Comparison of Acute Thrombogenicity for Metallic and Polymeric Bioabsorbable Scaffolds: Magmaris Versus Absorb in a Porcine Arteriovenous Shunt Model.

BACKGROUND: A comparison in acute thrombogenicity between the Magmaris sirolimus-eluting bioabsorbable magnesium scaffold and the Absorb bioresorbable vascular scaffold has not been performed. This study assessed acute thrombogenicity of Magmaris compared with Absorb and the Orsiro hybrid drug-eluting stent in a porcine arteriovenous shunt model. METHODS AND RESULTS: An ex vivo porcine carotid jugular arteriovenous shunt was established and connected to SYLGARD tubing containing the Magmaris, Absorb, and Orsiro scaffolds/stents and allowed to run in the shunt for a maximum of 1 hour. Twelve shunts (2 shunt runs per pig) were run comparing the 3 scaffolds in alternating order. Nested generalized linear mixed models were used to compare variables between scaffold groups while adjusting for variability between shunt runs. Confocal fluorescent microscopy costaining CD61/CD42b demonstrated that both Magmaris (3.0%) and Orsiro (4.6%) had less platelet coverage of the total scaffold compared with Absorb (21.8%). Scanning electron microscopy demonstrated significantly less thrombus deposition to Magmaris as a percentage of the total scaffold compared with Absorb (5.0% versus 16.1%, P=0.02). Magmaris had significantly less PM-1-positive neutrophil and CD14-positive monocyte adherence compared with both Orsiro and Absorb. Orsiro had significantly less monocyte deposition compared with Absorb. CONCLUSIONS: Despite a similar scaffold strut thickness, the Magmaris sirolimus-eluting bioabsorbable magnesium scaffold was significantly less thrombogenic compared with the Absorb bioresorbable vascular scaffold in an ex vivo porcine arteriovenous shunt model. Further studies are needed to determine whether the reduced thrombogenicity of Magmaris will result in reductions in major cardiovascular events.

Intravenously Delivered Mesenchymal Stem Cells: Systemic Anti-Inflammatory Effects Improve Left Ventricular Dysfunction in Acute Myocardial Infarction and Ischemic Cardiomyopathy.

RATIONALE: Virtually all mesenchymal stem cell (MSC) studies assume that therapeutic effects accrue from local myocardial effects of engrafted MSCs. Because few intravenously administered MSCs engraft in the myocardium, studies have mainly utilized direct myocardial delivery. We adopted a different paradigm. OBJECTIVE: To test whether intravenously administered MSCs reduce left ventricular (LV) dysfunction both post-acute myocardial infarction and in ischemic cardiomyopathy and that these effects are caused, at least partly, by systemic anti-inflammatory activities. METHODS AND RESULTS: Mice underwent 45 minutes of left anterior descending artery occlusion. Human MSCs, grown chronically at 5% O2, were administered intravenously. LV function was assessed by serial echocardiography, 2,3,5-triphenyltetrazolium chloride staining determined infarct size, and fluorescence-activated cell sorting assessed cell composition. Fluorescent and radiolabeled MSCs (1×106) were injected 24 hours post-myocardial infarction and homed to regions of myocardial injury; however, the myocardium contained only a small proportion of total MSCs. Mice received 2×106 MSCs or saline intravenously 24 hours post-myocardial infarction (n=16 per group). At day 21, we harvested blood and spleens for fluorescence-activated cell sorting and hearts for 2,3,5-triphenyltetrazolium chloride staining. Adverse LV remodeling and deteriorating LV ejection fraction occurred in control mice with large infarcts (≥25% LV). Intravenous MSCs eliminated the progressive deterioration in LV end-diastolic volume and LV end-systolic volume. MSCs significantly decreased natural killer cells in the heart and spleen and neutrophils in the heart. Specific natural killer cell depletion 24 hours pre-acute myocardial infarction significantly improved infarct size, LV ejection fraction, and adverse LV remodeling, changes associated with decreased neutrophils in the heart. In an ischemic cardiomyopathy model, mice 4 weeks post-myocardial infarction were randomized to tail-vein injection of 2×106 MSCs, with injection repeated at week 3 (n=16) versus PBS control (n=16). MSCs significantly increased LV ejection fraction and decreased LV end-systolic volume. CONCLUSIONS: Intravenously administered MSCs for acute myocardial infarction attenuate the progressive deterioration in LV function and adverse remodeling in mice with large infarcts, and in ischemic cardiomyopathy, they improve LV function, effects apparently modulated in part by systemic anti-inflammatory activities.

A comparison of cangrelor, prasugrel, ticagrelor, and clopidogrel in patients undergoing percutaneous coronary intervention: A network meta-analysis.

BACKGROUND: Newer P2Y12 inhibitors have more rapid onset of platelet inhibition compared with clopidogrel, especially the intravenous P2Y12 inhibitor cangrelor. Direct comparisons between cangrelor and oral P2Y12 inhibitors ticagrelor and prasugrel do not exist. Thus, we performed a network meta-analysis to directly and indirectly compare different P2Y12 inhibitors in patients undergoing percutaneous coronary intervention (PCI). METHODS: MEDLINE/PubMed and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) that compared at least two P2Y12 inhibitors including cangrelor, clopidogrel, prasugrel, and ticagrelor. Network meta-analysis with a Bayesian approach was performed to directly and indirectly compare the effects of the aforementioned P2Y12 inhibitors on clinical outcomes. Odds ratios with credible intervals (OR [CrIs]) were generated with random-effects models to compare outcomes. RESULTS: This analysis included 15 RCTs with 54,025 patients randomized to cangrelor (n=12,475), clopidogrel (n=26,903), prasugrel (n=7455), or ticagrelor (n=7192) at time of PCI. Patients had a mean age of 63±10, 74% were male, and 82% underwent PCI for acute coronary syndrome. No significant differences between cangrelor and clopidogrel were found with respect to cardiovascular death (OR 1.01 [CrI 0.23-4.39]), myocardial infarction (OR 0.94 [CrI 0.69-1.25]), major adverse cardiac events (OR 0.91 [CrI 0.69-1.18]), stent thrombosis (OR 0.66 [CrI 0.37-1.19]), or major bleeding (OR 1.52 [CrI 0.79-2.98]). Rank probability data suggested that ticagrelor and prasugrel were better than cangrelor for reducing ischemic events, though these differences were not significant. CONCLUSION: Despite rapid platelet inhibition provided by cangrelor, newer oral P2Y12 inhibitors such as ticagrelor and prasugrel have comparable clinical outcomes.

Inflammation as a Driver of Adverse Left Ventricular Remodeling After Acute Myocardial Infarction.

Treatment of acute myocardial infarction (AMI) has improved significantly in recent years, but many patients have adverse left ventricular (LV) remodeling, a maladaptive change associated with progressive heart failure. Although this change is usually associated with large infarcts, some patients with relatively small infarcts have adverse remodeling, whereas other patients with larger infarcts (who survive the first several days after AMI) do not. This paper reviews the relevant data supporting the hypothesis that individual differences in the intensity of the post-AMI inflammatory response, involving 1 or more inflammatory-modulating pathways, may contribute to adverse LV remodeling. It concludes by outlining how individual variations in the inflammatory response could provide important novel therapeutic targets and strategies.

Multimodality imaging demonstrates trafficking of liposomes preferentially to ischemic myocardium.

INTRODUCTION: Nanoparticles may serve as a promising means to deliver novel therapeutics to the myocardium following myocardial infarction. We sought to determine whether lipid-based liposomal nanoparticles can be shown through different imaging modalities to specifically target injured myocardium following intravenous injection in an ischemia-reperfusion murine myocardial infarction model. METHODS: Mice underwent ischemia-reperfusion surgery and then either received tail-vein injection with gadolinium- and fluorescent-labeled liposomes or no injection (control). The hearts were harvested 24h later and underwent T1 and T2-weighted ex vivo imaging using a 7 Tesla Bruker magnet. The hearts were then sectioned for immunohistochemistry and optical fluorescent imaging. RESULTS: The mean size of the liposomes was 100nm. T1-weighted signal intensity was significantly increased in the ischemic vs. the non-ischemic myocardium for mice that received liposomes compared with control. Optical imaging demonstrated significant fluorescence within the infarct area for the liposome group compared with control (163±31% vs. 13±14%, p=0.001) and fluorescent microscopy confirmed the presence of liposomes within the ischemic myocardium. CONCLUSIONS: Liposomes traffic to the heart and preferentially home to regions of myocardial injury, enabling improved diagnosis of myocardial injury and could serve as a vehicle for drug delivery.

The use of statins in patients with heart failure: more questions than answers.

The use of statins to treat patients with heart failure (HF) is controversial due to conflicting results from large, prospective, randomized, placebo-controlled trials and other smaller studies. A recent comprehensive, well-conducted meta-analysis from Preiss and colleagues sought to determine whether statin therapy had an effect on major HF outcomes such as hospitalization and death. Although the study demonstrated a significant effect of statin therapy on HF hospitalizations, several limitations involving the participant data and nature of statin used in the analyzed trials raise questions about the inferences that can be drawn from the study results.