Katharyn J Mitchell

Echocardiographic Assessment of Left Ventricular Function in Healthy Horses and in Horses with Heart Disease Using Pulsed-Wave Tissue Doppler Imaging

Background Assessment of left ventricular (LV) function by tissue Doppler imaging (TDI) is not well established in horses with heart disease. Objectives To describe the use of pulsed‐wave (PW) TDI for the assessment of LV function, establish reference intervals, investigate effects of mitral regurgitation (MR), aortic regurgitation (AR), and primary myocardial disease (MD), and provide proof of concept for the use of PW TDI in Warmblood horses with heart disease. Animals Thirty healthy horses, 38 horses with MR, 25 with AR, 8 with MD. Methods Echocardiograms were retrospectively analyzed. Reference intervals were calculated. PW TDI indices of healthy horses and horses with MR, AR, and MD were compared by one‐way ANOVA and Dunnetts test. Results A complete set of PW TDI variables could be obtained in 94 of 101 horses. Variables corresponding to isovolumic intervals were most difficult to measure. Valvular regurgitation influenced variables describing isovolumic contraction and ejection. Horses with MD had significantly shortened ETm (−118.5 [−154.1 to −82.9] ms; mean difference [95% CI of difference of means]), increased PEPm/ETm (0.11 [0.05 to 0.17]), prolonged IMPm (0.28 [0.18 to 0.37]), increased S 1 (8.9 [5.2 to 12.6] cm/s), and decreased E 1 (−2.6 [−4.7 to −0.5] cm/s), E m (−14.2 [−19.9 to −8.5] cm/s), and E m/A m ratio (−1.6 [−2.6 to −0.6]). Conclusions and Clinical Importance Pulsed‐wave TDI might be useful for detection of LV dysfunction in horses with primary MD. The clinical value of TDI in horses with MR and AR remains uncertain.

Echocardiography for the Assessment of Congenital Heart Defects in Calves

Congenital heart disease should be considered when evaluating calves with chronic respiratory signs, failure to thrive, poor growth, or if a murmur is heard on physical examination. Echocardiography is currently the gold standard for diagnosing congenital heart defects. A wide variety of defects, either alone or in combination with a ventricular septal defect, are possible. A standardized approach using sequential segmental analysis is required to fully appreciate the nature and severity of more complex malformations. The prognosis for survival varies from guarded to poor and depends on the hemodynamic relevance of the defects and the degree of cardiac compensation.

Effect of Sodium-Glucose Cotransport Inhibition on Polycystic Kidney Disease Progression in PCK Rats.

The sodium-glucose-cotransporter-2 (SGLT2) inhibitor dapagliflozin (DAPA) induces glucosuria and osmotic diuresis via inhibition of renal glucose reabsorption. Since increased diuresis retards the progression of polycystic kidney disease (PKD), we investigated the effect of DAPA in the PCK rat model of PKD. DAPA (10 mg/kg/d) or vehicle was administered by gavage to 6 week old male PCK rats (n=9 per group). Renal function, albuminuria, kidney weight and cyst volume were assessed after 6 weeks of treatment. Treatment with DAPA markedly increased glucose excretion (23.6 ± 4.3 vs 0.3 ± 0.1 mmol/d) and urine output (57.3 ± 6.8 vs 19.3 ± 0.8 ml/d). DAPA-treated PCK rats had higher clearances for creatinine (3.1 ± 0.1 vs 2.6 ± 0.2 ml/min) and BUN (1.7 ± 0.1 vs 1.2 ± 0.1 ml/min) after 3 weeks, and developed a 4-fold increase in albuminuria. Ultrasound imaging and histological analysis revealed a higher cyst volume and a 23% higher total kidney weight after 6 weeks of DAPA treatment. At week 6 the renal cAMP content was similar between DAPA and vehicle, and staining for Ki67 did not reveal an increase in cell proliferation. In conclusion, the inhibition of glucose reabsorption with the SGLT2-specific inhibitor DAPA caused osmotic diuresis, hyperfiltration, albuminuria and an increase in cyst volume in PCK rats. The mechanisms which link glucosuria to hyperfiltration, albuminuria and enhanced cyst volume in PCK rats remain to be elucidated.

Echocardiographic Assessment of Left Atrial Size and Function in Warmblood Horses: Reference Intervals, Allometric Scaling, and Agreement of Different Echocardiographic Variables

Background Echocardiographic assessment of left atrial (LA) size and function in horses is not standardized. Objectives The aim of this study was to establish reference intervals for echocardiographic indices of LA size and function in Warmblood horses and to provide proof of concept for allometric scaling of variables and for the clinical use of area‐based indices. Animals Thirty‐one healthy Warmblood horses and 91 Warmblood horses with a primary diagnosis of mitral regurgitation (MR) or aortic regurgitation (AR). Methods Retrospective study. Echocardiographic indices of LA size and function were measured and scaled to body weight (BWT). Reference intervals were calculated, the influence of BWT, age, and valvular regurgitation on LA size and function was investigated and agreement between different measurements of LA size was assessed. Results Allometric scaling of variables of LA size allowed for correction of differences in BWT. Indices of LA size documented LA enlargement with moderate and severe MR and AR, whereas most indices of LA mechanical function were not significantly altered by valvular regurgitation. Different indices of LA size were in fair to good agreement but still lead to discordant conclusions with regard to assessment of LA enlargement in individual horses. Conclusions and Clinical Importance Allometric scaling of echocardiographic variables of LA size is advised to correct for differences in BWT among Warmblood horses. Assessment of LA dimensions should be based on an integrative approach combining subjective evaluation and assessment of multiple measurements, including area‐based variables. The clinical relevance of indices of LA mechanical function remains unclear when used in horses with mitral or aortic regurgitation.

Hyperglycaemia-induced epigenetic changes drive persistent cardiac dysfunction via the adaptor p66Shc

AIMS Hyperglycaemia-induced reactive oxygen species (ROS) are key mediators of cardiac dysfunction. Intensive glycaemic control (IGC) has failed to reduce risk of heart failure in patients with diabetes but the underlying mechanisms remain to be elucidated. The present study investigates whether epigenetic regulation of the pro-oxidant adaptor p66Shc contributes to persistent myocardial dysfunction despite IGC. METHODS AND RESULTS p66Shc expression was increased in the heart of diabetic mice, and 3-week IGC by slow-release insulin implants did not revert this phenomenon. Sustained p66Shc upregulation was associated with oxidative stress, myocardial inflammation and left ventricular dysfunction, as assessed by conventional and 2D speckle-tracking echocardiography. In vivo gene silencing of p66Shc, performed during IGC, inhibited ROS production and restored cardiac function. Furthermore, we show that dysregulation of methyltransferase DNMT3b and deacetylase SIRT1 causes CpG demethylation and histone 3 acetylation on p66Shc promoter, leading to persistent transcription of the adaptor. Altered DNMT3b/SIRT1 axis in the diabetic heart was explained by upregulation of miR-218 and miR-34a. Indeed, in human cardiomyocytes exposed to high glucose, inhibition of these miRNAs restored the expression of DNMT3b and SIRT1 and erased the adverse epigenetic signatures on p66Shc promoter. Consistently, reprogramming miR-218 and miR-34a attenuated persistent p66Shc expression and ROS generation. CONCLUSIONS In diabetic left ventricular dysfunction, a complex epigenetic mechanism linking miRNAs and chromatin modifying enzymes drives persistent p66Shc transcription and ROS generation. Our results set the stage for pharmacological targeting of epigenetic networks to alleviate the clinical burden of diabetic cardiomyopathy.

Atrial fibrillation management in a breeding stallion

A 20-year-old warmblood breeding stallion presented to a University practice for semen collection and evaluation was incidentally diagnosed with atrial fibrillation (AF). Electrocardiogram recordings during breeding revealed inappropriately rapid tachycardia and occasional ventricular premature depolarizations/aberrant ventricular conduction. Transvenous electrical cardioversion was performed. After successful cardioversion the horse displayed supraventricular ectopy and atrial contractile dysfunction and was administered sotalol hydrochloride in an attempt to decrease the risk of AF recurrence. Supraventricular ectopy and echocardiographic evidence of atrial dysfunction gradually improved and normalized over 6 months. No direct adverse effects of the chronic anti-arrhythmic treatment were observed and libido and semen quality were unaffected. AF recurred 6 months after cardioversion and sotalol therapy was continued to control the ventricular ectopy/aberrant ventricular conduction during semen collection. Considerations regarding pathologic arrhythmias and inappropriately high heart rates in breeding stallions with AF may be similar to those in riding horses. Sotalol hydrochloride was a safe anti-arrhythmic drug in the management of this case.

Heart rate variability parameters in horses distinguish atrial fibrillation from sinus rhythm before and after successful electrical cardioversion

BACKGROUND Atrial fibrillation (AF) is the most common pathological arrhythmia in horses. After successful treatment, recurrence is common. Heart rate monitors are easily applicable in horses and some devices offer basic heart rate variability (HRV) calculations. If HRV can be used to distinguish between AF and sinus rhythm (SR), this could become a monitoring tool for horses at risk for recurrence of AF. OBJECTIVES The purpose of this study was to assess whether in horses AF (before cardioversion) and SR (after cardioversion) can be differentiated based upon HRV parameters. STUDY DESIGN Cohort study with internal controls. METHODS Six HRV parameters were determined in 20 horses, both in AF and in SR, at rest (2- and 5-min and 1- and 4-h recordings) and during exercise (walk and trot, 2-min recordings). Time-domain (standard deviation of the NN intervals, root mean squared successive differences in NN intervals and triangular index), frequency domain (low/high frequency ratio) and nonlinear parameters (standard deviation of the Poincaré plot [SD]1 and SD2) were used. Statistical analysis was done using paired Wilcoxon signed rank tests and receiver operating characteristic curves. RESULTS HRV was higher during AF compared to SR. Results for the detection of AF were good (area under the receiver operating characteristic curve [AUC] 0.8-1) for most HRV parameters. Root mean squared successive differences in NN intervals and SD1 yielded the best results (AUC 0.9-1). Sensitivity and specificity were high for all parameters at all recordings, but highest during exercise. Although AUCs improved with longer recordings, short recordings were also good (AUC 0.8-1) for the detection of AF. In horses with frequent second degree atrioventricular block, HRV at rest is increased and recordings at walk or trot are recommended. MAIN LIMITATIONS Animals served as their own controls and there was no long-term follow-up to identify AF recurrence. CONCLUSIONS AF (before cardioversion) and SR (after cardioversion) could be distinguished with HRV. This technique has promise as a monitoring tool in horses at risk for AF development.

High Resolution Ultrasonography for Assessment of Renal Cysts in the PCK Rat Model of Autosomal Recessive Polycystic Kidney Disease

Background/Aims: The PCK rat model of polycystic kidney disease is characterized by the progressive development of renal medullary cysts. Here, we evaluated the suitability of high resolution ultrasonography (HRU) to assess the kidney and cyst volume in PCK rats, testing three different ultrasound image analysis methods, and correlating them with kidneys weights and histological examinations. Methods: After inducing anesthesia, PCK rats (n=18) were subjected to HRU to visualize the kidneys, to perform numeric and volumetric measurements of the kidney and any cysts observed, and to generate 3-dimensional images of the cysts within the kidney parenchyma. Results: HRU provided superior information in comparison to microscopic analysis of stained kidney sections. HRU-based kidney volumes correlated strongly with kidney weights (R2=0.809; P<0.0001). Conclusion: HRU represents a useful diagnostic tool for kidney and cyst volume measurements in PCK rats. Sequential HRU examinations may be useful to study the effect of drugs on cyst growth without the need to euthanize experimental animals.

Ultrasound diagnosis of a diaphragmatic hernia in a 23-year-old Hanoverian gelding

While rectal and auscultatory findings may suggest a diaphragmatic hernia (an ‘empty’ feeling abdomen on rectal palpation, partially absent bronchovesicular sounds or borborygmi audible during cardiothoracic auscultation), a final diagnosis was historically only achieved during exploratory laparotomy or necropsy (Hart and Brown, 2009; Romero and Rodgerson, 2010). Gas-filled intestine within the thoracic cavity is pathognomonic for a diaphragmatic hernia (Hassel, 2007) however, thoracic and abdominal radiography in adult horses is often not practical or available in a field setting.

Transnasal, Endoscopically Guided Skull-based Surgery by Pharyngotomy for Mass Removal from the Sphenopalatine Sinus in a Horse

OBJECTIVE To report a transnasal, endoscopically guided ventral surgical approach for accessing the cranial and caudal segments of the sphenopalatine sinus for mass removal in a horse. STUDY DESIGN Case report. ANIMAL Adult horse with acute onset blindness referable to a soft tissue mass within the sphenopalatine sinus. CLINICAL REPORT A 7-year-old Warmblood gelding presented with a history of running into a fence and falling. No neurologic signs were identified at initial examination but acute blindness was noted 3 weeks later. On computed tomography (CT) the sphenopalatine sinus was filled with a large homogeneous mass with poor contrast enhancement that extended dorsally with thinning to the dorsal cortex of the sphenoid bone, just rostral to the entrance of the optic canals into the cranial cavity. Surgical access to the sphenopalatine sinus was achieved using a transnasal, endoscopically guided ventral pharyngotomy approach and the mass lesion was removed. A presumptive diagnosis of chondroma was made based on histopathology. The horse recovered well from surgery, and although it has not regained vision as of 6.5 years postoperatively, the disease has not progressed. CONCLUSION Transnasal, endoscopically-guided ventral surgical access to the sphenopalatine sinus is possible in horses and may improve access in horses with disease extending caudally beyond the palatine portion of the sinus. Use of smaller diameter or specialized instruments, such as various endoscopic bone cutting instruments, and CT image guidance may improve sinus access by this route.