Background-Matrix metalloproteinases (MMPs) are thought to play a prominent role in atherogenesis and destabilization of plaque. Pericellularly localized membrane-type (MT)-MMPs activate secreted MMPs. We investigated the hypothesis that MT3-MMP is expressed in human atherosclerotic plaques and is regulated by locally produced inflammatory cytokines and oxidized low-density lipoprotein (Ox-LDL). Methods and Results-Expression and cellular localization of MT3-MMP in normal and atherosclerotic human coronary arteries were examined using specific antibodies. Abundant MT3-MMP expression was noted in medial smooth muscle cells (

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Atherosclerotic arteries frequently become calcified, and these calcium deposits are associated with a high risk of adverse clinical events. Descriptive studies suggest calcification is an organized and regulated process with many similarities to osteogenesis, yet the mechanism and its relationship to atherosclerosis remain largely unknown. In bone development and homeostasis, mineral deposition by osteoblasts and mineral resorption by osteoclasts are delicately balanced such that there is no overall gain or loss in bone mass. We hypothesize that there exists in arteries a mechanism that similarly balances mineral deposition with resorption. We propose that the cellular mediators of arterial mineral resorption are osteoclast-like cells (OLCs) derived from hematopoietic precursors of the mononuclear phagocytic lineage. In arterial microenvironments, mononuclear precursors are induced to differentiate toward OLCs by macrophage-colony stimulating factor and receptor activator of NF-kappaB ligand, both of which are necessary and sufficient for osteoclastogenesis and mineral resorption in bone. OLCs may participate in normal mineral homeostasis within the arterial wall or, alternatively, may be recruited to specific sites within developing plaque. Net calcium deposition occurs as a result of focal perturbation of the balance between the activity of osteoblast-like cells and OLCs. Our proposed mechanism thus views arterial mineral deposition not so much as an active pathological process, but as a localized failure of protective mechanisms that actively oppose mineral deposition within the disordered metabolic milieu of developing atherosclerotic plaque.

Experimental data suggest that cryoenergy is associated with less endothelial damage and thrombus formation than radiofrequency energy. This study aimed to compare the impact of pulmonary vein isolation (PVI) on the endothelial damage, myocardial damage, inflammatory response, and prothrombotic state between the two latest technologies, second-generation cryoballoon (CB2) and contact force-sensing radiofrequency catheter (CFRF) ablation. Eighty-six paroxysmal atrial fibrillation (AF) patients (55 men; 65 ± 12 years) underwent PVI with either the CB2 (n = 64) or CFRF (n = 22). Markers of the endothelial damage (L-arginine/asymmetric dimethylarginine [ADMA]), myocardial injury (creatine kinase-MB [CK-MB], troponin-T, and troponin-I), inflammatory response (high-sensitive C-reactive protein), and prothrombotic state (D-dimer, soluble fibrin monomer complex, and thrombin-antithrombin complex) were determined before and up to 24-h post-procedure. The total application time was shorter (1,460 ± 287 vs. 2,395 ± 571 [sec], p < 0.01) and total procedure time tended to be shorter (199 ± 37 vs. 218 ± 38 [min], p = 0.06) with CB2 than CFRF ablation. The amount of myocardial injury was greater (CK-MB: 45 ± 17 vs. 11 ± 3 [IU/l], p < 0.01) with CB2 than CFRF ablation. The L-arginine/ADMA ratio was lower (160 ± 51 vs. 194 ± 38, p = 0.028) after CB2 than CFRF ablation. Inflammatory and all prothrombotic markers were significantly elevated post-ablation; however, the magnitude was similar between the two groups. During a mean follow-up of 20 ± 6 months, the single-procedure AF freedom was similar between the CB2 and CFRF groups (60/64 vs. 20/22, p = 0.82). CB2-PVI produces significantly lesser endothelial damage with greater myocardial injury than CFRF-PVI; however, similar anticoagulant regimens are required during the peri-procedural periods in both technologies.

AimsMatrix metalloproteinase (MMP) is up‐regulated during heart failure (HF) and influences ventricular remodeling. We hypothesized that disparity between MMP‐9 and tissue inhibitors of MMP‐1 (TIMP‐1) results in clinical manifestations and is related to prognostic risk in patients with chronic HF.Methods and resultsPlasma levels of MMP‐9, TIMP‐1, and brain natriuretic peptide (BNP) were measured in 173 patients with chronic HF. Combined endpoints of worsening HF events were assessed during follow‐up (median 109 months). MMP‐9 and TIMP‐1 levels and the MMP‐9/TIMP‐1 ratio increased with increasing severity of the New York Heart Association class (P for trend = 0.003, 0.011, and 0.005, respectively). Patients with HF events (n = 35) had significantly higher MMP‐9 than those without HF events (P = 0.004). Kaplan–Meier analysis demonstrated a higher probability of HF events with high MMP‐9 values (>23.2 ng/mL; P = 0.005). A multivariate Cox proportional hazard model showed that high MMP‐9 values were an independent predictor of HF events (hazard ratio, 3.73; 95% confidence interval (CI), 1.03–13.46; P = 0.043). In patients with lower BNP levels (≤210 pg/mL), the adjusted hazard ratio for HF events was 3.63 (95% CI, 1.20–11.02; P = 0.023) among patients with high MMP‐9 values compared with patients with low BNP and low MMP‐9 values.ConclusionsMMP‐9 and TIMP‐1 levels correlate with the severity of chronic HF. MMP‐9 is a strong predictor of HF events, suggesting that a disparity between MMP‐9 and TIMP‐1 levels and increased MMP‐9 levels may help predict HF events.