Godfred K. Yankey, Tieluo Li, Ahmet Kilic, Sina Moainie, Nathan Weidenhamer, Timothy Nolan, Guangming Cheng, Deyanira Prastein, Gary Schwartzbauer, Zhongjun Wu, Bartley Griffith; University of Maryland, Baltimore, MD
Objective: We hypothesized that the progressive remodeling strain alters the regional myocardial structure and initiates myocardial apoptosis, leading to regional myocardial dysfunction.Methods: Sixteen sonomicrometry crystals were placed in the LV free wall of 8 sheep to measure the regional deformation in the infarct, adjacent, and remote myocardial regions. Hemodynamic, echocardiographic and sonomicrometry data were collected at baseline, 30mins, and 2 and 8 weeks post-MI. At end study, regional apoptosis was quantified by measuring the cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) using western blot, immunohistochemistry and Terminal deoxynucleotidyl transferase (TdT)-mediated-dUTP in situ Nick End Labeling method.
Results: During the 8-week study period, an increase in LV end diastolic pressure of 6.7 ± 0.4 mmHg, a decrease in ejection fraction of 19.3 ± 3.3 % along with an end diastolic volume increase of 49.9 ± 8.8ml were observed. At the time of termination, areal fractional shortening in three regionally distinct zones (remote, adjacent and infarct) of myocardium were measured to be -16.63 ± 1.94 %, -6.78 ± 0.67 %*, and -0.65 ± 0.73 %* (*p<0.0001 as compared to remote region) respectively. The areal expansion in term of regional remodeling strain at 8 weeks in the remote, adjacent and infarct regions were 30.7 ± 6.91 %, 39.9 ± 8.47 %, and 51.1 ± 11.5 %, respectively. The remodeling strain at 8 weeks correlated well with the relative abundance of apoptotic protein expressions: cleaved caspase 3 (17kD) (r = 0.74), cleaved caspase 3 (19 kD) (r = 0.76) and PARP (89 kD) (r = 0.59). These myocardial apoptotic activities strongly correlated with the reduction in the areal fractional shortening: cleaved caspase 3 (17 kD) (r = 0.65), cleaved caspase 3 (19 kD) (r = 0.56) and PARP (89 kD) (r = 0.63). The above results are summarized in Table.
Conclusion: Increase in regional remodeling strain led to an increase in myocardial apoptosis resulting in deterioration of regional contractile function in heart failure.
Relative abundance of protein expression. a,p = 0.001 as compared to normal tissue. b,p = 0.01 as compared to normal tissue. c,p = 0.05 as compared to normal tissue. d,p = 0.001 as compared to infarct tissue. e,p = 0.01 as compared to infarct tissue. f,p = 0.05 as compared to infarct tissue. All values given as mean ± SEM.
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