Location and density of alpha- and beta-adrenoreceptor sub-types in myocardium after mechanical left ventricular unloading.

BACKGROUND: We hypothesized that not all subtypes of alpha- and beta-adrenoreceptors undergo similar upregulation and redistribution in human myocardium after mechanical unloading with an assist device. METHODS: We obtained core biopsy samples of the left ventricle in 19 patients before and after removal of a Jarvik or Thoratec left ventricular assist device (LVAD) to study the effect of mechanical unloading on the distribution of alpha- and beta-adrenoreceptors. Fresh, embedded tissue sections were incubated with receptor blockers and antibodies before the fluorescent labeling of receptors. Images were obtained by fluorescence deconvolution microscopy, and composite tissue renditions were made from the stacked images. Multiple adrenoreceptor subtypes were studied. RESULTS: We saw a reversal of myocyte hypertrophy in all patients, but the upregulation of receptors was not seen in all post-LVAD tissue samples. Furthermore, we noted receptor relocalization from an initial punctate/clumped pattern to a normal homogeneous distribution in many patients. Significant differences were seen in the distribution of beta(2)- and alpha(1)-receptors and in alpha(1A) subtypes. CONCLUSIONS: In this study we show not only the expected reversal of myocyte hypertrophy and the increase in adrenoreceptors after ventricular unloading, but also the relocalization of specific receptor subtypes.

Reversal of myocyte hypertrophy by ventricular unloading: cardiac improvement without adrenergic receptor up-regulation and relocalization.

In previous studies, we found that the improved contractile ability of cardiac myocytes from patients who have had left ventricular assist device (LVAD) support was due to a number of beneficial changes, most notably in calcium handling (increased sarcoplasmic reticulum calcium binding and uptake), improved integrity of cell membranes due to phospholipid reconstruction (reduced lysophospholipid content), and an upregulation of adrenoreceptors (increased adrenoreceptor numbers). However, in the case presented here, there was no increase in adrenoreceptor number, which is something that we usually find in core tissue at the time of LVAD removal or organ transplantation; also, there was no homogeneous postassist device receptor distribution. However, the patient was well maintained for 10 months following LVAD implantation, until a donor organ was available, regardless of the lack of adrenoreceptor improvement. We conclude from these studies that cardiac recovery is the result of the initiation of multiple repair mechanisms, and that the lack of expected changes, in this case increased adrenoreceptors, is not always an accurate indicator of anticipated outcome. We suggest that interventions and strategies have to consider multiple, beneficial changes due to unloading and target a number of biochemical and structural areas to produce improvement, even if not all of these improvements occur.

Left ventricular unloading with an assist device results in receptor relocalization as well as increased beta-adrenergic receptor numbers: are these changes indications for outcome?

BACKGROUND: The use of left ventricular (LV) assist devices (LVADs) can improve performance and recovery of failing human hearts. AIM: Following our alpha-adrenergic receptor work, we hypothesized that mechanical unloading in patients with low output syndrome and LV failure would yield similar results with beta-adrenergic receptors ((beta)AR), that being increased numbers and intra-myocytic relocalization. METHODS: (beta)AR density and localization were investigated by fluorescence deconvolution microscopy and compared at LVAD insertion and removal in 13 heart failure patients, the patients therefore acting as their own control. (beta)AR densities and distribution were determined in snap frozen sections of human core biopsy left ventricular apical tissue. Samples were probed with tagged CGP 12177 for visualization of (beta)AR and challenged with cold agonists and antagonists. (beta)AR density was measured by two independent methods. Localization of receptors was examined in reconstructed, deconvoluted, stacked section images. RESULTS: There was an increase in (beta)AR density following ventricular unloading in most of the patients, and also significant normalization in the location of the receptors in the myocardium comparing pre- and post-LVAD tissue. CONCLUSIONS: These findings suggest that supporting an ailing heart via unloading initiates mechanisms and pathways responsible for myocardial recovery and repair. With appropriate pharmacological support, patients with LVAD might recover to the point where they no longer depend on eventual organ transplantation, and (beta)AR number, type, and distribution in pre-LVAD myocardial tissue, could predict outcome with regard to recovery, repair, and improvement in cardiac function.