INTRODUCTION

Severe and mostly progressive pulmonaryvascular disease with unknown aetiology isdefined as primary pulmonary hyperten-sion (PPH). This is believed to be a pul-monary vascular reaction to exogenoustoxic agents in animals with a genetic predisposition to the condition (Winkler1993). Another hypothesis suggests thatthe inhibition of endothelial-derived relax-ing factor and nitric oxide potentiates theaccumulation of an endothelial-derivedcontracting factor (Geiger and others2000, Berger and others 2001). The epi-demic of anorexogenic-associated PPH in Europe (Gurtner 1979, 1985) led to the first World Health Organization(WHO) conference on pulmonary hyper-tension in 1973 (Ghamra and Dweik2003). According to the results of this conference, PPH was classified into threedifferent pathomorphological subtypes:plexogenic pulmonary arteriopathy (PPA),recurrent thrombotic pulmonary arteri-opathy (TPA), and pulmonary veno-

occlusive disease (PVOD) (Edwards andEdwards 1977, Winkler 1993).

The most common lesion seen in PPHis PPA, which mainly affects the musculararteries and is characterised by non-specificmedial hypertrophy and muscularisation ofarterioles, concentric intimal proliferation,concentric laminar intimal fibrosis, fibri-noid degeneration, necrosis of small arter-ies, and dilatation and plexiform lesions(Heath and Edwards 1958, Wagenvoort1985, 1994, Tuder and others 1994,Berger and others 2001, Buchanan 2001).Depending on the extent and type of pul-monary vascular lesions, PPA is classifiedusing six grades (Heath and Edwards1958). It tends to progress to an irreversiblestage (Wagenvoort 1994, Geiger and others2000). None of the histopathological pat-terns seen in PPA are pathognomonic sincethe diagnosis still relies on the exclusion ofsecondary causes (Pietra 1994).

PPA can be triggered by a variety ofaetiological stimuli and is most commonlyassociated with congenital heart disease,particularly post-tricuspid shunts inhumans (Wagenvoort 1994, Epting andothers 2002) and dogs (Turk and others1982). The increase in pulmonary bloodflow and the consequent elevation of pul-monary artery pressure accelerates the pro-gression of the structural lung changes(Botney 1999). Hyperreactivity of pul-monary arteries, probably geneticallydetermined, seems to be involved in thepathogenesis of primary as well as sec-ondary PPA (Wagenvoort 1994).

During the second WHO conferenceon PPH, held in Evian, France in 1998, thedisease was divided into five classes (Evianclassification): pulmonary arterial hyper-tension, pulmonary venous hypertension,pulmonary hypertension associated withdisorders of the respiratory system orhypoxaemia, pulmonary hypertension dueto chronic thrombotic and/or embolic dis-ease, and pulmonary hypertension due todisorders directly affecting the pulmonaryvasculature (Ghamra and Dweik 2003).

In humans, PPH is still incurable andtreated, where possible, by heart-lung

U. S. KOLM, C. N. AMBERGER*, C. E. BOUJON* AND C. W. LOMBARD†

Journal of Small Animal Practice (2004)45, 461–466

A 21-month-old, male Pembroke Welsh corgi was referred for

investigation of respiratory distress and progressive lethargy.

Cardiac evaluation revealed a grade 4 pansystolic murmur over

the left and right heart base. A heart murmur, dyspnoea, cyanosis,

prolonged capillary refill time and ascites led to the tentative

diagnosis of a cardiac malformation with a right-to-left shunt,

with likely additional pulmonary disease. Pulmonary hypertension

became evident during echocardiography, when the estimated

systolic pulmonary artery pressure was over 70 mmHg. Angiography

revealed abnormal pulmonary vascular markings consistent with

pulmonary hypertension and a small right-to-left shunting patent

ductus arteriosus (PDA). The diagnosis of PDA was confirmed at

postmortem examination. Histology of the pulmonary arteries

showed lesions of plexogenic pulmonary arteriopathy. The question

of whether both conditions were separate or part of the same

clinical syndrome is discussed in this report.

Plexogenic pulmonary arteriopathy in a Pembroke Welsh corgi

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Medical Clinic for Small Animals andInfectious Diseases, University ofVeterinary Medicine Vienna,Veterinärplatz 1, A-1210 Vienna,Austria

*Small Animal Practice, 96, Rue de la Servette, CH-1202 Geneva, Switzerland

†Department of Internal Medicine,Faculty of Veterinary Medicine,University of Berne, Länggassstraße128, CH-3012 Berne, Switzerland

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transplantation. The conventional treat-ment includes oral vasodilators, usuallycalcium channel blockers and anticoagu-lants. Treatments now being developedinclude thromboxane synthesis inhibitors,endothelin receptor antagonists, specificphosphodiesterase inhibitors and prosta-cyclin analogues (Gaine and Rubin 1998).Survival in humans was shown to beimproved by sustained intravenous prostacyclin treatment and by chronicanti-coagulation (Haworth 1998). Thenon-selective endothelin-1 receptor antag-onist, bosentan, attenuated the vascularremodelling in a canine model of chronicembolic pulmonary hypertension (Kimand others 2000).

CASE HISTORY

A 21-month-old, male Pembroke Welshcorgi was presented to the emergency ser-vice of the Small Animal Hospital, Univer-sity of Berne, with a one-week history ofanorexia, lethargy and weakness. The doghad been breathless from very early on inlife. Dyspnoea and exercise intolerance hadworsened recently. The referring veterinar-ian treated the dog with antibiotics andpimobendan. This therapy had worsenedthe clinical signs.

The dog’s weight was 11·2 kg. Physicalexamination revealed depression, a respira-tory rate of 44 breaths/minute and a heartrate of 148 bpm. Body temperature was

37·8°C. Dyspnoea, observed both oninspiration and expiration, was present atrest. The dog was slightly dehydrated.Mucous membranes appeared pale andslightly cyanotic and capillary refill timewas three seconds. The femoral pulse wasweak but regular. Increased respiratorysounds were heard dorsally on both sidesof the lung field. A grade 4 pansystolicmurmur was heard over the left and right heart base. Abdominal palpationrevealed hepatomegaly and a moderateundulation suggestive of ascites.

Survey radiographs of the thorax revealeda pleural effusion and dorsal deviation of the trachea. The cardiac silhouette was par-tially masked by thoracic fluid accumula-tion. The visible pulmonary arteries seemedto be slightly increased in diameter. Dorsallycompressed lung lobes showed an interstitialalveolar pattern. Focal consolidation with

air bronchograms was detected in the right cranial lobe. Hepatomegaly and ascites were evident (Figs 1 and 2).

Electrocardiographic findings showed anormal sinus rhythm (160 bpm) withincreased P wave duration (0·06 seconds)and amplitude (0·5 mV), consistent withbiatrial enlargement. Mean electrical axiswas 60° (Fig 3).

Echocardiography revealed right ven-tricular concentric and eccentric hyper-

FIG 1. Thoracicradiograph, rightlateral view. A pleuraleffusion, partiallymasking the cardiacsilhouette, and dorsaldisplacement of thetrachea are visible

FIG 2. Thoracic radiograph, dorsoventral view.The visible pulmonary arteries appear slightlyincreased in diameter. In the right cranial lobe, a focal consolidation with air bronchograms can be seen

FIG 3. Six-leadelectrocardiogram, 50 mm/second, 1 mV = 10 mm. A rapid sinus rhythm(160 bpm) withincreased P waveduration (0·06seconds) andamplitude (0·5 mV) is present

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trophy, severe right atrial dilatation anddilatation of the pulmonary trunk (Figs 4 and 5). M-mode echocardiographyshowed paradoxical septal motion.

Doppler examination revealed tricuspidinsufficiency (vmax 4 m/second) as well as turbulent flow in the right ventric-ular outflow tract. The pulmonary flowprofile showed a reduced flow velocitywith diastolic regurgitation (vmax 3 m/second), probably due to pulmonaryhypertension. A patent ductus arteriosus(PDA) was seen in a short axis two-dimensional (2D) view of the heart base, but the positive flow in the right ventricular outflow tract was abnormallylow (Fig 6), compatible with increasedresistance in thepulmonary vascular bed. Turbulence in the right atrium was also present on colour flow Dopplerevaluation (Fig 7). A right-to-left shunt-ing atrial septal defect (ASD) was sus-pected. The turbulent flow could also have been caused by vena caval flow or an artefact.ll

A complete blood count and chemistryprofile were unremarkable, except for mild hypoproteinaemia (51·8 g/litre, reference range 60 to 72 g/litre). Theabdominal fluid was characterised as modified transudate.

Assessment and treatmentThe predominant problem in this case wasright ventricular heart failure, probablydue to congenital heart disease (PDA, possible ASD). The suspected pulmonaryhypertension was treated with 1 mg/kg ofthe calcium channel blocker diltiazemthree times daily (Dilzem; Parke Davis).Mild diuresis was treated with 1 mg/kg

spironolactone once daily (Aldactone;Roche) and 1 mg/kg frusemide (Lasix;Hoechst) twice daily. As the prognosis for long term survival was poor, the owneragreed to a heart catheterisation procedure,but refused treatment if the diagnosis was not compatible with a normal quality of life.

AngiographyThe dog was sedated with intravenous injec-tions of 0·03 mg/kg acepromazine (Vanas-tress; Vana) and 0·5 mg/kg butorphanoltartrate (Morphasol; Graeub), followed byinduction with 3 mg/kg propofol (PropofolFresenius; Fresenius) and general anaesthesia

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FIG 4. 2D echocardiogram, right parasternal short axis view of the heartbase. Note the dilatation of the pulmonary trunk. RVOT Right ventricularoutflow tract, Ao Aorta, PV Pulmonary valve

FIG 5. 2D echocardiogram, left apical four-chamber view. Severedilatation of the right atrium (RA), and moderate right ventricular (RV)dilatation and hypertrophy are present. The vena cava (Vc) is seen as anecholucent space adjacent to the atria. LV Left ventricle, LA Left atrium

FIG 6. 2D and spectral Doppler echocardiogram, left cranial short axisview of the heart base. The Doppler sample volume had been placed in the ductus arteriosus. Turbulent, continuous low-velocity flow is present,related to a reduced gradient between the aorta and pulmonary trunk

FIG 7. 2D and colour flow Doppler echocardiogram, left apical four-chamber view. Turbulence in the right atrium (RA) is present. This flow turbulence was thought to be due to severe tricuspidregurgitation and to a shuntflow from the RA through an ‘apparent’ atrialseptal defect in the direction of the left atrium (LA) and mitral valve. Asthis suspected atrial septal defect (ASD) could not be found at necropsy,the appearance of this turbulent jet crossing the atrial septum could bedue to an artefact. Another explanation would be that vena caval flow isregistered. RV Right ventricle

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with isoflurane (Forene; Abbott). A 5 French gauge arteriography catheter wasintroduced percutaneously into the rightjugular vein and advanced under fluoro-scopic guidance into the main pulmonaryartery. Injection of contrast material showeda small, primarily right-to-left shuntingPDA (Fig 8). Intermittent minimal shuntreversal could be observed on fluoroscopy,depending on variations of the aortic pres-sures. The size of the pulmonary arteries wasrather small.

Because of the poor prognosis and thelack of effective therapeutic options,euthanasia was requested by the owner.

Postmortem examinationThe heart showed severe right ventriculareccentric hypertrophy with muscular sub-valvular thickening, dilatation of the annu-lus fibrosus at the tricuspid level and severeright atrial dilatation and hypertrophy. APDA was observed (the opening into thepulmonary trunk was about 3 mm indiameter) (Fig 9), but no ASD could bedetected. Histological examination of thelungs revealed plexiform lesions of arteriesand small arterioles with intimal cellular

proliferation and fibrosis, medial hypertro-phy, fibrinoid degeneration and arteritis(Fig 10). Some small arteries seemed to be

completely obliterated. The liver showeddilated centrilobular veins and slight centrilobular fibrosis.

FIG 10. Cross section through a small pulmonary artery, showing plexiform arteriopathy. (A) A plexiform lesion. (B) Eccentric intimal cellular proliferation (arrow), medial hypertrophy (star),fibrinoid degeneration (triangle) and arteritis

FIG 8. Selective angiogram of the pulmonary trunk, with a jugularcatheter that has passed through the cranial vena cava, right atrium andright ventricle. Note the dilated pulmonary trunk. A right-to-left flow ofcontrast material from the pulmonary outflow tract through a smallpatent ductus arteriosus into the aorta is visible (arrow)

FIG 9. The heart viewed from the top. Windows have been cut into themain pulmonary artery and the descending aorta. A probe has beenpassed through the patent ductus arteriosus (PDA)

A B

PDA

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DISCUSSION

Pulmonary hypertension is defined asmean pulmonary arterial pressure of morethan 25 mmHg at rest and more than 30mmHg during exercise (Perry 1991). Inthis case, the peak velocity of tricuspidregurgitation (4 m/second) was translatedinto a pressure gradient across the tricuspidvalve of 64 mmHg using the modifiedBernoulli equation. As the dog was in rightheart failure, a right atrial pressure of 8 to 15 mmHg was estimated. Right ven-tricular pressure was therefore assumed to be about 72 to 79 mmHg by adding theright atrial pressure to the transtricuspidgradient (Oh 1999).

In the absence of pulmonic stenosis, the right ventricular systolic pressure is equalto systolic pulmonary artery pressure, indi-cating severe pulmonary hypertension. Pul-monary insufficiency over 2·5 to 3 m/secondis consistent with a pressure gradient of morethan 25 mmHg. Normal diastolic pul-monary artery pressure would be around 5to 15 mmHg. Since pulmonary systolicpressure was increased, it is reasonable toassume that diastolic pulmonary artery pres-sure was also increased by a similar amount.Because of the elevated peak of pulmonaryregurgitation velocity (PPRV), mean pul-monary artery pressure (MPAP) was esti-mated as 36 mmHg (MPAP = 4�PPRV2),consistent with severe pulmonary hyper-tension (Masuyama and others 1986).

In dogs, pulmonary hypertension usu-ally develops secondarily to a predisposingcondition, such as left-to-right shuntingcardiac malformations (Pyle and others1981, Turk and others 1981, 1982). As thedog was dyspnoeic from very early on inlife, it was more likely that the animal was genetically predisposed to develop plexogenic arteriopathy or PPH, whichoccurred independently of the PDA. Con-versely, the coexistence of a PDA couldhave contributed to and/or accelerated theprogression of PPA. A breed predispositionfor PPH which could be considered as anaccelerated development of pulmonaryhypertension associated with PDA has

been described in a family of PembrokeWelsh corgis (Oswald and Orton 1993).lll

A dog of this age presented with anuntreated PDA would be expected to beprimarily in left-sided heart failure. A left-to-right shunting PDA may be accompa-nied by mild pulmonary hypertension,due to the pulmonary hyperperfusion, but,in general, pulmonary arterial pressureremains much lower than the systemicarterial pressure, and pulmonary hyperten-sion and right-sided heart failure would beexpected at a later stage of the disease. Pul-monary hypertension in a dog with PDAyounger than 24 months of age might berelated to another primary pulmonarycondition (Van Israel and others 2003). Incases of primary right-to-left shuntingPDA, the development of pulmonaryhypertension is described as a slow, gradualprocess (Pyle and others 1981).

Pulmonary hypertension associated withright-to-left shunting PDA in dogs could be the result of maintained pulmonary vascular resistance at birth, or an acquiredlung disease due to the pulmonary hyper-perfusion (Oswald and Orton 1993).

Echocardiography in this case revealedweak positive systolic flow signals throughthe main pulmonary artery and throughthe PDA, whereas during anaesthesia andangiography the flow was reversed. Thiswas explained by the anaesthesia-induceddrop in systemic arterial blood pressure,because Eisenmenger’s syndrome (definedas pulmonary vascular obstructive diseasethat develops as a consequence of a largepre-existing left-to-right shunt, so that pul-monary artery pressures approach systemiclevels and the direction of the flowbecomes bidirectional or right-to-left) usu-ally develops after a longer period ofincreased pulmonary blood flow (Barst2001) and would only be expected in dogswith large PDAs (Buchanan 2001). As thesize of the PDA in this case was small(Schneider and others 2003), the rapiddevelopment of clinical signs cannot beexplained by the PDA alone.

Contrary to cases of primary right-to-left shunting where left ventricular volume

overload would be expected, left ventricu-lar pseudohypertrophy was evident in thiscase. Reduction of left ventricular end-diastolic and systolic volumes supportedthe hypothesis of left ventricular underfill-ing due to PPH. The concentric andeccentric right ventricular hypertrophy,which was confirmed by necropsy, wouldbe expected in acquired rather than in pri-mary pulmonary hypertension. Pure con-centric ventricular hypertrophy is morecommonly observed in PPH. In acquiredpulmonary hypertension a greater degreeof pulmonary artery dilatation would alsobe expected (Fig 4).

In cases of PPH, haematological andbiochemical blood testing are usually nor-mal, whereas a polycythaemia should bepresent in cases of chronic right-to-leftshunts. This could not be found in thiscase.

The increased size of the pulmonaryarteries apparent on radiography was dueto intimal cellular proliferation and fibro-sis, and medial hypertrophy, leading toincreased wall thickness and the impres-sion of increased pulmonary vasculature.Angiography reflects only the amount ofblood within the pulmonary arteries,which was certainly reduced due to plexo-genic alterations.

In humans, the distribution of plexi-form lesions varies depending upon theaetiology of pulmonary hypertension. Insevere cases of pulmonary hypertension,due to congenital heart disease, PPA is seenin early infancy (Yamaki and others 1998).The frequency of preacinar plexiformlesions was higher in PPA than in cases of acquired pulmonary hypertension (Jamison and Michel 1995). In PPA, thepulmonary veins are usually not involved.In sustained pulmonary hypertension dueto plexogenic arteriopathy, cellular intimalproliferation and concentric laminar inti-mal fibrosis are characteristic intimal reac-tions, which usually do not occur in thefirst year. Thrombotic or fibrinoid lesionsare found increasingly with long-standingpulmonary hypertension (Wagenvoort1994).

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The pulmonary vascular lesions in thiscase were not pathognomonic for PPH butrepresentative of a chronic, severe pul-monary hypertensive state, which couldnot be explained by a small- to medium-sized left-to-right shunting PDA alone.

ConclusionsTherapeutic management of pulmonaryhypertension depends on the possibility ofidentifying the underlying cause and thetimeliness of initiating therapy to reversethe progression. In cases of PDA, definitiveidentification of the underlying cause ofpulmonary hypertension is important, inorder to estimate the prognosis for surgicalintervention and to recognise operativecontraindications in time. PPA increasesthe risk of vasoconstrictive crisis of the pul-monary arteries during surgical proceduresor immediately thereafter. Any dog with asmall PDA (clinical type 1 or 2) showingearly development of clinical signs shouldbe considered to have additional PPH. In cases where severe pulmonary disease is suspected, lung biopsies should beanalysed preoperatively. If primary pul-monary lesions are present, surgery shouldbe avoided because of the poor prognosis.ll

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