Stephan B. Felix

Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy

BACKGROUND The natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood. METHODS The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome. RESULTS Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year. CONCLUSIONS Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).

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.

Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20–79

AIMS Although the association of low serum testosterone levels with mortality has gained strength in recent research, there are few population-based studies on this issue. This study examined whether low serum testosterone levels are a risk factor for all-cause or cause-specific mortality in a population-based sample of men aged 20-79. METHODS AND RESULTS We used data from 1954 men recruited for the prospective population-based Study of Health in Pomerania, with measured serum testosterone levels at baseline and 195 deaths during an average 7.2-year follow-up. A total serum testosterone level of less than 8.7 nmol/L (250 ng/dL) was classified as low. The relationships of low serum testosterone levels with all-cause and cause-specific mortality were analysed by Cox proportional hazards regression models. Men with low serum testosterone levels had a significantly higher mortality from all causes than men with higher serum testosterone levels (HR 2.24; 95% CI 1.41-3.57). After adjusting for waist circumference, smoking habits, high-risk alcohol use, physical activity, renal insufficiency, and levels of dehydroepiandrosterone sulfate, low serum testosterone levels continued to be associated with increased mortality (HR 2.32; 95% CI 1.38-3.89). In cause-specific analyses, low serum testosterone levels predicted increased risk of death from cardiovascular disease (CVD) (HR 2.56; 95% CI 1.15-6.52) and cancer (HR 3.46; 95% CI 1.68-6.68), but not from respiratory diseases or other causes. CONCLUSION Low serum testosterone levels were associated with an increased risk of all-cause mortality independent of numerous risk factors. As serum testosterone levels are inversely related to mortality due to CVD and cancer, it may be used as a predictive marker.

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.

Angioscopic evaluation of atherosclerotic plaques: Validation by histomorphologic analysis and association with stable and unstable coronary syndromes

OBJECTIVES We validated coronary angioscopic observations with histologic assessment of material removed by atherectomy. BACKGROUND Up to now, angioscopic findings have been primarily descriptive, and the clinical significance still needs to be substantiated. The proposed Ermenoville classification is relevant but has not yet been validated by histomorphologic analysis. METHODS We compared angioscopic findings in patients with different coronary syndromes and used atherosclerotic material retrieved by directional coronary atherectomy to validate the angioscopic observations. Coronary angioscopy was performed in 63 patients (56 men, 7 women) with stable (26 patients) and unstable angina (37 patients) before and after directional coronary atherectomy. The identity of atherectomized material was confirmed by ex vivo visualization with the angioscope and by postatherectomy angioscopy. Angioscopic and histologic findings could be compared in 44 of 63 patients. RESULTS Angioscopic findings were grouped into gray-white and yellow lesions (gray-yellow, deep yellow, yellow-red or yellow-pink). We found that patients with unstable angina had predominantly yellow lesions (89%). In patients with stable angina, gray-white (43%) or yellow (57%) lesions were similarly distributed. Ruptured yellow plaques and red or pink thrombi were identified in 11% of patients with stable angina and 39% of patients with unstable or early postmyocardial infarction angina. Histologically, gray-white lesions represented fibrous plaque without degeneration in 64% and with degeneration in 36% of patients. Gray-yellow lesions were associated predominantly with degenerated plaque (64%) and, to a lesser extent, with fibrous plaque (14%) or atheroma (14%). Deep yellow and yellow-red lesions represented either atheroma (53%) or degenerated plaque (42%). CONCLUSIONS Our study establishes a histomorphologic basis for classification and interpretation of angioscopic findings. Yellow plaque color is closely related to degenerated plaque or atheroma and is associated with unstable coronary syndromes.

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.

Short-term Hemodynamic Effects of Immunoadsorption in Dilated Cardiomyopathy

BACKGROUND Previous studies have shown that the sera of many patients with dilated cardiomyopathy (DCM) are positive for several antibodies directed against cardiac antigens. Anti-beta1-adrenergic receptor antibodies occur in 70% to 90% of DCM patients. These antibodies are extractable by immunoadsorption (IA). In an investigation of the functional significance of antibodies for hemodynamics, IA was performed throughout 5 consecutive days on nine patients with severe DCM who were on stable drug therapy. METHODS AND RESULTS Immunoglobulins were eliminated in nine patients with severe DCM (mean age, 43.5 years; range, 25 to 58 years; left ventricular ejection fraction, <25%). IA was performed over 5 consecutive days with an immunoadsorber for immunoglobulin. All patients were on stable medication, including ACE inhibitors, digitalis, and diuretics. All patients received beta-blockers. During therapy, hemodynamic parameters (mean+/-SD) were monitored with a Swan-Ganz thermodilution catheter. IA elicited a decrease of anti-beta1-adrenergic receptor antibodies from 6.4+/-1.3 to 1.0+/-0.5 relative units. During IA, cardiac output increased from 3.7+/-0.8 to 5.5+/-1.8 L/min, P<.01. Mean arterial pressure decreased from 76.0+/-9.9 to 65.0+/-11.2 mm Hg, P<.05; mean pulmonary arterial pressure, from 27.6+/-7.7 to 22.0+/-6.5 mm Hg, P<.05; left ventricular filling pressure, from 16.8+/-7.4 to 12.8+/-4.7 mm Hg, P<.05; and systemic vascular resistance, from 1465+/-332 to 949+/-351 dyne x s x cm(-5), P<.01. CONCLUSIONS In addition to conventional medical treatment, IA may be an additional therapeutic possibility for acute hemodynamic stabilization of patients with severe DCM.

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.

Riociguat for Patients With Pulmonary Hypertension Caused by Systolic Left Ventricular Dysfunction A Phase IIb Double-Blind, Randomized, Placebo-Controlled, Dose-Ranging Hemodynamic Study

Background— Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality; however, no treatment is approved for this indication. We hypothesized that riociguat, a novel soluble guanylate cyclase stimulator, would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction. Methods and Results— Overall, 201 patients with heart failure resulting from pulmonary hypertension caused by systolic left ventricular dysfunction were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg 3 times daily) for 16 weeks in 4 parallel arms. The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure. Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group (−6.1±1.3 mm Hg; P <0.0001 versus baseline) was not significantly different from placebo ( P =0.10), cardiac index (0.4 L·min−1·m−2; 95% confidence interval, 0.2–0.5; P =0.0001) and stroke volume index (5.2 mL·m−2; 95% confidence interval, 2.0–8.4; P =0.0018) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo. Both pulmonary (−46.6 dynes·s−1·cm−5; 95% confidence interval, –89.4 to –3.8; P =0.03) and systemic vascular resistance (−239.3 dynes·s−1·cm−5; 95% confidence interval, –363.4 to –115.3; P =0.0002) were significantly reduced with riociguat 2 mg. Riociguat reduced the Minnesota Living With Heart Failure score ( P =0.0002). Discontinuation of treatment was similar between treatment groups. Conclusions— Although the primary end point of the study was not met, riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance. Clinical Trial Registration— URL: . Unique identifier: [NCT01065454][1]. # Clinical Perspective {#article-title-31} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01065454&atom=%2Fcirculationaha%2F128%2F5%2F502.atomBackground— Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality; however, no treatment is approved for this indication. We hypothesized that riociguat, a novel soluble guanylate cyclase stimulator, would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction. Methods and Results— Overall, 201 patients with heart failure resulting from pulmonary hypertension caused by systolic left ventricular dysfunction were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg 3 times daily) for 16 weeks in 4 parallel arms. The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure. Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group (−6.1±1.3 mm Hg; P<0.0001 versus baseline) was not significantly different from placebo (P=0.10), cardiac index (0.4 L·min−1·m−2; 95% confidence interval, 0.2–0.5; P=0.0001) and stroke volume index (5.2 mL·m−2; 95% confidence interval, 2.0–8.4; P=0.0018) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo. Both pulmonary (−46.6 dynes·s−1·cm−5; 95% confidence interval, –89.4 to –3.8; P=0.03) and systemic vascular resistance (−239.3 dynes·s−1·cm−5; 95% confidence interval, –363.4 to –115.3; P=0.0002) were significantly reduced with riociguat 2 mg. Riociguat reduced the Minnesota Living With Heart Failure score (P=0.0002). Discontinuation of treatment was similar between treatment groups. Conclusions— Although the primary end point of the study was not met, riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01065454.

Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial

BACKGROUND In May 2011, an outbreak of Shiga toxin-producing enterohaemorrhagic E coli O104:H4 in northern Germany led to a high proportion of patients developing post-enteritis haemolytic uraemic syndrome and thrombotic microangiopathy that were unresponsive to therapeutic plasma exchange or complement-blocking antibody (eculizumab). Some patients needed ventilatory support due to severe neurological complications, which arose 1 week after onset of enteritis, suggesting an antibody-mediated mechanism. Therefore, we aimed to assess immunoadsorption as rescue therapy. METHODS In our prospective non-controlled trial, we enrolled patients with severe neurological symptoms and confirmed recent E coli O104:H4 infection without other acute bacterial infection or raised procalcitonin concentrations. We did IgG immunoadsorption processing of 12 L plasma volumes on 2 consecutive days, followed by IgG replacement (0·5 g/kg intravenous IgG). We calculated a composite neurological symptom score (lowest score was best) every day and assessed changes before and after immunoadsorption. FINDINGS We enrolled 12 patients who initially presented with enteritis and subsequent renal failure; 10 (83%) of 12 patients needed renal replacement therapy by a median of 8·0 days (range 5-12). Neurological complications (delirium, stimulus sensitive myoclonus, aphasia, and epileptic seizures in 50% of patients) occurred at a median of 8·0 days (range 5-15) and mandated mechanical ventilation in nine patients. Composite neurological symptom scores increased in the 3 days before immunoadsorption to 3·0 (SD 1·1, p=0·038), and improved to 1·0 (1·2, p=0·0006) 3 days after immunoadsorption. In non-intubated patients, improvement was apparent during immunoadsorption (eg, disappearance of aphasia). Five patients who were intubated were weaned within 48 h, two within 4 days, and two patients needed continued ventilation for respiratory problems. All 12 patients survived and ten had complete neurological and renal function recovery. INTERPRETATION Antibodies are probably involved in the pathogenesis of severe neurological symptoms in patients with E coli O104:H4-induced haemolytic uraemic syndrome. Immunoadsorption can safely be used to rapidly ameliorate these severe neurological complications. FUNDING Greifswald University and Hannover Medical School.