Impact of a combination of pimobendan, furosemide, and enalapril on heart rate variability in naturally occurring, symptomatic, myxomatous mitral valve degeneration dogs.

BACKGROUND: Pimobendan, diuretics, and an angiotensin-converting enzyme inhibitor (ACEi) are widely used for the management of chronic valvular heart disease in dogs; however, the effects of that combination on heart rate variability (HRV) are unknown. The purpose of this study was to assess the HRV of symptomatic myxomatous mitral valve degeneration (MMVD) dogs in response to therapy with a combination of pimobendan, diuretics, and ACEi. RESULTS: MMVD stage C (n = 17) dogs were enrolled and a 1-hour Holter recording together with echocardiography, blood pressure measurement, and blood chemistry profiles were obtained before and 1, 3, and 6 months after oral treatment with pimobendan (0.25 mg/kg), enalapril (0.5 mg/kg), and furosemide (2 mg/kg) twice daily. The results revealed that MMVD stage C dogs at the baseline had lower values of time-domain indices, low frequency (LF), high frequency (HF), and total power, as well as higher value of LF/HF. Triple therapy significantly increases these parameters in MMVD stage C dogs (P < 0.05). A positive moderate correlation was observed between time domain parameters and a left ventricular internal diastole diameter normalized to body weight (P < 0.05). CONCLUSIONS: It can be concluded that MMVD stage C dogs possess low HRV due to either the withdrawal of parasympathetic tone or enhanced sympathetic activation, and a combination therapy was shown to enhance cardiac autonomic modulation inferred from the increased heart rate variability. Therefore, a combination therapy may be useful for restoring normal autonomic nervous system activity in dogs with MMVD stage C.

Histological study of seventeen organs from dugong (Dugong dugon).

Background: Dugongs are marine mammals with a crescent-shaped tail fluke and a concave trailing margin that belong to the family Dugongidae., They are distributed widely in the warm coastal waters of the Indo-Pacific region. Importantly, the population of dugongs has decreased over the past decades as they have been classified as rare marine mammals. Previous studies have investigated the habitat and genetic diversity of dugongs. However, a comprehensive histological investigation of their tissue has not yet been conducted. This study provides unique insight into the organs of dugongs and compares them with other mammal species. Methods: Tissue sections were stained with Harris's hematoxylin and eosin Y. The histological structure of 17 organ tissues obtained from eight systems was included in this study. Tissue sections were obtained from the urinary system (kidney), muscular system (striated skeletal muscle and smooth muscle), cardiovascular system (cardiac muscle (ventricle), coronary artery, and coronary vein), respiratory system (trachea and lung), gastrointestinal system (esophagus, stomach, small intestine, liver, and pancreas), reproductive system (testis), lymphatic system (spleen and thymus), and endocrine system (pancreas). Results: While most structures were similar to those of other mammal species, there were some differences in the tissue sections of dugongs when compared with other mammalian species and manatees. These include the kidneys of dugongs, which were non-lobular and had a smooth, elongated exterior resulting in a long medullary crest, whereas the dugong pyloric epithelium did not have overlying stratified squamous cells and was noticably different from the Florida manatee. Discussion: Histological information obtained from various organs of the dugong can serve as an essential foundation of basal data for future microanatomical studies. This information can also be used as high-value data in the diagnosis and pathogenesis of sick dugongs or those with an unknown cause of death.

Short-Term Effects of Sacubitril/valsartan on Echocardiographic Parameters in Dogs With Symptomatic Myxomatous Mitral Valve Disease.

Background and Objective: Sacubitril/valsartan (SV) is an angiotensin receptor-neprilysin inhibitor that works by inhibiting the neprilysin enzyme as well as blocking angiotensin receptors. The benefits of using SV in congestive heart failure patients has been demonstrated in several clinical trials; however, limited data are available for dogs with heart failure. The aim of this study was to investigate the short-term effects of SV in comparison with ramipril in the standard therapy of symptomatic dogs suffering from myxomatous mitral valve disease (MMVD). Methods: In this prospective, randomized, single-blind study, 21 dogs with MMVD stage C were randomly assigned to received SV (20 mg/kg orally twice a day) or ramipril (0.125 mg/kg, orally once a day) in addition to pimobendan and furosemide. Echocardiography, electrocardiography, blood pressure, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and urinary aldosterone per creatinine ratio were obtained at baseline (D0) and at follow-up (4 weeks). Results: When comparing the percent change from baseline between groups, the left atrium to aortic root ratio (LA/Ao) and left ventricular internal diameter diastole normalized to body weight (LVIDDN) were significantly reduced in the SV group (P < 0.001 and P < 0.01, respectively). The end-diastolic volume index (EDVI), end-systolic volume index (ESVI), and stroke volume were lower in the SV group (P < 0.001, P < 0.05, and P < 0.01, respectively). No changes were observed between groups for NTproBNP, blood pressure, ECG parameters, and urinary aldosterone per creatinine ratio. Conclusion: The current study suggested that the short-term effects of SV can reverse myocardial remodeling, as inferred from several echocardiographic indices (i.e., the reduction in LA/Ao, LVIDDN, EDVI and ESVI) in dogs with MMVD stage C. These findings would support the use of SV in clinically symptomatic heart failure in dogs.

Acute effect of ivabradine on heart rate and myocardial oxygen consumption in dogs with asymptomatic mitral valve degeneration.

Degenerative mitral valve disease (DMVD) is a common cardiac disease in geriatric dogs characterized by the degeneration of the mitral valve, leading to decreased cardiac output and activation of the sympathetic and renin-angiotensin-aldosterone system. This disease results in an increased resting heart rate (HR) and myocardial oxygen consumption (MVO2). A recent publication demonstrated that dogs with asymptomatic DMVD had a significantly higher HR and systemic blood pressure (BP) than age-matched control dogs. This higher HR will eventually contribute to increased MVO2. This study aimed to determine the effects of a single oral dose of ivabradine on the HR, MVO2 as assessed by the rate-pressure product, and BP in dogs with asymptomatic DMVD. Seven beagles with naturally occurring DMVD were instrumented by the Holter recorder and an oscillometric device to measure electrocardiogram and BP for 24 and 12 h, respectively. Each dog was randomly subjected to receive either placebo or ivabradine (0.5, 1.0 and 2.0 mg/kg). The results revealed that oral administration of ivabradine significantly decreased the HR and rate-pressure product in a dose-dependent manner without adverse effects. The highest dose of 2.0 mg/kg significantly reduced systolic and mean BP. Therefore, the findings imply that a single oral ivabradine administration at a dose of 1.0 mg/kg is suitable for dogs with asymptomatic DMVD to reduce the HR and MVO2 without marked effects on BP. This may potentially make ivabradine promising for management of an elevated HR in DMVD dogs.

An increasing electromechanical window is a predictive marker of ventricular fibrillation in anesthetized rabbit with ischemic heart.

The QTc interval is widely used in Safety Pharmacological studies to predict arrhythmia risk, and the electromechanical window (EMW) and short-term variability of QT intervals (STVQT) have been studied as new biomarkers for drug-induced Torsades de Pointes (TdP). However, the use of EMW and STVQT to predict ventricular fibrillation (VF) has not been elucidated. This study aimed to evaluate EMW and STVQT to predict VF in anesthetized rabbit model of VF. VF was induced by ligation of the left anterior descending and a descending branch of the left circumflex coronary arteries in a sample population of rabbits (n=18). VF was developed 55.6% (10/18). In rabbit with VF, the EMW was significantly higher than in rabbits without VF (96.3 ± 15.6 ms and 49.5 ± 5.6 ms, respectively, P<0.05). STVQT had significantly increased before the onset of VF in rabbits that experienced VF, but not in rabbits that did not experience VF (11.7 ± 1.8 ms and 3.7 ± 0.4 ms, respectively, P<0.05). The EMW and STVQT had better predictive power for VF with higher sensitivity and specificity than the QTc measure. The result suggested that the increasing of EMW, as well as the elevation of STVQT, can potentially be used as biomarkers for predicting of VF.

Sildenafil improves heart rate variability in dogs with asymptomatic myxomatous mitral valve degeneration.

Myxomatous mitral valve degeneration (MMVD) causes an imbalance of sympathovagal activity resulted in poor cardiac outcomes. Phosphodiesterase-5 inhibitors have been revealed cardioprotective effect in patients with heart diseases. This study aimed to 1) compare the heart rate variability (HRV) between asymptomatic MMVD and healthy dogs and 2) assess long-term effects of sildenafil and enalapril on time- and frequency-domains analyzes. Thirty-four dogs with MMVD stage B1 or B2 and thirteen healthy dogs were recruited into the study. MMVD dogs were divided into 3 subgroups: control (n=13), sildenafil (n=12) and enalapril (n=9). HRV was analyzed from 1-hr Holter recording at baseline (D0) in all dogs and at 30, 90 and 180 days after treatment. The results showed that MMVD dogs had significant higher heart rate (HR), systemic blood pressures, the ratio of low to high frequency (LF/HF) and had significant decreased standard deviation of all normal to normal RR intervals (SDNN) and the percentage of the number of normal-to-normal sinus RR intervals with differences >50 msec computed over the entire recording (pNN50) when compared with healthy dogs (P<0.05). Neither time nor frequency domain parameters were different among subgroups of MMVD dogs at D0. After treatment with sildenafil for 90 days, both time- and frequency-domain parameters were significantly increased when compared with control and enalapril groups. This study demonstrated that sildenafil improves HRV in asymptomatic MMVD dogs suggesting that sildenafil should be used in the MMVD dogs to restore the sympathovagal balance.

Long-term effect of sildenafil on echocardiographic parameters in dogs with asymptomatic myxomatous mitral valve degeneration.

Sildenafil is a selective phosphodiesterase-5 inhibitor that has been demonstrated to delay ventricular remodeling in humans and experimental animals. The aim of this prospective study was to assess the chronic effects of sildenafil administration on echocardiographic indices and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in dogs with naturally occurring, asymptomatic myxomatous mitral valve degeneration. Thirty client-owned dogs with ACVIM class B1 or B2 were enrolled. Dogs were randomly assigned to treatment (sildenafil 1-3 mg/kg, PO, BID for 180 days) or control groups. A total of 12 dogs completed the 180 days trial in the sildenafil group, whereas 10 dogs remained in control group. When comparing the difference from baseline values obtained over time between groups, the stroke volume (SV) at day 30 was significantly higher in the sildenafil group (P=0.038). The LA/Ao and the MR jet area were significantly lower beginning at day 30 (only MR jet area; P=0.006), day 90 (P=0.006 and P=0.027, respectively) and day 180 (P=0.029 and P=0.032, respectively). The 2D-LA was significantly lower at day 90 when compared with control group (P=0.028). The differences of NTproBNP from baseline were significantly lower when compared with control group at the same timepoint (D90, P=0.017 and D180, P=0.013). In conclusion, this study suggested that long-term treatment with sildenafil prevented aggravation of disease progression as suggested by several echocardiographic indices (i.e. SV, LA/Ao, MR jet area, 2D-LA) and reduced NTproBNP level at the indicated timepoints in dogs with asymptomatic mitral valve degeneration.

Heart rate variability and plasma norepinephrine concentration in diabetic dogs at rest.

Cardiac autonomic neuropathy in dogs with diabetic mellitus (DM) was evaluated using measurement of heart rate variability (HRV) and plasma norepinephrine (NE) concentration. Dogs were divided into 2 groups; the control non-DM group (n = 13) and the diabetic group (n = 22) which was further divided into the well-controlled DM (n = 11) and the poorly-controlled DM subgroups (n = 11) according to their fasting plasma fructosamine concentrations. The electrocardiogram (ECG) was recorded continuously for at least 30 min to yield HRV. The results showed that in the poorly-controlled DM subgroup, the average of normal R-R interval (mean N-N), SD of the mean of all 5-min segments of normal RR intervals (SDANN) were lower than the control group while heart rate was higher (P < 0.05). The NNA, SDNN, SDNN index and pNN50% were significantly lower when compared with the well-controlled DM subgroup (P < 0.05). The high frequency (HF) and total power were significantly lower while the ratio of low to high frequency (LF/HF) was higher (P < 0.05) when compared with the well-controlled DM subgroup. Moreover, in the poorly-controlled DM subgroup, plasma NE concentration was lower than the control group (210 ± 37 vs. 479 ± 74 pg/ml, P < 0.05). There was a significantly negative correlation between plasma NE and plasma fructosamine concentrations. It is concluded that cardiac autonomic neuropathy occurred in poorly-controlled DM dogs. The sympathetic activity was suppressed as shown by decrease in both plasma NE concentration and LF component.