Zaczkiewicz Myron, Kostenzer Katharina, Graf Matthias, Mayer Benjamin, Zimmermann Oliver, Torzewski Jan
Cardiovascular Center Oberallgäu-Kempten, 87439 Kempten, Germany.
Institute of Epidemiology and Medical Biometry, University of Ulm, 89081 Ulm, Germany.
J Clin Med. 2022 Mar 22;11(7):1762. doi: 10.3390/jcm11071762.
Recent randomized controlled multi-center trials JUPITER, CANTOS and COLCOT impressively demonstrated the effect of anti-inflammatory therapy on secondary prevention of cardiovascular events. These studies also rapidly re-vitalized the question of whether the C-reactive protein (CRP), the prototype human acute phase protein, is actively involved in atherosclerosis and its sequelae. Direct CRP inhibition may indeed improve the specificity and effectiveness of anti-inflammatory intervention. In the present paper, we report on the final results of our single-center C-reactive protein-Digoxin Observational Study (C-DOS). Methods and Results: Based on the experimental finding that cardiac glycosides potently inhibit hepatic CRP synthesis on the transcriptional level in vitro, 60 patients with decompensated heart failure, NYHA III−IV, severely reduced Left Ventricular Ejection Fraction (LVEF < 40%), and elevated CRP plasma levels were treated by either digoxin + conventional heart failure therapy (30 patients) or by conventional heart failure therapy alone (30 patients). Plasma CRP levels in both groups were assessed for 21 d. Plasma CRP levels on d1, d3 and d21 were compared by regression analysis. CRP levels d21−d1 significantly declined in both groups. Notably, comparative CRP reduction d21−d3 in digoxin versus the control group also revealed borderline significance (p = 0.051). Conclusions: This small observational trial provides the first piece of evidence that cardiac glycosides may inhibit CRP synthesis in humans. In case of further pharmacological developments, cardiac glycosides may emerge as lead compounds for chemical modification in order to improve the potency, selectivity and pharmacokinetics of CRP synthesis inhibition in cardiovascular disease.
近期的随机对照多中心试验JUPITER、CANTOS和COLCOT令人印象深刻地证明了抗炎治疗在心血管事件二级预防中的作用。这些研究也迅速重新引发了一个问题，即作为人类急性期蛋白原型的C反应蛋白（CRP）是否积极参与动脉粥样硬化及其后遗症。直接抑制CRP可能确实会提高抗炎干预的特异性和有效性。在本文中，我们报告了单中心C反应蛋白-地高辛观察性研究（C-DOS）的最终结果。方法与结果：基于心脏糖苷在体外转录水平上有效抑制肝脏CRP合成的实验发现，对60例失代偿性心力衰竭、纽约心脏协会（NYHA）III-IV级、左心室射血分数严重降低（左心室射血分数<40%）且血浆CRP水平升高的患者，采用地高辛+传统心力衰竭治疗（30例患者）或仅采用传统心力衰竭治疗（30例患者）。两组均评估21天的血浆CRP水平。通过回归分析比较第1天、第3天和第21天的血浆CRP水平。两组中第21天-第1天的CRP水平均显著下降。值得注意的是，地高辛组与对照组相比，第21天-第3天CRP的降低也显示出临界显著性（p = 0.051）。结论：这项小型观察性试验提供了首个证据，表明心脏糖苷可能在人体内抑制CRP合成。如果有进一步的药物研发进展，心脏糖苷可能会成为化学修饰的先导化合物，以提高心血管疾病中CRP合成抑制的效力、选择性和药代动力学。
