C

200 mmHg

T5me

T5me

Zero-flow. global Ischemia reper fusion

Figure 5. A, Schematic of a Latigendûrff perfused rat heart model. Retrograde perfusion is established through the aorta. Perfusate oxygenated with 95% O, and 5% CO, is circulated by a peristaltic pump and the How can be adjusted. Left ventricular pressure is monitored through a balloon which is inserted into the empty left ventricle. Heart rhythm is controlled by pacing.

B. Recording of left ventricular developed pressure (LVDP is defined as the difference between systolic and diastolic left ventricular pressure) from Langcndorff perfused heart after stabilization followed by complété flow cessation (zero-flow global ischemia) and flow re-establish ment (rcpcrfusion). Note the development of ischemic contracture (black arrow) and hypcrcontracturc early at the time of rcpcrfusion (white arrow).

C. Left ventricular pressure recording of a perfused rat heart model of zero-flow global ischemia and rcpcrfusion. A progressive increase in LVDP occurs at reperfusion. This corresponds to myocardial stunning (data from our laboratory).

dysfunction is induced through an inflammatory signal cascade.87 Thus, it is suggested that microembolization (derived from subclinical plaque Assuring and rapture) is likely in hibernation. Alterations in calcium handling and adrenergic control are also seen in hibernation but their causal role remains to be elucidated.80 See also chapter 6.

Hibernating myocardium is prone to arrhythmias. Scar formation and reduction and inhomogeneity of connexin 43 expression in human myocardium may contribute to alterations in electrical impulse propagation and re-entry. Furthermore, cardiomyocytes from hibernating myocardium in pigs are hypertrophied and have reduced contraction and striking prolongation of the action potential rendering them more prone to after depolirizations.88'89

1.6. Ischemia-reperfusion induced arrhythmias

Under ischemic conditions, increase in extracellular potassium and the existence of inward currents result in increased depolarization of the resting membrane potential while the increased outward currents through potassium and chloride channels result in shortening of the action potential. Figure 6. Potassium currents which are activated under physiological conditions are inhibited under ischemic conditions and several other new channels come to the operation (IKATp, IKNi, IKFFA). Figure 6. Shortening of the action potential also occurs from injury currents generated from current differences between ischemic and non ischemic areas. This is mainly observed in the border zone of the ischemic area. At reperfusion, shortening of the action potential is mainly due to the excessive stimulation of the sodium pump (Na7K+-ATPase). Under ischemia, membrane action potential is altered due to the accumulation of metabolites, such as fatty acids, free oxygen radical species production, the release of endogenous molecules, such as catecholamines, acetylcholine and adenosine as well as the stretch and the changes in cell volume. Changes in action potential and its conductance constitute the basis of ischemia and reperfusion arrhythmias, reviewed by Carmeliet.55

Arrhythmias are observed during the ischemic phase as well as at reperfusion in most of the animal models. In the first 2-10 min of ischemia, a burst of irregular ventricular tachycardia occurs but evolution to ventricular fibrillation is rare. These arrhythmias are mainly of a reentry nature. A second phase of arrhythmias is evident after 20-30 min of ischemia. The percentage of animals that show this delayed phase of arrhythmias is small and the evolution to ventricular fibrillation is more frequent and the animals can die. This phase is associated with a massive release of catecholamines, changes in calcium overload and an increase in extracellular potassium, reviewed by Carmeliet.55

Arrhythmias occur within a few seconds after reperfusion, following ischemic periods of 10-30 min long. They start by a spontaneous stimulus in the reperfused zone and change afterward in a re-entry multiple wavelet type of ventricular tachycardia (VT) or ventricular fibrillation (VF). Extremely short action potential, short refractory period and slow conduction are the main contributing factors. Increased hyperpolarization and elevated intracellular calcium that act negatively on gap conductance impair conduction. Unidirectional conduction is favored by the marked heterogeneity in extracellular potassium, action potential and refractory period. The extra stimulus is initiated in the reperfused zone, probably by early (EAD) and late (DAD) afterdepolirizations.

Delayed reperfusion arrhythmias appear as a second phase of irregular rhythm when the occlusion period has been longer than 10-20 min. Extrasystoles and runs of

Voltage (mV)

Normoxia

Voltage (mV)

Ischemia

Duration

Duration

Figure 6. Resting membrane potential under normoxia (left) and ischemia (right). Increased outward potassium current during ischemia causes shortening of the resting membrane potential. Potassium currents activated under physiological conditions are inhibited under ischemia and several other new channels come to the operation (IKATpJ IK^, IKFFA). Resting membrane potential is less negative due to the increased extracellular potassium and inward currents.

tachycardia probably originate in surviving Purkinje system due to the abnormal au-tomaticity. Oscillatory release of calcium or even stretch depolarizations may also be involved, reviewed by Carmeliet.55

Concluding remarks

Lack of oxygen availability and metabolites result in myocardial ischemia and cellular injury of reversible or irreversible nature. Reperfusion, generally pre-requisite for tissue survival may also increase injury over and above that sustained by ischemia, a phenomenon known as reperfusion injury. Necrotic and apoptotic cell death are the two major forms of cell death recognized in the pathology of myocardial injury. Apoptosis is an energy dependent process, executed through the mitochondrial and/or death receptor pathways and does not involve an inflammatory response. Cell to cell communication (Gap junctions) contributes to spread of injury but survival signals can also be transferred depending on the intensity of stimulus. Myocardial ischemia is accompanied by the inflammatory response that further contributes to myocardial injury and ultimately leads to myocardial healing and scar formation. Myocardial necrosis is associated with complement activation and reactive oxygen species triggering cytokine cascades and resulting in chemokine upregulation. Cytokines exert direct negative inotropic effects via paracrine and autocrine modulation and induce apoptosis. Chemokine expression may play a role in the pathogenesis of non-infarctive ischemic cardiomyopathy, where early ischemia-induced chemokine expression may be followed by activation of inhibitory mediators that suppress inflammation, but induce fibrosis. Endothelial dysfunction and microvascular injury start at the interphase of the endothelium with the bloodstream. During reperfusion severe microvascular dysfunction can arrest the microcirculation, a phenomenon known as the no-reflow phenomenon.

Metabolism is altered during myocardial ischemia contributing to cell survival or cell death depending on the severity of the ischemic insult. Mitochondrial activity decreases and slowing and ultimately cessation of TCA and FAO cycles occurs. Glucose increases due to the enhanced glucose uptake and glycogen breakdown. The activity of the regulatory enzyme PDH declines and less pyruvate enters the TCA cycle. Enhanced glycolysis provides the ATP that is required for maintaining cell membrane integrity. Intermediates of fatty acid metabolism accumulate and damage heart cell membranes. AMPK is stimulated due to the breakdown of ATP to AMP. AMPK stimulates glycolysis but also inhibits the malonyl-CoA synthesis, removes the negative regulatory effect of malonyl-CoA on FFAs transport to mitochondria and facilitates FFA metabolism. As a consequence FFAs use residual oxygen, instead of the energy-friendly glucose substrate. Energy depletion and acidosis change ion homeostasis causing potassium leakage and calcium and sodium overload. Calcium and sodium excess results in cell damage.

During prolonged ischemia, ATP levels decline and the strong cross-bridge between myosin heads and actin is maintained resulting in the development of the ischemic contracture. Ischemic contracture has been related to preischemic myocardial glycogen content, at least in the setting of zero-flow global ischeamia and reperfusion. Severity of contracture does not correlate to postichaemic recovery of function. At the time of reperfusion, hypercontracture develops due to calcium oscillations or to severe ATP depletion (rigor type). Hypercontracture can contribute to cell death at early reperfusion.

Myocardial stunning is defined as transient contractile dysfunction that appears after reperfusion despite the absence of irreversible damage and restoration of normal or near normal coronary flow. Although the pathogenesis of stunning has not been definitively established, the two major hypotheses are that it is caused by the generation of oxygen free radicals or by calcium overload. The absence of irreversible cellular damage in stunned myocardium may correspond to an increased resistance of the heart to ischemia. Survival genes are upregulated in stunned myocardium. Stunning may explain much delayed contractile recovery after thrombolytic therapy in acute myocardial infarction.

Myocardial hibernation is an adaptation caused by chronic or intermittent reduction in coronary flow characterized as reduced regional contractile function that recovers after removal of the artery stenosis. Two current hypotheses are perfusion contraction matching with downgraded myocardial energy requirements and repetitive cumulative stunning. Salient features of the hibernating myocardium are the increase in glucose uptake out of proportion to coronary flow (metabolism/perfusion mismatch) and the increase in myocardial glycogen content with ultrastructural characteristics resembling those of the fetal heart. In long-term hibernation, changes seem to correspond to a genetic program of cellular survival that is induced probably by the repetitive episodes of ischemia and reperfusion. Hibernation is searched for and diagnosed in efforts to improve left ventricular contractile function by revascularization.

Increased outward potassium currents during ischemia cause shortening of membrane potential. Potassium currents activated under physiological conditions are inhibited under ischemia and several other new channels come to the operation (IKATp, IK^, IKpFA). Resting membrane potential is less negative due to the increased extracellular potassium and inward currents. Changes in action potential and its conductance constitute the basis of ischemia and reperfusion arrhythmias.

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