J. F. SPANN, JR. AND G. M. LEMOLE 
149 
absolute levels of force and rate of force devel- 
i opment in the muscles from failing hearts were 
augmented by these procedures, they did not 
reach even the basal level observed in normal 
muscles. Thus, the contractile state is reduced 
even in the presence of potentiation and the in- 
trinsic defect in heart failure can be only par- 
tially corrected by these positive inotropic 
procedures. 
Biochemical Abnormalities 
Considerable attention has been devoted to a 
search for a specific biochemical abnormality 
responsible for the altered performance of fail- 
ing myocardium. It is useful to divide the possi- 
ble abnormalities of myocardial energy supply 
and utilization into the following areas: sub- 
strate availability, energy production, energy 
storage, energy utilization and conversion, 
and excitation-contraction coupling. 
Substrate Availability. It is known that over 
a 24-hour period, fatty acids are normally the 
principal substrate of the energy metabolism of 
the heart. Recent investigation in isolated prep- 
arations of myocardial homogenates have dem- 
onstrated a lesion that appears to prevent the 
full utilization of fatty acids by the failing 
myocardium.-*^ In the heart, metabolism of 
fatty acids requires a carnitine-dependent sys- 
tem that allows the entrance of free fatty acid 
into the mitochrondria for beta oxidation. In 
preparations from the failing heart of experi- 
mental animals, this carnitine-dependent sys- 
tem is depressed to one half of normal. It has 
not been proved, however, that this observed de- 
fect is causally related to the abnormalities of 
performance in the failing heart. Other studies 
have concluded that fatty acid metabolism is 
normal in the failing heart.^^ Further work is 
needed to evaluate these conflicting views. 
Energy Utilization. In cardiac mitochrondia, 
the energy from substrate oxidation is con- 
verted into the terminal bond energy of creat- 
ing phosphate (CP) and adenosine triphosphate 
(ATP). This process, oxidative phosphory- 
lation, has been studied extensively in animals 
and man, and more recent data indicate that it 
is not impaired in heart f ailure.^^ 
Energy Storage. The terminal bond energy 
resulting from oxidative phosphorylation is 
stored in the myocardium in the form of CP 
which serves as a reservoir to maintain ATP, 
the more immediate source of chemical energy 
for the heart muscle. The energy stores of CP 
are depressed in chronically failing hearts of 
experimental animals. Since the depression of 
high energy phosphate stores can be experimen- 
tally disassociated from the depression of con- 
tractibility, however, depression of energy 
stores is not thought to be a primary cause of 
the weakness of the failing heart muscle.^^ 
Energy Utilization and Conversion. To date 
there have been no conclusive demonstrations of 
the alteration in the physical properties of the 
contractile proteins from failing heart muscle. 
In addition, the experimental failing heart mus- 
cle is not inefficient in the conversion of chemi- 
cal energy to mechanical work.-^ On the other 
hand, the activity of myofibrillar ATPase, 
which splits the terminal phosphate bond off 
ATP and thereby liberates the energy from the 
contractile process, is severely depressed in the 
failing heart and may reduce the rate of energy 
release.-^ 
Excitation-Contraction Coupling. The final 
biochemical area to be considered is excitation- 
contraction coupling which occurs within the 
sarcoplasmic reticulum surrounding each my- 
ofibril. Since the release of calcium ions from 
the sarcoplasmic reticulum into the vicinity of 
the contractile protein is of fundamental impor- 
tance for cardiac muscle contraction, a meta- 
bolic defect in this area has been proposed as a 
basic mechanism in the failing myocardium. 
Thus, it is possible that a fundamental subcellu- 
lar abnormality responsible for myocardial fail- 
ure is related to an inadequate release of calcium 
from the sarcoplasmic reticulum, which could re- 
sult in improper excitation-contraction coupling 
and weak contraction. Data to support or reject 
this hypothesis are not yet available. 
From these observations, it can be seen that 
many areas in biochemistry of the experimental 
failing heart have been evaluated, a number of 
possible lesions have been excluded, and al- 
though considerable understanding has been 
gained, no single basic mechanism underlying 
the depressed performance of the failing heart 
has been elucidated with certainty. It appears 
