Prognostic value of pretreatment plasma D-dimer level in dogs with intermediate to high-grade non-Hodgkin lymphoma.

Pretreatment D-dimer levels have been reported to predict survival in several types of malignancies in human patients. The objective of this study was to evaluate the prognostic value of pretreatment D-dimer level in dogs with intermediate to high-grade non-Hodgkin lymphoma (NHL). In a prospective, randomized, double-blind study of F14512 vs etoposide phosphate, we assessed the prognostic value of pretreatment plasma D-dimer level in 48 client-owned dogs diagnosed with intermediate to high-grade NHL. The correlation between pretreatment plasma D-dimer level and various clinical features, progression-free survival (PFS) and overall survival (OS) was analysed. The median value of pretreatment plasma D-dimer level was 0.4 µg/mL (range: 0.1-14.3 µg/mL). High pretreatment plasma D-dimer level (>0.5 µg/mL) was detected in 44% (21/48) of dogs. High D-dimer levels were not correlated with naive vs relapsed lymphoma, clinical stage, substage, immunophenotype or treatment group. D-dimer levels >0.5 µg/mL were significantly associated with inferior median PFS (54 vs 104 days, P = .011) and OS (93 vs 169 days, P = .003). In the multivariate analysis, high D-dimer levels remained an independent predictor for worse PFS (HR: 3.21, 95% CI: 1.57-6.56, P = .001) and OS (HR: 3.87, 95% CI: 1.88-7.98; P < .001). This study suggests that pretreatment plasma D-dimer level can serve as a predictor of prognosis in dogs with intermediate to high-grade NHL. Further studies are warranted to confirm these findings.

Phase I dose escalation study of 12b80 (hydroxybisphosphonate linked doxorubicin) in naturally occurring osteosarcoma.

PURPOSE: 12b80 combines doxorubicin bound to a bone targeting hydroxybisphosphonate vector using a pH-sensitive linker, designed to specifically trigger doxorubicin release in an acidic bone tumor microenvironment. This phase I study aimed to determine the safety and toxicity profiles of 12b80 in dogs with naturally occurring osteosarcoma, with the objective to translate findings from dogs to humans. EXPERIMENTAL DESIGN: Ten client-owned dogs with osteosarcoma were enrolled in an accelerated dose-titration design followed by 3 + 3 design. Dogs received three cycles of 12b80 intravenous injection at 4 mg/kg (n = 1), 6 mg/kg (n = 2), 8 mg/kg (n = 3), and 10 mg/kg (n = 4). Endpoints included safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicity (DLT). RESULTS: The MTD of 12b80 was 8 mg/kg (i.e., equivalent dose of doxorubicin of 110 mg/m2, range: 93-126). Most adverse events included grade ≤ 2 gastrointestinal disorders and hypersensitivity reactions. No hematological or cardiac DLT were observed at any dose tested. CONCLUSIONS: In dogs, 12b80 is overall well tolerated and expends the MTD of doxorubicin up to four times the standard dose of 30 mg/m2. These results demonstrate the potential therapeutic benefit of 12b80 in canine and human osteosarcoma.

Randomized, double-blind trial of F14512, a polyamine-vectorized anticancer drug, compared with etoposide phosphate, in dogs with naturally occurring lymphoma.

Purpose: F14512 is an epipodophyllotoxin derivative from etoposide, combined with a spermine moiety introduced as a cell delivery vector. The objective of this study was to compare the safety and antitumor activity of F14512 and etoposide phosphate in dogs with spontaneous non-Hodgkin lymphoma (NHL) and to investigate the potential benefit of F14512 in P-glycoprotein (Pgp) overexpressing lymphomas. Experimental Design: Forty-eight client-owned dogs with intermediate to high-grade NHL were enrolled into a randomized, double-blind trial of F14512 versus etoposide phosphate. Endpoints included safety and therapeutic efficacy. Results: Twenty-five dogs were randomized to receive F14512 and 23 dogs to receive etoposide phosphate. All adverse events (AEs) were reversible, and no treatment-related death was reported. Hematologic AEs were more severe with F14512 and gastrointestinal AEs were more frequent with etoposide phosphate. F14512 exhibited similar response rate and progression-free survival (PFS) as etoposide phosphate in the global treated population. Subgroup analysis of dogs with Pgp-overexpressing NHL showed a significant improvement in PFS in dogs treated with F14512 compared with etoposide phosphate. Conclusion: F14512 showed strong therapeutic efficacy against spontaneous NHL and exhibited a clinical benefice in Pgp-overexpressing lymphoma superior to etoposide phosphate. The results clearly justify the evaluation of F14512 in human clinical trials.

Evaluation of intracavitary carboplatin chemotherapy for treatment of pleural carcinomatosis in cats: a retrospective study of eight cases.

OBJECTIVES: The aim of this study was to evaluate the benefit of intracavitary carboplatin chemotherapy in cats with malignant pleural effusion of epithelial origin. METHODS: The medical records of cats with a cytological diagnosis of neoplastic pleural effusion of epithelial origin were reviewed at three referral institutions between January 2013 and June 2018. Only cats treated with intracavitary carboplatin chemotherapy were enrolled. Data collection included signalment, medical history, clinical signs, pleural effusion analysis, diagnostic imaging findings, intracavitary carboplatin chemotherapy protocol, adverse events, response to chemotherapy, outcome and underlying primary tumour, if possible. RESULTS: Eight cats met the inclusion criteria. Three cats had previous surgical removal of a tumour, including a poorly differentiated primary lung carcinoma, a uterine adenocarcinoma and a benign mammary tumour. The main clinical signs were tachypnoea and/or dyspnoea, inappetence and weight loss. Thoracic radiographs revealed marked bilateral pleural effusion in all cats. Pleural fluid analysis was consistent with a modified transudate, with malignant epithelial cells on cytology, leading to a diagnosis of pleural carcinomatosis. All cats received only one cycle of intracavitary carboplatin chemotherapy at a dose of 200-240 mg/m2. Recurrence of pleural effusion was reported in 7/8 cats within 4-15 days of chemotherapy, and death was recorded in all cats within 5-16 days, owing to recurrent pleural effusion or poor general condition. The primary cancer was suspected to be of pulmonary, mammary and pancreatic origin in four cats, two cats and one cat, respectively, and of unknown origin in the remaining cat. CONCLUSIONS AND RELEVANCE: In this study, intracavitary carboplatin chemotherapy seems ineffective in managing neoplastic pleural effusion of epithelial origin in cats with pleural carcinomatosis. Other cytotoxic drugs and/or techniques should be investigated in the future to improve the quality of life and survival of cats with pleural carcinomatosis.

Evaluation of serum thymidine kinase 1 activity as a biomarker for treatment effectiveness and prediction of relapse in dogs with non-Hodgkin lymphoma.

BACKGROUND: Serum thymidine kinase 1 (sTK1) activity is closely correlated with DNA synthesis. OBJECTIVES: Evaluate sTK1 activity as a biomarker for treatment response and early detection of relapse in dogs with lymphoma. ANIMALS: Ninety-seven client-owned dogs with naive or relapsed lymphoma and 23 healthy dogs. METHODS: Prospective study. Serum TK1 activity measured by refined ELISA-based method (DiviTum assay, Biovica International) before treatment, at clinical response, and every 4 weeks until relapse or last follow-up. RESULTS: Serum TK1 activity was ≤20 Du/L in 96% (22/23) of healthy dogs. Pretreatment sTK1 activity was >20 Du/L in 88% (85/97) dogs with lymphoma. At clinical response, sTK1 activity was significantly lower in dogs with complete (CR, n = 36) versus partial (PR, n = 29) response (P < .0001). Sensitivity (Se) and specificity (Sp) of sTK1 activity for detecting nonfully responders were 76% and 100%, respectively, with cutoff of 119.5 Du/L (AUC, 0.90; 95%-CI, 0.81-0.98; P < .0001). In dogs with CR, a 5-fold increase in sTK1 activity at a 4-week interval predicted relapse at the subsequent 4-week assessment with a Se 50% and Sp 94% (AUC, 0.72; 95%-CI, 0.55-0.90; P = .02). An increase of sTK1 activity (>2.7-fold value measured at clinical response) predicted relapse at subsequent 4-week assessment with a Se 61% and Sp 88% (AUC, 0.79; 95%-CI, 0.64-0.95; P = .004). CONCLUSIONS AND CLINICAL IMPORTANCE: Monitoring sTK1 activity could help to detect complete responders and early disease progression in dogs with lymphoma.

Isolation and characterization of two canine melanoma cell lines: new models for comparative oncology.

BACKGROUND: Metastatic melanoma is one of the most aggressive forms of cancer in humans. Among its types, mucosal melanomas represent one of the most highly metastatic and aggressive forms, with a very poor prognosis. Because they are rare in Caucasian individuals, unlike cutaneous melanomas, there has been fewer epidemiological, clinical and genetic evaluation of mucosal melanomas. Moreover, the lack of predictive models fully reproducing the pathogenesis and molecular alterations of mucosal melanoma makes its treatment challenging. Interestingly, dogs are frequently affected by melanomas of the oral cavity that are characterized, as their human counterparts, by focal infiltration, recurrence, and metastasis to regional lymph nodes, lungs and other organs. In dogs, some particular breeds are at high risk, suggesting a specific genetic background and strong genetic drivers. Altogether, the striking homologies in clinical presentation, histopathological features, and overall biology between human and canine mucosal melanomas make dogs invaluable natural models with which to investigate tumor development, including tumor ætiology, and develop tailored treatments. METHODS: We developed and characterized two canine oral melanoma cell lines from tumors isolated from dog patients with distinct clinical profiles; with and without lung metastases. The cells were characterized using immunohistochemistry, pharmacology and genetic studies. RESULTS: We have developed and immunohistochemically, genetically, and pharmacologically characterized. Two cell lines (Ocr_OCMM1X & Ocr_OCMM2X) were produced through mouse xenografts originating from two clinically contrasting melanomas of the oral cavity. Their exhaustive characterization showed two distinct biological and genetic profiles that are potentially linked to the stage of malignancy at the time of diagnosis and sample collection of each melanoma case. These cell lines thus constitute relevant tools with which to perform genetic and drug screening analyses for a better understanding of mucosal melanomas in dogs and humans. CONCLUSIONS: The aim of this study was to establish and characterize xenograft-derived canine melanoma cell lines with different morphologies, genetic features and pharmacological sensitivities that constitute good predictive models for comparative oncology. These cell lines are relevant tools to advance the use of canine mucosal melanomas as natural models for the benefit of both veterinary and human medicine.

Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma.

Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans' solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs. Etoposide phosphate is a water-soluble prodrug of etoposide which is expected to be better tolerated in dogs. The objectives of this study were to assess the safety, the tolerability and the efficacy of intravenous etoposide phosphate in dogs with multicentric lymphoma. Seven dose levels were evaluated in a traditional 3+3 phase I design. Twenty-seven owned-dogs with high-grade multicentric lymphoma were enrolled and treated with three cycles of etoposide phosphate IV injections every 2 weeks. Adverse effects were graded according to the Veterinary Cooperative Oncology Group criteria. A complete end-staging was realized 45 days after inclusion. The maximal tolerated dose was 300 mg/m2. At this dose level, the overall response rate was 83.3% (n = 6, 3 PR and 2 CR). Only a moderate reversible gastrointestinal toxicity, no severe myelotoxicity and no hypersensitivity reaction were reported at this dose level. Beyond the characterization of etoposide clinical efficacy in dogs, this study underlined the clinical and therapeutic homologies between dog and human lymphomas.

Phase I Clinical Pharmacology Study of F14512, a New Polyamine-Vectorized Anticancer Drug, in Naturally Occurring Canine Lymphoma.

PURPOSE: F14512 is a new topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells and increases topoisomerase II poisoning. F14512 is currently in a phase I/II clinical trial in patients with acute myeloid leukemia. The aim of this study was to investigate F14512 potential in a new clinical indication. Because of the many similarities between human and dog lymphomas, we sought to determine the tolerance, efficacy, pharmacokinetic/pharmacodynamic (PK/PD) relationship of F14512 in this indication, and potential biomarkers that could be translated into human trials. EXPERIMENTAL DESIGN: Twenty-three dogs with stage III-IV naturally occurring lymphomas were enrolled in the phase I dose-escalation trial, which consisted of three cycles of F14512 i.v. injections. Endpoints included safety and therapeutic efficacy. Serial blood samples and tumor biopsies were obtained for PK/PD and biomarker studies. RESULTS: Five dose levels were evaluated to determine the recommended dose. F14512 was well tolerated, with the expected dose-dependent hematologic toxicity. F14512 induced an early decrease of tumoral lymph node cells, and a high response rate of 91% (21/23) with 10 complete responses, 11 partial responses, 1 stable disease, and 1 progressive disease. Phosphorylation of histone H2AX was studied as a potential PD biomarker of F14512. CONCLUSIONS: This trial demonstrated that F14512 can be safely administered to dogs with lymphoma resulting in strong therapeutic efficacy. Additional evaluation of F14512 is needed to compare its efficacy with standards of care in dogs, and to translate biomarker and efficacy findings into clinical trials in humans.

Comparison of Doppler ultrasonography and high-definition oscillometry for blood pressure measurements in healthy awake dogs.

OBJECTIVE: To determine the intra- and interobserver variability of systolic arterial pressure (SAP) and diastolic arterial pressure (DAP) measurements obtained with 2 indirect methods in awake dogs and percentage of successful measurements. ANIMALS: 6 healthy conscious adult dogs. PROCEDURES: 4 observers with different levels of training measured SAP and DAP on 4 days by use of Doppler ultrasonography (DU) and high-definition oscillometry (HDO). The examinations were randomized. Measurements for each technique were recorded 5 consecutive times, and mean values (total, 720 measurements) were used for statistical analysis. RESULTS: All within- and between-day coefficients of variation (CVs) for SAP were < 15% irrespective of the observer or method (HDO, 3.6% to 14.1%; DU, 4.1% to 12.4%). Conversely, half the CVs for DAP were > 15% with the highest within- and between-day CVs obtained by the least experienced observer by use of DU (19.5% and 25.9%, respectively). All attempts with HDO were successful, whereas DAP could not be measured by use of DU by the least experienced observer in 17% of attempts. CONCLUSIONS AND CLINICAL RELEVANCE: SAP may be assessed in healthy dogs by use of DU and HDO with good repeatability and reproducibility after a short period of training. Conversely, the variability of DAP is higher and longer training is required to assess DAP via DU than via HDO.

Plasma N-terminal pro-B-type natriuretic peptide concentration helps to predict survival in dogs with symptomatic degenerative mitral valve disease regardless of and in combination with the initial clinical status at admission.

OBJECTIVES: Although mitral valve disease (MVD) is the most common canine heart disease, readily available prognostic markers of the disease are still lacking. The aim of this study was to evaluate the comparative ability of N-terminal pro-B-type natriuretic peptide plasma concentration (NT-proBNP) and various echocardiographic variables to predict outcome in dogs with MVD. ANIMALS, MATERIALS AND METHODS: Seventy-four dogs with ISACHC classes 2 and 3 MVD (Groups A and B, respectively) were prospectively recruited. NT-proBNP and several echo-Doppler variables at inclusion were compared as predictors of outcome at 6 months in 54/74 dogs. RESULTS: NT-proBNP was significantly higher in Group B than in Group A (P<0.0001), and was the only tested variable significantly different between survivor and non-survivor dogs in both groups (P<0.05). In the whole canine population, a threshold of 1500 pmol/L could discriminate survivor from non-survivor dogs with a sensitivity and specificity of 80% and 73%, respectively. When combining ISACHC class with NT-proBNP levels, a cut-off of 1265 pmol/L was predictive of survival in Group A, whereas the cut-off was 2700 pmol/L for Group B. CONCLUSIONS: NT-proBNP is correlated with MVD severity and could be used in combination with clinical status to predict cardiac outcome.

Quantification of pulmonary to systemic flow ratio by a Doppler echocardiographic method in the normal dog: Repeatability, reproducibility, and reference ranges.

OBJECTIVE: To determine if the pulmonary to systemic flow ratio (Qp/Qs) could be assessed in healthy awake dogs using Doppler echocardiography. BACKGROUND: Qp/Qs could provide reliable information in assessing the severity of intracardiac shunts (ICS) by quantifying pulmonary overcirculation. Qp/Qs has been validated against electromagnetic flowmeter methods in experimental canine models. However, its clinical applicability in awake dogs has never been assessed. ANIMALS, MATERIALS AND METHODS: Six healthy dogs were used to determine the repeatability and reproducibility of the technique (Study 1); Qp/Qs was then prospectively assessed in 50 healthy dogs (Study 2). In both studies Qp/Qs was calculated in awake animals using a standardized Doppler echocardiographic method. RESULTS: Within- and between-day coefficients of variation for Qp/Qs were <10% (Study 1). For Study 2, a relatively wide range of Qp/Qs was found (reference range=0.71-1.29; mean+/-SD=1.00+/-0.15). CONCLUSIONS: Qp/Qs can be assessed with good repeatability and reproducibility in healthy dogs. However, the wide range of Qp/Qs obtained in the healthy population may suggest a limited usefulness of this variable for accurately assessing ICS severity in diseased animals. This needs to be assessed in further prospective and longitudinal studies including a large number of animals with ICS of various grades.

Ante-mortem diagnosis of persistent truncus arteriosus in an 8-year-old asymptomatic dog.

Persistent truncus arteriosus (PTA) was diagnosed in an 8-year-old neutered male Poodle referred for echocardiographic examination prior to anesthesia for surgical correction of bilateral cataract. A single large artery limited by a bicuspid valve and overriding both ventricles was observed with 2 distinct pulmonary arteries arising from the common arterial trunk. A large size interventricular septal defect was associated with a low velocity bidirectional shunt. The lesion was identified as a Type 3 PTA according to Collett and Edwards' classification. Although no clinical signs were reported, the dog presented polycythemia (packed cell volume=68%) at the time of diagnosis. To our knowledge, this is the first report of an echocardiographic diagnosis of PTA in the dog. Until now, the ante-mortem diagnosis of this congenital heart disease has only been described in the cat. This case is also of interest because of the age of the animal and the total absence of cardio-respiratory signs at the time of diagnosis.

Quadricuspid aortic valve and associated abnormalities in the dog: report of six cases.

OBJECTIVES: To describe the clinical and echocardiographic findings in dogs with quadricuspid aortic valve (QAV). BACKGROUND: QAV is a rare canine congenital heart disease which has been reported only three times in the young dog. ANIMALS, MATERIALS AND METHODS: Six dogs (0.3- to 13-year-old) with QAV diagnosed by two-dimensional echocardiography were retrospectively evaluated. Medical records, echocardiograms, and follow-ups were reviewed. RESULTS: According to aortic cusp morphology, QAV was classified as type A (n=1), type B (n=4) or type C (n=1). QAV was associated with at least one other heart disease in all of the dogs including, ventricular septal defect (n=1), enlarged left coronary ostium (n=4), degenerative mitral valve disease (MVD, n=1) and patent ductus arteriosus (PDA, n=3). Mild to moderate aortic regurgitation was also detected in all dogs by continuous-wave and color-flow Doppler echocardiography. QAV was diagnosed in four asymptomatic dogs referred for evaluation of a heart murmur. The remaining two dogs had QAV and PDA with evidence of mild exercise intolerance and moderately retarded growth. The PDA was surgically corrected in both dogs and at the time of writing, 1-2.5 years after the initial diagnosis, none of the six animals shows evidence of clinical signs. CONCLUSION: QAV is a cause of aortic insufficiency. It may incidentally be found by two-dimensional echocardiography in dogs of various ages in association with other congenital or acquired cardiac abnormalities.

Radial strain and strain rate by two-dimensional speckle tracking echocardiography and the tissue velocity based technique in the dog.

OBJECTIVES: Two-dimensional (2D) speckle tracking echocardiography (STE) is a new angle-independent ultrasound technique based on tracking of speckles within the myocardium on 2D grayscale images. The aims of this prospective study were as follows: (1) to assess the variability of left ventricular peak systolic radial strain (St) and strain rate (SR) in awake dogs using STE (Protocol 1); and (2) to quantify these variables in a healthy canine population and compare them with tissue Doppler imaging (TDI)-based St and SR values (Protocol 2). BACKGROUND: St and SR may be assessed using TDI, which is limited by angle dependency. ANIMALS, MATERIALS AND METHODS: Thirty-six STE examinations were performed on 6 healthy dogs for Protocol 1 and 37 healthy dogs were recruited for Protocol 2. In both studies, STE measurements were obtained offline from the right parasternal short-axis view by the same trained observer using automatic frame-to-frame tracking of grayscale speckle patterns. RESULTS: All within- and between-day coefficients of variation were <10% (Protocol 1). In Protocol 2, St (46.7+/-12.2%) and SR (2.7+/-0.6s(-1)) measured by STE were correlated with heart rate (p<0.01), but not with the ratio of early mitral inflow velocity to early mitral annular velocity. There was a good correlation between STE and TDI for both St and SR values (p<0.001). CONCLUSIONS: STE is a repeatable and reproducible non-Doppler method for assessing radial St and SR. The combination of these indices with conventional echo-Doppler variables could provide a new approach for accurately quantifying canine systolic function.

Assessment of regional systolic and diastolic myocardial function using tissue Doppler and strain imaging in dogs with dilated cardiomyopathy.

BACKGROUND: Tissue Doppler Imaging (TDI) or strain (St) imaging could provide sensitive indices for early detection and treatment follow-up of canine dilated cardiomyopathy (DCM). Analysis of TDI and St features in dogs with overt DCM is a prerequisite before using these new criteria in prospective screenings of predisposed families or in clinical trials. HYPOTHESIS: Radial and longitudinal right and left myocardial motion, assessed by TDI and St variables, is altered in dogs with DCM. ANIMALS: Case records for 26 dogs; 14 with DCM and 12 healthy controls of comparable age and weight were reviewed. METHODS: A retrospective analysis was conducted of conventional echocardiography, 2-dimensional color TDI, and St imaging data. RESULTS: The DCM group was characterized by decreases in radial and longitudinal systolic velocity gradients of the left ventricular free wall (LVFW), radial and longitudinal absolute values of peak systolic St of the LVFW, and longitudinal systolic right ventricular (RV) velocities (all P < .001 versus control) associated with longitudinal postsystolic contraction waves in 7/14 dogs. Early diastolic LVFW velocities also were decreased for longitudinal (P < .01) and radial (P < .05) motions. All radial LVFW, longitudinal basal LVFW, and RV systolic velocities were negatively correlated with heart rate (P < .01). CONCLUSIONS AND CLINICAL IMPORTANCE: LV contractility along both the short and long axes is impaired in dogs with spontaneous DCM, as is systolic RV and diastolic LVFW function. These myocardial alterations are associated with an inverse force-frequency relationship. Studies now are needed to determine the comparative sensitivity of TDI and St variables for the early detection of canine DCM.

Comparative adverse cardiac effects of pimobendan and benazepril monotherapy in dogs with mild degenerative mitral valve disease: a prospective, controlled, blinded, and randomized study.

BACKGROUND: Pimobendan (PIMO) is an inodilator that may have some beneficial effects in canine degenerative mitral valve disease (MVD). However, little information is available about its cardiac effects in dogs without systolic myocardial dysfunction. HYPOTHESIS: Compared to benazepril (BNZ), an angiotensin-converting enzyme inhibitor, PIMO may worsen valve regurgitation in early canine MVD. ANIMALS: Twelve Beagles with asymptomatic MVD were randomized into 2 groups (n = 6) receiving BNZ or PIMO at dosages of 0.25 mg/kg PO q24h and q12h respectively, for 512 days. METHODS: The study followed a blinded, randomized, prospective, and parallel group design. After day 512, the dogs were necropsied, and cardiac histopathology was performed in a blinded manner. RESULTS: A significant treatment effect was observed as soon as day 15 with increased systolic function in the PIMO group by comparison to baseline value as assessed by fractional shortening (P < .0001) and tissue Doppler variables (P = .001). Concurrently, the maximum area and peak velocity of the regurgitant jet signal increased (P < .001), whereas these variables remained stable in the BNZ group. Histologic grades of mitral valve lesions were more severe in the PIMO group than in the BNZ group. Moreover, acute focal hemorrhages, endothelial papillary hyperplasia, and infiltration of chordae tendinae with glycosaminoglycans were observed in the mitral valves of dogs from the PIMO group but not in those of the BNZ group. CONCLUSIONS AND CLINICAL IMPORTANCE: PIMO has adverse cardiac functional and morphologic effects in dogs with asymptomatic MVD. Additional investigation in dogs with symptomatic MVD is now warranted.

Quantification of mitral valve regurgitation in dogs with degenerative mitral valve disease by use of the proximal isovelocity surface area method.

OBJECTIVE: To determine the within-day and between-day variability of regurgitant fraction (RF) assessed by use of the proximal isovelocity surface area (PISA) method in awake dogs with degenerative mitral valve disease (MVD), measure RF in dogs with MVD, and assess the correlation between RF and several clinical and Doppler echocardiographic variables. DESIGN: Prospective study. ANIMALS: 6 MVD-affected dogs with no clinical signs and 67 dogs with MVD of differing severity (International Small Animal Cardiac Health Council [ISACHC] classification). PROCEDURES: The 6 dogs were used to determine the repeatability and reproducibility of the PISA method, and RF was then assessed in 67 dogs of various ISACHC classes. Mitral valve regurgitation was also assessed from the maximum area of regurgitant jet signal-to-left atrium area (ARJ/LAA) ratio determined via color Doppler echocardiographic mapping. RESULTS: Within- and between-day coefficients of variation of RF were 8% and 11%, respectively. Regurgitation fraction was significantly correlated with ISACHC classification and heart murmur grade and was higher in ISACHC class III dogs (mean +/- SD, 72.8 +/- 9.5%) than class II (57.9 +/- 20.1%) or I (40.7 +/- 19.2%) dogs. Regurgitation fraction and left atriumto-aorta ratio, fractional shortening, systolic pulmonary arterial pressure, and ARJ/LAA ratio were significantly correlated. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that RF is a repeatable and reproducible variable for noninvasive quantitative evaluation of mitral valve regurgitation in awake dogs. Regurgitation fraction also correlated well with disease severity. It appears that this Doppler echocardiographic index may be useful in longitudinal studies of MVD in dogs.

Chordae tendineae rupture in dogs with degenerative mitral valve disease: prevalence, survival, and prognostic factors (114 cases, 2001-2006).

BACKGROUND: Degenerative mitral valve disease (MVD) is the most common heart disease in small breed dogs, and chordae tendineae rupture (CTR) is a potential complication of this disease. The survival time and prognostic factors predictive of survival in dogs with CTR remain unknown. HYPOTHESIS: The prevalence and prognosis of CTR in dogs with MVD increases and decreases, respectively, with heart failure class. ANIMALS: This study used 706 dogs with MVD. METHODS: The diagnosis of CTR was based on a flail mitral leaflet with the tip pointing into the left atrium during systole, which was confirmed in several 2-dimension imaging planes using the left and right parasternal 4-chamber views. RESULTS: CTR was diagnosed in 114 of the 706 dogs with MVD (16.1%) and most of these (106/114, 93%) had severe mitral valve regurgitation as assessed by color Doppler mode. CTR prevalence increased with International Small Animal Cardiac Health Council (ISACHC) clinical class (i.e., 1.9, 20.8, 35.5, and 69.6% for ISACHC classes Ia, Ib, II, and III, respectively [P < .05]). Long-term follow-up was available for 57 treated dogs (angiotensin-converting enzyme inhibitors and diuretics) and 58% of these (33/57) survived > 1 year after initial CTR diagnosis (median survival time, 425 days). Clinical class, the presence of ascites or acute dyspnea at the time of diagnosis, heart rate, plasma urea concentration, and left atrial size were predictors of survival. CONCLUSIONS AND CLINICAL RELEVANCE: CTR is associated with a higher overall survival time than previously supposed. Its prognosis mostly depends on a combination of clinical and biochemical factors.

Diagnostic value of echo-Doppler and tissue Doppler imaging in dogs with pulmonary arterial hypertension.

BACKGROUND: Diagnosis of pulmonary arterial hypertension (PAH) relies on Doppler measurement of pulmonic and tricuspid regurgitation (TR). However, these are not always detectable. HYPOTHESIS: Tissue Doppler imaging (TDI), a novel noninvasive ultrasound technique, provides indirect but sensitive and specific assessment of elevated systolic pulmonary artery pressure (SPAP) in dogs. ANIMALS: One hundred and five dogs with TR. METHODS: Prospective observational study. Dogs were categorized as presenting normal (group 1, n = 45), mildly increased (group 2, n = 19), or moderately to severely increased (group 3, n = 41) SPAP, based on TR peak velocities (< 2.5, 2.5-3.0, and > 3.0 m/s, respectively). Ten quantitative echo-Doppler- and TDI-derived variables were assessed, including the main pulmonary arterial diameter to aortic diameter ratio, pulmonary flow acceleration time, and acceleration-to-ejection time ratio, the Tei index of right ventricular function, and 6 longitudinal basal right ventricular TDI variables. RESULTS: A significant correlation was observed between SPAP and each of the 10 tested variables (P < .05). Conventional echo-Doppler variables were less discriminating than the TDI for predicting increased SPAP. The combined systolic and diastolic right TDI index had the highest sensitivity and specificity (89% and 93% respectively, for a cutoff of 11.8 cm/s) and could discriminate between dogs in group 1 from dogs in group 2. CONCLUSIONS AND CLINICAL IMPORTANCE: TDI provided effective predictors of systolic PAH and demonstrated that both alterations in right-sided systolic and diastolic myocardial function can occur with mild increases in SPAP.

Doppler echocardiography-derived evidence of pulmonary arterial hypertension in dogs with degenerative mitral valve disease: 86 cases (2001-2005).

OBJECTIVE: To determine the prevalence of Doppler echocardiography-derived evidence of pulmonary arterial hypertension (DEE-PAH) in dogs with mitral valve disease (MVD) classified according to the International Small Animal Cardiac Health Council (ISACHC) heart failure classification scheme and various echocardiographic and Doppler indices of MVD severity. DESIGN: Retrospective case series. ANIMALS: 617 dogs examined from 2001 to 2005 with MVD in ISACHC classes I to III. PROCEDURES: Dogs were examined echocardiographically. Criteria used for systolic and diastolic DEE-PAH were detection of high tricuspid (> or = 2.5 m/s) and telediastolic pulmonic (> or = 2.0 m/s) valvular peak regurgitant jet velocities, respectively, by use of continuous-wave Doppler echocardiography. RESULTS: 86 (13.9%) dogs with MVD had a diagnosis of DEE-PAH. Severity and prevalence of DEE-PAH increased with ISACHC class (3.0%, 16.9%, 26.7%, and 72.2% prevalences for ISACHC classes Ia, Ib, II, and III, respectively). A significant correlation between systolic or diastolic pulmonary arterial pressure and left atrial-to-aortic diameter ratio (LA/Ao) was detected. Doppler echocardiography-derived evidence of pulmonary arterial hypertension was detected in 18 dogs with values of LA/Ao within reference range, all of which had moderate (n = 2 dogs) or severe (16) mitral valve regurgitation on color Doppler imaging. CONCLUSIONS AND CLINICAL RELEVANCE: The prevalence and degree of DEE-PAH were related to the severity of MVD. Changes associated with DEEPAH may be detected in early stages of the disease, but only in dogs with severe mitral valve regurgitation.