Connective tissue growth factor and cardiac diastolic dysfunction: human data from the Taiwan diastolic heart failure registry and molecular basis by cellular and animal models.
OBJECTIVE
Connective tissue growth factor (CTGF) is an emerging marker for tissue fibrosis. We investigated the association between CTGF and cardiac diastolic function using cellular and animal models and clinical human data.


RESULTS
A total of 125 patients with a diagnosis of diastolic heart failure (DHF) were recruited from 1283 patients of the Taiwan Diastolic Heart Failure Registry. The severity of DHF was determined by tissue Doppler imaging (E/e'). Cardiac magnetic resonance imaging (CMRI) was used to evaluate myocardial fibrosis in some of the patients (n = 25). Stretch of cardiomyocytes on a flexible membrane base serves as a cellular phenotype of cardiac diastolic dysfunction (DD). A canine model of DD was induced by aortic banding. A significant correlation was found between plasma CTGF and E/e' in DHF patients. The severity of cardiac fibrosis evaluated by CMRI also correlated with CTGF. In the cell model, stretch increased secretion of CTGF from cardiomyocytes. In the canine model, myocardial tissue CTGF expression and fibrosis significantly increased after 2 weeks of aortic banding. Notably, the expression of CTGF paralleled the severity of LV DD (r = 0.40, P < 0.001 for E/e') and haemodynamic changes (r = 0.80, P < 0.001). After adjusting for confounding factors, CTGF levels still correlated with diastolic parameters in both human and canine models (human plasma CTGF, P < 0.001; canine tissue CTGF, P = 0.04).


CONCLUSIONS
Plasma CTGF level correlated with the severity of DD and tissue fibrosis in DHF patients. The mechanism may be through myocardial stretch. Our study indicated that CTGF may serve as an early marker for DHF.
Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, and Yun-Lin, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Cho-Kai
CK
Wu
Yi-Chih
YC
Wang
Jen-Kuang
JK
Lee
Sheng-Nan
SN
Chang
Mao-Yuan
MY
Su
Huei-Ming
HM
Yeh
Ming-Jai
MJ
Su
Jin-Jer
JJ
Chen
Fu-Tien
FT
Chiang
Juey-Jen
JJ
Hwang
Jiunn-Lee
JL
Lin
Chia-Ti
CT
Tsai
D000368:Aged; D000818:Animals; D055513:Connective Tissue Growth Factor / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D015150:Echocardiography, Doppler; D005260:Female; D005355:Fibrosis; D054144:Heart Failure, Diastolic / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D051379:Mice; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D012042:Registries; D012720:Severity of Illness Index
C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D055513:Connective Tissue Growth Factor
Canine model; Connective tissue growth factor; Diastolic heart failure; Fibrosis