Impaired systolic function in heart failure is not due to reduced myocardial adenine nucleotide

,J Mel Cell Cardiol 24 (Supplement V) (1992)

Oral presentation I (Minisymposium

October 3,1992

IX): 8.00 - 9.40

Readjustment or Impairment of Energy Balance in Heart Failure 264

ACROMEGALIC VS PRESSURE OVERLOAD MYOCARDIAL HYPERTROPHY Jean-Jacques Mercadier, Yves Lecarpentier, RenCe Ventura-Clapier, Saul Winegrad, JosCTimsit. CNRS UA 1159, INSERM U 25,241,275, France; University of Pennsylvania, PA, USA. Chronic growth hormone (GH) hypersecretion in rats led to marked cardiac growth associated with increased left vennicular papillary muscle isometric force and unchanged unloaded shortening velocity, despite myosin phenoconversion towards the p-myosin heavy chain isofonn (p-MHC). The involvement of p-MIX in force development was supported by the increased economy of contraction as evidenced by the increased G curvature of the force-velocity relationship. Myosin-associated ATPase activities measured on frozen sections were unaltered and decreased after alkaline preincubation, which also demonstrated the involvement of p-MI-K. These findings suggested an increase in the apparent number of active cross-bridges in GH rats. They contrast with what is observed during pressure-overload hypertrophy where myosin phenoconversion to P-MI-K is associated with decreased contractile performances and myosin-associated ATFase activities.The mechanical properties of skinned fibers from papillary muscles were studied to investigate the mechanisms involved at the level of contractile proteins without interference with excitationcontraction coupling mechanisms. Active tension and stiffness, and to a lesser extent fiber sensitivity to calcium, were increased in GH rats. The cross bridge cycling rate, reflected by the response to quick length changes, was decreased. This parameter correlated with the proportion of a- or !3-MHC in GH rats as well as in controls and pressure overloaded rats. In conclusion, chronic GH hypersecretion in rats leads to a unique pattern of cardiac adaptation which takes place, at least in part, at the level of the contractile apparatus and involves an increase in the apparent total number of active cross-bridges.

351

HYOCARDIAL

328

ENERGY

SUPPLY

IN

HEART

FAILURE

Heinz-Peter Schultheiss, Department of Cardiology, Pneumology and Angiology, University of Duesseldorf, F.R.G. Several indications exist that the availability of energy for cardisc function is decreased in chronic heart failure (CHF). To prove this hypothesis, we analysed the lactate dehydrogenase isoenzyme (LHD) pattern by microisoelectfic focussing, the ATP content by HPLC and the concentration ?f the adenine nucleotide transloc.+or (VT) by an immuno dot assay in myocardial biopsies from 49 patients with dilated cardiomyopathy (DCM). The ANT is the only active nucleotide transport system in mitochondria. In patients with severe CHF (LVEDP>20 mmHG) a significant shift of the LDH-isoenzyme pattern (increase of LDH ,decrease of LDH ) an increase of the ANT concentration (65.1+12.? vs. p<0.001) 52.3f3.4 fg/mg &tein, and decrease of the ATP- content (15.?J+5.0 vs. 22.455.8 nmol/mg protein, p>0.001) was observed. Similar data were obtained using explanted hearts from patients with DCM The ANT concentration was significantly increased (74.3+17 vs. k!JZ~3:4 fgfmg protein) LDHl reduced (38.5 vs. 54.2%) and LDH elevatea (19.8 vs. 8.9%, p55%. exclusion of coronary or valvular heart disease and myocarditis). In contrast, myocardial norepinephrine in the same biopsies was significantly reduced. ATP TAN Norepinephrine nmol/mg protein pg/mg protein DCM 23.4 f 2.9 39.2 f 3.4 5.8 f l.O* *: p 4.01 vs con HF 18.0 f 2.0 29.9 f 2.7 6.4 + 1.3* Con 23.2 zk3.2 36.9 f 3.9 12.0 * 3.4 Normal myocardial total adenine nucleotides and ATP content in biopsies with reduced myocardial norepinephrine indicate that a loss of myocardial ATF’ or total adenine nucleotides is not the cause of contractile dysfunction in heart failure regardless of the underlying etiology. s.111