Sebastian Kerber

Systemic Inflammatory Parameters in Patients With Atherosclerosis of the Coronary and Peripheral Arteries

Plasma concentration of markers of inflammation are increased in patients with atherosclerosis. However, it is unclear whether the pattern and magnitude of this increase vary with the site and extent of disease. In 147 patients undergoing semiquantitative coronary angiography, we measured the acute-phase reactants C-reactive protein (CRP) or serum amyloid A (SAA); the proinflammatory cytokine interleukin 6 (IL-6); the active and total fractions of the anti-inflammatory cytokine transforming growth factor-beta (TGF-beta); the macrophage activation marker neopterin; and the infection marker procalcitonin. Compared with 62 patients without either coronary artery disease (CAD) or peripheral artery disease (PAD), 57 patients with CAD but no PAD showed greater median CRP (0. 4 versus 0.2 mg/dL, P=0.004) and IL-6 (3.8 versus 1.6 pg/mL, P=0. 007) levels and a lower level of active-TGF-beta (57 versus 100 ng/mL, P=0.038). Moreover, CRP, IL-6, and neopterin levels showed a positive and the active TGF-beta level a negative correlation with the extent of coronary atherosclerosis. Compared with these 57 patients with CAD alone, 15 patients with PAD and CAD had higher median levels of SAA (17 versus 7 mg/mL, P=0.008), IL-6 (12 versus 4 pg/mL, P=0.002), neopterin (14 versus 11 mg/dL, P=0.006), and total TGF-beta (11834 versus 6417 ng/L, P=0.001). However, these strong univariate associations of markers of inflammation and atherosclerosis were lost in multivariate analysis once age, sex, and high density lipoprotein cholesterol or fibrinogen were taken into account. Increased plasma levels of CRP, SAA, IL-6, TGF-beta, neopterin, and procalcitonin constitute an inflammatory signature of advanced atherosclerosis and are correlated with the extent of disease but do not provide discriminatory diagnostic power over and above established risk factors.

Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction: a randomised trial.

BACKGROUND Intracoronary administration of an abciximab bolus during a primary percutaneous coronary intervention results in a high local drug concentration, improved perfusion, and reduction of infarct size compared with intravenous bolus application. However, the safety and efficacy of intracoronary versus standard intravenous bolus application in patients with ST-elevation myocardial infarction (STEMI) undergoing this intervention has not been tested in a large-scale clinical trial. METHODS The AIDA STEMI trial was a randomised, open-label, multicentre trial. Patients presenting with STEMI in the previous 12 h with no contraindications for abciximab were randomly assigned in a 1:1 ratio by a central web-based randomisation system to intracoronary versus intravenous abciximab bolus (0·25 mg/kg bodyweight) during percutaneous coronary intervention with a subsequent 12 h intravenous infusion 0·125 μg/kg per min (maximum 10 μg/min). The primary endpoint was a composite of all-cause mortality, recurrent infarction, or new congestive heart failure within 90 days of randomisation. Secondary endpoints were the time to occurrence of the primary endpoint, each individual component of that endpoint, early ST-segment resolution, thrombolysis in myocardial infarction (TIMI) flow grade, and enzymatic infarct size. A masked central committee adjudicated the primary outcome and its components. Treatment allocation was not concealed from patients and investigators. This trial is registered with ClinicalTrials.gov, NCT00712101. FINDINGS Between July, 2008, and April, 2011, 2065 patients were randomly assigned intracoronary abciximab (n=1032) or intravenous abciximab (n=1033). Intracoronary, as compared with intravenous abciximab, resulted in a similar rate of the primary composite clinical endpoint at 90 days in 1876 analysable patients (7·0%vs 7·6%; odds ratio [OR] 0·91; 95% CI 0·64-1·28; p=0·58). The incidence of death (4·5%vs 3·6%; 1·24; 0·78-1·97; p=0·36) and reinfarction (1·8%vs 1·8%; 1·0; 0·51-1·96; p=0·99) did not differ between the treatment groups, whereas less patients in the intracoronary group had new congestive heart failure (2·4%vs 4·1%; 0·57; 0·33-0·97; p=0·04). None of the secondary endpoints or safety measures differed significantly between groups. INTERPRETATION In patients with STEMI undergoing primary percutaneous coronary intervention, intracoronary as compared to intravenous abciximab did not result in a difference in the combined endpoint of death, reinfarction, or congestive heart failure. Since intracoronary abciximab bolus administration is safe and might be related to reduced rates of congestive heart failure the intracoronary route might be preferred if abciximab is indicated. FUNDING Lilly, Germany. University of Leipzig-Heart Centre. University of Leipzig, Clinical Trial Centre Leipzig, supported by the Federal Ministry of Education and Research (BMBF).

Supported High-Risk Percutaneous Coronary Intervention With the Impella 2.5 Device: The Europella Registry

OBJECTIVES This retrospective multicenter registry evaluated the safety and feasibility of left ventricular (LV) support with the Impella 2.5 (Abiomed Europe GmbH, Aachen, Germany) during high-risk percutaneous coronary intervention (PCI). BACKGROUND Patients with complex or high-risk coronary lesions, such as last remaining vessel or left main lesions, are increasingly being treated with PCI. Because periprocedural hemodynamic compromise and complications might occur rapidly, many of these high-risk procedures are being performed with mechanical cardiac assistance, particularly in patients with poor LV function. The Impella 2.5, a percutaneous implantable LV assist device, might be a superior alternative to the traditionally used intra-aortic balloon pump. METHODS The Europella registry included 144 consecutive patients who underwent a high-risk PCI. Safety and feasibility end points included incidence of 30-day adverse events and successful device function. RESULTS Patients were older (62% >70 years of age), 54% had an LV ejection fraction < or = 30%, and the prevalence of comorbid conditions was high. Mean European System for Cardiac Operative Risk Evaluation score was 8.2 (SD 3.4), and 43% of the patients were refused for coronary artery bypass grafting. A PCI was considered high-risk due to left main disease, last remaining vessel disease, multivessel coronary artery disease, and low LV function in 53%, 17%, 81%, and 35% of the cases, respectively. Mortality at 30 days was 5.5%. Rates of myocardial infarction, stroke, bleeding requiring transfusion/surgery, and vascular complications at 30 days were 0%, 0.7%, 6.2%, and 4.0%, respectively. CONCLUSIONS This large multicenter registry supports the safety, feasibility, and potential usefulness of hemodynamic support with Impella 2.5 in high-risk PCI.

Intracoronary compared with intravenous bolus abciximab application during primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: cardiac magnetic resonance substudy of the AIDA STEMI trial.

OBJECTIVES The aim of the AIDA STEMI (Abciximab i.v. Versus i.c. in ST-elevation Myocardial Infarction) cardiac magnetic resonance (CMR) substudy was to investigate potential benefits of intracoronary versus intravenous abciximab bolus administration on infarct size and reperfusion injury in ST-segment elevation myocardial infarction. BACKGROUND The AIDA STEMI trial randomized 2,065 patients to intracoronary or intravenous abciximab and found similar rates of major adverse cardiac events at 90 days with significantly less congestive heart failure in the intracoronary abciximab group. CMR can directly visualize myocardial damage and reperfusion injury, thereby providing mechanistic and pathophysiological insights. METHODS We enrolled 795 patients in the AIDA STEMI CMR substudy. CMR was completed within 1 week after ST-segment elevation myocardial infarction. Central core laboratory-masked analyses for quantified ventricular function, volumes, infarct size, microvascular obstruction, hemorrhage, and myocardial salvage were performed. RESULTS The area at risk (p = 0.97) and final infarct size (16% [interquartile range: 9% to 25%] versus 17% [interquartile range: 8% to 25%], p = 0.52) did not differ significantly between the intracoronary and the intravenous abciximab groups. Consequently, the myocardial salvage index was similar (52 [interquartile range: 35 to 69] versus 50 [interquartile range: 29 to 69], p = 0.25). There were also no differences in microvascular obstruction (p = 0.19), intramyocardial hemorrhage (p = 0.19), or ejection fraction (p = 0.95) between both treatment groups. Patients in whom major adverse cardiac events occurred had significantly larger infarcts, less myocardial salvage, and more pronounced ventricular dysfunction. CONCLUSIONS This largest multicenter CMR study in ST-segment elevation myocardial infarction patients to date demonstrates no benefit of intracoronary versus intravenous abciximab administration on myocardial damage and/or reperfusion injury. Infarct size determined by CMR was significantly associated with major adverse cardiac events.

The relation of interleukin-6, tumor necrosis factor-alpha, IL-2, and IL-2 receptor levels to cellular rejection, allograft dysfunction, and clinical events early after cardiac transplantation.

Immunoregulatory cytokines have been implicated in the pathophysiology of graft dysfunction after heart transplantation (HTx). In 15 consecutive patients undergoing HTx we prospectively determined levels of interleukin-6 (IL-6), tumor-necrosis-factor-alpha (TNF-alpha), interleukin-2 (IL-2), and soluble-interleukin-2-receptor (sIL-2-R) at eight points in time during biopsy and right heart catheterization and within 12 hr of echocardiography during the first three months after HTx. Blood was taken from the pulmonary arterial line. IL-6-levels correlated positively with hemodynamic and echocardiographic parameters of pump dysfunction--namely, pulmonary capillary wedge pressure, pulmonary arterial pressure, right atrial pressure, heart rate--and negatively with isovolumic relaxation time and stroke volume independent of the degree of cellular rejection as classified by the ISHLT criteria. A similar pattern was found for TNF-alpha- and sIL-2-R, while IL-2 correlated negatively with left and right heart filling pressures and positively with fractional shortening. In the three patients who died of sepsis or multiorgan failure within the study period IL-6-, TNF-alpha, and sIL-2-R-levels were elevated and IL-2-levels were suppressed compared with the 12 patients with a stable clinical course. IL-6 and sIL-2-R correlated positively while IL-6 and IL-2 correlated negatively. In this pilot study, a cytokine pattern with elevated levels of IL-6, TNF-alpha, and sIL-2-R as well as suppressed levels of IL-2 in the early period after HTx corresponds to impaired hemodynamics independent of cellular rejection and may indicate an unfavorable prognosis. These cytokines may therefore be useful for monitoring and warrant further study.

Relation of serum levels of sex hormone binding globulin to coronary heart disease in postmenopausal women

Hyperandrogenemia and low levels of sex hormone binding globulin (SHBG) are frequently found in women with metabolic syndrome, which is characterized by low high-density lipoprotein cholesterol, hypertriglyceridemia, obesity, and hyperinsulinemia. The specific contribution of these various factors to coronary heart disease (CHD) is controversial. The coronary angiograms of 87 consecutive postmenopausal women were evaluated using 2 semiquantitative scoring systems to estimate the extent of focal and diffuse vessel wall alterations. Fasting sera were analyzed for levels of glucose, lipids, insulin, leptin, dehydroepiandrosterone sulfate, testosterone, and SHBG. Obesity was assessed by measuring body mass index, waist-to-hip ratio, skinfold thicknesses, and body impedance. After adjusting for age, there were significant differences in 55 women with CHD compared with 32 women without CHD: higher levels of low-density lipoprotein cholesterol (159 +/- 51 vs 132 +/- 39 mg/dl), apolipoprotein B (121 +/- 33 vs 102 +/- 29 mg/dl), triglycerides (115 vs 91 mg/dl), and basal insulin (7.5 vs 4.6 mU/L), as well as lower levels of high-density lipoprotein cholesterol (59.9 +/- 18.0 vs 69.0 +/- 17.1 mg/dl), SHBG (44.6 vs 68.1 nmol/L) and the quantitative insulin sensitivity check index (0.66 +/- 0.41 vs 0.93 +/- 0.73). Multivariate analysis by logistic regression identified age (odds ratio [OR] 1.22, 95% confidence intervals [CI] 1.09 to 1.37), smoking (OR 11.46, 95% CI 2.56 to 51.39), SHBG (OR 0.98, 95% CI 0.96 to 0.99), and apolipoprotein B (OR 1.02, 95% CI 1.01 to 1.04) as independently associated with the presence of CHD. Thus, low plasma levels of SHBG are associated with CHD in women independently of insulin, obesity markers, and dyslipidemia.

Selection and management of ventricular assist device patients : The Muenster experience

BACKGROUND Because of the growing discrepancy between the availability of donor organs and the number of patients with end-stage heart disease who need heart transplantation, a larger proportion of patients waiting for a suitable donor heart require pre-operative mechanical circulatory assistance. The criteria for the selection and management of these patients as applied at Muenster University Hospital are reviewed. METHODS The study population consists of 631 patients referred to our center for transplantation between January 1, 1990, and December 31, 1996. Two hundred ninety-seven patients were listed for transplantation and 157 were transplanted. Of 41 patients who underwent implantation of a ventricular assist device (n = 34, Novacor; n = 6, TCI HeartMate; n = 1, Medos), 39 received the device as a bridge to transplantation and 2 as permanent support. For the purpose of the analysis, the study population was divided into 3 groups (elective bridging, urgent bridging, emergency bridging) and compared with heart transplant candidates who did not require mechanical circulatory assistance. RESULTS Patients who underwent elective or urgent assist-device implantation were younger and had greater hemodynamic compromise than the remainder of patients waiting for heart transplantation, as suggested by a higher functional class and lower mean arterial pressure, cardiac index, serum sodium, and pulmonary artery wedge pressure. Survival of patients who electively underwent implantation of an assist device was better than that of patients who were stable on the waiting list and did not undergo heart transplantation during follow-up. CONCLUSIONS This finding suggests that earlier implantation of assist devices may facilitate resolution of organ dysfunction before heart transplantation.

Cardiac Pacemaker Infection: Surgical Management With and Without Extracorporeal Circulation

BACKGROUND Pacemaker infections are rare, but serious complications of pacemaker therapy. The generator pocket, the pacing leads, or both may be involved. METHODS We report on 12 patients with infected pacemaker systems. Four patients suffered from localized generator pocket infections, 6 had infected leads, and 2 patients had both. Pacemaker systems were completely removed in all patients. When the infection was limited to the generator pocket, the pacemaker system was removed at the original implantation site. Extracorporeal circulation was employed for the explantation of infected pacing leads. RESULTS No complications occurred in patients with localized generator pocket infections. One patient with infected leads who was preoperatively already in a serious clinical condition died of septic shock in the early postoperative period; another patient died of pulmonary complications after tricuspid valve replacement 14 months after pacemaker explantation. No recurrent infections were observed. CONCLUSIONS Explantation of the complete pacemaker system has proved a reliable method to eradicate infection. Complications have been rare, except in patients in a critically ill state who undergo cardiopulmonary bypass.

Intracoronary compared with intravenous bolus abciximab application during primary percutaneous coronary intervention: Design and rationale of the Abciximab Intracoronary versus intravenously Drug Application in ST-Elevation Myocardial Infarction (AIDA STEMI) trial

BACKGROUND Intravenous abciximab reduces major adverse cardiac events in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Intracoronary abciximab bolus application during PCI results in high local drug concentration, improved perfusion, reduction of infarct size, and less microvascular obstruction. The hypothesis of this trial is that abciximab bolus intracoronary in comparison to standard intravenous application will improve the outcome of patients undergoing primary PCI in STEMI. STUDY DESIGN The Abciximab Intracoronary versus intravenously Drug Application in STEMI (AIDA STEMI) study is a 1,912-patient, prospective, multicenter, randomized, open-label, controlled trial. The study is designed to compare the efficacy and safety of intracoronary versus intravenous bolus abciximab administration during primary PCI with subsequent intravenous infusion for 12 hours. Patients will be randomized in a 1:1 fashion to 1 of the 2 treatments. The primary efficacy end point of AIDA STEMI is the composite of all-cause mortality, recurrent MI, or new congestive heart failure within 90 days of randomization. The primary safety outcome assessment will be major bleeding. CONCLUSIONS The AIDA STEMI study addresses important questions regarding the efficacy and safety of intracoronary abciximab bolus administration during primary PCI in patients with STEMI, potentially optimizing the route of administration of glycoprotein IIb/IIIa inhibitors in the catheterization laboratory.

T-cell and monocyte subsets, inflammatory molecules, rejection, and hemodynamics early after cardiac transplantation.

BACKGROUND In the early period after cardiac transplantation, differential diagnosis of graft failure due to rejection, infection, and other causes is important but difficult. METHODS In 22 consecutive patients undergoing heart transplantation, we prospectively determined levels of interleukin-6 as well as T-cell and monocyte subsets at eight points in time during biopsy and right heart catheterization and within 12 hr of echocardiography during the first 3 months after transplantation. RESULTS Worse hemodynamic parameters, as characterized by dichotomization according to median values (pulmonary capillary wedge pressure >10 mmHg, mean pulmonary arterial pressure > 18 mmHg, pulmonary vascular resistance > 115 dyn x sec x cm(-5), right atrial pressure > 5 mmHg, cardiac index <3 L/min/m2, early mitral deceleration time < 135 msec, and isovolumic relaxation time <80 msec), were associated with higher levels of interleukin-6, C-reactive protein, polymorphonuclear cells, CD71+/CD14+ monocytes, and IgM levels and, in contrast, with lower levels of immunocompetence markers such as CD3+ T cells, CD4+ T cells, CD8+ T cells, CD3+/CD25+ T cells, CD4+/ CD45RO+ T cells, NK cells, and lower biopsy scores. CONCLUSION Early after cardiac transplantation, elevated levels of inflammatory cells and soluble inflammatory molecules and lower levels of immunocompetence markers are associated with impaired allograft function in the absence of cellular rejection.