Protective effect of pyridoxal-5-phosphate (MC-1) on perioperative myocardial infarction is independent of aortic cross clamp time: results from the MEND-CABG trial.

AIM: Aortic cross-clamp time remains a significant marker of mortality and morbidity after coronary artery bypass graft (CABG) surgery. Pyridoxal-5-phosphate (MC-1), blocking purinergic receptors and intracellular influx of calcium, was shown to decrease the incidence of perioperative myocardial infarction in the prospective, randomized, double-blinded MC-1 to Eliminate Necrosis and Damage in CABG (MEND-CABG) clinical trial. METHODS: We studied the relationship between treatment with MC-1 and aortic cross-clamping relative to the incidence of cardiovascular (CV) death and myocardial infarction (MI) in the trial that enrolled 901 high-risk patients undergoing CABG with cardiopulmonary bypass. Patients were randomized to receive either placebo, MC-1 250 mg/day or MC-1 750 mg/day starting 3-10 h before CABG and continued for 30 days after surgery. Serial creatine kinase-myocardial band (CK-MB) determinations, ECGs and clinical evaluations were performed. RESULTS: Cross-clamping time increased the event rate of death and MI with an odds ratio (95% confidence interval) of 1.67 (1.17-2.37, P=0.0044). Treatment with MC-1 decreased the rate of events (P=0.0073) with odds ratios of 0.52 (0.31-0.88 for MC-1 250 mg/day versus placebo) and 0.48 (0.29-0.82 for MC-1 750 mg/day versus placebo). There was no interaction between cross-clamp time and treatment (P=0.61) on the occurrence of the combined endpoint. CONCLUSION: MC-1 decreased the incidence of CV death and MI (CK-MB >or=100 ng/mL) during the first 90 days after CABG in the MEND-CABG trial. Although longer aortic clamping time increased the risk of cardiovascular events, the protective effect of MC-1 was independent of ischemic time during CABG.

Stent thrombosis associated with first-generation drug-eluting stents: issues with antiplatelet therapy.

Notice of the rare but catastrophic occurrence of stent thrombosis in association with deployment of drug-eluting stents has focused attention on the adequacy of the current dual antiplatelet regimen of aspirin and clopidogrel. Some patients will not respond to clopidogrel and a glycoprotein (GP) IIb/IIIa inhibitor may be strongly considered during stenting procedures, especially in high-risk patients or those not receiving pretreatment with clopidogrel. Insisting upon and confirming adherence to antiplatelet therapy are complicated tasks, especially because the reasons for premature discontinuation are myriad, from cost to bleeding complications to the need for minor surgery. Nevertheless, the concern about adherence to antiplatelet therapy represents a new and significant clinical reality in our stenting era, one previously less appreciated with the deployment of bare metal stents. (Neth Heart J 2007;15:148-50.).

Polymer-based or polymer-free stents in patients at high bleeding risk

BACKGROUND Polymer-free drug-coated stents provide superior clinical outcomes to bare-metal stents in patients at high bleeding risk who undergo percutaneous coronary intervention (PCI) and are treated with 1 month of dual antiplatelet therapy. Data on the use of polymer-based drug-eluting stents, as compared with polymer-free drug-coated stents, in such patients are limited. METHODS In an international, randomized, single-blind trial, we compared polymer-based zotarolimus-eluting stents with polymer-free umirolimus­coated stents in patients at high bleeding risk. After PCI, patients were treated with 1 month of dual antiplatelet therapy, followed by single antiplatelet therapy. The primary outcome was a safety composite of death from cardiac causes, myocardial infarction, or stent thrombosis at 1 year. The principal secondary outcome was target-lesion failure, an effectiveness composite of death from cardiac causes, target-vessel myocardial infarction, or clinically indicated target-lesion revascularization. Both outcomes were powered for noninferiority. RESULTS A total of 1996 patients at high bleeding risk were randomly assigned in a 1:1 ratio to receive zotarolimus-eluting stents (1003 patients) or polymer-free drugcoated stents (993 patients). At 1 year, the primary outcome was observed in 169 of 988 patients (17.1%) in the zotarolimus-eluting stent group and in 164 of 969 (16.9%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% confidence interval [CI], 3.5; noninferiority margin, 4.1; P=0.01 for noninferiority). The principal secondary outcome was observed in 174 patients (17.6%) in the zotarolimus-eluting stent group and in 169 (17.4%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% CI, 3.5; noninferiority margin, 4.4; P=0.007 for noninferiority). CONCLUSIONS Among patients at high bleeding risk who received 1 month of dual antiplatelet therapy after PCI, use of polymer-based zotarolimus-eluting stents was noninferior to use of polymer-free drug-coated stents with regard to safety and effectiveness composite outcomes. (Funded by Medtronic; ONYX ONE ClinicalTrials.gov number, NCT03344653.). (AU)

The effects of altered strain environments on bone tissue kinetics.

This study defines the alteration in bone tissue kinetics responsible for the "adaptive remodeling" response to altered strain environments. Adult beagle dogs were separated into three experimental groups: ulnar osteotomy, ulnar osteotomy with fracture fixation plate spanning the gap and sham surgery. Four sets of double fluorochrome labels were administered. Prior to sacrifice at 1, 3, and 6 months, strains were measured through rosette strain gages on the cranial and caudal surfaces of the intact radius. Histomorphometric analysis indicated that the increased bone mass in response to elevated strain results from increased activation frequency of modeling with more sites undergoing formation processes than resorption processes on periosteal and endocortical surfaces. Increased remodeling activation did not lead to increased bone mass. There was no evidence that elevated strain changes the individual vigor of osteoclasts or osteoblasts, or that the sigma period was altered by elevated strain.

Advanced coronary artery disease: Appropriate end points for trials of novel therapies.

BACKGROUND: The segment of patients with advanced coronary artery disease, or disease that is not amenable to conventional revascularization therapies, continues to grow. Because the natural history of these patients is less defined, the appropriate end points for trials of novel revascularization therapies involving patients with advanced coronary artery disease are not certain. METHODS AND RESULTS: The Mediators of Social Support Study (MOSS) prospectively followed up outcomes of long-term survival, quality of life, resource use, and costs for 1189 patients and compared outcomes of patients with advanced coronary artery disease with those of a reference group who underwent bypass surgery or angioplasty. CONCLUSIONS: Despite greater disease burden, cost, and mortality for patients with advanced coronary artery disease, a number of self-reported measures of general health status improved in a similar fashion to that of patients eligible for angioplasty or bypass surgery. These findings should inform the design of trials involving novel therapies, suggesting that angina status and mortality be included as primary end points in the consideration of efficacy. This work also suggests that additional studies of novel therapies involving larger sample sizes may be required to confidently characterize efficacy.

Sex-based outcomes after PCI in highbleeding risk patients: Results from the onyx one clear trial

BACKGROUND: While dual antiplatelet therapy (DAPT) constitutes the cornerstone of post-PCI pharmacotherapy, duration of DAPT in high bleeding risk (HBR) patients has not been fully defined especially with regard to sex. The results from the Onyx ONE Clear trial demonstrated favorable safety and efficacy after PCI with 1-month dual antiplatelet therapy (DAPT) in HBR patients treated with Resolute Onyx drug-eluting stents (DES). We sought to evaluate impact of sex on clinical outcomes in this trial. METHODS: In this prespecified subgroup analysis from Onyx ONE Clear, patients were divided into 2 groups according to sex. Primary endpoint was cardiac death or myocardial infarction (MI) from 1 month to 1 year. RESULTS: A total of 487 female patients (32%) and 1019 males (68%) were free from major ischemic events 1-month after PCI and were transitioned to single antiplatelet therapy.Women were older (p<0.001), had more HBR criteria (p=0.02), and higher rates of moderate/severe calcific lesions (p=0.03) compared to men. Men had higher rates of previous MI (p=0.003), atrial fibrillation (p=0.001), and multivessel coronary artery disease (p<0.001). Clinical outcomes between 1 and 12 months are shown in (Figure) and were similar for males and females except for target vessel revascularization which was greater for males (p=0.04). CONCLUSIONS: In HBR patients treated with Resolute Onyx DES and an abbreviated DAPT course of one month, rates of the primary endpoint of cardiac death or MI between 1 and 12 months were low and did not show any sex-based differences. These data support the use of an abbreviated DAPT regimen in men and women with HBR after PCI with Resolute Onyx DES.

Percutaneous stenting of right pulmonary artery stenosis in fibrosing mediastinitis.

Pulmonary artery stenosis is an uncommon complication of fibrosing mediastinitis. Previous medical and surgical therapies have provided limited clinical efficacy without objective evidence of clinical improvement. With the advantages of limited invasiveness and absent need for prolonged drug therapy, percutaneous stent deployment to relieve pulmonary artery obstruction represents a novel treatment for this rare disorder.

Growth factor receptors, phospholipases, phospholipid kinases and actin reorganization.

Upon binding to their ligand, several growth factor receptors that contain a tyrosine kinase within their cytoplasmic domain [receptor tyrosine kinases (RTKs)] induce a substantial reorganization of the actin cytoskeleton. This change in actin superstructure is necessary to produce multiple motile responses within the target cells. RTKs catalyse the clustering of effector proteins within functional units underneath the plasma membrane. Upon reaching a critical mass, RTK-effector units send out signals through the metabolism of membrane phospholipids and other second messenger molecules that regulate the interaction of actin with its satellite regulatory molecules. Several actin binding proteins interact transiently with small clusters of membrane inositol phospholipids in vitro (4 to 5 phospholipid molecules per actin binding protein). Such transient complex formation can either down-regulate or up-regulate the interaction of regulatory proteins with actin. The phospholipids involved in the surface catalytic control of the actin cytoskeleton are metabolically very active and abundant in cells, and are therefore poised to mediate reactions linking signal transduction molecules to the reorganization of the actin cytoskeleton upon cell activation.

EJ-Ras inhibits phospholipase C gamma 1 but not actin polymerization induced by platelet-derived growth factor-BB via phosphatidylinositol 3-kinase.

Transformation of fibroblast-like cells (NIH 3T3) by a constitutively activated GTP-bound isoform of p21ras (EJ-Ras) produces morphogenic changes characterized by decreased attachment to the substratum, with retraction and rounding of the cell body. Transformed fibroblasts lose their "stressed" conformation and adopt a "relaxed" morphology. The specific molecular mechanisms responsible for these changes remain uncharacterized. We found that EJ-Ras transformation of NIH 3T3 cells decreased the cellular content of polymerized actin, particularly at the expense of actin stress fibers, but induced the accumulation of actin filaments in peripheral ruffling membranes. Polymerization of actin could be induced in EJ-Ras-transformed cells by exposure to platelet-derived growth factor (PDGF)-BB to an extent similar to that observed in wild-type NIH 3T3 cells. In EJ-Ras cells, actin polymerization was independent of phospholipase C gamma 1 (PLC gamma 1) activity, because inositol tris-phosphate (IP3) production observed in control NIH 3T3 cells in response to PDGF-BB was absent. Although PDGF-BB did stimulate tyrosine phosphorylation of PLC gamma 1, the phospholipase was strongly inhibited by an inhibitory factor present in the cytoplasm of EJ-Ras-transformed cells. In addition, cytoplasmic extracts of EJ-Ras, but not of control cells, inhibited phosphatidylinositol 4,5-diphosphate (PIP2) hydrolysis catalyzed by a recombinant PLC gamma 1 in vitro. Although PIP2 hydrolysis could not contribute to the reorganization of the actin cytoskeleton induced by PDGF-BB in EJ-Ras-transformed cells, phosphatidylinositol 3-kinase (PI3-K) was necessary for actin polymerization. Wortmannin, a specific PI3-K inhibitor, not only blocked actin polymerization in both control and EJ-Ras-transformed cells but actually led to rapid actin depolymerization when these cells were exposed to PDGF-BB. Thus, in EJ-Ras-transformed cells, cell morphogenic changes in response to PDGF-BB rely importantly on PI3-K and can occur in the complete absence of IP3 production despite tyrosine phosphorylation of PLC gamma 1.