Immunoadsorption therapy for dilated cardiomyopathy using tryptophan column-A prospective, multicenter, randomized, within-patient and parallel-group comparative study to evaluate efficacy and safety.

Over the past few decades, several cardiac autoantibodies have been reported in sera from patients with dilated cardiomyopathy (DCM). Immunoadsorption (IA) therapy is one of the therapeutic tools to remove such autoantibodies. The objective of this study was to investigate functional effects of IA therapy using a tryptophan column in severe DCM patients. Of 49 patients enrolled, 44 were randomized from 10 sites in Japan. IA therapy was conducted in 40 patients with DCM (refractory to standard therapy for heart failure, New York Heart Association [NYHA] class III/IV, left ventricular ejection fraction [LVEF] <30%). Mean echocardiographic LVEF was significantly improved (23.8 ± 1.3% to 25.9 ± 1.3%, P = 0.0015). However, mean radionuclide LVEF over 3 months of IA therapy was not significantly improved (20.8 ± 1.1% to 21.9 ± 1%, P = 0.0605). The cardiothoracic ratio was also significantly decreased (P = 0.0010). NYHA functional class (P < 0.0001), subjective symptoms assessed by a quality of life questionnaire (P = 0.0022), maximum oxygen consumption (P = 0.0074), and 6-minute walk distance (P = 0.0050) were improved after IA therapy. Subgroup analysis revealed improvement of echocardiographic LVEF in patients with higher baseline autoantibody scores but not in those with lower scores. IA therapy improved subjective symptoms and exercise capacity in patients with refractory heart failure resulting from DCM. Favorable effect on cardiac function was noted in patients with higher autoantibody scores. J. Clin. Apheresis 31:535-544, 2016. © 2015 Wiley Periodicals, Inc.

Specific immunoadsorption therapy using a tryptophan column in patients with refractory heart failure due to dilated cardiomyopathy.

BACKGROUND: Certain cardiac-specific autoantibodies found in patients with dilated cardiomyopathy (DCM) play a role in mediating myocardial damage and fatal ventricular arrhythmias resulting in sudden cardiac death. Immunoadsorption therapy (IA) is one of the therapeutic tools to remove such autoantibodies. Clinical studies from Germany have shown that nonspecific IA using columns loaded by sheep antihuman IgG or protein A improved hemodynamic data and affected favorably cardiac function and survival in patients with heart failure (HF) due to DCM. The goal of this study is to determine if IA therapy using the high-profile tryptophan column, which has high affinity for IgG3 subclass, affects favorably cardiac function in patients with severe HF who are refractory to conventional therapy. METHODS AND RESULTS: IA therapy was conducted in 16 patients with DCM (age 53 ± 4, male 8, New York Heart Association functional class III/IV, mean ejection fraction 18 ± 2%). Study subjects had autoantibodies directed against either ß1-adrenergic or M2-muscarinic receptors. Plasma brain natriuretic peptide levels were significantly decreased after IA (P = 0.016). Plasma inflammatory cytokines including interleukin-6 and tumor necrosis factor-α did not change after each session of IA. Six-minute walk distance was significantly increased after IA (P = 0.01). Left ventricular ejection fraction increased by 3% 3 months after IA (P = 0.039). CONCLUSIONS: Our initial experience demonstrated safety and short-term efficacy of IA using a new IgG3-specific tryptophan column for patients with advanced HF due to DCM. Long-term follow-up is needed to confirm the effects on cardiac function and morbidity/mortality in such patients.

Complete elimination of cardiodepressant IgG3 autoantibodies by immunoadsorption in patients with severe heart failure.

BACKGROUND: Cardiodepressant IgG3 autoantibodies (CD-Abs) can be targeted by apheresis. Using blinded measurements of CD-Abs before and after immunoadsorption (IA), the cardiac function of patients who did or did not achieve complete CD-Abs elimination was compared. METHODS AND RESULTS: Autoantibodies were completely removed from 18 patients with heart failure (New York Heart Association class 3 or 4, left ventricular ejection fraction (LVEF) <30%) using a selective IgG3 adsorption column. All patients had anti-beta1-adrenergic and/or M2-muscarinic autoantibodies before IA, and all LVEF were measured on radionuclide ventriculography. CD-Abs were measured before and after IA, and patient status was blinded until all measurements were collected. Treatment was defined as complete when CD-Abs status changed from positive to negative after IA. Other instances were defined as incomplete. Six-min walk test results and brain natriuretic peptide levels improved significantly after IA (P<0.01). The increase in LVEF 3 months after IA was significantly greater after complete treatment in comparison to the incomplete treatment group (19+/-8-29+/-9% vs 18+/-9-17+/-8%, P<0.01). Cardiac insufficiency events were also more frequent in the incomplete treatment group. CONCLUSIONS: Complete elimination of CD-Abs with apheresis may be related to improved cardiac function in the treatment of heart failure.

Vasorelaxation by L-arginine after L-NAME administration in rabbits consuming moderate amounts of red wine.

Red wine and its constituents have been shown to stimulate endothelium-dependent and nitric oxide (NO)-mediated vasorelaxation in vitro in the isolated and precontracted aortic rings. The present study investigated if this occurred in vivo in rabbits, which chronically consumed a moderate amount of red wine. N(omega)nitro-L-arginine-methyl ester (L-NAME) and L-arginine was infused into the rabbits that consumed red wine (7 mL/kg/d), ethanol (99.5%, 0.8 mL/kg/d), or water alone for 4 weeks, and the vaso-constrictive/-dilative response was studied in the renal artery. Following treatment with L-NAME (30 mg/kg), the renal blood flow rate decreased and renal vascular resistance increased. Only in the animals consuming red wine did a subsequent administration of L-arginine (300 mg/kg) increase the renal blood flow rate and decrease the renal vascular resistance. The effects were associated with the increase in the renal NO metabolite (nitrite/nitrate, NO2(-)/NO3(-)) production rate. From the present in vivo model, it is suggested that vasorelaxation by L-arginine is through the NO pathway and that the effects observed in the animals consuming the red wine cannot be attributed to alcohol alone.