What is the clinical evidence from this study?

Study design: Other. Population: In vitro cardiomyocyte stretch model (n=68). Intervention: GRGDS (Gly-Arg-Gly-Asp-Ser) vs. PBS (control) or SDGRG. Primary outcome: Release of intact cardiac troponin I (cTnI) (p=<0.001).

October 1, 2007Open Access

Release of cardiac troponin I from viable cardiomyocytes is mediated by integrin stimulation

Q: What are the key findings of this study?

GRGDS-induced integrin stimulation caused increased release of intact cardiac troponin I (9.6%) from viable cardiomyocytes compared to control (3.0%, p<0.001) without inducing cell necrosis.

Key Result

GRGDS-induced integrin stimulation caused increased release of intact cardiac troponin I (9.6%) from viable cardiomyocytes compared to control (3.0%, p<0.001) without inducing cell necrosis.

Structured PICO

Population

Cultured cardiomyocytes (n=68 total: 22 GRGDS, 8 SDGRG, 38 control)

Intervention

Gly-Arg-Gly-Asp-Ser (GRGDS) treatment to stimulate integrins

Comparator

Ser-Asp-Gly-Arg-Gly (SDGRG) treatment (non-stimulating) or phosphate-buffered saline (control)

Outcome

Release of intact cardiac troponin-I (cTnI)surrogate

Intact cardiac troponin I can be released from viable cardiomyocytes via stimulation of stretch-responsive integrins, providing a potential mechanism for cTnI elevation in patients without acute coronary syndromes.

Main Result

Absolute Event Rate: 9.6% vs 3%

p-value: p=<0.001

Limitations

In vitro model using neonatal rat cardiomyocytes may not fully represent adult human myocardium.
The reason for the lack of cTnI degradation in the presence of GRGDS-induced MMP2 activation remains unclear.

Abstract

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 stretch-responsive 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.

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