Severe pulmonary hypertension and cardiovascular sequelae in dogs - Veterinary Medicine
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Severe pulmonary hypertension and cardiovascular sequelae in dogs
Once thought to be caused mostly by dirofilariasis, pulmonary hypertension is still being seen despite heartworm preventive measures, signifying additional important causes. Technologic advances may help us recognize the signs in time.


Follow-up and outcome

The dog was returned to the teaching hospital a week after discharge. The owner indicated that coughing and general weakness continued. An arterial blood gas analysis (pH = 7.365, normal = 7.324 to 7.459; PCO2 = 24.9 mm Hg, normal = 27.7 to 41.2 mm Hg; PO2 = 64.9 mm Hg, normal = 84.7 to 116.1 mm Hg; oxygen saturation = 91.3%, normal = 96% to 98.2%) continued to reveal severe hypoxemia. The prednisone was discontinued but the antibiotics and prazosin were continued.

Four additional teaching hospital visits were made over the ensuing 10 weeks. Although the dog was never without clinical signs related to hypoxemia, there was a period when the echocardiographic signs of cor pulmonale improved. While substantial right ventricular hypertrophy remained, the right ventricular chamber appeared to be smaller than at previous examinations, and the tricuspid regurgitation was minimal in volume and at times was difficult to identify. During this time, the pulmonary regurgitation jet could not be seen, but the PO2 in the arterial blood remained at 60 mm Hg. Several complete blood counts were performed in this dog, and they did not show evidence of polycythemia. Therapy included 20 mg/kg theophylline given orally twice a day and 0.33 mg/kg prednisone given orally every other day.

At an evaluation done 12 weeks after the surgery at the teaching hospital, the dog was exhibiting extreme dyspnea, and the owner reported a recent syncopal episode and seizure. Since the dog's quality of life was unacceptable to the owner, the dog was euthanized. A complete necropsy was performed.

The necropsy revealed an enlarged spleen with tan foci throughout. Histologic examination of the spleen showed multiple lipid foci with some hematopoietic cells. The right medial and lateral liver lobes were enlarged and adhered by fibrin. Multiple tan nodules were noted in all liver lobes. Histologic evaluation of the liver revealed portal fibrosis. Grossly, there were numerous 1- to 2-mm mineralized masses in the pleura and all lung lobes. The caudal lung lobes had distinct red areas that formed a mosaic pattern. Histologically, the terminal bronchioles contained lymphocytes, plasma cells, and neutrophils, and these cells extended into the adjacent alveoli. Cultures of the pulmonary parenchyma were not done. Arteriosclerosis was evident in some pulmonary arteries (Figure 5), and in situ thrombosis was apparent. Right ventricular hypertrophy was noted. The pathologic diagnoses were splenic lipomas with hematopoiesis, muscular atrophy of the larynx, branchial cyst of the thymus, mild bronchopneumonia, and adnexal dysplasia of the skin.

Types of pulmonary hypertension

Pulmonary hypertension is either primary or secondary. Primary pulmonary hypertension cases are those without a known cause; secondary pulmonary hypertension cases relate to discernible causes.3 Primary pulmonary hypertension in dogs is rare.4 Secondary pulmonary hypertension in people is a common sequela of chronic obstructive pulmonary disease (COPD). A diagnosis of COPD in people is based on abnormal expiratory flow results that do not change spontaneously over short periods or after administration of bronchodilators.5 The two most common causes of COPD are bronchitis and emphysema. Secondary pulmonary hypertension in dogs can be caused by many factors, including bronchiectasis, emphysema, infiltrative pulmonary diseases, pulmonary thromboembolism, and heartworms.1

Control of pulmonary vascular tone

In recent years, great progress has been made in understanding the mechanisms involved in the control of pulmonary arterial function. Multispecies research has shown that pulmonary vascular resistance can vary widely, and, increasingly, the endothelial cells lining the pulmonary vessels appear to play a principal role because they are directly or indirectly involved with many of the substances that can cause vasodilation or vasoconstriction of the pulmonary arteries.3 Indeed, endothelial cells can look normal histologically but function abnormally. Prostaglandins, produced by lung tissue, are important in pulmonary vascular regulation. PGI2 (prostacyclin) and PGE2 are vasodilators, while PGF and PGA2 are vasoconstrictors. Prostacyclin is also released by the endothelial cells. In addition to causing vasodilation, it can inhibit platelet aggregation by activating adenylate cyclase. Nitric oxide has a biologic action similar to prostacyclin in that it causes relaxation of vascular smooth muscle. This is the rationale for using sildenafil in patients with pulmonary hypertension. Nitric oxide is released from endothelial cells in response to physiologic stimuli including thrombin, bradykinin, and blood flow (shear stress). Nitric oxide inhibits platelet activation and creates an antithrombotic property on the endothelial surface.3

Vasoconstrictors include thromboxane from platelets and macrophages, endothelin from endothelial cells, and angiotensin II that is generated in the lung from the conversion of angiotensin I. Endothelin has a long half-life, which can lead to prolonged vasoconstriction. Serotonin, derived from platelets, can be a vasodilator or vasoconstrictor depending on the clinical circumstances. Serotonin can act as a growth factor and contribute to vascular medial hypertrophy and promote vascular remodeling.3

Low alveolar oxygen tension is a strong stimulus for rapid pulmonary vasoconstriction. This vasoconstriction is a well-recognized adaptive mechanism for shunting blood flow away from poorly ventilated areas of the lung to better ventilated areas. Hypoxia inhibits outward potassium currents throughout the pulmonary vasculature, resulting in depolarization of the pulmonary vascular smooth muscle. This depolarization allows calcium entry into voltage-dependent calcium channels, promoting vascular contraction. Calcium can also be mobilized intracellularly from the sarcoplasmic reticulum, mitochondrial membrane, and inner aspect of the cell membrane. A reduction in nitric oxide production has been demonstrated in chronically hypoxic piglets and rats, and prolonged inhalation of nitric oxide attenuates hypoxic pulmonary vasoconstriction and vascular remodeling.3,5

Changes in alveolar oxygenation can directly affect the oxygenation of small pulmonary arteries and arterioles by direct gaseous diffusion as well as promote low oxygen tension in the blood of these small vessels. The arteries and arterioles appear to be the primary site for vasoconstriction and increased resistance during hypoxia. Acidosis frequently accompanies hypoxia and can act synergistically with hypoxia to promote pulmonary vasoconstriction.5

Vascular remodeling from hypoxia is mediated by growth factors including platelet-derived growth factor A and B in hypoxic rats.5 Vascular endothelial growth factor is an endothelial-cell–specific mitogen that can be involved in pulmonary vascular injury and endothelial cell proliferation because of its permeability, angiogenesis, proinflammatory properties, and specificity for endothelial cells. Angiotensin-converting enzyme (ACE) and angiotensin II may play important roles in the development of right ventricular hypertrophy. ACE inhibitors have been shown to attenuate the development of pulmonary hypertension in rats exposed to chronic hypoxia.5


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