Experimental Mitral Regurgitation Research Articles

Dose-dependent effects of isoflurane and dobutamine on cardiovascular function in dogs with experimental mitral regurgitation

ObjectiveTo investigate the dose-dependent effects of isoflurane and dobutamine on haemodynamics in dogs with experimentally induced mitral valve insufficiency (MI). Study designExperimental, dose–response study. AnimalsSix healthy Beagle dogs. MethodsDogs with surgically induced MI were anaesthetized once. First, anaesthesia was maintained at an end-tidal isoflurane concentration (Fe′Iso) 1.0% (ISO1.0) for 20 minutes. Then, dobutamine was infused successively at 2, 4, 8 and 12 μg kg−1 minute−1 (DOB2–12) for 10 minutes at each dose rate. Measurements were recorded at each stage. Dobutamine was discontinued and Fe′Iso was increased to 1.5% (ISO1.5) for 20 minutes. Dobutamine was administered similarly to ISO1.0, and cardiovascular variables were recorded. The same sequence was repeated for Fe′Iso 2.0% (ISO2.0). Aortic pressure (AoP) and left atrial pressure (LAP) were recorded by radiotelemetry. The combination method of the pressure–volume loop analysis and transoesophageal echocardiography was used to measure cardiovascular variables: end-systolic elastance (Ees), effective arterial elastance (Ea), Ea/Ees, forward stroke volume (FSV), heart rate (HR), and cardiac output (CO). ResultsHigh isoflurane concentration resulted in reduced Ees and increased Ea/Ees, which indicated low arterial pressure. High-dose dobutamine administration resulted in increased Ees and FSV at all isoflurane concentrations. In ISO1.5 and ISO2.0, HR was lower at DOB4 than baseline (BL) but increased at DOB12 compared with DOB4. CO increased at ≥ DOB8 compared with BL. In ISO1.5 and ISO2.0, systolic and mean AoP increased at ≥ DOB4 and ≥ DOB8, respectively. LAP did not change under all conditions. Conclusions and clinical relevanceThe dose-dependent hypotensive effect of isoflurane in MI dogs was mainly derived from the decrease in contractility. Dobutamine increased AoP without increasing LAP by increasing the contractility attenuated by isoflurane. Our findings may improve the cardiovascular management of dogs with MI undergoing general anaesthesia with isoflurane.

僧帽弁閉鎖不全症モデル犬に対するβ遮断薬 (メトプロロール) の作用効果の検討

僧帽弁閉鎖不全症モデル犬に対するβ遮断薬 (メトプロロール) の作用効果の検討

Quantification of mitral regurgitation using proximal isovelocity surface area method in dogs

The present study was performed to determine the accuracy and reproducibility of calculating the mitral regurgitant orifice area with the proximal isovelocity surface area (PISA) method in dogs with experimental mitral regurgitation and in canine patients with chronic mitral insufficiency and to evaluate the effect of general anesthesia on mitral regurgitation. Eight adult, Beagle dogs for experimental mitral regurgitation and 11 small breed dogs with spontaneous mitral regurgitation were used. In 8 Beagle dogs, mild mitral regurgitation was created by disrupting mitral chordae or leaflets. Effective regurgitant orifice (ERO) area was measured by the PISA method and compared with the measurements simultaneously obtained by quantitative Doppler echocardiography 4 weeks after creation of mitral regurgitation. The same procedure was performed in 11 patients with isolated mitral regurgitation and in 8 Beagle dogs under two different protocols of general anesthesia. ERO and regurgitant stroke volume (RSV) by the PISA method correlated well with values by the quantitative Doppler technique with a small error in experimental dogs (r = 0.914 and r = 0.839) and 11 patients (r = 0.990 and r = 0.996). The isoflurane anesthetic echocardiography demonstrated a significant decrease of RSV, and there was no significant change in fractional shortening (FS), ERO area, LV end-diastolic and LV end-systolic volume. ERO area showed increasing tendency after ketamine-xylazine administration, but not statistically significant. RSV, LV end-systolic and LV end-diastolic volume increased significantly (p < 0.01), whereas FS significantly decreased (p < 0.01). The PISA method is accurate and reproducible in experimental mitral regurgitation model and in a clinical setting. ERO area is considered and preferred as a hemodynamic-nondependent factor than other traditional measurements.

Cardiac mast cell- and chymase-mediated matrix metalloproteinase activity and left ventricular remodeling in mitral regurgitation in the dog

The present study tested the hypothesis that cardiac mast cells and chymase are associated with matrix metalloproteinase (MMP) activation and extracellular matrix (ECM) degradation in the evolution of left ventricular (LV) chamber remodeling secondary to experimental mitral regurgitation (MR) in dogs. LV mast cell density, chymase activity, and angiotensin II (ANG II) levels were significantly increased 2 and 4 weeks post-MR, while an increase in angiotensin-converting enzyme (ACE) activity was not seen prior to the chronic 24 week stage. As early as 2 and 4 weeks, there was a significant decrease in interstitial myocardial collagen content that was associated with an increase in LV end-diastolic diameter (LVEDD) but a normal LVEDD/wall thickness ratio. While mast cell density decreased to normal at 24 weeks, both chymase and MMP-2 activity remained increased throughout the entire 24-week period post-MR. By 24 weeks a transition to an adverse pattern of LV remodeling characterized by a 2-fold increase in the LVEDD/wall thickness ratio had occurred. Thus, this study supports the hypothesis that mast cells and chymase are important modulators of MMP activity and ECM degradation, contributing to adverse LV remodeling in chronic volume overload secondary to MR.

Differential effects of the angiotensin-converting enzyme inhibitor lisinopril versus the beta-adrenergic receptor blocker atenolol on hemodynamics and left ventricular contractile function in experimental mitral regurgitation.

The goal of this study was to determine the therapeutic efficacy of angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic receptor blockers in experimental chronic mitral regurgitation (MR), gaining knowledge using methods difficult to apply in humans. Both ACE inhibitors and beta-blockers are cornerstones in the treatment of human congestive heart failure. However, the roles of these treatments for chronic MR is unclear. Mitral regurgitation was created in 11 closed-chest dogs. Three months after the creation, the ACE inhibitor lisinopril 20 mg was given orally daily. After three months of lisinopril therapy, the beta-blocker atenolol was added to lisinopril for another three months. Atenolol was begun at a dose of 12.5 mg daily and increased gradually to 100 mg daily. Hemodynamics and left ventricular (LV) function were assessed throughout the study. Regurgitant fraction was consistently >50% over the course of this study. Pulmonary capillary wedge pressure and LV end-diastolic pressure were significantly increased after three months of MR and decreased during both lisinopril and the combined therapy in which it was not different from baseline. Left ventricular contractility measured by the end-systolic stiffness constant was depressed from 3.66 +/- 0.20 to 2.65 +/- 0.12 (p < 0.05) at three months of MR and rose insignificantly after lisinopril treatment (2.99 +/- 0.17). When atenolol was added, it rose significantly and returned to normal (3.50 +/- 0.22, p < 0.05). Although lisinopril significantly reduced preload, its effect on LV contractility was insignificant in experimental MR. Conversely, atenolol, when added to lisinopril, achieved maximum hemodynamic benefit and also restored LV contractility.

Noninvasive estimation of cardiac systolic function using continuous-wave Doppler echocardiography in dogs with experimental mitral regurgitation

ObjectiveTo evaluate the feasibility of noninvasive estimation of cardiac systolic function using transthoracic continuous-wave Doppler echocardiography in dogs with mitral regurgitation. Procedure Seven mongrel dogs with experimental mitral regurgitation were used. Left ventriculography and measurement of pulmonary capillary wedge pressure were performed under inhalational anaesthesia. A micromanometer-tipped catheter was placed into the left ventricle and transthoracic echocardiography was carried out. The peak rate of left ventricular pressure rise (peak dP/dt) was derived simultaneously by continuous-wave Doppler and manometer measurements. The Doppler-derived dP/dt was compared with the catheter-measured peak dP/dt in the dogs. Results Classification of the severity of mitral regurgitation in the dogs was as follows: 1+, 2 dogs; 2+, 1 dog; 3+, 2 dogs; 4+, 1 dog; and not examined, 1 dog. We were able to derive dP/dt from the transthoracic continuous-wave Doppler echocar-diography in all dogs. Doppler-derived dP/dt had a significant correlation with the catheter-measured peak dP/dt (r = 0.90, P < 0.0001). Conclusion It was demonstrated that transthoracic continuous-wave Doppler echocardiography is a feasible method of noninvasive estimation of cardiac systolic function in dogs with experimental mitral regurgitation and may have clinical usefulness in canine patients with spontaneous mitral regurgitation.

Association between exogenous atrial natriuretic peptide and hemodynamics in dogs with congestive heart failure produced by experimental mitral regurgitation.

Association between exogenous atrial natriuretic peptide (ANP) and hemodynamic changes was ascertained in 3 dogs with overt congestive heart failure (CHF(+)) and 3 dogs without congestive heart failure (CHF(-)) caused by experimental mitral regurgitation (MR). The hemodynamic measurements were recorded in all dogs during and after 1 hr infusion of ANP at the rate of 0.1 (low dose), 0.5 (medium dose) and 1.0 (high dose) microg/kg/min, respectively. Heart rate, mean arterial pressure, pulmonary capillary wedge pressure (PCWP) and systemic vascular resistance decreased significantly during and after ANP infusion even with low dose in the CHF(+). Stroke volume, stroke volume index and cardiac output in the CHF(+) during and after ANP infusion showed an increasing trend as compared with the CHF(-). Double product, an indicator of myocardial oxygen consumption, significantly decreased during and after ANP administration at all doses in the CHF(+). These findings indicate that even at low dose, exogenous ANP improves cardiac performance and reduces myocardial oxygen consumption in the CHF(+), and suggest that ANP has beneficial effects in the treatment of dogs with overt congestive heart failure resulting from MR.

Plasma digoxin concentration in dogs with mitral regurgitation.

Fifteen and eight mature beagles, without (normal group) and with experimental mitral regurgitation (MR group), respectively, were given 0.02 mg/kg/day digoxin powder for 10 days orally. The optimum time for sample collection after administration of digoxin was observed to be 8-18 hr and 10-22 hr in the normal and MR groups, respectively. In both groups, a stable concentration was reached after 3-5 days of treatment. No differences in plasma level were observed between sexes. The optimum concentration of digoxin was attained at an earlier stage than has been previously reported for both dogs and humans.

Plasma atrial and brain natriuretic peptide levels in dogs with congestive heart failure.

Plasma concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured in 6 dogs with experimental mitral regurgitation (MR) and 19 canine patients with asymptomatic and symptomatic congestive heart failure (CHF). In dogs with experimental MR, ANP and BNP concentrations were significantly correlated with pulmonary capillary wedge pressure (PCWP) (ANP; r=0.852, P=0.0004, BNP; r=0.832, P=0.0008). ANP level was shown to have a predominant effect on PCWP in comparison with BNP using multiple regression analysis. In canine patients with asymptomatic and symptomatic CHF, ANP and BNP concentrations were significantly different among the heart failure classes according to the New York Heart Association functional classification (ANP; P=0.0165, BNP; P=0.0005). In addition, ANP and BNP levels in dogs with decompensated heart failure (n=10) significantly increased in comparison with those in dogs with compensated heart failure (n=9). There was however no correlation between ANP and BNP levels in each heart failure class. In conclusion, plasma ANP and BNP levels may become predictors of PCWP and the severity of heart failure in dogs with MR, although further investigations on ANP and BNP levels in more clinical cases are required.

Mechanisms of cardiac hypertrophy in canine volume overload.

This study tested whether the modest hypertrophy that develops in dogs in response to mitral regurgitation is due to a relatively small change in the rate of protein synthesis or, alternatively, is due to a decreased rate of protein degradation. After 3 mo of severe experimental mitral regurgitation, the left ventricular (LV) mass-to-body weight ratio increased by 23% compared with baseline values. This increase in LV mass occurred with a small, but not statistically significant, increase in the fractional rate of myosin heavy chain (MHC) synthesis (Ks), as measured using continuous infusion with [3H]leucine in dogs at 2 wk, 4 wk, and 3 mo after creation of severe mitral regurgitation. Translational efficiency was unaffected by mitral regurgitation as measured by the distribution of MHC mRNA in polysome gradients. Furthermore, there was no detectable increase in translational capacity as measured by either total RNA content or the rate of ribosome formation. These data indicate that translational mechanisms that accelerate the rate of cardiac protein synthesis are not responsive to the stimulus of mitral regurgitation. Most of the growth after mitral regurgitation was accounted for by a decrease in the fractional rate of protein degradation, calculated by subtracting fractional rates of protein accumulation at each time point from the corresponding Ks values. We conclude that 1) volume overload produced by severe mitral regurgitation does not trigger substantial increases in the rate of protein synthesis and 2) the modest increase in LV mass results primarily from a decrease in the rate of protein degradation.

Beta Blockade Must be Added to ACE Inhibition to Improve Hemodynamics and Contractile Function in Experimental Mitral Regurgitation

Beta Blockade Must be Added to ACE Inhibition to Improve Hemodynamics and Contractile Function in Experimental Mitral Regurgitation

Beta blockade must be added to ACE inhibition to improve hemodynamics and contractile function in experimental mitral regurgitation

Beta blockade must be added to ACE inhibition to improve hemodynamics and contractile function in experimental mitral regurgitation

実験的僧帽弁閉鎖不全犬におけるニトログリセリン軟膏の口腔粘膜塗布効果

The hemodynamic effect of nitroglycerin ointment (NGO) administered on oral mucosa was investigated at 30 min intervals in five normal and five experimental mitral regurgitation (MR) dogs. After administration of 15 or 100 mg, the mean arterial pressure (MAP) decreased in all cases. MAP were observed attaining the lowest at 90 and 30 min in the normal and MR groups respectively and subsequently returning to the level before administration except for the MR-15 mg cases. Showing a significant increase even after 150 min. The mean pulmonary arterial pressure (MPAP) decreased and subsequently returned to the level before administration except for the MR-15 mg cases. Showing significant increase after 300 min. In the normal-15 mg cases, there were significant increase in cardiac index at 270 min and in heart rate at 30 min but not in other cases. The double product (systolic arterial pressure × heart rate) decreased in all cases, later significantly increased at 240 min in the MR-15 cases.

Effects of chronic beta-adrenergic blockade on the left ventricular and cardiocyte abnormalities of chronic canine mitral regurgitation.

The mechanism by which beta blockade improves left ventricular dysfunction in various cardiomyopathies has been ascribed to improved contractile function of the myocardium or to improved beta-adrenergic responsiveness. In this study we tested two hypotheses: (a) that chronic beta blockade would improve the left ventricular dysfunction which develops in mitral regurgitation, and (b) that an important mechanism of this effect would be improved innate contractile function of the myocardium. Two groups of six dogs with chronic severe mitral regurgitation were studied. After 3 mo both groups had developed similar and significant left ventricular dysfunction. One group was then gradually beta-blocked while the second group continued to be observed without further intervention. In the group that remained unblocked, contractile function remained depressed. However, in the group that received chronic beta blockade, contractile function improved substantially. The contractility of cardiocytes isolated from the unblocked hearts and then studied in the absence of beta receptor stimulation was extremely depressed. However, contractility of cardiocytes isolated from the beta-blocked ventricles was virtually normal. Consistent with these data, myofibrillar density was much higher, 55 +/- 4% in the beta-blocked group vs. 39 +/- 2% (P < 0.01) in the unblocked group; thus, there were more contractile elements to generate force in the beta-blocked group. We conclude that chronic beta blockade improves left ventricular function in chronic experimental mitral regurgitation. This improvement was associated with an improvement in the innate contractile function of isolated cardiocytes, which in turn is associated with an increase in the number of contractile elements.

The effects of complete versus incomplete mitral valve repair in experimental mitral regurgitation

Severe mitral regurgitation (regurgitant fraction 0.75 +/- 0.02) was created in eight dogs by our closed-chest chordal rupture technique. After 3 months of chronic mitral regurgitation all indices of contractile function were depressed. Mitral valve repair was then attempted. Postoperative regurgitant fraction was reduced compared with the preoperative value in all eight dogs. Concomitantly, forward cardiac output increased in all dogs and pulmonary capillary wedge pressure fell in all dogs. However, in some dogs, significant regurgitation persisted despite repair. Postoperative regurgitant fraction ranged from 0% to 60%. Postoperative residual regurgitant fraction was related significantly to postoperative cardiac output (r = 0.99), pulmonary capillary wedge pressure (r = 0.77), ejection fraction (r = 0.75), and two indices of contractile function--the mass-corrected end-systolic stress volume relationship (r = 0.87) and end-systolic stiffness (r = 0.93). In general, these parameters returned to their normal values before mitral regurgitation when postoperative regurgitant fraction was less than 30%. Myocytes isolated from the ventricles at the end of study also demonstrated normal contractile function when regurgitant fraction was less than 30%.

Native beta-adrenergic support for left ventricular dysfunction in experimental mitral regurgitation normalizes indexes of pump and contractile function.

It is generally accepted that the adrenergic nervous system provides inotropic support for the failing heart. However, the magnitude of this support has never been studied extensively. The present study was performed to test the hypothesis that the adrenergic nervous system is capable of maintaining indexes of pump and contractile function in the normal range despite significant innate myocardial depression. We used our model of experimental canine mitral regurgitation, which produces left ventricular dysfunction after 3 months of volume overload. We studied indexes of contractile function on and off beta-blockade at baseline and again on and off beta-blockade 3 months after chronic mitral regurgitation had induced significant contractile dysfunction. At baseline, acute beta-blockade caused insignificant reductions in the mass-corrected slope of the end-ejection stress-volume relation (EESVR), the end-systolic stiffness constant, and the ejection fraction-end-systolic stress and the mean velocity of circumferential fiber shortening (VCF)-end-systolic stress relations. After 3 months of chronic mitral regurgitation, all indexes of contractile function were normal in the unblocked state except for the VCF-stress relation, which was mildly reduced. However, after acute beta-blockade after 3 months of chronic mitral regurgitation, the EESVR fell to 303 +/- 27 versus 443 +/- 24 during acute beta-blockade before mitral regurgitation was created (P < .05), and the end-systolic stiffness constant was reduced to 2.54 +/- 0.15 versus 3.27 +/- 0.11 (P < .05). Only after beta-blockade was the ejection fraction-stress relation significantly reduced for dogs with chronic mitral regurgitation. The VCF-stress relation became markedly more abnormal. The viscosity-velocity relation of myocytes isolated from the ventricles of the dogs with mitral regurgitation confirmed that substantial innate contractile depression was present. After 3 months of chronic mitral regurgitation, the adrenergic nervous system was able to maintain most indexes of contractile function in the normal range despite significant depression in innate contractile function. Thus, in the absence of beta-blockade, significant innate contractile depression may be obscured by adrenergic support.

HIGH DOSE NARCOTIC ANAESTHESIA USING SUFENTANIL IN SWINE AND DOGS

Protocols for utilizing intravenous infusions of sufentanil were developed for experimental cardiac surgery in swine and dogs. After initial experiences with fentanyl, sufentanil was selected for these procedures due to its increased potency and shorter half life thus requiring a smaller volume for infusion and more control. In dogs with experimental mitral valve regurgitation, an initial bolus of sufentanil 3 γg/kg IV was followed by a continuous IV infusion at a rate of 9–13 γg/kg/hr. Swine used in experiments involving cardiac conduction system ablation received ketamine 33 mg/kg IM and acepromazine 1.1 mg/kg IM as a preanesthetic combination. Following the preanesthetic, an initial infusion of sufentanil 15 γg/kg/hr was started and a loading dose of sufentanil 7 γg/kg IV was administered as a bolus for induction. They were then maintained by a continuous IV infusion at a rate of 15–30 γg/kg/hr. Dogs but not pigs required periodic supplementation of anaesthesia with isoflurane and/or nitrous oxide during portions of the experimental protocol. No anaesthetic related deaths have occurred in either species using these anaesthetic protocols for cardiac procedures.

Coronary blood flow in dogs with contractile dysfunction due to experimental volume overload.

Abnormalities in coronary blood flow are responsible for stress-induced reductions in contractile function in pressure overload hypertrophy. Less is known about coronary blood flow in volume overload. In this study, we tested the hypothesis that coronary blood flow abnormalities were responsible for contractile abnormalities in experimental volume overload hypertrophy. We examined coronary blood flow at rest and during pacing in seven dogs with contractile dysfunction secondary to chronic experimental mitral regurgitation (average regurgitant fraction at 3 months, 0.58 +/- 0.05). After 3 months of mitral regurgitation, left ventricular mass had increased from 92 +/- 8 g at baseline to 118 +/- 10 g (p less than 0.002). The slope of the end-ejection stress-volume relation, one of our indexes used to estimate contractile function, had fallen from 5.4 +/- 0.3 at baseline to 3.0 +/- 0.3 at 3 months of mitral regurgitation (p less than 0.001). In the mitral regurgitation dogs, coronary blood flow at rest was similar to that of control dogs (endocardial blood flow: control dogs, 1.33 +/- 0.12 ml/min/g; mitral regurgitation dogs, 1.16 ml/min/g, p = NS; epicardial blood flow at rest: control dogs, 1.30 +/- 0.16 ml/min/g; mitral regurgitation dogs 1.13 +/- 0.2 ml/min/g, p = NS). With pacing-induced stress, coronary blood flow increased appropriately in control and mitral regurgitation dogs. Ultrasonic dimension gauges placed in the endocardium and epicardium demonstrated no further deterioration in ventricular function during pacing in the mitral regurgitation dogs. In a separate group of five control dogs and five dogs with mitral regurgitation and left ventricular dysfunction, coronary blood flow was examined in the conscious closed-chest state at rest, during adenosine infusion, and during rapid atrial pacing (240 beats/min). Blood flow increased similarly in both groups during pacing and adenosine infusion. We conclude that in dogs with mitral regurgitation that have developed contractile dysfunction, abnormalities in coronary blood flow do not explain the resting contractile dysfunction. Furthermore, studies during pacing-induced stress and coronary vasodilation with adenosine demonstrate that substantial coronary blood flow reserve is present in this type of volume overload hypertrophy.

The Role of the Left Ventricle in Atrial Natriuretic Peptide Secretion in Acute Mitral Regurgitation

To examine the role of the ventricle in ANP secretion, the atrial natriuretic peptide (ANP) concentration in the plasma, left atrial tissue and left ventricular tissue were observed in a canine during the course of experimental reversible mitral regurgitation (MR). For reversible MR, a basket catheter was inserted into the left atrium via the pulmonary vein and fixed at the mitral valve. The regurgitation arose when the tip basket wire was extended and disappeared immediately when it was closed. Left atrial pressure (LAP), right atrial pressure (RAP) and pulmonary artery pressure (PAP) increased significantly during MR, and decreased to the normal level after recovery from MR. Plasma ANP concentration showed a reversible change in correlation with LAP and RAP in each canine studied. The ANP level in the atrial and ventricular tissue decreased during MR, and the low levels were maintained after recovery from MR. Both the left arterial and left ventricular tissue ANP levels showed the same changes in acute MR. Therefore, it was suggested that normal ventricles might play a role in ANP secretion in acute MR.

Left ventricular function in experimental volume overload hypertrophy

Left ventricular function in volume overload hypertrophy is controversial. In humans, chronic severe volume overload eventually results in left ventricular dysfunction; paradoxically, experimental volume overload hypertrophy has nearly always been associated with normal left ventricular function. However, in most cases, experimental volume overload hypertrophy has either been mild or only present for a short duration. To help resolve the issue of contractile function in volume overload hypertrophy, we examined ventricular function in a recently described model of severe chronic experimental mitral regurgitation. Left ventricular function was measured before and 3 mo after the creation of severe mitral regurgitation (averaged regurgitant fraction 0.64 +/- 0.04). At 3 mo end-diastolic volume had increased from 78 +/- 5 to 114 +/- 7 ml (P less than 0.01). Significant left ventricular hypertrophy had occurred with an increase in the left ventricular weight-to-body weight ratio from 3.84 +/- 0.2 to 5.22 +/- 0.2 (P less than 0.01). All indicators of left ventricular function (ejection fraction, the end ejection stress-volume relationship, this relationship corrected for eccentric hypertrophy, and mean velocity of circumferential fiber shortening at a common stress) were reduced at 3 mo. Our study produced 64% volume overload which was maintained for 3 mo at which time there was a 36% increase in left ventricular mass. This amount of volume overload of this duration produced significant left ventricular dysfunction.