Alexander Staudt

Hemodynamic effects of immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy: Three-month results from a randomized study☆

OBJECTIVES The objective of our study was to assess the hemodynamic effects of immunoadsorption (IA) and subsequent immunoglobulin G (IgG) substitution in comparison with the effects of conventional medical treatment in patients with dilated cardiomyopathy (DCM). BACKGROUND Various circulating cardiac autoantibodies have been detected among patients suffering from DCM. These antibodies are extractable by IA. METHODS Patients with DCM (n = 18, New York Heart Association III-IV, left ventricular ejection fraction <30%) and who were on stable medication participated in the study. Hemodynamic measurements were performed using a Swan-Ganz thermodilution catheter. The patients were randomly assigned either to the treatment group with IA and subsequent IgG substitution (IA/IgG group, n = 9) or to the control group without IA/IgG (n = 9). In the IA/IgG group, the patients were initially treated in one IA session daily on three consecutive days. After the final IA session, 0.5 g/kg of polyclonal IgG was substituted. At one-month intervals, IA was then repeated for three further courses with one IA session daily on two consecutive days, until the third month. RESULTS After the first IA course and IgG substitution, cardiac index (CI) increased from 2.1 (+/-0.1) to 2.8 (+/-0.1) L/min/m2 (p < 0.01) and stroke volume index (SVI) increased from 27.8 (+/-2.3) to 36.2 (+/-2.5) ml/m2 (p < 0.01). Systemic vascular resistance (SVR) decreased from 1,428 (+/-74) to 997 (+/-55) dyne x s x cm(-5) (p < 0.01). The improvement in CI, SVI and SVR persisted after three months. In contrast, hemodynamics did not change throughout the three months in the control group. CONCLUSIONS Immunoadsorption and subsequent IgG substitution improves cardiovascular function in DCM.

Immunohistological Changes in Dilated Cardiomyopathy Induced by Immunoadsorption Therapy and Subsequent Immunoglobulin Substitution

Background—Immunoadsorption (IA) and subsequent immunoglobulin (Ig) G substitution represent an additional therapeutic approach in dilated cardiomyopathy (DCM). It remains to be elucidated whether this treatment modulates myocardial inflammation, which is possibly a causal factor of ventricular dysfunction. Methods and Results—From 25 DCM patients (EF <30%), 12 patients were randomized for IA therapy and subsequent IgG substitution at 1-month intervals until month 3. Before (<7 days) and after IA therapy, right ventricular biopsies were obtained from all patients. Biopsies were also obtained at intervals of 3 months from 13 patients without IA/IgG treatment (controls). IA/IgG treatment induced improvement in left ventricular ejection fraction from 21.3±1.7% (±SEM) to 27.0±1.3% (P <0.01 versus baseline/controls) and reduction of the &bgr;-receptor autoantibody serum levels (P <0.01 versus baseline/controls). The number of CD3 cells decreased from 5.7±0.8 to 2.9±0.5 cells/mm2 (P <0.01 versus baseline/controls). This decline was paralleled by a decrease in CD4 (P <0.01 versus baseline/controls) and CD8 (P <0.05 versus baseline/controls) lymphocytes. The number of leukocyte common antigen–positive cells (leukocytes) was reduced from 20.0±3.2 to 9.9±2.8 cells/mm2 (P <0.01 versus baseline/ P <0.05 versus controls). HLA class II expression decreased from 2.1±0.7% to 1.1±0.4% (P <0.05 versus controls/baseline). The number of immunopositive cells and the expression of HLA class II in controls remained stable. In both groups, the degree of fibrosis remained unchanged. Conclusions—IA and subsequent IgG substitution mitigate myocardial inflammation in DCM.

Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption.

OBJECTIVES The objective of this study was to investigate whether immunoadsorption (IA) removes cardiodepressant antibodies from the plasma of patients with dilated cardiomyopathy (DCM), as well as to describe their effects on isolated rat cardiomyocytes. BACKGROUND Immunoadsorption induces early hemodynamic improvement in patients with DCM. The mechanisms for this improvement remain to be elucidated. METHODS Patients with DCM (n = 11; left ventricular ejection fraction < 30%, cardiac index [CI] < 2.5 l/min per m(2)) were treated with IA on three consecutive days, with one IA session daily, by application of specific antibody columns directed against human immunoglobulin (Ig). Immunoadsorption was also conducted on 500 ml of blood taken from nine healthy donors (control subjects). After passage of plasma, the IA columns were regenerated. Column eluent (CE) was collected and dialyzed (100 kD). Confocal laser scanning microscopy was used to analyze the effects of CE on cell contraction and on Ca(2+)-dependent fluorescence in isolated, field-stimulated adult rat cardiomyocytes loaded with cell-permeable Fluo-3. Immunoprecipitation with different preparations of myocardial protein fractions was used for characterization of cardiotropic antibodies. RESULTS During IA, the IgG plasma level decreased from 10.7 +/- 0.6 to 2.4 +/- 0.1 g/l (mean +/- SEM), and the CI increased from 2.2 +/- 0.1 to 2.7 +/- 0.2 l/min per m(2) (p < 0.01). The CE obtained from control subjects did not influence Ca(2+) transients or cell shortening of cardiomyocytes. In contrast, in patients with DCM, the CE collected during the first regeneration cycle of the first IA session caused an immediate and dose-related decrease of Ca(2+) transients (dilution 1:5; -22.7 +/- 5.5%; p < 0.01) and cell shortening (dilution 1:5; -29.9 +/- 6.0%, p < 0.01). Early hemodynamic improvement among the patients correlated with the cardiodepressant effect of CE on the isolated cardiomyocytes. Purification of CE by protein A adsorption indicated that the cardiodepressant substances are antibodies. Immunoprecipitation revealed that the eliminated antibodies are capable of binding to various myocardial proteins. CONCLUSIONS Cardiac autoantibodies play a functional role in DCM, and their removal may induce early hemodynamic improvement.

Potential Role of Autoantibodies Belonging to the Immunoglobulin G-3 Subclass in Cardiac Dysfunction Among Patients With Dilated Cardiomyopathy

Background—Immunoadsorption capable of removing circulating autoantibodies represents an additional therapeutic approach in dilated cardiomyopathy (DCM). The role played by autoantibodies belonging to the immunoglobulin (Ig) subclass G-3 in cardiac dysfunction remains to be elucidated. Methods and Results—Patients with DCM (left ventricular ejection fraction <30%) participated in this case-control study. Nine patients underwent immunoadsorption with protein A (low affinity to IgG-3), and 9 patients were treated with anti-IgG, which removes all IgG subclasses. Immunoadsorption was performed in 4 courses at 1-month intervals until month 3. In the 2 groups, immunoadsorption induced comparable reduction of total IgG (>80%). IgG-3 was effectively eliminated only by anti-IgG adsorption (eg, during the first immunoadsorption course; protein A, −37±4%; anti-IgG, −89±3%;P <0.001 versus protein A). The &bgr;1-receptor autoantibody was effectively reduced only by anti-IgG (P <0.01 versus protein A). Hemodynamics did not change in the protein A group. In the anti-IgG group during the first immunoadsorption course, cardiac index increased from 2.3±0.1 to 3.0±0.1 L · min−1 · m−2 (P <0.01 versus protein A). After 3 months, before the last immunoadsorption course, cardiac index was 2.2±0.1 L · min−1 · m−2 in the protein A group and 3.0±0.2 L · min−1 · m−2 in the anti-IgG group (P <0.01 versus protein A). Left ventricular ejection fraction increased only in the anti-IgG group (P <0.05 versus protein A). Conclusions—Autoantibodies belonging to IgG-3 may play an important role in cardiac dysfunction of DCM. The removal of antibodies of the IgG-3 subclass may represent an essential mechanism of immunoadsorption in DCM.

A randomized trial of 5 vs. 6 french transradial percutaneous coronary interventions

Transradial coronary interventions (TCI) are occasionally limited by radial spasms and postprocedural radial occlusions, which are related to the radial diameter and which possibly may be reduced by the use of smaller guiding catheter. However, 5 Fr, 0.058″ lumen diameter guiding catheter affords less strength, visibility, and backup. In a randomized study, we investigated procedural and clinical success and vascular access complications of 5 Fr in comparison to 6 Fr guiding catheter. One hundred seventy‐one patients with coronary lesions suitable for at least 5 Fr transradial approach (i.e., normal Allen test, only balloon angioplasty and stent) were randomly assigned for 5 or 6 Fr TCI. The primary combined endpoint was procedural and clinical success, and secondary endpoints were vascular access complications and the occurrence of postprocedural radial occlusions at 1‐month follow‐up. Procedural success was achieved in 95.4% of 5 Fr and 92.9% of 6 Fr patients. Selective cannulation of the coronary ostium failed in 1.1% of 5 Fr and 4.8% of 6 Fr patients (P = 0.08). Minor hematomas without need for surgical repair or blood transfusions occurred in 1.1% (5 Fr) and 4.8% (6 Fr; P = 0.07); 1.1% of 5 Fr and 5.9% of 6 Fr patients (P = 0.05) suffered loss of radial pulse due to radial occlusion. Selected noncomplex coronary lesions can successfully and safely be treated either with 5 or 6 Fr guiding catheters. A tendency of higher procedural success rates and lower vascular access complications was documented after 5 Fr in comparison to 6 Fr TCI. This was particularly the case among patients with small radial diameters. Cathet Cardiovasc Intervent 2002;57:172–176.

Association Between High Serum Ferritin Levels and Carotid Atherosclerosis in the Study of Health in Pomerania (SHIP)

Background and Purpose— Several studies have provided evidence for a relationship between body iron load and cardiovascular disease. We analyzed the association of serum ferritin levels with carotid atherosclerosis. Methods— We assessed intima-media thickness and plaque prevalence in the carotid arteries by high-resolution ultrasound among 2443 participants (1200 women; age, 45 to 79 years) in the Study of Health in Pomerania (SHIP), a population-based study in northeast Germany. Results— In multivariate analysis, serum ferritin levels were not independently associated with carotid intima-media thickness among women or men. In contrast, the relationship between serum ferritin levels and carotid plaque prevalence was significant among men (odds ratio per 1-SD increase of serum ferritin levels, 1.33; 95% confidence interval, 1.08 to 1.44) yet not among women (odds ratio, 1.29; 95% confidence interval, 0.98 to 1.75). However, both men and women showed a dose-response relation between serum ferritin levels and carotid atherosclerosis in which higher serum ferritin levels were associated with greater odds ratios for carotid plaque prevalence. Additionally, there was an interaction of serum ferritin levels with low-density lipoprotein (LDL) cholesterol (P =0.039) among men in which the association of serum ferritin levels with carotid plaque prevalence became stronger with increasing LDL cholesterol levels. Conclusions— Our study identified a relationship between serum ferritin levels and carotid atherosclerosis that was potentiated by LDL cholesterol. This relationship adds support to the hypothesis of a link between iron and cardiovascular disease.

Hemodynamic improvement and removal of autoantibodies against β1-adrenergic receptor by immunoadsorption therapy in dilated cardiomyopathy

The removal of beta(1)-adrenergic receptor (beta(1)AR) autoantibodies by immunoadsorption (IA) has been proposed as a potential mechanism for the improvement of the left ventricular function in dilated cardiomyopathy (DCM). In the present study, the possible association between removal of the autoantibodies against the human beta(1)AR with the hemodynamic improvement induced by IA was investigated.IA was performed in 22 DCM patients (n=22; NYHA III-IV, EF<30%, stable medication). The beta(1)AR autoantibodies from column eluents (CE) were detected by enzyme-linked immunosorbent assay (ELISA) and BIAcore methods. CE of 32% (7/22) of the patients was found to be antibody-positive with ELISA or BIAcore. In addition, a bioassay system was also used for the detection of this autoantibody. Seventy-three percent (16/22) of the patients were found to be antibody-positive by this method. However, independent of the beta(1)AR antibody detection method, both antibody-positive and antibody-negative groups showed similar acute and prolonged hemodynamic improvements during IA therapy. Furthermore, antibody-positive and -negative groups received a comparable improvement of left ventricular ejection fraction. These results suggest that different mechanisms are involved in the hemodynamic improvement induced by IA. The beneficial hemodynamic effects induced by IA are not directly associated with the removal of beta(1)AR autoantibodies.

Human Apolipoprotein A-I Gene Transfer Reduces the Development of Experimental Diabetic Cardiomyopathy

Background— The hallmarks of diabetic cardiomyopathy are cardiac oxidative stress, intramyocardial inflammation, cardiac fibrosis, and cardiac apoptosis. Given the antioxidative, antiinflammatory, and antiapoptotic potential of high-density lipoprotein (HDL), we evaluated the hypothesis that increased HDL via gene transfer (GT) with human apolipoprotein (apo) A-I, the principal apolipoprotein of HDL, may reduce the development of diabetic cardiomyopathy. Methods and Results— Intravenous GT with 3×1012 particles/kg of the E1E3E4-deleted vector Ad.hapoA-I, expressing human apoA-I, or Ad.Null, containing no expression cassette, was performed 5 days after streptozotocin (STZ) injection. Six weeks after apoA-I GT, HDL cholesterol levels were increased by 1.6-fold (P<0.001) compared with diabetic controls injected with the Ad.Null vector (STZ-Ad.Null). ApoA-I GT and HDL improved LV contractility in vivo and cardiomyocyte contractility ex vivo, respectively. Moreover, apoA-I GT was associated with decreased cardiac oxidative stress and reduced intramyocardial inflammation. In addition, compared with STZ-Ad.Null rats, cardiac fibrosis and glycogen accumulation were reduced by 1.7-fold and 3.1-fold, respectively (P<0.05). Caspase 3/7 activity was decreased 1.2-fold (P<0.05), and the ratio of Bcl-2 to Bax was upregulated 1.9-fold (P<0.005), translating to 2.1-fold (P<0.05) reduced total number of cardiomyocytes with apoptotic characteristics and 3.0-fold (P<0.005) reduced damaged endothelial cells compared with STZ-Ad.Null rats. HDL supplementation ex vivo reduced hyperglycemia-induced cardiomyocyte apoptosis by 3.4-fold (P<0.005). The apoA-I GT-mediated protection was associated with a 1.6-, 1.6-, and 2.4-fold induction of diabetes-downregulated phospho to Akt, endothelial nitric oxide synthase, and glycogen synthase kinase ratio, respectively (P<0.005). Conclusion— ApoA-I GT reduced the development of streptozotocin-induced diabetic cardiomyopathy.

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

Doxorubicin is a frequently used anticancer drug, but its therapeutic benefit is limited by acute and chronic cardiotoxicity, often leading to heart failure. The mechanisms underlying doxorubicin-induced cardiotoxicity remain unclear. It was previously shown in men that doxorubicin leads to increased endothelin-1 plasma levels. In addition, cardiac-specific overexpression of endothelin-1 in mice resulted in a cardiomyopathy resembling the phenotype following doxorubicin administration. We therefore hypothesized that endothelin-1 is involved in the pathogenesis of doxorubicin cardiotoxicity. In mice (C57Bl/10), we found that doxorubicin (20 mg/kg body weight, i.p.) impaired cardiac function with decreased ejection fraction, diminished cardiac output, and decreased end-systolic pressure points recorded by a microconductance catheter. This impaired function was accompanied by the up-regulation of endothelin-1 expression on mRNA and protein level. In vitro investigations confirmed the regulation of endothelin-1 by doxorubicin and indicated that the doxorubicin-mediated increase of endothelin-1 expression involves epidermal growth factor receptor signaling via the MEK1/2-ERK1/2 cascade, which was further confirmed by immunoblotting studies in the left ventricle of treated animals. Pretreatment of mice with the endothelin receptor antagonist bosentan (100 mg/kg body weight, p.o.) strikingly inhibited doxorubicin-induced cardiotoxicity with preserved indices of contractility. Moreover, bosentan pretreatment resulted in reduced tumor necrosis factor-alpha content, lipid peroxidation, and Bax expression, as well as increased GATA-4 expression. Thus, endothelin-1 plays a key role in mediating the cardiotoxic effects of doxorubicin and its inhibition may be of therapeutic benefit for patients receiving doxorubicin.

Relation of degree of laser debulking of in-stent restenosis as a predictor of restenosis rate

precludes a precise estimate of coronary disease, the increased prevalence of traditional risk factors (e.g., smoking, hypertension, diabetes) among the cases compared with the controls is consistent with the presence of underlying coronary atherosclerosis in a signifi cant proportion of the sudden death cases. Because of the community-based nature of the study, paramedics were able to obtain blood specimens only from patients for whom an intravenous line was placed as part of provision of emergency medical care once the patient was clinically stable or resuscitation had proved ineffective. Thus, the circumstances of the cardiac arrest or the provision of medical care often precluded the blood draw, and specimens for genotyping were available from only a fraction (25%) of all sudden deaths that occurred during the study period, which may introduce some bias. However, the characteristics of study participants with and without blood drawn were similar among cases as well as controls. Although medical history data were collected through spousal interviews and not fully validated by medical record review, a small validation study demonstrated that spouses accurately provide