahnel U (2005) Differential effects of human ether-a-go-go-related gene (HERG) blocking agents on QT duration variability in conscious dogs. Eur J Pharmacol 512:53–60. https://doi.org/10.1016/j.ejphar.2005.01.042
Schober P, Boer C, Schwarte L (2018) Correlation coefficients: Appropriate use and interpretation. Anesth Analg 126:1. https://doi.org/10.1213/ANE.0000000000002864
Schofield I, Brodbelt DC, Niessen SJM, Church DB, Geddes RF, O’Neill DG (2021) Frequency and risk factors for naturally occurring Cushing’s syndrome in dogs attending UK primary-care practices. J Small Anim Pract. https://doi.org/10.1111/jsap.13450
Schwartz PJ, Wolf S (1978) QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation 57:1074–1077. https://doi.org/10.1161/01.cir.57.6.1074
Shantsila E, Watson T, Lip GYH (2007) Drug-induced QT-interval prolongation and proarrhythmic risk in the treatment of atrial arrhythmias. Europace 9(Suppl 4):iv37-44. https://doi.org/10.1093/europace/eum169
Shenasa M, Shenasa H, El-Sherif N (2015) Left ventricular hypertrophy and arrhythmogenesis. Card Electrophysiol Clin 7:207–220. https://doi.org/10.1016/j.ccep.2015.03.017
Spier AW, Meurs KM, Muir WW, Lehmkuhl LB, Hamlin RL (2001) Correlation of QT dispersion with indices used to evaluate the severity of familial ventricular arrhythmias in Boxers. Am J Vet Res 62:1481–1485. https://doi.org/10.2460/ajvr.2001.62.1481
Straus SMJM, Kors JA, De Bruin ML, van der Hooft CS, Hofman A, Heeringa J, Deckers JW, Kingma JH, Sturkenboom MCJM, Stricker BHC, Witteman JCM (2006) Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol 47:362–367. https://doi.org/10.1016/j.jacc.2005.08.067
Takano H, Kokubu A, Sugimoto K, Sunahara H, Aoki T, Fijii Y (2015) Left ventricular structural and functional abnormalities in dogs with hyperadrenocorticism. J Vet Cardiol 17:173–181. https://doi.org/10.1016/j.jvc.2015.07.002
Terzolo M, Allasino B, Pia A, Peraga G, Daffara F, Laino F, Ardito A, Termine A, Paccotti P, Berchialla P, Migliaretti G, Reimondo G (2014) Surgical remission of Cushing’s syndrome reduces cardiovascular risk. Eur J Endocrinol 171:127–136. https://doi.org/10.1530/EJE-13-0555
Van der Hooft C, Heeringa J, Brusselle GG, Hofman A, Witteman JCM, Kingma JH, Sturkenboom MCJM, Stricker BHC (2006) Corticosteroids and the risk of atrial fibrillation. Arch Intern Med 166:1016–1020. https://doi.org/10.1001/archinte.166.9.1016
Van Der Linde H, Van De Water A, Loots W, Van Deuren B, Lu HR, Van Ammel K, Peeters M, Gallacher DJ (2005) A new method to calculate the beat-to-beat instability of QT duration in drug-induced long QT in anesthetized dogs. J Pharmacol Toxicol Methods 52:168–177. https://doi.org/10.1016/j.vascn.2005.03.005
Verdecchia P, Reboldi G, Gattobigio R, Bentivoglio M, Borgioni C, Angeli F, Carluccio E, Sardone MG, Porcellati C (2003) Atrial fibrillation in hypertension: predictors and outcome. Hypertension 41:218–223. https://doi.org/10.1161/01.hyp.0000052830.02773.e4
Vidal PN, Miceli DD, Arias ES, D’Anna E, García JD, Castillo VA (2018) Decrease of nitric oxide and increase in diastolic blood pressure are two events that affect renal function in dogs with pituitary dependent hyperadrenocorticism. Open Vet J 8:86–95. https://doi.org/10.4314/ovj.v8i1.14
Vila BCP, Camacho AA, Sousa MG (2021) T-wave peak-end interval and ratio of T-wave peak-end and QT intervals: novel arrhythmogenic and survival markers for dogs with myxomatous mitral valve disease. J Vet Cardiol 35:25–41. https://doi.org/10.1016/j.jvc.2021.02.004
Yelamanchi VP, Molnar J, Ranade V, Somberg JC (2001) Influence of electrolyte abnormalities on interlead variability of ventricular repolarization times in 12-Lead electrocardiography. Am J Ther 8:117–122. https://doi.org/10.1097/00045391-200103000-00006
Zeugswetter FK, Carranza Valencia A, Glavassevich K, Schwendenwein I (2021) Patterns of the low-dose dexamethasone suppression test in canine hyperadrenocorticism revisited. Vet Clin Pathol 50:62–70. https://doi.org/10.1111/vcp.12958
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Beatriz de Carvalho Pato Vila, Marcela Sigolo Vanhoni, and Marlos Gonçalves Sousa contributed to acquisition of the data, participated in the statistical analysis, and wrote and edited the manuscript.
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Vila, B.d.P., Vanhoni, M.S. & Sousa, M.G. QT interval instability and variability in dogs with naturally-occurring hypercortisolism. Vet Res Commun 47, 121–130 (2023). https://doi.org/10.1007/s11259-022-09936-1
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DOI: https://doi.org/10.1007/s11259-022-09936-1