Nutrient supply vs oxygen supply.
Cardiologists use the tension time index (TPI) as a measure of
myocardial work each minute, the TPI being derived from the product of the
area under the systolic portion of the left ventricular pressure curve and
the heart rate. They have also used it as a measure of minute myocardial
oxygen demand because the two are correlated. They have used it to define
the threshold minute myocardial oxygen consumption above which angina
occurs in accordance with the Burns thesis by inducing an artifical
tachycardia by pacing the right atrium at progressively increasing rates.
The problem is that no such threshold can be found in some patients and no
universally accepted explanation for this fact has been proposed.
Furthermore there is no satisfactory explanation for the reduction in
exercise tolerance after food. In seeking to explain these anomalies
cardiologists have assumed the latest embodiment of the idea that
ischaemia occurs when the myocardium is stressed beyond the limit of its
metabolic reserve with maximum vasodilatation and oxygen extraction so
that oxygen demand exceeds supply, a thesis that was first proposed by
Burns in 1809, 201 years ago.
We now know that metabolic work depletes ATP pools some 10%, ADP
pools some 0% and increase AMP pools some 600% and that the increase in
AMP is accompanied by a fall in pH for the two are closely related
stochiometrically. This is convenient for the increase in AMP activates
AMPK, and the enzymatic cascade that triggers, the fall in pH has a
negative inotropic effect, seemingly due to inhibiting the inward calcium
slow current, releasing calcium from the sarcoplasmic reticulum and/or
possibly to opening the Katp channel. Collectively these changes act to
preserve and even to restore to normality myocardial tissue energetics
just as presumed to occur following the administration of beta blockers.
But, as the biochemistry textbooks point out, the rise in AMP may be
induced not only by an increase in workload but also by a decrease in the
availablity of nutrient for ATP resynthesis. Indeed were it not for the
availability of nutrient, fatty acids, glucose and lactate in the case of
the heart, no ATP could be produced. The same cannot be said for oxygen.
On the contrary the most active metabolic states, such as the growth of an
embryo, wound healing and neoplastic growth, rely upon anaerobic
metabolism to generate their ATP needs. This is not surprising for the
products of glycolysis and the Krebs cycle include protons, NADH and FADH2
and carbon dioxide and it is only the electron transport chain that
requires oxygen to be the last electron acceptor before the formation of
water. Furthermore in our dog experiments, cited in my earlier rapid
response, "the intramural pH and O2 consumption did not decrease in the
hypoxic group". Thus it would seem that is the availability of nutrient
and not of oxygen that is ever likely to be the rate limiting factor even
in stable angina.
Herein may lie a satisfactory explanation for the reduction in
exercise tolerance after food and the failure to find a threshold in some
Competing interests: No competing interests