Donor cell-type specific paracrine effects of cell transplantation for post-infarction heart failure.

Cell transplantation is an emerging therapy for treating post-infarction heart failure. Although the paracrine effect has been proposed to be an important mechanism for the therapeutic benefits, details remain largely unknown. This study compared various aspects of the paracrine effect after transplantation of either bone marrow mononuclear cells (BMC) or skeletal myoblasts (SMB) into the post-infarction chronically failing heart. Three weeks after left coronary artery ligation, adult rats received intramyocardial injection of either BMC, SMB or PBS only. Echocardiography demonstrated that injection of either cell type improved cardiac function compared to PBS injection. Interestingly, BMC injection markedly improved neovascularization in the border areas surrounding infarcts, while SMB injection decreased fibrosis in both the border and remote areas. Injection of either cell type similarly reduced hypertrophy of cardiomyocytes as assessed by cell-size planimetry using isolated cardiomyocytes. Quantitative RT-PCR revealed that, among 15 candidate mediators of paracrine effects studied, Fgf2 and Hgf were upregulated only after BMC injection, while Mmp2 and Timp4 were modulated after SMB injection. Additional investigations of signalling pathways relevant to heart failure by western blotting showed that p38 and STAT3 were temporarily activated after BMC injection, in contrast, ERK1/2 and JNK were activated after SMB injection. There was no difference in activation of Akt, PKD or Smad3 among groups. These data suggest that paracrine effects observed after cell transplantation in post-infarction heart failure were noticeably different between cell types in terms of mediators, signal transductions and consequent effects.

Modulated inflammation by injection of high-mobility group box 1 recovers post-infarction chronically failing heart.

BACKGROUND: Inflammation plays an important role in the progress of adverse ventricular remodeling after myocardial infarction. High-mobility group box 1 (HMGB1) is a nuclear protein, which has recently been uncovered to also act as a modifier of inflammation when released. We hypothesized that HMGB1 injection could preferentially modulate local myocardial inflammation, attenuate ventricular remodeling, and subsequently improve cardiac performance of postinfarction chronic heart failure. METHODS AND RESULTS: Three weeks after left coronary artery ligation, HMGB1 (2.5 mug) or PBS was intramyocardially injected into rat hearts. At 28 days after injection, left ventricular ejection fraction was significantly improved after HMGB1 injection compared to PBS (39.3+/-1.4 versus 33.3+/-1.8%; P<0.01). Accumulation of CD45(+) inflammatory cells, two thirds of which were OX62(+) dendritic cells, in the peri-infarct area was significantly attenuated by HMGB1 injection. Dramatic changes in the expression of major proinflammatory cytokines were not detected by microarray or RT-PCR. Adverse ventricular remodeling including cardiomyocyte hypertrophy (cardiomyocyte cross-sectional area; 439+/-7 versus 458+/-6 mum(2); P<0.05) and extracellular collagen deposition (collagen volume fraction; 11.9+/-0.4 versus 15.2+/-0.6%; P<0.01) was attenuated by HMGB1 injection. Analyses of signal transduction pathways revealed that HMGB1 injection activated ERK1/2, but not p38, Akt, and Smad3. Cardiac regeneration and neovascularization were not observed. CONCLUSIONS: HMGB1 injection modulated the local inflammation in the postinfarction chronically failing myocardium, particularly via reducing the accumulation of dendritic cells. This modulated inflammation resulted in attenuated fibrosis and cardiomyocyte hypertrophy, which thereby improved global cardiac function. These data suggest that HMGB1 may be valuable for the chronic heart failure treatment.

Possible association between telomere length and renal dysfunction in patients with chronic heart failure.

Renal function impairment relates to poor outcome in patients with chronic heart failure (HF). Differences in biological aging could affect the susceptibility to develop renal dysfunction in chronic HF. In the present study, we explored the association of leukocyte telomere length with renal function in patients with chronic HF. We studied 610 patients with HF, aged 40 to 80 years, NYHA class II-IV, with left ventricular ejection fraction of 0.40 or less. Glomerular filtration rate was estimated by the Modification of Diet in Renal Diseases (MDRD) formula, and telomere length of leukocytes was determined by a validated quantitative polymerase chain reaction-based method. Age-and gender-adjusted telomere length ratio decreased steadily with decreasing quartile of the MDRD formula (mean 0.80, 95% confidence interval [CI] 0.73 to 0.88; mean 0.74, 95% CI 0.68 to 0.81; 0.70 mean, 95% CI 0.63 to 0.76; mean 0.67, 95% CI 0.61 to 0.73; p <0.01). Telomere length of leukocytes correlated positively with the MDRD formula (correlation coefficient 0.141; p <0.001). These findings remained significant after adjustment for baseline differences and sensitivity analysis based on propensity score one-to-one matching. In conclusion, shorter leukocyte telomere length is associated with decreased renal function as estimated by the MDRD formula in patients with HF. Further studies will be needed to determine whether shorter leukocyte telomere length is the cause or consequence in this population and whether it plays a role in the prognosis of renal dysfunction in HF.

Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study.

BACKGROUND: Inter-individual differences in biological ageing could affect susceptibility to coronary heart disease. Our aim was to determine whether mean leucocyte telomere length is a predictor of the development of coronary heart disease. METHODS: We compared telomere lengths at recruitment in 484 individuals in the West of Scotland Primary Prevention Study (WOSCOPS) who went on to develop coronary heart disease events with those from 1058 matched controls who remained event free. We also investigated whether there was any association between telomere length and observed clinical benefit of statin treatment in WOSCOPS. FINDINGS: Mean telomere length decreased with age by 9% per decade (95% CI 3.6-14.1; p=0.001) in controls; much the same trend was seen in cases (-5.9% per decade, -3.1 to 14.1; p=0.1902). Individuals in the middle and the lowest tertiles of telomere length were more at risk of developing a coronary heart disease event than were individuals in the highest tertile (odds ratio [OR] for coronary heart disease: 1.51, 95% CI 1.15-1.98; p=0.0029 in the middle tertile; 1.44, 1.10-1.90, p=0.0090 in the lowest). In placebo-treated patients, the risk of coronary heart disease was almost double in those in the lower two tertiles of telomere length compared with those in the highest tertile (1.93, 1.33-2.80, p=0.0005 in the middle tertile; 1.94, 1.33-2.84, p=0.0006 in the lowest). By contrast, in patients treated with pravastatin, the increased risk with shorter telomeres was substantially attenuated (1.12, 0.75-1.69, p=0.5755 in the middle tertile; 1.02, 0.68-1.52, p=0.9380 in the lowest). INTERPRETATION: Mean leucocyte telomere length is a predictor of future coronary heart disease events in middle-aged, high-risk men and could identify individuals who would benefit most from statin treatment. Our findings lend support to the hypothesis that differences in biological ageing might contribute to the risk--and variability in age of onset--of coronary heart disease.