animals : this study was conducted in compliance with the guidelines for 
 the care and use of laboratory animals , and the protocol was approved by the animal 
 experimentation committee of nippon veterinary and life science university ( approval number 
 1083 ) . twelve mixed - breed male and female cats ( age , 2.2  0.3 years ; range , 1.72.5 years ; 
 and weight , 3.3  0.9 kg ) were used . before experimentation , all cats underwent general 
 clinical examination , blood and serum biochemical analyses , electrocardiography , radiography 
 and echocardiography . cats were housed in individual cages and fed a commercial maintenance diet 
 ( royal canin male care and female care , tokyo , japan ) . study design : the study design was based on a similar study conducted in 
 dogs . one group received the angiotensin - converting - enzyme inhibitor ( acei ) , 
 benazepril ( fortekor , elanco animal health , kobe , japan ) and was labeled the acei group ; and 
 the other group received pimo ( vetmedin , boehringer ingelheim vetmedica , inc . , each group was composed of an equal number of animals of 
 both sexes ( 3 males and 3 females ) . cats in the acei group received benazepril at a dosage 
 of 0.25 mg / kg q24 hr at 08:00 am for 506 days . cats in the pimo group received pimo at a 
 dosage of 0.25 mg / kg q12 hr at 8:00 am and 8:00 pm for 506 days . all cats underwent cardiac auscultation , heart rate measurement , echocardiography , doppler 
 examination and blood pressure measurement . we also performed hematocrit measurement and 
 serum biochemical analyses that included total protein , albumin , blood urea nitrogen , 
 creatinine , sodium and potassium levels . all analyses were performed before drug 
 administration ( day 0 ) and at days 16 , 50 , 118 , 202 , 320 , 409 and 506 after starting drug 
 administration . plasma iohexol clearance ( pcio ) was performed to measure the glomerular 
 filtration rate ( gfr ) on days 0 , 125 , 323 and 506 . all examinations were performed to assess 
 whether cardiac pathological findings occurred in connection with hemodynamic and cardiac 
 structural changes . animals were not fed for 8 hr prior to examinations , but were allowed 
 free access to drinking water . to allow the same investigator the time to examine all 12 
 cats , the examinations were performed between 2:00 pm and 6:00 pm on each assessment 
 day . echocardiography and doppler examination : cats underwent continuous 
 echocardiography monitoring with an ultrasound unit ( vivid 7 , ge healthcare japan , tokyo , 
 japan ) equipped with a 3.56.9 mhz transducer , without sedation or anesthesia . the same 
 trained investigator ( takemura ) performed all examinations to exclude possible 
 inter - observer variability , and all measurements were obtained from three consecutive 
 cardiac cycles within the same time frame . the ratio of the left atrial diameter to the 
 aortic diameter was obtained from the right parasternal short - axis view using the b - mode 
 method . the thickness of the anterior and posterior mitral valve leaflet was measured using 
 the left apical four - chamber view , whereas end - diastolic interventricular septum thickness , 
 end - diastolic left - ventricular internal dimension , end - diastolic left - ventricular free - wall 
 thickness and fractional shortening ( fs ) were measured from the right parasternal short - axis 
 view using the m - mode method ( the leading edge to leading edge method ) . fs was calculated 
 according to the following equation : fs ( % ) = [ ( diastolic left - ventricular internal 
 diameter - systolic left - ventricular internal diameter)/diastolic left - ventricular internal 
 diameter ] 100 . any development of mitral valve or tricuspid valve regurgitation was 
 monitored by doppler examination . all cats were well - hydrated and had fasted 
 for 12 hr before measurements . iohexol ( omnipaque 300 , daiichi sankyo co. , ltd . , tokyo , 
 japan ) was administered at a dosage of 90 mg iodine / kg via the cephalic vein ( time 0 ) , and 
 heparinized blood was sampled at 120 , 180 and 240 min after administration . the area under 
 the curve ( auc ) was estimated from the slope ( a ) and intercept ( a ) of the elimination phase 
 of the curve , as determined by linear regression analysis of the final three plasma samples . clearance ( cl ) values were calculated using the following formula : cl 
 ( ml / min)=dose of iohexol / auc , where auc = a / a . the pcio values were then 
 calculated as follows : pcio 
 ( ml / min)=(0.990778cl)(0.001218cl ) , with the pcio values 
 standardized for body weight . measurement of blood pressure : blood pressure was measured non - invasively 
 by the oscillometric method using a hemomanometer ( bp100d , fukuda m - e kogyo co. , ltd . , 
 tokyo , japan ) according to the 2007 american college of veterinary internal medicine 
 guidelines . necropsy examination and histopathology : all cats were euthanized by 
 intravenous administration of sodium pentobarbital and potassium chloride on day 507 . histopathological examinations were performed by a veterinary pathologist ( machida ) who was 
 blinded to the treatment groups . a complete post - mortem examination was performed on each 
 cat immediately after euthanasia . tissue samples collected at necropsy were fixed in 10% 
 neutral buffered formalin and processed using routine methods for paraffin embedding . we 
 then stained 5-m thick sections with hematoxylin and eosin for light 
 microscopy . selected sections of cardiac tissue , including the septal and parietal valve 
 leaflets of the mitral valve and myocardia , were stained with masson s trichrome , periodic 
 acid - schiff , alcian blue ( ph 2.5 ) and toluidine blue . parameters were not normally distributed by kolmogorov - smirnov 
 analysis and were expressed as medians ( 25th and 75th percentiles ) . comparison between the 
 baseline parameters of both groups was performed using the mann - whitney u 
 test . changes in parameters measured after drug administration were evaluated by repeated 
 measures analysis of the variance with a split plot design . this test was conducted with the 
 observation day as the intra - subject factor and the drugs ( pimo and benazepril ) and animals 
 as the inter - subject factors . if p<0.05 was found for the observation 
 day and drug interactions in the analysis of variance , a post - hoc multiple comparison was 
 conducted using the mann as shown in table 1table 1.summary of characteristics at day 0 in both groupsacei grouppimo groupp valuebody weight ( kg)3.6 ( 2.6 , 4.2)3.1 ( 2.6 , 3.9)0.937age ( year)1.8 ( 1.8 , 1.8)1.8 ( 1.8 , 2.3)0.937heart rate ( bpm)154 ( 136 , 210)166 ( 162 , 180)0.588sbp ( mmhg)113 ( 110 , 134)139 ( 129 , 154)0.180dbp ( mmhg)67 ( 57 , 85)82 ( 75 , 84)0.380alb ( g / dl)2.1 ( 2.0 , 2.1)2.1 ( 2.1 , 2.2)0.310alt ( u / l)57.0 ( 51.8 , 69.8)82.0 ( 72.5 , 89.3)0.093bun ( mg / dl)20.6 ( 19.4 , 22.8)24.8 ( 22.5 , 25.4)0.093cre ( mg / dl)0.9 ( 0.8 , 1.0)0.9 ( 0.9 , 1.0)0.818na ( meq / l)156.0 ( 156.0 , 157.5)157.5 ( 157.0 , 158.8)0.132k ( meq / l)3.8 ( 3.6 , 4.0)3.7 ( 3.5 , 3.8)0.818cl ( meq / l)122.5 ( 121.3 , 123.8)123.0 ( 122.3 , 124.5)0.589pcio ( ml / min / kg)2.9 ( 2.7 , 3.2)2.8 ( 2.2 , 3.9)0.937laao1.4 ( 1.3 , 1.4)1.3 ( 1.2 , 1.3)0.485ivsd ( mm)0.4 ( 0.3 , 0.4)0.3 ( 0.3 , 0.4)0.132lvidd ( mm)1.6 ( 1.5 , 1.6)1.6 ( 1.2 , 1.7)0.818lvpwd ( mm)0.4 ( 0.4 , 0.4)0.3 ( 0.3 , 0.4)0.310fs(%)33.9 ( 33.2 , 38.3)37.6 ( 35.0 , 41.0)0.394aml ( mm)0.1 ( 0.1 , 0.1)0.1 ( 0.1 , 0.1)0.394pml ( mm)0.1 ( 0.1 , 0.1)0.1 ( 0.1 , 0.1)0.699values are presented as medians ( 25th and 75th percentile ) . abbreviations : pcio , 
 plasma iohexol clearance ; laao , left atrium to aortic root ratio ; ivsd , end - diastolic 
 interventricular septum thickness ; lvidd , end - diastolic left - ventricular internal 
 dimension ; lvpwd , end - diastolic left - ventricular posterior wall thickness ; fs , 
 fractional shortening ; aml , anterior mitral valve leaflet ; pml , posterior mitral valve 
 leaflet . , there were no significant differences in baseline parameters between the 
 groups ( p>0.05 ) . body weight , heart rate , and systolic and diastolic 
 blood pressures did not show significant changes during the 506-day study period , and there 
 were no significant differences between the groups ( p0.162 ; table 2table 2.cardiovascular measurements by day of treatment with pimobendan or 
 benazeprilday01650118202320409506body weight ( kg)acei group3.7 ( 2.7 , 4.2)3.7 ( 2.7 , 4.2)3.8 ( 2.6 , 4.2)3.8 ( 2.6 , 4.2)4.2 ( 3.1 , 4.6)4.3 ( 3.2 , 4.6)4.2 ( 3.3 , 4.3)4.4 ( 3.5 , 4.5)pimo group3.2 ( 2.6 , 4.0)3.2 ( 2.6 , 4.0)3.2 ( 2.5 , 4.1)3.2 ( 2.5 , 4.2)3.7 ( 2.8 , 4.7)3.7 ( 3.0 , 4.6)3.8 ( 2.9 , 4.6)3.9 ( 2.9 , 4.6)heart rate ( bpm)acei group155 ( 136 , 211)150 ( 139 , 174)161 ( 146 , 201)165 ( 139 , 179)np171 ( 153 , 177)169 ( 151 , 191)185 ( 157 , 196)pimo group166 ( 163 , 181)172 ( 138 , 188)163 ( 157 , 175)170 ( 159 , 177)np172 ( 170 , 180)177 ( 160 , 195)188 ( 163 , 200)sbp ( mmhg)acei group113 ( 111 , 134)110 ( 106 , 122)126 ( 123 , 137)131 ( 129 , 131)np130 ( 125 , 138)138 ( 127 , 143)139 ( 135 , 145)pimo group139 ( 130 , 154)133 ( 124 , 147)130 ( 126 , 142)141 ( 128 , 147)np122 ( 115 , 147)136 ( 128 , 143)141 ( 127 , 147)dbp ( mmhg)acei group67 ( 58 , 85)59 ( 55 , 72)66 ( 63 , 77)68 ( 65 , 76)np76 ( 62 , 80)72 ( 67 , 79)90 ( 86 , 93)pimo group82 ( 75 , 84)68 ( 63 , 79)68 ( 66 , 83)79 ( 76 , 84)np87 ( 77 , 90)80 ( 77 , 83)80 ( 69 , 95)values are presented as medians ( 25th and 75th percentile ) for body weight , heart 
 rate , and systolic and diastolic blood pressure ( sbp and dbp , respectively ) in both 
 groups before ( day 0 ) and at days 16 , 50 , 118 , 202 , 320 , 409 and 506 after drug 
 administration . no significant differences were observed for all parameters between 
 two groups ( p0.059 ) . ) . in addition , no significant differences were observed for any parameters 
 between the groups during the study ( p0.093 ; table 3table 3.hematocrit and biochemistry measurements by day of treatment with pimobendan or 
 benazeprilday01650118202320409506hematocrit ( % ) acei group36 ( 35 , 38)34 ( 32 , 38)34 ( 33 , 38)40 ( 36 , 42)37 ( 35 , 44)38 ( 38 , 40)35 ( 32 , 39)39 ( 36 , 42)pimo group38 ( 36 , 41)35 ( 34 , 38)36 ( 33 , 40)40 ( 38 , 41)37 ( 34 , 38)37 ( 32 , 41)33 ( 33 , 39)37 ( 35 , 40)total protein ( g / dl)acei group7.0 ( 6.5 , 7.2)7.3 ( 6.8 , 7.6)7.0 ( 6.7 , 7.3)6.7 ( 6.5 , 6.9)7.4 ( 7 , 7.4)7.4 ( 7.1 , 7.6)7.0 ( 6.7 , 7.1)7.3 ( 7.1 , 7.5)pimo group6.8 ( 6.7 , 6.8)7.1 ( 6.8 , 7.2)7.3 ( 7.0 , 7.3)6.5 ( 6.4 , 6.7)7.2 ( 7.0 , 7.4)7.1 ( 7.0 , 7.2)6.7 ( 6.5 , 6.8)7.1 ( 6.6 , 7.2)albumin ( g / dl)acei group2.1 ( 2.1 , 2.1)2.2 ( 2.1 , 2.2)2.2 ( 2.1 , 2.2)2.0 ( 1.9 , 2.2)2.2 ( 2.1 , 2.2)2.1 ( 2.0 , 2.1)2.1 ( 2.1 , 2.2)2.3 ( 2.2 , 2.4)pimo group2.1 ( 2.1 , 2.2)2.2 ( 2.2 , 2.3)2.2 ( 2.1 , 2.2)2.1 ( 2.1 , 2.2)2.2 ( 2.2 , 2.3)2.2 ( 2.1 , 2.3)2.2 ( 2.1 , 2.2)2.3 ( 2.3 , 2.4)bun ( mg / dl)acei group20.6 ( 19.4 , 22.8)26.7 ( 26.0 , 27.0)26.8 ( 25.4 , 29.3)24.4 ( 23.4 , 25.3)32.1 ( 28.7 , 32.3)23.8 ( 20.8 , 24.3)23.3 ( 21.4 , 26.5)21.8 ( 21.3 , 25.9)pimo group24.8 ( 22.5 , 25.4)28.3 ( 26.2 , 30.7)26.9 ( 26.6 , 28.5)25.5 ( 23.3 , 28.6)33.7 ( 30.9 , 36.9)26.7 ( 24.6 , 27.9)27.7 ( 24.3 , 30.4)23.9 ( 23.3 , 24.4)creatinine ( mg / dl)acei group0.9 ( 0.8 , 1.0)0.9 ( 0.8 , 1.0)1.0 ( 0.8 , 1.1)0.8 ( 0.7 , 0.8)0.9 ( 0.7 , 0.9)1.1 ( 0.9 , 1.1)1.0 ( 0.8 , 1.0)0.9 ( 0.8 , 0.9)pimo group0.9 ( 0.9 , 1.0)0.9 ( 0.8 , 0.9)0.9 ( 0.8 , 0.9)0.8 ( 0.8 , 0.9)0.8 ( 0.7 , 0.9)0.9 ( 0.9 , 1.0)0.8 ( 0.7 , 1.0)0.8 ( 0.8 , 0.9)sodium ( meq / l)acei group156 ( 156 , 158)155 ( 153 , 155)156 ( 154 , 157)153 ( 152 , 154)154 ( 153 , 155)154 ( 153 , 154)152 ( 151 , 153)148 ( 147 , 150)pimo group158 ( 157 , 159)155 ( 155 , 155)156 ( 155 , 157)153 ( 153 , 154)156 ( 154 , 156)156 ( 153 , 158)154 ( 153 , 154)149 ( 148 , 151)potassium ( meq / l)acei group3.8 ( 3.6 , 4.0)3.9 ( 3.7 , 3.9)3.9 ( 3.7 , 3.9)4.5 ( 4.2 , 5.1)4.0 ( 4.0 , 4.0)4.1 ( 4.0 , 4.3)3.8 ( 3.5 , 3.9)4.3 ( 4.2 , 4.6)pimo group3.7 ( 3.5 , 3.8)3.9 ( 3.7 , 4.3)4.3 ( 4.1 , 4.6)4.3 ( 4.1 , 4.5)3.8 ( 3.7 , 3.8)3.9 ( 3.6 , 4.1)3.7 ( 3.6 , 3.8)4.1 ( 4.0 , 4.3)values are presented as medians ( 25th and 75th percentile ) for hematocrit and 
 biochemistry measurements in both groups before ( day 0 ) and at days 16 , 50 , 118 , 202 , 
 320 , 409 and 506 after drug administration . no significant differences were observed 
 for all parameters between the two groups ( p0.093 ) . abbreviations : 
 acei , angiotensin - converting enzyme inhibitor ; pimo , pimobendan . ) . specifically , we did not detect any cardiac murmurs , and the hematocrit and 
 serum biochemical parameters remained unchanged and comparable between groups . however , 
 although pcio remained stable for both groups ( p0.200 ) , it was 
 significantly lower at day 506 than at baseline in the acei group 
 ( p<0.05 ; table 
 4table 4.plasma iohexol clearance by day of treatment with pimobendan or 
 benazeprilpcio ( ml / min / kg)day0125323506acei group2.9 ( 2.7 , 3.2)2.4 ( 2.2 , 2.9)2.3 ( 2.1 , 2.9)2.1 ( 2.0 , 2.2)pimo group2.8 ( 2.2 , 3.9)2.8 ( 2.4 , 3.1)2.5 ( 2.1 , 2.8)2.3 ( 2.1 , 2.6)values are presented as medians ( 25th and 75th percentile ) for plasma iohexol 
 clearance ( pcio ) values in the two groups before drug administration ( day 0 ) , and at 
 days 125,323 and 506 after drug administration . no significant differences were 
 observed for pcio value between the two groups ( p0.200 ) . abbreviations : acei , angiotensin - converting enzyme inhibitor ; pimo , pimobendan . ) . there were no significant changes in echocardiographic measurements during 
 the treatment period ( table 5table 5.echocardiography measurements and the radiographic vertebral heart score by day 
 of treatment with pimobendan or benazeprilday01650118202320409506laao ( cm)acei group1.37 ( 1.34 , 1.39)1.35 ( 1.28 , 1.43)1.37 ( 1.24 , 1.45)1.43 ( 1.27 , 1.5)1.47 ( 1.28 , 1.6)1.24 ( 1.19 , 1.44)1.16 ( 1.1 , 1.23)1.15 ( 1.12 , 1.17)pimo group1.26 ( 1.23 , 1.33)1.42 ( 1.36 , 1.5)1.31 ( 1.22 , 1.5)1.3 ( 1.21 , 1.32)1.34 ( 1.11 , 1.4)1.37 ( 1.33 , 1.42)1.37 ( 1.24 , 1.39)1.15 ( 1.09 , 1.19)ivsd ( cm)acei group0.37 ( 0.34 , 0.44)0.36 ( 0.34 , 0.38)0.44 ( 0.39 , 0.49)0.36 ( 0.34 , 0.45)0.4 ( 0.39 , 0.43)0.39 ( 0.38 , 0.39)0.43 ( 0.43 , 0.44)0.41 ( 0.38 , 0.44)pimo group0.31 ( 0.3 , 0.35)0.35 ( 0.34 , 0.37)0.42 ( 0.38 , 0.43)0.34 ( 0.3 , 0.37)0.38 ( 0.33 , 0.43)0.35 ( 0.34 , 0.38)0.44 ( 0.42 , 0.46)0.43 ( 0.36 , 0.46)lvidd ( cm)acei group1.57 ( 1.52 , 1.58)1.7 ( 1.49 , 1.84)1.56 ( 1.43 , 1.76)1.74 ( 1.47 , 1.75)1.67 ( 1.54 , 1.79)1.55 ( 1.48 , 1.66)1.62 ( 1.48 , 1.7)1.67 ( 1.59 , 1.74)pimo group1.56 ( 1.25 , 1.67)1.62 ( 1.48 , 1.68)1.5 ( 1.37 , 1.68)1.61 ( 1.35 , 1.66)1.58 ( 1.5 , 1.75)1.52 ( 1.33 , 1.72)1.52 ( 1.44 , 1.58)1.46 ( 1.32 , 1.58)lvpwd ( cm)acei group0.38 ( 0.36 , 0.41)0.34 ( 0.33 , 0.37)0.4 ( 0.35 , 0.42)0.38 ( 0.33 , 0.41)0.4 ( 0.36 , 0.41)0.41 ( 0.38 , 0.42)0.42 ( 0.37 , 0.47)0.43 ( 0.42 , 0.44)pimo group0.35 ( 0.32 , 0.37)0.35 ( 0.32 , 0.44)0.4 ( 0.35 , 0.46)0.34 ( 0.33 , 0.37)0.38 ( 0.37 , 0.41)0.4 ( 0.36 , 0.42)0.43 ( 0.39 , 0.47)0.4 ( 0.4 , 0.47)fs ( % ) acei group33.9 ( 33.2 , 38.3)36 ( 35.4 , 36.9)40.8 ( 37.9 , 43.8)34.4 ( 31.3 , 39)43.4 ( 39.7 , 46.4)41.4 ( 36.3 , 46.6)44.5 ( 39.4 , 47.9)43.9 ( 42.7 , 45.2)pimo group37.6 ( 35 , 41)32.5 ( 30.4 , 38.5)43.7 ( 36.1 , 52.4)37.8 ( 29.3 , 39.2)33.9 ( 28.9 , 41.9)40.4 ( 32 , 47.5)42.7 ( 38.9 , 47.4)42.7 ( 35.8 , 48.3)aml ( cm)acei group0.1 ( 0.09 , 0.12)0.09 ( 0.08 , 0.09)0.16 ( 0.14 , 0.19)0.14 ( 0.11 , 0.15)0.13 ( 0.1 , 0.15)0.12 ( 0.1 , 0.13)0.11 ( 0.1 , 0.11)0.14 ( 0.09 , 0.16)pimo group0.09 ( 0.08 , 0.1)0.1 ( 0.09 , 0.1)0.13 ( 0.1 , 0.15)0.14 ( 0.12 , 0.15)0.14 ( 0.12 , 0.16)0.13 ( 0.1 , 0.16)0.11 ( 0.08 , 0.12)0.1 ( 0.09 , 0.13)pml ( cm)acei group0.13 ( 0.1 , 0.14)0.1 ( 0.09 , 0.1)0.13 ( 0.11 , 0.14)0.14 ( 0.12 , 0.14)0.1 ( 0.08 , 0.11)0.1 ( 0.09 , 0.11)0.12 ( 0.11 , 0.13)0.12 ( 0.09 , 0.14)pimo group0.12 ( 0.11 , 0.12)0.1 ( 0.09 , 0.11)0.12 ( 0.1 , 0.13)0.14 ( 0.12 , 0.14)0.16 ( 0.12 , 0.19)0.11 ( 0.11 , 0.13)0.11 ( 0.1 , 0.14)0.11 ( 0.09 , 0.16)values are presented as medians ( 25th and 75th percentile ) for echocardiography 
 measurements and the radiographic vertebral heart score in both groups before ( day 0 ) 
 and at days 16 , 50 , 118 , 202 , 320 , 409 and 506 after drug administration . abbreviations : acei , angiotensin - converting enzyme inhibitor ; pimo , pimobendan ; laao , 
 left atrium to aorta ratio ; ivsd , end - diastolic interventricular septum thickness ; 
 lvfwd , end - diastolic left - ventricular free - wall thickness ; lvidd , end - diastolic 
 left - ventricular internal dimension ; fs , fractional shortening ; aml , anterior mitral 
 valve leaflet ; pml , posterior mitral valve leaflet ; vhs , vertebral heart score . ) , and no significant differences were observed between the two treatment 
 groups ( p0.148 ) . abbreviations : pcio , 
 plasma iohexol clearance ; laao , left atrium to aortic root ratio ; ivsd , end - diastolic 
 interventricular septum thickness ; lvidd , end - diastolic left - ventricular internal 
 dimension ; lvpwd , end - diastolic left - ventricular posterior wall thickness ; fs , 
 fractional shortening ; aml , anterior mitral valve leaflet ; pml , posterior mitral valve 
 leaflet . values are presented as medians ( 25th and 75th percentile ) for body weight , heart 
 rate , and systolic and diastolic blood pressure ( sbp and dbp , respectively ) in both 
 groups before ( day 0 ) and at days 16 , 50 , 118 , 202 , 320 , 409 and 506 after drug 
 administration . no significant differences were observed for all parameters between 
 two groups ( p0.059 ) . values are presented as medians ( 25th and 75th percentile ) for hematocrit and 
 biochemistry measurements in both groups before ( day 0 ) and at days 16 , 50 , 118 , 202 , 
 320 , 409 and 506 after drug administration . no significant differences were observed 
 for all parameters between the two groups ( p0.093 ) . values are presented as medians ( 25th and 75th percentile ) for plasma iohexol 
 clearance ( pcio ) values in the two groups before drug administration ( day 0 ) , and at 
 days 125,323 and 506 after drug administration . no significant differences were 
 observed for pcio value between the two groups ( p0.200 ) . values are presented as medians ( 25th and 75th percentile ) for echocardiography 
 measurements and the radiographic vertebral heart score in both groups before ( day 0 ) 
 and at days 16 , 50 , 118 , 202 , 320 , 409 and 506 after drug administration . abbreviations : acei , angiotensin - converting enzyme inhibitor ; pimo , pimobendan ; laao , 
 left atrium to aorta ratio ; ivsd , end - diastolic interventricular septum thickness ; 
 lvfwd , end - diastolic left - ventricular free - wall thickness ; lvidd , end - diastolic 
 left - ventricular internal dimension ; fs , fractional shortening ; aml , anterior mitral 
 valve leaflet ; pml , posterior mitral valve leaflet ; vhs , vertebral heart score . the septal and parietal valve 
 leaflets of the mitral valve were slightly thickened in three cats in the acei group and two 
 cats in the pimo group ( fig 1fig . 1.macroscopic and histological findings of the mitral valves from cats administered 
 either pimobendan ( a & b ) or benazepril ( c & d ) . ) . the thickened valves were opaque and white , but the surface was smooth and 
 glistening with no evidence of thrombus formation . macroscopic and histological findings of the mitral valves from cats administered 
 either pimobendan ( a & b ) or benazepril ( c & d ) . all cats had mild - to - moderate histopathological changes in both mitral valve leaflets , with 
 the distal halves being more affected than the proximal halves . the main pathological 
 condition was deposition of acid mucopolysaccharides , primarily within the spongiosa layer 
 of the valve leaflet ( fig 1 ) . valvular fibrosis 
 was also present , although it was not the predominant histological feature , and inflammatory 
 infiltrates were absent . therefore , the spongiosa layer was expanded , with focal disruption 
 of the fibrosa by mucopolysaccharide - rich spongiosa , although there were no apparent 
 qualitative or quantitative differences between the groups with respect to the development 
 of these valvular lesions . no other valvular , vascular or myocardial lesions were detected 
 in either of the groups , and no histopathological changes were detected in other visceral 
 organs . this study demonstrates that long - term administration of pimo did not produce significant 
 pathological cardiac lesions / adverse effects in healthy cats , which suggests that pimo might 
 not have the same adverse effects in cats as those reported in dogs . however , although no other valvular , vascular or myocardial lesions 
 were detected , all cats did develop mild - to - moderate myxomatous mitral valve degeneration . the lesions of the mitral valve leaflets included deposition of acid mucopolysaccharides , 
 primarily within the spongiosa layer of the valve leaflet , and valvular fibrosis . all cats 
 in both groups had these changes , and the magnitude of change was equivalent between the two 
 groups . indeed , 
 neither pimo nor benazepril showed any tendency toward a change in echocardiography 
 measurements or gfr during the study , making it unlikely that these caused the myxomatous 
 mitral valve degeneration . in an early study of the incidence of cardiovascular disease in 
 cats , of the 202 cats examined at necropsy , 12 ( 5.9% ) had mitral valve lesions ( including 
 endocarditis , fibrosis and stenosis ) and 17 ( 8.4% ) had myocardial lesions ( including 
 hypertrophy , hemorrhage , infarct and fibrosis ) . in our cats , the prevalence of mitral valve degeneration was much higher , but no cat had 
 clinical evidence of mitral regurgitation during the study period . these pathological mitral 
 valve changes were only slight compared with the degree of myxomatous mitral valve 
 degeneration previously observed in dogs . because no studies have been reported on the 
 development of mitral valve changes with age in healthy cats , it is unclear whether the 
 myxomatous mitral valve degeneration seen in our cats occurred spontaneously , as a natural 
 consequence of aging . myocardial lesions 
 were not detected in cats treated with either benazepril or pimo . in a previous case report 
 of two dogs treated with pimo however , these 
 dogs were treated with pimo without any prior echocardiographic examination . excluding this 
 case report , no adverse effect has been demonstrated conclusively on the myocardia following 
 treatment with pimo in cats , dogs or humans . the adverse effect of pimo on mitral valves in dogs may be caused by increased cardiac 
 contraction , although a direct effect on the valves can not be excluded . this effect has not 
 been reported in humans , suggesting that there may be species specificity in the 
 pharmacological action of pimo . it has been reported that , even with the same dose of pimo 
 administered to cats and dogs , the plasma elimination half - life ( 1.3  0.2 hr and 0.5 hr , 
 respectively ) and cmax ( 34.5  6.59 ng / ml and 3.09  0.76 
 ng / ml , respectively ) differed considerably . in addition , the elimination half - life and effect on 
 cardiac contractility of pimo are simply not associated in dogs . thus , the tissue concentration and hemodynamic effects of pimo might 
 be different in cats . in cats with hypertrophic cardiomyopathy , it has been shown that the 
 addition of pimo to the standard treatment for congestive heart failure can prolong survival 
 times . these cats received a median dose of 0.49 
 mg / kg / day ( 25th to 75th percentile , 0.400.67 mg / kg / day ) of pimo . the dosage used in our 
 study , which was 0.25 mg / kg twice daily , could therefore be considered sufficient for 
 clinical efficacy in improving cardiac function in cats . however , there was no difference in 
 cardiac changes between the cats administered pimo ( 0.25 mg / kg twice daily ) and benazepril . it is unlikely that pimo at 0.25 mg / kg twice daily has a direct cardiac effect in healthy 
 cats . the present study has shown only that pimo with clinically effective dose for cats may 
 not have cardiac adverse effect on cats . extra - cardiac adverse effects of pimo in cats 
 include salivation , vomiting , agitation , anorexia and constipation [ 7 , 9 , 13 ] . however , no such adverse effects were evident in any cat in this 
 study . in this study , there were no significant changes in heart rate , blood pressure or gfr after 
 administration of pimo , suggesting that pimo does not influence the hemodynamics of healthy 
 cats . in dogs with experimental mitral insufficiency , kanno et al . reported 
 that pimo significantly increased renal blood flow , but not gfr . furthermore , research has shown that pimo did not alter renal 
 function in healthy dogs   and that gfr in dogs 
 receiving pimo was not significantly different from gfr in dogs receiving benazepril . first , because the optimal dose of pimo is unknown for 
 cats , we used the same dose of pimo as that used to treat dogs . in all prior studies into 
 the use of pimo in cats , the dosage used was 0.25 mg / kg q12 hr [ 7 , 9 , 13 ] . given that the plasma elimination half - life and cmax differ 
 considerably between cats and dogs , the required 
 dose and frequency of administration of pimo in cats may differ from those in dogs . despite 
 all previous studies on pimo for cats selected the dosage based on that previously used 
 dosages for dogs [ 7 , 9 , 13 , 16 ] , no clinical adverse effects were reported . in addition , one study showed that 
 using the same dose of pimo in cats as in dogs prolonged the survival time in cats with 
 hypertrophic cardiomyopathy . these results 
 suggest that the use of pimo in cats at the same dosage as that used in dogs does not 
 produce a clinical disadvantage . other methods  such as the ejection fraction  may be required to 
 observe the true effect of pimo on cardiac contraction . in addition , pimo has been shown to 
 accelerate left - ventricular isovolumetric relaxation and to improve distensibility in 
 conscious dogs with tachycardia - induced heart failure . in our study , evaluation of cardiac relaxation , including the e / a ratio and 
 isovolumetric relaxation time , was not performed . thus , the cardiac effects of pimo on 
 echocardiography might not have been accurately assessed . a third limitation is that only 
 healthy cats were used , which contrasts with a prior study in dogs . however , no study has evaluated the adverse effects of pimo on the 
 mitral valves of healthy dogs . mitral regurgitation in cats is often caused by systolic 
 anterior motion associated with cardiomyopathy . a further study is justified to evaluate the 
 possible effects of pimo on mitral regurgitation in cats with cardiomyopathy . in conclusion , neither pimo nor benazepril administration was associated with cardiac 
 lesions in healthy cats , suggesting that both agents can be used in cats without the risk of 
 cardiotoxicity . however , future studies are needed to examine the adverse cardiac effects of 
 pimo in cats with pre - existing heart disease . in addition , there is a need to examine 
 age - related alterations in the hearts of healthy cats .
pimobendan ( pimo ) can cause adverse effects , such as mitral valve degeneration , in dogs ; 
 however , it is unclear whether these effects occur in cats . therefore , we aimed to 
 determine whether pimo or benazepril produces adverse cardiac effects in healthy cats . 
 this was a blinded , randomized , prospective parallel study . 
 twelve cats were randomly 
 divided into two groups of six cats , namely , an angiotensin - converting - enzyme inhibitor 
 group that received benazepril and a pimo group . 
 cats were administered their respective 
 treatments for 506 days , and we evaluated cardiac parameters , blood biochemistry and 
 glomerular filtration rates during that time . at the end of the trial , 
 the cats were 
 euthanized , and histopathological examinations were performed by a pathologist who was 
 blinded to the treatment groups . 
 no significant changes were observed in any of the 
 parameters measured in either of the groups . in particular , no significant cardiac lesions 
 were observed in either of the groups . in healthy cats , 
 neither pimo nor benazepril 
 appears to cause cardiac lesions , but future studies are needed to examine the effects of 
 pimo in cats with heart disease .