Cross-regulation between the renin-angiotensin system and inflammatory mediators in cardiac hypertrophy and failure.

One of the major conceptual advances in our understanding of the pathogenesis of heart failure has been the insight that heart failure may progress as the result of the sustained overexpression of biologically active "neurohormones", such as norepinephrine and angiotensin II, which by virtue of their deleterious effects are sufficient to contribute to disease progression by provoking worsening left ventricular (LV) remodeling and progressive LV dysfunction. Recently, a second class of biologically active molecules, termed cytokines, has also been identified in the setting of heart failure. Analogous to the situation with neurohormones, the overexpression of cytokines is sufficient to contribute to disease progression in heart failure phenotype. Although important interactions between proinflammatory cytokines and the adrenergic system have been recognized in the heart for over a decade, the nature of the important interactions between proinflammatory cytokines and the renin-angiotensin system has become apparent only recently. Accordingly, in the present review, we will discuss the evidence which suggests that there is a functionally significant cross-talk between neurohormonal and inflammatory cytokine signaling in cardiac hypertrophy and failure.

Selective matrix metalloproteinase inhibition with developing heart failure: effects on left ventricular function and structure.

The matrix metalloproteinases (MMPs) are an endogenous family of proteolytic enzymes implicated to contribute to LV remodeling. However, broad-spectrum MMP inhibition (MMPi), particularly inhibition of interstitial collagenase (MMP-1), may not be clinically applicable. This study examined the effects of selective MMPi (sparing MMP-1) in a model of developing congestive heart failure. Pigs were randomly assigned to 3 groups: (1) rapid pacing for 3 weeks (240 bpm, n=10); (2) selective MMPi (20 mg/kg per day-PO;PGE7113313) and rapid pacing (n=12); and (3) controls (n=10). LV peak wall stress increased from controls with rapid pacing (140+/-6 versus 319+/-18 g/cm2; P<0.05) and was reduced with selective MMPi (208+/-9 g/cm2; P<0.05. Preload recruitable stroke work was reduced with rapid pacing (4.3+/-0.4 versus 1.2+/-0.2 dyne. cm/mm Hg; P<0.05) and was increased with selective MMPi (2.6+/-0.3 dyne. cm/mm Hg; P<0.05). Plasma norepinephrine increased by 6-fold in the rapid pacing group (P<0.05) and was reduced from untreated values with selective MMPi (P<0.05). At the myocardial level, myocyte cross-sectional area was increased with selective MMPi but fibrillar collagen volume fraction remained unchanged relative to control values. These results suggest that targeting a selective portfolio of myocardial MMP species for inhibition may provide a more rational therapeutic strategy in the setting of congestive heart failure.

Plasma matrix metalloproteinase and inhibitor profiles in patients with heart failure.

BACKGROUND: Changes in myocardial matrix metalloproteinases (MMPs) and the inhibitors of MMPs (TIMPs) have been demonstrated in congestive heart failure (CHF). The first objective of this study was to measure plasma profiles of MMPs and TIMPs in CHF patients (n = 24; 62 +/- 3 years; left ventricular ejection fraction [LVEF] = 24 +/- 2%) and age-matched nonfailing patients (n = 48; 63 +/- 2 years; LVEF >/= 55%). Cytokines such as tumor necrosis factor (TNF)-alpha can induce MMP expression in vitro. The second objective of this study was to determine the relationship between soluble TNF-alpha receptors (TNFR1; TNFR2) and MMP plasma profiles. METHODS AND RESULTS: Plasma levels of MMP-2, MMP-9, MMP-8, TIMP-1, TIMP-2, TNF-alpha, TNFR1, and TNFR2 were measured by enzyme-linked immunosorbent assay kits. Plasma MMP-9 levels were increased in CHF patients (25 +/- 6 versus 72 +/- 15 ng/mL, P <.05). Interestingly, plasma levels of MMP-8 were decreased in CHF patients (16 +/- 2 versus 9 +/- 2 ng/mL, P <.05). The MMP-9/TIMP-1 ratio was increased by 3-fold, whereas the MMP-9/TIMP-2 ratio was increased by 16-fold in CHF patients (both P <.05). With a 48-week follow-up in CHF patients, an absolute reduction in plasma TNFR1 from baseline was accompanied by reduced MMP-9 levels (-30 +/- 16 ng/mL; P =.058), whereas stable or increased plasma TNFR1 resulted in persistently elevated MMP-9 levels. CONCLUSIONS: The unique findings of this study were 2-fold. First, a discordant change in plasma MMP and TIMP levels occurred in CHF patients. Second, changes in cytokine activity were related to changes in plasma MMP levels. These changes in MMP/TIMP levels likely reflect the progression and/or acceleration of the LV remodeling process in CHF. Thus serial measurements of plasma MMP/TIMP levels may hold diagnostic/prognostic significance in CHF patients.