There are two general theories for explaining the pathomechanisms underlying myocardial stunning, and they are generally not considered to be mutually exclusive. Episodes of ischemia are caused by: (1) the formation of free radical reactive species and/or (2) alterations in intracellular calcium regulation [5]. Furthermore, in such cases, intracellular acidosis occurring during ischemia can potentially generate intracellular calcium oscillations and calcium overload upon reperfusion via activation of the sarcolemmal Na⁺/H⁺ exchanger (NHE) (Fig. 16.4) [6].

Experimental studies have shown that the calcium sensitivity of the contractile apparatus is decreased in the stunned myocardium, thereby resulting in lower maximal force generation even at higher than normal transient calcium levels [7, 8]. Furthermore, decreased myofilament sensitivity to calcium is considered primarily responsible for systolic dysfunction; for example, the stunned myocardium is still responsive to inotropic stimulation. Of additional interest is the finding that troponin I (cTnI) degradation products were discovered in the human myocardium during aortic cross-clamping with bypass and that serum levels of cTnI increased during reperfusion, peaking approximately 24 h following cross-clamp removal [9]. This preliminary evidence further suggests that cTnI degradation products may potentially be utilized as biomarkers for occurrence of myocardial stunning.

During the early stage of stunning, it is considered beneficial to prevent calcium oscillations and thus attenuate significant injury caused by reperfusion. This has been accomplished experimentally by utilizing Ca²⁺ antagonists, inorganic blockers, ryanodine, low-calcium reperfusion buffers, and/or NHE blockers [10]. Conversely, when contractility is suppressed, as in the late stage of stunning, therapies should include those that increase the amplitudes of intracellular calcium transients, inducing inotropic responses. Included in this subset of therapeutics are high calcium buffers, Ca²⁺ agonists, catecholamines, and/or phosphodiesterase inhibitors. Importantly, many of these therapies are specific to the stage or degree of stunning, and hence, the timing of their use is critical, so as not to become a detrimental therapy. For instance, hypocalcemia during and following cardiopulmonary bypass is a common occurrence mainly attributed to the utilization of priming fluids, citrated blood, and large doses of heparin during bypass [11]. Normally, hypocalcemia is successfully corrected with the administration of calcium chloride; however, calcium levels may return to preoperative levels prior to removal from cardiopulmonary bypass without supplemental calcium [12]. Therefore, the risk of stunning and myocardial damage may actually be increased with generalized calcium chloride administration. While it may be used for post-bypass cardiac resuscitation, current Advanced Cardiac Life Support (ACLS) guidelines do not indicate calcium chloride for general resuscitation purposes, and administration if done at all is on an “as necessary” basis [13].

As previously discussed, myocardial stunning and hibernation are related in that a depressed state of contractility exists and, yet importantly, there is the potential to reversibly return the dysfunctional myocardium back to normal. However, it must again be restated that while stunning can be attributed to the reperfusion following a brief bout of ischemia, the hibernating myocardium is in a chronic hypocontractile state, due to a decreased oxygen supply and thus may only recover full function with revascularization therapy. In other words, this reduction in oxygen delivery is attributable to reductions in local perfusion, and the corresponding reduction in contractility has been shown to be a proportional response of the myocardium, termed perfusion-contraction matching and elucidated by John Ross [14]. It may be beneficial to consider the hibernating myocardium as a viable tissue which is simply eliciting necessary physiological compromises in response to locally limited blood flow. Additionally, many of the underlying mechanisms of stunning are considered directly related to the detrimental effects of reperfusion injury (to be discussed later) [15]. While there is a general absence of necrosis with myocardial hibernation, morphological changes to the myocardial architecture, such as loss of myofibrils and increased interstitial fibrosis, may occur if this state persists [16].

The maimed myocardium closely resembles that of a heart with a classic myocardial infarction in that ischemia-induced necrosis leads to loss of contractile performance. In these cases, unlike in myocardial stunning, the duration of ischemia is long enough to result in necrosis. Importantly there can be partial recovery of function in this ischemic region, i.e., following timely reperfusion [17]. An example of the maimed myocardium syndrome would be a patient that exhibits an incomplete recovery of myocardial function following drug-induced or mechanical (angioplasty) reperfusion of an occluded coronary artery and then subsequently demonstrates regions of viable myocardium in the original ischemic area.

Ischemic preconditioning is a biological phenomenon whereby brief ischemic episodes followed by adequate reperfusion protect tissue from a subsequent prolonged ischemic event [18]. In general, cardiac protection from ischemic preconditioning has been characterized as biphasic. The first window of protection occurs immediately following the ischemic event for approximately 3 h mediated by effectors. The second window of protection occurs some 24 h after the ischemic event and can last for up to 3 days and is mediated by an upregulation of cardioprotective proteins. There are several signaling pathways that are involved in these mechanisms of ischemic preconditioning, including the activation of potassium channels that are located in the inner membrane of the mitochondria of the cardiac myocytes [19]. These pathways can be utilized as drug delivery targets for the therapeutic treatment of prevention for ischemic injury, by mimicking the natural progression of limited ischemic preconditioning. In the myocardium, ischemic preconditioning has been shown to be potentially infarct limiting [18] as well as antiarrhythmic [20], although the latter of these effects can be agent specific. It is also well established that endogenous opioid receptor activation participates in myocardial ischemic preconditioning [21] and that preischemic administration of synthetic opioid agonists can mimic the benefits of ischemic preconditioning [22]. While ischemic and opioid preconditioning have both been convincingly shown to delay cell death in various experimental animal models, the clinical applicability of these therapies in humans may be limited to situations where the ischemic event can be anticipated (e.g., on- or off-bypass cardiac surgery, percutaneous transluminal coronary angioplasty, or stenting procedures) [23]. For a more comprehensive review of ischemic and opioid preconditioning, see articles by Yellon and Downey [24] (ischemic preconditioning) and Gross [25] (opioid preconditioning).

Silent ischemia refers to single or multiple asymptomatic episodes of transient ischemia. In some cases, silent ischemia can occur in the week(s) following an acute myocardial infarction in patients with a history of coronary artery disease. In other scenarios, seemingly normal healthy individuals may experience episodes of silent ischemia that go relatively unnoticed. Detection of silent ischemia primarily relies on electrocardiographic monitoring, either in the form of 24-h Holter monitoring (ambulatory) or exercise- and/or stress-induced assessment. In both cases, ischemia is typically detected by asymptomatic ST-segment elevations in an ECG tracing [26]; see also Chap. 19. Silent ischemia is postulated to be related to a lack of oxygen supply rather than an increase in oxygen demand; however, controversy remains regarding the mechanisms whereby silent ischemia can proceed unnoticed.

As shown in Fig. 16.1, there are several means of decreasing myocardial oxygen demand when the oxygen supply is compromised. These include hypothermia, pharmacologically decreasing the heart rate, and/or controlled cardiac arrest. Additionally, as mentioned above, ischemic and pharmacological preconditioning of the heart are other ways to protect the myocardium from an ischemic episode and, hence, induce cardioprotection. However, these therapies require the anticipation of the ischemic event, such that treatment can be administered prior to or early during the ischemia. In situations where anticipation of ischemia is not possible, for example, in acute myocardial infarction, interventions which reestablish blood flow and oxygen to the ischemic zone (reperfusion) are the primary therapies. Nevertheless, it should be noted that dietary supplements such as omega-3 fatty acids have been considered as a potential means for prevention [27, 28].