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In anemic patients with heart failure (HF), erythropoietin-type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin-[alpha] (DARB) on left ventricular (LV) function and remodeling in nonanemic dogs with advanced HF. HF [LV ejection fraction (EF) ~25%] was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 [micro]g/kg, n = 7) or to no therapy (HF, n = 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[alpha], 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-l[alpha] 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

Acute intravenous infusion of ranolazine (Ran), an anti-ischemic/ antiangina drug, was previously shown to improve left ventricular (LV) ejection fraction (EF) without a concomitant increase in myocardial oxygen consumption in dogs with chronic heart failure (HF). This study examined the effects of treatment with Ran alone and in combination with metoprolol (Met) or enalapril (Ena) on LV function and remodeling in dogs with HF. Dogs (n = 28) with microembolization-induced HF were randomized to 3 mo oral treatment with Ran alone [375 mg twice daily (bid); n = 7], Ran (375 mg bid) in combination with Met tartrate (25 mg bid; n = 7), Ran (375 mg bid) in combination with Ena (10 mg hid; n = 7), or placebo (PL; Ran vehicle bid; n = 7). Ventriculographic measurements of LV enddiastolic volume (EDV) and end-systolic volume (ESV) and LV EF were obtained before treatment and after 3 mo of treatment. In PL-treated dogs, EDV and ESV increased significantly. Ran alone prevented the increase in EDV and ESV seen in the PL group and significantly increased EF, albeit modestly, from 35 [+ or -] 1% to 37 [+ or -] 2%. When combined with either Ena or Met, Ran prevented the increase in EDV, significantly decreased ESV, and markedly increased EF compared with those of PL. EF increased from 35 [+ or -] 1% to 40 [+ or -] 1% with Ran + Ena and from 34 [+ or -] 1% to 41 [+ or -] 1% with Ran + Met. Ran alone or in combination with Ena or Met was also associated with beneficial effects at the cellular level on histomorphometric parameters such as hypertrophy, fibrosis, and capillary density as well as the expression for pathological hypertrophy and [Ca.sup.2+] cycling genes. In conclusion, Ran prevented progressive LV dysfunction and global and cellular myocardial remodeling, and Ran in combination with Ena or Met improved LV function beyond that observed with Ran alone. ventricular remodeling; sodium current; transcription factors; left ventricle

When recovering from heart failure (HF), the myocardium displays a marked plasticity and can regain normal gene expression and function; however, recovery of substrate oxidation capacity has not been explored. We tested whether cardiac functional recovery is matched by normalization of energy substrate utilization during post-HF recovery. HF was induced in dogs by pacing the left ventricle (LV) at 210-240 beats/min for 4 wk. Tachycardia was discontinued, and the heart was allowed to recover. An additional group was studied in HF, and healthy dogs served as controls (n = 8/group). Cardiac free fatty acids (FFAs) and glucose oxidation were measured with [[sup.3]H]oleate and [[sup.14]C]glucose. At 10 days of recovery, hemodynamic parameters returned to control values; however, the contractile response to dobutamine remained depressed, LV end-diastolic volume was 28% higher than control, and the heart mass-to-body mass ratio was increased (9.8 [+ or -] 0.4 vs. 7.5 [+ or -] 0.2 g/kg, P < 0.05). HF increased glucose oxidation (76.8 [+ or -] 19.7 nmol x [min.sup.-1] x [g.sup.-1]) and decreased FFA oxidation (20.7 [+ or -] 6.4 nmol x [min.sup.-1] x [g.sup.-1]), compared with normal dogs (24.5 [+ or -] 6.3 and 51.7 [+ or -] 9.6 nmol x [min.sup.-1] x [g.sup.-1], respectively), and reversed to normal values at 10 days of recovery (25.4 [+ or -] 6.0 and 46.6 [+ or -] 6.7 nmol x [min.sup.-1] x [g.sup.-1], respectively). However, similar to HF, the recovered dogs failed to increase glucose and fatty acid uptake in response to pacing stress. The activity of myocardial citrate synthase and aconitase was significantly decreased during recovery compared with that in control dogs (58 and 27% lower, respectively, P < 0.05), indicating a persistent reduction in mitochondrial oxidative capacity. In conclusion, cardiac energy substrate utilization is normalized in the early stage of post-HF recovery at baseline, but not under stress conditions. dilated cardiomyopathy; fatty acids; glucose; tachypacing

Matrix metalloproteinases (MMPs) contribute to the progression of left ventricular (LV) dysfunction and remodeling associated with heart failure (HF). The present study examined the long-term effects of a selective MMP inhibitor PG-530742 (PG) on the progression of LV dysfunction and remodeling in dogs with HF. Chronic HF [LV ejection fraction (LVEF), [greater than or equal to] 36%] was produced by multiple sequential intracoronary microembolizations in 24 dogs. Two weeks after the last embolization, dogs were randomized to 3 mo of therapy with either high-dose (HD) PG (3.5 mg/kg, n = 8), low-dose (LD) PG (0.2 mg/kg, n = 8), or to a matched placebo (PL, n = 8). PG has been shown to produce complete inhibition of MMP-2, -3, -9, and -13, while sparing MMPs-1 and -7. Hemodynamic and echocardiographic measurements were made before and 3 mo after initiating therapy. In PL and LD dogs, LVEF decreased significantly, and LV end-systolic volume (ESV) and LV end-diastolic volume (EDV) increased significantly during the 3-mo follow-up period. Whereas in HD dogs ejection traction increased from 36 [+ or -] 1 to 40 [+ or -] 1% (P = 0.003), EDV and ESV decreased (59 [+ or -] 4 vs. 57 [+ or -] 4 ml, P = 0.02; and 38 [+ or -] 2 vs. 34 [+ or -] 2 ml, P = 0.00001, respectively). When compared with controls, HD-treated dogs showed 30% reduction in replacement fibrosis, 29% reduction in interstitial fibrosis, and 28% reduction in myocyte cross-sectional area. mRNA expression of selective MMPs was also reduced in LV tissue in HD- but not LD-treated dogs. In conclusion, in dogs with moderate HF, long-term monotherapy with HD selective MMP inhibitor PG prevents LV remodeling and the progression of global LV dysfunction. hemodynamics; PG-530742; left ventricular ejection fraction

It has been proposed that the hemodynamic deterioration associated with heart failure (HF) may be due in part to ongoing loss of viable cardiac myocytes through apoptosis. Hypoxia has been shown to promote apoptosis in normal cardiomyocytes. Adaptation and maladaptations inherent to heart failure can modify the susceptibility of cells to different stress factors. We hypothesized that HF modifies the threshold of cardiomyocytes to hypoxia-induced apoptosis. Cardiomyocytes were isolated from 18 human hearts explanted at the time of cardiac transplantation due to either ischemic cardiomyopathy (ICM) (n = 9) or idiopathic dilated cardiomyopathy (IDC) (n = 9). Tissue from five normal donor hearts (NL) for whom no suitable recipient was available was used as control. Cardiomyocytes were incubated for 3 h under normoxic (95% air-5% C[O.sub.2]) or hypoxic (95% [N.sub.2]-5% C[O.sub.2]) conditions. Expression of caspase-3 and DNA fragmentation factor-45 (DFF45)/inhibitor of caspase-3-activated DNase (ICAD) was detected by Western blot analysis. Three hours of hypoxia did not affect the expression of these proteins in NL cardiomyocytes. In contrast, hypoxia led to cleavage of caspase-3 and DFF45/ICAD both in ICM and IDC. In conclusion, failing cardiomyocytes exhibit increased susceptibility to hypoxia-induced apoptosis. heart failure; apoptosis

Early long-term therapy with the AT(sub 1)-receptor blocker valsartan decreases preload and afterload for dogs with moderate heart failure, but has few benefits in attenuating the progression of left ventricular dysfunction and chamber remodeling. This was concluded in a study that sought to determine the effects of early long-term monotherapy with the angiotensin II AT(sub 1)-receptor antagonist valsartan on the progression of left ventricular dysfunction and remodeling in dogs with moderate heart failure. Treatment with valsartan substantially reduced mean aortic pressure and left ventricular end-diastolic pressure compared with control.

Research was conducted to examine the hypothesis that early long-term treatment with angiotensin-converting enzyme (ACE) inhibition in dogs with moderate heart failure (HF) is related to reduced cardiomyocyte apoptosis as supported by a reduced incidence of cardiomyocyte nDNAf. The reduction in the overall incidence of cardiomyocyte apoptosis in dogs treated with enalapril was caused by a substantial reduction in the number of cardiocyte apoptotic events of left ventricular (LV) regions. Thus, the attenuation of cardiomyocyte apoptosis is shown to preserve global LV function in HF.

Early use of enalapril or metoprolol helps maintain the proportion of fatigue-resistant type I skeletal muscle fiber in dogs having had moderate heart failure. Angiotensin-converting enzyme inhibitors decrease the congestive heart failure incidence in patients with LV dysfunction. The compounds also prevent progressive LV dysfunction and dilation. Beta-blockers improve LV ejection fraction, and decrease chamber dimensions in patients with dilated cardiomyopathy.

A modified version of the coronary embolization technique that eliminates the need for thoracoscopy is used to produce chronic left ventricular (LV) dysfunction in rats with symptoms resembling that of coronary ligation. Aorto-caval fostula is suitable for producing myocardial hypertrophy, characterized by enhanced plasma atrial natriuretic factor. The evaluation of LV performance and clear presence of systolic and/or diastolic dysfunction are crucial to render the above models as accurate representations of heart failure.