Long-term impact of diabetes in patients with ST-segment elevation myocardial infarction: Insights from the EXAMINATION randomized trial.

BACKGROUND: Long-term outcomes of diabetic patients suffering from ST-segment elevation myocardial infarction (STEMI) and treated with second-generation drug-eluting stent have been scarcely evaluated. The aim of this posthoc subanalysis of the EXAMINATION trial was to compare 5-year outcomes according to the presence of diabetes mellitus. METHODS: From a total of 1,497 patients included in the trial, 258 were diabetics (n = 137, received everolimus-eluting stent (EES) and n = 121 bare-metal stent (BMS); whereas 1,239 were nondiabetics (n = 613 treated with EES and n = 626 with BMS). Patient-oriented combined endpoint (POCE) defined as all-cause death, any MI or any revascularization, and other clinical parameters were collected up to 5-years. All results were adjusted for various potential confounders. RESULTS: At 5-years, patients with diabetes showed similar rates of POCE between diabetics treated with EES and those treated with BMS (32.8% vs. 32.2%; p = 0.88). However, rates of TLR were significantly lower in the EES group (4.4% vs. 9.9%; HR 0.52 (0.29-0.94); P = 0.03). In non-diabetics, the use of EES was associated with a significant improvement in all-clinical parameters except for MI rate: POCE: [10.0% vs. 12.6%; HR 0.78(0.62-0.98); P = 0.038], all cause death: [7.0% vs. 12.1%; HR 0.62(0.42-0.90); P = 0.014], and [TLR: 4.2 vs. 6.7; HR 0.60 (0.37-0.98); P = 0.04]. Overall, diabetics showed higher rate of POCE at 5-years (32.6% vs. 21.5% in nondiabetics HR1.45[1.03-2.04];p = 0.03) driven by increased rates of MI and the need for revascularization that occurred in coronary segments remote from target lesions [2.7% vs. 1.1%; HR: 2.27 (1.12-5.23); P = 0.02 and 14% vs. 6.2%; HR: 2.11 (1.38-3.22); P = 0.001, respectively]. CONCLUSIONS: Diabetics had worse clinical outcomes than nondiabetics after STEMI mainly due to atherosclerosis progression. At 5-years, the treatment with EES did not reduce the rate of POCE in diabetics but reduced the need for revascularization compared with BMS.

Reperfusion-triggered stress protein response in the myocardium is blocked by post-conditioning. Systems biology pathway analysis highlights the key role of the canonical aryl-hydrocarbon receptor pathway.

AIMS: Ischaemic post-conditioning (IPost-Co) exerts cardioprotection by diminishing ischaemia/reperfusion injury. Yet, the mechanisms involved in such protection remain largely unknown. We have investigated the effects of IPost-Co in cardiac cells and in heart performance using molecular, proteomic and functional approaches. METHODS AND RESULTS: Pigs underwent 1.5 h mid-left anterior descending balloon occlusion and then were sacrificed without reperfusion (ischaemia; n= 7), subjected to 2.5 h of cardiac reperfusion and sacrificed (n= 5); or subjected to IPost-Co before reperfusion and sacrificed 0.5 h (n= 4) and 2.5 h (n= 5) afterwards. A sham-operated group was included (n= 4). Ischaemic and non-ischaemic myocardium was obtained for molecular/histological analysis. Proteomic analysis was performed by two-dimensional electrophoresis followed by matrix-assisted laser desorption/ionization-time-of-flight identification. Potential protein networks involved were identified by bioinformatics and Ingenuity Pathway Analysis (IPA). Cardiac function was assessed by echocardiography. IPost-Co diminished (up to 2.5 h) reperfusion-induced apoptosis of both the intrinsic and extrinsic pathways whereas it did not affect reperfusion-induced Akt/mammalian target of rapamycin (mTOR)/P70S6K activation. Proteomic studies showed that IPost-Co reverted 43% of cardiac cytoplasmic protein changes observed during ischaemia and ischaemia + reperfusion. Systems biology assessment revealed significant changes in the aryl-hydrocarbon receptor (AhR) pathway (cell damage related). Bioinformatic data were confirmed since the expression of HSP90, AhR, ANRT, and ß-tubulin (involved in AhR-signalling transduction) were accordingly modified after IPost-Co. IPost-Co rescued 52% of the left ventricle-at-risk compared with reperfusion alone and resulted in a ≈30% relative improvement in left ventricular ejection fraction (P <0.05). CONCLUSION: IPost-Co improves cardiac function post-myocardial infarction and reduces reperfusion-induced cell damage by down-regulation of the AhR-signalling transduction pathway ultimately leading to infarct size reduction.

Linking In Vitro Models of Endothelial Dysfunction with Cell Senescence.

Endothelial cell dysfunction is the principal cause of several cardiovascular diseases that are increasing in prevalence, healthcare costs, and mortality. Developing a standardized, representative in vitro model of endothelial cell dysfunction is fundamental to a greater understanding of the pathophysiology, and to aiding the development of novel pharmacological therapies. We subjected human umbilical vein endothelial cells (HUVECs) to different periods of nutrient deprivation or increasing doses of H2O2 to represent starvation or elevated oxidative stress, respectively, to investigate changes in cellular function. Both in vitro cellular models of endothelial cell dysfunction-associated senescence developed in this study, starvation and oxidative stress, were validated by markers of cellular senescence (increase in ß-galactosidase activity, and changes in senescence gene markers SIRT1 and P21) and endothelial dysfunction as denoted by reductions in angiogenic and migratory capabilities. HUVECs showed a significant H2O2 concentration-dependent reduction in cell viability (p < 0.0001), and a significant increase in oxidative stress (p < 0.0001). Furthermore, HUVECs subjected to 96 h of starvation, or exposed to concentrations of H2O2 of 400 to 1000 µM resulted in impaired angiogenic and migratory potentials. These models will enable improved physiological studies of endothelial cell dysfunction, and the rapid testing of cellular efficacy and toxicity of future novel therapeutic compounds.

Erythrocyte-heme proteins and STEMI: implications in prognosis.

The role of erythrocytes in thrombus formation has been often neglected, but some studies have highlighted their active role in thrombotic events. Free-haemoglobin (Hb) has shown to induce oxidative-stress damage. Herein we have investigated the coordinated changes in heme-related proteins in patients with acute-coronary-syndromes (ACS), their association to ongoing thrombosis and their impact on patients' prognosis. The serum proteome of STEMI-patients (N=27) within the first 6h after event-onset and 3d after were compared to controls (N=60). Changes in heme-metabolism were characterized in a second STEMI-group by a dual proteomic approach analyzing in-vivo aspirated coronary thrombi at PCI (N=24) and the associated peripheral-blood changes (N=10). A third STEMI-group (N=132) was studied to analyze the impact of the observed changes in prognosis at 6-months-follow-up. The haptoglobin/hemopexin(Hpg/Hpx)-scavenging-system revealed a time-dependent response after STEMI with an early increase in Hpg circulating levels in the acute phase (P=0.01) and a late increase in Hpx levels 3d after (P=0.045). Beta-Hb content in coronary thrombi was directly correlated with systemic beta-Hb and Hpg (R=0.804,P=0.0029; R=0.859,P=0.0007) levels. The presence of a fully-occlusive thrombus was associated to higher circulating levels of beta-Hb (P=0.03) and unbound-Hpg (P=0.03). ELISA validation demonstrated a decreased survival rate at 6-months follow-up in STEMI-patients with lower Hpg plasma levels at admission (P=0.027). Our results show active Hb-release form erythrocytes in ACS. This release is followed by a systemic early increase in Hpg levels and a late increase in Hpx levels that can co-ordinately help to prevent systemic pro-oxidative effects. The Hb-scavenging ability of haptoglobin is related to patients' prognosis.

2015 ESC Guidelines for the Diagnosis and Management of Pericardial Diseases.

Full text available at: http://eurheartj.oxfordjournals.org/content/early/2015/08/28/eurheartj.ehv318.

Effectiveness and safety beyond 10 years of percutaneous transluminal septal ablation in hypertrophic obstructive cardiomyopathy.

INTRODUCTION AND OBJECTIVES: Percutaneous transluminal septal ablation is an alternative treatment in patients with hypertrophic obstructive cardiomyopathy. However, due to the relatively new introduction of this technique, there is no information on its very long term results (>10 years). METHODS: The present study included consecutive patients treated in 5 centers between 1998 and 2003. We analyzed clinical, hemodynamic, and echocardiographic data at baseline and follow-up. RESULTS: A total of 45 patients were included; there were 31 (69%) women, the mean age was 62.4 (14) years, and 39 patients (86.6%) showed functional class III or IV. Septal thickness was 21.8 (3.5) mm, the peak resting gradient on echocardiography was 77 (39) mmHg, and mitral regurgitation was at least moderate in 22 patients (48.8%). During hospitalization, permanent pacemaker implantation was required in 3 patients and ventricular perforation (by pacing lead) occurred in 1 patient, requiring surgery. After a follow-up of 12.3 years (11.0-13.5 years), 2 patients (4.4%) died from cardiac causes (heart failure and posttransplantation), 3 patients required an implantable cardioverter-defibrillator (1 for primary prevention and 2 due to sustained ventricular tachycardia after cardiac surgery), and 2 underwent cardiac surgery (due to endocarditis and mitral regurgitation). In the last clinical review, functional class was I-II in 39 patients (86.6%) (P<.0001), the peak resting gradient was 16 (23) mmHg (P<.0001), and mitral regurgitation was absent or mild in 34 patients (75.5%) (P<.03). CONCLUSIONS: The results of this study suggest that septal ablation is safe and effective in the very long term. The procedure was not associated with a significant incidence of sudden death or symptomatic ventricular arrhythmias.

High-molecular-weight kininogen and the intrinsic coagulation pathway in patients with de novo acute myocardial infarction.

After an acute ischaemic event serum proteins may change reflecting the ischaemic damage. Proteomic studies could provide new insights into potential biomarkers in the evolution of ischaemic syndromes. In this study we have investigated the coordinated changes in coagulation-related proteins in the evolution after an acute myocardial infarction (AMI). Serum proteome (2D-electrophoresis and MALDI-TOF/TOF) of AMI-patients within the first 6 hours after event onset (admission-time) and 3 days after were compared to controls. Systems biology and bioinformatic analysis were performed to identify the differentially expressed canonical pathways. In silico analysis of differential proteins revealed changes in the intrinsic coagulation pathway in the early phase post-AMI. The two identified high-molecular weight kininogen (HMWK) clusters were inversely correlated in AMI patients at admission, being the intensity of the low-molecular-weight form inversely related to myocardial necrosis (p<0.05). Factor XI (FXI) levels were decreased in AMI patients at admission and normalised 3 days after (p<0.05). There was an early increase in fibrinogen gamma and D-dimer at admission, followed by a decrease in fibrinogen turnover 3 days after (p<0.05). The influence of elapsed time of ischaemia on fibrinogen distribution changes was validated in coronary thrombi retrieved by thromboaspiration. In conclusion, our results demonstrate an active exchange between HMWK forms and a decrease in FXI indicative of intrinsic pathway activation, together with an increase in fibrinogen gamma turnover and D-dimer formation in the early phase post-AMI. Moreover, coronary thrombi showed a dynamic evolution in fibrinogen composition depending on the duration of ischaemia influencing serum fibrinogen-related products content.

Update on interventional cardiology.

This article provides a detailed review of the most important studies on interventional cardiology reported in publications or presentations during the year 2012. With regard to coronary interventions, ST-elevation myocardial infarction is extensively addressed in studies focusing on the relevance of reducing the reperfusion time and the utility of various devices and pharmacological strategies in primary angioplasty. Multiple comparative studies involving different generations of drug-eluting stents are available and indicate a favorable progression in terms of safety and efficacy. The risk of late thrombosis with the new generations of drug-eluting stents seems to be equivalent to that observed with bare-metal stents. The clinical outcomes with these stents in the elderly, in left main coronary artery, or in multivessel disease have also been the subject of important trials. Among the studies on intracoronary diagnostic techniques, those correlating imaging and pressure-based techniques are of special interest. The percutaneous treatment of structural heart disease, particularly transcatheter aortic valve implantation, followed by mitral repair, continues to be the subject of a great number of publications. Finally, renal denervation is currently being widely discussed in the literature.