Pulmonary hypertension (PH) is defined as persistently increased pressure within the pulmonary vasculature (17,18). Right heart catheterization is regarded as the gold standard diagnostic method for PH. However, there is a risk of general anesthesia it being relatively invasive. Doppler-echocardiography, instead, can aid in non-invasive measurement of systolic or diastolic pulmonary arterial pressure in the presence of tricuspid or pulmonic regurgitation using the simplified Bernoulli equation (3,20).

Dogs with PH can be categorized into 6 groups according to their contributing factors, and PH due to respiratory disease and/or hypoxia corresponds to Group 3 (17,21). Brachycephalic obstructive airway syndrome (BOAS), along with tracheal collapse, interstitial lung disease, and infectious pneumonia., is a known cause of PH in Group 3 (17). BOAS refers to a combination of the elongated soft palate, stenotic nares, and everted laryngeal saccules, all of which are commonly shown in brachycephalic breeds (24). BOAS parallels obstructive sleep apnea/sleep-disordered breathing in human models (8). Both syndromes predispose patients to chronic airway obstruction and can lead to chronic intermittent hypoxia (5). In dogs, hypoxia acts as a very strong vasoconstrictor and directs the blood flow from alveoli with poor ventilation to the better-oxygenated areas of the lungs, optimizing ventilation-perfusion matching (24). Vasoconstriction and vascular remodeling by hypoxia lead to increased pulmonary vein resistance, ultimately resulting in PH (2). Notably, PH is often associated with right-sided heart failure (RCHF) (17).

Albeit respiratory disease/hypoxia (Group 3) being the second most common cause of PH in dogs, with a median prevalence of 22% across several studies (10,14,19,23), there is only a paucity of information on clinical and diagnostic characteristics of PH solely caused by BOAS, with one study reporting that it accounts for only 2% among Group 3 patients (9).

This report shows successful management and follow-up of PH solely caused by breed-specific predisposition.

A 15-year-old, neutered male, Shih-Tzu weighing 6.47 kg was presented at the Chonnam National Veterinary Medical Teaching Hospital for evaluation of a 1-month history of persistent coughing, exercise intolerance, and abnormal heart sound without any preceding event. The dog had been showing stridor and open mouth breathing at home since young as well. The patient was up-to-date with its vaccinations and anthelminthic treatments.

Physical examination showed bilateral stenotic nares and a very overweight body type, with a BCS of 7/9, and stenotic nares. On thoracic auscultation, a split-second heart sound and a wheezing sound were detected on both sides of the chest walls. Thoracic radiographs revealed cardiomegaly (VHS 11.2; reference interval = 8.9-10.1), mild MPA bulging, mild interstitial infiltration, and hepatomegaly. There was no tracheal or bronchial collapse (Fig. 1). The electrocardiogram showed right axis deviation, suggesting right ventricular hypertrophy (Fig. 2). The echocardiographic study showed no signs of congenital defects, left heart disease, or parasitic disease (Fig. 3A, B). The left ventricle was severely under-filled, with low end of the fractional shortening (FS) (36.5%; reference interval = 33-46%) and low left ventricular internal diameter end diastole (LVIDd) (13.1; reference range = 18.3-23.6). The left ventricular end diastolic diameter normalized for body weight (LVIDdN) was 1.36 (reference range = 1.27-1.85) (Fig. 3C) Moderate tricuspid regurgitation (TR) that filled approximately 40% of the right atrium during the systolic phase was detected. The maximal tricuspid systolic velocity was 3.86 m/s (reference <2.8 m/s) (9) with a peak tricuspid pressure gradient of approximately 59.6 mmHg, which is graded as moderate PH (reference of peak TR velocity <2.8 m/s ; reference interval of moderate PH = 3.4-4.3 mmHg) (20) (Fig. 3D). The rapid acceleration of the pulmonic flow profile was not identified. Blood tests confirmed thrombocytosis (746 K/µL; reference interval = 148-484 K/µL). As coagulation factors (prothrombin time, activated partial thromboplastin time, D-dimer test) showed no remarkable findings and no vascular abnormalities were detected on chest x-rays, the possibility of pulmonary emboli/thrombi/thromboemboli was excluded. Both the immunological examination (SNAP 4Dx Plus Test; IDEXX Laboratories, Inc., Westbrook, ME) for adult heartworms and the microscopic test for microfilariae were negative. Respiratory infection was ruled out by Realtime Polymerase Chain Reaction (Respiratory Disease (CRD) RealPCR™ Panel (Comprehensive) – Canine; IDEXX Laboratories, Inc., Westbrook, ME).

Figure 1. Right lateral (A) and ventrodorsal (B) thoracic radiographs at presentation. Radiographs demonstrated cardiomegaly (VHS: 11.2; reference interval = 8.9-10.1), mild MPA bulging (white arrow), mild increase in lung opacity with diffuse interstitial lung pattern, and hepatomegaly. Note that the cardiac silhouette is seen as a “reverse D” shape on the ventrodorsal view due to right cardiac hypertrophy (B).

Figure 2. Electrocardiogram at presentation. Right axis deviation is identified, which might indicate the presence of right ventricular hypertrophy.

Figure 3. Echocardiographic images at presentation. No hints of myxomatous change of mitral valve, congenital defects, or parasitic disease were found on the right parasternal 4-chamber view (A). No pathological mitral regurgitation was detected on the color Doppler map (B). Note the poorly filled left ventricle in M-mode (C). In the left apical 4-chamber view, moderate TR was detected. Tricuspid systolic velocity was 3.86 m/s (reference <2.8 m/s), indicating a peak tricuspid pressure gradient of approximately 59.6 mmHg, which is graded as moderate pulmonary hypertension (reference interval of moderate PH = 3.4-4.3 m/s) (D). RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle.

Based on the clinical signs and diagnostic findings, the dog was diagnosed with PH caused by BOAS. To address recognized offending triggers of the respiratory clinical signs, the dog was instructed to start weight control by restricting caloric intake and managing susepcted concurrent Cushing’s syndrome. Medical therapy with selective phosphodiesterase five inhibitors (PDE5i) (sildenafil citrate, 2 mg/kg PO twice daily; PalPal tab, Hanmi Pharm, Seoul, Korea) and heart failure medications, including pimobendan (0.3 mg/kg PO twice daily; Vetmedin^® tab, Boehringer Ingelheim Vetmedica GmbH, Ingelheim, Germany), ramipril (0.125 mg/kg PO once daily; Triace^® tab, Handok Pharm, Seoul, Korea), and furosemide (0.5 mg/kg PO twice daily; Lasix^® tab, Handok Pharm, Seoul, Korea), was initiated. The patient was also prescribed a commercially available dietetic food. Hyperadrenocirticism was diagnosed on the basis of clinical symptoms, blood tests, and endocrinological tests using the administration of a synthetic ACTH compound (tetracosactide acetate, 1 mg/dog, intravascular injection (iv); Synacthen inj, Dalim Pharm, Seoul, Korea). Serum cortisol concentration before ACTH stimulation was >10 µg/dL (reference interval = 2-6 µg/dL), which increased to >30 µg/dL after stimulation (reference interval = 6-18 µg/dL). The case was diagnosed with pituitary-dependent hyperadrenocorticism after high-dose dexamethasone suppression test (baseline cortisol concentration = 3.0 µg/dL, cortisol post 4 hours = 1.1 µg/dL, cortisol post 8 hours = 1.6 µg/dL). The dose of trilostane (Vetoryl^® Cap, Dechra Pharm, Northwich, England) was adjusted over 5 months with a monthly ACTH-stimulation test, with a starting dose of 0.3 mg/kg PO once daily to be finally settled to 0.3 mg/kg PO twice daily.

After five months of management with medications and diet, the patient’s clinical signs including coughing and exercise intolerance improved. The patient reached its ideal bodyweight, 5.1 kg, with a BCS of 5/9. On thoracic radiographs, a mild decrease in cardiac size (VHS 10.9; reference interval = 8.9-10.1) was noted and hepatomegaly was improved (Fig. 4). The echocardiographic study showed partial improvement in FS and LVIDd. The maximal tricuspid systolic velocity was 3.4 m/s with an approximate peak tricuspid pressure gradient of 46.57 mmHg which is graded as mild PH (reference interval of mild PH = 2.8-3.4 m/s) (20), which suggests significant improvement in the severity of PH (Fig. 5).

Figure 4. Right lateral (A) and ventrodorsal (B) thoracic radiographs were obtained 5 months after treatment. Radiographs demonstrated a mild decrease in cardiac size (VHS 10.9; reference interval = 8.9-10.1) and improvement in hepatomegaly.

Figure 5. Echocardiographic images were obtained 5 months after treatment. Note the partial improvement in LVIDd and FS (A). Tricuspid systolic velocity was 3.41 m/s, indicating a peak tricuspid pressure gradient of approximately 46.57 mmHg, which is graded as mild PH (B).

During a follow-up period of 5 months, the patient did not report further recurrence of respiratory distress.

This study illustrates a clinical case of PH caused by BOAS in a dog. Presumptive diagnoses of PH due to respiratory disease/hypoxia in dogs are often made based on clinical signs alone and exclusion of left-sided heart disease without definitive diagnostics to determine the underlying etiology (23). In history taking, cough (72.0%), increased respiratory effort (30%), and exercise intolerance (2.3%) are the most common clinical signs presented by a dog with pulmonary hypertension (9). In this case, at the time of diagnosis, the patient had stridor and stenotic nares which are key characteristics of BOAS, and respiratory clinical signs such as exercise intolerance and coughing. The patient had RHF, moderate TR, and moderate PH. All the other potential causes of PH were ruled out, including pulmonary emboli/thrombi/thromboemboli, parasitic diseases such as Dirofilaria, congenital defects, and left heart disease. Other obstructive airway disorders and primary pulmonary parenchymal disease were excluded as well. Based on these results, the dog was diagnosed with PH caused by BOAS.

Canine pulmonary hypertension patients with BOAS are recommended to undergo surgical procedures early in life (e.g. surgery of elongated soft palate, stenotic nares, aberrant rostral and caudal turbinates, and everted saccules) to minimize the progression of clinical signs and avoid the potential development of PH (4,16). However, as PH and associated right-sided heart failure signs mostly appear in middle-aged to senior dogs (12), surgical treatment might be frustrated due to their high anesthetic risk.

In humans, the standard treatment for PH due to respiratory disease/hypoxia is long-term oxygen supplementation rather than management with medications (e.g. sildenafil) (6). However, in veterinary medicine, long-term oxygen therapy is impractical for most pet owners, highlighting the importance of medications. Currently, in veterinary medicine, only phosphodiesterase inhibitors are used for PH treatment (22). There are reports demonstrating the efficacy of sildenafil citrate, a phosphodiesterase 5 inhibitor, in ameliorating clinical signs of PH in dogs (13). Pimobendan, a calcium sensitizer and phosphodiesterase 3 inhibitor, has also been suggested as a treatment for pulmonary hypertension (24). Although pimobendan has no direct or clear evidence ton its benefits in pre-capillary pulmonary hypertension (17), in the present case, dual therapy with pulmonary arterial dilators was initiated to ameliorate the potential progression of congestive heart failure and persistent clinical signs (1).

In obese patients, weight loss can decrease the severity of respiratory distress by increasing thoracic wall compliance and decreasing extra-thoracic and intra-abdominal adipose tissue (15). Moreover, hormonal diseases such as hyperadrenocorticism are reported correlate with obesity in dogs and cats (7). Therefore, the present case was instructed to lose weight by limiting caloric intake and managing concurrent Cushing’s syndrome.

This case report has some limitations. First of all, we could not completely rule out the influence of hyperadrenocorticism on the development of PH. However, PH caused by hyperadrenocorticism is generally related to pulmonary thromboemboli (11,17). Since in this case the possibility of thromboembolism was excluded by coagulation tests and thoracic radiographs, its influence would be minimal. Secondly, this study did not completely resolve the underlying respiratory disorder, BOAS. As mentioned earlier, pulmonary hypertension patients with BOAS are recommended to undergo surgical procedures (4,16). Thirdly, the diagnosis of BOAS was only tentative because we could not identify the presence of everted laryngeal saccule or paralysis which should be done under light anesthesia. However, the surgical procedures or confirmation of other structural abnormalities associated with BOAS of the patient in this study were frustrated by the owner’s reluctance to anesthesia. Lastly, it is unclear what was direct to improving pulmonary hypertension, between weight loss and administration of phosphodiesterase inhibitors. Despite these limitations, the present case is a rare report demonstrating that breed predisposition can independently induce PH and RHF in dogs.

In conclusion, based on our findings, we suggest regular cardiovascular function check-ups and management of ideal body weight in middle-aged to senior brachycephalic dogs to prevent congestive heart failure or pulmonary hypertension.

This report shows a significant improvement with medication therapy in PH due to BOAS. In addition, it highlights the importance of identifying underlying respiratory disorders and implementing medication therapy whenever possible.

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2020R1A2C2005364).

The authors have no conflicting interests.