rmplete atrioven_)athol 2006;.135:

tpathy in appar_

j0 cases (1979_

tr- f,

-)-.f-f))IttIt,ttt,t,ttttIttttttJ

J

)J

J

J

;

----

Canine DegenerativeMyxomatous M itralValve Disease:Natural History,Clinical Presentationand TherapyMichele Borgarelli, DMV, phDu.*, Jens Haggstrom, ovr,r, pr,ob

Chronic degenerative mitral valve disease as a result of myxomatoi..lil r,4c){li ,--ratrur,(MMVD)isthemostcommonacquiredcardiovasculardiseaseinthedor:,,-:,,:ii,rir-r.-75o/o af all cardiovascular disease in this species.l-3 Although the e:,1 . !(lilcommonly diagnosed in small-breed dogs, it can also occur in large,.i,r .., ' , . .1

The prevalence of the disease has been correlated with the age r.li ,,.: , -:.,.:::i rrsome breeds, such as the cavalier King charles spaniel, the prevaleni€ i*;: ,i . i .li$e;,:$i.:in animals older than 10 years is greater than 90%.Fs Males are:,,ir,:, , .ri:.,i ir,develop the disease at a younger age than females, which means th::r. .,:, . . .,_ ,. r ri. E:.

at a given age is higher in males than in females.2,3

NATURAL HISTORY

Although MMVD is a common cause of left-sided congestive [s6r., ],_:;,,

dogs, there are few studies documenting its naturat history, and nir., , . , :

data on survival for the affected dogs come from clinical trials ri ,,.:studies.lc16 The disease is characterized by a long preclinical r'::i,,i l

dogs affected die for other reasons and do not progress to CHfr. , r

including 558 dogs affected by MMVD at different stages of CHF, ;.,of asymptomatic dogs were alive at the end of the follow_up per.li,,(Fig' 1).10 ln another recent study, 82o/o of asymptomatic dogs were stili ,r.:i,

''. ilr i:l r

, sti :,..,1 70';':

- :-i year.:itomatii

a Department of Clinical Sciences, Kansas state university, A-106 Mosier irr,:;:,K5 66s05, uSAb Departmentof clinical sciences,swedishUniversityof Agricultural sciences i-i,,r .i.5E-75r07, Uppsala, Sweden* Corresponding author.E-ma i I ad d ress: mborgarelli@gmail.com

Vet Clin Small Anim 40 (2010) 651-663doi: l 0,1 01 6/j.cvsm.201 0.03.008 velgy:r;i,..t., ,r:r_ j,L L:r;,0195-56i6/10/$ -see front matter o 2010 Ersevier rnc. All rights reserved.

i2 Borgarelli & Haggstrom

Fig' 1' Survival in 558 dogs with MMVD by heart failure classification according to thelsAcHc. More than 600/o of class I dogs were still alive at the end of the 70 months of obser-vation period. Class ISACHC 2 dogs have 28 months median survival time. Class ISACHC 3 hada median survival time of 9 months. (From Borgarelli M, savarino p, crosara s, et al. survivalcharacteristics and prognostic variables of dogs with mitral regurgitation attributable tomyxomatous valve disease. J vet rntern Med 200g;22:123; with fiermission.)

i\-

differences in inclil4

that dogs with nrclsurvival with medicp

\_

DIAGNOSIS 4\-

Mitral valve requrc-the left cardiac apg_tory finding is entr-murmur has beerx

Lmore severe caseshemithorax as a c\_

patients, the cona-the murmur may rl\:be because largeffibrillation and m5,9-the murmur. ln thd:the oresence of an

I\

heard using the C;-mitral valve prolappostulated to be.-'Icieceleration of bic*

Although the p'r-suggestive of the--.\-nosts ts requtreo :

'I

to mitral regurgili1.College of Veter'i:that echocardiocl:

'4the cause of thaenlargement in c:of MMVD include\is characteriz"" aieaflets from thE;-that the right pa:--tifu the Dresenca-tMVP is a right pa'-(Fig. 38). ln pecs-

,4tP4\-\F4

t,4a

-1a2-\P-\>1

Fig. 2. Left apic"-irregular mrtra; ,r-

?4

at 12 months from inclusion in the study.l6 A study aimecl at evaluating the efficacy oftreatment witlr enaraprir, an angiotensin-converting enzyme inhibitor tlcg-r), in deLy-ing the onset of hearl failure in asymptomatic dogs showed a median time free of cHFof 851 days for the treated group and 778 days for the placebo group. i T Another studywith the same aim but including only cavalier King Charles splniels reached similarresults.rl These data provide some evidence that asymptomatic MMVD is a relativelybenign condition similar to what has been repofted in people.

For dogs that progress to cHF, survivar time can be related to severar factorsincluding owner compliance in providing adequate care, treatment, cardiovascularcomplications such as pulmonary hyperlension or rupture of chordae tendinae, andthe presence of other concomitant diseases. ln our study of survival in MMVD, dogswith moderate or severe CHF (classes 2 and 3 according to the lnternational SmallAnimal Cardiac Health Council [S_ACHC] classification) hJd median survival times ofQ3 and 9 months, respectively.l' Estimates of survival time in cHF ";r;;;-tMMVD can also be inferred from the existing clinical trial data. The Long-Term lnrres-tigation of Veterinary Enalapril (LIVE) and BENazepril in canine Heart Disease (BENCH)trials compared enaraprir and benazeprir; respectivery, with pracebo in canine patientswith hearl failure caused by either MMVD or dirated cardiomyopathy. More recenry,QUEST was designed to compare the efficacy of pimobendan to benazeprir in dogsreceiving background therapy for furosemide with or without digoxin; heart failurecaused by MMVD was the primary inclusion criterion. ln the eUEdT triat, the medianlurvival time for ail dogs to reach the primary end point represented by sudden cardiacdeath, euthanasia as a consequence of the cardiac disease, or treatment fairure, wasabout 6 months.18 survival time was similar for the group of dogs in LlvE that weretreated with enaraprir.l2 rn the BENCH study the mean survivar time for dogs receivingbenazepril was about 14 months.13 Differences in these studies can be related to

on according to the'70 months of obser_e. Class ISACHC 3 had,sara 5, et al. Survivalltion attributable to;ion.)

iting the efficacy ofrr (ACE-I), in detay_an time free of CHF.tp.17 Another studyels reached similaiIMVD is a relatively

to several factors)nt, cardiovascularrdae tendinae, andual in MMVD, dogsInternational Smallln sulvival times ofr CHF caused bV

' Long-Term lnves_t Disease (BENCH)) tn canine patients

lhy. Vor" recentiy,oenazepril in dogsloxin; heart failureiT trial, the medianby sudden cardiac

atment failure, was; in LIVE that were, for dogs receivingcan be related to

Myxomatous Mitral Valve Disea-se

differences in inclusion.criteria and end points. The results of these stu<lies oirr:1{r,;,that dogs with moderate to severe cHF caused by MMVD can have r€rativeiv !r_.i:r;s.urvival with medicar management - vr rrrryr v s var | | rdv

DIAGNOSIS

Mitral valve regurgitatio.n results in a systolic murmur that generally is heard ir"i:.i. ,.,.,,, ,the left cardiac apex. The diagnosis oi vvvo can be suspected when this auscijl;:r.tory finding is encountered in a patient or lpicar signarment. TJre intensity of ,-remurmur has been -correrated with the ""uuiity

of nl]*rrrvo in "o*" studies.1s,Zo ir.:more severe cases, the murmur radiates toward the reft neart oase *l""ii

" ,.,r1,,hemithorax as a consequence of reft atriar and ventricurar enrargement and in somepatients, the concomitant presence of tricuspio regurgitation. in iuis"-or"ud dogs-rhe rnurmur may not correlate with the severity

"t t|u oi"l""".u ft,i"iirur"nce migtrtbe because rarse-breed dogs affected ov rrrH,l'vo ;;r;;;;;"nry'i[r"n, with atria,fibrillation and myocardial failure; both thlse londitions can influence the intensity r.,r.the murmur' rn the very earry stage ot tne ollase the onry auscurtatory finding mayr ;-,r.the presence of a midsystolic crick.2r rnis souno is often interm;tt"ni uno may be ililrrheard using the diaphragm,of the stetho""op". lt is considered a reliable indicator ofmitral.valve prolapse (MVP) in people. ftre'oiigin of the midsystolic click has {:+r,rrrpostulated to be caused by the tensing of redundant chordae tenoina" arid rt,,S_;:rdeceleration of brood against the leafletJ at maximum prorapse into the reft atrium.1,:,Although the presence of a systoric reft apicar murmur in a typicai ureeo is strongrysuggestive of the presence of MMVD, echocardiographic

"ontir.ution of the diag.nosis is required to exclude the presence oitt'ur. cardiovascular diseases leadinrito mitral regurgitation, such as mitralvalve dysplasia. fn" r"""ntf' p";ffi;;#il::college of Veterinary rnternar Medicine tnivirw consensus statement recommendr-ithat echocardiography shourd be performed io un.*u,. specific questions regardingthe cause of the murmur of mitrar rugrrgit"tion and presence of cardiac chambeienlargement in dogs with suspecteo rrrr"rrlvb.idrhe echocardiographic characteristicsof MMVD incrude prorapse orthickening of i or both mitrar *r,i" r"uri"t" iFig. 2). MVpis characterized by an aflgrmar systoiic oispiacement or bowing of the mitrar varvrleaflets from the reft ventricre toward ttre teilatrium. rn dogs, soir. siroies suggesithat the right parasternar 4-chambet, rong u"i" ui"* is the gord standard view to iden-tify the presence of MVP, (Fig. 34.2; tn 6;;", the gotd slanoarJ uiu* *o reccgn!,:r:MVP is a right parasternal long axis view'trrai-ln"rro"" the left ventricular outflow trar-,i(Fig. 3B). ln peopre, the mitraivarve has u .'JJI" shape and ,.etiance on other image

The arrows indicate the thick itn.j

\-

\-'4

atrial size was 1 of tfMMVD.IB L

TheACVIM conseurMMVD to assess theY

Iwhen the patient is-help in diagnosing ccr-disease or lung tunl:'-lhoracrc raolograpL!toring dogs with M!-atrial size has higltvr.rentricular size in c-\-the hea.rt size and iqg,

\-CLINICAL PRESENT/4

L

MMVD is a chronic lremain comPletelY s.edema. The authoru-a staging system tfthis schema, dogs;,risk factors for the r-the concept of Pat''-have a heart disea,Ft

MMVD including thgof this stage shotf-screening prograrn\cf developing the -are considered: the-ence of CHF. :The Asymptomati*.

This category inclLft'.ence. Ints qroup'\_

Table,,1

Clairif icittjqn.syste-\-Defitr-

-L

Doqs-"dr-

Stage A

Stage Bl Dog:ra$

1Stage 82 Dogr_

raL(iq-

Stage C DogFr"-iY-

,ifStage D Dogf,,i

--Adapted from Atkins-canine chronic valvuF

Borgarelli & Haggstrom

Fig. 3. MVP in 2 dogs. (A) Right parasternal 4-chamber view. The anterior mitral valve leafletappears displaced toward the left atrium. (8) Right parasternal long axis view. There is

a mild prolapse of the mid portion of the anterior mitral valve leaflet with the parachuteappearance of the valve.

planes, such as the apical view, can overestimate the prevalence of MVP.25 ln dogs,the mitral valve can have 1 of 2 different annular geometries, either circular or elliptical,and this could influence the echocardiographic estimation of the MVP (Borgarelli,personal communication, ACVIM Forum, Montreal, 2009). According to these data,we suggest that th_e presence of MVP in dogs should be confirmed in at least 2 echo-cardiographic views.

Echocardiography can also provide important information concerning the severityof the disease, such as the degree of left atrial and left ventricular enlargement, thepresence of systolic or diastolic dysfunction and the diagnosis of pulmonary hypeften-liop.z6-zs Some echocardiographic variables may be useful to identify individuals atincreased risk of progression of the disease. Among these variables, left atrial enlarge-ment seems to represent the most reliable independent indicator. ln our study, the riskof death from cardiac disease for dogs with a left atrium/aorlic root ratio exceeding 1.7was 2.1 times that of dogs with smaller atria (Fig. 4).1o Also, in the QUEST study, left

I{.R. = 2.1

< 1 .7 p< o-oool

> 1.7

Fig. 4. Survival in 558 dogs with MMVD with a left atrium to aortic root ratio (LalAo) lessthan 1.7 and in dogs with a LAIAo greaterthan 1.7. Dogs without left atrial enlargementhave a significantly longer survival time. OR, odds ratio.

eo

mitral valve leafletrxis view. There isrith the parachute

MVp.25 In dogs,cular or elliptical,MVP (Borgarefii,rg to these data,'l at least 2 echo_

ning the severitylnlargement, the1onary hyperten_:ify individuals ateft atrial enlarge-,ur study, the risk:io exceeding 1.7TUEST study, left

ratio (La/Ao) lesstrial enlargement

JL-,L:JL:,E"vr):.vrrr):.v.v.J;,v,v.);.v,v.)-.);,);,);.l-ul--E),-.,-J:):l:):):):):):V):VJ:):VVV.Vv

Myxomatous Mitral Vaive [Jisear."

atrial size was '1 of the independent predictors of outcome in dogs wilr sy;-;-rp,rr,r. ,*,r ;

MMVD.18The ACVIM consensus statement recommends thoracic radiography for ail dogs vuittr

MMVD to assess the hemodynamic significance of the murmu.. ui.o io tutuin :r h:r::eiii,.,,whel th9 patient is asymptomatic.23 careful evaluation of thoracic radiogi"anl.rs r:ryhelp in diagnosing concomitant primary respiratory diseases, such

"" tru;l;-;;,,-,; . , ,,,.,disease or lung tumors that may be the cause for the clinicar signs, sucrr e.s ,:..,.,ii.ji.i

Thoracic radiographs, together with physical examination, are also essential f rjr f r ,r :; ;r-toring dogs with MMVD. A recent study shows that radiographic assessmerrl i,i *,ilatrial size has higher interobserver agreement compared with assessmeilr . : ,. ,

ventricular size in dogs with MMVD, and thgt left atrial size is most useful to assc$:lthe heart size and indirectry, the severity, of mitrar regurgitation on radiographs.:3r

CLINICAL PRESENTATION AND TREATMENT

MMVD is a chronic disease in which the clinical presentation is variable; son-xe i.:rir i ;..:r.1. .

remain completely asymptomatic, whereas others develop life-threateninrl pr-,tr,r :r rr,r riedema' The authors of the ACVIM consensus statement proposed a moriifioi:iin:r, 1ia staging system that has been used to classify human patients with heaft tailur e. irrthis schema, dogs are placed in 1 of 4 categories according to clinical stafr.rr,i ;,tirr-irisk factors for the devetopment of MMVD gaUfe 1).23 This

"L."iti"rti* ;;;;;,..fr;_.the concept of patients at risk for developing heaft disease but that currenilir dci norhave a hearl disease. rnc-ruded in_this category are dogs of breeds predisposed toMMVD including the cavalier King Charles spaniLt and the dachshund. The rec,:rjrritioriof this stage shourd encourage the veterinary community to deverop appr*priatescreening programs antJ adopt nleasures intenoeo to reduce the risk for an anjmalof develcping ttle disease. For the purpose of this review, 3 categories of parients:are considered: the asymptomatic, the coughing, and the dog with d-ocumented pres-ence of CHF.

655

The Asymptomatic Dog (Stage B ACVIM Consensus)This category incrudes dogs with MMVD that have not deveroped cHF. ln;,,.;i;;,;,,ence, this group represents most dogs presenting with MMVD. Tr"-,,,;,,,,,,u,,,

DefinitionStage A Dogs at risk for deveroping MMVD that have no ioentitiaote cardiac struituJ

disorder (ie, Cavalibr King Charles spaniel, dachsunds)Stage B i

Stage 82 Dogs with MMVD that have never developed clinical signs but have

,*',"^g:tl:: :r echoca rdiogra ph ic evidence ot card ia"c remodet in gie. left-sided heart

Adapted from Atkins c, Bonagura J, Ettinger 5, et al. Guidelines for the diagnosis arrci tr r, ,, rirr.canine chronic valvurar heart disease. J vlt rntern vted zoog;zo:t t+z-so; ,iritn fern?issron.

Dogs with MMVD that have never developed clinical signs and have noradiographic or echocardiographic evidence of cardiac remoderind

Borgarelli & Haggstrom

suoqested database for these dogs includes a physical examination. and thoracic

#.ffiil'rfnl*rJ'ography is recommended to confirm the diagnosis' The

AcvlM consensus staterieni includes the suggestion that asymptomatic dogs can

be further subdivided: jog; *ithout raoiograptric or echocardiographic evidence of

cardiac enlargement u'" ii 'tug"

81 and dogs with left atrial and ventricular enlarge-

ment are in stage 82. This subilassitication emphasizes that asymptomatic dogs are

a nonhomogen"ou' g'o'*p tnat inctuOes paiients with very mild disease and others

thathavenotdevelopedcHFbuthavemoreadvanceddiseaseandareatriskforprogressiontoCHF'fh"n"t"'og"neityofthisgroupofdogsmaybeanexplanationfor the conflicting data con"erniig neurohormo-nal activation presented in the veteri-

nary literature for dogs *ltfi "ty*pt"matic Ii4l''lVD'31-36 The recognition that asymp-

tomaticdogsareaheterogeneousgroup,-rnderlinestheimportanceofidentifyingrisk factors for the o"*ropi-l"nt ot cHr. P.roposed risk factors for death or progres-

sion of MMVD ln"luoJ'lg"' gender' intensity of heart murmur" degree of valvg

pr_olapse, severity of uJu"j"riJns, degree of mitral valve regurgitation, and left atrial

enlarqemen!.o'c'-"' 4 'l""ni't'oy't'ggests

that a change in radiographic or echocar-

diographiccardiacOimensionsoO'"t"Obetween2difierenttimepointsmaybea mo,re powerlul preollior Lioutcome than the absolute value of the measurement'40

ln people, Oruin nut'i-ui"t'rc peptide (BNP) has been showed not only to be an'excel-

lent biomarke, to,. iountiiying ihJpr".ln"e of cHF but also for identifying patients that

are at high rist< of cuio'r i""u11-l.+r-+s A recent study conducted on 72 asymptomatic

dogs with MMDV .no*uo, in ugreement with previbus studies,3l that the N-terminal

fragment of proBNP tl'ii:pt"SNFl is correlated with the severity of mitral regurgitation'

ln this study a.cutott oi+o'o- pmo/L rrao 80% sensitivity andT6Yo specificity for predict-

ing 12-month progr".,io" icarOiac death or CHF)'16 Although these data seem very

promising,furtherstudiesareneededtoconfirmthevalueofBNPindistinguishing'amongasymptomati"oog.,tho""thatwillprogresstoCHF,lnour.opiniontheevalu-ation of risk progression-{or these dogs srroui-o be based on evaluation of multiple

parameters.TreatmentofdogswithasympiomaticMMVDhasbeenthesubjectofcontroversy.

The ACVIM consensus group did not recommend treating dogs with MMVD in stage

81o{thedisease.Thesamegrouphoweverdidnotreachaconsensusfordogswithcardiac enlargement.23 Two'multicenter double-blinded studies evaluating the effi-

cacy of enalapril on Oefaying tfre onset-ot CHF in dogs with MMVD withoutclinical

signs have shown no "ig;ifi";nt

effect of ACE-I therapy on the primarv outcome vart-

abte, which wa" tim" iiom inctusion in 1," ,tuJv io'ir't" on-t"iof signs of CHF'1117

Anotherrecentlypuutistreostudyreporledapossiblebenefitofearl-vtreaimentwithf"""t"o;u;; However, this was a retrospective case series' and studies of this type

areinvariablyu,"o"i"t"dwithsystematicerrors.Consequently,theresultsshouldbe interpreted wittr cautlon. A piospective, randomized, multicenter double-blinded

studyinvolvingalargernumberofdogswouldbenecessarytoconfirmtheresults,of this study.aa ln our opinion' the currently available data from clinical trials and the

observation that onlf a relatively small percentage of dogs with asymptomatic disease

progress to cHF or die as a consequence of ihe disease, do not support the early

treatmentwithanACE-I.However,itispossible,althoughnotproved,thatdogswith MMVD and severe cardiac enlargement, but not cHF, may benefit from medical

treatment.Theauthorsbelievethatasymptomaticcasesshouldbeindividuallyevalu-atedandtherapeuticdecisionstakenonacase-by.casebasis.TheavailabledataconcernonlytreatmentwithanACE-I.Hitherto,qostudieshavebeenconductedw.ith other classes of O'ugt, such as B-blockers' pimobendan' spironolactone' or

45;rlodiPine.

ilto pr"r"n"" of iou!the clinician. Cough-*

The Coughing Dog

in dogs. However' c---

ence in a dog with arsmall-breed dogs ar;ln these Patients, thq

not heart disease' T

u"1,3$:[T"Y$-inut tr"n to cougri Ithan worsening of c/ jITJJ"'J:il,*i": IhAon suooested tei

Imalacia.as lndeed'':;rhYPotnesrs."'o"'-- Iciated v;ith the c'=-

tassociated with r:UnPrb,,rn"o aoia l-rl

5H:5JJtrl";Jtf'" 0""r"u." in cr+ I

:li"".'.:'JI:.T:;=of furosemide in c+ |draie the dog bu:

-rhe slmPtomatic T*fiAccording to th: i'-ft#i"l."'=\J

same dog 1 montll Ithe presence of coYJstem bronchus but'- |nary edema. (t

t)

I

j

!-

j-

L-;;t-'I

lJl-I

-IJ!E

,>

,-

-

J

J

J

])I,II,,

,

,

I

I-r

tion and thoracice diagnosis. Theiomatic dogs canrphic evidence of;ntricular enlarge_Itomatic dogs aresease and othersrnd are at risk forle an explanationnted in the veteri_rition that asymp_nce of identifvinodeath or progi"ridegree of valve

ion, and left atrialaphic or echocar_re points may be: measurement.aorly to be an excel_fying patients that72 asymptomatictat the N_terminalitral regurgitation.:ificity for predict_e data seem veryrn distinguishing,

lptnton the evalu_uation of muitiple

ct of controversv.h MMVD in stagersus for dogs withualuating the effi_D without clinicalary outcome vari_;igns of CHF.r1,17rly treatment withudies of this typene results should-.r double-blindedrnfirm the resultsrical trials and therptomatic diseasesupport the early,roved, that dogsrefit from medicalndividually evalu_he available databeen conducted

pironolactone, or

Myxomatous Mitral Valve Disease 657

The Coughing Dog

ence in a dog with a murmur shourd not o" *,"',rrJu;;??:?iffi;Siffi#l:;ru;,small-breed dogs are commonry affected by tiacheobron"r-'iur-oiJui.e an,-r oy l4; ,1jr :rn these patients, the cough i" .tt""

',," l"tuti ot'reir primary respiratory ,ii,... . ,1.not heaft disease. ThoracL radiosrapr-,s s-h;io ut*uv" b";bt;;d;'a cougrring docrwith a murmur typicar tor n,nrvvd t;;r#" if nlmary respiratory disease is thr.cause of the cough. This is arso true L, '"ri"",.

wi*, a io"u-,ir"iilJ n,",o.y of cHi:jthat start to cough' ln these patients-in!*"Jugh, ,nuy be rerated to reasons other*ilry""J:,::':1 il-"J,: lTn-

d) .;;;; ;;n" witn ^,rrrva;;;; be rerated tr;

beensusses."o,-n"i#.1:.6..i,f &?r,;".J":1,Til:?XJ::":,:,:i;tr*H[llmalacia'as rndeed, some_ unpubrishe; data fro, o* group seems to c*nfirrn thi;ihypothesis. ln a qroup ot oa oogs wiil Mffi; ut oifr"runt stages, cough was r,., ,;--:ciated with the dimension or *ri tert airir* L ,,.'" pru""n"u -of cnrlii was. h,:.1.associated with conc_omitant presen"" oJ tr""r,"ooroncrriai'Jisease (Borg.r:rirunpubtished data, 2002), It is possili" iiui"orgl.',ing dogs with moderate t' severrieft atriar enrargement without'evide"""

"i'cHr but with a primary tracheobronchit:ldisease could benefit from treatments aimJ at decreasing th;;i utliur uorrn-'u, *,,the decrease in pressure on the main "tem

olonchus courd decrease the stimurustor coughing' However. the,types "t

Jrrg. ii"have the potentiar to achieve this are:l',fi ::#[:,{ H:nffiijil:ffi fi i;1;1l'l',,

nn",.'o,,;, ; ;;;;,o h ish d ose,

::l:::T"::-:':tl:"*".*'""o-'gi;;::n'"u,:"';$:iJ#fl ff'j:,H"x:'

The presence of cough and mitral uuruuffithe clinician. coush;r;;#;;:""':"lj::l'ltepresents a challensins prob,or:, ,

l: jtr;*.:"J:niff #:j}#:riirW,""$T:f;i:::fJ";':"1:'$;

The Symptomatic Doo I_ _._ __, ,,Stage C ACVIM Consensus)According to the ACVIM

"on".disease ur" tf.',o"u *,"ti ".r^.,,h6^+^r ^^_r: t,. patients with stage C ait,J"ro..io.,,,disease are those with a docum"nr"O_"#iu"",r,

palenrs wtth stage C miirai ,;eijr.,structural abnormality and curf..n, .

Ij?; j;..1;il'll:H"j,ffJ;fi ,.0 .,"'iffi the ieit,radiosraph shows a normauy..outri""i ,ighi .";T #:1.'^"f?:#H";""?*:,;"#,il:same dos r rnonth rater',fi6sriesp"pr,r *J."

"ii"i""o il;;;;"';;"",;;;:r ",..,,'o trr,i, r,.:,.

,,"u,np||:ru,:i j::r.^;:|" ",,;; :;;;;,i""iil,"n.u or a co ua pie,,, ( i :, i (,i,_{, 1

nary edema. - "lrsening of pulmonary venous congestion oi r;,..c,,.r r. ! ,

Borgarelli & Haggstrom

previous clinical signs of CHF.23 Management of these patients is based on adminis-tration of a combination of several drugs including diuretics, pimobendan, ACE-1, andothers. Although no study has specifically addressed the question of efficacy of furo-semide in dogs with MMVD, there is a general consensus that diuretics are essentialfor patients with CHF. Most dogs enrolled in the multicenter studies evaluating the effi-cacy of the ACE-I and pimobendan in symptomatic dogs r,n",ith MMVD receivedconcomitant treatment with furosem16".12-14'18'aG ln our opinion, the diagnosis ofCHF should be reevaluated if it is possible to discontinue the furosemide administra-tion in a patient without a reoccurrence of clinical signs. The dosage of furosemideshould be adjusted to keep the patients free from clinical signs; the optimal dose likelybeing the lowest effective dose. Although the suggested mean dosage for theseoatients is 2 mg/kg by mouth every 12 hours, in our experience it could range from0.5 mg/kg by mouth every 12 hours to 4 to 6 mg/kg by mouth every B hours. .Dogswith refractory heart failure could also benefit from administration of 1 of the dosesof Jhe drug by subcutaneous injectiop. lt has been shown in people that teachingthe patients to adjust their furosemide dosage on the base of monitoring their weightand their clinical signs significantly reduces the number of hospitalizations and may beassociated with prolonged survival.aT The authors try to use this approach with theowners whendver possible. The use of an ACE-I together with furosemide in dogswith CHF caused by MMVD is based on evidence provided by several multicenterdouble-blind studies.l2-14'48 These studies, although recently the subject of criti-cism,ae provide evidence that an ACE-I added to standard therapy improves qualityof life and survival time in dogs with CHF caused by MMVD. ACE-I should be usedat the dosage that has been shown to be effective in the clinical trials. There is noproven evidence that using ACE-I at dosages higher than the recommended dosepresents any clinical advantage.

Two recent studies have shown that pimobendan improves survival and quality oflife in dogs with MMVD and overt hearl failure compared with standard treatmentconsisting of an ACE-I and furosemide. The first study was conducted as a blinded,randomized, positive-controlled, multicenter study and included 76 dogs. The studyhad a mandatory 56-day treatment period that was followed by optional long-termtreatment. ln this study pimobendan significantly improved the primary study variablerepresented by heart insufficiency score and also significantly improved survival.a6One criticism of this study concerned concomitant treatment as only 56 dogs (31

in the pimobendan group and 25 in the standard treatment group) were on concur-rent furosemide treatment, suggesting that the diagnosis of hearl failure could bequestioned in the remaining dogs. However, the results of a subanalysis of dataprovided only by dogs receiving concurrent furosemide were consistent with thoseof the entire dataset. Moreover, the long-term part of the study was conductedunblinded. The results of this study led to a larger study conducted on 260 dogswith MMVD and overt CHF. This was a prospective multicenter, randomized,single-blinded study and the primary end point was a composite of cardiac death,euthanasia for heart failure, or treatment failure. ln this study treatment with pimo-bendan was associated with a significant improvement in survival time and thisbenefit persisted after adjusting for all baseline variables.l8 All dogs enrolled in thisstudy were on concomitant furosemide treatment. lt should be stressed that noneof these studies addressed the possibility of an interaction between ACE-I and pimo-bendan; it is not known whether or ng!_lfiple therapv consan.The ACVIM consensus recommends that chronic management of stage C dogsincludes all these drugs.23

--b

)Sprronolacion" .F i

iiY"'3;f"Ti:H:LJdeath and the risk oe -lwas 2 mgrxg "u",ifnormal dogs.s1 Or=-.1to the antifibrotic'+studies.s2's3 n recq/intramyocardial an--tment fibrosis.'" Tf,Sto oe ciarifieo as isr-

brino disease in doos..'""='.n-rwrth a specrlrc an!phenomenon si 2:i.--has been shovrn FMMvD recetvtng r.fdose of furosemidr--completely block Atsenzymes such as fexact mechanism;.-in improving outco-

Otherdrugsfreq-are digoxin ana arr,l-atrial fibrillation to *medicine evaluatir#

-could improve clir[-the effect of digoxrneutral. However.,;-subpopulatiors otll-on longevity."' An-ain the ACVIM cons-advanced staqe of:'load'" and imProi'Lthis drug can leaci pr=.of amlodipine dosPserious hypotensifdilators. such as sgi-CHF that experiene

ln our experiendl-Uslno a comDlnaljtTreatment shouldLdogs free of clinicF-

P4SUMMARY \.

-MMVD is a comm?,-asymptomattc Tol-a progression to [-Left atrial enlarqedlmost reliable pretTneeded to clarify h2=

-

)

L-El'-:l-'l-:Lj't-:'l-:"'l-''J:1-:"t:t:';t;L-L'-L.-;L-L.

-

-tst

--

-

:

lased on adminis-tndan, ACE_1, andtf efficacy of furo_etics are essential:valuating the effi_MMVD receivedthe diagnosis of

:mide administra-rge of furosemiderptimal dose likelvdosage for thesecould range from:ry 8 hours Doosof 1 of tire doses,ple that teachingorng their weightitrons and may beLpproach with the'osemide in dogs.'veral multicenter: subject of criti_improves quality

.l should be usedlrials. There is noommended dose

val and quality r:irndard treatment;ted as a blinded,dogs. The study

ptional long_termlry study variablelroved survival.a6rnly 56 dogs (3.1

were on concur_failure could be

:analysis of data;istent with thosewas conducted

led on 260 dooster, randomizei,:f cardiac death,.ment with pimo_'al time and thiss enrolled in thisessed that noneACE-I and pimo_rosemide, ACE_1,plus furosemide.lf stage C dogs

-

a

Myxomatous N4itral Vaive Dise.r<.

spironoractone has recen'y been approved in Europe fortreatment of rr ,-r:.. .,.,MMVD. A recent study shows tnat in ffi i,ith moderate t"""""r".frrivVD sg.: .. . ,tone added to an ACE--1, furosemide +itg;xinJreut,.nuntiJrJ"""'ir,e ri"t or carciacdeSth and the risk of severe worsening of

"cHr.50 The dosage used in this crir:ir:r:i ,,, ,iwas 2 mg/kg every 24 hours and triJ oosaqe seems to have rit e diuretir ; i'e. :normal dogs.51 one possibre mectranis. oilction for spironoractone courd i:r,. ;, . :to the antifibrotic

Tu."r: of this Orug-th"t have been "h;;;"in exp..,,,..r,,

;\1ffi;ljtli:iJi studv has "r.'o*n

ir'ut"seriarric oos" ;u;q by Mturv; i,,:,ri

to be clarified as is the possible antifibrotic effect of spironolictone in naturai uu\ r:,ring disease in dogs. positive "ru"t" J Jrolklng ardosterone in dogs with hea.r fairu'.,with a specific antagonist

"r"r.' u" .oiro"*ractone courd arso be rerated to th,,phenomenon of ardosterone escaps55s6 tr.'ui

"un occur in dogs with severe i..,-i:--. ,has been shown the ardosteronu

"on""nLion can o" i""r""""0 in dogs wii:rMMVD receiving furosemide and an ncE-r.ri *,i" phenomenon is d€penderlt r:r : :r .dose of furosemide and has oeen attriluted to the fact that ACE inhibition d|,es i:,..completely brock ACE activity. rn o"g" ,n pu'ti"urar, it has been specurated th;,:i rrth.:XIffi:""r:T# jlJT."." can pray u ,ujo'..j:i: in, p.d;;l;;!-n!tt.n"in l.i rhr,inimprovins.,i"";;:;'il;:11,'J#ff 3'#:::ffi i"J".n:::;;;;ssib,eben,if iiother drugs frequenry useo tor treatr"ni o"ioog. with overt cHF caused by MMVDare digoxin and amrodipine. Digoxin is comm-onry used to treat dogs with concomitantatriat fibri'arion to contror the rieart ,"t;. il;;; are no controred itudies in veterinarymedicine evaruating digoxin, but it is gunur"i expert opinion that its administrationcoutd improve crinicar signs of rr"un tirur"'in- dogs. rn huru";,;;;;;ive to pracebothe effect of digoxin on morlarity of amburatory human patients with heart fairure isneutrar' However, this drug 0""r"u"""

-*teJ ot rrospitarization ano *rere may br:,subpopulations of patients with heart tairure in whic' digoxin has a favorabre ef-+eclon rongevity's7 Amrodioine at the dosage

"i o bs to 0.1 mg/kg every l2hours is iiste.in the ACV,M consensus.statement as'a poss-ibre agent for those dogs with . .advanced stage of heart fairure ct"d-Dit;;;tarn a more effective reduction !,:, ;_,i , ,.load23 and improve cardiac output.lr-teriJJrlasooitation associated with the use

'.,this drug can read to severe hypotension in *'ese patients. Therefore, srow up,;ii11; ;. , .of amlodipine dosage with monitori;n

"; ;i.; pressure is recommended rr: .i,,,serious hypotension. ln our experiencu, tr e use of this drug or other intravenci,,,; i : i,,dilators, such as sodium nitroprusside,

"un J.lt

"ome herp for dogs with uncontrorieciCHF that experience an acute episode of pulmonary edema.ln our experience, most dogs with huurt;;ii;;" caused by MMVD can be rn:inagr-:,.1using a combination of furolemid",

""'n6i-', pimobendan, and spiron.in{rri}ni,Treatment shourd be individuarized for "uc"rr

pati"nts and the goar is to ,., r ,dogs free of ctinicat signs of CHF as ronJIJ pj"rior"

SUMMARY

659

MMVD is a common condition in geriatric dogs. Most dogs affected are clinicalilasymptomatic for a long time. frl*"uui alout soZ oith"ru unirut" presenia progression to hearl Hu,o uLo eventuaity oie as a consequence of the ri ;,:+;i,,;.,Left atriar enrargement, and particurarrv u "riuls" in reft atriar size, seenrs tc r-.. ,most reliabre predictor of progression'in

"o.n'"'"tudies, however further ii;tli,.iiineeded to clarify how to recognize asymptomaiic patients at higher;isft qf 6r6rryolr; .

Borgarelli & Haggstrom

heart failure. According to the published data on the natural history of the disease andthe results of published studies evaluating the effect of early therapy on delaying theprogression of the disease, it seems that no currently available treatment delays theonset of clinical signs of CHF. Although the ideal treatment of more severely affecteddogs is probably surgical mitral valve repair or mitral valve replacement, this is nota currently available option. The results of several clinical trials together with clinicalexperience suggest that dogs with overl cHF can be managed with acceptable qualityof life for a relatively long time period with medical treatment including furosemide, anACE-|, pimobendan, and spironolactone.

REFERENCES

1. Haggstrom J, Hoglund K, Borgarelli M. An update on treatment and prognosticindicators in canine myxomatous mitral valve disease. J Small Anim pract2009;50(Suppl 1 ):25-33.

2. Haggstrom J, Kvart c, Pedersen HD. Acquired valvular heart disease. ln:Ettinger sJ, Feldman EC, editors. Textbook of veterinary internal medicine. 6thedition. St. Louis (MO): Elsevier Saunders; 2005. p. 1022-39.

3 Sisson D, Kvart c, Darke P. Acquired valvular heart disease in dogs and cats. ln:Fox PR, Sisson D, Moise NS, editors. Textbook of canine and fellne cardiology.2nd edition. Philadelphia: WB Saunders Company; 1999. p. 536_65

4. BorgarelliM.Mitral valveinsufficiencyinlargebreeddogsIphDthesis].Grugliasco,Italy: Dept of Patologia Animale, University of Turin; 2004.

5. Borgarelli M, Zini E, D'Agnolo G, et al. comparison of primary mitral valve diseasein German Shepherd dogs arrd is small breeds. J vet cardiol z-0o4,6'.2s-31 .

6. Haggstrom J, Hansson K, Kvart c, et al. chronic valvular disease in the cavalierKing Charles spaniels in Sweden. Vet Rec 1992;j31:549-53.

7. Haggstrom J. Chronic valvular disease in Cavalier King Charles Spaniels: epide-miology, inheritance and pathophysiology IphD thesis]. Uppsala, Sweden:Department of Physiology, Swedish University of Agricultural sciences; 1996.

B. Pedersen HD, Lorentzen KA, Kristensen Bo. Echocardiographic mitral valveprolapse in cavalier King charles spaniels: epidemiology and prognosticsignificance for regurgitation. Vet Rec 1999;144:315-20.

9. olsen LH, Fredholm M, Pedersen HD. Epidemiology and inheritance of mitralvalve prolapse in dachshunds. J Vet lntern Med 1999;13:448_56

10. Borgarelli M, Savarino P crosara S, et al. Survival characteristics and prognosticvariabrles of dogs with mitral regurgitation attributable to myxomatous valvedisease. J Vet lntern Med 2008;22:120-8.

1 1. Kvart c, Haggstrom J, Pedersen HD, et al. Efficacy of enalapril for prevention ofcongestive heart failure in dogs with myxomatous valve disease and asymptom-atic mitral regurgitation. J Vet lntern Med 2002;16:80_g.

12. Ettinger sJ, Benitz AM, Ericsson GF, et ai. Effects of enalapril maleate on survivalof dogs with naturally acquired heart failure. The Long-Term lnvestigation ofVeterinary Enalapril (LIVE) Study Group. J Am Vet Med Assoc 1998;213:1523-7.

13. The BENCH Study Group. The effect of benazepril on survival times and clinicalsigns of dogs with congestive heart failure: results of a multicenter, prospective,randomized, double-blinded, placebo-controlled, long-term clinical trial. J VetCardiol 1999;1:7-18.

14. Cove T. Controlled clinical evaluation o{ enalapril in dogs with heart failure: resultsof the cooperative veterinary Enalapril Study Group. The coVE Study Group.J Vet lntern Med .1995;9:243

52.

15

lf)

-a'4I"1a

Pouchelon JL '-zcardiac evenls 'lStUOy OI Ia I /-::'aChetboul V. S;.-=;Jnatriuretic peci -!,doos with as,-'4zodg;zg:gea gj a

17. Atkins CE. Ke:-iProve reduct'i' "-alone for comc:a

4

Med Assoc 2l- *'-18" Haggstrom J E:;-

hydrochlorioe :'lnaturallY occ-''Flntern Meci 2a::

19. Liungvall l. Ai,-':and murmurs:-aF

amatous mitraj .'. _

20. Haggstrom i i.r"to severity 6f -*.:

, -^^+lntern lvleo lvl:'.4

21. Pedersen HD --valve prolaPs= *e

22. Fonlana lv'lE l.i!---tron. ln. tJo-l--\

mitral valve c'--G^ ooa !n1 Lp. 4UJ-JU1

23 Atkins C Bl-:fment of c?r,.=:1142,50 \

24. Pedersen HD "-Lvalve prolao:= .-

25. Levine RA. Tr,, r.the diagnosrs :;-

26. Borgarelli l/ Ta!equate hyPert'*ficiencY J Vei l'-

27. Bonaoura JD S'ograpny ln c- !SO(SupPl 1\ 12-.*

28. Chiavegato D !ewith mitral reSjUltrasound 20C.-

29. Stepien RL. Pscardiac dvsfun--!

30. Hansson K H:1-diagnosis of s=J Small Anim P#

' ,L31. Haggslrom J r_-

peptides and r,_

chronic mYXorrP#!_

-4

/4\_14

\_4

r

)f the disease and)y on delaying theltment delays theseverely affected

ement, this is notether with clinicallcceptable qualityng furosemide, an

It and prognosticlmall Anim pract

eart disease. ln:nal medicine. 6th

logs and cats. ln:feline cardiologyJO-b5.

resisl. Grugliasco,

itral valve disease20O4,6:25-31.rse in the cavalier

; Spaniels: epide-cpsala, Sweden:ciences; 1996.phic mitral valveand prognostic

eritance of nritral)6.;s and prognosticyxomatous valve

for prevention of: and asymptom-

aleate on survivalr lnvestigation ofI 998;213:1 523-7.rimes and clinicalnter, prospective,linical trial. J Vet

,art failure: resultsVE Study Group.

Myxomatous Mitrai v,aive ijrrea:+:

15. Pouchelon JL, Jamet N Gouni V el al. Ef{ect oi benazepril oncardiac events in dogs with asymptomatic mitrar varve diseasei 3 ir.-il , r. .i. ,,study of 141 cases. J Vet lntern Med ZOOB,22:905_14.l6 Chetboul V Serres F, Tissier R, et al. Association of plasma N-terminat iri.-; i-r r\,,j.i,1natriuretic peptide concentration with mitral regurgitation severity and cut{rr;, r,* ,, rdogs with asymptomatic degenerative mitrar varve disease. J vet iirr:,,ii, ,\4eu2009;23.984-94.

17' Atkins cE' Keene BW, Brown wA, et ar. Resurts of the veterinary eni:r';r; r. ir . , ,prove reduction in onset of heart failure in dogs chronically treaied with c;1.:i:r'i-i:alone for compensated, naturariy occurring mitrar varve insufficienr-..,, r ..r1,,,

,,.,jrr:

Med Assoc 2007;231:iO6j 9.lB HaggstromJ,BoswoodA,o'GradyM,etar.EffectofpimobendanorhL)f:,,.,r:-:r:,

hydrochloride on survival times in dogs with congeslive he;art failure causetl tr,naturally occurring myxomatous mitral valve disease: the eUEST,,,, ,,:,r. ., r,..'lntern Med 2008,22.1 1 24_35.

19, Llungvall l, Ahlstrom c, Hoglund K, et al. Use of signal analysis of r..er:ri.r r;.,, , ,and murmurs to assess severity of mitrai valve reguigitation ;ftribui;.'i.rir r, i,r,.matous mitrar varve disease in dogs. Am J Vet nes ioog;zo:604,-ir:l

20. Haggstrom J, Kvart c, Hansson K. Heart sounds and murmurs: chariges reid.L;.:,,to severity of chronic valvurar disease in the cavalier King charres srJri ii;r . _

lntern Med j995;9:75-8521. Pedersen HD, Haggstrom J. Mitrar varve prorapse in the dog: a m.ri.i .,i iilrtr.r,

valve prolapse in man. Cardiovasc Res 2000;42:234_43.22- Fonlana ME. Mitrar varve prorapse and froppy mitral valve: physicai iiri rrfri.

tion. ln: Boudouras HK, woorey cF, editors. Mitrar varve: fropfiy mitrar v;:iv.,mitral valve prolapse, rilitral varve regurgitation. Armonk (Nyj: i.iLr,r,,; :rrlur ,p. 283-304Atkins c, Bonagura J, Ettinger S, et ar. Guiderines for the diagnosis and tre;lrment of canine chronic valvular heart disease. J Vet lntern Meci 2ocg;;ri.1142-50.

24. Pedersen HD, Kristensen B, Norby B, et ar. Echocardiographic sri:r-J,v lrf :niir..valve prolapse in dachshunds. Zentralbl Veterinarmeo Rlggo;+g:lr.r:l rrr

25. Levrne RA, Triurzi Mo, Harrigan p, et ar. The rerationship of mitrar annuiar shape Li;the diagnosis of mitral valve prolapse. Circulation 1987;75:756--67

26. Borgarelli M, Tarduccj A,ZananaR, et ar. Decreased systolic functrr,, r iii-r,.,;,-,,,equate hypertrophy in rarge and smail breed dogs with thronic mitr.r ,,.:ri, ,: i :r ,,,ficiency. J Vet lntern Med 2OO7:21 .6j_7.

27' Bonagura JD, Schober KE. Can ventricular function be assessed L:y,rr..irr..cirrcl;ography in chronic canine mitral vatve disease? J Smail Anim F,i:r,.:l r{i0rl50(Suppl 1):12 24.

28 Chiavegato D, Borgareili M, D'Agnoro G, et ar. purmonary hypertensicir : rn doc:with mitral regurgltation attributable to myxomatous valve disease. Vet RadictUltrasound 2009;50:253,g.

29' Stepien RL Pulmonary arterial hypertension secondary to chronrc i,:rft-sidec-cardiac dysfunctron in dogs. J smail Anim pract 2009;s0(Suppr l)3a a3.30 Hansson K, Haggstrom J, Kvart c, et ar. Reader performance in radiographirdiagnosis of signs of mitrar regurgitation in cavarier King charres spanierrJ Small Anim pract 2009;50(Suppl 1):44-53.

31. Haggstrom J, Hansson K, Kvart c, et al. Relationship between differe, il ,,,:peptides and severity of naturaily acquired mitrar regurgitaticn ir; r, .,chronic myxomatous varve disease. J Vet cardior 2000.2:7-16

2a

J+

.J5

36

3/

3B

39

40

Borgarelli & Haggstrom

32. Moesgaard SG, Pedersen LG, Teerlink T, et al. Neurohormonal lqd circulatoryeffects of short-term treatment with enalapril and quinapril in dogs with asymp-tomatic mitral regurgitation. J Vet lntern Med 2005;19:712 g.

Pedersen HD. Effects of mild mitral valve insufficiencv, sodlum intake, and placeof blood sampling on the renin-angiotensin system in dogs Acta Vet Scand '1996;

37: 1 09-1 B.

Dell'ltaiia LJ, Meng QC, Balcells E, et al. lncreased ACE and chymase-likeactivity in cardiac tissue of dogs with chronic mitral regurgitation. Am J Physiol1995;269:H2065-73.Su X, Wei CC, Machida N, et al. Differential expression of angiotensin-convertingenzyme and chlrma.se in dogs with chronic mitral regurgitation. J Mol Cell Cardiol1999;31 : 1033 thFujii Y, Orito i.., Muto M, et al. lViodulation of the tissue renin-angiotensin-aldoste-rone system in dogs'with chronic miid regurgitation through the mitral valve. Am JVet Res 2007;68:1045 50.Buchanan JW. Chronic valvular disease (endocardiosis) in dogs. Adv Vet SciComp Med 1977,21:75-106Olsen LH, Mow T, Koch J, et al. Heart rate variability in young, clinically healthydachshunds: influence of sex, mitral valve prolapse status, sampling periodand time of day. J Vet Cardiol 1999;1:7-16.Olsen LH, Martinussen T, Pedersen HD. Early echocardiographic predictorsof myxomatous mitral valve disease in dachshunds. Vet Rec 2003;i52:293-7.Lord PF, Hansson K, Kvart C, et al. Rate of change of heart size before conges-tive heart failure in dogs witn mitral regurgitation. J Small Anim Pract 2010;5i:21 0-8.

41. Campbell DJ. Can measurement of B-type natriuretic peptide levels improvecardiovascular disease prevention'? Clin Exp Pharmacol Physiol 2008;35'

44.

442-6.de Lemos JA, Hildebrandt P. Aminolerminal Pro-B-type natriuretic peptides:testing in general populations. Am J Cardiol 2008;i0i(Suppl):164 20A.Hinderliter AL, Blumenthal JA, O'Conner C, et al. lndependent prognostic valueof echocardiography and N-terminal pro-B{ype natriuretic peptide in patientswith heart failure. Am Heart J 2008;156:119i 5Kittleson M, Rishniw M, Pion P et al. Effect of benazepril on survival and cardiacevents in dogs with asymptomatic mitral valve disease: a retrospective study of141 cases. J Vet lntern Med 2009;23:953-4 [author reply: 955-6].Ettinger S, Kantrowitz B. Disease of the trachea ln: Ettinger S, Feldman EC,editors. Textbook of veterinary internal medicine. 6th edition. st. Louis (Mo):Elsevier Saunders; 2005. p. 1217-32.Lombard CW, Jons O, Bussadori C. Clinical efficacy of pimobendan versus be-nazepril for the treatment of acquired atrioventricular valvular disease in dogs.J Am Anim Hosp Assoc 2006;42:249-61 .

Gonseth J, Guallar-castillon P, Banegas JR, et al. The effectiveness of diseasemanagement programmes in reducing hospital re-admission in older patientswith heart failure: a systematic review and meta-analysis of published reports.Eur Heart J 2004.25:1570-95.

48. lmprove TAcute and short-term hemodynamic, echocardiographic, and clinicaleffects of enalapril maleate in dogs with naturally acquired heart failure: resultsof the lnvasive Multicenter PROspective Veterinary Evaluation of Enalapril study.The IMPROVE Study Group. J Vet lntern Med 1995;9:22442.

42.

43.

45

46

47

49

50

51

E'JL

53

--3

rll

Pion P, Rinshi,")jbLrllet. ln: Procr. I

p. eB-100 2Bernay F Bla'1-.idogs with nai*valve disease ,-rJeunesse E. ';',lf

'-Jand u|ne soclG9 63-8 -----Brilla CG, Ma;*venting myoca'-71.12A 64.

-Miric G, Dalier-pirfenidone ai*2001 :133:68;-Y

t--

54 Falk T. Jonsst-lung, and kid:--mitral valve or3

^Fo5. Strutners AL. -failure. Eur J l;-

56. Ubaid-Girioii IOlUletlU Ur 3-blocker comr-i'J Clin HYPert-i*

57. Ahmed A. Rrc:+talization in h::.Heart J 2O0e -s

\'4\--4!'4L.4a-

t.ra-JL

'+

-JL

g

F,u

,4\'€'.i

J"J

b

4b

tFtY

'1!

t't-

!

434!

4!

!

t

a

.J1

,-t

'1

I

al and circulatorylogs with asymp_

intake, and piaceI VetScand 1996;

lnd chyrnaseJikelon Am J physiol

rtensin_convertinoJ MotCeilCardio]

giotensin-aldoste_mitrai valve. Am J

cgs. Adv Vet Sci

clinically heatthysampling period

aphic predictorsRec 2003;152:

e before conges_n Pract 2O1O;5i:

e ievels improve)hysiol 2008;35:

'iuretic peptides:6A-20A.prognostic valuerptide in patients

yival and cardiac:pective study of61.

S, Feldman EC,St. Louis (MO):

'ndan versus be_Jisease in dogs.

rness of diseasein older patientsrbiished reports.

rhic, and ciinicalrut failure: resultsf Enalapril study.

Myxomatous Mitral Valve Disease

49' Pion p, Rinshiw M...canine chronic mitrar varve_djsease _ the search ftli. 1.:o ,i;,,,.,,

i:g?11;r:tceedinss ot tre nCvirr,r'nlrr'. san Antonio (rX), June 4 i,, .i;iri-1

50' Bernay E Bland JM, Haggstrom J, et al. Efficacy of spironolactone on srirvil,,?r ii_idogs with naturaily occriing ritruii*!r-rgitrtion caused by myxomatcu$ i-.ritraivalve disease. J Vet lntern f,l|*O eOlO,i+,33i_4j.5l Jeunesse E, woehrle E scnneioei rti,' "i

.r Effect of spironolactone or) {jir., ::..i.A[LT*

sodium and potassiu, ur",.uti* in heatthy jo;;;;; Erll,"i ,1,. ,

52' Brilla cG, Matsubara LS, weber KT. Antifibrotic effects of spironoractone irr prc..

;?ltlf_H*ardidfibrosis in systemic arilriarhypertensionlnml caraioi re93,

53' Miric G, Daremagne c, Endre z, et ar. ReyeJsal of .cardiac and renar fibrosis by

t[o:]r."#r?l$o'oi..onotuctone in tt,.upiJ.oto"i"-oln"i" rir" 'r"l , rrira:rn;: ci

54 Falk r, Jonsson L, orsen LH, et ar. Arterioscrerotic changes in the rny'ceidirrr :r.lung, and kidney in dogs with chronil'coigert,ve heart fairure and myxoml,ii,irsmitral valve disease. Cirdiovasc p"ir.,oi zobo;r5: j85_93.55' struthers AD. The crinicai impricutio,.,s'or-uioo"t"ronu escape in congestive rrt_.artfailure. Eur J Heart Fail 200i;6:SS9_aS. *'

56' Ubaid-Giriori s, Ferreira-Mero sE, souza LA, et ar. Ardosterone trsc;ri,fr ,.;;iildiuretic or angiote-nsln_converting-;;;;r. inhibitor/angioi""", rr re!eprijibrocker combination therapy in p"uti"ntl *ith mird to moderate hypertension_- j,Clin Hypertens (Greenwich) ZOOZ;S:lliOZ.5/ Anmed A' Rich MW Love TE, et ar. Digoxin and reduction in mortariiy anri hc,l;oi-lii:xt:?si,#,t;r:;::a co.np,."nen-r'e post hoc anarysis oitnl'orr., iriar f:rri

563