Signalment:  

Five-month-old, female, Yorkshire terrier, caninePresented to referring veterinarian at 3 months of age with V/VI continuous murmur. Referred to University of Tennessee Veterinary Teaching Hospital 2 months later:
Radiographs: Right-sided cardiomegaly with enlarged right pulmonary artery segment (Fig. 1-1) Echocardiogram and Doppler measurements used to estimate pulmonary artery pressures:
First Pass Cardiac Nuclear Scintigraphy: Cephalic vein bolus injection traced first to right atrium and then to liver and other abdominal organs - very little went to the lungs - interpreted to reflect high magnitude right to left shunt.

Patient was euthanized after developing apnea and bradycardia. Necropsy was delayed due to scintigraphy study, resulting in some autolysis. Owners requested cosmetic exam restricted to thorax.


Gross Description:  

Two ml of a clear red-tinged fluid was present in the pericardial sac. The right atrium and ventricle were markedly dilated, the right auricle approximately 2-3 times the size of the left. The main pulmonary arterial segment (PAS) was greatly dilated with a diameter of approximately 1 cm extending 2 cm from the heart base to the area of the patent ductus arteriosus (PDA) where the PAS and proximal descending aorta appeared to be fused from the exterior aspect (Fig. 1-2). The connection between the two vessels was 0.33 cm externally and the internal diameter was approximately 3 mm (Fig. 1-3). Distal to the PDA the pulmonary artery narrowed abruptly entering the lung. 


Histopathologic Description:

Lung: There are scattered areas of soft tissue mineralization (alveolar walls, bronchial basement membranes) with some emphysema, edema, proliferation of type II pneumocytes and accumulation of alveolar macrophages (Fig. 1-4). Some large to medium sized pulmonary arteries contain asymmetric areas of intimal thickening and basophilia (reactive myxomatous matrix) or dense proteinic eosinophilia (Fig. 1-5, 1-6) . Scattered smaller arteries have segmental areas of intimal to medial basophilia or marked smooth muscle thickening of the wall - in some cases vessels are largely obscured by knots of proliferating plump spindle cells, sometimes forming capillaries (fibroblasts and/or endothelium) and sometimes forming bulging masses apparently at branch points. Trichrome stains reveal alveolar wall collagen deposition in scattered areas, sometimes associated with emphysema, increased collagen around some affected small arteries and the fibrotic nature of intimal proliferative lesions (Fig. 1-7, 1-8, 1-9, 1-10).


Morphologic Diagnosis:  

1. Marked multifocal pulmonary arterial intimal sclerosis and medial hypertrophy with fibro-endothelial proliferation
2. Mild multifocal alveolar fibrosis and emphysema
3. Moderate multifocal bronchial and alveolar mineralization


Lab Results:  

CBC, blood glucose, electrolytes and coagulation panel unremarkable except for low platelet count Urinalysis: SG 1.019, pH 5.5, 2+ proteinuria, 0-1 WBC/hpf, 1-3 RBC/hpf, many granular casts, trace bacteria


Condition:  

Pulmonary hypertension


Contributor Comment:  

The clinical and necropsy findings, including pulmonary arterial lesions, are essentially identical to those described by J.W. Buchanan in dogs with hereditary PDA and a right to left pressure gradient.2 The clinical work up clearly indicated a right to left shunting of blood flow in this case. There are two possible explanations for this right to left pressure gradient in the context of a PDA:
1. The pulmonary vasculature does not respond (dilate) as it should at birth, with inflation of the lung, and the prenatal pressure gradient from right heart to left is maintained after birth. 
2. After birth the normal shift in pressure gradient occurs across the ductus and shunting of blood across the PDA from the left to right outflow tracts results in increased circulation through the pulmonary vasculature. Eventually this over-circulation induces arterial sclerosis, hypertension and reversal of the gradient across the ductus from right to left.
While either scenario is possible with this clinical presentation, the histologic arterial changes and pulmonary arterial pressures, as per analysis of echocardiograms, are more consistent with the latter. The vascular lesions in the lung are most consistent with a reactive change and would also exacerbate the progression of hypertension over time. The distinct murmur detected at 3 months of age and absent 2 months later, just before euthanasia, likely reflects this dynamic process as hypertension developed and resulted in changes in blood flow through the ductus. 

The etiology of pulmonary mineralization is most likely related to azotemia. Urinalysis suggested significant tubular damage but BUN and creatinine values were not available and kidneys were not examined because necropsy was restricted to the thorax. 


JPC Diagnosis:  

1. Lung, artery: Pulmonary arteriopathy characterized by subintimal and medial hypertrophy, intimal fibrosis and cellular thickening, plexiform lesions, and arteritis, Yorkshire terrier (Canis familiaris), canine.
2. Lung: Mineralization, interstitial, vascular, multifocal.
3. Lung: Edema, multifocal, moderate. 


Conference Comment:  

Pulmonary hypertension occurs when the mean pulmonary arterial pressure is greater than 25 mmHg at rest or more than 30 mmHg during exercise.9,13 Secondary pulmonary hypertension may occur following conditions that lead to increased left atrial pressure or increased pulmonary vascular resistance (heartworm disease, chronic respiratory disease, thromboembolism, and vascular remodeling).5,6,8 Primary pulmonary hypertension on the other hand is defined as pulmonary hypertension of unknown cause.3,6

Pulmonary arteriopathy (plexogenic pulmonary arteriopathy) is a condition characterized by constrictive and complex, obstructive, and proliferative vascular lesions in the pre- and intra-acinar pulmonary arteries that results in pulmonary arterial hypertension and eventually right-sided heart failure.20 Pulmonary arterial hypertension with pulmonary arteriopathy can be subdivided into idiopathic, familial and associated with risk factors or conditions. Most cases in dogs have been idiopathic or associated with congenital heart disease, particularly patent ductus arteriosus.9,16 Histologic lesions include plexiform lesions of the small arterioles with concentric intimal cellular proliferation and fibrosis, non-specific medial hypertrophy, muscularization of arterioles, fibrinoid degeneration and arteritis.1,2,7,9,15,16 The association between pulmonary hypertension and the development of pulmonary arteriopathy is not fully understood as each may contribute to the formation of the other.

The pathogenesis of the changes within the small and medium sized pulmonary arteries seen in cases of pulmonary hypertension is not clear. Potential factors associated with this condition may be due to a genetically based hyperreactivity of pulmonary arteries18, sheer stresses on the pulmonary arteries, injury to the pulmonary endothelium, or changes induced by toxins, drugs and infections.6,11,14,19 Chronic changes within the pulmonary arteries due to increased flow have been associated with altered nitric oxide and endothelin respones.4 Endothelin-1, a potent vasoconstrictor, has been associated with increased pulmonary flow in left-to-right shunts independent of pulmonary artery pressure.4,17 Pulmonary arteries exposed to high flow and pressure also have been reported to have increased levels of VEGF, which suggests the ongoing process of tissue remodeling.10,12


References:

1. Berger RMF, Geiger R, Hess J, Bogers AJ, Mooi WJ: Altered arterial expression patterns of inducible and endothelial nitric oxide synthase in pulmonary plexogenic arteriopathy caused by congenital heart disease. Am J Respir Crit Care Med 163:1493-1499, 2001
2. Buchanan, JW: Patent ductus arteriosis morphology, pathogenesis, types and treatment. J Vet Cardiol 3:7-16, 2001
3. Fishman AP: Pulmonary hypertension. In: Hurst's The Heart, eds. Alexander RW, Schlant RC, Fuster V, 9th ed., pp. 1699-1717. McGraw-Hill, New York, NY, 1998
4. Gavaghan BJ, Lapointe JM, Thomas WP: Acute onset of pulmonary necrotising arteritis in a dog with a left-to-right patent ductus arteriosus. Aust Vet J 76:786-791, 1998
5. Glaus TM, Hauser K, Hassig M, Lipp B, Reusch CE: Non-invasive measurement of the cardiovascular effects of chronic hypoxaemia on dogs living at moderately high altitude. Vet Rec 152:800-803, 2003
6. Glaus TM, Soldati G, Maurer R, Ehrensperger F: Clinical and pathological characterisation of primary pulmonary hypertension in a dog. Vet Rec 154:786-789, 2004
7. Heath D, Edwards J: The pathology of hypertensive pulmonary vascular disease: a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 18:533-547, 1958
8. Johnson L, Boon J, Orton EC: Clinical characteristics of 53 dogs with Doppler-derived evidence of pulmonary hypertension: 1992-1996. J Vet Intern Med 13:440-447, 1999
9. . Kolm US, Amberger CN, Boujon CE, Lombard CW: Plexogenic pulmonary arteriopathy in a Pembroke Welsh corgi. J Sm Anim Pract 45:461-466, 2004
10. Lam CF, Peterson TE, Croatt AJ, Nath KA, Katusie ZS: Functional adaptation and remodeling of pulmonary artery in flow-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 289:H2334-H2341, 2005
11. Lee S, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM: Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 101:927-934, 1998
12. Mata-Greenwood E, Meyrick B, Soifer SJ, Fineman JR, Black SM: Expression of VEGF and its receptors Flt-1 and Flk-1/KDR is altered in lambs with increased pulmonary blood flow and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 285:L222-L231, 2003
13. Perry LA, Dillon AR, Bowers TL: Pulmonary hypertension. Comp Cont Educ Pract 13:226-232, 1991
14, Rubin LJ: Primary pulmonary hypertension. N Engl J Med 336:111-117, 1997
15. Tuder RM, Groves B, BAdesch DB, Voelkel NF: Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 144:275-285, 1994
16. Turk JR, Miller JB, Sande RD: Plexogenic pulmonary arteriopathy in a dog with ventricular septal defect and pulmonary hypertension. J Am Anim Hosp Assoc 18:608-612, 1982
17. Vincent JA, Ross RD, Kassab J, Hsu JM, Pinsky WW: Relation of elevated plasma endothelin in congenital heart disease to increased pulmonary blood flow. Am J Cardiol 71:1204-1207, 1993
18. Wagenvoort CA: Open lung biopsies in congenital heart diseases for evaluation of pulmonary vascular disease: predictive value with regard to corrective operability. Histopathol 9:417-436, 1985
19. Yeager ME, Halley GR, Golpon HA, Voelkel NF Tuder RM: Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res 88:e2-e11, 2001
20. Zabka TS, Campbell FE, Wilson DW: Pulmonary arteriopathy and idiopathic pulmonary arterial hypertension in six dogs. Vet Pathol 43:510-522, 2006

A virtual slide is not available for this case.


(Fig 1-1) Thoracic radiograph


(Fig 1-2) Heart, great vessels and lungs


(Fig 1-3) Heart, great vessels and lungs


(Fig 1-4) Lung, vessel


(Fig 1-5) Lung, vessel


(Fig 1-6) Lung, vessel


(Fig 1-7) Lung


(Fig 1-8) Lung


(Fig 1-9) Lung


(Fig 1-10) Lung


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