Sildenafil treatment attenuates ventricular remodeling in an experimental model of aortic regurgitation.

BACKGROUND: Currently there is no reliable medical treatment for aortic regurgitation (AR). METHODS: Thirty-nine Sprague-Dawley rats underwent creation of AR or sham operation. Treated rats were assigned to early or late institution of sildenafil therapy (100 mg/kg/day) for a total of 10 weeks. Treatment-effects were measured by serial echocardiography, invasive hemodynamic measurements, and tissue analysis. RESULTS: Rats assigned to early treatment developed less remodeling than untreated rats. Thus, left ventricular (LV) dilation was blunted by sildenafil with end-systolic diameter being significantly smaller (6.6 ± 0.4 vs. 7.7 ± 0.4 mm, respectively, p < 0.05). Also, LV wall thickness was significantly decreased in treated rats compared to controls (2.23 ± 0.08 vs. 2.16 ± 0.05 mm, p < 0.01). Fractional shortening was improved by treatment (p < 0.05). Myocardial fibrosis was borderline decreased by treatment (p = 0.09). Akt was increased in treated compared to controls (p < 0.05). CONCLUSION: Sildenafil slightly inhibits LV remodeling and improves fractional shortening in rats with AR when treatment is initiated early.

Effects of early and late-onset treatment with carvedilol in an experimental model of aortic regurgitation.

BACKGROUND: Beta-blockade is contraindicated in severe aortic regurgitation (AR) due to the fear of prolonging diastole and thus aggravate regurgitation. However, this has never been scientifically proven and positive effects of targeting the sympathetic system in AR has been demonstrated in several studies. METHOD: Thirty-nine Sprague-Dawley rats with AR were randomized to ten weeks of medical treatment with carvedilol or no treatment. Treatment was initiated either early or late after AR induction. The effect of carvedilol was assessed by serial echocardiography and invasive hemodynamic measurements. RESULTS: AR resulted in eccentric hypertrophy and left ventricular (LV) dysfunction. LV remodeling and function as measured by echocardiography was unaffected by treatment. LV dimensions were similar between treated and untreated groups and measures of LV performance (including strain and strain rate) were also unaltered. This result was confirmed by invasive measurements showing maximal and minimal pressure-time development, LV volumes, and LV pressures, to be unaltered by treatment. On the contrary, despite relative bradycardia carvedilol did not reflect any negative impact on the heart. CONCLUSION: Carvedilol did not improve left ventricular remodeling or function in rats with surgically induced AR. Despite relative bradycardia, we did not find carvedilol to negatively impact the heart, either when treatment was initiated early or late in the course of disease.

Hypertrophy signaling pathways in experimental chronic aortic regurgitation.

The development of left ventricular hypertrophy and dysfunction in aortic regurgitation (AR) has only been sparsely studied experimentally. In a new model of chronic AR in rats, we examined activation of molecular pathways involved in myocardial hypertrophy. Chronic AR was produced by damaging one or two valve cusps, resulting in eccentric remodeling and left ventricular dysfunction, with no increase in overall fibrosis. Western blotting showed increased activation of Akt and p38 at 12 weeks and of c-Jun amino-terminal kinase at 2 weeks, decreased activation of extracellular regulated kinase 5 at both 2 and 12 weeks, while activation of calcium/calmodulin-dependent protein kinase II and extracellular regulated kinase 1/2 was unchanged. Expression of calcineurin and ANF was also unchanged. Eccentric hypertrophy and early cardiac dysfunction in experimental AR are associated with a pattern of activation of intracellular pathways different from that seen with pathological hypertrophy in pressure overload, and more similar to that associated with benign physiological hypertrophy.

New approach to intracardiac hemodynamic measurements in small animals: echo-guided percutaneous apical puncture.

OBJECTIVES: Invasive measurements of intracardiac hemodynamics in animal models have allowed important advances in the understanding of cardiac disease. Currently they are performed either through a carotid arteriotomy or via a thoracotomy and apical insertion. Both of these techniques have disadvantages and are not conducive to repeated measurements. Therefore, the purpose of this study was to develop a new technique for measuring intracardiac hemodynamics. METHODS: In 13 male rats, hemodynamic measurements were performed using a new echocardiographically guided percutaneous apical technique. An intravenous catheter was percutaneously inserted into the left ventricle (LV) in the direction of the LV long axis. Through this catheter, a micromanometer-tipped pressure catheter was inserted, and invasive hemodynamic traces were recorded. After LV recordings, the pressure catheter was advanced into the aorta where pressures were obtained. In 11 rats, measurements were repeated after 1 week (n = 2), 2 weeks (n = 4), 3 weeks (n = 4), or 4 weeks (n = 1). In 3 rats, invasive measurements were performed using a carotid arteriotomy before the percutaneous technique. RESULTS: Among the 13 rats subjected to the procedure, the survival rate was 85%. Of the 11 rats that had the procedure repeated, 3 died (27%). The mean differences ± SD when comparing the two techniques were 10 ± 4 mm Hg for the LV end-systolic pressure and 1 ± 1 mm Hg for the LV end-diastolic pressure. The mean procedure times were 21 ± 3 and 6 ± 1 minutes for the carotid and percutaneous techniques, respectively. CONCLUSIONS: We have successfully developed a percutaneous technique for insertion of LV microtip catheters in rats.