Comparison of four alternative national universal anterior cruciate ligament injury prevention programme implementation strategies to reduce secondary future medical costs.

BACKGROUND/AIM: Anterior cruciate ligament (ACL) injury is a common and devastating sporting injury. With or without ACL reconstruction, the risk of knee osteoarthritis (OA) and permanent disability later in life is markedly increased. While neuromuscular training programmes can prevent 50-80% of ACL injuries, no national implementation strategies exist in Australia. The aim of this study was to compare the ability of four alternative national universal ACL injury prevention programme implementation strategies to reduce future medical costs secondary to ACL injury. METHODS: A Markov economic decision model was constructed to estimate the value in lifetime future medical costs prevented by implementing a national ACL prevention programme among four hypothetical cohorts: high-risk sport participants (HR) aged 12-25 years; HR 18-25 years; HR 12-17 years; all youths (ALL) 12-17 years. RESULTS: Of the four programmes examined, the HR 12-25 programme provided the greatest value, averting US$693 of direct healthcare costs per person per lifetime or US$221 870 880 in total. Without training, 9.4% of this cohort will rupture their ACL and 16.8% will develop knee OA. Training prevents 3764 lifetime ACL ruptures per 100 000 individuals, a 40% reduction in ACL injuries. 842 lifetime cases of OA per 100 000 individuals and 584 TKRs per 100 000 are subsequently averted. Numbers needed to treat ranged from 27 for the HR 12-25 to 190 for the ALL 12-17. CONCLUSIONS: 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.

Fibrosis as a therapeutic target post-myocardial infarction.

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.

p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat.

OBJECTIVES: The aim of this study was to examine the effect of the p38 mitogen-activated protein kinase (MAPK) inhibitor, RWJ-67657 (RWJ), on left ventricular (LV) dysfunction and remodeling post-myocardial infarction (MI) in rats. BACKGROUND: p38 MAPK signaling has been implicated in the progression of chronic heart failure. METHODS: From day 7 post-MI (coronary artery ligation), rats received either RWJ (50 mg/day, by gavage, n = 8, MI+RWJ) or vehicle (by gavage, n = 8, MI+V) for 21 days. Echocardiography was performed on day 6, before the commencement of treatment, and on day 27. In vivo hemodynamic measurements were made on day 28. Sham-operated rats served as controls. RESULTS: The LV end-diastolic pressure and lung/body weight ratio were reduced, whereas the maximum rate of rise of LV pressure was increased towards sham levels in MI+RWJ compared with MI+V. Baseline echocardiographic studies demonstrated uniform LV remodeling and dysfunction in MI rats. Fractional shortening (FS) further deteriorated in MI+V, whereas FS was preserved in MI+RWJ. Progressive LV dilation and infarct expansion observed in MI+V were inhibited in MI+RWJ. MI+RWJ also demonstrated increased myocyte hypertrophy in the peri-infarct and non-infarct zones, and reduced myocardial collagen and alpha-smooth muscle actin (SMA) immunoreactivity compared with MI+V. The antifibrotic effects of RWJ in vivo may reflect direct effects on cardiac fibroblasts, because RWJ attenuated transforming growth factor beta-1-stimulated collagen synthesis and alpha-SMA expression in isolated cardiac fibroblasts. RWJ also protected cultured myocytes from hydrogen peroxide-induced apoptosis. CONCLUSIONS: 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.