Romain Pariaut

Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays a major role in integrin signaling pathways. Although cardiovascular defects were observed in FAK total KO mice, the embryonic lethality prevented investigation of FAK function in the hearts of adult animals. To circumvent these problems, we created mice in which FAK is selectively inactivated in cardiomyocytes (CFKO mice). We found that CFKO mice develop eccentric cardiac hypertrophy (normal LV wall thickness and increased left chamber dimension) upon stimulation with angiotensin II or pressure overload by transverse aortic constriction as measured by echocardiography. We also found increased heart/body weight ratios, elevated markers of cardiac hypertrophy, multifocal interstitial fibrosis, and increased collagen I and VI expression in CFKO mice compared with control littermates. Spontaneous cardiac chamber dilation and increased expression of hypertrophy markers were found in the older CFKO mice. Analysis of cardiomyocytes isolated from CFKO mice showed increased length but not width. The myocardium of CFKO mice exhibited disorganized myofibrils with increased nonmyofibrillar space filled with swelled mitochondria. Last, decreased tyrosine phosphorylation of FAK substrates p130Cas and paxillin were observed in CFKO mice compared with the control littermates. Together, these results provide strong evidence for a role of FAK in the regulation of heart hypertrophy in vivo.

Combination Therapy with Digoxin and Diltiazem Controls Ventricular Rate in Chronic Atrial Fibrillation in Dogs Better than Digoxin or Diltiazem Monotherapy: A Randomized Crossover Study in 18 Dogs

BACKGROUNDnAtrial fibrillation (AF) with excessively high ventricular rates (VR) occurs in dogs with advanced heart disease. Rate control improves clinical signs in these patients. Optimal drug therapy and target VR remain poorly defined.nnnHYPOTHESISnDigoxin-diltiazem combination therapy reduces VR more than either drug alone in dogs with high VR AF.nnnANIMALSnEighteen client-owned dogs (>15 kg) with advanced heart disease, AF, and average VR on 24-hour Holter > 140 beats per minute (bpm).nnnMETHODSnAfter baseline Holter recording, dogs were randomized to digoxin or diltiazem monotherapy, or combination therapy. Repeat Holter evaluation was obtained after 2 weeks; dogs were then crossed over to the other arm (monotherapy or combination therapy) for 2 weeks and a third Holter was acquired. Twenty-four hour average VR, absolute and relative VR changes from baseline, and percent time spent within prespecified VR ranges (>140, 100-140, and <100 bpm) were compared. Correlations between serum drug concentrations and VR were examined.nnnRESULTSnDigoxin (median, 164 bpm) and diltiazem (median, 158 bpm) decreased VR from baseline (median, 194 bpm) less than the digoxin-diltiazem combination (median, 126 bpm) (P < .008 for each comparison). With digoxin-diltiazem, VR remained <140 bpm for 85% of the recording period, but remained >140 bpm for 88% of the recording period with either monotherapy. Serum drug concentrations did not correlate with VR.nnnCONCLUSIONS AND CLINICAL IMPORTANCEnAt the dosages used in this study, digoxin-diltiazem combination therapy provided a greater rate control than either drug alone in dogs with AF.

Use of transesophageal echocardiography for visualization of the patent ductus arteriosus during transcatheter coil embolization.

Transesophageal echocardiography (TEE) enhances our ability to see the patent ductus arteriosus in the dog. The improved visualization may potentially improve our ability to perform transcatheter coil embolization in patients that are more likely to have a successful outcome. This report uses still and video images to detail the specifics of coil embolization as performed with the assistance of TEE and compares the images with those of angiography, surgery and postmortem examination.

Cardioversion with lidocaine of vagally associated atrial fibrillation in two dogs.

Two dogs with acute onset atrial fibrillation (AF) were cardioverted to sinus rhythm by the administration of 2mg/kg lidocaine given intravenously. Each dog was believed to have AF initiated because of elevated vagal tone. This report has potential clinical impact for a subset of dogs because it offers a treatment to circumvent persistent AF. Furthermore, this encouraging result of a pharmacologic cardioversion suggests that further investigation would be of interest to ascertain the effectiveness and mechanism of the antiarrhythmic action of lidocaine in vagally induced AF.

Complete atrioventricular canal defect in a foal: Clinical and pathological features

Atrioventricular (AV) canal defects comprise a rare category of congenital heart disease associated with abnormal development of the endocardial cushions. These anomalies include a broad spectrum of lesions involving the atrial septum primum, the inlet portion of the ventricular septum, and the atrioventricular valves. In severe cases heart failure may result. The present report describes cardiopulmonary findings in a six-week-old, female Thoroughbred foal with persistent tachypnea and tachycardia since birth. Clinical, echocardiographic, cardiac catheterization, and pathologic findings were compatible with complete AV canal defect with bi-directional shunting, congestive heart failure, and pulmonary hypertension. Gross cardiac pathologic findings included a large atrioventricular septal defect, a common atriovalvular orifice, five atrioventricular leaflets, with two free-floating bridging leaflets. Histopathologic lesions in the lung included hypertrophy of the pulmonary arteriolar walls due to thickening of the tunica media. This represents a well documented case of complete endocardial cushion defect with anomalous development of the atrioventricular valves and resultant pulmonary hypertension and heart failure.

Structural and molecular pathology of the atrium in boxer arrhythmogenic right ventricular cardiomyopathy

OBJECTIVEnTo investigate the expression and distribution of desmosomal and gap junction proteins of the intercalated disc in the atria of boxers with arrhythmogenic right ventricular cardiomyopathy (ARVC).nnnANIMALSnNineteen control dogs and 13 boxers with histopathologically confirmed ARVC.nnnMETHODSnRight and left atrial samples were examined using immunofluorescence and Western blots. The intercalated disc proteins investigated included total and phosphorylated connexin43 (Cx43 and pCx43), connexin45, connexin40, plakoglobin, plakophilin-2, desmoplakin, and N-cadherin.nnnRESULTSnHistopathological changes characteristic of ARVC were present in the left or right atrium of 12 out of 13 boxersxa0and were absent in all control dogs. When compared to the 19 control dogs, immunofluorescence analysis revealed a decrease in signal intensity for pCx43 and plakoglobin in the left (pxa0=xa00.03 and pxa0=xa00.014, respectively) and right atrium (pxa0=xa00.015 and pxa0=xa00.002, respectively) of affected boxers. Connexin43 and pCx43 Western blot band density was significantly decreased in the left (pxa0=xa00.025 and pxa0=xa00.027, respectively) and right atrium (pxa0=xa00.001 and pxa0=xa00.044, respectively) of affected boxers.nnnCONCLUSIONnAltered intercalated disc and gap junction proteins were identified in atrial myocardium of ARVC boxers, supporting atrial involvement as part of this disorder. Reduction in pCx43 in conjunction with histological changes could represent the substrate for atrial arrhythmias associated with ARVC. Furthermore, these findings detected in boxer dogs, lend support for the broader term, arrhythmogenic cardiomyopathy, as preferred nomenclature used to describe this disease in humans.

Tricuspid annular plane systolic excursion-to-aortic ratio provides a bodyweight-independent measure of right ventricular systolic function in dogs

OBJECTIVESnTo evaluate whether tricuspid annular plane systolic excursion (TAPSE) can be normalized to aortic valve (Ao) measurements in dogs. To determine TAPSE:Ao reference intervals for healthy dogsxa0and examine diagnostic performance of TAPSE:Ao in dogs with pulmonary hypertension (PH).nnnANIMALSnOne hundred and thirty-seven healthy adult dogs; 115 dogs with myxomatous mitral valve disease (MMVD) but no PH; 91 dogs with PH.nnnMETHODSnA combined prospective and retrospective study. Full echocardiographic evaluations were performed on all dogs; TAPSE was indexed to Ao to produce a unitless TAPSE:Ao. Reference intervals for TAPSE:Ao were generated, and TAPSE:Ao was regressed on tricuspid regurgitant jet velocity in dogs with PH and on LA:Ao in dogs with MMVD without PH. Diagnostic test analysis was used to examine the ability of TAPSE:Ao to identify severe PH. An adjusted TAPSE:Ao (TAPSE:Ao(adj)) was derived to account for MMVD in dogs with PH.nnnRESULTSnThe ratio, TAPSE:Ao, removed the effect of bodyweight from TAPSE measurements. Healthy dogs had TAPSE:Aoxa0>xa00.65. The ratio, TAPSE:Ao, showed a linear negative relationship with tricuspid regurgitation velocity and positive relationship with LA:Ao. The adjusted ratio, TAPSE:Ao(adj), increased the sensitivity of diagnosis of PH in dogs with moderate-severe MMVD without affecting the diagnosis of PH in dogs with PH and with no or mild MMVD.nnnCONCLUSIONSnThe ratios, TAPSE:Ao and TAPSE:Ao(adj), are a bodyweight-independent means of assessing right ventricular systolic function in dogs and for identifying severe PH in dogs with or without MMVD.

Low-energy ablation of anteroseptal accessory pathways in two dogs

In humans, accessory pathways (APs) in an anteroseptal and midseptal position are often challenging to ablate because of their close proximity with the conduction pathways of the atrioventricular junction. The use of low-energy ablation techniques can be useful to reduce the risk of permanently damaging the atrioventricular node and the His bundle. This report describes the use of low-energy radiofrequency catheter ablation to successfully and permanently ablate anteroseptal APs in two dogs with orthodromic atrioventricular reciprocating tachycardia. In the first dog, a transient first degree atrioventricular block persisted for 30xa0s after radiofrequency energy delivery. In the second dog, transient paroxysmal atrioventricular conduction block was observed during the procedurexa0but resolved within 3 days. First degree atrioventricular block was again identified 2 months later. In conclusion, anteroseptal APs can be effectively treated by low-energy radiofrequency catheter ablation with minimal and transient damage to the atrioventricular junction.

Atrial Fibrillation: Current Therapies

A rate control, or a rhythm control, strategy can be applied to the management of atrial fibrillation. Rate control of atrial fibrillation consists of decreasing the ventricular response rate by limiting the number of supraventricular impulses that can travel through the atrioventricular node. The goal of decreasing heart rate in dogs with atrial fibrillation is usually achieved with a combination of the calcium channel blocker diltiazem and digoxin. Rhythm control of atrial fibrillation encompasses pharmacologic and nonpharmacologic methods to terminate the arrhythmia and restore sinus rhythm. Transthoracic synchronized electrical cardioversion is commonly used to stop atrial fibrillation.