Diastolic heart failure associated with hemangiosarcoma infiltrating left ventricular walls in a dog

Abstract

A 9-year-old Shetland sheepdog was diagnosed with cardiogenic pulmonary edema. Echocardiography revealed focally thickened left ventricular free wall and interventricular septum and left atrial dilation. Left ventricular systolic function was preserved. Doppler echocardiography of transmitral flow indicated restrictive left ventricular filling. Cardiac histopathology demonstrated hemangiosarcoma infiltrating the left ventricular walls.

Cardiac tumors occur infrequently in the canine population. A previous large retrospective study reported 1383 dogs with cardiac tumors from a population of 729 265 dogs (0.19% incidence) in a veterinary medical database from 1983 to 1995 (1). The most common primary cardiac tumor in dogs is hemangiosarcoma, followed by aortic body tumors, whereas common secondary (metastatic) cardiac tumors include hemangiosarcoma, carcinoma, and lymphoma (1,2). The clinical manifestations caused by cardiac tumors are more closely associated with their anatomic location and resultant hemodynamic changes than with their histologic types. Clinical signs are commonly related to cardiac tamponade caused by pericardial effusion, arrhythmia, or obstruction of ventricular inflow or outflow tract secondary to an intracavitary or intramural lesion (3–6).

Cardiogenic pulmonary edema is a rare clinical manifestation in dogs with cardiac tumors, and has been reported to be associated with systolic heart failure secondary to hemangiosarcoma infiltrating into the left ventricular wall (3), left ventricular inflow tract obstruction secondary to a myxoma involving the mitral leaflets (7), and mitral regurgitation related to a schwannoma involving the mitral leaflets (8). This report describes the first canine case of cardiogenic pulmonary edema associated with diastolic heart failure secondary to cardiac hemangiosarcoma involving the left ventricular walls.

Case description

A 9-year-old, spayed female, Shetland sheepdog weighing 16.4 kg was referred for evaluation of acute dyspnea. Cardiogenic pulmonary edema was suspected by the referring veterinarian based on the presence of a sinus tachycardia (heart rate: 164 beats/min) and radiographic findings including cardiomegaly, a perihilar alveolar pattern, and pulmonary venous distension. The respiratory status had partially improved with 2 intravenous boluses of 1.2 mg/kg furosemide (Lasix Injection; Sanofi K. K., Tokyo, Japan) administered by the referring veterinarian. In addition, the patient had a 1-week history of a head tilt to the left and bilateral elevations of the third eyelids. There was no additional significant medical history.

On presentation, cardiac auscultation revealed a regular rhythm (heart rate: 112 beats/min) with no detectable cardiac murmur. The dog was tachypneic (respiratory rate: 60 breaths/min) with harsh lung sounds and pink mucous membranes. The patient was normothermic. As well as the head tilt and bilateral elevation of third eyelids, neurological examination revealed bilateral dilated pupils unresponsive to light, bilateral atrophy of the temporal and masseter muscles, and positional horizontal nystagmus with fast phase toward the right and ventrolateral strabismus in the left eye. Decreased postural reactions in left thoracic and pelvic limbs were observed, and spinal reflexes in those legs were exaggerated. The mental status, vision, and gait were normal. Otoscopic evaluation of the ear canal and tympanic membrane revealed no abnormalities. These neurological findings indicated a diffuse or multifocal brainstem lesion. Blood was obtained for evaluation of a complete blood (cell) count (CBC), blood chemistry, and hemostatic panel including prothrombin time, activated partial thromboplastin time, fibrinogen concentration, and D-dimer concentration. The results were unremarkable except for an elevated plasma D-dimer concentration [3.71 mg/L, reference range (RR): < 1.00 mg/L].

Thoracic radiographs indicated cardiomegaly (vertebral heart score 11.5, RR: < 10.5) comprised primarily of left ventricular and atrial enlargement with a perihilar alveolar pattern and pulmonary venous distension, indicating the presence of cardiogenic pulmonary edema (9).

Two-dimensional echocardiography revealed focal left ventricular thickenings involving the anterior, lateral, posterior, inferior, and septal walls of the left ventricle [body weight (BW)-normalized thicknesses 0.55 to 0.87, RR: < 0.53] (10). The thickened left ventricular posterior wall contained an ill-delineated hyperechoic area (Figures 1A, 1B). The BW-normalized left ventricular internal diameters at end-diastole (1.68, RR: 1.27 to 1.85) and end-systole (1.03, RR: 0.71 to 1.26) along with the fractional shortening (35.2%, RR: 23% to 47%) were within the RRs (10). The left atrium was dilated [left atrial to aortic diameter ratio (LA/Ao) from the right parasternal short axis view 3.0, RR: < 1.6] (11). The right ventricular free wall was thickened (BW-normalized thickness 3.88, RR: < 3.73) (12). There was an isoechoic pedunculated nodular mass (12.3 × 8.7 mm) involving the ventricular aspect of the pulmonary valve leaflet (Figure 1C). All other cardiac structures appeared normal. Color-flow Doppler evaluation identified no abnormalities except for trivial mitral regurgitation. Pulsed-wave Doppler echocardiography of transmitral flow indicated severe left ventricular diastolic dysfunction with elevated filling pressure (restrictive left ventricular filling) [early diastolic transmitral velocity (E) 0.65 m/s; late diastolic transmitral velocity (A) 0.22 m/s; ratio of E to A (E/A) 3.0]. Other left ventricular diastolic parameters were as follows (the RRs appropriate for the age, heart rate, and breed of the patient were unavailable): deceleration time of early diastolic transmitral flow (Edt) 53 ms; early diastolic septal mitral annular velocity (E′) derived from tissue Doppler imaging 3.0 cm/s; isovolumic relaxation time (IVRT) derived from septal mitral annular velocity 81 ms; ratio of E to E′ (E/E′) 21.7. No arrhythmia was detected throughout the echocardiogram. No mass lesions or ascites were identified by abdominal ultrasound.

Figure 1.

Transthoracic echocardiography in the dog. A — The right parasternal short axis view at the level of the papillary muscles, showing focal left ventricular thickenings involving the anterior, lateral, posterior, inferior, and septal walls of the left ventricle. The thickened left ventricular posterior wall contains an ill-delineated hyperechoic area (solid arrow). B — The right parasternal long axis view, showing the thickened left ventricular posterior wall, which contains an ill-delineated hyperechoic area (solid arrow). The left atrium appears dilated. C — The right parasternal short axis view at the level of the pulmonary arteries, showing a pedunculated nodular mass involving the ventricular aspect of the pulmonary valve leaflet (dashed arrow). The right ventricular wall appears thickened.

Differential diagnoses for the focal left ventricular hypertrophy included infiltrative neoplasia (3), myocarditis (13), hypertrophic cardiomyopathy (14), and secondary cardiomyopathies, such as amyloidosis and Fabry’s disease (a genetic lysosomal storage disease). Also, differential diagnoses for the pedunculated intracardiac mass comprised neoplasia, thrombus, and infective endocarditis. Following treatment with 2 additional boluses of 1.2 mg/kg furosemide and oxygen supplementation via a nasal cannula, the respiratory distress completely resolved 15 h after initial presentation. Then, the patient was discharged with a dose of enalapril (Enacard; Merial Japan, Tokyo, Japan), 0.30 mg/kg body weight (BW), PO, q24h, pimobendan (Vetmedin; Nippon Boehringer Ingelheim, Tokyo, Japan), 0.23 mg/kg BW, PO, q12h, torasemide (Luprac; Tanabe Mitsubishi Pharma, Osaka, Japan), 0.10 mg/kg BW, PO, q24h, aspirin (Aspirin; Mylan Seiyaku Ltd., Tokyo, Japan), 0.10 mg/kg BW, PO, q24h, and enrofloxacin (Baytril; Bayer Yakuhin, Osaka, Japan), 6.1 mg/kg BW, PO, q24h.

The dog was rechecked 1 wk after the initial visit. The respiratory status remained stable, and thoracic radiographs revealed the complete resolution of the perihilar alveolar pattern. Echocardiography demonstrated a reduction in the left atrial size (LA/Ao 2.2). The improvements of the left ventricular diastolic function and filling pressure were indicated by decreases in E/A (E 0.66 m/s; A 0.45 m/s; E/A 1.5) and E/E′ (10.5), and the increases in Edt (65 ms), E′ (6.2 cm/s), and IVRT (91 ms). The mass involving the pulmonary valve disappeared. On the next recheck (3 wk after the initial presentation), the dog remained free of respiratory signs, and neurological examination demonstrated partial improvement of the head tilt and strabismus, and bilateral normal-sized pupils partially responsive to light. However, 6 wk after the initial visit, the patient exhibited dyspnea and was returned to the referring hospital. Thoracic radiographs indicated the recurrence of cardiogenic pulmonary edema. The dog died at the referring hospital despite treatment.

A cardiac necropsy was performed by a board-certified veterinary pathologist. The necropsy of other organs was declined by the owner. The left ventricular free wall and papillary muscles, interventricular septum, and right ventricular free wall were markedly thickened with multiple dark red mottled foci diffusely located throughout the myocardium (Figure 2). No macroscopic lesions were observed in the atrial walls, valves, and pericardium. Histologically, all of the dark red foci in the left ventricular free wall and papillary muscles, interventricular septum, and right ventricular free wall were consistent with hemorrhages. The hemorrhagic lesions contained neoplastic mesenchymal cells, forming solid cellular aggregates and irregular, slit-like spaces lined by the neoplastic cells. The tumor cells showed features of malignancy, including moderate anisocytosis, moderate nuclear atypia, and low mitotic activity. There was occasional cardiomyofiber degeneration within the hemorrhagic lesions. Neoplastic involvement of the atrial walls, valves, and pericardium was not evident. The final diagnosis was hemangiosarcoma.

Figure 2.

Postmortem appearance of the heart of the dog. Longitudinal cross-section through the left ventricle demonstrating the thickened left ventricular free wall and papillary muscle with multiple dark red mottled foci diffusely located throughout the myocardium.

Discussion

Diastolic heart failure is generally defined as heart failure with preserved ventricular systolic function (15). In the present case, on the basis of the echocardiographic evidence of preserved left ventricular systolic function (i.e., normal left ventricular internal diameter at end-systole and fractional shortening), the pulmonary edema could have been associated with diastolic heart failure secondary to neoplastic invasion of the left ventricular walls. To our knowledge, there have been no reports of cardiogenic pulmonary edema associated with diastolic heart failure related to intramural ventricular tumors in veterinary medicine. In humans, however, cardiogenic pulmonary edema secondary to diastolic heart failure has been reported to occur in hematopoietic tumors (e.g., lymphoma) involving the left ventricular walls (16).

The underlying mechanism of diastolic heart failure is ventricular diastolic dysfunction, which can lead to abnormal ventricular filling (i.e., decreased ventricular end-diastolic volume or maintained ventricular end-diastolic volume with increased ventricular filling pressure). Therefore, diastolic heart failure ideally should be diagnosed on the basis of the clinical evidence of ventricular diastolic dysfunction. However, the clinical diagnosis of diastolic heart failure generally does not require evidence of ventricular diastolic dysfunction for the following reasons (15). Firstly, the left heart catheterization, the gold standard for evaluation of left ventricular diastolic properties, is impractical due to its invasiveness and limited availability. Secondly, despite its noninvasiveness and widespread availability, Doppler echocardiography is much less reliable for evaluation of left ventricular diastolic function than the left heart catheterization. This is mainly because: i) the eventual changes in Doppler echocardiographic indices are intricately determined by a multitude of cardiovascular factors (e.g., active ventricular myocardial relaxation, passive ventricular myocardial compliance, ventricular filling pressure); and ii) the confounding influences of physiological variables (e.g., age, heart rate) on Doppler echocardiographic indices may require establishment of the reference ranges appropriate for the physiological variables of the individual patients (15,17).

In the present case, some echocardiographic findings at the initial presentation could have indicated left ventricular diastolic dysfunction. The left atrial enlargement evidenced by the increase in LA/Ao could have reflected chronic effects of left ventricular diastolic dysfunction (17). Also, the increase in E/A, the backbone of the Doppler echocardiographic evaluation of left ventricular diastolic function, could have indicated severe left ventricular diastolic dysfunction with elevated filling pressure (restrictive left ventricular filling) (17). The supplemental Doppler echocardiographic indices of left ventricular diastolic function (i.e., Edt, E′, IVRT, E/E′) seemed difficult to interpret only at the initial presentation due to lack of the reference ranges appropriate for the age, heart rate, and breed herein. However, the changes in these indices following medical treatments (i.e., the increases in Edt, E′, and IVRT, and the decrease in E/E′) could have been due to the improvements in left ventricular diastolic function and filling pressure, considering the concurrent improvements in clinical signs, left atrial size, and E/A.

Echocardiography indicated thickening of the right ventricular free wall in addition to the left ventricular walls. The thickened right ventricular free wall could have been mainly due to neoplastic invasion of the right ventricular wall detected at cardiac necropsy. However, the possibility that pulmonary hypertension associated with left-sided heart disease might also have caused the thickening of the right ventricular free wall cannot be ruled out because tricuspid and pulmonary regurgitations, which could have enabled the estimation of the pulmonary arterial pressure, could not be detected on echocardiography.

Cardiac necropsy in this case revealed that neoplastic cells exclusively infiltrated the ventricular walls without any intracardiac mass formation. Although a full necropsy could not be performed, the origin of the tumor could have been the ventricular walls based on a lack of detectable lesions by antemortem diagnostic imaging. The clinical presentations related to intramural tumors located in the left ventricle and interventricular septum are variable, including arrhythmia (e.g., ventricular tachycardia, third-degree atrioventricular block) (18), systolic heart failure (3), pericardial effusion, or left ventricular outflow tract obstruction (5). Furthermore, it is possible that cardiac tumors infiltrating the left ventricular wall and interventricular septum did not cause any cardiac symptoms (2).

In addition to cardiogenic pulmonary edema, this dog exhibited acute, non-progressive neurological signs indicating a brainstem lesion. Ante- and postmortem examinations of the brain could not be conducted. Considering the clinical course, the underlying diseases, and the possible intracardiac thrombus on echocardiography, these signs might have occurred secondary to cerebrovascular disease. Canine hemangiosarcoma can cause various neurological signs related to cerebrovascular disease associated with brain metastases and coagulopathy (19).

The early antemortem histologic diagnosis of cardiac tumors can be useful for appropriate treatment and prognostication. Although echocardiography is an invaluable diagnostic test for the detection of intracardiac lesions, the accuracy of echocardiography-based presumptive histologic diagnosis of cardiac tumors is not high (6,20). Cytology of pericardial effusions or intracardiac lesions and histopathology of intracardiac lesions are necessary for antemortem histologic diagnosis (6,21). Transvenous endomyocardial biopsy allowed the antemortem diagnosis of hemangiosarcoma infiltrating the left ventricular wall of a previously reported dog (3). Therefore, in the present case, this procedure could have enabled the early diagnosis of hemangiosarcoma. CVJ