RESUMEN
In heart failure (HF), dysregulated cardiac ryanodine receptors (RyR2) contribute to the generation of diastolic Ca2+ waves (DCWs), thereby predisposing adrenergically stressed failing hearts to life-threatening arrhythmias. However, the specific cellular, subcellular, and molecular defects that account for cardiac arrhythmia in HF remain to be elucidated. Patch-clamp techniques and confocal Ca2+ imaging were applied to study spatially defined Ca2+ handling in ventricular myocytes isolated from normal (control) and failing canine hearts. Based on their activation time upon electrical stimulation, Ca2+ release sites were categorized as coupled, located in close proximity to the sarcolemmal Ca2+ channels, and uncoupled, the Ca2+ channel-free non-junctional Ca2+ release units. In control myocytes, stimulation of ß-adrenergic receptors with isoproterenol (Iso) resulted in a preferential increase in Ca2+ spark rate at uncoupled sites. This site-specific effect of Iso was eliminated by the phosphatase inhibitor okadaic acid, which caused similar facilitation of Ca2+ sparks at coupled and uncoupled sites. Iso-challenged HF myocytes exhibited increased predisposition to DCWs compared to control myocytes. In addition, the overall frequency of Ca2+ sparks was increased in HF cells due to preferential stimulation of coupled sites. Furthermore, coupled sites exhibited accelerated recovery from functional refractoriness in HF myocytes compared to control myocytes. Spatially resolved subcellular Ca2+ mapping revealed that DCWs predominantly originated from coupled sites. Inhibition of CaMKII suppressed DCWs and prevented preferential stimulation of coupled sites in Iso-challenged HF myocytes. These results suggest that CaMKII- (and phosphatase)-dependent dysregulation of junctional Ca2+ release sites contributes to Ca2+-dependent arrhythmogenesis in HF.
Asunto(s)
Arritmias Cardíacas/metabolismo , Señalización del Calcio , Calcio/metabolismo , Insuficiencia Cardíaca/metabolismo , Frecuencia Cardíaca , Microdominios de Membrana/metabolismo , Miocitos Cardíacos/metabolismo , Función Ventricular Izquierda , Agonistas Adrenérgicos beta/farmacología , Animales , Arritmias Cardíacas/fisiopatología , Canales de Calcio Tipo L/metabolismo , Señalización del Calcio/efectos de los fármacos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Estimulación Cardíaca Artificial , Diástole , Modelos Animales de Enfermedad , Perros , Femenino , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Potenciales de la Membrana , Miocitos Cardíacos/efectos de los fármacos , Periodo Refractario Electrofisiológico , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Sarcolema/metabolismo , Sus scrofa , Factores de Tiempo , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
The aims of this study were to evaluate left atrial size in cats with acute left-sided congestive heart failure. We hypothesized that left atrial size as determined by thoracic radiography can be normal in cats with acute left-sided congestive heart failure. One hundred cats with acute left-sided congestive heart failure in which thoracic radiography and echocardiography were performed within 12 h were identified. Left atrial size was evaluated using right lateral and ventrodorsal radiographs. Measurements were compared to two-dimensional echocardiographic variables of left atrial size and left ventricular size. On echocardiography, left atrial enlargement was observed in 96% cats (subjective assessment) whereas maximum left atrial dimension was increased (>15.7 mm) in 93% cats. On radiographs left atrial enlargement (subjective assessment) was found in 48% (lateral view), 53% (ventrodorsal view), and 64% (any view) of cats whereas left atrial enlargement was absent in 36% of cats in both views. Agreement between both methods of left atrial size estimation was poor (Cohen's kappa 0.17). Receiver operating characteristic curve analysis identified a maximum echocardiographic left atrial dimension of approximately 20 mm as the best compromise (Youden index) between sensitivity and specificity in the prediction of radiographic left atrial enlargement. Left atrial enlargement as assessed by thoracic radiography may be absent in a clinically relevant number of cats with congestive heart failure. Therefore, normal left atrial size on thoracic radiographs does not rule out presence of left-sided congestive heart failure in cats with clinical signs of respiratory distress.
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Enfermedades de los Gatos/diagnóstico por imagen , Atrios Cardíacos/patología , Insuficiencia Cardíaca/veterinaria , Animales , Enfermedades de los Gatos/patología , Gatos , Ecocardiografía Doppler/veterinaria , Femenino , Atrios Cardíacos/diagnóstico por imagen , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/patología , Masculino , Curva ROC , Radiografía Torácica/veterinaria , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: To describe the clinical presentation and outcome in dogs diagnosed with Trypanosoma cruzi infection in nonendemic areas and to survey veterinary cardiologists in North America for Chagas disease awareness. ANIMALS: 12 client-owned dogs; 83 respondents from a veterinary cardiology listserv. PROCEDURES: A retrospective, multicenter medical records review to identify dogs diagnosed with American trypanosomiasis between December 2010 and December 2020. An anonymous online survey was conducted August 9 to 22, 2022. RESULTS: Diagnosis was made using indirect fluorescent antibody titer (n = 9), quantitative PCR assay (1), or postmortem histopathology (2). Time spent in Texas was < 1 year (n = 7) or 2 to 8 years (5). Time in nonendemic areas prior to diagnosis was < 1 year (n = 10) and > 3 years (2). Eleven had cardiac abnormalities. Of the 12 dogs, 5 had died unexpectedly (range, 1 to 108 days after diagnosis), 4 were still alive at last follow-up (range, 60 to 369 days after diagnosis), 2 were euthanized because of heart disease (1 and 98 days after diagnosis), and 1 was lost to follow-up. Survey results were obtained from 83 cardiologists in North America, of which the self-reported knowledge about Chagas disease was limited in 49% (41/83) and 69% (57/83) expressed interest in learning resources. CLINICAL RELEVANCE: Results highlight the potential for encountering dogs with T cruzi infection in nonendemic areas and need for raising awareness about Chagas disease in North America.
Asunto(s)
Enfermedad de Chagas , Enfermedades de los Perros , Trypanosoma cruzi , Animales , Perros , Estudios Retrospectivos , Enfermedad de Chagas/diagnóstico , Enfermedad de Chagas/epidemiología , Enfermedad de Chagas/veterinaria , Texas , Encuestas y Cuestionarios , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/epidemiologíaRESUMEN
OBJECTIVE: To assess whether cardiac MRI or various biomarkers can be used to detect myocardial ischemia and fibrosis in dogs with cardiomegaly secondary to myxomatous mitral valve disease (MMVD). ANIMALS: 6 dogs with cardiomegaly secondary to naturally occurring stage B2 MMVD being treated only with pimobendan with or without enalapril and 6 control dogs with no cardiac disease. All dogs were ≥ 5 years old with no systemic illness. PROCEDURES: Serum cardiac troponin I and concentrations were measured, and dogs were anesthetized for cardiac MRI with ECG-triggered acquisition of native T1- and T2-weighted images. Gadolinium contrast was administered to evaluate myocardial perfusion and late gadolinium enhancement (LGE). Mean T1 and T2 values and regions of LGE were measured with dedicated software. Extracellular volume (ECV) was estimated on the basis of Hct and T1 values of myocardium and surrounding blood. Subjective analysis for myocardial perfusion deficits was performed. RESULTS: Dogs with MMVD had significantly (P = .013) higher cardiac troponin I concentrations than control dogs, but galectin-3 concentrations did not differ (P = .08) between groups. Myocardial fibrosis was detected in 4 dogs with MMVD and 3 control dogs; no dogs had obvious myocardial perfusion deficits. Native T1 and T2 values, postcontrast T1 values, and ECV values were not significantly different between groups (all P > .3). CLINICAL RELEVANCE: Results suggest that some dogs with cardiomegaly secondary to MMVD may not have clinically relevant myocardial fibrosis.
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Enfermedades de los Perros , Enfermedades de las Válvulas Cardíacas , Isquemia Miocárdica , Animales , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/veterinaria , Medios de Contraste , Enfermedades de los Perros/diagnóstico por imagen , Enfermedades de los Perros/etiología , Perros , Fibrosis , Gadolinio , Enfermedades de las Válvulas Cardíacas/veterinaria , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/veterinaria , Válvula Mitral , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/etiología , Isquemia Miocárdica/veterinaria , Troponina IRESUMEN
BACKGROUND: There is a lack of clinical data on hypertrophic cardiomyopathy (HCM) in dogs. HYPOTHESIS/OBJECTIVES: To investigate signalment, clinical signs, diagnostic findings, and survival in dogs with HCM. ANIMALS: Sixty-eight client-owned dogs. METHODS: Retrospective multicenter study. Medical records were searched between 2003 and 2015. The diagnosis of left ventricular (LV) hypertrophy was made by echocardiographic examination. RESULTS: Three hundred and forty-five dogs with LV hypertrophy were identified, of which 277 were excluded. The remaining 68 dogs were 0.3 to 14 years old and predominantly <10 kg (85%), and without a sex predilection. Twenty-four % were Shih Tzu and 24% terrier breeds. Most (80%) had a systolic heart murmur. Owner-determined exercise intolerance (37%) and syncope (18%) were most commonly reported signs. The majority (84%) of dogs had symmetrical LV hypertrophy, whereas asymmetrical septal and LV free wall hypertrophy was observed in 9% and 6% of dogs, respectively. Isolated basal interventricular septal hypertrophy was not observed. Commonly recorded were systolic anterior motion of the mitral valve (60%) and LV diastolic dysfunction (89% of dogs where diastolic function was evaluated). Six dogs died unexpectedly, and 3 developed congestive heart failure. Known survival times were between 1 day and 114 months after diagnosis. CONCLUSIONS AND CLINICAL IMPORTANCE: Hypertrophic cardiomyopathy in dogs should be considered as a differential diagnosis if LV hypertrophy is identified. Small breed dogs are overrepresented, and it is uncommon for dogs with HCM to develop CHF although sudden death can occur.
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Cardiomiopatía Hipertrófica , Enfermedades de los Perros , Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Animales , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/veterinaria , Enfermedades de los Perros/diagnóstico por imagen , Perros , Ecocardiografía/veterinaria , Insuficiencia Cardíaca/veterinaria , Hipertrofia Ventricular Izquierda/veterinaria , Estudios Retrospectivos , Disfunción Ventricular Izquierda/veterinariaRESUMEN
BACKGROUND: Arterial thromboembolism is a sequela of hypertrophic cardiomyopathy (HCM) in cats related to left atrial (LA) enlargement and dysfunction. HYPOTHESIS: Pimobendan improves LA transport function in cats. ANIMALS: Twenty-two client-owned cats with HCM and 11 healthy cats. METHODS: Prospective, double-blind, randomized, placebo-controlled clinical cohort study. Cats were randomized to receive either pimobendan (0.25 mg/kg PO q12h) or placebo for 4 to 7 days. Nineteen echocardiographic variables of LA size and function were evaluated. Statistical comparisons included t tests, analysis of variance, and multivariable analyses. RESULTS: Peak velocity of left auricular appendage flow (LAapp peak; mean ± SD, 0.85 ± 0.20 vs 0.71 ± 0.22 m/s; P = .01), maximum LA volume (P = .03), LA total emptying volume (P = .03), peak velocity of late diastolic transmitral flow (A peak velocity; 0.77 ± 0.12 vs 0.62 ± 0.17 m/s; P = .05), and A velocity time integral (A VTI; 3.05 ± 0.69 vs 3.37 ± 0.49; P = .05) were increased after pimobendan. Mean change after pimobendan was larger in cats with HCM compared to healthy cats for LA fractional shortening (2.1% vs -2.1%; P = .05), A VTI (0.58 vs 0.01 cm; P = .01), LAapp peak (0.20 vs 0.02 m/s; P = .02), LA kinetic energy (3.51 vs -0.10 kdynes-cm; P = .05), and LA ejection force (1.93 vs -0.07 kdynes; P = .01) in the multivariable model. The stronger effect of pimobendan in cats with HCM was independent of LA size. CONCLUSIONS AND CLINICAL IMPORTANCE: We identified positive, albeit minor, effects of pimobendan on LA function in cats with HCM. Whether or not treatment with pimobendan decreases the risk of cardiogenic embolism deserves further study.
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Cardiomiopatía Hipertrófica , Enfermedades de los Gatos , Piridazinas , Animales , Función del Atrio Izquierdo , Cardiomiopatía Hipertrófica/veterinaria , Enfermedades de los Gatos/tratamiento farmacológico , Gatos , Estudios de Cohortes , Atrios Cardíacos , Estudios Prospectivos , Piridazinas/farmacologíaRESUMEN
BACKGROUND: The benefits of pimobendan in the treatment of congestive heart failure (CHF) in cats with hypertrophic cardiomyopathy (HCM) have not been evaluated prospectively. HYPOTHESIS/OBJECTIVES: To investigate the effects of pimobendan in cats with HCM and recent CHF and to identify possible endpoints for a pivotal study. We hypothesized that pimobendan would be well-tolerated and associated with improved outcome. ANIMALS: Eighty-three cats with HCM and recently controlled CHF: 30 with and 53 without left ventricular outflow tract obstruction. METHODS: Prospective randomized placebo-controlled double-blind multicenter nonpivotal field study. Cats received either pimobendan (0.30 mg/kg q12h, n = 43), placebo (n = 39), or no medication (n = 1) together with furosemide (<10 mg/kg/d) with or without clopidogrel. The primary endpoint was a successful outcome (ie, completing the 180-day study period without a dose escalation of furosemide). RESULTS: The proportion of cats in the full analysis set population with a successful outcome was not different between treatment groups (P = .75). For nonobstructive cats, the success rate was 32% in pimobendan-treated cats versus 18.2% in the placebo group (odds ratio [OR], 2.12; 95% confidence interval [CI], 0.54-8.34). For obstructive cats, the success rate was 28.6% and 60% in the pimobendan and placebo groups, respectively (OR, 0.27; 95% CI, 0.06-1.26). No difference was found between treatments for the secondary endpoints of time to furosemide dose escalation or death (P = .89). Results were similar in the per-protocol sets. Adverse events in both treatment groups were similar. CONCLUSIONS AND CLINICAL IMPORTANCE: In this study of cats with HCM and recent CHF, no benefit of pimobendan on 180-day outcome was identified.
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Cardiomiopatía Hipertrófica , Enfermedades de los Gatos , Enfermedades de los Perros , Insuficiencia Cardíaca , Animales , Cardiomiopatía Hipertrófica/tratamiento farmacológico , Cardiomiopatía Hipertrófica/veterinaria , Cardiotónicos/uso terapéutico , Enfermedades de los Gatos/tratamiento farmacológico , Gatos , Enfermedades de los Perros/tratamiento farmacológico , Perros , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/veterinaria , Estudios Prospectivos , PiridazinasRESUMEN
Background: Multiple cardiac troponin I (cTnI) immunoassays are commercially available. Overall, assays have not been standardized, and inter-assay differences in the detection of the analyte cardiac troponin I can be clinically relevant. Objective: To compare the diagnostic accuracy of the commercially available Abbott i-STAT®1 cTnI immunoassay (i-STAT) and the previously validated ADVIA Centaur TnI-Ultra immunoassay (Centaur) in cattle. Hypothesis: There will be significant differences in bovine serum cTnI results measured by the Centaur and i-STAT methods. Animals: Ten dairy cows with experimentally induced myocardial injury due to monensin administration. Thirty apparently healthy dairy cows with no history of monensin exposure served as controls. Methods: Blood was collected at various time points after administration of a single dose of monensin (20 to 50 mg/kg) via orogastric tube. A total of 112 blood samples were collected. Cardiac TnI concentration was analyzed with the two methods and the association between methods analyzed via linear regression. Bland-Altman analysis to evaluate agreement between methods was performed on samples divided into groups (cTnI < 1.0 ng/mL and cTnI ≥ 1.0 ng/mL). Results: Analyzer results were linearly correlated with each other (R 2 = 0.931). Samples with cTnI concentrations <1.0 ng/mL had a bias of -0.13 ± 0.20 ng/mL and samples with cTnI concentrations >1.0 ng/mL had a bias of -9.81 ± 13.26 ng/mL. Conclusions and clinical importance: The results of this study reveal that cTnI concentrations determined with the i-STAT are systematically lower compared to the concentrations determined by the Centaur.
RESUMEN
CASE SUMMARY: An 8-year-old spayed female domestic shorthair cat was presented for a recheck evaluation of hypertrophic cardiomyopathy and chronic kidney disease. Three years prior to presentation, the patient was diagnosed with obstructive hypertrophic cardiomyopathy and started on atenolol. The left ventricular outflow tract obstruction subsequently resolved. Biochemical analysis a week prior to presentation demonstrated severe azotemia. Transthoracic echocardiograph revealed pericardial effusion, pleural effusion, severe left ventricular concentric hypertrophy, severe left atrial enlargement and continuous left-to-right flow through the interatrial septum near the fossa ovalis. The patient was euthanized owing to poor prognosis, and gross examination at necropsy revealed a valve-incompetent patent foramen ovale secondary to severe left atrial dilation. RELEVANCE AND NOVEL INFORMATION: To our knowledge, this is the first report of an acquired left-to-right shunt through a valve-incompetent foramen ovale in a cat with hypertrophic cardiomyopathy. Severe left atrial dilation was suspected to cause interatrial shunting through the valve-incompetent foramen ovale, and this finding may be relevant to echocardiographic evaluations in other cats.
RESUMEN
BACKGROUND: Left-sided congestive heart failure (CHF) is characterized by increased filling pressures and related Doppler echocardiographic (DE) filling patterns. HYPOTHESIS: Doppler echocardiographic variables of left ventricular filling derived from transmitral flow, pulmonary vein flow, and tissue Doppler can be used to detect CHF in cats with hypertrophic cardiomyopathy (HCM). ANIMALS: Forty-seven client-owned cats. METHODS: Prospective clinical cohort study. Cats underwent physical examination, thoracic radiography, analysis of N-terminal pro-brain natriuretic peptide (NT-proBNP), and transthoracic echocardiography and were divided into 3 age-matched groups: Group 1 (apparently healthy control), Group 2 (preclinical HCM), and Group 3 (HCM and CHF). Measured and calculated variables included respiratory rate, DE estimates, serum NT-proBNP concentration, and radiographic CHF score. Groups were compared using ANOVA, and receiver operating characteristic (ROC) curve and multivariate analyses were used to identify diagnostic cutoffs for the detection of CHF. RESULTS: Fifteen cats were in Group 1, 17 in Group 2, and 15 in Group 3. The ROC analysis indicated that the ratio of peak velocity of early diastolic transmitral flow to peak velocity of late diastolic transmitral flow (area under the curve [AUC], 1.0; diagnostic cutoff, 1.77; P = .001), ratio of left atrial size to aortic annular dimension (AUC, 0.91; diagnostic cutoff, 1.96; P = .003), left atrial diameter (AUC, 0.89; cutoff, 18.5 mm; P = .004), diastolic functional class (AUC, 0.89; cutoff, class 2; P = .005), respiratory (AUC, 0.79; cutoff, 36 breaths per minute [brpm]; P = .02), and the ratio of the peak velocity of fused early and late transmitral flow velocities to the peak velocity of the fused early and late diastolic tissue Doppler waveforms (AUC, 0.74; cutoff, 15.1; P = .05) performed best for detecting CHF. CONCLUSIONS AND CLINICAL IMPORTANCE: Various DE variables can be used to detect CHF in cats with HCM. Determination of the clinical benefit of such variables in initiating treatments and assessing treatment success needs further study.
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Cardiomiopatía Hipertrófica/veterinaria , Enfermedades de los Gatos/diagnóstico por imagen , Ecocardiografía Doppler/veterinaria , Insuficiencia Cardíaca/veterinaria , Animales , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Gatos , Estudios de Cohortes , Ecocardiografía Doppler/métodos , Femenino , Insuficiencia Cardíaca/diagnóstico por imagen , Masculino , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Estudios Prospectivos , Frecuencia RespiratoriaRESUMEN
Cardiomyopathies are a heterogeneous group of myocardial disorders of mostly unknown etiology, and they occur commonly in cats. In some cats, they are well-tolerated and are associated with normal life expectancy, but in other cats they can result in congestive heart failure, arterial thromboembolism or sudden death. Cardiomyopathy classification in cats can be challenging, and in this consensus statement we outline a classification system based on cardiac structure and function (phenotype). We also introduce a staging system for cardiomyopathy that includes subdivision of cats with subclinical cardiomyopathy into those at low risk of life-threatening complications and those at higher risk. Based on the available literature, we offer recommendations for the approach to diagnosis and staging of cardiomyopathies, as well as for management at each stage.
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Cardiomiopatías/veterinaria , Enfermedades de los Gatos/diagnóstico , Animales , Cardiomiopatías/clasificación , Cardiomiopatías/diagnóstico , Cardiomiopatías/terapia , Enfermedades de los Gatos/clasificación , Enfermedades de los Gatos/terapia , Gatos , Consenso , Corazón/anatomía & histología , Corazón/fisiopatología , Guías de Práctica Clínica como Asunto , Sociedades VeterinariasRESUMEN
AIMS: Bradycardia contributes to tachy-brady arrhythmias or sinus arrest during heart failure (HF). Sinoatrial node (SAN) adenosine A1 receptors (ADO A1Rs) are upregulated in HF, and adenosine is known to exert negative chronotropic effects on the SAN. Here, we investigated the role of A1R signaling at physiologically relevant ADO concentrations on HF SAN pacemaker cells. MAIN METHODS: Dogs with tachypacing-induced chronic HF and normal controls (CTL) were studied. SAN tissue was collected for A1R and GIRK mRNA quantification. SAN cells were isolated for perforated patch clamp recordings and firing rate (bpm), slope of slow diastolic depolarization (SDD), and maximum diastolic potential (MDP) were measured. Action potentials (APs) and currents were recorded before and after addition of 1 and 10⯵M ADO. To assess contributions of A1R and G protein-coupled Inward Rectifier Potassium Current (GIRK) to ADO effects, APs were measured after the addition of DPCPX (selective A1R antagonist) or TPQ (selective GIRK blocker). KEY FINDINGS: A1R and GIRK mRNA expression were significantly increased in HF. In addition, ADO induced greater rate slowing and membrane hyperpolarization in HF vs CTL (pâ¯<â¯0.05). DPCPX prevented ADO-induced rate slowing in CTL and HF cells. The ADO-induced inward rectifying current, IKado, was observed significantly more frequently in HF than in CTL. TPQ prevented ADO-induced rate slowing in HF. SIGNIFICANCE: An increase in A1R and GIRK expression enhances IKAdo, causing hyperpolarization, and subsequent negative chronotropic effects in canine chronic HF at relevant [ADO]. GIRK blockade may be a useful strategy to mitigate bradycardia in HF.
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Agonistas del Receptor de Adenosina A1/farmacología , Adenosina/farmacología , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/agonistas , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Receptor de Adenosina A1/metabolismo , Nodo Sinoatrial/citología , Nodo Sinoatrial/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Antagonistas del Receptor de Adenosina A1/farmacología , Animales , Venenos de Abeja/farmacología , Relojes Biológicos , Enfermedad Crónica , Perros , Femenino , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/antagonistas & inhibidores , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/efectos de los fármacos , Técnicas In Vitro , Masculino , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Receptor de Adenosina A1/efectos de los fármacos , Xantinas/farmacologíaRESUMEN
In this study, we characterized the pharmacokinetics of OSU-2S, a fingolimod-derived, non-immunosuppressive phosphatase activator, in mice, rats, and dogs, as well as tolerability and food effects in dogs. Across all species tested, plasma protein binding for OSU-2S was > 99.5%, and metabolic stability and hepatic intrinsic clearance were in the moderate range. OSU-2S did not significantly modulate CYP enzyme activity up until 50 µM, and Caco-2 data suggested low permeability with active efflux at 2 µM. Apparent oral bioavailability in mice was 16% and 69% at 10 and 50 mg/kg, respectively. In rats, bioavailability was 24%, 35%, and 28% at 10, 30, and 100 mg/kg, respectively, while brain/plasma ratio was 36 at 6-h post-dose at 30 mg/kg. In dogs, OSU-2S was well tolerated with oral capsule bioavailability of 27.5%. Plasma OSU-2S exposures increased proportionally over a 2.5-20 mg/kg dose range. After 4 weeks of 3 times weekly, oral administration (20 mg/kg), plasma AUClast (26.1 µM*h), and Cmax (0.899 µM) were nearly 2-fold greater than those after 1 week of dosing, and no food effects were observed. The elimination half-life (29.7 h), clearance (22.9 mL/min/kg), and plasma concentrations of repeated oral doses support a 3-times weekly dosing schedule in dogs. No significant CBC, serum biochemical, or histopathological changes were observed. OSU-2S has favorable oral PK properties similar to fingolimod in rodents and dogs and is well tolerated in healthy animals. This work supports establishing trials of OSU-2S efficacy in dogs with spontaneous tumors to guide its clinical development as a cancer therapeutic for human patients.
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Análisis de Datos , Clorhidrato de Fingolimod/farmacocinética , Inmunosupresores/farmacocinética , Glicoles de Propileno/farmacocinética , Esfingosina/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Perros , Relación Dosis-Respuesta a Droga , Clorhidrato de Fingolimod/administración & dosificación , Haplorrinos , Humanos , Inmunosupresores/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Glicoles de Propileno/administración & dosificación , Ratas , Ratas Sprague-Dawley , Esfingosina/administración & dosificación , Esfingosina/farmacocinéticaRESUMEN
OBJECTIVE: To evaluate the accuracy of a commercial ultrasonographic cardiac output (CO) monitoring system (UCOMS) in anesthetized Beagles as assessed by comparison with thermodilution CO (TDCO). ANIMALS: 8 healthy anesthetized Beagles. PROCEDURES: Simultaneous UCOMS and TDCO measurements of CO were obtained during 4 hemodynamic states: baseline anesthesia (0.5% to 1.5% isoflurane), a higher depth of anesthesia (2% to 3.5% isoflurane) to yield a >or= 15% reduction in systolic arterial blood pressure, IV infusion of colloidal solution to a mean right atrial pressure of >or= 15 mm Hg, and IV infusion of dobutamine at 5 microg/kg/min. Measurements were obtained at 2 probe positions: the subxiphoid region and the right thoracic inlet. Correlation and agreement of results between methods were determined via linear regression analysis and Bland-Altman plots. RESULTS: A significant positive correlation was detected between UCOMS andTDCO measurements obtained at the subxiphoid (R = 0.86) and thoracic inlet (R = 0.83) positions. Bland-Altman plots revealed minimal bias between methods (bias +/- SD, -0.03 +/- 0.73 L/min and -0.20 +/- 0.80 L/min for subxiphoid and thoracic inlet measurements, respectively). However, the percentage error associated with UCOMS measurements made at the 2 positions was > 45%. CONCLUSIONS AND CLINICAL RELEVANCE: When compared with the results of TDCO, CO measured with the UCOMS exceeded commonly accepted limits of error in healthy dogs. The UCOMS was, however, able to track changes in CO across hemodynamic states. Additional research is needed to assess the usefulness of the UCOMS for monitoring CO in critically ill dogs.
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Gasto Cardíaco/fisiología , Perros/fisiología , Ultrasonografía/veterinaria , Animales , Femenino , Masculino , Ultrasonografía/instrumentaciónRESUMEN
BACKGROUND: Epidemiologic knowledge regarding noncardiovascular and all-cause mortality in apparently healthy cats (AH) and cats with preclinical hypertrophic cardiomyopathy (pHCM) is limited, hindering development of evidence-based healthcare guidelines. OBJECTIVES: To characterize/compare incidence rates, risk, and survival associated with noncardiovascular and all-cause mortality in AH and pHCM cats. ANIMALS: A total of 1730 client-owned cats (722 AH, 1008 pHCM) from 21 countries. METHODS: Retrospective, multicenter, longitudinal, cohort study. Long-term health data were extracted by medical record review and owner/referring veterinarian interviews. RESULTS: Noncardiovascular death occurred in 534 (30.9%) of 1730 cats observed up to 15.2 years. Proportion of noncardiovascular death did not differ significantly between cats that at study enrollment were AH or had pHCM (P = .48). Cancer, chronic kidney disease, and conditions characterized by chronic weight-loss-vomiting-diarrhea-anorexia were the most frequently recorded noncardiovascular causes of death. Incidence rates/risk of noncardiac death increased with age in AH and pHCM. All-cause death proportions were greater in pHCM than AH (65% versus 40%, respectively; P < .001) because of higher cardiovascular mortality in pHCM cats. Comparing AH with pHCM, median survival (study entry to noncardiovascular death) did not differ (AH, 9.8 years; pHCM, 8.6 years; P = .10), but all-cause survival was significantly shorter in pHCM (P = .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: All-cause mortality was significantly greater in pHCM cats due to disease burden contributed by increased cardiovascular death superimposed upon noncardiovascular death.
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Cardiomiopatía Hipertrófica/veterinaria , Enfermedades de los Gatos/mortalidad , Animales , Cardiomiopatía Hipertrófica/mortalidad , Gatos , Femenino , Incidencia , Masculino , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: To identify Doppler echocardiographic (DE) variables that correlate with left ventricular filling pressure (LVFP). ANIMALS: 7 healthy dogs (1 to 3 years old). PROCEDURES: Dogs were anesthetized and instrumented to measure left atrial pressure (LAP), left ventricular pressures, and cardiac output. Nine DE variables of LVFP derived from diastolic time intervals, transmitral and pulmonary venous flow, and tissue Doppler images were measured over a range of hemodynamic states induced by volume loading and right atrial pacing. Associations between simultaneous invasive measures of LVFP and DE measures of LVFP were determined by use of regression analysis. Receiver operating characteristic analysis was used to predict increases in mean LAP on the basis of DE variables. RESULTS: Mean LAP was correlated with several DE variables: the ratio between peak velocity during early diastolic transmitral flow and left ventricular isovolumic relaxation time (peak E:IVRT) during sinus rhythm and during right atrial pacing, IVRT, the ratio between late diastolic transmitral flow velocity and pulmonary venous flow duration, and the interval between onset of early diastolic mitral annulus motion and onset of early diastolic transmitral flow. Cutoff values of 2.20 and 2.17, for peak E:IVRT in dogs with sinus rhythm and atrial pacing predicted increases in mean LAP (> or = 15 mm Hg) with sensitivities of 90% and 100% and specificities of 92% and 100%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Doppler echocardiography can be used to predict an increase in LVFP in healthy anesthetized dogs subjected to volume loading.
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Volumen Sanguíneo/fisiología , Ecocardiografía Doppler/métodos , Ecocardiografía Doppler/veterinaria , Función Ventricular Izquierda/fisiología , Anestesia General , Animales , Gasto Cardíaco/fisiología , PerrosRESUMEN
CASE DESCRIPTION: 4 dogs with acquired pulmonary artery stenosis (PAS) were examined for various clinical signs. One was a mixed-breed dog with congenital valvular PAS that subsequently developed peripheral PAS, one was a Golden Retriever with pulmonary valve fibrosarcoma, one was a Pembroke Welsh Corgi in which the left pulmonary artery had inadvertently been ligated during surgery for correction of patent ductus arteriosus, and one was a Boston Terrier with a heart-base mass compressing the pulmonary arteries. CLINICAL FINDINGS: All 4 dogs were evaluated with 2-dimensional and Doppler echocardiography to characterize the nature and severity of the stenoses; other diagnostic tests were also performed. TREATMENT AND OUTCOME: The mixed-breed dog with valvular and peripheral PAS was euthanized, surgical resection of the pulmonic valve mass was performed in the Golden Retriever, corrective surgery was performed on the Pembroke Welsh Corgi with left pulmonary artery ligation, and the Boston Terrier with the heart-base mass was managed medically. CLINICAL RELEVANCE: Acquired PAS in dogs may manifest as a clinically silent heart murmur, syncope, or right-sided heart failure. The diagnosis is made on the basis of imaging findings, particularly results of 2-dimensional and Doppler echocardiography. Treatment may include surgical, interventional, or medical modalities and is targeted at resolving the inciting cause.
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Enfermedades de los Perros/patología , Arteria Pulmonar/patología , Animales , Constricción Patológica/etiología , Diagnóstico Diferencial , Enfermedades de los Perros/diagnóstico por imagen , Enfermedades de los Perros/cirugía , Perros , Conducto Arterioso Permeable/complicaciones , Conducto Arterioso Permeable/patología , Conducto Arterioso Permeable/cirugía , Conducto Arterioso Permeable/veterinaria , Ecocardiografía/veterinaria , Ecocardiografía Doppler en Color/veterinaria , Resultado Fatal , Femenino , Masculino , Arteria Pulmonar/cirugía , Resultado del TratamientoRESUMEN
A 4-week-old American Quarter Horse colt presented with a recent history of diarrhea and decreased activity level. On initial physical examination, the animal was bright and alert and major findings were limited to a loud systolic heart murmur radiating widely over both sides of the thorax. While in the hospital, the clinical condition of the foal warranted further imaging to determine the cause and extent of cardiac disease. A variety of congenital cardiac malformations were identified during echocardiographic examination and autopsy, including a double outlet right ventricle and a subpulmonary interventricular septal defect (Taussig-Bing anomaly), ventricular inversion with atrioventricular discordance, tricuspid valve atresia, a septum primum interatrial septal defect, mitral valve dysplasia with a cleft in the septal mitral valve cusp, aortic, and subaortic stenosis, tubular hypoplasia of the ascending aorta and the aortic arch, a patent ductus arteriosus, an aberrant circumflex coronary artery, and aberrant left and right subclavian arteries. Echocardiographic and postmortem findings of the cardiac defects in this foal are presented and discussed.
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Ventrículo Derecho con Doble Salida/veterinaria , Cardiopatías Congénitas/veterinaria , Defectos del Tabique Interventricular/veterinaria , Caballos/anomalías , Animales , Ventrículo Derecho con Doble Salida/diagnóstico por imagen , Ventrículo Derecho con Doble Salida/patología , Ecocardiografía/veterinaria , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/patología , Defectos del Tabique Interventricular/diagnóstico por imagen , Defectos del Tabique Interventricular/patología , MasculinoRESUMEN
BACKGROUND: Hypertrophic cardiomyopathy is the most prevalent heart disorder in cats and principal cause of cardiovascular morbidity and mortality. Yet, the impact of preclinical disease is unresolved. HYPOTHESIS/OBJECTIVES: Observational study to characterize cardiovascular morbidity and survival in cats with preclinical nonobstructive (HCM) and obstructive (HOCM) hypertrophic cardiomyopathy and in apparently healthy cats (AH). ANIMALS: One thousand seven hundred and thirty client-owned cats (430 preclinical HCM; 578 preclinical HOCM; 722 AH). METHODS: Retrospective multicenter, longitudinal, cohort study. Cats from 21 countries were followed through medical record review and owner or referring veterinarian interviews. Data were analyzed to compare long-term outcomes, incidence, and risk for congestive heart failure (CHF), arterial thromboembolism (ATE), and cardiovascular death. RESULTS: During the study period, CHF, ATE, or both occurred in 30.5% and cardiovascular death in 27.9% of 1008 HCM/HOCM cats. Risk assessed at 1, 5, and 10 years after study entry was 7.0%/3.5%, 19.9%/9.7%, and 23.9%/11.3% for CHF/ATE, and 6.7%, 22.8%, and 28.3% for cardiovascular death, respectively. There were no statistically significant differences between HOCM compared with HCM for cardiovascular morbidity or mortality, time from diagnosis to development of morbidity, or cardiovascular survival. Cats that developed cardiovascular morbidity had short survival (mean ± standard deviation, 1.3 ± 1.7 years). Overall, prolonged longevity was recorded in a minority of preclinical HCM/HOCM cats with 10% reaching 9-15 years. CONCLUSIONS AND CLINICAL IMPORTANCE: Preclinical HCM/HOCM is a global health problem of cats that carries substantial risk for CHF, ATE, and cardiovascular death. This finding underscores the need to identify therapies and monitoring strategies that decrease morbidity and mortality.
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Cardiomiopatía Hipertrófica/veterinaria , Enfermedades de los Gatos/mortalidad , Factores de Edad , Animales , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/mortalidad , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/veterinaria , Estudios de Casos y Controles , Gatos , Ecocardiografía/veterinaria , Femenino , Incidencia , Masculino , Estudios Retrospectivos , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
BACKGROUND: Atrial contractile dysfunction occurs in some species after conversion of atrial fibrillation (AF) to normal sinus rhythm (NSR) but has not been reported in horses with naturally occurring AF. HYPOTHESIS: Transthoracic echocardiography allows detection of left atrial (LA) mechanical dysfunction in horses after conversion of AF to NSR. ANIMALS: Five Standardbreds with AF and 6 healthy Standardbreds of similar age, weight, and athletic condition were included in this study. METHODS: Four horses were treated pharmacologically (quinidine), and 1 horse was treated by means of transvenous electrical cardioversion. Echocardiographic examinations were performed in normal horses (once) and in AF horses (24 hours and 72 hours after conversion to NSR) by means of 2-dimensional echocardiography (2DE), transmitral flow Doppler, and tissue Doppler imaging (TDI) techniques. Echocardiographic indices of LA mechanical function were compared between normal horses and AF horses. RESULTS: Two-dimensional echocardiography and TDI indices of LA mechanical function revealed significant decreases in LA contractile function and LA reservoir function 24 hours after cardioversion. This decrease was no longer statistically significant 72 hours after cardioversion, but changes in echocardiographic variables between 24 and 72 hours varied among horses. CONCLUSIONS AND CLINICAL IMPORTANCE: LA contractile dysfunction can be evaluated in horses by use of 2DE, transmitral Doppler flow velocity profiles, and analyses of LA wall motion by TDI. The results of this study are consistent with AF-induced atrial remodeling, although residual treatment effects or influence of underlying primary myopathy cannot be excluded.