Cytoskeletal Role in the Transition From Compensated to Decompensated Hypertrophy During Adult Canine Left Ventricular Pressure Overloading

Abstract

Abstract-Increased microtubule density causes cardiocyte contractile dysfunction in right ventricular (RV) pressureoverload hypertrophy, and these linked phenotypic and contractile abnormalities persist and progress during the transition to failure. Although more severe in cells from failing than hypertrophied RVs, the mechanical defects are normalized in each case by microtubule depolymerization. To define the role of increased microtubule density in left ventricular (LV) pressure-overload hypertrophy and failure, in a given LV we examined ventricular mechanics, sarcomere mechanics, and free tubulin and microtubule levels in control dogs and in dogs with aortic stenosis both with LV hypertrophy alone and with initially compensated hypertrophy that had progressed to LV muscle failure. In comparing initial values with those at study 8 weeks later, dogs with hypertrophy alone had a very substantial increase in LV mass but preservation of a normal ejection fraction and mean systolic wall stress. Dogs with hypertrophy and associated failure had a substantial but lesser increase in LV mass and a reduction in ejection fraction, as well as a marked increase in mean systolic wall stress. Cardiocyte contractile function was equivalent, and unaffected by microtubule depolymerization, in cells from control LVs and those with compensated hypertrophy. In contrast, cardiocyte contractile function in cells from failing LVs was quite depressed but was normalized by microtubule depolymerization. Microtubules were increased only in failing LVs. These contractile and cytoskeletal changes, when assayed longitudinally in a given dog by biopsy, appeared in failing ventricles only when wall stress began to increase and function began to decrease. Thus, the microtubule-based cardiocyte contractile dysfunction characteristic of pressure-hypertrophied myocardium, originally described in the RV, obtains equally in the LV but is shown here to have a specific association with increased wall stress. (Circ Res. 1998;82:751-761.)Key Words: heart failure Ⅲ myocardial contraction Ⅲ cytoskeleton Ⅲ microtubule A major long-term focus of this laboratory has been the attempt to establish a molecular basis for the contractile defects characteristic of myocardium hypertrophying in response to a pressure overload. We have now established in the feline right ventricle (RV) that the contractile defect originally observed at the tissue level 1 is intrinsic to the isolated cardiac muscle cell, 2 or cardiocyte, and that this defect is accounted for by an increased density of the microtubule component of the extramyofilament cytoskeleton.3,4 Furthermore, we have found that upregulation of ␣-tubulin and ␤-tubulin, the major microtubule proteins, on both the message and the protein levels persists not only during prolonged, functionally compensated RV pressureoverload hypertrophy 5 but also after the transition to RV failure.6 Importantly, the contractile defects of cardiocytes isolated from RVs either with compensated hypertrophy alone or with associated deco...

Cytoskeletal networks and the regulation of cardiac contractility: microtubules, hypertrophy, and cardiac dysfunction

“…A. Carabello and M. R. Zile, into the clinically more important LV in a large animal model, where cellular and myocardial function could be characterized in the same animals (27). Figure 8 shows that when canine LV afterload was increased in stages at 2-wk intervals, the animals self-segregated into two groups: one developed very extensive but compensated LV hypertrophy, and the other ceased to hypertrophy in response to increasing load and developed LV failure.…”

mRNA cargo no longer on time

“…It is concluded that microtubular densification may be the cause of "decompensated failure" characterized by elevated LV wall stress and systolic myocardial and chamber dysfunction. This was found in the "decompensated" group in the canine study (17) and in patients with aortic stenosis (19). The most important finding is the fact that compensatory hypertrophy stops in the presence of a dense, MAP4-decorated MT network, resulting in decompensation and heart failure.…”

“…Here there was an attempt to gain insight into the causes of hypertrophic growth cessation that occurs well before the biological limits of cardiocyte hypertrophy have been reached (3,6). This work is based on the recent experimental observation by Cooper's group (17) that during the progression of pressure overload in canine hearts the dogs broke into two groups: one group developed extensive hypertrophy while retaining normal left ventricle (LV) stress and contractile function; the LVs of the second group initially developed hypertrophy but then stopped growing and developed high LV wall stress and very depressed contractile function. On histological examination, differences in the density of the microtubular network were discovered, and it was hypothesized that this might represent an important cellular mechanism involved in growth inhibition.…”

Serial left-ventricular biopsy sampling using a minimally invasive trans-thoracic approach in adult dogs

“…Serial myocardial sampling using needle biopsies in a chronic experimental setting is generally limited by the invasiveness of a thoracotomy, which results in only few sampling points, e.g., at the control stage and before sacrifice of the dogs [17]. We circumvented this by choosing a trans-thoracic, percutaneous approach, thus avoiding the thoracotomy.…”

“…This technique was first described using limited thoracotomy [7], but needle biopsies have generally been confined to the use in patients and animals undergoing standard thoracotomy for direct vision of the puncture site and potential bleeding [17]. Today, needle biopsies can be safely and quickly obtained during open-heart surgery using automatic biopsy devices [14,20].…”