Leslie L. Clark

Specific Temporal Profile of Matrix Metalloproteinase Release Occurs in Patients After Myocardial Infarction Relation to Left Ventricular Remodeling

Background— Changes in matrix metalloproteinase (MMP) and tissue inhibitors of MMPs (TIMPs) contribute to left ventricular (LV) remodeling after myocardial infarction (MI). We tested the hypothesis that a specific plasma MMP/TIMP profile would emerge after MI and be associated with the degree of LV dilation. Methods and Results— LV end-diastolic volume and MMP/TIMP plasma profiles were determined in 53 age-matched control subjects and 32 post-MI patients from day 1 through 180 after MI. LV end-diastolic volume increased by >38% at day 90 after MI (P<0.05). MMP-9 increased by >150% from control at day 1 after MI (P<0.05) and remained elevated. MMP-8 rose to >120% at day 3 after MI (P<0.05) and fell to control values by day 5. TIMP-1 increased by >60% from control at day 1 after MI (P<0.05), whereas TIMP-2 increased only at later time points. Cardiac-specific TIMP-4 fell by 40% at day 5 after MI and remained reduced. A persistent or elevated MMP-9 at day 5 was accompanied by a 3-fold end-diastolic volume increase at day 28 (P<0.05). Conclusions— A specific temporal pattern of MMP/TIMPs occurred in post-MI patients that included an early and robust rise in MMP-9 and MMP-8 and a uniform fall in TIMP-4. These findings suggest that a specific MMP/TIMP plasma profile occurs after MI and holds both prognostic and diagnostic significance.

Expression of Matrix Metalloproteinases and Endogenous Inhibitors Within Ascending Aortic Aneurysms of Patients With Marfan Syndrome

Background— Marfan syndrome (MFS) is known to cause ascending thoracic aortic aneurysms (ATAAs). Transforming growth factor beta (TGF-&bgr;) has recently been implicated in this process. Imbalances between the matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) have also been shown to contribute to aneurysm formation. Whether and to what degree MMP, TIMP, and TGF-&bgr; signaling profiles are altered in ATAAs in MFS compared with non-MFS patients remains unknown. Methods and Results— ATAA samples taken during aortic replacement from age-matched MFS (n=9) and non-MFS (n=18) patients were assessed for representative subtypes of all MMP classes, all 4 known TIMPs, and type 2 TGF-&bgr; receptors (TGFBR2). Results were expressed as a percentage (mean±SEM) of reference control samples (100%; n=18) obtained from patients without ATAA. In MFS, decreased MMP-2 (76±7; P<0.05 versus control), increased MMP-12 (161±27% versus control; P<0.05), and increased MT1-MMP (248±64% versus 91±21 non-MFS and control; P<0.05) were observed. TIMP-3 (74±23%) was reduced compared with control values (P<0.05) and TIMP-2 was elevated (128±31%) compared with non-MFS (73±19%; P<0.05). In non-MFS samples, MMP-1 (70±16%), MMP-3 (77±18%), MMP-8 (75±11%), MMP-9 (69±14%), and MMP-12 (85±15%) were decreased compared with control (P<0.05). TIMPs 1 to 3 were reduced in non-MFS compared with control values (P<0.05). TGFBR2 were increased in MFS (193±32%) compared with non-MFS (95±16%) and controls (P<0.05). Conclusions— A unique MMP and TIMP portfolio was observed in ATAAs from MFS compared with non-MFS patients. In addition, MFS samples showed evidence of increased TGF-&bgr; signaling. These differences suggest disparate mechanisms of extracellular matrix remodeling between these 2 groups of patients.

Chronic Matrix Metalloproteinase Inhibition Following Myocardial Infarction in Mice: Differential Effects on Short and Long-Term Survival

Left ventricular (LV) remodeling occurs after myocardial infarction (MI), and the matrix metalloproteinases (MMPs) contribute to adverse LV remodeling after MI. Short-term pharmacological MMP inhibition (MMPi; days to weeks) in animal models of MI have demonstrated a reduction in adverse LV remodeling. However, the long-term effects (months) of MMPi on survival and LV remodeling after MI have not been examined. MI was induced in adult mice (n = 131) and, at 3 days post-MI, assigned to MMPi [MI-MMPi: (s)-2-(4-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid (PD200126), 7.5 mg/day/p.o., n = 64] or untreated (MI-only, n = 67). Unoperated mice (n = 16) served as controls. The median survival in the MI-only group was 5 days, whereas median survival was significantly greater in the MI-MMPi group at 38 days (p < 0.05). However, with prolonged MMPi (>120 days), a significant divergence in the survival curves occurred in which significantly greater mortality was observed with prolonged MMPi (p < 0.05). LV echocardiography at 6 months revealed LV dilation in the MI-only and MI-MMPi groups (154 ± 14 and 219 ± 24 μl) compared with control (67 ± 4 μl, p < 0.05), with a greater degree of dilation in the MI-MMPi group (p < 0.05). MMPi conferred a beneficial effect on survival early post-MI, but prolonged MMPi (>3 months) was associated with higher mortality and adverse LV remodeling. These unique results suggest that an optimal temporal window exists with respect to pharmacological interruption of MMP activity in the post-MI period.

Cost-Utility of Treatments for Pulmonary Arterial Hypertension: A Markov State-Transition Decision Analysis Model

AbstractBackground and Objective: Clinicians must choose between an increasing number of medications for the treatment of pulmonary arterial hypertension (PAH) with different routes of administration, adverse effects, costs and efficacies. We constructed a decision analysis to help inform treatment choices in PAH. Methods: We created a Markov-type model to evaluate 1-year treatment with bosentan, treprostinil, epoprostenol, inhaled iloprost, sildenafil, sitaxentan and ambrisentan. Transition probabilities were based on observed transitions between WHO functional classes, adjusted by relative risk of improvement in a 6-minute walk test. Utilities were based on reported values for each functional class, adjusted for burden of treatment administration. Costs were estimated from Medicare and Medicaid reimbursement data. Sensitivity analyses evaluated changes in efficacy, utilities and costs. Results: Treatment with sildenafil was less costly and resulted in a greater gain in quality-adjusted life-years (QALYs) compared with other treatments. Treatment with ambrisentan and bosentan resulted in the same gain in QALYs as sildenafil, but at a higher cost. Sensitivity analyses had minimal impact on these results. Conclusions: Based on this model, sildenafil is a cost-effective treatment for PAH with a low price and a net increase in QALYs. The results from this analysis are a tool to help guide clinicians in deciding which PAH medications to use; however, the final decisions should be individualized because the effectiveness of therapy, resulting utilities and acceptable costs will differ with each patient.

Myocardial Interstitial Matrix Metalloproteinase Activity Is Altered by Mechanical Changes in LV Load Interaction With the Angiotensin Type 1 Receptor

LV myocardial remodeling is a structural hallmark of hypertensive hypertrophy, but molecular mechanisms driving this process are not well understood. The matrix metalloproteinases (MMPs) can cause myocardial remodeling in chronic disease states, but how MMP activity is altered with a mechanical load remains unknown. The present study quantified interstitial MMP activity after a discrete increase in LV load and dissected out the contributory role of the angiotensin II Type 1 receptor (AT1R). Pigs (38kg) were randomized to undergo (1) increased LV load by insertion of an intra-aortic balloon pump (IABP) triggered at systole for 3 hours, then deactivated (n=11); (2) IABP and AT1R blockade (AT1RB; valsartan, 3 ng/kg/hr; n=6). MMP activity was directly measured in the myocardial interstitium using a validated inline digital fluorogenic microdialysis system. IABP engagement increased LV peak pressure from 92±3 to 113±5 and 123±7 mm Hg in the vehicle and AR1RB group, respectively, and remained elevated throughout the IABP period (P<0.05). With IABP disengagement, segmental shortening (% change from baseline of 0) remained depressed in the vehicle group (-32.2±11.8%, P<0.05) but returned to baseline in the AT1RB group (2.3±12.5%). MMP activity decreased with IABP in both groups. At IABP disengagement, a surge in MMP activity occurred in the vehicle group that was abrogated with AT1RB (3.03±0.85 versus 0.07±1.55 MMP units/hr, P<0.05). A transient increase in LV load caused a cyclic variation in interstitial MMP activity that is regulated in part by the AT1R. These temporally dynamic changes in MMP activity likely influence myocardial function and structure with increased LV load.

OR 22: The relationship of matrix metalloproteinase and tissue inhibitor of MMP and diastolic function in left ventricular hypertrophy

Abstract OR-22 Key Words: Left Ventricular Hypertrophy, Matrix Metalloproteinases, Diastolic Function