Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure

present, process of myocardial necrosis in subsets of wellcharacterized non-ischemic cardiomyopathy. RC

the high morbidity rate in this population, a longer term study with hospitalization and morbid events outcomes would be valuable. RC

Dilated Cardiomyopathy in Dialysis PatientsBeneficial Effects of Carvedilol: A Double-Blind, Placebo-Controlled Trial

Immunomodulating Therapy With Intravenous Immunoglobulin in Patients With Chronic Heart Failure

Cice C, Ferrara L, Di Benedetto A, et al. J Am Coll Cardiol 2001; 37:407–11.

Gullestad L, Aass H, Fjeld JG, et al. Circulation 2001;103:220 – 5.

Study Question: Congestive heart failure (CHF) in chronic hemodialyzed patients, particularly when associated with dilated cardiomyopathy, represents an ominous complication and is an independent risk factor for cardiac mortality. The aim of this study was to investigate in dialysis patients with symptomatic heart failure New York Heart Association (NYHA) functional class II or III whether the addition of carvedilol to conventional therapy is associated with beneficial effects on cardiac architecture, function and clinical status. Methods: The study consisted of 114 dialysis patients with dilated cardiomyopathy. All patients were treated with carvedilol for 12 months in a double-blind, placebo-controlled, randomized trial. The patients underwent M-mode and two-dimensional echocardiography at baseline, 1, 6 and 12 months after the randomization. Each patient’s clinical status was assessed using an NYHA functional classification that was determined after 6 and 12 months of treatment. Results: In the active-treatment group, the increase in LV ejection fraction (from 26.3% to 34.8%, p ⬍ 0.05 vs. basal and placebo group) and the reduction of both LV enddiastolic volume (from 100 mL/m2 to 94 mL/m2, p ⬍ 0.05 vs. basal and placebo group) and end-systolic volume (from 74 mL/m2 to 62 mL/m2, p ⬍ 0.05 vs. basal and placebo group) reached statistical significance after 6 months of therapy. The clinical status of patients, assessed by NYHA functional classification, improved during the treatment period. Moreover, at the end of the trial, there were no patients in NYHA functional class IV in the carvedilol group, compared with 5.9% of the patients in the placebo arm. Conclusions: One year of therapy with the carvedilol in dialysis patients with CHF and dilated cardiomyopathy reduces LV volumes and improves LV function and clinical status. Perspective: Approximately 68% of patients in this study had ischemic heart disease as the etiology of cardiomyopathy, with only 24% of patients with cardiomyopathy based on a hypertensive etiology. These findings demonstrate that carvedilol is not only safe in this population but also associated with evidence of clinical benefit. The study design minimizes the variability one would expect in a dialysis population. The benefit may be associated with a reduction of blood pressure in the carvedilol treatment group. With

Study Question: Congestive heart failure (CHF) is characterized by enhanced immune activation, and immune-mediated mechanisms may play a pathogenic role in this disorder. Intravenous immunoglobulin (IVIG) could downregulate inflammatory responses in CHF patients and have potential beneficial effects on the left ventricular ejection fraction (LVEF). Methods and Results: Forty patients with chronic symptomatic CHF and LVEF ⬍40%, stratified according to cause (i.e., ischemic and idiopathic dilated cardiomyopathy), were randomized in a double-blind fashion to receive therapy with IVIG or placebo for a total period of 26 weeks. IVIG, but not placebo, induced a marked rise in plasma levels of the anti-inflammatory mediators interleukin (IL)10, IL-1 receptor antagonist and soluble tumor necrosis factor receptors. Significantly correlated with these antiinflammatory effects, IVIG, but not placebo, induced a significant increase in LVEF from 26⫾2% to 31⫾3% (p ⬍ 0.01), and this was found independent of the cause of heart failure. N-terminal pro-atrial natriuretic peptide decreased significantly after induction therapy and continued to decrease toward the end of study during IVIG therapy (p ⬍ 0.001) but remained unchanged during placebo. Conclusions: This study demonstrated an IVIG-induced change in the balance between inflammatory and antiinflammatory cytokines that favored an anti-inflammatory net effect in CHF. This effect was significantly correlated with an improvement in LVEF, suggesting a potential role for immunomodulating therapy in addition to optimal conventional cardiovascular treatment regimens in CHF patients. Perspective: The important finding in this study is the suggestion that an ongoing inflammatory response characterizes some forms of heart failure. Since this population was of mixed etiology, no strong relationship between etiology and inflammation can be inferred. Additionally, one cannot rule out a secondary process, reversed by immune therapy, that resulted in amelioration of the heart failure process. The correlation of response to IVIG with an increase in EF is less impressive. The selective reduction of N-terminal proANP in the IVIG group is more compelling, suggesting a physiologic correlation with reduced myocardial wall stress. RC

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