SUMMARY. We have recently described rapid cardiac atrophy in response to decreased load. The present study was designed to determine whether this atrophy is solely a degenerative response of damaged myocardium or is, instead, an adaptive response of viable myocardium. A discrete portion of cat myocardium was unloaded by severing the chordae tendinae of a single right ventricular papillary muscle. One week later, the muscle was reloaded by attachment of its apex to the ventricular free wall. This allowed the load to be removed and restored without altering the blood supply, innervation, or frequency of contraction of the tissue. In myocardium unloaded for 1 week, the cardiocyte cross-sectional area and the volume densities of mitochondria and myofibrils decreased significantly. Large areas of cytoplasm were devoid of organelles, and the few remaining myofilaments were oriented in a variety of directions rather than longitudinally within the cell. Upon reloading for 1 week, the cardiocyte cross-sectional area, volume density of mitochondria, and ultrastructural organization all returned to normal. The volume density of the myofibrils increased toward control, and they reoriented with respect to the long axis of the cardiocyte. The contractile function of the papillary muscles, which was depressed as early as 1 day after unloading and almost absent at times later than 3 days after unloading, returned to normal after 2 weeks of reloading. This study demonstrates that adult mammalian myocardium responds to unloading with a marked loss of cellular differentiation, organization, and function which is fully reversible with reloading. This plasticity in response to load may well be the basic mechanism responsible for the development and maintenance of normal cardiac structure and function. (CircRes 54: 367-377, 1984)

Norepinephrine stimulates the growth in size of nondividing neonatal cardiocytes. During this time the neonatal cardiocyte is in a period of transition in which the cell can synthesize DNA and yet does not divide. Because the cell undergoes karyokinesis without cytokinesis the objective of this study was to determine whether the norepinephrine-induced growth in size of the neonatal cardiocyte was accompanied by an increase in a) the number of cardiocytes synthesizing DNA, b) the number of binucleate cardiocytes, and c) organized myofibrils. One- to four-d-old neonatal rat heart cells were isolated and placed in serum-free medium which was then supplemented with serum, norepinephrine, norepinephrine plus propranolol, or isoproterenol. After 4 d the number and size of the cells was determined using a Coulter counter. In other cultures cardiocytes were fixed on Days 0, 1, 2, and 4, and an increase in the number of binucleate cardiocytes was found in all treatment groups including controls. However, the rate of binucleation was faster in the norepinephrine group. It was also determined by proliferating cell nuclear antigen (PCNA) antibody staining that by Day 4, over 50% of the cardiocytes were in the cell cycle. The percentage of cells in which PCNA could be detected was higher in the norepinephrine and norepinephrine plus propranolol groups. Furthermore, there was a concomitant increase in the amount and organization of myofibrils in the catecholamine-treated cardiocytes.

SUMMARY. Chronic, progressive pressure overload of the cat right ventricle produces persistent, ongoing abnormalities of contractile, energetic, and biochemical function in vitro at a time when in vivo pump function is still normal. The present study tested the reversibility of the in vitro changes in this clinically relevant hypertrophy model. Fourteen sham-operated and 14 reversal cats were studied. After banding the animals as 1-kg kittens, right ventricular pressures were normal. Before band removal (25.2 ± 0.5 weeks later for the control group and 25.5 ± 0.3 weeks later for the hypertrophy reversal group), systolic right ventricular pressures were 24 ± 1 mm Hg for controls and 71 ± 5 mm Hg for the hypertrophy reversal group (P < 0.05). At study, 19.5 ± 1.1 weeks after a second sham operation for controls or 18.7 ± 0.7 weeks after band removal for the hypertrophy reversal group, these pressures were 24 ± 1 mm Hg for controls and 23 ± 1 mm Hg for the hypertrophy reversal group (P = NS); cardiac output was 0.18 ± 0.01 liters/kg per min for controls and 0.19 ± 0.01 liters/kg per min for the hypertrophy reversal group (P = NS). The ratio of right ventricle to body weight was normal in both groups, as was the right ventricular papillary muscle myocyte cross-sectional area and the myocardial collagen concentration. A right ventricular papillary muscle from each cat was studied at 29°C in a polarographic myograph. Preloaded shortening velocity was 0.79 ± 0.04 muscle lengths/sec for controls and 0.86 ± 0.03 muscle lengths/sec for the hypertrophy reversal group (P = NS); extent of shortening was 0.15 ± 0.01 muscle lengths for controls and 0.16 ± 0.01 muscle lengths for the hypertrophy reversal group (P = NS). At optimum isometric length, active tension was 59.7 ± 3 1 mN/mm for controls and 57.0 ±1.9 mN/mm 2 for the hypertrophy reversal group (P = NS); resting tension was 15.6 ±1.2 mN/mm 2 for controls and 13.6 ±1.6 mN/mm 2 for the hypertrophy reversal group (P = NS). Active and resting oxygen consumption levels did not differ in the two groups. This study demonstrates that-in the compensated stage of chronic, progressive pressure overload of the cat right ventricle-the contractile, energetic, and biochemical abnormalities of the hypertrophied myocardium are fully reversible. (Circ Res 54: 323-331, 1984)