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(Circulation. 1995;91:2071-2079.)
© 1995 American Heart Association, Inc.
Articles |
Pyruvate Dehydrogenase Influences Postischemic Heart Function
Presented in part as an abstract at the 64th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 11 to 14, 1991.
From the NMR Center, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
Correspondence to E. Douglas Lewandowski, PhD, Massachusetts General Hospital, NMR Center, Bldg 149, 13th St, Charlestown, MA 02129.
Background The pyruvate dehydrogenase (PDH) enzyme complex determines the extent of carbohydrate oxidation in the myocardium. PDH is in a largely inactive state during early reperfusion of postischemic myocardium. The resultant decrease in pyruvate oxidation in postischemic hearts has been documented with 13C nuclear magnetic resonance (NMR) spectroscopy. This study demonstrates that counteracting depressed pyruvate oxidation can enhance contractile recovery in the absence of increases in either glycolytic activity or glucose oxidation. The findings indicate that increased incorporation of carbon units from pyruvate into the intermediates of the oxidative pathways by PDH influences the metabolic efficiency and mechanical work of postischemic hearts.
Methods and Results Isolated rabbit hearts were situated in an
NMR magnet and perfused or reperfused (10 minutes of ischemia) with 2.5
mmol/L [3-13C]pyruvate as sole substrate to target PDH
directly and bypass the glycolytic pathway. Hearts were observed with
or without activation of PDH with dichloroacetate. Mechanical function
and oxygen consumption
(M
O2) were
monitored. 13C and 31P NMR spectroscopy allowed
observations of pyruvate oxidation and bioenergetic state in intact,
functioning hearts. Metabolite content and 13C enrichment
levels were then determined with in vitro NMR spectroscopy
and biochemical assay. PDH activation did not affect performance of
normal hearts. Postischemic hearts with augmented pyruvate oxidation
(dichloroacetate-treated) sustained improved mechanical function
throughout 40 minutes of reperfusion. Rate-pressure-product (RPP)
increased from 8300±1800 (mean±SEM) in untreated postischemic
hearts
to 21 300±2400 in hearts treated with dichloroacetate
(P<.05). Oxygen use per unit work
[MO2 multiplied by
104
divided by RPP] was improved from 1.50±0.13 to 1.14±0.11
(P<.05) without differences in high-energy phosphate
content between treated and untreated hearts. Values of dP/dt were also
consistently higher, by as much as 185%, during reperfusion with
dichloroacetate. Postischemic hearts displayed reduced pyruvate
oxidation from the incorporation of 13C into the tissue
glutamate pool. With the tissue alanine level as a marker of
13C-enriched pyruvate availability in the cell, the ratio
of labeled glutamate to alanine was only 58% of the control value
during early reperfusion. With dichloroacetate, that ratio was 167%
greater than that of untreated hearts (P<.05). By the end
of the reperfusion period, the 13C enrichment of the tissue
glutamate pool by pyruvate oxidation was elevated from dichloroacetate
treatment (untreated, 62±7%; DCA-treated, 81±6%;
P<.05), but glycogen content was similar in both groups and
13C enrichment of tissue alanine remained unchanged, near
60%, indicating no increases in glycolytic end-product formation.
Conclusions Metabolic reversal of contractile dysfunction was achieved in isolated hearts by counteracting depressed PDH activity in the postischemic myocardium. Improved cardiac performance did not result from, nor require, increased glycolysis secondary to the activation of PDH. Rather, restoring carbon flux through PDH alone was sufficient to improve mechanical work by postischemic hearts.
Key Words: myocardium • reperfusion • NMR spectroscopy
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