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 (99m)Tc-annexin-V ((99m)Tc-annexin) scintigraphy and study whether the reduction in apoptosis resulting from chronic treatment with valsartan can be detected by (99m)Tc-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 (99m)Tc-annexin scintigraphy were performed. Apoptosis was confirmed by (99m)Tc-annexin autoradiography and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling. Fibrosis was assessed by picrosirius red staining.


RESULTS
In monocrotaline rats, in vivo (99m)Tc-annexin uptake peaked early and declined thereafter but remained elevated, compared with baseline. These stage-dependent changes of in vivo (99m)Tc-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.


CONCLUSIONS
RV disease progression is associated with an early increase in RV apoptosis, as monitored using serial in vivo (99m)Tc-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 (99m)Tc-annexin scintigraphy.
Campian
Maria E
ME
Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.
Verberne
Hein J
HJ
Hardziyenka
Maxim
M
de Bruin
Kora
K
Selwaness
Mariana
M
van den Hoff
Maurice J B
MJ
Ruijter
Jan M
JM
van Eck-Smit
Berthe L F
BL
de Bakker
Jacques M T
JM
Tan
Hanno L
HL
D000818:Animals; D017304:Annexin A5; D017209:Apoptosis; D018450:Disease Progression; D008297:Male; D015609:Organotechnetium Compounds; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D018497:Ventricular Dysfunction, Right / Q000000981:diagnostic imaging* / Q000473:pathology
D017304:Annexin A5; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C417036:technetium Tc 99m annexin V