Background-In heart failure (HF), aldosterone has been implicated in the formation of reactive interstitial fibrosis, a maladaptation that contributes to left ventricular (LV) remodeling. Eplerenone is a novel selective aldosterone blocker. The present study examined the effects of long-term monotherapy with eplerenone on the progression of LV dysfunction and remodeling in dogs with chronic HF. Methods and Results-HF was produced in 14 dogs by intracoronary microembolizations that were discontinued when LV ejection fraction (EF) was between 30% and 40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with eplerenone (10 mg/kg twice daily, nϭ7) or no therapy at all (control, nϭ7). Hemodynamic measurements were made just before randomization and were repeated at the end of 3 months of therapy. In control dogs, LV end-diastolic and end-systolic volume increased significantly (62Ϯ4 versus 68Ϯ4 mL, PϽ0.001, and 38Ϯ3 versus 47Ϯ3 mL, PϽ0.001, respectively), and EF decreased significantly (38Ϯ1% versus 31Ϯ2%, PϽ0.001). In contrast, end-diastolic volume, end-systolic volume, and EF remained unchanged during the 3 months of treatment in eplerenone-treated dogs. LV end-diastolic wall stress increased significantly in control dogs but decreased significantly in eplerenone-treated dogs. Compared with control, eplerenone was associated with a 28% reduction in cardiomyocyte cross-sectional area, a 37% reduction of volume fraction of reactive interstitial fibrosis, and a 34% reduction of volume fraction of replacement fibrosis. Conclusions-Our results indicate that long-term therapy with eplerenone prevents progressive LV dysfunction and attenuates LV remodeling in dogs with chronic HF.

Abstract-Passive mechanical containment of failing left ventricle (LV) with the Acorn Cardiac Support Device (CSD) was shown to prevent progressive LV dilation in dogs with heart failure (HF) and increase ejection fraction. To examine possible mechanisms for improved LV function with the CSD, we examined the effect of CSD therapy on the expression of cardiac stretch response proteins, myocyte hypertrophy, sarcoplasmic reticulum Ca 2ϩ -ATPase activity and uptake, and mRNA gene expression for myosin heavy chain (MHC) isoforms. HF was produced in 12 dogs by intracoronary microembolization. Six dogs were implanted with the CSD and 6 served as concurrent controls. LV tissue from 6 normal dogs was used for comparison. Compared with normal dogs, untreated HF dogs showed reduced cardiomyocyte contraction and relaxation, upregulation of stretch response proteins (p21ras, c-fos, and p38 ␣/␤ mitogen-activated protein kinase), increased myocyte hypertrophy, reduced SERCA2a activity with unchanged affinity for calcium, reduced proportion of mRNA gene expression for ␣-MHC, and increased proportion of ␤-MHC. Therapy with the CSD was associated with improved cardiomyocyte contraction and relaxation, downregulation of stretch response proteins, attenuation of cardiomyocyte hypertrophy, increased affinity of the pump for calcium, and restoration of ␣-and ␤-MHC isoforms ratio. The results suggest that preventing LV dilation and stretch with the CSD promotes downregulation of stretch response proteins, attenuates myocyte hypertrophy and improves SR calcium cycling. These data offer possible mechanisms for improvement of LV function after CSD therapy. Key Words: heart failure Ⅲ myocyte hypertrophy Ⅲ sarcoplasmic reticulum Ⅲ myosin heavy chain H eart failure (HF) is a progressive disorder mediated through multiple signaling pathways. Once initiated, HF is characterized by increased neurohumoral activation and ventricular dilation. Although such compensatory changes are initially beneficial, over the long-term they cause adverse structural and functional changes collectively referred to as ventricular remodeling. Ventricular dilation also causes increased mechanical stress and myocardial stretch. Upregulation of stretch response proteins, such as p21ras, 1 c-fos, 2,3 and p38 ␣/␤ mitogen-activated protein kinase (MAPK), 4 have been shown to induce cardiomyocyte hypertrophy.The Acorn Cardiac Support Device (CSD) has been shown to halt progressive left ventricular (LV) dilation and improve ejection fraction. [5][6][7] However, the mechanism(s) underlying the improved cardiac function has not been elucidated. In the present study, we tested the hypothesis that improvement in LV systolic function in dogs with HF after long-term therapy with the CSD results, in part, from downregulation of stretch response proteins, attenuation of cardiomyocyte hypertrophy, 1-4 and improvement of sarcoplasmic reticulum (SR) calcium cycling. To further understand the mechanisms for the improvement in LV systolic function, we also explored the influence of ...

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The present study assesses whether ranolazine increases left ventricular (LV) function without an increase in myocardial oxygen consumption (MV O 2 ) and thus improves LV mechanical efficiency in dogs with heart failure (HF). Ranolazine did not change MV O 2 and LV mechanical efficiency increased (22.4؎2.8% to 30.9؎3.4% (P<0.05). In contrast, dobutamine significantly increased MV O 2 and did not improve mechanical efficiency. Thus, short-term treatment with ranolazine improved LV function without an increase in MV O 2 , resulting in an increased myocardial mechanical efficiency in dogs with HF. F ree fatty acids (FFAs) are the primary energy substrate of the myocardium; however, they are not as efficient as glucose and lactate. 1 Studies in isolated rat hearts, 1 dogs, 2 pigs, 3 and humans 4 show that external power is reduced for a given myocardial oxygen consumption (MV O 2 ) when the heart has elevated FFA oxidation. Abnormalities of energy metabolism may contribute to the poor left ventricular (LV) function that characterizes heart failure (HF). 5,6 Patients with HF designated as New York Heart Association (NYHA) class II-III have greater myocardial FFA oxidation and lower carbohydrate oxidation compared with healthy individuals. 7 Impaired carbohydrate oxidation may contribute to mechanical dysfunction in the failing heart, as suggested by improved contractile function and efficiency in HF patients when carbohydrate oxidation is stimulated with dichloroacetate 8 or intracoronary pyruvate. 9 It has been suggested that pharmacological inhibition of myocardial FFA oxidation improves LV function without an increase in MV O 2 , and thus increases LV mechanical efficiency. 5 Ranolazine inhibits FFA ␤-oxidation and significantly improves treadmill time to onset of angina and 1-mm STsegment depression in patients with chronic stable angina. 10,11 The purpose of this investigation was to measure MV O 2 , LV function, and mechanical efficiency during short-term treatment with ranolazine. We used dobutamine, a positive inotropic agent that should not improve the mechanical efficiency, as a comparator. In addition, the net myocardial uptake of FFAs, glucose, and lactate was assessed. Materials and MethodsThe canine model of chronic HF was previously described in detail. 12,13 Chronic LV dysfunction and failure were produced by multiple sequential intracoronary embolizations, which results in loss of viable myocardium. 12 Eight healthy dogs (Hodgins Kennel, Howell, Mich) underwent microembolizations to induce HF. This study was approved by the Henry Ford Health System Institutional Animal Care and Use Committee.Dogs were anesthetized 12,13 and catheters placed in the femoral vein, coronary sinus, and left ventricle under fluoroscopic guidance, and LV pressure was measured. Cardiac function and coronary flow measurements were made 12,13 and arterial and coronary sinus (cs) blood samples drawn at baseline and after 30 minutes of treatment with either ranolazine (0.5 mg/kg bolus, followed by a constant infusion of 1.0 mg ·...

Reverse remodeling with reduced systolic wall stress and improved adrenergic signaling can be achieved by passive external support that does not generate diastolic constriction. This approach may prove useful in the treatment of chronic heart failure.