Precise Metabolomics Defines Systemic Metabolic Dysregulation Distinct to Acute Myocardial Infarction Associated With Diabetes.

BACKGROUND: Acute myocardial infarction (AMI) is a leading cause of death and disability. Diabetes is an important risk factor and a common comorbidity in AMI patients. The higher mortality risk of diabetes-AMI relative to nondiabetes-AMI indicates a need for specific treatment to improve clinical outcome. However, the global metabolic dysregulation of AMI complicated with diabetes is still unclear. We aim to systematically interrogate changes in the metabolic microenvironment immediate to AMI episodes in the absence or presence of diabetes. METHODS: In this work, quantitative metabolomics was used to investigate plasma metabolic differences between diabetes-AMI (n=59) and nondiabetes-AMI (n=59) patients. A diverse array of perturbed metabolic pathways involving carbohydrate metabolism, lipid metabolism, glycolysis, tricarboxylic acid cycle, and amino acid metabolism emerged. RESULTS: In all, our omics-oriented approach defined a metabolic signature of afflicted mitochondrial function aggravated by concurrent diabetes in AMI patients. In particular, our analyses uncovered N-lactoyl-phenylalanine and lysophosphatidylcholines as key functional metabolites that skewed the metabolic picture of diabetes-AMI relative to nondiabetes-AMI. N-lactoyl-phenylalanine was strongly associated with metabolic indicators reflective of mitochondrial overload and negatively correlated with HbA1c (glycosylated hemoglobin, type A1C) specifically in hyperglycemic AMI, suggestive of its central role in glucose utilization and mitochondrial energy production instrumental to the clinical outcome of diabetes-AMI. Reductions in lysophosphatidylcholines, which were negatively correlated with blood glucose and inflammatory markers, might further compromise glucose expenditure and aggravate inflammation leading to poorer prognosis in diabetes-AMI. CONCLUSIONS: As circulating metabolite levels are amenable to therapeutic intervention, such shifts in metabolic signatures provide new clues and potential therapeutic targets specific to the treatment of diabetes-AMI.

Dynamic Changes in Plasma Urotensin II and Its Correlation With Plaque Stability.

ABSTRACT: Urotensin II (UII) is involved in the formation of atherosclerosis, but its role in the stability of atherosclerotic plaques is unknown. The purpose of this study was to observe the dynamic changes in plasma UII and analyze its relationship to the stability of atherosclerotic plaques. One hundred thirty-five consecutive patients with acute coronary syndrome (ACS) were enrolled. The plasma UII levels were measured immediately after admission and during three-month follow-up. A vulnerable plaque model was established using local transfection of a recombinant P53 adenovirus into plaques in rabbits fed with a high-cholesterol diet and subjected to balloon arterial injury. The levels of plasma UII were measured weekly. The changes in plasma UII during the formation of atherosclerotic plaques and before and after plaque transfection were observed. The morphology of the plaques and the expression, distribution, and quantitative expression of UII in the plaques also were observed. Our results showed that the levels of plasma UII in patients with ACS at admission were lower than levels observed at the three-month follow-up. UII dynamic changes and its correlation with plaque stabilities were further verified in rabbits with atherosclerotic vulnerable plaques. The UII levels in rabbits were significantly decreased immediately after the P53 gene transfection, which led to plaque instability and rupture. These results suggested that UII expression was down-regulated in ACS, which may be related to its ability to modulate mechanisms involved in plaque stability and instability.

Comparative Biomechanical Behavior and Healing Profile of a Novel Thinned Wall Ultrahigh Molecular Weight Amorphous Poly-l-Lactic Acid Sirolimus-Eluting Bioresorbable Coronary Scaffold.

BACKGROUND: Mechanical strength of bioresorbable scaffolds (BRS) is highly dependent on strut dimensions and polymer features. To date, the successful development of thin-walled BRS has been challenging. We compared the biomechanical behavior and vascular healing profile of a novel thin-walled (115 µm) sirolimus-eluting ultrahigh molecular weight amorphous poly-l-lactic acid-based BRS (APTITUDE, Amaranth Medical [AMA]) to Absorb (bioresorbable vascular scaffold [BVS]) using different experimental models. METHODS AND RESULTS: In vitro biomechanical testing showed no fractures in the AMA-BRS when overexpanded 1.3 mm above nominal dilatation values (≈48%) and lower number of fractures on accelerated cycle testing over time (at 21 K cycles=20.0 [19.5-20.5] in BVS versus 4.0 [3.0-4.3] in AMA-BRS). In the healing response study, 35 AMA-BRS and 23 BVS were implanted in 58 coronary arteries of 23 swine and followed-up to 180 days. Scaffold strut healing was evaluated in vivo using weekly optical coherence tomography analysis. At 14 days, the AMA-BRS demonstrated a higher percentage of embedded struts (71.0% [47.6, 89.1] compared with BVS 40.3% [20.5, 63.2]; P=0.01). At 21 days, uncovered struts were still present in the BVS group (3.8% [2.1, 10.2]). Histopathology revealed lower area stenosis (AMA-BRS, 21.0±6.1% versus BVS 31.0±4.5%; P=0.002) in the AMA-BRS at 28 days. Neointimal thickness and inflammatory scores were comparable between both devices at 180 days. CONCLUSIONS: A new generation thinned wall BRS displayed a more favorable biomechanical behavior and strut healing profile compared with BVS in normal porcine coronary arteries. This novel BRS concept has the potential to improve the clinical outcomes of current generation BRS.

[Midterm follow-up outcomes of ticagrelor on acute ST segment elevation myocardial infarction undergoing emergency percutaneous coronary intervention].

OBJECTIVE: To evaluate the safety and efficacy of antiplatelet therapy of ticagrelor on patients suffering from acute ST segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. METHODS: In the study, 96 patients suffering from acute ST segment elevation myocardial infarction onset within 12 h undergoing primary percutaneous coronary intervention from May to October in 2013 were randomly divided into ticagrelor group (n=48) and clopidogrel group (n=48) by using the method of random number table. Ticagrelor and clopidogrel antiplatelet treatment were used before and after operation. Their baseline data, coronary artery disease characteristics, platelet count, adenosine diphosphate(ADP)-induced platelet inhibition rate by thrombelastograph after 5 days of treatment, the major adverse cardiovascular events of the follow up for 6 months and bleeding complications were observed and compared in the two groups. RESULTS: The differences between the two groups of patients with their baseline data, the features of coronary artery lesions, platelet count before and after 5 days of treatment had no statistical significance (P>0.05). ADP induced platelet inhibition rate [(80.2±10.7)%] after 5 days of treatment in ticagrelor group was significantly higher than that in clopidogrel group [(75.3±12.1)%, P<0.05]. The two groups of patients were followed up for 6 months, 8 cases of major adverse cardiovascular events occurred in clopidogrel group, 2 cases of major adverse cardiovascular events occurred in ticagrelor group, and there was significant difference between the two groups (P<0.05). The two groups (7 cases of 48 patients in ticagrelor group vs. 3 cases of 48 patients in clopidogrel group) had no statistically significant difference in bleeding complications (P>0.05). CONCLUSION: Antiplatelet therapy of ticagrelor on patients suffering from acute ST segment elevation myocardial infarction undergoing emergency PCI has good efficacy and safety.

[Cardioprotective effect and mechanism of intensive lipid modulation on patients with coronary artery disease undergoing noncardiac surgery].

OBJECTIVE: To explore the protective effect and possible mechanism of intensive lipid modulation on the perioperative period of patients with stable coronary artery disease undergoing noncardiac surgery. METHODS: In the study, 60 patients with stable coronary artery disease undergoing elective noncardiac surgery were randomly divided into intensive lipid modulation group (n = 30) and conventional group (n = 30). In intensive lipid modulation group, the patients were given atorvastatin 40 mg every night before surgery, 80 mg 12 h before surgery, and 40 mg 2 h before surgery, and 40 mg every night after noncardiac surgery. In conventional group, the patients were given atorvastatin 20 mg every night before surgery and also after the surgery. The occurrence of perioperative major adverse cardiac events (including sudden cardiac death, acute myocardial infarction, unplanned revascularization) were compared in the two groups. Preoperative and 48 h postoperative changes of lipid levels and inflammatory markers were also compared in the two groups. RESULTS: In conventional group, one patient suffered myocardial infarction with acute anterior ST-segment elevation and was given emergency left anterior descending artery interventional reperfusion therapy, and 7 patients suffered asymptomatic myocardial infarction. In intensive lipid modulation group, one patient suffered asymptomatic myocardial infarction, and the incidence rate of perioperative acute myocardial infarction reduced significantly compared with conventional group (P < 0.05). There was no significant difference in preoperative and postoperative changes of lipid levels in the two groups (P > 0.05), and compared with conventional group, there was significantly lower levels of inflammatory markers in intensive lipid modulation group (P < 0.05). CONCLUSION: The intensive lipid modulation group significantly reduced the incidence of perioperative major adverse cardiac events especially asymptomatic myocardial infarction, and the inhibition of the inflammatory response may be one of the protective mechanisms, which still needs to be further confirmed by large multicenter randomized controlled clinical trials.

Atorvastatin post-conditioning attenuates myocardial ischemia reperfusion injury via inhibiting endoplasmic reticulum stress-related apoptosis.

The present study examined whether atorvastatin, when used for pharmacological postconditioning, attenuated myocardial ischemia-reperfusion (I/R) injury in a manner similar to ischemic postconditioning (I-PostC), that is, by inhibition of endoplasmic reticulum (ER) stress-related apoptosis. In the present study, markers for myocardial injury, infarct area, and hemodynamics, and indicators of ER stress and apoptosis were compared in ischemic and atorvastatin-induced postconditioning as a means of evaluating the protective effect of atorvastatin postconditioning in I/R injury and whether, as in I-PostC, inhibition of ER stress is involved. Both ischemic and atorvastatin-mediated postconditioning significantly decreased indications of cardiac damage and reduced serum concentrations of markers for myocardial injury, reduced the infarct area seen at the end of reperfusion, and improved left ventricular systolic function. We found that high-dose atorvastatin- and I-PostC significantly downregulated expression of glucose-regulating protein 78 and calreticulin (CRT; ER stress markers), expression of C/EBP homologous protein (CHOP), and caspase 12 (markers for ER stress-related apoptosis), and Bax (downstream molecule of CHOP), in the myocardial area at risk. Atorvastatin and I-PostC have similar cardioprotective effects in I/R injury and inhibit the ER stress-related apoptotic pathway.

Short-term follow-up of tirofiban as alternative therapy for urgent surgery patients with an implanted coronary drug-eluting stent after ST-elevation myocardial infarction.

BACKGROUND: Patients with a recently diagnosed ST-elevation myocardial infarction (STEMI) and implanted coronary drug-eluting stent (DES) who need urgent surgery are at increased risk of surgical bleeding unless aspirin and clopidogrel are discontinued beforehand. However, discontinuation of aspirin and clopidogrel is associated with a high rate of recurrent myocardial infarction, heart failure, and malignant arrhythmias because of stent thrombosis. The main point of debate is how to treat these patients. We hypothesized that perioperative intravenous administration of tirofiban, a GPIIb/IIIa inhibitor, would allow the safe withdrawal of aspirin and clopidogrel without increasing the risk of surgical bleeding. METHODS: Twenty-one patients implanted with a coronary DES after STEMI who underwent urgent surgery were selected for this clinical trial. Tirofiban was used to replace aspirin and clopidogrel (dual antiplatelet drugs) before and after urgent surgery. Major adverse cardiovascular and bleeding events were observed during hospitalization and within 3 months of discharge. RESULTS: Twenty-one patients with recently diagnosed STEMI and implanted DES [median (range) 6 (3-8) months] and high-risk characteristics for stent thrombosis underwent urgent major surgery. Tirofiban was used to replace aspirin and clopidogrel 5 days before surgery, stopped 4 h before surgery, and resumed until oral aspirin and clopidogrel was resumed after surgery. There were no deaths, myocardial infarction, stent thrombosis, or surgical re-exploration because of bleeding during hospitalization and within 3 months of discharge. There was one case of acute left ventricular failure during hospitalization. CONCLUSION: In patients who need urgent surgery after recently diagnosed STEMI and implanted DES, a strategy using tirofiban may allow temporary withdrawal of dual antiplatelet drugs without increasing the risk of bleeding. This conclusion needs to be further confirmed by large-scale randomized clinical trials.