Background—Contrast MRI enhancement patterns in several pathophysiologies resulting from ischemic myocardial injury are controversial or have not been investigated. We compared contrast enhancement in acute infarction (AI), after severe but reversible ischemic injury (RII), and in chronic infarction. Methods and Results—In dogs, a large coronary artery was occluded to study AI and/or chronic infarction (n=18), and a second coronary artery was chronically instrumented with a reversible hydraulic occluder and Doppler flowmeter to study RII (n=8). At 3 days after surgery, cine MRI revealed reduced wall thickening in AI (5±6% versus 33±6% in normal, P<0.001). In RII, wall thickening before, during, and after inflation of the occluder for 15 minutes was 35±5%, 1±8%, and 21±10% and Doppler flow was 19.8±5.3, 0.2±0.5, and 56.3±17.7 (peak hyperemia) cm/s, respectively, confirming occlusion, transient ischemia, and reperfusion. Gd-DTPA–enhanced MR images acquired 30 minutes after contrast revealed hyperenhancement...

Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function.

We tested the hypothesis that myocyte loss in failing human hearts occurs by different mechanisms: apoptosis, oncosis, and autophagic cell death. Explanted hearts from 19 patients with idiopathic dilated cardiomyopathy (EF< or =20%) and 7 control hearts were analyzed. Myocyte apoptosis revealed by caspase-3 activation and TUNEL staining occurred at a rate of 0.002+/-0.0005% (P<0.05 versus control) and oncosis assessed by complement 9 labeling at 0.06+/-0.001% (P<0.05). Cellular degeneration including appearance of ubiquitin containing autophagic vacuoles and nuclear disintegration was present at the ultrastructural level. Nuclear and cytosolic ubiquitin/protein accumulations occurred at 0.08+/-0.004% (P<0.05). The ubiquitin-activating enzyme E1 and the ligase E3 were not different from control. In contrast, ubiquitin mRNA levels were 1.8-fold (P<0.02) elevated, and the conjugating enzyme E2 was 2.3-fold upregulated (P<0.005). The most important finding, however, is the 2.3-fold downregulation of the deubiquitination enzyme isopeptidase-T and the 1.5-fold reduction of the ubiquitin-fusion degradation system-1, which in conjunction with unchanged proteasomal subunit levels and proteasomal activity results in massive storage of ubiquitin/protein complexes and in autophagic cell death. A 2-fold decrease of cathepsin D might be an additional factor responsible for the accumulation of ubiquitin/protein conjugates. It is concluded that in human failing hearts apoptosis, oncosis, and autophagy act in parallel to varying degrees. A disturbed balance between a high rate of ubiquitination and inadequate degradation of ubiquitin/protein conjugates may contribute to autophagic cell death. Together, these different types of cell death play a significant role for myocyte disappearance and the development of contractile dysfunction in failing hearts.

Myocytes Die by Multiple Mechanisms in Failing Human Hearts

The acute effects of reperfusion on myocardium reversibly damaged by 15 minutes of severe ischemia in vivo, were studied Changes in the adenine nucleotide pool, cell volume regulation, myocardial calcium, and ultrastructure were studied at the end of 15 minutes of ischemia and after 05, 30, and 20 minutes of reflow Before reperfusion, adenosine triphosphate and the adenylate pool decreased by 63% and 44% of control, respectively, and the adenylate charge was reduced to 065 After 3 minutes of reperfusion, the adenylate charge was restored to control by the rephosphorylation of adenosine mono- and diphosphate, but adenosine triphosphate was still reduced by 45% Mild tissue edema was detected after 05 minute of reflow and persisted throughout 20 minutes of reperfusion The increased tissue water was accompanied by a slight increase in sodium and a marked increase in tissue potassium Although massive calcium accumulation develops when irreversibly injured tissue is reperfused, no calcium overload was detected during early reperfusion of reversibly injured myocytes Reperfusion for 3 minutes exaggerated the mitochondrial swelling induced by 15 minutes of ischemia but after 20 minutes of reperfusion, myocardial ultrastructure was essentially normal except for rare swollen, or disrupted, mitochondria Thus, the cellular abnormalities associated with brief periods of ischemia persist for variable periods of time after reperfusion of reversibly injured myocytes First: although adenine nucleotide repletion occurs very slowly, the adenylate charge was restored after 3 minutes, indicating rapid resumption of mitochondrial adenosine triphosphate production Second: calcium overload was not detected, but myocardial edema and increased potassium persisted throughout the 20 minutes of reperfusion Third: the ultrastructural consequences of ischemia were nearly reversed after 20 minutes of reperfusion

Effect of reperfusion late in the phase of reversible ischemic injury. Changes in cell volume, electrolytes, metabolites, and ultrastructure

Myocardial ischemia revisited. The osmolar load, membrane damage, and reperfusion

A selective history of the pathophysiological, structural, and metabolic changes found during an episode of severe myocardial ischemia in the canine heart is presented. The changes that cause ischemic injury to become irreversible are discussed in detail because these changes are the target of any successful therapy designed to prevent ischemic cell death. Of these, the disruption of the sarcolemma, an injury the development of which is accelerated in vivo by the contraction of viable tissue elsewhere in the heart traumatizing the ischemic area, plus the changes in high-energy phosphate and the total adenine nucleotide pool are considered to be the critical events leading to the development of irreversibility. The discovery of preconditioning with ischemia is discussed, together with a brief description of postconditioning. Finally, reperfusion injury is discussed in a summary fashion. The evidence for the fact that myocytes are salvaged by reperfusion is presented, as is the evidence that myocytes become unsalvageable by reperfusion as the duration of ischemia increases. The concept that some of the myocytes that die after successful reperfusion with arterial blood actually are killed by changes initiated by reperfusion, so-called lethal reperfusion injury, is attractive in that prevention of this change would lead to greater salvage; however, the prevalence of this phenomenon in clinical practice remains to be determined.

Historical Perspective on the Pathology of Myocardial Ischemia/Reperfusion Injury

Contraction-band necrosis, a striking morphologic lesion, is common to many types of myocardial injury including the calcium paradox and ischaemic injury with reperfusion. This lesion is characterized by explosive swelling, massive calcium overload, and severe disruption of the myofibrils due to the formation of contraction bands. The studies reviewed in this paper provide evidence that in ischaemia and reperfusion, these changes are preceded by sarcolemmal injury that occurs during the period of ischaemia. Sarcolemmal injury was evaluated by electron microscopy and by measurements of inulin diffusible space (IDS) in thin slices of myocardium incubated in vitro . Reversibly injured ischaemic myocvtes have ultra-structurally intact plasma membranes which are impermeable to inulin. Longer durations of ischaemia, sufficient to produce contraction-band necrosis during reperfusion. result in fragmentation of plasma membranes during the ischaemic intervals, and the IDS is markedly increased during subsequent incu bation. Thus ultrastructural evidence of membrane damage is present early in ischaemia and is associated temporally with the increased IDS. The role of anoxia, per s.c. in inducing membrane damage was in vestigated in tissue slices incubated at 37ΰC in crystalloidal media gassed with nitrogen. Anoxic slices produced lactate and lost ATP and adenine nucleotides, but cell volume and the IDS were not significantly increased for at least jive hours (twice the time required for severe membrane damage to develop in total ischaemia) and the plasmalemma remained intact by electron microscopy. Thus, despite depletion of high energy phosphates, membrane damage, detectable by alterations in IDS or ultrastructure, occurs much more slowly during anoxia alone than during ischaemia. These results suggest that anoxia, per Se, may not be the cause of membrane damage in ischaemia.

Comparison of the effect of ischaemia and anoxia on the sarcolemma of the dog heart

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Comparison of the effect of ischaemia and anoxia on the sarcolemma of the dog heart