Quiet timer blanking in a dog with sick sinus syndrome and a permanent transvenous pacemaker.

A 14-year-old, 5.8 kg (12.7 lb) male castrated Jack Russell Terrier was referred for investigation of syncope and an arrhythmia. Electrocardiogram showed pronounced variation in the sinus rate including long periods of sinus arrest and an inconsistent escape rhythm. Sick sinus syndrome was the presumptive diagnosis. A single lead permanent transvenous pacemaker was implanted and was programmed to perform ventricular-demand pacing. Postoperative pacemaker interrogation revealed undersensing and asynchronous pacing during episodes of supraventricular tachycardia (SVT). This intermittent pacemaker malfunction was attributed to a specific pacemaker programming feature called quiet timer blanking. Adjustment of pacemaker parameters did not restore normal function. Treatment with sotalol (5 mg per os q 12 h) was used to medically treat the SVT, and asynchronous pacing was not observed during follow-up visits. To the authors' knowledge, this is the first documented case of quiet timer blanking causing paroxysmal undersensing and asynchronous pacing in a dog with a permanent pacemaker.

Reproducibility of geometric and flow-based echocardiographic measurements used for quantification of left ventricular total and forward stroke volume in healthy dogs.

BACKGROUND: Cardiac structure and function in dogs are commonly assessed using echocardiography. A variety of linear, area, and flow-based measurements can be used to calculate left ventricular (LV) total stroke volume (TSV) and forward stroke volume (FSV), but the reproducibility of many of these measurements has not been fully studied. We hypothesized that survey of echocardiographic variables would identify those with high reproducibility and inform future investigation of different methods to measure LV TSV and FSV. METHODS: The reproducibility of 25 geometric and flow-based echocardiographic measurements was prospectively evaluated in 23 healthy dogs by two experienced observers. Reproducibility (i.e., interobserver agreement) was described using intraclass correlation coefficients. The reproducibility of various methods to calculate LV TSV and FSV was explored. RESULTS: Reproducibility was generally good to excellent. Variables of LV width, length, and area and aortic and sinotubular junction diameter and velocity time integral were among measures with the highest reproducibility. Measurements of mitral annular diameter and mitral inflow velocity time integral possessed lower reproducibility. Calculation of LV TSV using measurements involved in the cube and bullet formulas demonstrated higher reproducibility than the Simpson's method of disks or mitral inflow methods. Calculation of LV FSV using LV outflow tract and aortic diameters from the right parasternal view generally demonstrated higher reproducibility compared with the left-sided view. CONCLUSIONS: The reproducibility of many simple geometric and flow-based echocardiographic measurements is high. Comparison of the reliability of different measurement informs future investigation of echocardiographic methods to determine LV TSV and FSV in dogs.

Measurements of echocardiographic indices and biomarkers of kidney injury in dogs with chronic kidney disease.

Pathophysiological cardiac and renal interactions are termed cardiovascular-renal disorder (CvRD). Cardiovascular disease/dysfunction secondary to kidney disease (CvRDK), is a leading cause of death in human chronic kidney disease (CKD) patients. The presence and clinical impact of CvRDK in dogs with CKD is unknown. We hypothesized that echocardiographic measurements, and cardiac and renal biomarkers, will be altered in dogs with CKD and associated with survival. Eleven dogs with CKD (n = 6 IRIS stage 2, n = 5 IRIS stage 3) and without primary cardiac disease, plus 12 healthy age-matched control dogs, were recruited to this prospective observational study. Dogs underwent standard echocardiography, glomerular filtration rate (GFR) estimation by iohexol clearance, and measurement of plasma cardiac troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP), plasma and urinary cystatin B, and urinary clusterin and neutrophil gelatinase-associated lipocalin (NGAL). Values were compared between groups, and their association with all-cause mortality explored. Dogs with CKD had significantly lower GFR and higher NT-proBNP, urinary cystatin B, clusterin, and NGAL, compared to controls (P < 0.05). Echocardiographic measurements were similar between dogs with CKD and controls. Median follow-up time was 666 days, during which six dogs with CKD died. Risk of death was associated with increasing age, serum total protein, and normalized left ventricular posterior wall thickness (LVPWDN) and decreasing bodyweight and packed cell volume. Although baseline differences in echocardiographic measurements were not evident between dogs with moderate CKD and controls, the presence of CvRDK was suggested by the association between LVPWDN and survival.

CD73 complexes with emmprin to regulate MMP-2 production from co-cultured sarcoma cells and fibroblasts.

BACKGROUND: Interaction between cancer cells and fibroblasts mediated by extracellular matrix metalloproteinase inducer (emmprin, CD147) is important in the invasion and proliferation of cancer cells. However, the exact mechanism of emmprin mediated stimulation of matrix metalloprotease-2 (MMP-2) production from fibroblasts has not been elucidated. Our previous studies using an inhibitory peptide against emmprin suggested the presence of a molecule on the cell membrane which forms a complex with emmprin. Here we show that CD73 expressed on fibroblasts interacts with emmprin and is a required factor for MMP-2 production in co-cultures of sarcoma cells with fibroblasts. METHODS: CD73 along with CD99 was identified by mass spectrometry analysis as an emmprin interacting molecule from a co-culture of cancer cells (epithelioid sarcoma cell line FU-EPS-1) and fibroblasts (immortalized fibroblasts cell line ST353i). MMP-2 production was measured by immunoblot and ELISA. The formation of complexes of CD73 with emmprin was confirmed by immunoprecipitation, and their co-localization in tumor cells and fibroblasts was shown by fluorescent immunostaining and proximity ligation assays. RESULTS: Stimulated MMP-2 production in co-culture of cancer cells and fibroblasts was completely suppressed by siRNA knockdown of CD73, but not by CD99 knockdown. MMP-2 production was not suppressed by CD73-specific enzyme inhibitor (APCP). However, MMP-2 production was decreased by CD73 neutralizing antibodies, suggesting that CD73-mediated suppression of MMP-2 production is non-enzymatic. In human epithelioid sarcoma tissues, emmprin was immunohistochemically detected to be mainly expressed in tumor cells, and CD73 was expressed in fibroblasts and tumor cells: emmprin and CD73 were co-localized predominantly on tumor cells. CONCLUSION: This study provides a novel insight into the role of CD73 in emmprin-mediated regulation of MMP-2 production.

Curcumin potentiates the fungicidal effect of dodecanol by inhibiting drug efflux in wild-type budding yeast.

Drug resistance commonly occurs when treating immunocompromised patients who have fungal infections. Curcumin, is a compound isolated from Curcuma longa, has been reported to inhibit drug efflux in several human cell lines and nonpathogenic budding yeast Saccharomyces cerevisiae cells that overexpresses the ATP-binding cassette (ABC) transporters S. cerevisiae Pdr5p and pathogenic Candida albicans Cdr1p and Cdr2p. The aim of this study was to examine the effects of curcumin on multidrug resistance in a wild-type strain of the budding yeast with an intrinsic expression system of multidrug efflux-related genes. The antifungal activity of dodecanol alone was temporary against S. cerevisiae; however, restoration of cell viability was completely inhibited when the cells were co-treated with dodecanol and curcumin. Furthermore, restriction of rhodamine 6G (R6G) efflux from the cells and intracellular accumulation of R6G were observed with curcumin treatment. Reverse transcription-polymerase chain reaction analysis revealed that curcumin reduced the dodecanol-induced overexpression of the ABC transporter-related genes PDR1, PDR3 and PDR5 to their control levels in untreated cells. Curcumin can directly restrict the glucose-induced drug efflux and inhibits the expression of the ABC transporter gene PDR5, and can thereby inhibit the efflux of dodecanol from S. cerevisiae cells. Curcumin is effective in potentiating the efficacy of antifungal drugs via its effects on ABC transporters. SIGNIFICANCE AND IMPACT OF THE STUDY: Drug resistance is common in immunocompromised patients with fungal infections. Curcumin, isolated from Curcuma longa, inhibits drug efflux in nonpathogenic budding yeast Saccharomyces cerevisiae cells overexpressing ABC transporters S. cerevisiae Pdr5p and pathogenic Candida albicans Cdr1p and Cdr2p. We examined the effects of curcumin on multidrug resistance in a wild-type strain of the budding yeast with an intrinsic expression system of multidrug efflux-related genes. Curcumin directly inhibited drug efflux and also suppressed the PDR5 expression, thereby enhancing the antifungal effects. Thus, curcumin potentially promotes the efficacy of antifungals via its effects on ABC transporters in wild-type fungal strains.

Retrospective Evaluation of the Effect of Heart Rate on Survival in Dogs with Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) usually is associated with a rapid ventricular rate. The optimal heart rate (HR) during AF is unknown. HYPOTHESIS/OBJECTIVES: Heart rate affects survival in dogs with chronic AF. ANIMALS: Forty-six dogs with AF and 24-hour ambulatory recordings were evaluated. METHODS: Retrospective study. Holter-derived HR variables were analyzed as follows: mean HR (meanHR, 24-hour average), minimum HR (minHR, 1-minute average), maximum HR (maxHR, 1-minute average). Survival times were recorded from the time of presumed adequate rate control. The primary endpoint was all-cause mortality. Cox proportional hazards analysis identified variables independently associated with survival; Kaplan-Meier survival analysis estimated the median survival time of dogs with meanHR <125 bpm versus ≥125 bpm. RESULTS: All 46 dogs had structural heart disease; 31 of 46 had congestive heart failure (CHF), 44 of 46 received antiarrhythmic drugs. Of 15 dogs with cardiac death, 14 had CHF. Median time to all-cause death was 524 days (Interquartile range (IQR), 76-1,037 days). MeanHR was 125 bpm (range, 62-203 bpm), minHR was 82 bpm (range, 37-163 bpm), maxHR was 217 bpm (range, 126-307 bpm). These were significantly correlated with all-cause and cardiac-related mortality. For every 10 bpm increase in meanHR, the risk of all-cause mortality increased by 35% (hazard ratio, 1.35; 95% CI, 1.17-1.55; P < 0.001). Median survival time of dogs with meanHR<125 bpm (n = 23) was significantly longer (1,037 days; range, 524-open) than meanHR ≥125 bpm (n = 23; 105 days; range, 67-267 days; P = 0.0012). Mean HR was independently associated with all-cause and cardiovascular mortality (P < 0.003). CONCLUSIONS AND CLINICAL IMPORTANCE: Holter-derived meanHR affects survival in dogs with AF. Dogs with meanHR <125 bpm lived longer than those with meanHR ≥ 125 bpm.

Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo: The EPIC Study.

BACKGROUND: Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described. OBJECTIVES: To investigate the effect of pimobendan on clinical variables and the relationship between a change in heart size and the time to congestive heart failure (CHF) or cardiac-related death (CRD) in dogs with MMVD and cardiomegaly. To determine whether pimobendan-treated dogs differ from dogs receiving placebo at onset of CHF. ANIMALS: Three hundred and fifty-four dogs with MMVD and cardiomegaly. MATERIALS AND METHODS: Prospective, blinded study with dogs randomized (ratio 1:1) to pimobendan (0.4-0.6 mg/kg/d) or placebo. Clinical, laboratory, and heart-size variables in both groups were measured and compared at different time points (day 35 and onset of CHF) and over the study duration. Relationships between short-term changes in echocardiographic variables and time to CHF or CRD were explored. RESULTS: At day 35, heart size had reduced in the pimobendan group: median change in (Δ) LVIDDN -0.06 (IQR: -0.15 to +0.02), P < 0.0001, and LA:Ao -0.08 (IQR: -0.23 to +0.03), P < 0.0001. Reduction in heart size was associated with increased time to CHF or CRD. Hazard ratio for a 0.1 increase in ΔLVIDDN was 1.26, P = 0.0003. Hazard ratio for a 0.1 increase in ΔLA:Ao was 1.14, P = 0.0002. At onset of CHF, groups were similar. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan treatment reduces heart size. Reduced heart size is associated with improved outcome. At the onset of CHF, dogs treated with pimobendan were indistinguishable from those receiving placebo.

Feasibility, safety, and tolerance of subcutaneous synthetic canine B-type natriuretic peptide (syncBNP) in healthy dogs and dogs with stage B1 mitral valve disease.

INTRODUCTION: An important aspect of heart failure is the progressive ineffectiveness of the salutary natriuretic peptide system and its secondary messenger, 3',5'-cyclic guanosine monophosphate (cGMP). In humans with acute heart failure, administration of exogenous natriuretic peptide is associated with improvement in clinical signs and reduction of cardiac filling pressures. This study aimed to determine the feasibility, tolerance, and safety of subcutaneous (SC) synthetic canine B-type natriuretic peptide (syncBNP) administration in dogs. ANIMALS: Six privately owned dogs. MATERIALS AND METHODS: Dogs were enrolled in a modified 3 + 3 phase I trial. Three dogs initially received doses of 2.5 and 5 µg/kg SC syncBNP followed by an additional three dogs dosed at 5 and 10 µg/kg. Hemodynamic monitoring was performed for 120 min after each injection. Blood and urine samples were collected at 45 and 120 min after injection of 5 µg/kg. Major adverse clinical events that would potentially halt testing were pre-defined. RESULTS: Four healthy dogs and two dogs with stage B1 mitral valve disease were recruited. Synthetic canine B-type natriuretic peptide was well tolerated at all doses. Synthetic canine B-type natriuretic peptide at 5 µg/kg significantly increased median plasma cGMP (baseline cGMP, 131.5 pmol/mL [range, 91.9-183.6 pmol/mL]; 45 min, 153.6 pmol/mL [140.3-214.3 pmol/mL]; 120 min, 192.7 pmol/mL [139.1-240.1 pmol/mL]; p=0.041). DISCUSSION AND CONCLUSIONS: We report for the first time administration of syncBNP in privately owned dogs. Administration of SC syncBNP was feasible, well tolerated, safe, and increased plasma cGMP concentration. Further studies using exogenous syncBNP for treatment of heart disease are warranted.

Clinical Trials in Veterinary Medicine: A New Era Brings New Challenges.

Randomized clinical trials (RCTs) are among the most rigorous ways to determine the causal relationship between an intervention and important clinical outcome. Their use in veterinary medicine has become increasingly common, and as is often the case, with progress comes new challenges. Randomized clinical trials yield important answers, but results from these studies can be unhelpful or even misleading unless the study design and reporting are carried out with care. Herein, we offer some perspective on several emerging challenges associated with RCTs, including use of composite endpoints, the reporting of different forms of risk, analysis in the presence of missing data, and issues of reporting and safety assessment. These topics are explored in the context of previously reported veterinary internal medicine studies as well as through illustrative examples with hypothetical data sets. Moreover, many insights germane to RCTs in veterinary internal medicine can be drawn from the wealth of experience with RCTs in the human medical field. A better understanding of the issues presented here can help improve the design, interpretation, and reporting of veterinary RCTs.

Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study-A Randomized Clinical Trial.

BACKGROUND: Pimobendan is effective in treatment of dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD). Its effect on dogs before the onset of CHF is unknown. HYPOTHESIS/OBJECTIVES: Administration of pimobendan (0.4-0.6 mg/kg/d in divided doses) to dogs with increased heart size secondary to preclinical MMVD, not receiving other cardiovascular medications, will delay the onset of signs of CHF, cardiac-related death, or euthanasia. ANIMALS: 360 client-owned dogs with MMVD with left atrial-to-aortic ratio ≥1.6, normalized left ventricular internal diameter in diastole ≥1.7, and vertebral heart sum >10.5. METHODS: Prospective, randomized, placebo-controlled, blinded, multicenter clinical trial. Primary outcome variable was time to a composite of the onset of CHF, cardiac-related death, or euthanasia. RESULTS: Median time to primary endpoint was 1228 days (95% CI: 856-NA) in the pimobendan group and 766 days (95% CI: 667-875) in the placebo group (P = .0038). Hazard ratio for the pimobendan group was 0.64 (95% CI: 0.47-0.87) compared with the placebo group. The benefit persisted after adjustment for other variables. Adverse events were not different between treatment groups. Dogs in the pimobendan group lived longer (median survival time was 1059 days (95% CI: 952-NA) in the pimobendan group and 902 days (95% CI: 747-1061) in the placebo group) (P = .012). CONCLUSIONS AND CLINICAL IMPORTANCE: Administration of pimobendan to dogs with MMVD and echocardiographic and radiographic evidence of cardiomegaly results in prolongation of preclinical period and is safe and well tolerated. Prolongation of preclinical period by approximately 15 months represents substantial clinical benefit.

Anodal stimulation in two dogs with transvenous permanent bipolar pacemakers.

Management of symptomatic bradyarrhythmias such as complete atrioventricular block often involves permanent implantation of a transvenous pacemaker. Both during and after implantation, the operator can telemetrically assess and adjust a variety of electrical parameters associated with the pacemaker function in order to optimize the sensitivity, reliability, and power consumption of the device. Herein, we report an unexpected change in the paced electrocardiographic QRS complex morphology in two dogs undergoing bipolar pacing associated with changes in the pacemaker output amplitude settings first detected during threshold testing. The exclusivity of the electrocardiographic changes solely on pacemaker output settings, consistency between the surface electrocardiogram and ventricular endocardial electrogram, and resolution of this phenomenon when dogs were re-programmed to unipolar pacing is consistent with depolarization of the ventricular myocardium by the anodal electrode of the pacing lead at high pacemaker amplitudes. Anodal stimulation is a potential cause of varying QRS complex morphology witnessed during pacemaker evaluation and interrogation.

Differentiation of Cardiac from Noncardiac Pleural Effusions in Cats using Second-Generation Quantitative and Point-of-Care NT-proBNP Measurements.

BACKGROUND: Pleural effusion is a common cause of dyspnea in cats. N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement, using a first-generation quantitative ELISA, in plasma and pleural fluid differentiates cardiac from noncardiac causes of pleural effusion. HYPOTHESIS/OBJECTIVES: To determine whether NT-proBNP measurements using second-generation quantitative ELISA and point-of-care (POC) tests in plasma and pleural fluid distinguish cardiac from noncardiac pleural effusions and how results compare to the first-generation ELISA. ANIMALS: Thirty-eight cats (US cohort) and 40 cats (UK cohort) presenting with cardiogenic or noncardiogenic pleural effusion. METHODS: Prospective cohort study. Twenty-one and 17 cats in the US cohort, and 22 and 18 cats in the UK cohort were classified as having cardiac or noncardiac pleural effusion, respectively. NT-proBNP concentrations in paired plasma and pleural fluid samples were measured using second-generation ELISA and POC assays. RESULTS: The second-generation ELISA differentiated cardiac from noncardiac pleural effusion with good diagnostic accuracy (plasma: sensitivity, 95.2%, specificity, 82.4%; pleural fluid: sensitivity, 100%, specificity, 76.5%). NT-proBNP concentrations were greater in pleural fluid (719 pmol/L (134-1500)) than plasma (678 pmol/L (61-1500), P = 0.003), resulting in different cut-off values depending on the sample type. The POC test had good sensitivity (95.2%) and specificity (87.5%) when using plasma samples. In pleural fluid samples, the POC test had good sensitivity (100%) but low specificity (64.7%). Diagnostic accuracy was similar between first- and second-generation ELISA assays. CONCLUSIONS AND CLINICAL IMPORTANCE: Measurement of NT-proBNP using a quantitative ELISA in plasma and pleural fluid or POC test in plasma, but not pleural fluid, distinguishes cardiac from noncardiac causes of pleural effusion in cats.

Cardiovascular-renal axis disorders in the domestic dog and cat: a veterinary consensus statement.

OBJECTIVES: There is a growing understanding of the complexity of interplay between renal and cardiovascular systems in both health and disease. The medical profession has adopted the term "cardiorenal syndrome" (CRS) to describe the pathophysiological relationship between the kidney and heart in disease. CRS has yet to be formally defined and described by the veterinary profession and its existence and importance in dogs and cats warrant investigation. The CRS Consensus Group, comprising nine veterinary cardiologists and seven nephrologists from Europe and North America, sought to achieve consensus around the definition, pathophysiology, diagnosis and management of dogs and cats with "cardiovascular-renal disorders" (CvRD). To this end, the Delphi formal methodology for defining/building consensus and defining guidelines was utilised. METHODS: Following a literature review, 13 candidate statements regarding CvRD in dogs and cats were tested for consensus, using a modified Delphi method. As a new area of interest, well-designed studies, specific to CRS/CvRD, are lacking, particularly in dogs and cats. Hence, while scientific justification of all the recommendations was sought and used when available, recommendations were largely reliant on theory, expert opinion, small clinical studies and extrapolation from data derived from other species. RESULTS: Of the 13 statements, 11 achieved consensus and 2 did not. The modified Delphi approach worked well to achieve consensus in an objective manner and to develop initial guidelines for CvRD. DISCUSSION: The resultant manuscript describes consensus statements for the definition, classification, diagnosis and management strategies for veterinary patients with CvRD, with an emphasis on the pathological interplay between the two organ systems. By formulating consensus statements regarding CvRD in veterinary medicine, the authors hope to stimulate interest in and advancement of the understanding and management of CvRD in dogs and cats. The use of a formalised method for consensus and guideline development should be considered for other topics in veterinary medicine.

Alpha-smooth muscle actin and serotonin receptors 2A and 2B in dogs with myxomatous mitral valve disease.

Canine Myxomatous mitral valve disease (MMVD) is an age-related disease. Serotonin (5-HT) is implicated in the pathogenesis as locally-produced or platelet-derived. Involvement of the 5-HT2A receptor (R) and 5-HT2BR in the induction of myxomatous-mediating valvular myofibroblasts (MF) has been suggested. In an age-matched population of dogs with non-clinical and clinical MMVD, the objectives were to investigate (1) gene expression of 5-HT2AR and 5-HT2BR, (2) protein expression and spatial relationship of 5-HT2AR, 5-HT2BR and MF in the mitral valve (MV) and the cardiac anterior papillary muscle (AP) and (3) serum 5-HT concentrations. Gene expression of 5-HT2BR was significantly higher in MV and AP among dogs with clinical MMVD. This was not found for 5-HT2BR protein expression, though association of 5-HT2BR with myxomatous pathology and co-localization of 5-HT2BR and MF in MV and AP support a functional relationship, perhaps perpetuation of clinical MMVD. 5-HT2AR-expression and serum 5-HT showed no differences between groups.

Serotonin markers show altered transcription levels in an experimental pig model of mitral regurgitation.

Serotonin (5-hydroxytryptamine, 5-HT) signalling is implicated in the pathogenesis of myxomatous mitral valve disease (MMVD) through 5-HT1B receptor (R), 5-HT2AR and 5-HT2BR-induced myxomatous pathology. Based on increased tryptophan hydroxylase-1 (TPH-1) and decreased serotonin re-uptake transporter (SERT) in MMVD-affected valves, increased valvular 5-HT synthesis and decreased clearance have been suggested. It remains unknown how haemodynamic changes associated with mitral regurgitation (MR) affect 5-HT markers in the mitral valve, myocardium and circulation. Twenty-eight pigs underwent surgically induced MR or sham-operation, resulting in three MR groups: control (CON, n = 12), mild MR (mMR, n = 10) and severe MR (sMR, n = 6). The gene expression levels of 5-HT1BR, 5-HT2AR, 5-HT2BR, SERT and TPH-1 were analysed using quantitative PCR (qPCR) in the mitral valve (MV), anterior papillary muscle (AP) and left ventricle (LV). MV 5-HT2BR was also analysed with immunohistochemistry (IHC) in relation to histological lesions and valvular myofibroblasts. All 5-HTR mRNAs were up-regulated in MV compared to AP and LV (P <0.01). In contrast, SERT and TPH-1 were up-regulated in AP and LV compared to MV (P <0.05). In MV, mRNA levels were increased for 5-HT2BR (P = 0.02) and decreased for SERT (P = 0.03) in sMR vs. CON. There were no group differences in 5-HT2BR staining (IHC) but co-localisation was found with α-SMA-positive cells in 91% of all valves and with 33% of histological lesions. In LV, 5-HT1BR mRNA levels were increased in sMR vs. CON (P = 0.01). In conclusion, these data suggest that MR may affect mRNA expression of valvular 5-HT2BR and SERT, and left ventricular 5-HT1BR in some pigs.

Relationship of plasma N-terminal pro-brain natriuretic peptide concentrations to heart failure classification and cause of respiratory distress in dogs using a 2nd generation ELISA assay.

BACKGROUND: Cardiac biomarkers provide objective data that augments clinical assessment of heart disease (HD). HYPOTHESIS/OBJECTIVES: Determine the utility of plasma N-terminal pro-brain natriuretic peptide concentration [NT-proBNP] measured by a 2nd generation canine ELISA assay to discriminate cardiac from noncardiac respiratory distress and evaluate HD severity. ANIMALS: Client-owned dogs (n = 291). METHODS: Multicenter, cross-sectional, prospective investigation. Medical history, physical examination, echocardiography, and thoracic radiography classified 113 asymptomatic dogs (group 1, n = 39 without HD; group 2, n = 74 with HD), and 178 with respiratory distress (group 3, n = 104 respiratory disease, either with or without concurrent HD; group 4, n = 74 with congestive heart failure [CHF]). HD severity was graded using International Small Animal Cardiac Health Council (ISACHC) and ACVIM Consensus (ACVIM-HD) schemes without knowledge of [NT-proBNP] results. Receiver-operating characteristic curve analysis assessed the capacity of [NT-proBNP] to discriminate between dogs with cardiac and noncardiac respiratory distress. Multivariate general linear models containing key clinical variables tested associations between [NT-proBNP] and HD severity. RESULTS: Plasma [NT-proBNP] (median; IQR) was higher in CHF dogs (5,110; 2,769-8,466 pmol/L) compared to those with noncardiac respiratory distress (1,287; 672-2,704 pmol/L; P < .0001). A cut-off >2,447 pmol/L discriminated CHF from noncardiac respiratory distress (81.1% sensitivity; 73.1% specificity; area under curve, 0.84). A multivariate model comprising left atrial to aortic ratio, heart rate, left ventricular diameter, end-systole, and ACVIM-HD scheme most accurately associated average plasma [NT-proBNP] with HD severity. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma [NT-proBNP] was useful for discriminating CHF from noncardiac respiratory distress. Average plasma [NT-BNP] increased significantly as a function of HD severity using the ACVIM-HD classification scheme.

Serotonin concentrations in platelets, plasma, mitral valve leaflet, and left ventricular myocardial tissue in dogs with myxomatous mitral valve disease.

HYPOTHESIS/OBJECTIVES: Altered serotonin (5-hydroxytryptamine, 5HT) signaling is postulated in development and progression of canine myxomatous mitral valve disease (MMVD). Little is known regarding platelet, plasma, valvular, or myocardial 5HT concentration ([5HT]) in affected dogs. We quantified [5HT] in platelet-rich plasma (PRP), platelet-poor plasma (PPP), mitral valve leaflets (MV), and left ventricular myocardium (LV). ANIMALS: Forty-five dogs comprised 4 plasma groups of Cavalier King Charles Spaniels (CKCS) or non-CKCS, either healthy (CON) or MMVD affected: CKCS CON (n = 12); non-CKCS CON (n = 8); CKCS MMVD (n = 14); non-CKCS MMVD (n = 11). Twenty-four dogs comprised 3 tissue groups: MMVD (n = 8); other-HD (heart disease) (n = 7); non-HD, extracardiac disease (n = 9). METHODS: High-performance liquid chromatography measured PRP, PPP, MV, and LV [5HT]. RESULTS: Platelet-rich plasma platelet [5HT] was greater in CKCS CON (1.83 femtograms/platelet [fg/plt]; range, 0.20-4.76; P = .002), CKCS MMVD (1.58 fg/plt; range, 0.70-4.03; P = .005), and non-CKCS MMVD (1.72 fg/plt; range, 0.85-4.44; P = .003) versus non-CKCS CON (0.92 fg/plt; range, 0.63-1.30). There was no group difference in PPP [5HT]. MV [5HT] was significantly higher in MMVD (32.4 ng/mg; range, 8.4-106.7) versus non-HD (3.6 ng/mg; range, 0-28.3; P = .01) and LV [5HT] was significantly higher in MMVD (11.9 ng/mg; range, 4.0-104.8) versus other-HD (0.9 ng/mg; range, 0-10.1; P = .011) and non-HD (2.5 ng/mg; range, 0-6.9; P = .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Platelet [5HT] was highest in healthy CKCS and both MMVD groups, but plasma [5HT] showed no group differences. Tissue [5HT] was highest in MV and LV of MMVD-affected dogs, suggesting altered 5HT signaling as a potential feature of MMVD. Interactions of platelet, valvular, and myocardial 5HT signaling warrant further investigation.

Prediction of long-term outcome by measurement of serum concentration of cardiac troponins in critically ill dogs with systemic inflammation.

BACKGROUND: Myocardial injury, detected by cardiac troponin I and T (cTnI and cTnT), has been associated with long-term death in the noncardiac human intensive care unit (ICU). HYPOTHESIS: Presence of myocardial injury predicts 1-year case fatality in critically ill dogs with systemic inflammation. ANIMALS: Thirty-eight dogs with evidence of systemic inflammation and no primary cardiac disease. METHODS: Prospective cohort study. In dogs admitted to the ICU with evidence of systemic inflammation, blood samples were obtained at ICU admission for measurement of cTnI and cTnT, and cTnI was measured once daily during ICU hospitalization. Receiver operating characteristic (ROC) curves were used to examine prognostic capacity of admission cTnI, admission cTnT, and peak cTnI concentrations. RESULTS: One-year case fatality rate was 47% (18/38 dogs). Admission cTnI concentrations were (median [range]) 0.48 [0.004-141.50] ng/mL, and peak cTnI concentrations were 1.21 [0.021-141.50] ng/mL. Admission cTnT concentrations were 15 [<13-3744] ng/L. For each marker, non-survivors had significantly higher concentrations than survivors (P = .0082-.038). ROC analyses revealed areas under curves [95% CI] of 0.707 [0.537-0.843] for peak cTnI and 0.739 [0.571-0.867] for admission cTnT, respectively. At the optimal cut-off, concentrations were 1.17 ng/mL (peak cTnI) and 23 ng/L (admission cTnT), sensitivities were 72% and 72%, and specificities were 70% and 80%, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: While peak cTnI and admission cTnT are significantly related to 1-year case fatality in critically ill dogs with systemic inflammation, low sensitivities and specificities prevent their prediction of long-term outcome in individual patients. Troponins might play a role in identification of dogs at long-term risk of death.