My colleague and I were doing case together the other day and we discussed why I typically give calcium chloride only after the heart is warm, and has been re-perfused + in normal sinus rhythm for at least 10 minutes. I mentioned the concept of stone heart, a perfusion nightmare that I have never seen, and certainly never want to. I told him I wasn’t exactly sure about the mechanism of injury or the pathology behind it other than more often than not it is linked to the administration of calcium. I told him no one was really certain depending on the event, what the true pathology to this rare complication actually was. It may differ depending on the patient, and the circumstances of the myocardial injury and subsequent bypass run.
Adam Findlay (a chemical engineer that currently works with me – on his way to becoming a perfusionist sometime in the near future)
Anyway, Adam took it upon himself to look up two articles- one of which in particular I found to be quite cogent and definitely worth sharing.
Thank you Mr. Findlay, and good luck to you on your path to becoming a perfusionist.
Click Image above to View Source Article
As of yet, only a few strategies to prevent myocardial reperfusion injury have been tested clinically. In the first minutes of reperfusion, the myocardium can be damaged by contracture development, causing mechanical stiffness, tissue necrosis, and the “stone heart” phenomenon. Reperfusion-induced contracture can have two different causes, namely, Ca2+overload–induced contracture or rigor-type contracture. Ca2+ contracture results from rapid re-energization of contractile cells with a persistent Ca2+ overload. Strategies to prevent this type of injury are directed at cytosolic Ca2+ control or myofibrillar Ca2+ sensitivity. Rigor-contracture occurs when re-energization proceeds very slowly. It does not depend on Ca2+ overload. It may be prevented by strategies improving early mitochondrial reactivation
Two causes of reoxygenation-induced contracture
Contracture (ie, a sustained shortening and stiffening of myocardium) can have several causes. In ischemic myocardium contracture develops by means of a rigor-type mechanism. Studies on skinned cardiac cells or muscle fibers have shown that a force-generating cross bridge cycling is initiated when cytosolic adenosine triphosphate (ATP) is reduced to a low (<100 μmol/L) but nonzero level [1, 2]. In ischemia, this window of low cytosolic ATP concentrations is open only during a brief period, because cellular ATP reserves are quickly exhausted. The myofibrillar shortening then stays fixed, as all cross bridges between actin and myosin remain in an attached state. The contracture developed by this ischemic mechanism does not actually cause major structural damage but leads to cytoskeletal defects. These defects render cardiomyocytes more fragile and thus susceptible to mechanical damage . When energy depletion is rapidly relieved, ischemic rigor contracture is usually reversible.
After prolonged ischemia myocardial cells may develop severe contracture, which can lead to cytoskeletal defects that consequently increase the fragility of cardiomyocytes upon reperfusion. As a consequence, end-diastolic ventricular pressure increases and ventricular compliance decreases. Substantial contracture is accompanied by a specific form of tissue necrosis, the so-called contraction band necrosis . The histologic picture is characterized by coexistence of supercontracted sarcomeres, overextension of spaces in between, and sarcolemmal disruptions, all in the same cells. This picture results from strong and inhomogeneous mechanical forces. In a number of studies we have shown that pathogenesis of reperfusion-induced contracture can be analyzed on the cellular level. This analysis revealed two independent causes of reperfusion-induced contracture: (1) Ca2+overload–induced contracture, and (2) rigor contracture. Ca2+ overload–induced contracture is elicited in a cardiomyocyte, if it develops Ca2+ overload during ischemia and is then rapidly reenergized. High cytosolic Ca2+plus energy leads to uncontrolled activation of the contractile machinery. Rigor-contracture may be activated during reoxygenation, if reenergization of the ischemic cardiomyocytes occurs at a very low rate. It may, therefore, be observed after prolonged or severe ischemia. Rigor-contracture is not essentially dependent on Ca2+ overload. These two causal mechanisms for reperfusion-induced contracture are described separately below.
Ca2+ overload–induced contracture
Ischemic cells become energy depleted and subsequently develop a Ca2+ overload of the cytosol due to a reverse-mode operation of the sarcolemmal Na+/Ca2+ exchanger (Fig 1). If the ability of mitochondria to resume ATP synthesis is not critically impaired during the ischemic period, reoxygenation leads to a rapid recovery of energy production. Resynthesis of ATP can enable cardiomyocytes to recover from the loss of cytosolic cation balance, but it also reactivates the contractile machinery that had been fixed in rigor contracture after ischemic loss of ATP. The latter effect is normally faster then the former, which leads to an uncontrolled Ca2+-dependent contraction. When analyzed in detail, it was found that cyclic uptake and release of Ca2+ by the sarcoplasmic reticulum (SR) in the reoxygenated cardiomyocytes triggers a Ca2+ overload–induced contracture [5, 6] (Fig 2). These oscillatory Ca2+ shifts lead to high cytosolic peak Ca2+ concentrations (Fig 3). The frequency of these Ca2+peaks is influenced by an ongoing Ca2+ influx across the sarcolemma during the early phase of reoxygenation . During this period the transsarcolemmal Na+ gradient is still reduced and the Na+/Ca2+exchanger still operates in reverse mode. Experimentally, various protocols have been shown to interfere with Ca2+ overload–induced contracture: First, contracture can be prevented by an initial, time-limited inhibition of the contractile machinery. For this purpose, the chemical phosphatase 2,3 butane dione monoxime has been used [7, 8]. Part of the protective effects of cGMP-mediated effectors (NO, atrial natriuretic peptides) or cytosolic acidosis can also be attributed to contractile inhibition, as these agents reduce Ca2+ sensitivity of myofibrils. Second, contracture can be reduced by reducing SR-dependent Ca2+ oscillations. This can either be achieved by agents interfering with SR–Ca2+ sequestration or by inhibition of the Ca2+ influx into the cells still occurring during the early phase of reoxygenation. Ca2+ cycling across the SR can be inhibited by specific agents interfering with SR Ca2+ ATPase or SR Ca2+ release  or with less specific means such as the anesthetic halothane or intracellular acidosis [9, 10].
Reoxygenation-induced rigor contracture
As long as mitochondrial energy production recovers rapidly upon reperfusion/reoxygenation, reoxygenated cardiomyocytes are in acute jeopardy by Ca2+ overload–induced contracture. After prolonged ischemia the ability of mitochondria to rapidly restore a normal cellular state of energy is reduced. However, during the early phase of reoxygenation cardiomyocytes may then contain very low (even though rising) concentrations of ATP which provoke rigor contracture (see above) (Fig 4). In comparison to ischemia, upon reoxygenation cardiomyocytes may spend much more time at the window of low cytosolic ATP suitable to induce rigor-type contracture. Therefore, cell shortening can be much more pronounced than observed in ischemic rigor contracture. In fact, the rigor mechanism may become the major contributor to reoxygenation-induced contracture (Piper HM, unpublished data). In the event that rigor contracture prevails in acute reperfusion injury, therapeutic actions aiming at cytosolic Ca2+ overload are not effective, inasmuch as rigor contracture is essentially Ca2+ independent (Fig 5). It can be shown experimentally that one can reduce rigor contracture by improving the conditions for energy recovery. A first approach is application of mitochondrial energy substrates, eg, succinate, with the aim of accelerating oxidative energy production. Second, one may speculate about means to protect mitochondria and resume respiratory activity in the early phase of reperfusion from compulsory calcium uptake.
Reperfusion injury: the second act
The pathologic mechanisms described so far occur during the first minutes of reperfusion. Other mechanisms originating from the vasculature and blood elements can enhance reperfusion injury by mechanisms activated during the subsequent hours. To place the early mechanisms in perspective, these additional causes of injury are briefly summarized. The endothelial lining of blood vessels subjected to ischemia-reperfusion becomes permeable, thus causing interstitial edema with the resumption of blood flow. Endothelial cells in reperfused myocardium assume an activated state in which they express adhesion proteins, release cytokines, and reduce production of NO. This promotes adherence, activation, and accumulation of neutrophils and monocytes in the ischemic-reperfused tissue. The release of reactive oxygen species and proteolytic enzymes from these activated leukocytes can contribute to the damage of myocytes and vascular cells. Vascular plugging by adherent leukocytes can also promote a slow- or no-reflow phenomenon, already favored by tissue contracture and increased pressure of interstitial water. It seems that these additional reperfusion-induced noxes contribute to infarct development predominantly during the first 2 hours of reperfusion, as myocardial necrosis almost reaches its final size during this period.
In summary, the early phase of reperfusion represents an important target for strategies protecting ischemic-reperfused myocardium. Adaptation of these protective strategies to clinical therapeutic use would represent a major advance in the field of cardiology for treatment of acute myocardial infarction and for myocardial protection in cardiac surgery.