Plasma Connective Tissue Growth Factor Research Articles

The association of plasma connective tissue growth factor levels with left ventricular diastolic dysfunction in patients with overt hyperthyroidism.

Left ventricular (LV) diastolic dysfunction is an independent predictor of future cardiovascular events. Early detection of patients with LV diastolic dysfunction can improve clinical outcomes through active management. However, the assessment of diastolic function is very complicated, and there are currently lack of effective biomarkers to assess the risk of LV diastolic dysfunction. Connective tissue growth factor (CTGF) plays a significant role in cardiac remodeling and dysfunction. We aimed to investigate the associations between plasma CTGF level and the risk of LV diastolic dysfunction in this study and judge its effectiveness in diagnosing LV diastolic dysfunction. A total of 169 patients with overt hyperthyroidism were included. LV diastolic function was evaluated and the subjects were divided into normal LV diastolic function group and LV diastolic dysfunction group. Routine clinical medical data, biochemical data, thyroid related parameters and echocardiographic parameters were recorded for analysis. Compared with normal LV diastolic function group, the LV diastolic dysfunction group had higher age and BMI, as well as lower heart rate, lower serum albumin, lower eGFR, higher serum TgAb and BNP level, and the incidences of hypertension were also higher (all P <0.05). Circulating plasma CTGF levels in the LV diastolic dysfunction group were significantly higher (normal LV diastolic function group: 7.026 [5.567-8.895], LV diastolic dysfunction group: 8.290 [7.054-9.225] ng/ml, median [(Interquartile range)], P = 0.004); Compared with the lowest quartile group, the crude odds ratios (OR) of LV diastolic dysfunction in the second, third, and fourth quartile group were 3.207, 5.032 and 4.554, respectively (all P<0.05). After adjustment for the potentially confounding variables, the adjusted OR values of the third and fourth quartile group had no obvious change. The results of ROC showed that the plasma CTGF had the largest area under the ROC curve, and the value was 0.659 (P = 0.005). The level of circulating plasma CTGF in the LV diastolic dysfunction group was significantly increased. Plasma CTGF level is an independent risk factor for LV diastolic dysfunction. Compared with serum BNP level, the plasma CTGF level may have auxiliary diagnostic value for LV diastolic dysfunction in hyperthyroid patients.

Plasma Connective Tissue Growth Factor as a Biomarker of Pulmonary Arterial Hypertension Associated With Congenital Heart Disease in Adults.

Connective tissue growth factor (CTGF) has diagnostic value for pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) in children; however, its value in adult patients remains unclear. This study evaluated CTGF as a biomarker in adult PAH-CHD patients.Methods and Results: Based on mean pulmonary artery pressure (mPAP), 56 CHD patients were divided into 3 groups: without PAH (W; mPAP <25 mmHg; n=28); mild PAH (M; mPAP 25-35 mmHg; n=18); and moderate and severe PAH (H; mPAP ≥35 mmHg; n=10). The control group consisted of 28 healthy adults. Plasma CTGF and B-type natriuretic peptide (BNP) concentrations were determined. Plasma CTGF concentrations were higher in the H and M groups than in the W and control groups, and were higher in the H than M group. Plasma CTGF concentrations were positively correlated with pulmonary artery systolic pressure (PASP), mPAP, and pulmonary vascular resistance, and negatively correlated with mixed venous oxygen saturation. CTGF, BNP, red blood cell distribution width, and World Health Organization Class III/IV were risk factors for PAH in CHD patients, and CTGF was an independent risk factor for PAH-CHD. The efficacy of CTGF in the diagnosis of PAH was not inferior to that of BNP. CTGF is a biomarker of PAH associated with CHD. It can be used for early diagnosis and severity assessment in adult patients with CHD-PAH.

Role of Plasma Connective Tissue Growth Factor Levels in Assessment of Pulmonary Arterial Hypertension in Children with Congenital Heart Disease

Abstract Background: To investigate plasma Connective Tissue Growth Factor (CTGF) levels in Pulmonary Arterial Hyper-tension (PAH) associated with Congenital Heart Disease (PAH-CHD) in children and the relationships of CTGF with hemodynamic parameters. Plasma CTGF levels were calculated in 30 children with PAH-CHD and 30 health volunteers, using the subtraction method. Aim of Study: To assess plasma Connective Tissue Growth Factor (CTGF) levels in children with CHD and study its role in assessment of PAH that can be promising diagnostic and prognostic biomarkers for PAH in children with CHD. Patients and Methods: Our study was conducted in Pedi-atric Cardiology Clinic and Cardiology Catheter Laboratory of Ain Shams University Pediatric Hospital, in the period from Jan. 2019 to May 2020, including 30 patient and 30 healthy controls of matched age and sex. Results: The patients with PAH, 17 were acyanotic and 13 were cyanotic. The health control group and patient groups did not differ significantly in terms of age, gender and BSA (p>0.05). Height, weight and BMI were significantly lower in PAH-CHD group compared with the HCG (p 0.05). In addition, CTGF levels were higher in PAH-CHD group than health control group. Depicts that, PAH-CHD group had higher PASP, PADP, RVSP, mPAP, Qp, Rp and Rp/Rs (p < 0.01). Conclusion: Plasma CTGF levels could be a promising diagnostic biomarker for PAH-CHD in children.

Association of Plasma Connective Tissue Growth Factor Levels with Hyperthyroid Heart Disease

Hyperthyroid heart disease (HHD) is one of the most severe complications of overt hyperthyroidism and increases the risk of mortality in affected patients. Early identification of patients at a higher risk of developing HHD can improve clinical outcomes through active surveillance and management. Connective tissue growth factor (CTGF), a secreted extracellular protein, plays a significant role in cardiac remodeling and dysfunction. We aimed to investigate the association between plasma CTGF level and the risk of HHD in this study. A total of 142 overt hyperthyroid patients without HHD and 99 patients with HHD were included. The plasma CTGF levels were measured using ELISA kits. Routine clinical medical data and echocardiography parameters were recorded for analysis. The plasma CTGF level was significantly higher in patients with HHD than in those without HHD (P=0.002). The plasma CTGF level was positively correlated with free triiodothyronin, tryrotropin receptor antibody, troponin I and lactate dehydrogenase levels and the left atrium diameters, right atrium diameters, and right ventricular end-diastolic diameters (all P<0.05). Logistic regression analysis showed that quartiles 3 and 4 of plasma CTGF levels were significantly associated with the increased risk of HHD (crude OR: 2.529; 95% CI: 1.188-5.387). However, after adjustment for the potentially confounding variables, quartile 4 alone was significantly associated with the higher risk of HHD relative to quartile 1. Hyperthyroid patients with HHD display higher plasma CTGF levels. Furthermore, CTGF is an independent risk factor for HHD. Therefore, the plasma CTGF level may be a potential biomarker for the risk of HHD.

Diagnostic and predictive values of plasma connective tissue growth factor in children with pulmonary hypertension associated with CHD.

To evaluate the diagnostic and predictive values of plasma connective tissue growth factor in children with pulmonary hypertension (PH)-related CHD. Forty patients with PH-related CHD were enrolled as group I, and 40 patients with CHD and no PH served as group II. Forty healthy children of matched age and sex served as a control group. Echocardiographic examinations and plasma connective tissue growth factor levels were performed for all included children. Cardiac catheterisation was performed for children with CHD only. Plasma connective tissue growth factor levels were significantly higher in children with PH-related CHD compared to CHD-only patients and to control group and this elevation went with the severity of PH. There was a significant positive correlation between connective tissue growth factor levels and mean pulmonary pressure, pulmonary vascular resistance, and right ventricular diameter. A significant negative correlation was noticed between connective tissue growth factor levels, oxygen saturation, and right ventricular diastolic function. The sensitivity of plasma connective tissue growth factor as a diagnostic biomarker for PH was 95%, and the specificity was 90% at a cut-off value ≥650 pg/mL. The predictive value of plasma connective tissue growth factor for adverse outcome had a sensitivity of 88% and a specificity of 83% at a cut-off value ≥1900 pg/mL. Connective tissue growth factor is a promising biomarker with good diagnostic and predictive values in children with PH-related CHD.

Circulating Connective Tissue Growth Factor Is Associated with Diastolic Dysfunction in Patients with Diastolic Heart Failure

Background: Connective tissue growth factor (CTGF) and transforming growth factor β1 (TGF-β1) are emerging biomarkers for tissue fibrosis. The aim of this study was to investigate the association between circulating CTGF, TGF-β1 levels and cardiac diastolic dysfunction in patients with diastolic heart failure (DHF). Methods: Admitted subjects were screened for heart failure and those with left ventricular (LV) ejection fraction <45% were excluded. Diastolic dysfunction was defined as functional abnormalities that exist during LV relaxation and filling by echocardiographic criteria. Totally 114 patients with DHF and 72 controls were enrolled. Plasma levels of CTGF, TGF-β1, and B-type natriuretic peptide (BNP) were determined. Results: The plasma CTGF and TGF-β1 levels increased significantly in patients with DHF. Circulating CTGF and TGF-β1 levels were correlated with echocardiographic parameter E/e’ and diastolic dysfunction grading in DHF patients. In multivariate logistic analysis, CTGF was significantly associated with diastolic dysfunction (odds ratio: 1.027, p < 0.001). Plasma CTGF (AUC: 0.770 ± 0.036, p < 0.001) and CTGF/BNP (AUC: 0.839 ± 0.036, p < 0.001) showed good predictive power to the diagnosis of DHF. Conclusions: This finding suggested CTGF could be involved in the pathophysiology of diastolic heart failure and CTGF/BNP might have auxiliary diagnostic value on diastolic heart failure.

Connective Tissue Growth Factor Is Related to All-cause Mortality in Hemodialysis Patients and Is Lowered by On-line Hemodiafiltration: Results from the Convective Transport Study.

Connective tissue growth factor (CTGF) plays a key role in the pathogenesis of tissue fibrosis. The aminoterminal fragment of CTGF is a middle molecule that accumulates in chronic kidney disease. The aims of this study are to explore determinants of plasma CTGF in hemodialysis (HD) patients, investigate whether CTGF relates to all-cause mortality in HD patients, and investigate whether online-hemodiafiltration (HDF) lowers CTGF. Data from 404 patients participating in the CONvective TRAnsport STudy (CONTRAST) were analyzed. Patients were randomized to low-flux HD or HDF. Pre-dialysis CTGF was measured by sandwich ELISA at baseline, after six and 12 months. CTGF was inversely related in multivariable analysis to glomerular filtration rate (GFR) (p < 0.001) and positively to cardiovascular disease (CVD) (p = 0.006), dialysis vintage (p < 0.001), interleukin-6 (p < 0.001), beta-2-microglobulin (p = 0.045), polycystic kidney disease (p < 0.001), tubulointerstitial nephritis (p = 0.002), and renal vascular disease (p = 0.041). Patients in the highest quartile had a higher mortality risk compared to those in the lowest quartile (HR 1.7, 95% CI: 1.02–2.88, p = 0.043). HDF lowered CTGF with 4.8% between baseline and six months, whereas during HD, CTGF increased with 4.9% (p < 0.001). In conclusion, in HD patients, CTGF is related to GFR, CVD and underlying renal disease and increased the risk of all-cause mortality. HDF reduces CTGF.

Connective Tissue Growth Factor and Renal Fibrosis.

CCN2, also known as connective tissue growth factor (CTGF), is one of important members of the CCN family. Generally, CTGF expresses at low levels in normal adult kidney, while increases significantly in various kidney diseases, playing an important role in the development of glomerular and tubulointerstitial fibrosis in progressive kidney diseases. CTGF is involved in cell proliferation, migration, and differentiation and can promote the progression of fibrosis directly or act as a downstream factor of transforming growth factor β (TGF-β). CTGF also regulates the expression and activity of TGF-β and bone morphogenetic protein (BMP), thereby playing an important role in the process of kidney repair. In patients with chronic kidney disease, elevated plasma CTGF is an independent risk factor for progression to end-stage renal disease and is closely related to glomerular filtration rate. Therefore, CTGF may be a potential biological marker of kidney fibrosis, but more clinical studies are needed to confirm this view. This section briefly describes the role and molecular mechanisms of CTGF in renal fibrosis and also discusses the potential value of targeting CCN2 for the treatment of renal fibrosis.

Plasma CTGF is independently related to an increased risk of cardiovascular events and mortality in patients with atherosclerotic disease: the SMART study

Aims: Connective tissue growth factor (CTGF) plays a key role in tissue fibrogenesis and growing evidence indicates a pathogenic role in cardiovascular disease. Aim of this study is to investigate the association of connective tissue growth factor (CTGF/CCN2) with cardiovascular risk and mortality in patients with manifest vascular disease. Methods and results: Plasma CTGF was measured by ELISA in a prospective cohort study of 1227 patients with manifest vascular disease (mean age 59.0 ± 9.9 years). Linear regression analysis was performed to quantify the association between CTGF and cardiovascular risk factors. Results are expressed as beta (β) regression coefficients with 95% confidence intervals (CI). The relation between CTGF and the occurrence of new cardiovascular events and mortality was assessed with Cox proportional hazard analysis. Adjustments were made for potential confounding factors. Plasma CTGF was positively related to total cholesterol (β 0.040;95%CI 0.013–0.067) and LDL cholesterol (β 0.031;95%CI 0.000–0.062) and inversely to glomerular filtration rate (β −0.004;95%CI −0.005 to −0.002). CTGF was significantly lower in patients with cerebrovascular disease. During a median follow-up of 6.5 years (IQR 5.3–7.4) 131 subjects died, 92 experienced an ischemic cardiac complication and 45 an ischemic stroke. CTGF was associated with an increased risk of new vascular events (HR 1.21;95%CI 1.04–1.42), ischemic cardiac events (HR 1.41;95%CI 1.18–1.67) and all-cause mortality (HR 1.18;95%CI 1.00–1.38) for every 1 nmol/L increase in CTGF. No relation was observed between CTGF and the occurrence of ischemic stroke. Conclusions: In patients with manifest vascular disease, elevated plasma CTGF confers an increased risk of new cardiovascular events and all-cause mortality.

Suppression of connective tissue growth factor mediates the renoprotective effect of Sitagliptin rather than Pioglitazone in type 2 diabetes mellitus

AimDiabetic nephropathy (DN) is a leading cause of end-stage renal disease, and thus, the ability of antidiabetic drugs to ameliorate renal microvascular disease may be as important as their ability to control blood glucose. Therefore, we investigated the reno-protective effect of the antidiabetic drugs, Sitagliptin and Pioglitazone, versus combined Metformin/Enalapril in a rat model of type 2 diabetes. MethodMale Wistar rats were randomly assigned to be either normal control or diabetic. Induction of type 2 diabetes was done by intraperitoneal injection of\\ low dose streptozotocin (35mg/kg) on top of 2 weeks of high fat diet. Hyperglycemic animals were divided into 4 groups: untreated diabetic, Sitagliptin (10mg/kg), Pioglitazone (10mg/kg) and Metformin/Enalapril (500, 10mg/kg, respectively) treated. After 6 weeks, fasting blood glucose, plasma insulin, β-cell function, insulin resistance, serum lipids, urea & creatinine, albuminurea, kidney weight, renal oxidative stress, plasma connective tissue growth factor (CTGF) and renal histopathology were assessed. Key findingsSitagliptin decreased microalbuminurea, urea & creatinine, renal tropism, oxidative stress and CTGF to levels similar to Metformin/Enalapril group. It also preserved near normal renal histology. Although Pioglitazone treatment reduced urea, creatinine, renal tropism and oxidative stress, it did not improve renal pathological changes or significantly alter CTCF. SignificanceEarly Sitagliptin treatment in type 2 diabetes can equally ameliorate renal functions and structural changes as combined Metformin/Enalapril. Moreover Sitagliptin is a better renoprotective than Pioglitazone, probably due to its suppressor effect on CTGF, a key factor mediating diabetic renal injury.

Elevated Plasma Connective Tissue Growth Factor Levels in Children with Pulmonary Arterial Hypertension Associated with Congenital Heart Disease.

We aimed to investigate plasma connective tissue growth factor (CTGF) levels in pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) (PAH-CHD) in children and the relationships of CTGF with hemodynamic parameters. Plasma CTGF levels were calculated in 30 children with CHD, 30 children with PAH-CHD and 25 health volunteers, using the subtraction method. Cardiac catheterization was performed to measure clinical hemodynamic parameters. Plasma CTGF levels were significantly higher in PAH-CHD than in those with CHD and health volunteers (p < 0.01). In cyanotic PAH-CHD, plasma CTGF levels were significantly elevated compared with acyanotic PAH-CHD in the same group (p < 0.05). Plasma CTGF levels showed positive correlation with B-type natriuretic peptide (BNP) in PAH-CHD (r = 0.475, p < 0.01), while oxygen saturation was inversely related to plasma CTGF levels (r = -0.436, p < 0.05). There was no correlation between CTGF and hemodynamic parameters. Even though the addition of CTGF to BNP did not significantly increase area under curve for diagnosis of PAH-CHD compared with BNP alone (p > 0.05), it revealed a moderately better specificity, positive predictive value and positive likelihood ratio than BNP alone. Plasma CTGF levels could be a promising diagnostic biomarker for PAH-CHD in children.

Plasma connective tissue growth factor levels as potential biomarkers of airway obstruction in patients with asthma

BackgroundBronchial asthma is a chronic inflammatory disorder characterized by airway hyperresponsiveness and airflow limitation. Connective tissue growth factor (CTGF), one of the key profibrotic factors associated with transforming growth factor β, may be related to airway remodeling in asthma. However, no data are available on the association between plasma CTGF levels and clinical and physiologic parameters in patients with asthma. Recently, we developed a novel subtraction method for determination of plasma CTGF levels. ObjectiveTo investigate the utility of plasma CTGF level as a surrogate biomarker in asthma. MethodsPlasma CTGF levels were measured in 67 patients with stable asthma and 81 healthy volunteers, using the subtraction method. We evaluated correlations between plasma CTGF levels and clinical and physiologic parameters in patients with asthma. ResultsPlasma CTGF levels were higher in patients with asthma than in healthy volunteers. Asthmatic patients with a percentage of predicted forced expiratory volume in 1 second (FEV1) less than 80% had significantly higher levels of plasma CTGF than those with a percentage of predicted FEV1 of 80% or more. In patients with asthma, plasma CTGF levels had significantly negative correlations with forced vital capacity (FVC), FEV1, percentage of predicted FEV1, FEV1/FVC ratio, forced expiratory flow at 50% of the FVC (FEF50%), percentage of predicted FEF50%, forced expiratory flow at 75% of the FVC (FEF75%), and percentage of predicted FEF75%, parameters that reflect the degree of airway obstruction. Plasma CTGF levels were negatively correlated with Asthma Control Test scores, a patient-based index of clinical control of asthma. ConclusionPlasma CTGF may be a potential biomarker for stable asthma when evaluating the degree of persistent airway obstruction. Trial Registrationumin.ac.jp/ctr Identifier: UMIN000013081

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

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. 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). 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.

Protective effect of statin therapy on connective tissue growth factor induction by diabetes in vivo and high glucose in vitro

Transcriptional activity of connective tissue growth factor (CTGF) promoter in transfected HEK293 cells was determined by luciferase assays. Secreted CTGF in cultured human mesangial cells was measured by enzyme-linked immunosorbent assay (ELISA). CTGF in urine and plasma was also measured in 405 subjects with/without type 2 diabetes. Our results showed that high glucose significantly increased transcription of the promoter in the transfected cells by more than 2.5-folds (p < 0.0005). CTGF secretion was induced by high glucose in the cells (p < 0.0005). These increases were inhibited by simvastatin. Urine CTGF was positively associated with plasma CTGF in both type 2 diabetes (p = 0.0005) and controls (p = 0.01). Urine CTGF levels in patients with macroalbuminuria were significantly higher than patients without macroalbuminuria (p < 0.05). In conclusion, our in vitro study suggests that statin may have a renal-protective effect through the inhibition of CTGF expression. Urine CTGF may be a good marker for the prediction of diabetic nephropathy.

Connective Tissue Growth Factor (CTGF) Expression Modulates Response to High Glucose

Connective tissue growth factor (CTGF) is an important mediator of fibrosis; emerging evidence link changes in plasma and urinary CTGF levels to diabetic kidney disease. To further ascertain the role of CTGF in responses to high glucose, we assessed the consequence of 4 months of streptozotocin-induced diabetes in wild type (+/+) and CTGF heterozygous (+/−) mice. Subsequently, we studied the influence of glucose on gene expression and protein in mice embryonic fibroblasts (MEF) cells derived from wildtype and heterozygous mice. At study initiation, plasma glucose, creatinine, triglyceride and cholesterol levels were similar between non-diabetic CTGF+/+ and CTGF+/− mice. In the diabetic state, plasma glucose levels were increased in CTGF+/+ and CTGF+/− mice (28.2 3.3 mmol/L vs 27.0 3.1 mmol/L), plasma triglyceride levels were lower in CTGF+/− mice than in CTGF+/+ (0.7 0.2 mmol/L vs 0.5 0.1 mmol/L, p<0.05), but cholesterol was essentially unchanged in both groups. Plasma creatinine was higher in diabetic CTGF+/+ group (11.7±1.2 vs 7.9±0.6 µmol/L p<0.01), while urinary albumin excretion and mesangial expansion were reduced in diabetic CTGF+/− animals. Cortices from diabetic mice (both CTGF +/+ and CTGF +/−) manifested higher expression of CTGF and thrombospondin 1 (TSP1). Expression of nephrin was reduced in CTGF +/+ animals; this reduction was attenuated in CTGF+/− group. In cultured MEF from CTGF+/+ mice, glucose (25 mM) increased expression of pro-collagens 1, IV and XVIII as well as fibronectin and thrombospondin 1 (TSP1). In contrast, activation of these genes by high glucose was attenuated in CTGF+/− MEF. We conclude that induction of Ctgf mediates expression of extracellular matrix proteins in diabetic kidney. Thus, genetic variability in CTGF expression directly modulates the severity of diabetic nephropathy.

FG-3019, a human monoclonal antibody to CTGF, with gemcitabine/erlotinib in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma.

213 Background: Connective tissue growth factor (CTGF) is overexpressed in PDAC and facilitates local desmoplasia, tumor survival and metastasis. FG-3019 is a CTGF-specific monoclonal antibody that decreases tumor growth and metastases and prolongs survival in orthotopic and KPC mouse models. This study evaluates safety and efficacy of FG-3019 with gemcitabine/erlotinib in patients with PDAC. Methods: In a nongoing open-label, dose-escalation study, FG-3019 was used in combination with gemcitabine and erlotinib in patients with previously untreated, measurable, locally advanced or metastatic PDAC. Cohorts 1−6 received FG-3019 Q2W at 3, 10, 15, 25, 35 or 45 mg/kg. Cohort 7 received 35 mg/kg on Day 1 and then 17.5 mg/kg QW. Cohort 8 received 45 mg/kg on Day 1 and then 22.5 mg/kg QW. Results: 75 patients were enrolled at 7 centers. Baseline data: Stage III= 15, Stage IV=60; ECOG=0 (n=32), ECOG=1 (N=43). No SAEs or DLTs related to FG-3019 occurred at any dose. In per protocol population (n=68) median PFS and OS were 4.3 and 9.4 months respectively. Baseline plasma CTGF levels correlated inversely with PFS and OS (p=0.0029) (ITT population). Median FG-3019 Cmax and Cmin increased linearly with dose. Because of considerable overlap between subjects across cohorts, outcomes are correlated with drug exposure. OS, but not PFS, correlated with exposure after the first FG-3019 dose (Day 1 Cmax, p=0.009; Day 15 Cmin, p=0.005; ITT population). 47% of evaluable subjects had &gt;50% decrease in CA19.9.The magnitude of reduction correlated with Day 1 Cmax (p=0.04) and inversely with baseline plasma CTGF (p=0.01). As FG-3019 accumulated over time, minimum FG-3019 exposure (Cmin) of 150 ug/mL on Day 43 appeared to be a threshold. Median OS was 7.7 and &gt;8.6 months for subjects &lt; (n=15) or ≥ (n=43) 150 ug/mL respectively on Day 43 (p=0.0034). Day 43 Cmin &lt; 150, none alive at 12 months: Day 43 Cmin &gt;150, 8 alive at 12 months, 17 alive 6.7-12 months. Conclusions: FG-3019 combined with gemcitabine/erlotonib is well tolerated. Interim results in this open-label study suggest OS improves with increasing exposure to FG-3019. Clinical trial information: NCT01181245.

Abstract 19068: Connective Tissue Growth Factor in Human Diastolic Heart Failure from the Taiwan Diastolic Heart Failure Registry and a Canine Model of Diastolic Dysfunction

BACKGROUND: Diastolic heart failure (DHF) is characterized by myocardial interstitial fibrosis and left ventricular hypertrophy. The study investigated the association between connective tissue growth factor (CTGF) and DHF from animal model to clinical indices. METHODS: The participants of current study were enrolled from the Taiwan Diastolic Heart Failure Registry (TDHFR). 1284 patients were screened and a total of 125 patients with a diagnosis of DHF confirmed by echocardiography were recruited. The severity of DHF was decided according to tissue doppler imaging (E/e’). Soluble plasma levels of CTGF were measured in all subjects and the associations with diastolic function parameters were calculated. Canine model of DHF was induced by aortic banding. Hemodynamic and echocardiographic data were obtained before and after pressure loading (at baseline and after 2 weeks). Myocardium tissues were collected, and western blotting was used to detect the protein expression of CTGF for each dog. The correlation between CTGF, the severity of diastolic dysfunction and hemodynamic changes was then calculated. RESULTS: Patients with severe DHF presented significantly higher plasma CTGF levels than the controls. Significant correlation were found for plasma CTGF and E/e’ (r = 0.80, p&lt;0.001) in advanced DHF patients (E/e’ &gt;15). After 2 weeks in canine models, the protein expression of CTGF from LV myocardial tissue was significantly increased (p&lt;0.01) compared with the controls (shame dogs). Moreover, the expression of CTGF paralleled the severity of LV diastolic dysfunction parameters (r= 0.70, p= 0.03 for E/e’) and hemodynamic changes (r= 0.75, p= 0.02). After adjusting the possible confounding factors for diastolic dysfunction, CTGF levels were associated with diastolic parameters both in human and canine models (Plasma CTGF, B=0.064, p&lt;0.001; tissue CTGF, B= 9.87, p = 0.05). CONCLUSIONS: Both Plasma and myocardium CTGF levels had significant correlations to the severity of DHF. Our study offered the evidence to apply novel therapies for DHF patients aim to down-regulate the overexpression of CTGF.

Consumption of a High Monounsaturated Fat Diet Reduces Oxidative Phosphorylation Gene Expression in Peripheral Blood Mononuclear Cells of Abdominally Overweight Men and Women1–4

The Mediterranean (MED) diet is often considered health-promoting due to its high content of MUFA and polyphenols. These bioactive compounds can affect gene expression and accordingly may regulate pathways and proteins related to cardiovascular disease prevention. This study aimed to identify the effects of a MED-type diet, and the replacement of SFA with MUFA in a Western-type diet, on peripheral blood mononuclear cell (PBMC) gene expression and plasma proteins. Abdominally overweight men and women (waist: women ≥80 cm, men ≥94 cm) were allocated to an 8-wk, completely controlled SFA diet (19% daily energy as SFA), a MUFA diet (20% daily energy MUFA), or a MED diet (21% daily energy MUFA). Concentrations of 124 plasma proteins and PBMC whole-genome transcriptional profiles were assessed. Consumption of the MUFA and MED diets, compared with the SFA diet, decreased the expression of oxidative phosphorylation (OXPHOS) genes, plasma connective tissue growth factor, and apoB concentrations. Compared with the MED and SFA diets, the MUFA diet changed the expression of genes involved in B-cell receptor signaling and endocytosis signaling. Participants who consumed the MED diet had lower concentrations of proinflammatory proteins at 8 wk compared with baseline. We hypothesize that replacement of SFA with MUFA may improve health, thereby reducing metabolic stress and OXPHOS activity in PBMC. The MED diet may have additional antiatherogenic effects by lowering proinflammatory plasma proteins.

Plasma and synovial fluid connective tissue growth factor levels are correlated with disease severity in patients with knee osteoarthritis

Background: Connective tissue growth factor (CTGF) has been implicated in development of osteoarthritis (OA).Objective: To determine the correlation between plasma and synovial fluid CTGF levels and the severity in knee osteoarthritis patients.Methods: A total of 100 subjects were recruited into this study (75 OA patients and 25 controls). CTGF concentrations in plasma and synovial fluid were analyzed by enzyme-linked immunosorbent assay.Results: Plasma and synovial fluid CTGF concentrations were correlated with radiographic severity. There was a positive correlation between plasma and synovial fluid CTGF levels.Conclusion: CTGF could be useful for monitoring the severity and progression of OA.

Clinical significance of inflammatory and fibrogenic cytokines in diabetic nephropathy

To study the role of inflammatory chemokine; monocyte chemoattractant protein-1 (MCP-1), and fibrogenic markers [transforming growth factor beta-1 (TGF-β(1)), connective tissue growth factor (CTGF) and fibronectin (FN)] in diabetic nephropathy (DN). This study included 17 control and 65 type 2 diabetic subjects (18 normoalbuminuric, 22 microalbuminuric and 25 macroalbuminuric). Demographic characteristics, diabetic index and kidney function tests were monitored. Serum TGF-β(1), plasma CTGF, MCP-1 and FN levels were assayed. Microalbuminuric and macroalbuminuric subjects showed a significant elevation in TGF-β(1), CTGF, MCP-1 and FN levels as compared with control and normoalbuminuric subjects. There was positive correlation between these markers and fasting plasma glucose, albumin excretion rate and with each other. This study revealed the importance of these markers in DN pathogenesis which is powered by their association and thus the possibility of their use as biochemical markers in DN was suggested.