Cardiac remodeling and angiotensin II-forming enzyme activity of the left ventricle in hamsters with chronic pressure overload induced by ascending aortic stenosis

Cardiac remodeling and angiotensin II-forming enzyme activity of the left ventricle on chronic pressure overload were studied in male Syrian hamsters, whose chymase activity is similar to that of dogs. Pressure overload was achieved by banding at the ascending aorta (aortic stenosis). Echocardiography, histological analysis, and analysis of cardiac angiotensin-converting enzyme and chymase-like activities were performed. At 10 weeks after banding, concentric hypertrophy of the left ventricle was evident. At 20 weeks after banding, the ventricular weight-to-body ratio, cardiac fibrosis, and cardiac chymase-like activity were significantly increased, while cardiac angiotensin-converting enzyme activity was significantly decreased. This suggests that cardiac chymase, compared with cardiac angiotensin-converting enzyme, was activated against the chronic pressure overload and was responsible for the cardiac remodeling through the formation of angiotensin II. Considering the utility of the rodents, the interspecies similarity of the Ang II-forming pathway, and the effect of chymase in the hamsters, the present model is considered useful for studies evaluating the effect of Ang II and chymase in the canine heart with chronic pressure overload.     

Angiotensin converting enzyme and chymase activity in the feline heart and serum

The feline cardiac and serum angiotensin converting enzyme (ACE) and chymase activities were determined and compared in dogs, and hamsters. In all three species, cardiac chymase activity exceeded ACE activity; however, there were some differences. In cats, left ventricular ACE and chymase activities (0.15 +/- 0.01 and 0.59 +/- 0.1 mU/mg-protein, respectively) were lower than in dogs (0.42 +/- 0.05: p<0.01 and 2.0 +/- 0.4 mU/mg-protein: p<0.01) and hamsters (0.93 +/- 0.06: p<0.001 and 2.1 +/- 0.2 mU/mg-protein: p<0.01); in contrast, serum ACE activities was higher in cats (12.7 +/- 1.0 mU/ml) than in dogs (5.9 +/- 0.6 mU/ml: p<0.001). The relative contribution of chymase (cats: 84.0 +/- 5.1%, dogs: 81.4 +/- 3.4%, and hamsters: 72.6 +/- 5.6 %) to ANG-II formation in the heart was greater than that of ACE in these animals (cats: 10.9 +/- 4.1%, dogs: 11.5 +/- 3.6%, and hamsters: 17.2 +/- 0.8%). These species-specific differences suggest that the efficacy of renin-angiotensin system modulating agents may differ among species.     

Modulation of the tissue reninangiotensin-aldosterone system in dogs with chronic mild regurgitation through the mitral valve

OBJECTIVE: To investigate whether the tissue and plasma renin-angiotensin-aldosterone system (RAAS) is activated in dogs with mild regurgitation through the mitral valve and determine the contribution of chymase and angiotensin-converting enzyme (ACE) to the activation of the RAAS and potential production of angiotensin II during the chronic stage of mild mitral valve regurgitation. ANIMALS: 5 Beagles with experimentally induced mild mitral valve regurgitation and 6 clinically normal (control) Beagles. PROCEDURES: Tissue ACE and chymase-like activities and plasma RAAS were measured and the RAAS evaluated approximately 1,000 days after experimental induction of mitral valve regurgitation in the 5 dogs. RESULTS: Dogs with experimentally induced mitral valve regurgitation did not have clinical signs of the condition, although echocardiography revealed substantial eccentric hyper- trophy. On the basis of these findings, dogs with mitral valve regurgitation were classified as International Small Animal Cardiac Health Council class Ib. Plasma activity of renin and plasma concentrations of angiotensin I, angiotensin II, and aldosterone were not significantly different between dogs with mitral valve regurgitation and clinically normal dogs. Tissue ACE activity was significantly increased and chymase-like activity significantly decreased in dogs with mitral valve regurgitation, compared with values in clinically normal dogs. CONCLUSIONS AND CLINICAL RELEVANCE: The tissue RAAS was modulated without changes in the plasma RAAS in dogs with mild mitral valve regurgitation during the chronic stage of the condition. An ACE-dependent pathway may be a major route for production of angiotensin II during this stage of the condition.     

Increased chymase-like activity in a dog with congenital pulmonic stenosis

ObjectivesThis study was intended to compare the tissue chymase-like activity and angiotensin converting enzyme (ACE) activity in the right and left ventricles of a dog with congenital pulmonic stenosis (PS), with normal dogs, and to discuss the potential clinical implications of these findings.Animals, materials and methodsStudy subjects included a one-year-old Beagle dog with spontaneous PS and six clinically normal Beagles. Chymase-like and ACE activities were determined in all hearts by high pressure liquid chromatography.ResultsIn the PS dog right ventricular (RV) chymase-like activity (49.79 nmol/min/g tissue) and left ventricular (LV) chymase-like activity (36.85 nmol/min/g tissue) were elevated vs normal Beagle dogs (mean ± standard deviation, RV: 20.17 ± 5.24 nmol/min/g, LV: 19.03 ± 3.27 nmol/min/g).ConclusionsActivation of the tissue RAA system was detected in a dog with congenital PS. This interesting finding should be pursued with further studies to validate this result, and to explore whether pharmacological blockade of chymase, or the angiotensin II receptor, represents a useful strategy to prevent myocardial remodeling in this condition.     

Evaluation of the renin-angiotensin system in cardiac tissues of cats with pressure-overload cardiac hypertrophy

OBJECTIVE: To clarify regulation of the renin-angiotensin (RA) system in cardiac tissues by measuring angiotensin-converting enzyme (ACE) and chymase activities in cats with pressure-overload cardiac hypertrophy. ANIMALS: 13 adult cats. PROCEDURES: Pressure-overload cardiac hypertrophy was induced by coarctation of the base of the ascending aorta in 6 cats, and 7 cats served as untreated control animals. Cats were examined before and 3 months and 2 years after surgery. Two years after surgery, cardiac hypertrophy was confirmed by echocardiography, and the blood pressure gradient was measured at the site of constriction. Cats were euthanized, and ACE and chymase activities were measured in cardiac tissues. RESULTS: Mean +/- SD pressure gradient across the aortic constriction was 63 +/- 6 mm Hg. Chymase activity predominated (75% to 85%) in the RA system of the cardiac tissues of cats. Fibrosis in the wall of the left ventricle was detected in cats with hypertrophy, and fibrosis of the papillary muscle was particularly evident. CONCLUSIONS AND CLINICAL RELEVANCE: Chronic pressure overload on the heart of cats can activate the RA system in cardiac tissues. A local increase in angiotensin II was one of the factors that sustained myocardial remodeling.     

No expression of angiotensin II receptors and angiotensin-converting enzyme in myxomatous canine mitral valve leaflets. An autoradiographic study

The renin-angiotensin system, including angiotensin (Ang) II and angiotensin-converting enzyme (ACE), plays an important role in cardiac fibrous tissue formation. Since changes in valvular collagen are a central part of myxomatous mitral valve disease in the dog, we speculated that Ang II and ACE might play a role in the pathogenesis of this disease. In 10 mitral valves, five with and five without clear myxomatous changes, the presence and distribution of Ang II receptors and ACE was examined autoradiographically, using 125I-Ang II and 125I-lisinopril, respectively. At postmortem examination, diseased valves were taken from old dogs, control valves from young adult dogs. No significant level of Ang II and lisinopril binding was found in normal as well as diseased valve leaflets. Equally low, insignificant levels of 125I-Ang II binding were found in the myocardium of dogs with and without valvular disease. No significant level of myocardial 125I-lisinopril binding was found. The lack of autoradiographic evidence of Ang II receptors and ACE in normal and diseased canine mitral valve leaflets suggests that the renin-angiotensin system does not play a major role in the pathogenesis of the valvular changes.     

血管紧张素转换酶Ⅱ在中毒大鼠肝脏中的作用与机制分析

本研究旨在观察血管紧张素转换酶Ⅱ(Angiotensin Converting EnzymeⅡ,ACE2)在CCl4中毒大鼠肝脏中的表达,并探讨其参与抗损伤的作用机制。16只120 g左右雄性SD大鼠随机分成对照组和试验组(n=8)。对照组大鼠腹腔注射生理盐水,试验组大鼠腹腔注射40%CCl4,首次剂量为5 mL.kg-1,以后每3 d 1次(剂量为3mL.kg-1),每周称重1次,4周后宰杀。测定平均日增体质量、血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、白蛋白(Alb)、总蛋白(TP)、总胆红素(TBIL)、血浆血管紧张素Ⅱ(AngⅡ)含量、肝组织中ACE2含量和Mas受体mR-NA的表达及ACE2 mRNA的分布。结果表明:与对照组相比,试验组大鼠平均日增体质量、血清Alb和TP含量均显著下降(P0.05),血清ALT和AST活性显著升高(P0.05),血清TBIL和血浆AngⅡ含量没有显著性变化,Real-time PCR结果提示肝脏中ACE2和Mas受体的mRNA表达均显著上升(3.21±0.52 vs 1.03±0.11,P0.01;1.64±0.22 vs 1.02±0.10,P0.05),原位杂交结果显示对照组大鼠ACE2 mRNA着色较少,主要集中在中央静脉周围细胞,试验组大鼠ACE2大量出现在病变区域、胆管周围细胞、血管及微管内皮细胞当中。本研究表明CCl4诱导的肝损伤大鼠肝脏中ACE2和Mas受体的mRNA表达均增加,提示ACE2参与了肝脏的抗损伤过程,其机制可能是通过激活ACE2-Ang 1-7-Mas轴,减少AngⅡ的产生,从而减轻肝损伤。     

Pathophysiologic mechanism of cardiac dysfunction in experimentally induced heartworm caval syndrome in dogs: an echocardiographic study

In dogs with experimentally induced heartworm infection, the onset of caval syndrome (CS) was characterized by a murmur, loudest over the tricuspid valve, and a large worm mass in the right ventricular lumen detectable during diastole by use of M-mode echocardiography. Two-dimensional echocardiography indicated that the worm mass was located in the right atrium and venae cavae and was "flowing" into the right ventricle during rapid diastolic filling. Paradoxical septal motion and vigorous right ventricular cranial wall motion also were observed. Other echocardiographic changes included decreased size of the left atrium and ventricle, aortic root, and ratio of left-to-right ventricular diastolic luminal diameter, compared with values obtained 6 months after experimentally induced heartworm infection. Right ventricular end diastolic diameter increased considerably. Most echocardiographic indices of left ventricular function (fractional shortening, velocity of circumferential fiber shortening, ejection fraction, and preejection period) were not altered appreciably, but estimates of cardiac index and stroke volume were markedly decreased. Electrocardiography revealed ventricular and supraventricular premature complexes in 7 of the 8 dogs studied, evidence of right ventricular enlargement in 6 of the 8 dogs studied, and increased mean heart rate, compared with that measured 6 months after inoculation of infective larvae, before the onset of CS. Cardiac catheterization was performed in 3 days at the onset of CS. Severe pulmonary arterial and right ventricular hypertension and decreased cardiac index (compared with values obtained before inoculation) were observed. Evidence of right ventricular inflow obstruction was not detected. Mean aortic blood pressure decreased with the onset of CS, but right ventricular end diastolic pressure increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of hypothyroidism on cardiac function in dogs

The thyroid hormones have direct and indirect effects on the heart. So it is possible that depression of left ventricular function is associated with hypothyroidism. This publication describes cardiac findings (auscultation, electrocardiography, echocardiography) in ten hypothyroid dogs. Low heart rates, reduced R-amplitudes and bradycardic arrhythmias (first and second-degree AV block) were found on the electrocardiogram before treatment. On the echocardiograms most of the dogs showed reduced contractillity and reduced left ventricular wall thickness. Seven dogs were reexamined after levothyroxine supplementation. Effects of treatment were increased heart rates and R-amplitudes as well as disappearance of the bradycardic arrhythmias in electrocardiographic examination. The echocardiographic examination showed increased contractility and increased left ventricular wall thickness.     

Neurohormonal and circulatory effects of short-term treatment with enalapril and quinapril in dogs with asymptomatic mitral regurgitation

The aim of the study was to compare the effect of 2 angiotensin-converting enzyme (ACE) inhibitors on neurohormonal and circulatory variables in Cavalier King Charles Spaniels (CKCSs) with asymptomatic mitral regurgitation (MR). Ten CKCSs with mild to severe untreated MR were treated with 2 ACE inhibitors, quinapril and enalapril (each at 0.5 mg/kg PO q24h for 7 days), in a double-blind, crossover study with a washout period of 7 days between treatments. Blood samples were drawn and echocardiography was performed on days 0, 7, 14, and 21. Both treatments reduced ACE activity (P < .001) and increased renin activity (P < .001) and atrial natriuretic peptide concentration (P < .005). The ACE inhibitors had no effect on the concentrations of nitrate and nitrite (NOx) or asymmetric dimethylarginine (ADMA). On day 0, a lower NOx concentration (P = .02) was found in samples taken in the clinic as compared to samples taken in the homes of the dogs. Quinapril caused a significant reduction in more variables that reflect the severity of MR (eg, jet size and left ventricular end diastolic diameter) than did enalapril. However, in terms of specific variables, no significant difference was identified between the effects of the 2 treatments on MR. These results suggest that ACE inhibitors do not affect NOx and ADMA concentrations in asymptomatic dogs, but exercise, stress, or some combination may influence NOx concentrations in these dogs.     

Hormonal response to dobutamine cardiac stress testing in a conscious canine model of early left ventricular dysfunction induced by chronic rate overload

The aims of this study were to investigate (1) hormonal activation before and during dobutamine cardiac stress testing (DST) in a canine model of early left ventricular dysfunction (ELVD) induced by rapid right ventricular pacing (RRVP) and (2) the relationship between this hormonal profile and carnitine concentrations.Before the pacing period, the 6 dogs were assigned to 2 groups according their baseline total plasma carnitine concentration. A DST was performed on each dog before activation of the pacemaker and every 3 to 4 days during development of 3 progressive stages of ELVD (stages 1, 2 and 3). Plasma atrial natriuretic factor (ANF), angiotensin II (ANG II) and endothelin-1 (ET-1) levels were measured at the start and at the end of each DST. Effects of ELVD, DST and plasma carnitine concentration on these measurements were tested.The RRVP induced a significant increase of ANF and ANG II and a non significant trend toward increase of ET-1 in all dogs.Before the pacing period, ANF remained constant during the DST in dogs with normal total plasma carnitine concentration, while it significantly decreased in dogs with low total plasma carnitine concentration. Dobutamine stress testing induced a significant decrease in ANF in all dogs in ELVD. Dobutamine infusion induced a significant increase in ANG II in all dogs before as well as during the pacing period while ET-1 was unchanged.These results suggest that investigation of the hormonal profile before and after a dobutamine challenge might provide important diagnostic information in dogs with asymptomatic or mildly symptomatic cardiac dysfunction of different origins.     

Congenital cardiac disease in dogs

Pulmonic stenosis is caused by a malformed pulmonic valve, stricture of the right ventricular outflow tract or stricture of the pulmonary artery. English Bulldogs, Beagles, Samoyeds, Fox Terriers and Chihuahuas are predisposed. Clinical signs in severely affected dogs include exercise intolerance, stunting, dyspnea, syncope and ascites. Auscultation reveals a high-frequency, crescendo-decrescendo murmur during systole, loudest over the left side of the thorax, near the sternal cardiac border. An ECG may reveal a right-axis deviation of greater than 120 degrees, S waves in leads I, II and III, deep S waves in CV6LL, CV6LU and V10, Q waves deeper than 0.5 mv in leads II, III and AVF, and positive T waves in lead V10. Plain film LAT thoracic radiographs reveal an elevated carina, increased sternal contact of the heart, loss of the cranial cardiac waist and a widened cardiac silhouette, with normal pulmonary vasculature. A DV projection reveals an inverted "D" shape of the right ventricle and a pulmonary artery bulge. A nonselective angiocardiogram reveals poststenotic dilation of the main pulmonary artery. Treatment involves surgical correction of the stenosis.     

Normal and paradoxical ventricular septal motion in the dog

Normal and paradoxical ventricular septal motions were studied in dogs, using M-mode and 2-dimensional echocardiography. Normal ventricular septal motion was evaluated, using 35 clinically healthy dogs (group I), and was compared with characteristics of septal motion measured in 12 dogs with right ventricular overload (group II) and 14 dogs with left-sided heart disease (group III). Normal ventricular septal motion consisted of a series of active and passive anterior (right cranial) and posterior (left caudal) movements that were subjectively evaluated and quantitated during segments of the cardiac cycle. Maximum excursion of the ventricular septum occurred during systole, was directed toward the left ventricle, and was related to body size. Determination of a normalized radius of septal curvature from analysis of 2-dimensional echocardiogram indicated that the septal arc formed part of a generally circular left ventricle in group I dogs. In contrast to these findings, group II dogs with right ventricular pressure and volume overloads exhibited reduced systolic septal excursion, diminished or flat septal motion, and paradoxical systolic septal motion. Normalized radius of septal curvature was significantly greater in group II dogs than in group I or group III dogs. Septal motion and radius of septal curvature in dogs comprising group III were not significantly different from normal during most phases of the cardiac cycle. Results of this study support the concept that septal motion is a reflection of overall left ventricular shape and that abnormalities in ventricular septal motion, namely flat or paradoxical septal motion, should cause the clinician to suspect right ventricular volume or pressure overload.     

Changes of cardiac function in diabetic dogs

Objective

This study aimed to evaluate cardiac function and compare the concentration of cardiac biomarkers including cardiac troponin I (cTnI), galectin-3 (Gal-3), and N-terminal pro B-type natriuretic peptides (NT-proBNP) in diabetic and control dogs.

Changes in renin‐angiotensin‐aldosterone system during cardiac remodeling after mitral valvuloplasty in dogs

BackgroundInformation regarding changes in renin‐angiotensin‐aldosterone system (RAAS) during cardiac remodeling after mitral valvuloplasty (MVP) in dogs remains lacking.Hypothesis/ObjectivesTo assess the longitudinal effects of MVP on circulating RAAS activity.AnimalsEight client‐owned dogs receiving MVP for myxomatous mitral valve disease (MMVD).MethodsThis is a cohort study. Plasma renin activity (PRA), angiotensin II (AT2), aldosterone (PAC), blood urea nitrogen (BUN), and creatinine concentrations, were measured in these dogs before (baseline) and at 3 consecutive monthly follow‐ups (Post‐1M, Post‐2M, Post‐3M). Echocardiography was concomitantly used to assess the process of cardiac recovery after MVP.ResultsThe echocardiography revealed a significant decrease in LVIDDN, LA/Ao, FS, E velocity, E/A, E′ sep, S′ lat, E′ lat, and A′ lat after MVP compared with baseline (P < .05). There was a significant reduction in the PRA (2.45, 3.05, 2.74 vs 8.8 ng/mL/h; P = .002), AT2 (466, 315, 235 vs 1200 pg/mL; P = .009), and PAC (39.88, 47, 54.62 vs 179.5 pg/mL; P = .01), respectively at Post‐1M, Post‐2M, Post‐3M compared to the baseline. Additionally, BUN and creatinine concentrations decreased from Post‐1M. The RAAS variables showed significant, weak to moderate, relationship with selected echocardiographic variables.Conclusions and Clinical ImportanceMitral valvuloplasty contributes to decreased RAAS activity in MMVD dogs, which paralleled the process of cardiac reverse remodeling up to Post‐3M. This information facilitates formulating strategies to optimize clinical outcomes for dogs after MVP.     

The effect of 7.2% hypertonic saline solution with 6% dextran 70 on cardiac contractility as observed by an echocardiography in normovolemic and anesthetized dogs

We studied the effect of a small volume of 7.2% hypertonic saline solution (HSS) or HSS with 6% dextran 70 (HSD) on hemodynamic status, especially on cardiac contractility, in anesthetized dogs using the left ventricular end-systolic volume index (ESVI) and ejection fraction (EF), which can be obtained in noninvasive echocardiography. In the present study, the mean values of ESVI were unaffected by HSS and HSD infusion, whereas the left ventricular end-diastolic volume index (EDVI) was markedly and significant increased. As a result of the changes in EDVI but not in ESVI, EF increased transiently and significantly in the HSS and HSD group, whereas no such significant change was observed in the dogs that received isotonic saline solution. In addition, as a result of the increases in cardiac index but not arterial pressure, system vascular resistances (SVR) decreased transiently and significantly in the HSS and HSD groups, whereas no such significant change was observed in the ISS group. Therefore, the positive inotropic effects of HSS and HSD may be attributable to the increase in left ventricular preload and decreases in SVR rather than direct changes in myocardial contractility.     

Congenital cardiac disease in dogs

Patent ductus arteriosus, aortic stenosis, ventricular septal defect, pulmonic stenosis and tetralogy of Fallot are the most frequently reported cardiac anomalies of dogs. Systolic murmurs occur after the first heart sound but before the second, while diastolic murmurs occur after the second heart sound. Murmurs associated with the pulmonic, aortic and mitral valves are best heard at the left intercostal spaces 3, 4 and 5, respectively, and those of the tricuspid valve at the right intercostal space 3 or 4. Mucosae at both ends of the animal should be examined for cyanosis. Right ventricular enlargement is characterized by a mean electrical axis greater than 100 degrees, a Q wave amplitude greater than 0.5 mv in leads II, III and AVF, and a positive T wave in lead V10. Left ventricular enlargement causes an axis of less than 40 degrees, a QRS complex duration greater than 0.06 seconds, an R wave amplitude greater than 3 mv, and a slurred or depressed ST segment. Atrial enlargement is characterized by a P wave duration greater than 0.04 seconds and a P wave amplitude greater than 0.4 mv. The cardiac silhouette is more upright and round on DV radiographs than on VD projections.     

Echocardiographic evaluation of cardiac tamponade in dogs before and after pericardiocentesis: four cases (1984-1986)

The echocardiographic (M-mode and 2-dimensional) features (before and after pericardiocentesis) of 4 dogs with pericardial effusion and clinical evidence of cardiac tamponade were reviewed. M-Mode echocardiography revealed pericardial effusion, with exaggerated swinging motion of the heart and abnormal septal motion in all 4 dogs. In each case, 2-dimensional echocardiography demonstrated right ventricular diastolic free-wall collapse. Three dogs had right atrial diastolic collapse as well. Clinical signs improved, and right ventricular and right atrial diastolic collapse subsided after pericardiocentesis. Two-dimensional echocardiographic features of right atrial and ventricular collapse were used as indicators for determining the presence of cardiac tamponade.     

Effect of shock strength on survival and acute cardiac damage induced by open-thorax defibrillation of dogs

The safety of open thorax defibrillation with single damped sine-wave shocks and 6-cm-diameter electrodes was evaluated in healthy anesthetized dogs. Twenty-one dogs were allotted to 6 groups: Group A were nonshocked controls and groups B through F were given single shocks of 4-, 7-, 12-, 19-, or 32-fold, respectively, greater than a defibrillation threshold dose (30 mA/g of heart). Immediate postshock death resulted in group F dogs; group A through E dogs survived and were killed after 2 days. The incidence and severity of cardiac morphologic damage increased with shock strength (mild damage occurred in 1 of 3 dogs in group C and in 3 of 4 dogs in group D and severe damage occurred in 2 of 3 dogs in group E). The cardiac lesions were characterized grossly and microscopically. In dogs that died immediately after shocking, damage was apparent as pale circular zones of edema and myofibrillar degeneration in the ventricular free walls beneath the electrode placement sites on the cardiac surface. In the dogs that survived 2 days, the defibrillator-induced areas of myocardial necrosis and calcification were concentrated in arc or ringlike patterns beneath the periphery of the electrode placement sites. All dogs that were studied 2 days after shocking had mild fibrinous pericarditis. Postshock electrocardiographic changes were not good indicators of cardiac damage because the mild epicardial inflammatory reaction associated with the surgical procedure produced large ST and T wave changes which masked any changes associated with myocardial necrosis induced by the electric shocks. It was concluded that a substantial safety margin exists between the required defibrillation threshold shock dose and the large shocks required to produce marked cardiac damage or death in healthy dogs.