Elevated cardiac troponin-I (cTnI) levels have been demonstrated in serum of patients without acute coronary syndromes, potentially via a stretch-related process. We hypothesize that this cTnI release from viable cardiomyocytes is mediated by stimulation of stretchresponsive integrins. Cultured cardiomyocytes were treated with (1) Gly-Arg-Gly-Asp-Ser (GRGDS, n=22) to stimulate integrins, (2) Ser-Asp-Gly-Arg-Gly (SDGRG, n=8) that does not stimulate integrins, or (3) phosphate-buffered saline (control, n=38). Cells and media were analyzed for intact cTnI, cTnI degradation products, and matrix metalloproteinase (MMP)-2. Cell viability was examined by assay of lactate dehydrogenase (LDH) activity and by nuclear staining with propidium iodide. GRGDS-induced integrin stimulation caused increased release of intact cTnI (9.6±3.0%) as compared to SDGRG-treated cardiomyocytes (4.5 ± 0.8%, p < 0.001) and control (3.0 ± 3.4%, p<0.001). LDH release from GRGDS-treated cardiomyocytes (15.9±3.8%) equalled that from controls (15.2±2.3%, p=n.s.), indicating that the GRGDS-induced release of cTnI is not due to cell necrosis. This result was confirmed by nuclear staining with propidium iodide. Integrin stimulation increased the intracellular and extracellular MMP2 activity as compared to controls (both p<0.05). However, despite the ability of active MMP2 to degrade cTnI in vitro, integrin stimulation in cardiomyocytes was not associated with cTnI degradation. The present study demonstrates that intact cTnI can be released from viable cardiomyocytes by stimulation of stretch-responsive integrins.

We characterized hemodynamics and systolic and diastolic right ventricular (RV) function in relation to structural changes in the rat model of monocrotaline (MCT)-induced pulmonary hypertension. Rats were treated with MCT at 30 mg/kg body wt (MCT30, n = 15) and 80 mg/kg body wt (MCT80, n = 16) to induce compensated RV hypertrophy and RV failure, respectively. Saline-treated rats served as control (Cont, n = 13). After 4 wk, a pressure-conductance catheter was introduced into the RV to assess pressure-volume relations. Subsequently, rats were killed, hearts and lungs were rapidly dissected, and RV, left ventricle (LV), and interventricular septum (IVS) were weighed and analyzed histochemically. RV-to-(LV + IVS) weight ratio was 0.29 +/- 0.05 in Cont, 0.35 +/- 0.05 in MCT30, and 0.49 +/- 0.10 in MCT80 (P < 0.001 vs. Cont and MCT30) rats, confirming MCT-induced RV hypertrophy. RV ejection fraction was 49 +/- 6% in Cont, 40 +/- 12% in MCT30 (P < 0.05 vs. Cont), and 26 +/- 6% in MCT80 (P < 0.05 vs. Cont and MCT30) rats. In MCT30 rats, cardiac output was maintained, but RV volumes and filling pressures were significantly increased compared with Cont (all P < 0.05), indicating RV remodeling. In MCT80 rats, RV systolic pressure, volumes, and peak wall stress were further increased, and cardiac output was significantly decreased (all P < 0.05). However, RV end-systolic and end-diastolic stiffness were unchanged, consistent with the absence of interstitial fibrosis. MCT-induced pressure overload was associated with a dose-dependent development of RV hypertrophy. The most pronounced response to MCT was an overload-dependent increase of RV end-systolic and end-diastolic volumes, even under nonfailing conditions.

Chemokines are involved in the remodeling of the heart; however, their significance as biomarkers in heart failure is unknown. We observed that circulating CXCR3 receptor chemokines CXCL9 and CXCL10 in a rat model of heart failure were increased 1 week after myocardial infarction. CXCL10 was also increased in both remote and infarcted regions of the heart and remained elevated at 16 weeks; CXCL9 was elevated in the remote area at 1 week. In humans, hierarchical clustering and principal component analysis revealed that circulating CXCL10, MIP-1α, and CD40 ligand were the best indicators for differentiating healthy and heart failure subjects. Serum CXCL10 levels were increased in patients with symptomatic heart failure as indexed by NYHA classification II through IV. The presence of CXCL10, MIP-1α, and CD40 ligand appears to be dominant in patients with advanced heart failure. These findings identify a distinct profile of inflammatory mediators in heart failure patients.

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Background: In patients with heart failure cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling. Aim: To evaluate whether myocardial collagen metabolism in patients with heart failure is implicated in adverse ventricular remodelling and response to CRT. Methods: Collagen synthesis and degradation were assessed from the concentrations of aminoterminal propeptides of type I and type III collagen (PINP and PIIINP) and carboxyterminal telopeptide of type I collagen (ICTP), respectively, in serum of 64 patients with heart failure before and after 6 months of CRT. Forty-six patients (72%) showed a N 10% reduction in LV end-systolic volume at follow-up and were classified as responders to CRT, the other 18 patients (28%) were classified as non-responders. Results: Responders demonstrated a mean (± SEM) increase of serum PINP and PIIINP during follow-up, from 32.9 ± 2.2 to 46.7 ± 4.0 μg/L (p b 0.001) and from 4.59 ± 0.24 to 5.13 ± 0.36 μg/L (p b 0.05), respectively. In non-responders, serum PINP and PIIINP remained unchanged during follow-up. At baseline, responders had significantly lower serum PINP than non-responders (32.9 ± 2.2 vs. 41.8 ± 4.3 μg/L; p b 0.05). ICTP levels of responders at baseline tended to be higher than in non-responders (3.54 ± 0.56 vs. 2.08 ± 0.37 μg/L, p = ns), and in both groups ICTP levels did not change upon CRT. Conclusion: Reverse LV remodelling following CRT is associated with increased collagen synthesis rate in the first 6 months of follow-up.