Krzysztof Żmudka

Mechanisms of oxidative stress in human aortic aneurysms — Association with clinical risk factors for atherosclerosis and disease severity

Aortic abdominal aneurysms (AAA) are important causes of cardiovascular morbidity and mortality. Oxidative stress may link multiple mechanisms of AAA including vascular inflammation and increased metalloproteinase activity. However, the mechanisms of vascular free radical production remain unknown. Accordingly, we aimed to determine sources and molecular regulation of vascular superoxide (O2•−) production in human AAA. Methods and results AAA segments and matched non-dilated aortic samples were obtained from 40 subjects undergoing AAA repair. MDA levels (determined by HPLC/MS) were greater in plasma of AAA subjects (n = 16) than in risk factor matched controls (n = 16). Similarly, superoxide production, measured by lucigenin chemiluminescence and dihydroethidium fluorescence, was increased in aneurysmatic segments compared to non-dilated aortic specimens. NADPH oxidases and iNOS are the primary sources of O2•− in AAA. Xanthine oxidase, mitochondrial oxidases and cyclooxygenase inhibition had minor or no effect. Protein kinase C inhibition had no effect on superoxide production in AAA. NADPH oxidase subunit mRNA levels for p22phox, nox2 and nox5 were significantly increased in AAAs while nox4 mRNA expression was lower. Superoxide production was higher in subjects with increased AAA repair risk Vanzetto score and was significantly associated with smoking, hypercholesterolemia and presence of CAD in AAA cohort. Basal superoxide production and NADPH oxidase activity were correlated to aneurysm size. Conclusions Increased expression and activity of NADPH oxidases are important mechanisms underlying oxidative stress in human aortic abdominal aneurysm. Uncoupled iNOS may link oxidative stress to inflammation in AAA. Oxidative stress is related to aneurysm size and major clinical risk factors in AAA patients.

Extent of RV Dysfunction and Myocardial Infarction Assessed by CMR Are Independent Outcome Predictors Early After STEMI Treated With Primary Angioplasty

OBJECTIVES The aim of this study was to assess the prognostic value of right ventricular (RV) involvement diagnosed by cardiac magnetic resonance (CMR) early after ST-elevation myocardial infarction (STEMI). BACKGROUND CMR allows accurate and reproducible RV assessment. However, there is a paucity of data regarding the prognostic value of RV involvement detected by CMR early after STEMI. METHODS Ninety-nine patients (77 men, mean age 57 ± 11 years) who underwent CMR 3 to 5 days after STEMI treated with primary angioplasty were followed for 1,150 ± 337 days for cardiac events (cardiac death, nonfatal myocardial infarction [MI], and hospitalizations due to decompensated heart failure). Cox proportional hazards model was applied in stepwise forward fashion to identify outcome predictors. Event-free survival was estimated by Kaplan-Meier method and compared between groups by the log-rank test. RESULTS Cardiac events occurred in 34 patients (7 cardiac deaths, 8 MIs, 26 hospitalizations). By multivariable analysis, the independent outcome predictors were left ventricular (LV) MI transmurality index (hazard ratio: 1.03 per 1%; 95% confidence interval: 1.01 to 1.04; p = 0.001), RV ejection fraction (RVEF) (hazard ratio: 1.46 per 10% decrease; 95% confidence interval: 1.05 to 2.02; p = 0.03), and RVMI extent (hazard ratio: 1.50 per each infarcted RV segment; 95% confidence interval: 1.11 to 2.01; p = 0.007). Compared with clinical data (global chi-square = 5.2), LV ejection fraction [LVEF] (global chi-square = 11.1), RVEF (global chi-square = 17.1), LVMI transmural extent (global chi-square = 26.0), and RVMI extent (global chi-square = 34.9) improved outcome prediction in sequential Cox model analysis (p < 0.05 for all steps). RVEF stratified risk in patients with LVEF <40% in whom the 4-year event-free survival was 66.7% for RVEF ≥40% and 40.0% for RVEF <40% (p < 0.05). CONCLUSIONS The extent of RVMI and RV dysfunction assessed early after STEMI are independent outcome predictors, which provide incremental prognostic value to clinical data, LV systolic function, and infarct burden. Measurement of RVEF may be particularly useful to stratify risk in patients with depressed LV function after STEMI.

Number of Microparticles Generated During Acute Myocardial Infarction and Stable Angina Correlates with Platelet Activation

BACKGROUND AND AIMS Elevated levels of circulating microparticles (MPs) have been reported in patients with acute myocardial infarction (AMI) and coronary artery disease. Platelet activation and inflammation have been recognized during AMI and stable angina (SA). We hypothesize that the origin and count of MPs in AMI and SA patients are related to markers of inflammation and platelet activation. METHODS Platelet, monocytes and endothelial MPs and surface P-selectin were determined in 12 AMI patients, 10 SA patients and 9 controls by flow cytometry. Plasma P-selectin, CD40 ligand (sCD40L) and interleukin 6 (IL-6) levels were evaluated by ELISA methods. RESULTS The total MP count was compared in control subjects, AMI, and SA patients: 12,765 (8465) vs. 38,750 (11,931) vs. 29,715 (12,072) counts/μl (p = 0.01), respectively. Patients with AMI displayed higher levels of total and platelet origin- tissue factor-positive (CD42/CD142) MPs than patients with SA: 72.8 (6.2) vs. 56.2 (6.4) %, p = 0.001. Levels of soluble P-selectin were significantly elevated in patients with AMI as compared to SA patients: 146 (6.5) vs. 107 (2.7) ng/mL, p = 0.005; significant correlation between total MP count and relative number of CD34, CD51, CD42-positive MPs, and the P-selectin expression was observed in patients with AMI. CONCLUSIONS Platelet activation in AMI is associated with increased generation of MPs not only from platelets, but also monocytes and endothelial cells. It suggests that interactions between platelets, monocytes and endothelial cells play an important role in the pathogenesis of myocardial ischemia.

Facilitated percutaneous coronary intervention in patients with acute myocardial infarction transferred from remote hospitals

P percutaneous coronary intervention (PCI) is the preferred therapy for myocardial infarction (MI) in centers that have access to immediate invasive treatment because it confers higher patency rates, lower mortality, and lower intracranial hemorrhage rates than fibrinolysis alone.1–3 Current guidelines suggest that primary PCI could be offered as an alternative to thrombolytic therapy if performed by experienced operators within 90 30 minutes after admission.4 Recent studies have suggested that PCI for MI is superior to thrombolysis even if treatment is delayed by 120 minutes by transferring the patient to an interventional center.5,6 However, delay in restoring myocardial blood flow is known to adversely impact long-term outcome.7 If safe and feasible, restoration of myocardial blood flow by thrombolytic therapy during transfer would make longer transfer times to primary PCI acceptable without compromising myocardial salvage. In the present study we tested a combined therapy of a reduced dose of fibrinolytic drug and glycoprotein IIb/IIIa inhibitor during transfer of patients with acute MI from remote community hospitals to a routine emergency angiographic center and possible invasive treatment of MI. • • • The study was approved by the institutional review board and patients gave informed consent. Patients were enrolled at the community hospitals if: (1) they presented with an acute MI (onset of chest pain 12 hours earlier and ST elevation 1 mm in 2 contiguous electrocardiographic leads) to the emergency department of a hospital without a catheterization laboratory; (2) they had no contraindications to thrombolytic therapy and were 75 years of age; and (3) if anticipated transfer time to an interventional center was 90 minutes. Two hundred eligible patients received an IV bolus of 60 U/kg heparin (maximum 5,000), 15 mg alteplase, and 0.25 mg/kg abciximab at the remote center and were transferred, in the presence of a physician, to a single tertiary referral center for diagnostic angiography and possible PCI. Demographic data and time intervals between different stages of patient care are listed in Table 1. Infusion of alteplase (35 mg/60 min) was continued during transfer. Infusion of abciximab From the Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland. This study was financed entirely by the National Health Care Agency of Poland, Krakow Regional Division, as a part of the program to improve early detection and treatment of myocardial infarction in that region of Poland. Dr. Dudek’s address is: 2nd Department of Cardiology, Kopernika Str.17, 31-501 Krakow, Poland. E-mail: mcdudek@cyf-kr.edu.pl. Manuscript received July 8, 2002; revised manuscript received and accepted August 30, 2002. TABLE 1 Baseline Demographics, Risk Factors, Clinical Characteristics, and Time Intervals Between Different Stages of Patient Care

Atherosclerosis progression affects the relationship between endothelial function and aortic stiffness

Aortic stiffening is the most important determinant of elevated systolic blood pressure which in turn is the main contributor to the burden of disease attributable to hypertension. Endothelial function may affect arterial stiffening as has been shown for carotid-aorto-femoral segments in healthy humans or subjects with cardiovascular risk factors. We investigated whether this association is present selectively for aorta and whether it extends to patients with advanced atherosclerosis. Direct measurements of aortic pulse wave velocity (aPWV) to assess aortic stiffness and brachial artery flow-mediated dilatation (bFMD) tests to assess endothelial function were performed in 111 consecutive patients suspected of coronary artery disease. Progression of atherosclerosis was determined on the basis of the presence or absence of significant coronary artery stenosis, CAS (>or=50%) in angiography. bFMD was lower (P<0.001) and aPWV was higher (P<0.001) in a group of 72 patients with advanced atherosclerosis when compared with a group of 39 patients without significant CAS. bFMD was inversely associated with aPWV but only in patients without advanced atherosclerosis (r=-0.37, P=0.02), even after adjustment of confounding factors in a multivariate analysis model (R(2)=0.37, P<0.001). We concluded that endothelial function may influence aortic stiffness which is limited however by the progression of atherosclerosis.

Ten-year experience of an invasive cardiology centre with out-of-hospital cardiac arrest patients admitted for urgent coronary angiography.

BACKGROUND AND AIM The aim of the study was to evaluate survival and neurological function of out-of-hospital cardiac arrest (OHCA) patients admitted for urgent coronary angiography (UCA) with a view to percutaneous coronary intervention (PCI). METHODS Hospital records of OHCA patients admitted to an invasive cardiology centre (providing 24 h a day/7 days a week service) in 2000-2010 were reviewed retrospectively, and similar data collected in 2011 were reviewed prospectively. Reports from the pre-hospital phase from emergency medical services (EMS) in Krakow were also analysed. Long-term follow-up data were collected by retrieving records from other hospitals (for patients transferred after UCA/PCI) and by phone calls to patients or their relatives. RESULTS In 2000-2011, 405 OHCA patients were admitted for UCA/PCI. Most (78%) had ventricular fibrillation (VF) or ventricular tachycardia (VT) as the primary mechanism of cardiac arrest (asystole: 13%, pulseless electrical activity: 3%, unknown: 6%). The mean patient age was 61 (range 20-85) years, and 81% were males. On admission, about 70% of patients were unconscious and 11% were in cardiogenic shock. The mean resuscitation time (time to return of spontaneous circulation [ROSC]) was 26.7 (range 1-126) min. ST-T changes seen in an electrocardiogram recorded after ROSC included ST elevation and depression in 52% of cases, only ST depression in 21% of cases, only ST elevation in 17% of cases, unspecific changes (due to intraventricular conduction disturbances) in 7% of cases, negative T waves in 3% of cases, and no changes in 0.5% of cases. Coronary angiography revealed acute coronary occlusion in 48% of cases, critical coronary stenosis (> 90%) in 26% of cases, other significant coronary lesions (> 50% stenosis) in 15% of cases, and non-significant lesions in 11% of cases. An acute coronary syndrome (ACS) was diagnosed in 82% of patients (75% STEMI, 25% NSTEMI), and other cardiac cause (mostly ischaemic cardiomyopathy) was identified in 13% of patients. Among OHCA patients diagnosed with ACS, PCI was performed in 90% and additional 4% underwent coronary artery bypass grafting. Overall success rate of PCI, defined as TIMI 3 flow plus residual stenosis < 50% and resolution of ST elevation after PCI by > 30%, was 70%. Survival to hospital discharge in the entire group of OHCA patients was 63% and 30-day survival with good neurological outcomes (defined as Cerebral Performance Category 1 or 2) was 49%. Among patients who were initially unconscious, those figures were 52% and 33%, respectively. During long-term follow-up (up to 12 years), 49% of patients were alive and 42% had good neurological function (87% of those who survived). In multivariate analysis, independent predictors of survival with good neurological outcomes were preserved consciousness on admission, absence of shock, cardiac arrest witnessed by medical personnel, VF/VT as a primary mechanism of cardiac arrest, and preserved renal function. Successful PCI predicted survival until hospital discharge only when the neurological status of the patients was not taken into account. CONCLUSIONS The most important cause of OHCA is coronary artery disease, in particular ACS. UCA and PCI seem to be important elements of appropriate post-resuscitation care because such treatment could improve survival but it is still unclear whether PCI might influence neurological outcomes as well.

Acute and long-term outcomes of percutaneous balloon aortic valvuloplasty for the treatment of severe aortic stenosis.

This study aimed to evaluate the indications, short‐ and long‐term outcomes of balloon aortic valvuloplasty (BAV) in patients with severe aortic stenosis (AS).

Long-term follow-up of mesh-covered stent implantation in patients with ST-segment elevation myocardial infarction

BACKGROUND The MGuard stent (a bare-metal stent wrapped externally in a polymer mesh sleeve) was introduced to reduce the risk of distal embolisation and no-reflow phenomenon during percutaneous coronary intervention (PCI) in thrombus containing lesions, including ST-segment elevation myocardial infarction (STEMI). However, data on the long-term performance of the MGuard stent is limited. AIM To assess the long-term safety and efficacy of MGuard stent implantation during primary PCI for STEMI. METHODS AND RESULTS In this multicentre study, a total of 60 patients with STEMI ≤12 h treated with the MGuard stent were enrolled. Angiographic success of PCI was achieved in 96.7%, with the final TIMI grade 3 flow in 90.0% of patients. At six months, the overall rate of major adverse cardiac and cerebrovascular events (MACCE; composite of cardiac death, nonfatal target vessel reinfarction, target lesion revascularisation, and stroke) was 1.7%. A long-term follow-up of the study was successfully performed in 57 patients (mean follow-up of 38.7 ± 3.1 months). The long-term cardiac mortality was 7.0%, with a MACCE rate of 8.8%. There was no decrease in the left ventricular ejection fraction and no enlargement of the left ventriclebetween index and long-term follow-up echocardiogram. CONCLUSIONS The early safety and efficacy of the MGuard stent was maintained during the long-term follow-up. However, comparative data from ongoing randomised clinical trials are still required to confirm the long-term efficacy of MGuard stent implantation in patients with STEMI.

Dose escalation trial of the efficacy, safety, and pharmacokinetics of a novel fibrinolytic agent, BB-10153, in patients with ST elevation MI: Results of the TIMI 31 trial

Background: Currently available fibrinolytic agents are limited by their ability to restore normal blood flow in only half of patients, the risk of reocclusion, and the risk of intracranial hemorrhage. The genetically engineered agent BB-10153 is activated by thrombin, not plasminogen activator enzymes, which limits its activity to the site of thrombus which may in turn reduce the risk of systemic bleeding. BB-10153 also has a relatively long half-life of 3–4 hours, which may also limit the potential for early reocclusion [1, 2].Methods: The study was a phase II, open-label, multi-center, dose escalation, single-dose administration study to determine the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of BB-10153 in ST segment elevation MI (STEMI). STEMI patients (n = 50) received a single dose of BB-10153 at one of six dose levels (1.0, 2.0, 3.0, 5.0, 7.5 and 10 mg/kg). The primary endpoint was TIMI flow grade (TFG) 3 at 60 minutes following the intravenous bolus of BB-10153.Results: Mean area under the curve for drug concentration ranged from 48.0 μg⋅h/mL in the 1 mg/kg dose group to 788.6 μg⋅h/mL in the 10 mg/kg dose group. Likewise, mean Cmax generally increased with dose over the entire dose range, from 4.9 μg/mL in the 1 mg/kg dose group to 139.6 μg/mL in the 10 mg/kg dose group. The mean apparent terminal half-life (t1/2) was 4.4 hours (range 2.2 to 7.6 hours). Few patients in the 1–3 mg/kg dosage groups achieved TFG 3 on the one-hour post-dose angiogram (4/20, 20%), and no patients achieved complete ST segment resolution. The 5, 7.5 and 10 mg/kg doses were associated with similar rates of TIMI grade 3 flow of approximately three per seven patients. Pooling TFG 3 data from the 5, 7.5 and 10 mg/kg groups yielded a TIMI grade 3 flow rate of 34% (n = 10/29; range 29–43%). No patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study. One patient experienced recurrent angina and developed recurrent myocardial ischemia requiring urgent revascularization. Three patients sustained TIMI major bleeding events (one in 1 mg/kg group, two in 7.5 mg/kg group), six patients sustained TIMI minor bleeds (one in the 2, 3, 7.5 and 10 mg/kg groups, two in the 5 mg/kg group), twp patients sustained TIMI minimal bleeds (one in each of the 2 and 10 mg/kg groups) and no patients sustained intracranial hemorrhage (ICH).Conclusion: In a dose escalation study of a single intravenous bolus, the novel fibrinolytic agent, BB-10153 was associated with a rise in the mean area under the curve and Cmax for drug concentration over the dose range 1 to 10 mg/kg. Higher doses were associated with a range of TIMI grade 3 flow of 29–43%, and no patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study.Condensed abstractIn a dose escalation study of a single intravenous bolus, the novel fibrinolytic agent, BB-10153 was associated with a rise in the mean area under the curve and Cmax for drug concentration over the dose range 1 to 10 mg/kg. Higher doses were associated with a range of TIMI grade 3 flow of 29–43%, and no patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study.

Decision-making microRNAs (miR-124, -133a/b, -34a and -134) in patients with occluded target vessel in acute coronary syndrome

BACKGROUND Coronary artery occlusion does not always manifest with ST-elevation, and some patients can have patent coronary vessel. AIM We evaluated circulating microRNA (miRNA) profiles to discriminate subjects with infarct-related artery (IRA) occlusion. METHODS AND RESULTS Patients (n = 43) with uncomplicated acute coronary syndrome and positive troponins were classified with respect to patent vs. occluded IRA or ST-elevation vs. non-ST elevation MI (STEMI vs. NSTEMI). Expression levels of serum miRNAs (miR-1, -16, -34a, -122, -124, -208b, -133a/b, -375, and -499) were analysed. Out of 16 STEMI and 27 NSTEMI patients, IRA occlusion was noted in 12 and 15 patients, respectively. The remaining four STEMI and 12 NSTEMI patients had patent IRA. STEMI patients had higher troponin T levels and a 3.83-fold higher miR-134 expression (p < 0.025). Patients with the occluded vs. patent IRA had higher levels of miR-133a (fold change: 7.00), miR-133b (4.57), miR-34a (5.50), miR-124 (2.55), and miR-134 (3.45) but no difference in troponin T levels. Receiver operator characteristic analysis identified decision-making miRNAs in occluded vessels: miR-124 (AUC: 0.787, p < 0.001), miR-133b (AUC: 0.704, p = 0.006), and miR-134 (AUC: 0.686, p = 0.016). With respect to STEMI, only miR-134 showed a discriminating value (AUC: 0.725, p = 0.002). CONCLUSIONS The degree of IRA occlusion determines circulating miRNA expression, and specific miRNAs may be useful in indicating patients requiring urgent coronary revascularisation.