Serial Noninvasive Assessment of Apoptosis During Right Ventricular Disease Progression in Rats

Right ventricular (RV) function is the major determinant of survival in patients with pulmonary hypertension. Yet, the pathophysiologic basis of RV disease is unresolved. We aimed to study the role of apoptosis in RV disease by monitoring it serially during disease progression using in vivo Tc-99m-annexin-V (Tc-99m-annexin) scintigraphy and study whether the reduction in apoptosis resulting from chronic treatment with valsartan can be detected by Tc-99m-annexin scintigraphy. Methods: RV disease after pulmonary hypertension was induced by monocrotaline injection in rats. The following 3 groups were studied: rats treated with monocrotaline (monocrotaline rats), rats treated with monocrotaline plus valsartan (valsartan rats), and age-matched controls (control rats). Serial echocardiography and in vivo Tc-99m-annexin scintigraphy were performed. Apoptosis was confirmed by Tc-99m-annexin autoradiography and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling. Fibrosis was assessed by picrosirius red staining. Results: In monocrotaline rats, in vivo Tc-99m-annexin uptake peaked early and declined thereafter but remained elevated, compared with baseline. These stage-dependent changes of in vivo Tc-99m-annexin uptake were paralleled by changes in autoradiography and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling. Valsartan rats had longer RV failure free survival than did monocrotaline rats and had reduced apoptosis. These changes were accompanied by commensurate delays in RV hypertrophy and RV dilation. Valsartan rats also had less fibrosis than monocrotaline rats at all disease stages. Conclusion: RV disease progression is associated with an early increase in RV apoptosis, as monitored using serial in vivo Tc-99m-annexin scintigraphy. Delay in RV disease progression by valsartan is accompanied by reduction in RV apoptosis. Apoptosis plays a role in RV disease progression and may be assessed by serial in vivo Tc-99m-annexin scintigraphy.