Early regression of left ventricular hypertrophy after treatment with esmolol in an experimental rat model of primary hypertension

Hypertens Res. 2013 May;36(5):408-13

Quintana-Villamandos B, Delgado-Martos MJ, Sánchez-Hernández JJ, Gómez de Diego JJ, Fernández-Criado MC, Canillas F, Martos-Rodríguez A, Delgado-Baeza E.

Department of Anesthesiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

 

ABSTRACT

Certain b-adrenergic blockers have proven useful in the regression of ventricular remodeling when administered as long-term treatment. However, early regression of left ventricular hypertrophy (LVH) has not been reported, following short-term administration of these drugs. We tested the hypothesis that short-term administration of the cardioselective b-blocker esmolol induces early regression of LVH in spontaneously hypertensive rats (SHR). Fourteen-month-old male SHRs were treated i.v. with vehicle (SHR) or esmolol (SHR-E) (300 mg kg-1 min-1). Age-matched vehicle-treated male Wistar-Kyoto (WKY) rats served as controls. After 48 h, left ventricular morphology and function were assessed using M-mode echocardiograms [left ventricular mass index (LVMI), ejection fraction and transmitral Doppler (early-to-atrial filling velocity ratio (E/A), E-wave deceleration time (Edec time)]. The standardized uptake value (SUV) was applied to evaluate FDG (2-deoxy-2[18F]fluoro-D-glucose) uptake by the heart using PET/CT. Left ventricular subendocardial and subepicardial biopsies were taken to analyze changes in cross-sectional area (CSA) of left ventricular cardiomyocytes and the fibrosis was expressed as collagen volume fraction (CVF). LVMI was lower in SHR-E with respect to SHR (P=0.009). There were no significant differences in EF, E/A ratio or Edec time in SHR-E compared with SHR (P=0.17, P=0.55 and P=0.80, respectively). PET acquisitions in SHR-E showed lower 18F-FDG uptake than SHR (P=0.003). Interestingly, there were no significant differences in SUV in either SHR-E or WKY (P=0.63). CSA in subendocardial and subepicardial regions was minor in SHR-E with respect to SHR (P<0.001), and there were no significant differences in CVF between both groups. Esmolol reverses early LVH in the SHR model of stable compensated ventricular hypertrophy. This is the first study to associate early regression of LVH with administration of a short-term b-blocker.

 

SUPPLEMENTARY:

Our laboratory studies new therapies in early regression of cardiac remodeling because left ventricular hypertrophy (LVH) is a strong and independent predictor of cardiovascular morbidity and mortality in patients with hypertension.

Previous studies (in clinical and animal models of hypertension) by others groups have demostrated regression LVH after long-term treatments with antihypertensive drugs (beta-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonist, diuretics). However, early regression of LVH following short-term use of these agents has not been analyzed to date.

Our hypothesis was that esmolol, an ultrashort-acting cardioselective b-adrenergic blocker, could induce early regression of LVH in 14-month-old spontaneously hypertensive rats (SHR), using a model of stable compensated LVH (Figure 1).

Quintana-Villamandos et al. shows that short-term (48 h) i.v. infusion of esmolol in adult SHR induces early regression of left ventricular hypertrophy. We discovered that esmolol produces reduction of left ventricular mass and the transition from concentric to eccentric LVH (this transition may have favorable implications for prognosis), reduction of cross-sectional area of cardiomyocytes, and a marked decrease in the glucose metabolism of the hypertrophied ventricle. This reduction  LVH was produced by a b- blocker-specific effect.

The importance of this study is two-fold:

First, the study shows that small animal PET using 18F-FDG (2-deoxy-2-[18F]fluoro-D-glucose) can be performed in 14-month-old SHR to evaluate new therapies in the regression of LVH in SHR because pathological myocardial metabolism in the SHR differs from the normal metabolism.

Second, it is the first study to shows an association between early regression of left ventricular hypertrophy and short-term administration of a beta-blocker (esmolol). If these results were confirmed in humans, esmolol could be taken into consideration for the treatment of left ventricular hypertrophy in critical care units because the regression of LVH is one of the objectives of antihypertensive therapy and is associated with a reduction in the incidence of cardiovascular events.

Acknowledgements. This work was supported by a grant from the Spanish Health Ministry (Fondo de Investigaciones Sanitarias) under contract FIS 10/02831.

Dra Quintana Villamandos

Figure 1. Examples histological sections of left ventricle from a spontaneously hypertensive rat. Tintion Syrius red (collagen-specific).

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