Associations of inflammatory markers with impaired left ventricular diastolic and systolic function in collagen-induced arthritis

Abstract

Background: High-grade inflammation may play a pivotal role in the pathogenesis of left ventricular (LV) dysfunction. Evidence to support a role of systemic inflammation in mediating impaired LV function in experimental models of rheumatoid arthritis (RA) remains limited. The aim of the present study was to determine the effects of high-grade systemic inflammation on LV diastolic and systolic function in collagen-induced arthritis (CIA).

Methods: To induce CIA, bovine type-II collagen emulsified in incomplete Freund's adjuvant was injected at the base of the tail into 21 three-month old Sprague Dawley rats. Nine-weeks after the first immunisation, LV function was assessed by pulsed Doppler, tissue Doppler imaging and Speckle tracking echocardiography. Cardiac collagen content was determined by picrosirius red staining; circulating inflammatory markers were measured using ELISA.

Results: Compared to controls (n = 12), CIA rats had reduced myocardial relaxation as indexed by lateral e' (early diastolic mitral annular velocity) and e'/a' (early-to-late diastolic mitral annular velocity) and increased filling pressures as indexed by E/e'. No differences in ejection fraction and LV endocardial fractional shortening between the groups were recorded. LV global radial and circumferential strain and strain rate were reduced in CIA rats compared to controls. Higher concentrations of circulating inflammatory markers were associated with reduced lateral e', e'/a', radial and circumferential strain and strain rate. Greater collagen content was associated with increased concentrations of circulating inflammatory markers and E/e'.

Conclusion: High-grade inflammation is associated with impaired LV diastolic function and greater myocardial deformation independent of haemodynamic load in CIA rats.

Fig 1. Macroscopic observation of joint swelling in collagen-induced arthritis (CIA) rats.

(A) Photographs of hind paws, (B) arthritis scores, (C) paw thickness at the tarsometatarsal joint and (D) paw thickness at the ankle joint in control and CIA rats nine weeks after the primary immunisation. Open circles represent the control group (n = 12) and closed circles represent the CIA (n = 21) group (unpaired t-test). Data presented as mean ± SD. *P < 0.05 versus control group; **P < 0.01 versus control group; ***P < 0.0001 versus control group.

Fig 2. Total collagen content in cardiac tissue of control and collagen-induced arthritis (CIA) rats.

Representative Picrosirius red stained micrographs imaged at x100 magnification viewed in (a) bright-field and under (b) polarized light. (c) Total collagen content (% area fraction) calculated from Picrosirius red stained sections. Data presented as mean ± SD; unpaired t-test, **P < 0.05 versus control group; n = 6 per group. Scale bar = 20μm.

Fig 3. Associations of cardiac geometry and total collagen content with inflammatory cytokines.

TNF-α, tumor necrosis factor alpha; IL-6, interleukin 6; IL-1β, interleukin 1 beta; CRP, C-reactive protein. Open circles represent the correlation coefficient (r) and horizontal lines represent the 95% confidence intervals (Cl) (Pearson’s correlation).

Fig 4. Associations between left ventricular diastolic function markers and circulating inflammatory markers.

TNF-α, tumor necrosis factor alpha; IL-6, interleukin 6; IL-1β, interleukin 1 beta; CRP, C-reactive protein. Open circles represent the correlation coefficient (r) and horizontal lines represent the 95% confidence intervals (Cl) (Pearson’s correlation).

Fig 5. Associations between left ventricular myocardial deformation (strain and strain rate) and circulating inflammatory markers.

TNF-α, tumor necrosis factor alpha; IL-6, interleukin 6; IL-1β, interleukin 1 beta; CRP, C-reactive protein. Open circles represent the correlation coefficient (r) and horizontal lines represent the 95% confidence intervals (Cl) (Pearson’s correlation).