RWJ-67657 treatment post-MI had beneficial effects on LV remodeling and dysfunction, supporting a key role for p38 MAPK in pathologic cell signaling in these processes and its inhibition as a novel therapy.

p38 mitogen-activated protein kinase (p38 MAPK) inhibition exerts beneficial effects on left ventricular (LV) remodeling and dysfunction. p38 MAPK activity is transiently increased soon after myocardial infarction (MI), suggesting brief inhibition may afford the same benefit as long-term inhibition. We examined chronic 12-week p38 MAPK inhibition compared with short-term (7-day) inhibition, and then we discontinued inhibition after MI. Post-MI rats at day 7 received either vehicle, 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1-ol (RWJ67657; RWJ) for 12 weeks (long term; LT-RWJ), RWJ for 1 week and discontinued for 11 weeks (1-week RWJ), or continuous ramipril for 12 weeks. In separate groups of animals, 24 h after MI, vehicle or RWJ was administered for 7 days. Cardiac function was assessed by echocardiography and hemodynamic measurements. Percentage of fractional shortening improved after LT-RWJ and ramipril, but not after 1-week RWJ treatment. Likewise, LV contractility and maximal first derivative of left ventricular pressure (dP/dt max ) was improved (12.5 and 14.4%) and LV end diastolic pressure (LVEDP) was reduced (49.4 and 54.6%) with both treatments. Functional outcomes were accompanied by regression of interstitial collagen I and ␣-smooth muscle actin expression in LV noninfarct, border, and infarct regions with LT-RWJ and ramipril treatment. Hypertrophy was reduced in noninfarct (18.3 and 12.2%) and border regions (16.3 and 12.0%) with both treatments, respectively. Animals receiving RWJ 24 h after MI for 7 days showed similar improvements in fractional shortening, dP/dt max , LVEDP, including reduced fibrosis and hypertrophy. In vitro experiments confirmed a dose-dependent reduction in hypertrophy, with RWJ following tumor necrosis factor-␣ stimulation. Continuous but not short-term p38 MAPK blockade attenuates post-MI remodeling, which is associated with functional benefits on the myocardium.Myocardial infarction (MI) results in progressive structural changes to the myocardium that progress to left ventricular (LV) dysfunction. As a compensatory measure to the decrease in cardiac output following MI, angiotensin II (AngII) and norepinephrine are activated to maintain cardiac function. However, long-term activation promotes vasoconstriction and pathological cardiac remodeling, leading to cardiac dysfunction. In addition, the release of proinflammatory cytokines contributes to the pathological process. Post-MI remodeling is characterized by LV dilatation, necrosis, and thinning of the LV wall, infarct expansion, hypertrophy of myocytes in the viable myocardium, and an increased accumulation of extracellular matrix material (fibrosis) within the infarcted and noninfarcted heart, impeding ventricular function (Tzanidis et al., 2001;Remme, 2003;See et al., 2004).Evidence indicates that p38 mitogen-activated protein kinase (p38 MAPK) may be a common intracellular signaling pathway involved in cardiac remodeling, activated by

The extracellular matrix (ECM) is a dynamic microenvironment and a major contributor to the adverse ventricular remodelling that follows myocardial infarction (MI), via activation of both direct pro-fibrotic pathways and matrix metalloproteinases (MMPs) that enhance collagenase activity. Reactive fibrosis, i.e. deposition of ECM materials remote from the region of the MI is clearly detrimental to ventricular function and contributory to adverse outcomes post-MI. Therefore, reversal of this process represents an important therapeutic target in post-MI management and treatment of established heart failure. A number of existing agents exert their beneficial effects in part via reductions in ECM deposition. Furthermore, specific anti-fibrotic drugs have been developed and are currently being explored for these and other cardiac conditions where pathological ECM deposition is felt to be contributory to disease progression.

The HR 12-25 programme was the most effective implementation strategy. Estimation of the break-even cost of health expenditure savings will enable optimal future programme design, implementation and expenditure.