Cardiac structural and functional findings in Persian cats with autosomal dominant polycystic kidney disease

Achados estruturais e funcionais cardíacos em gatos persas com doença renal policística autossômica dominante

Juliana Mariotti Guerra Arine Pellegrino Alexandre Gonçalves Teixeira Daniel Mariana Ferreira de Freitas Natália Cavalca Cardoso Rebecca Bastos Pessoa Gabriel Garone de Lucca Maria Helena Matiko Akao Larsson Luiz Fernando Onuchic Felisbina Luisa Queiroga Bruno Cogliati About the authors

ABSTRACT:

Autosomal dominant polycystic kidney disease (ADPKD) has been related to left ventricular structural and functional abnormalities in human patients. The present study aimed to evaluate the cardiac structural and functional findings in Persian cats with ADPKD. Client-owned ADPKD (n=12) and non-ADPKD (n=12) Persian cats were enrolled in this study. The animals underwent echo- and electrocardiographic (ECG) examinations, and non-invasive measurements of systolic blood pressure (SBP) were obtained. Both groups were similar regarding hematological and biochemical parameters, including white blood cell count and levels of blood urea nitrogen, creatinine, total protein and thyroxine. There were no differences related to ECG parameters between ADPKD and non-ADPKD cats. Left ventricular hypertrophy (LVH) was demonstrated in 6/12 (50%) normotensive ADPKD cats with preserved renal function. There were no differences between animal groups regarding the echocardiographic parameters, including left ventricular ejection fraction and shortening fraction; however, basal interventricular septal thickness at end-diastole near the left ventricular outflow tract and aortic artery flow velocity showed slightly elevated values in ADPKD-cats. Our study revealed that Persian cats with ADPKD do not reproduce the functional and structural cardiac phenotype reported in human patients; however, large-scale cohort studies are necessary to distinguish the possibilities of a true linkage between ventricular myocardial hypertrophy and ADPKD in this breed.

Key words:
feline; genetic disease; renal disease; heart; echocardiography

RESUMO:

A doença renal policística autossômica dominante (DRPAD) tem sido relacionada a anormalidades estruturais e funcionais de ventrículo esquerdo em pacientes humanos. O objetivo do presente estudo foi avaliar os achados estruturais e funcionais cardíacos em gatos persas com DRPAD. Gatos persas pertencentes à clientes com DRPAD (n=12) e sem DRPAD (n=12) foram envolvidos neste trabalho. Os animais foram submetidos aos exames de eco e eletrocardiografia (ECG) e foram obtidas medições não-invasivas da pressão arterial sistólica (PAS). Ambos os grupos apresentaram valores semelhantes em relação aos parâmetros hematológicos e bioquímicos, incluindo contagem de glóbulos brancos e níveis séricos de ureia, creatinina, proteína total e tiroxina. Não houve diferença em relação aos parâmetros do ECG entre os gatos com ou sem DRPAD. A hipertrofia ventricular esquerda foi demonstrada em 6/12 (50%) dos gatos normotensos com DRPAD e função renal preservada. Não houve diferenças entre os grupos em relação aos parâmetros ecocardiográficos, incluindo fração de ejeção e fração de encurtamento do ventrículo esquerdo, entretanto a espessura septal interventricular basal na diástole na via de saída do ventrículo esquerdo e a velocidade do fluxo da artéria aórtica mostraram valores ligeiramente elevados em gatos com DRPAD. Nosso estudo revelou que gatos persas com DRPAD não reproduzem o fenótipo cardíaco funcional e estrutural encontrado em pacientes humanos. No entanto, estudos de coorte em larga escala são necessários para distinguir as possibilidades de uma verdadeira ligação entre a hipertrofia ventricular do miocárdio e a DRPAD nesta raça.

Palavras-chave:
felino; doença genética; doença renal; coração; ecocardiografia

INTRODUCTION:

Autosomal dominant polycystic kidney disease (ADPKD) is phenotypically characterized by the presence of multiple cysts in the renal parenchyma and, occasionally, in liver and pancreas, being an important cause of end-stage renal disease (BASTOS & ONUCHIC, 2011BASTOS, A.P.; ONUCHIC, L.F. Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease. Brazilian Journal of Medical and Biological Research, v.44, n.7, p.606-617, 2011. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/21625823 >. Accessed: Apr. 13, 2014. doi: 10.1590/s0100-879x2011007500068.
http://www.ncbi.nlm.nih.gov/pubmed/21625...
). In humans, 78% of the cases are caused by mutations in the PKD1 gene (type 1 ADPKD), while in 15% of the patients the disease occurs due to mutations in PKD2 (type 2 ADPKD) (CORNEC-LE GALL et al., 2018CORNEC-LE GALL, E. et al. Genetic complexity of autosomal dominant polycystic kidney and liver diseases. Journal of the American Society of Nephrology, v.29, n.1, p.13-23, 2018. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/29038287 >. Accessed: Dec. 21, 2019. doi: 10.1681/ASN.2017050483.
https://www.ncbi.nlm.nih.gov/pubmed/2903...
). Approximately 7% of the affected families; however, are currently genetically unresolved. The PKD1 and PKD2 genes, in turn, encode the integral membrane glycoproteins polycystin-1 and polycystin-2, respectively. Disruption of polycystins affects proliferation, apoptosis and planar cell polarity, and promotes transepithelial chloride and fluid secretion (DELMAS, 2004DELMAS, P. The gating of polycystin signaling complex. Biological Research, v.37, n.4, p.681-691, 2004. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/15709698 >. Accessed: Apr. 13, 2014. doi: 10.4067/s0716-97602004000400026.
http://www.ncbi.nlm.nih.gov/pubmed/15709...
).

Cardiovascular manifestations and complications, including systemic arterial hypertension, increased left ventricular mass and idiopathic dilated cardiomyopathy, are a major cause of morbidity and mortality in humans with ADPKD. Echocardiography in normotensive ADPKD individuals shows increased left and right ventricular mass and volume with normal ejection fractions and decreased end-diastolic relaxation compared to unaffected age and sex-matched controls, suggesting that deficiency of polycystin-1 or polycystin-2 is an independent factor for the development of the cardiac phenotype in affected individuals (CHAPMAN et al., 1997CHAPMAN, A.B. et al. Left ventricular hypertrophy in autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology, v.8, n.8, p.1292-1297, 1997. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/9259356 >. Accessed: Jun. 2, 2014. PubMed PMID: 9259356.
http://www.ncbi.nlm.nih.gov/pubmed/92593...
; ECDER et al., 1999ECDER, T. et al. Reversal of left ventricular hypertrophy with angiotensin converting enzyme inhibition in hypertensive patients with autosomal dominant polycystic kidney disease. Nephrology Dialysis Transplantation, v.14, n.5, p.1113-1116, 1999. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/10344347 >. Accessed: Jun. 22, 2014. doi: 10.1093/ndt/14.5.1113.
https://www.ncbi.nlm.nih.gov/pubmed/1034...
). Other potential cardiovascular alterations in ADPKD human patients include biventricular diastolic and endothelial dysfunction, increased thickness of the intima-media, impaired coronary flow velocity reserve, aneurysms and valvular defects (ECDER, 2013ECDER, T. Cardiovascular complications in autosomal dominant polycystic kidney disease. Current Hypertension Reviews, v.9, n.1, p.2-11, 2013. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/23971638 >. Accessed: Ago. 2, 2015. doi: 10.2174/1573402111309010002.
https://www.ncbi.nlm.nih.gov/pubmed/2397...
).

In recent years, seminal studies addressed more deeply the mechanisms underlying the cardiac phenotype associated with ADPKD. BALBO et al. (2016BALBO, B.E. et al. Cardiac dysfunction in Pkd1-deficient mice with phenotype rescue by galectin-3 knockout. Kidney International, v.90, n.3, p.580-597, 2016. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/27475230 >. Accessed: Dec. 21, 2019. doi: 10.1016/j.kint.2016.04.028.
https://www.ncbi.nlm.nih.gov/pubmed/2747...
) showed that different Pkd1-deficient mouse models, including noncystic normotensive Pkd1 +/- and cystic hypertensive Pkd1 flox/flox:Nestin cre animals, developed systolic dysfunction and reduced myocardial deformation. Pkd1 flox/flox:Nestin cre mice also presented diastolic dysfunction. These findings strongly supported a primary role for PKD1 deficiency in ADPKD-associated heart dysfunction, while suggested that hypertension may worsen this phenotype with age. In line with these findings, PEDROZO et al. (2015PEDROZO, Z. et al. Polycystin-1 is a cardiomyocyte mechanosensor that governs l-type Ca2+ channel protein stability. Circulation, n.131, v.24, p.2131-2142, 2015. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/25888683 >. Accessed: Dec. 21, 2019. doi: 10.1161/CIRCULATIONAHA.114.013537.
https://www.ncbi.nlm.nih.gov/pubmed/2588...
) have shown that polycystin-1 is required for the normal baseline function of cardiomyocytes. This study revealed, on the other hand, that this protein is also necessary for cardiomyocyte stretch-induced hypertrophy. Polycystin-2 has also been shown to play a significant role in cardiac function (PAAVOLA et al., 2013PAAVOLA, J. et al. Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. Journal of Molecular and Cellular Cardiology, v.58, p.199-208, 2013. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/23376035 >. Accessed: Dec. 21, 2019. doi: 10.1016/j.yjmcc.2013.01.015.
https://www.ncbi.nlm.nih.gov/pubmed/2337...
). This report not only revealed that ADPKD patients have an increased risk of developing idiopathic dilated cardiomyopathy, particularly type 2 ADPKD cases, but also showed that zebrafish lacking this protein develop manifestations consistent with heart failure.

The ADPKD is also a genetic disorder that affects 13-46% of Persian cats and Persian-related breeds populations worldwide (LEE et al., 2010LEE, Y.J. et al. Molecular detection of autosomal-dominant feline polycystic kidney disease by multiplex amplification refractory mutation system polymerase chain reaction. Journal of Veterinary Diagnostic Investigation, v.22, n.3, p.424-428, 2010. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/20453219 >. Accessed: Oct. 3, 2012. doi: 10.1177/104063871002200314.
https://www.ncbi.nlm.nih.gov/pubmed/2045...
). Ultrasound screening and molecular tests to detect the genetic point mutation (C-A transversion) at position 3284 in exon 29 of the PKD1 gene have been employed routinely in the diagnosis of the feline disease (LYONS et al., 2004LYONS, L.A. et al. Feline polycystic kidney disease mutation identified in PKD1. Journal of the American Society of Nephrology, v.15, n.10, p.2548-2555, 2004. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/15466259 >. Accessed: Oct. 3, 2012. doi: 10.1097/01.ASN.0000141776.38527.BB.
http://www.ncbi.nlm.nih.gov/pubmed/15466...
). Interestingly, cardiac abnormalities have been rarely described in cats with ADPKD; although cases involving LVH and biventricular cardiac dilation (BILLER et al., 1990BILLER, D.S. et al. Polycystic kidney disease in a family of Persian cats. Journal of the American Veterinary Medical Association, v.196, n.8, p.1288-1290, 1990. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/2185204 >. Accessed: Feb. 2, 2014. PubMed PMID: 2185204.
http://www.ncbi.nlm.nih.gov/pubmed/21852...
; EATON et al., 1997EATON, K.A. et al. Autosomal dominant polycystic kidney disease in Persian and Persian-cross cats. Veterinary Pathology, v.34, n.2, p.117-126, 1997. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/9066078 >. Accessed: Feb. 13, 2012. doi: 10.1177/030098589703400204.
http://www.ncbi.nlm.nih.gov/pubmed/90660...
), cardiomyopathy of unknown origin (BOSJE et al., 1998BOSJE, J.T. et al. Polycystic kidney and liver disease in cats. The Veterinary Quarterly, v.20, n.4, p.136-139, 1998. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/9810628 >. Accessed: Jul. 22, 2012. doi: 10.1080/01652176.1998.9694858.
https://www.ncbi.nlm.nih.gov/pubmed/9810...
), minor increases in mean arterial pressure, endocardial echogenicity, restrictive diastolic filling pattern, mild dilatation of the left ventricle, and slight mitral valve regurgitation (PEDERSEN et al., 2013PEDERSEN, K.M. et al. Increased mean arterial pressure and aldosterone-to-renin ratio in Persian cats with polycystic kidney disease. Journal of Veterinary Internal Medicine, v.17, n.1, p.21-27, 2013. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/12564723 >. Accessed: Feb. 3, 2014. PubMed PMID: 12564723.
http://www.ncbi.nlm.nih.gov/pubmed/12564...
) have been reported. The purpose of this study was to assess the echo- and electrocardiographic profiles of ADPKD-affected Persian cats.

MATERIALS AND METHODS:

An observational, transversal and descriptive study was carried out with a population comprised 82 Persian cats, males and females, originated from ten households. Initially, abdominal ultrasound scans were performed using an ultrasound machine with multifrequency (6-10 MHz) micro-convex or multifrequency (7.5-12 MHz) linear transducers (Logiq 7, GE Healthcare, Chalfont St Giles, UK). From those animals, twelve (14.6%) were diagnosed with ADPKD through abdominal ultrasonography, which revealed the presence of four to more than ten renal cysts per animal. Thereafter, genetic analysis confirmed the presence of the C-A mutation in exon 29 of the PKD1 gene in all animals, which was detected on DNA samples extracted from blood by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) (GUERRA et al., 2019GUERRA, J.M. et al. Age-based ultrasonographic criteria for diagnosis of autosomal dominant polycystic kidney disease in Persian cats. Journal of Feline Medicine and Surgery, v.21, n.2, p.156-164, 2019. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/29652208 >. Accessed: Jan. 28, 2019. doi: 10.1177/1098612X18764591.
https://www.ncbi.nlm.nih.gov/pubmed/2965...
). For comparison, twelve age and sex-matched Persian cats, with no evidences of systemic disease, were randomly selected as control group (non-ADPKD cats). All of heathy animals did not exhibit renal cysts and were negative for the referred PKD1 mutation.

After ultrasonography and genetic screening, each of 24 Persian cats underwent a complete physical examination that included measurement of systolic blood pressure (SBP) together with electrocardiogram (ECG), echocardiographic, hematological and biochemical analyses, carried out according to standard methodologies (TILLEY, 1992TILLEY, L.P. Essentials of canine and feline electrocardiography: interpretation and treatment. 3.ed. Philadelphia : Lea & Febiger, 1992. 470p.; BROWN et al., 2007BROWN, S. et al. Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. Journal of Veterinary Internal Medicine, v.21, n.3, p.542-558, 2007. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/17552466 >. Accessed: Jun. 22, 2014. doi: 0.1892/0891-6640(2007)21ENT#091;542:gftieaENT#093;2.0.co;2.
http://www.ncbi.nlm.nih.gov/pubmed/17552...
; BONAZZI et al., 2009BONAZZI, M. et al. Comparison between ultrasound and genetic testing for the early diagnosis of polycystic kidney disease in Persian and Exotic Shorthair cats. Journal of Feline Medicine and Surgery, v.11, n.6, p.430-434, 2009. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/19046910 >. Accessed: Oct. 3, 2011. doi: 10.1016/j.jfms.2008.10.003.
http://www.ncbi.nlm.nih.gov/pubmed/19046...
; BOON, 2011BOON, J.A. Veterinary Echocardiography. 2.ed. Ames, Iowa : Wiley-Blackwell, 2011. 610p.; GUERRA et al., 2015GUERRA, J.M. et al. Congenital hepatic fibrosis and polycystic kidney disease not linked to C >A mutation in exon 29 of PKD1 in a Persian cat. Journal of Feline Medicine and Surgery open reports, v.1, n.2, 2055116915619191, 2015. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/28491400 >. Accessed: Dec. 18, 2016. doi: 10.1177/2055116915619191.
https://www.ncbi.nlm.nih.gov/pubmed/2849...
; 2019). Clinical signs evaluated included emaciation, dyspnea, cough, fatigue, exercise intolerance, cyanosis, pre-syncope or syncope, edema or ascites, and convulsion.

Values of SBP were obtained by Doppler ultrasonography linked to an aneroid sphygmomanometer (Medmega DV610B instrument, Nova Med Tec, São Paulo, Brazil), according to the methodology previously described (LITTMAN, 2000LITTMAN, M.P. Hypertension. In: ETTINGER, S.J.; FELDMAN, E.C. Textbook of Veterinary Internal Medicine. 5.ed. Philadelphia : WB Saunders, 2000. p. 179-182.). Briefly, cats were placed in a quiet and undisturbed room prior to measurement of SBP, in order to acclimatize them to the new environment and strange people (BELEW et al., 1999BELEW, A.M. et al. Evaluation of the white-coat effect in cats. Journal of Veterinary Internal Medicine, v.13, n.2, p.134-142, 1999. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/10225603 >. Accessed: Jan. 12, 2016. doi: 10.1892/0891-6640(1999)013<0134:eotwce>2.3.co;2.
https://www.ncbi.nlm.nih.gov/pubmed/1022...
). Five consecutive measurements were performed and the results were expressed as arithmetic means. The ECG data were acquired using a standard six-lead device (Ecafix ECG6, Transform, São Paulo, Brazil), with non-sedated animals positioned in right lateral or sternal recumbency, evaluating the bipolar leads I, II and III and the unipolar leads aVR, aVL and VF, as well as the precordial leads CV5RL (rV2), CV6LL (V2), CV6LU (V4 ) and v10 at a recording speed of 25 mm/s and a calibration of 1 mV equal to 1 cm. Bipolar II lead was recorded at a speed of 50 mm/s. ECG traces were examined to rhythm and waveform according to standard procedures (TILLEY et al., 1992TILLEY, L.P. Essentials of canine and feline electrocardiography: interpretation and treatment. 3.ed. Philadelphia : Lea & Febiger, 1992. 470p.).

Blood was collected by jugular venipuncture and submitted to: (i) hematological examination - complete blood count (CBC), white blood cell count (WBC), hemoglobin (Hb) and blood urea nitrogen (BUN); (ii) biochemical assay - creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein, thyroxine (T4), sodium, calcium, potassium and phosphorus; and (iii) molecular analysis (PCR-RFLP).

Echocardiographic examinations were carried out with cats in right and left lateral recumbency using an ultrasound machine (Vivid-i, GE Healthcare, Chalfont St Giles, UK) with 8 and 12 MHz multifrequency phased array transducers as recommended by the Echocardiography Committee of the Specialty of Cardiology, American College of Veterinary Internal Medicine (THOMAS et al., 1993THOMAS, W.P. et al. Recommendations for standards in transthoracic two-dimensional echocardiography in the dog and cat. Echocardiography Committee of the Specialty of Cardiology, American College of Veterinary Internal Medicine. Journal of Veterinary Internal Medicine, v.7, n.4, p.247-252, 1993. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/8246215 >. Accessed: Nov. 25, 2015. doi: 10.1111/j.1939-1676.1993.tb01015.x.
https://www.ncbi.nlm.nih.gov/pubmed/8246...
) and by the American Society of Echocardiography (BOON, 2011BOON, J.A. Veterinary Echocardiography. 2.ed. Ames, Iowa : Wiley-Blackwell, 2011. 610p.). At least three determinations were performed for each parameter evaluated in the different phases of the cardiac cycle, considering the average of the values ​​obtained. Echocardiograms were analyzed using the commercial software package supplied with the system, and diagnosis was based on current literature (FERASIN, 2009FERASIN, L. Feline myocardial disease 2: diagnosis, prognosis and clinical management. Journal of Feline Medicine and Surgery, v.11, n.3, p.183-194, 2009. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/19237134 >. Accessed: May, 12, 2014. doi: 10.1016/j.jfms.2009.01.002.
https://www.ncbi.nlm.nih.gov/pubmed/1923...
). Images for the measurement of the left ventricle were acquired in the right parasternal window, cross-sectioned, at the time of insertion of the tendinous strings in the papillary muscles (M mode). The occurrence of myocardial hypertrophy was defined when the diastolic thickness of the interventricular septum (IVSd) and/or the left ventricular free wall (LVFWd) was equal to or greater than 0.6 cm. Cats with diastolic thicknesses less than 0.5 cm were considered normal. Concentric hypertrophy was considered symmetrical when the IVSd/LVFWd ratio was between 0.7 and 1.3. In the presence of asymmetric hypertrophy, segmental hypertrophy was measured by the two-dimensional mode. Measurements of the diameter of the aortic root (Ao) and the diameter of the left atrium (LA) were performed using the two-dimensional mode, right parasternal window, cross section, in the cardiac base region. An increase in AE was considered when the AE/Ao ratio was greater than 1.5 (WESS et al., 2010WESS, G. et al. Association of A31P and A74T polymorphisms in the myosin binding protein C3 gene and hypertrophic cardiomyopathy in Maine Coon and other breed cats. Journal of Veterinary Internal Medicine, v.24, n.3, p.527-532, 2010. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 20412438 >. Accessed: Feb. 13, 2017. PubMed PMID: 20412438.
http://www.ncbi.nlm.nih.gov/pubmed/ 2041...
). The left atrial-to-aortic root diameter ratio (LA/Ao) was established by echocardiography from the right parasternal short-axis heart base view. Doppler echocardiography (color, pulsed wave and continuous wave) was employed to characterize flow disturbances (KITTLESON et al., 1999KITTLESON, M.D. et al. Familial hypertrophic cardiomyopathy in maine coon cats: an animal model of human disease. Circulation, v.99, n.24, p.3172-3180, 1999. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/10377082 >. Accessed: Jun. 2, 2014. doi: 10.1161/01.cir.99.24.3172.
https://www.ncbi.nlm.nih.gov/pubmed/1037...
).

All statistical analyses were carried out using R-statistical environment software (http://r-project.org/). Continuous variables are presented as mean ± standard deviation (and median, minimum-maximum). The Shapiro-Wilk test was used to test data normality. Mann-Whitney or Student’s t tests were used to compare the means or the medians, respectively, of continuous variables between two groups (ADPKD and non-ADPKD cats). Correlations between variables that were not normally distributed were investigated by means of the Spearman rank correlation test. To assess the difference in categorical variables between groups, Fisher’s exact test was used. In all analyses, a two-tailed alternative hypothesis was employed, and the level of significance was set at 5%.

RESULTS:

Of the 24 Persian cats enrolled in the study, 10 (41.67%) were male and 14 (58.33%) were female. Five males (20.84%) and four females (16.67%) were sexually intact, whereas 5 males (20.84%) and 10 females had been neutered (41.67%). The mean body weight of males was 4.18 ± 1.54 kg (range 2.0 to 6.15 kg) and that of females was 3.57 ± 1.10 kg (range 2.0 to 4.80 kg), but these values were not significantly different (P = 0.445). The mean age of the entire cat population was 92.46 ± 38.92 months (range 28 to 162 months), while the mean ages of males and females (94.9 ± 42.3 vs. 90.7 ± 37.9 months, respectively) did not significantly differ (P = 0.802). There were no significant differences between the ADPKD and non-ADPKD cats in regard to gender (Male:Female ratio: 6/6 vs. 4/8, P = 0.691), age (96.0 ± 46.9 vs. 88.92 ± 30.55 months, P = 0.666) and body weight (3.75 ± 1.65 vs. 4.17 ± 0.80 kg, P = 0.475). The most common clinical signs in the ADPKD population were emaciation (20.0%) and fatigue (13.3%). However, there were no statistical differences between the groups regarding the frequency of the clinical signs (data not shown). Also, there were no significative differences regarding hematological and biochemical parameters between ADPKD and non-ADPKD cats, including T4 levels (Table 1). None of the animals manifested symptoms of hypothyroidism or hyperthyroidism.

Table 1
Hematological and biochemical profiles of Persian cats enrolled in the study.

Cardiovascular evaluations showed that all animals were normotensive, and no statistical differences were observed between the groups with respect to systolic blood pressure. Also, there was no difference in heart rate (HR) between ADPKD and non-ADPKD cats (Table 2). Presence of left-sided heart abnormalities was observed in 3/12 (25%) and 6/12 (50%) cats in ADPKD and non-ADPKD groups, respectively. No statistical difference was observed regarding the frequency of these alterations (P = 0.126). The ECG traces of all animals exhibited normal sinus rhythms, with the exception of 1/12 (8.3%) cat in the ADPKD-affected group that presented sinus tachycardia, considering cases in which HR was greater than 240 bpm (TILLEY et al., 1992TILLEY, L.P. Essentials of canine and feline electrocardiography: interpretation and treatment. 3.ed. Philadelphia : Lea & Febiger, 1992. 470p.). No animals revealed supraventricular arrhythmias.

Table 2
Cardiovascular and ECG profiles of Persian cats enrolled in the study.

No differences were observed between the two groups with respect to heart rate, P-wave width, PR interval, QRS interval, R-wave amplitude, QT interval and R-wave or S-wave amplitudes in precordial chest leads CV5RL (rV2), CV6LL (V2) and CV6LU (V4). P-wave amplitudes on lead II were slightly elevated in ADPKD-cats, especially in those with concurrent LVH (0.200 ± 0.054 mV); however, there is no statistical difference (P = 0.069) (Table 2). With respect to defects in the impulse conduction system, an incomplete right bundle branch block was observed in 3/12 (25%) animals of the non-ADPKD group and in 2/12 (16.67%) animals of ADPKD group, with no statistical difference (P = 1.000). A left anterior fascicular block and a first-degree atrioventricular block were detected in one animal with ADPKD and LVH, but differences regarding the occurrence of these defects were not significant (P = 1.000) between the two groups. Abnormal ventricular repolarization and ventricular premature complexes were observed, respectively, in two (16.67%) and one (8.33%) ADPKD-cats with LVH.

Echocardiographic measurements revealed that 3/12 (25.0%) and 3/12 (25.0%) animals enrolled in the ADPKD and non-ADPKD groups, respectively, displayed left ventricular hypertrophy, which involve the basal septum adjacent to the left ventricular outflow tract and/or involving portions of the ventricular septum as well as the contiguous anterolateral and posterior free walls. No statistical difference was observed between the proportions of LVH in these two groups (P = 0.400). AoIVSd, IVSd, LVFWd and LVIDd thicknesses, and the IVSd/LVFW ratio did not significantly differ between the groups. Additionally, basal interventricular septal thickness at end-diastole showed no statistical difference in ADPKD-affected animals (P = 0.084). Left ventricular ejection fraction (LVEF) and shortening fraction (LVSF) also did not differ between ADPKD and non-ADPKD cats. No significant differences related to the remaining echocardiographic parameters were observed between the two groups either. Similar to AoIVSd, aortic artery flow velocity showed no difference in the ADPKD group (P = 0.064) (Table 3).

Table 3
Echocardiographic profile of Persian cats enrolled in the study.

Additionally, neither a significant difference in SBP between ADPKD-affected cats with and without LVH (P = 0.902) nor a significant correlation between left ventricular wall thickness and SPB (IVSd, P = 0.843, r = 0.043; LVFWd, P = 0.171, r = -0.289) were observed.

Within the ADPKD group, 3/12 (25.0%) animals exhibited mild insufficiency of the mitral and tricuspid valves, and 1/12 (8.3%) exhibited only mitral valve insufficiency associated with increased ventricular septum echogenicity. Also, one (8.3%) animal presented mild obstruction of the left ventricular outflow tract. Among non-ADPKD cats, only 1/12 (8.33%) presented mild mitral valve insufficiency. No significant differences were observed between the two groups with regard to the frequency of appearance or movement of the valve leaflets (P = 0.316).

DISCUSSION:

The aim of the current study was to evaluate the cardiac phenotype of Persian cats diagnosed with ADPKD. In humans, 89% of ADPKD-patients that died due cardiac causes exhibited LVH, a manifestation that constitutes an important risk factor for sudden cardiac death (FICK et al., 1995FICK, G.M. et al. Causes of death in autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology, v.5, n.12, p.2048-2056, 1995. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/7579053 >. Accessed: Jul. 12, 2014. doi: PubMed PMID: 7579053.
http://www.ncbi.nlm.nih.gov/pubmed/75790...
). Various studies involving ADPKD in humans and experimental animal models have shown that both hypertension and activation of the renin-angiotensin system (RAS) contribute to the development of LVH (ECDER et al., 1999ECDER, T. et al. Reversal of left ventricular hypertrophy with angiotensin converting enzyme inhibition in hypertensive patients with autosomal dominant polycystic kidney disease. Nephrology Dialysis Transplantation, v.14, n.5, p.1113-1116, 1999. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/10344347 >. Accessed: Jun. 22, 2014. doi: 10.1093/ndt/14.5.1113.
https://www.ncbi.nlm.nih.gov/pubmed/1034...
; PHILLIPS et al., 2007PHILLIPS, J.K. et al. Temporal relationship between renal cyst development, hypertension and cardiac hypertrophy in a new rat model of autosomal recessive polycystic kidney disease.. Kidney and Blood Pressure Research, v.30, n.3, p.129-144, 2007. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/17446713 >. Accessed: Dec. 5, 2015. doi: 10.1159/000101828.
https://www.ncbi.nlm.nih.gov/pubmed/1744...
). Cyst expansion and local hypoperfusion activates intrarenal RAS causing hypertension, while increased pressure load stimulates myocyte hypertrophy, collagen formation and fibroblast proliferation, thereby remodeling the myocardium with a disproportionate amount of fibrous tissue (CHAPMAN et al. 1997CHAPMAN, A.B. et al. Left ventricular hypertrophy in autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology, v.8, n.8, p.1292-1297, 1997. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/9259356 >. Accessed: Jun. 2, 2014. PubMed PMID: 9259356.
http://www.ncbi.nlm.nih.gov/pubmed/92593...
; KAHAN et al., 2005KAHAN, T. Left ventricular hypertrophy in hypertension: its arrhythmogenic potential. Heart, v.91, n.2, p.250-256, 2005. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/15657259 >. Accessed: Nov. 25, 2014. doi: 10.1136/hrt.2004.042473.
https://www.ncbi.nlm.nih.gov/pubmed/1565...
; FONSECA et al., 2014FONSECA, J.M. et al. Renal cyst growth is the main determinant for hypertension and concentrating deficit in Pkd1-deficient mice. Kidney International, v.85, n.5, p.1137-1150, 2014. Avalaible from: < Avalaible from: https://www.ncbi.nlm.nih.gov/pubmed/24429399 >. Accessed: Dec. 19, 2019. doi: 10.1038/ki.2013.501.
https://www.ncbi.nlm.nih.gov/pubmed/2442...
).

Our results revealed; however, no significant differences between the two groups of animals in regard to SBP; only one animal in non-ADPKD group presented SPB of 180 mmHg, not associated with LVH. It is unclear why ADPKD cats did not reproduce the hypertensive pattern displayed by Pkd1-deficient cystic mice (FONSECA et al., 2014FONSECA, J.M. et al. Renal cyst growth is the main determinant for hypertension and concentrating deficit in Pkd1-deficient mice. Kidney International, v.85, n.5, p.1137-1150, 2014. Avalaible from: < Avalaible from: https://www.ncbi.nlm.nih.gov/pubmed/24429399 >. Accessed: Dec. 19, 2019. doi: 10.1038/ki.2013.501.
https://www.ncbi.nlm.nih.gov/pubmed/2442...
). A potentially lower renal cystic burden in cats than in the evaluated mice should be considered as a possible contributor to such a blood pressure behavior. Few reports are available addressing hypertension and alterations in hormonal determinants that regulate blood pressure in cats affected by ADPKD. However, PERDERSEN et al. (2003) showed that all cats with mild and severe forms of the disease (n = 14) exhibited higher mean arterial pressure and a trend towards higher SBP compared with healthy control animals. None of the cats; however, showed echocardiographic evidence of cardiac hypertrophy. Moreover, SNYDER et al. (2001SNYDER, P.S. et al. Effect of amlodipine on echocardiographic variables in cats with systemic hypertension. Journal of Veterinary Internal Medicine, v.15, n.1, p.52-56, 2001. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/11215913 >. Accessed: Sep. 24, 2014. doi: 10.1892/0891-6640(2001)015<0052:eoaoev>2.3.co;2.
https://www.ncbi.nlm.nih.gov/pubmed/1121...
) described that the frequency of LVH in hypertensive cats with systemic arterial pressure > 170 mm Hg was around 74%.

CHAPMAN et al. (1997CHAPMAN, A.B. et al. Left ventricular hypertrophy in autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology, v.8, n.8, p.1292-1297, 1997. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/9259356 >. Accessed: Jun. 2, 2014. PubMed PMID: 9259356.
http://www.ncbi.nlm.nih.gov/pubmed/92593...
) carried out echocardiographic tests in humans (77 healthy subjects and 116 adults diagnosed with ADPKD) and reported that LVH was present in 23% of normotensive ADPKD patients and 16% of the healthy controls; although, these parameters were not statistically significant. It is interesting to notice that, in both groups, presence of LVH did not correlate with blood pressure. Normotensive ADPKD adults; however, showed increased left ventricular mass index compared to controls. Similar findings have been reported by other studies (TIMIO et al., 1992TIMIO, M. et al. The spectrum of cardiovascular abnormalities in autosomal dominant polycystic kidney disease: a 10-year follow-up in a five-generation kindred. Clinical Nephrology, v.37, n.5, p.245-251, 1992. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/1606775 >. Accessed: Out. 18, 2014. PubMed PMID: 1606775.
http://www.ncbi.nlm.nih.gov/pubmed/16067...
; SAGGAR-MALIK et al., 1994SAGGAR-MALIK, A.K. et al. Left ventricular mass in normotensive subjects with autosomal dominant polycystic kidney disease. British Medical Journal, v.309, n.6969, p.1617-1618, 1994. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/7819937 >. Accessed: Aug. 14, 2014. doi: 10.1136/bmj.309.6969.1617.
https://www.ncbi.nlm.nih.gov/pubmed/7819...
). Moreover, increased left ventricular mass index has been reported in young normotensive humans with ADPKD and well-preserved renal function, and is apparently associated with biventricular diastolic and endothelial dysfunction, increased carotid intima-media thickness and impaired coronary flow velocity reserve, suggesting that cardiovascular involvement starts at early stages of ADPKD (MARTINEZ-VEA et al., 2000MARTINEZ-VEA, A. et al. Left ventricular hypertrophy in hypertensive patients with autosomal dominant polycystic kidney disease: Influence of blood pressure and humoral and neurohormonal factors. American Journal of Nephrology, v.20, n.3, p.193-200, 2000. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/10878400 >. Accessed: Nov. 13, 2012. doi: 10.1159/000013583.
https://www.ncbi.nlm.nih.gov/pubmed/1087...
; 2004MARTINEZ-VEA, A. et al. Exercise blood pressure, cardiac structure, and diastolic function in young normotensive patients with polycystic kidney disease: A prehypertensive state. American Journal of Kidney Diseases, v.44, n.2, p.216-223, 2004. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/15264179 >. Accessed: May. 13, 2015. doi: 10.1053/j.ajkd.2004.04.026.
https://www.ncbi.nlm.nih.gov/pubmed/1526...
). Such cardiac alterations have been associated with hemodynamic factors, including lower nocturnal fall in blood pressure rhythm (VALERO et al., 1999VALERO, F.A. et al. Ambulatory blood pressure and left ventricular mass in normotensive patients with autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology, v.10, n.5, p.1020-1026, 1999. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/10232688 >. Accessed: Nov. 30, 2014. PubMed PMID: 10232688.
http://www.ncbi.nlm.nih.gov/pubmed/10232...
). In the present study, no significant differences were observed between the two groups of animals with respect to systolic and diastolic function as well as valve morphology and movement. The lack of difference in LVEF and LVSF observed between ADPKD and non-ADPKD animals did not reproduce previous findings of systolic dysfunction in Pkd1-deficient mice (BALBO et al., 2016BALBO, B.E. et al. Cardiac dysfunction in Pkd1-deficient mice with phenotype rescue by galectin-3 knockout. Kidney International, v.90, n.3, p.580-597, 2016. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/27475230 >. Accessed: Dec. 21, 2019. doi: 10.1016/j.kint.2016.04.028.
https://www.ncbi.nlm.nih.gov/pubmed/2747...
). We presently have no robust explanation for this distinct heart functional pattern; however, it is possible that the allele harboring the PKD1 mutation common to all affected cats exerts a hypomorphic effect on the feline heart. WANG et al. (2000WANG, D. et al. Endothelium-dependent relaxation of small resistance vessels is impaired in patients with autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology, v.11, n.8, p.1371-1376, 2000. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/10906150 >. Accessed: Dec. 13, 2015. PubMed PMID: 10906150.
http://www.ncbi.nlm.nih.gov/pubmed/10906...
) reported the occurrence of endothelial dysfunction and reduced nitric oxide synthase (NOS) activity in humans diagnosed with ADPKD even before the development of hypertension or renal insufficiency; although the abnormalities were shown to be more severe in the setting of hypertension.

Hypertrophic cardiomyopathy (HCM), the most common type of cardiomyopathic phenotype in cats, is characterized by diffuse or regional increased left ventricle (LV) wall thickness with a nondilated LV chamber. The HCM remains a major source of feline morbidity and mortality, with congestive heart failure and arterial thromboembolism as the most common cause of clinical signs and sudden death in this species (LUIS FUENTES et al., 2020LUIS FUENTES, V. et al. ACVIM consensus statement guidelines for the classification, diagnosis, and management of cardiomyopathies in cats. Journal of Veterinary Internal Medicine, 2020. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/32243654 >. Accessed: May, 8, 2020. doi: 10.1111/jvim.15745.
https://www.ncbi.nlm.nih.gov/pubmed/3224...
). In some breeds, such as Maine Coon and Ragdoll cats, HCM is an autosomal dominant inherited disease caused by a mutation in the gene that encodes the cardiac myosin binding protein C (MYBPC3) (MEURS et al., 2005MEURS, K.M. et al. A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathya. Human Molecular Genetics, v.14, n.23, p.3587-3593, 2005. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/16236761 >. Accessed: May, 10, 2019. doi: 10.1093/hmg/ddi386.
https://www.ncbi.nlm.nih.gov/pubmed/1623...
; 2007 MEURS, K.M. et al. A substitution mutation in the myosin binding protein C gene in ragdoll hypertrophic cardiomyopathy. Genomics, v.90, n.2, p.261-264, 2007. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/17521870 >. Accessed: May, 10, 2019. doi: 10.1016/j.ygeno.2007.04.007.
https://www.ncbi.nlm.nih.gov/pubmed/1752...
). Although, there is some evidence of inherited familial HCM in Persian cats, inherited mutations have not yet been reported in this breed (RUSH et al., 2002RUSH, J.E. et al. Population and survival characteristics of cats with hypertrophic cardiomyopathy: 260 cases (1990-1999). Journal of the American Veterinary Medical Association, v.220, n.2, p.202-207, 2002. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/12126131 >. Accessed: Nov. 3, 2014. doi: 10.2460/javma.2002.220.202.
https://www.ncbi.nlm.nih.gov/pubmed/1212...
). In the present study, it was not possible to ascertain whether HCM was linked to ADPKD in Persian cats or if these two separate inherited diseases emerged concomitantly, since three animals in non-ADPKD group also displayed asymmetric LVH.

This study has some limitations; however, which included the observational nature of the investigation, the definition of hypertension in cats and the under-representation of animals within the groups. Nevertheless, the number of cats employed herein was equivalent to other ADPKD studies (PEDERSEN et al., 2013PEDERSEN, K.M. et al. Increased mean arterial pressure and aldosterone-to-renin ratio in Persian cats with polycystic kidney disease. Journal of Veterinary Internal Medicine, v.17, n.1, p.21-27, 2013. Available from: <Available from: http://www.ncbi.nlm.nih.gov/pubmed/12564723 >. Accessed: Feb. 3, 2014. PubMed PMID: 12564723.
http://www.ncbi.nlm.nih.gov/pubmed/12564...
; LEE et al., 2010LEE, Y.J. et al. Molecular detection of autosomal-dominant feline polycystic kidney disease by multiplex amplification refractory mutation system polymerase chain reaction. Journal of Veterinary Diagnostic Investigation, v.22, n.3, p.424-428, 2010. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/20453219 >. Accessed: Oct. 3, 2012. doi: 10.1177/104063871002200314.
https://www.ncbi.nlm.nih.gov/pubmed/2045...
). In humans, some echocardiographic measurements, including LV free-wall thickness, can be influenced by age. When analyzing cats; therefore, comparisons should also be made using age-matched controls (GERSTENBLITH et al., 1977GERSTENBLITH, G. et al. Echocardiographic assessment of a normal adult aging population. Circulation, v.56, n.2, p.273-278, 1977. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/872321 >. Accessed: Nov. 16, 2014. doi: 10.1161/01.cir.56.2.273.
https://www.ncbi.nlm.nih.gov/pubmed/8723...
). In this context, we have carefully selected animals of comparable age and sex for non-ADPKD and ADPKD groups. The definition of systolic hypertension in cats, in turn, is still debated in veterinary medicine; although, the American College of Veterinary Internal Medicine consensus panel considers an SBP between 170 and 180 mmHg a risky condition to target organ damage (JEPSON, 2011JEPSON, R.E. Feline systemic hypertension: Classification and pathogenesis. Journal of Feline Medicine and Surgery, v.13, n.1, p.25-34, 2011. Available from: <Available from: https://www.ncbi.nlm.nih.gov/pubmed/21215946 >. Accessed: Mar. 23, 2014. doi: 10.1016/j.jfms.2010.11.007.
https://www.ncbi.nlm.nih.gov/pubmed/2121...
). Of note, none of the animals had concurrent clinical signs that could support the diagnosis of hypertension. In this setting, abnormal high arterial pressure was not considered the cause of LVH in these animals.

CONCLUSION:

Based on the feline population employed herein, our study revealed that Persian cats with ADPKD do not reproduce the functional and structural cardiac phenotype reported in human patients with this disease nor the heart dysfunction observed in Pkd1-deficient mouse models. Further studies with large-scale cohort of Persian cats; however, are necessary to distinguish the possibilities of a true linkage between ADPKD and LVH and an association between two distinct diseases in this breed. Differential diagnosis is important to pet owners because it allows early detection and treatment of disease complications.

ACKNOWLEDGEMENTS

The authors wish to thank Associação dos Criadores de Gato Persa (São Paulo, SP, Brazil) in facilitating communication with the owners of the cats. The study was funded by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grants nº. 12/19614-6, 12/04990-2 and 13/06471-5), Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq, grants nº. 311929/2015-0 and 310557/2019-4) and by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brasil - Finance code 001. This work was also supported by European Investment Funds by FEDER/COMPETE/POCI - Operacional Competitiveness and Internacionalization Programme, under Project POCI-01-0145-FEDER-006958 and National Funds by FCT - Portuguese Foundation for Science and Technology, under the project UID/AGR/04033/2013.

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  • CR-2019-1020.R2

BIOETHICS AND BIOSSECURITY COMMITTEE APPROVAL

  • The owners were thoroughly informed about the research aims and protocols, and written informed consent was obtained from the owner of each pet prior the investigation. This study was approved by the Institution’s Ethical Committee of the Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo (Protocol nº. 1812010514) and it was conducted in accordance with the guidelines of Colégio Brasileiro de Experimentação Animal (COBEA).

Publication Dates

  • Publication in this collection
    07 Aug 2020
  • Date of issue
    2020

History

  • Received
    22 Dec 2019
  • Accepted
    15 May 2020
  • Reviewed
    25 June 2020
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