Initial white blood cell count is an independent risk factor for survival in patients with dilated cardiomyopathy.

BACKGROUND: The impact of white blood cell count (WBCc) on the outcome of patients with non-ischemic left ventricular (LV) dysfunction is unknown. In the present study we investigated the influence of WBCc on mortality and cardiac inflammation in patients with reduced LV systolic function in the absence of ischemic or valvular etiology. METHODS AND RESULTS: We included 381 patients with reduced left ventricular (LV) ejection fraction (LVEF ≤ 45%) quantified by two-dimensional echocardiography. Coronary artery disease and valvular diseases were excluded by angiography and echo, respectively, in all patients. WBCc was quantified routinely upon first hospital admission. In 291 patients, endomyocardial biopsies from the right ventricle were performed upon first hospital admission for assessment of cardiac inflammation. Follow-up was up to 5.5 years (median 2.93 [1.7;4.0]). Information on vital status of patients was obtained from official resident data files. WBCc >11 Gpt/l was associated with significantly increased mortality in patients with severe LV dilation (end-diastolic diameter (LVEDD) >70 mm quantified by echocardiography) in comparison to patients showing WBCc ≤ 11 Gpt/l (41.7% vs 13.6%, p=0.02). Multivariable Cox regression analysis showed that WBCc predicts mortality independently of other cardiovascular risk factors and LVEF (hazard ratio 1.14; p=0.04). Doses of heart failure medication did not differ significantly in patients with LVEDD >70 mm and WBCc >11 Gpt/l when compared to LVEDD >70 mm and WBCc ≤ 11 Gpt/l (percent of maximum doses: ß-blockers p=0.51, ACE inhibitors p=0.56, AT1 antagonists p=0.77, aldosterone antagonists p=0.35). WBCc including its subpopulations (monocytes, lymphocytes and granulocytes) did not show a significant correlation with cardiac amounts of CD3(+)-lymphocytes (r=0.02, p=0.78) or CD68(+)-macrophages (r=1.0, p=0.09) (n=291). CONCLUSION: WBCc at first hospital admission predicts long term-mortality in patients with dilated cardiomyopathy independently of cardiovascular risk factors.

Drug-like actions of autoantibodies against receptors of the autonomous nervous system and their impact on human heart function.

Antibodies against cholinergic and adrenergic receptors (adrenoceptors) are frequent in serum of patients with chronic heart failure. Their prevalence is associated with Chagas' disease, idiopathic dilated cardiomyopathy (DCM), and ischaemic heart disease. Among the epitopes targeted are first and second extracellular loops of the ß-adrenergic (ß-adrenoceptor) and M2 muscarinic receptor. ß(1)-adrenoceptor autoantibodies affect radioligand binding and cardiomyocyte function similar to agonists. Corresponding rodent immunizations induce symptoms compatible with chronic heart failure that are reversible upon removal of the antibodies, transferable via the serum and abrogated by adrenergic antagonists. In DCM patients, prevalence and stimulatory efficacy of ß(1)-adrenoceptor autoantibodies are correlated to the decline in cardiac function, ventricular arrhythmia and higher incidence of cardiac death. In conclusion, such autoantibodies seem to cause or promote chronic human left ventricular dysfunction by acting on their receptor targets in a drug-like fashion. However, the pharmacology of this interaction is poorly understood. It is unclear how the autoantibodies trigger changes in receptor activity and second messenger coupling and how that is related to the pathogenesis and severity of the associated diseases. Here, we summarize the available evidence regarding these issues and discuss these findings in the light of recent knowledge about the conformational activation of the human ß(2)-adrenoceptor and the properties of bona fide cardiopathogenic autoantibodies derived from immune-adsorption therapy of DCM patients. These considerations might contribute to the conception of therapy regimen aimed at counteracting or neutralizing cardiopathogenic receptor autoantibodies.

Cardioprotection of 17,18-epoxyeicostetraenoic acid in ischemia/reperfusion is mediated by cyclooxygenase-2: a study in a rat model.

BACKGROUND/PURPOSE: Arachidonic acid and related cardioprotective eicosanoids are released in myocardial ischemia/reperfusion injury. The present study analyzes the effects of the eicosapentaenoic acid derived 17,18-epoxyeicostetraenoic acid on isolated cardiomyocytes and investigates whether 17,18-epoxyeicostetraenoic acid serves as a potential factor in the cardio-depressant postischemic effluent. BASIC PROCEDURES: After 10 minutes of global ex vivo stop-flow ischemia, adult rat hearts were reperfused and coronary postischemic effluent was collected over a period of 30 seconds. Nonischemic effluent was collected prior to ischemia. The effects of 17,18-epoxyeicostetraenoic acid on calcium (Ca(2+)) metabolism and contraction frequency of isolated neonatal rat cardiomyocytes were tested and compared with the effects of prior collected postischemic and nonischemic effluents. Isolated neonatal cardiomyocytes were preincubated with selective (NS-398, SC-560) and nonselective cyclooxygenase inhibitors (indomethacin) to determine whether cardio-depressive effects are mediated by cyclooxygenase. FINDINGS: In contrast to the nonischemic effluent, both 17,18-epoxyeicostetraenoic acid and the postischemic effluent induced a comparable decrease of the Ca(2+) transient and the contraction frequency (P < .05 vs control). The cardio-depressive effects of 17,18-epoxyeicostetraenoic acid and the postischemic effluent were significantly attenuated after preincubation with the unselective cyclooxygenase inhibitor indomethacin and the selective cyclooxygenase-2 inhibitor NS-398 (P < .05 vs control). Selective cyclooxygenase-1 inhibition with SC-560 did not influence the effect of 17,18-epoxyeicostetraenoic acid and the postischemic effluent. CONCLUSIONS: Our data show that the cardio-depressive effects of 17,18-epoxyeicostetraenoic acid are comparable with the postischemic effluent and are mediated by cyclooxygenase-2. Our results suggest a potential cardioprotective role of the eicosanoid 17,18-epoxyeicostetraenoic acid in heart ischemia/reperfusion injury.

Fcgamma-receptor IIa polymorphism and the role of immunoadsorption in cardiac dysfunction in patients with dilated cardiomyopathy.

In patients with dilated cardiomyopathy (DCM), cardiac autoantibodies are able to bind with their Fab fragment to epitopes on cardiomyocytes, but thereafter they crosslink through their Fc fragment to cardiac Fc(gamma)-receptor IIa. Polymorphic variability of the Fc(gamma)-receptor IIa is associated with modified affinity of immunoglobin G (IgG) binding and may influence therapeutic effects. In this study, 103 consecutive DCM patients were treated with immunoadsorption (IA) therapy with subsequent IgG substitution (IA/IgG). Echocardiography was performed at baseline and again at 3 and 6 months after IA/IgG. Fc(gamma)-receptor IIa polymorphism R/H131 was genotyped using a nested sequence-specific primer polymerase chain reaction (PCR). Patients with the Fc(gamma)-receptor IIa genotype R/R131 showed significantly greater improvement in left ventricular (LV) function than patients with the R/H131 or H/H131 genotypes did. Irrespective of the Fc(gamma)-receptor polymorphism, patients with shorter disease duration and a more impaired LV function responded with a greater increase in LV ejection fraction (LVEF). Therefore, the Fc(gamma)-receptor polymorphism influences the efficacy of immunomodulatory therapy involving IA/IgG.

[Immunoadsorption for treatment of dilated cardiomyopathy]. / Immunadsorption als Therapieverfahren der dilatativen Kardiomyopathie.

Abnormalities of the cellular and humoral immune system have been described in patients with dilated cardiomyopathy (DCM). For patients with DCM, immunochemical analyses of myocardial biopsies have demonstrated myocardial inflammation. Various circulating cardiac antibodies have been detected among DCM patients. Circulating antibodies are extractable by immunoadsorption. Recent open controlled pilot studies showed that removal of antibodies by immunoadsorption induces improvement of cardiac function in DCM. Furthermore, it decreases myocardial inflammation. This may offer a new therapeutic option for patients with severe heart failure due to dilated cardiomyopathy.