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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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.

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In dogs with advanced HF, acute LV reduction with the Acorn CSD prevents progressive global LV dilatation and ameliorates functional MR.