Limitations of heart preservation by cold storage

Abstract

Clinical heart preservation is currently limited to only 4-6 hr, while the kidney, liver, and pancreas can tolerate 24-48 hr of cold ischemia. A fundamental difference between these organs is that the heart is contractile, containing large quantities of actin and myosin, and is susceptible to contracture-induced injury caused by energy deprivation. We have quantified and correlated the onset of contracture with levels of ATP and glycogen during cold storage in rabbit hearts flushed with UW solution, with and without 1 mM calcium (Ca), or 3 mM iodoacetate (IAA). A fluid-filled left ventricular balloon was used to generate pressure-volume curves (compliance) at 1, 6, 12, 18, and 24 hr of cold storage. Onset of contracture occurred in UW stored hearts at 18 hr, contracture in hearts exposed to Ca occurred between 6 and 12 hr. Compliance was significantly less in hearts exposed to Ca at 12, 18, and 24 hr (P less than .01) than in hearts without Ca. ATP levels were well maintained for up to 18 hr in the hearts preserved in UW solution (78%), but fell more rapidly in the presence of Ca at 12 hr (P less than .005), 18 hr (P less than .005), and 24 hr (P less than .05). In comparison, the ATP supply of the liver and kidney was exhausted by only 4 hr of cold storage. Onset of myocardial contracture correlated with a decrease in ATP to less than 80% of control, and contracture accelerated ATP decline 3-6-fold. IAA caused nearly complete myocardial contracture and ATP depletion within 2 hr. Isolated heart function was 77% and 73% at 6 and 12 hr of storage, but fell to 54% and 42% at 18 and 24 hr, respectively, coinciding with development of contracture. We conclude that ischemic contracture in this model is a major cause of myocardial damage during cold storage, and is accelerated by the presence of Ca. Other organs can be successfully stored despite exhaustion of ATP reserves. Thus successful cold-storage of the heart is highly ATP-dependent. Since cold storage inevitably leads to ATP depletion, extension of myocardial ischemic tolerance will depend on either reversible inhibition of ATP hydrolysis during storage, reversible uncoupling of contracture development from ATP depletion, or maintaining ATP production by continuous hypothermic perfusion.