Korean Circ J.  2011 Oct;41(10):603-611. 10.4070/kcj.2011.41.10.603.

Survival, Exercise Capacity, and Left Ventricular Remodeling in a Rat Model of Chronic Mitral Regurgitation: Serial Echocardiography and Pressure-Volume Analysis

• Kim KH
• Kim YJ
• Lee SP
• Kim HK
• Seo JW
• Sohn DW
• Oh BH
• Park YB

• KMID: 2297920
• DOI: http://doi.org/10.4070/kcj.2011.41.10.603

Abstract

BACKGROUND AND OBJECTIVES
The aims of this study were to establish a reliable model of chronic mitral regurgitation (MR) in rats and verify the pathophysiological features of this model by evaluating cardiac function using serial echocardiography and a pressure-volume analysis.
MATERIALS AND METHODS
MR was created in 37 Sprague-Dawley rats by making a hole with a 23 gauge needle on the mitral leaflet through the left ventricular (LV) apex under the guidance of transesophageal echocardiography.
RESULTS
Serial echocardiograms revealed that the LV began to dilate immediately after the MR operation and showed progressive dilation until the 14th week (LV end-systolic dimension at 14 weeks, 4.71+/-0.25 mm vs. 6.81+/-0.50 mm for sham vs. MR, p<0.01; LV end-diastolic dimension, 8.32+/-0.42 mm vs. 11.01+/-0.47 mm, p<0.01). The LV ejection fraction tended to increase immediately after the MR operation but started to decrease thereafter and showed a significant difference with the sham group from the 14th week (70.0+/-2.2% vs. 62.1+/-3.1% for sham vs. MR). In a pressure-volume analysis performed at the 14th week, the LV end-systolic pressure-volume relationship and +dp/dt decreased significantly in the MR group. A serial treadmill test revealed that exercise capacity remained in the normal range until the 14th week when it began to decrease (exercise duration, 406+/-45 seconds vs. 330+/-27 seconds, p<0.01). A pathological analysis showed no significance difference in interstitial fibrosis between the two groups.
CONCLUSION
We established a small animal model of chronic MR and verified its pathophysiological features. This model may provide a useful tool for future research on MR and volume overload heart failure.

Keyword

Mitral regurgitation; Hemodynamic study; Exercise test; Rat model

MeSH Terms

Animals
Echocardiography
Exercise Test
Fibrosis
Heart Failure
Mitral Valve Insufficiency
Models, Animal
Needles
Rats
Rats, Sprague-Dawley
Reference Values
Salicylamides
Ventricular Remodeling
Salicylamides

Figure

• 

  Fig. 1 Surgical procedures for creating mitral regurgitation (MR). A: a lateral thoracotomy was performed on the left side of the sternum through the 3rd or 4th intercostal space, and a needle was inserted. B: advancing the needle toward the mitral valve leaflet; red arrow indicates the needle. C: severe MR events were detected by color Doppler after the MR procedure. D: the MR jet and left atrial area were measured 1 week after MR development by transthoracic echocardiography.

• 

  Fig. 2 Left ventricular remodeling after mitral regurgitation. A: body weight changes between the mitral regurgitation (MR) and the sham group. B: serial changes in cardiac remodeling using echocardiographic measurements. Time course of typical M-mode echocardiograms. End-systolic dimension (mm), end-diastolic dimension (mm), left ventricular (LV) ejection fraction (%), LV mass index. g/kg. *p<0.05. C: serial changes in blood pressure and heart rate. MR: mitral regurgitation, LV: left ventricular, LVPWT: left ventricular posterior wall thickness, HR: heart rate, SBP: systolic blood pressure, DBP: diastolic blood pressure.

• 

  Fig. 3 The mitral regurgitation (MR) model phenotype. Pressure-volume loops depict the features of MR. The slope of the end-systolic pressure volume relation (ESPVR, red slope) is an excellent load-independent index of myocardial contractility. Compared with the sham heart (left) the MR heart is enlarged, and has depressed contractility.

• 

  Fig. 4 A comparison of exercise capacity measured by running duration to exhaustion in the two groups during the compensated and decompensated phases. p<0.01.

• 

  Fig. 5 Landmark analysis of Kaplan-Meier survival rate in rats with and without mitral regurgitation (MR). A phase; four rats died due to pulmonary edema during the acute stage within 2 weeks after the MR operation (12%, 4/34). All sham-operated rats (n=24) were alive. B phase; the survival rate during the chronic compensated stage tended to be worse in the MR group (83.3%, 25/30) than that in the sham group (100%; 24/24, p=0.038). C phase; ten rats in each group were followed up for 10 months. The 10 month survival rate was significantly lower in the MR group than that in the sham group (50% for MR vs. 90% for sham).

• 

  Fig. 6 Comparison of pathological results. Eccentric hypertrophy developed (E) and left ventricular mass increased (F). Masson's trichrome staining showed no significant difference in interstitial fibrosis (B, F, C and G). Picrosirius red staining showed similar collagen content in both groups (D and H).

• 

  Supplementary Fig. 1 A: serial change in mitral inflow E-septal tissue Doppler velocity E' ratio (E/E'). *p<0.05. B: a representative image at 9 weeks after development of mitral regurgitation.

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