Darbepoetin-α prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure

Abstract

Rastogi S, Imai M, Sharov VG, Mishra S, Sabbah HN. Darbepoetin-␣ prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure. Am J Physiol Heart Circ Physiol 295: H2475-H2482, 2008. First published October 24, 2008 doi:10.1152/ajpheart.00074.2008.-In anemic patients with heart failure (HF), erythropoietin-type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin-␣ (DARB) on left ventricular (LV) function and remodeling in nonanemic dogs with advanced HF. HF [LV ejection fraction (EF) ϳ25%] was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 g/kg, n ϭ 7) or to no therapy (HF, n ϭ 7). All procedures were performed during cardiac catheterization under general anesthesia and under sterile conditions. LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were measured before the initiation of therapy and at the end of 3 mo of therapy. mRNA and protein expression of caspase-3, hypoxia inducible factor-1␣, and the bone marrow-derived stem cell marker c-Kit were determined in LV tissue. In HF dogs, EDV and ESV increased and EF decreased after 3 mo of followup. Treatment with DARB prevented the increase in EDV, decreased ESV, and increased EF. DARB therapy also normalized the expression of HIF-1␣ and active caspase-3 and enhanced the expression of c-Kit. We conclude that chronic monotherapy with DARB prevents progressive LV dysfunction and dilation in nonanemic dogs with advanced HF. These results suggest that DARB elicits beneficial effects in HF that are independent of the presence of anemia. erythropoietin; anemia; ventricular remodeling; stem cells MANY PATIENTS with congestive heart failure (HF) are anemic or exhibit hemoglobin levels near the lower limit of normal (12). The severity of HF has been shown to positively correlate with the degree of anemia (38,45). The kidneys represent the main site of the synthesis of erythropoietin, the most important hormone regulating erythropoiesis (18,19). Darbepoetin-␣ (DARB) is a derivative of erythropoietin that contains two more carbohydrate groups than the native protein and increase its half-life by threefold compared with recombinant erythropoietin. DARB has been shown to be efficacious in maintaining hemoglobin levels in anemic patients (24). Clinical trials have shown that in anemic patients with HF, DARB increases and maintains hemoglobin and improves health-related quality of life and exercise duration (29,44).Erythropoietin has also been shown to possess a host of other nonerythropoietic properties including the ability to stimulate angiogenesis (20), attenuate apoptosis and hypoxia (28,41), and mobilize bone marrow-derived stem cells (BMSCs) (1, 2). Erythropoietin has also been shown to exert direct cytoprotective effects on cardiomyocytes through stimulation of the erythropoietin receptor and the phosphatidylinositol 3-kinase/Akt signaling pathway (4,46). In a rat model of my...

Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat

“…Caspase-3 activity increased in MA-ISO and was not altered in YA-ISO, supporting the idea that nonsenescent animals are more vulnerable to injury and stress than their younger counterparts. This finding is consistent with a previous study showing that caspase-3 overexpression depresses cardiac function in mice, and with a report that caspase-3 expression is elevated in a dog model of HF (14,45). An in vitro study demonstrated that caspase-3 activation leads to a reduction of contractile reserve in LV cardiomyocytes (30).…”

“…Additionally, pharmacological inhibition of caspase-3 improved postischemic contractile recovery in the isolated rat heart (49). The present in vivo results, along with data from several models of cardiovascular injury, support the notion that caspase activation plays a major role in the development of contractile dysfunction (9,30,45,49). The precise mechanisms of caspase-3-induced reductions in systolic performance are uncertain but may involve perturbations in Ca 2ϩ homeostasis or direct effects on the contractile proteins of the sarcomere (9,47,49).…”

The Anemia of Heart Failure

“…The usefulness of ESA in CHF has been shown in animal studies where its use in CHF after myocardial infarction or after production of cardiac damage from other causes, with or without improving the Hb, has improved endothelial dysfunction, increased neovascularization of the heart muscle, and reduced apoptosis of cardiomyocytes, oxidative stress, inflammation, fibrosis, and hypoxic damage, and prevented functional impairment of the heart [87,88,89]. At least part of these effects is due to the increase in number and activity of endothelial progenitor cells from the bone marrow [87,88,89].…”

“…At least part of these effects is due to the increase in number and activity of endothelial progenitor cells from the bone marrow [87,88,89]. …”

Is erythropoietin behind maladaptive anemic heart failure?

“…Recombinanthuman EPO administration has been shown to exert a broad tissue-protective effect in a variety of experimental models. In the cardiovascular system, EPO has been shown to exert marked myocardial protective effects against ischemia-reperfusion injury via a reduction of LV infarct size and a significantly decreased apoptotic cell death of cardiomyocytes, which leads to an enhanced recovery of LV function (5,16). Mechanistically, studies have shown that EPO-EPO-R signaling can stimulate the JAK/STAT, MAPK, and phosphatidylinositol 3-kinase/Akt signaling pathways in cardiac cells, much like the signaling in hematopoietic cells (13,14).…”