INTRODUCTION

Myocardial stunning or postischemic dysfunction is a contractile dysfunction that persists after reperfusion following a severe but brief ischemic insult. This is despite the absence of irreversible damage and restoration of adequate blood flow (Braunwald and Kloner, 1982; Bolli, 1990; Braunwald, 1991; Fine and Yellon, 1993; Gao et al., 1995). Metabolic analysis show the slow recovery of ATP concentrations while histologic analysis show normal histologic appearance of the stunned myocardium (Braunwald and Kloner, 1982; Kloner, 1993). Since no permanent damage has occurred to the myocardial cells this contractile dysfunction will gradually recover with time (refer figure 1) (Braunwald and Kloner, 1982; Kloner, 1993). However, full recovery may take hours to days or even weeks (Braunwald and Kloner, 1982; Gao et al., 1995).

Though the exact mechanism of myocardial stunning remains unknown, a variety of possible mechanisms, not necessarily mutually exclusive, have been hypothesised (Braunwald, 1991; Abd-Elfattah and Wechsler, 1995; Mohamed et al., 1995). These include insufficient energy production by mitochondria, impaired energy use by myofibrils, reduced myofilament responsiveness to calcium, calcium overload, reduced contractile protein activation due to sarcoplasmic reticulum dysfunction and generation of oxygen-derived free radicals (Bolli, 1990; Braunwald, 1991; Kusuoka and Marban, 1992; Mohamed et al., 1995). The underlying reasons for the remarkable growth of interest in myocardial stunning since the 1980's have been due to the recognition that it is a common phenomenon in patients with coronary artery disease, and its significance in delaying the benefits of reperfusion therapy (Bolli, 1990; Bolli, Hartley and Rabinovitz, 1991; Schaper 1991). It has also been shown that myocardial stunning occurs in various clinical settings (Bolli, Hartley and Rabinovitz, 1991; Bolli, 1992; Mohamed et al., 1995). These include percutaneous transluminal coronary angioplasty, unstable angina, variant angina, acute myocardial infarction with early reperfusion, cardiac surgery and cardiac transplantation (Bolli, Hartley and Rabinovitz, 1991; Bolli, 1992; Mohamed et al., 1995; Ambrosio et al., 1996). Thus, much talent and money are invested in understanding the mechanisms of this postischemic dysfunction. This essay discusses the possible mechanisms of myocardial stunning and to a lesser extent its clinical relevance.

Figure 1. Manifestation of myocardial stunning following 15 minutes of global ischemia and reperfusion, in the isolated ferret heart. The isovolumic left ventricular pressure drops with the occlusion of the coronary artery. With reperfusion, a short period of arrhythmia with potentiated beats followed by a phase of distinctly lower but recovering isovolumic left ventricular pressure is seen (Kusuoka and Marban, 1992).

MECHANISMS OF MYOCARDIAL STUNNING

Insufficient Energy Production by Mitochondria

It was observed in the early 1980s, that a coronary occlusion for 15 minutes caused adenosine triphospate (ATP) concentration in the stunned myocardium to fall and later to recover with cardiac function (Braunwald and Kloner, 1982). It was shown, that after the creatine phosphate (CP) stores are exhausted, myocardial ATP concentration declines with the accumulation of its metabolites such as adenosine, inosine and hypoxanthine (Braunwald and Kloner, 1982; Flameng et al., 1991). These accumulated metabolites capable of being used as precursors to resynthesise ATP through the salvage pathway, are washed away during reperfusion (refer figure 2) (Braunwald and Kloner, 1982; Flameng et al., 1991; Abd-Elfattah et al., 1995). Thus the "backbone" of ATP will now be resynthesised by the slow de novo pathway (Flameng et al., 1991; Abd-Elfattah et al., 1995). This process may take several days to occur (Flameng et al., 1991; Abd-Elfattah et al., 1995). Therefore, it was speculated that there is a causal relationship between depletion of adenine nucleotides and myocardial function (Braunwald and Kloner, 1982).

However, this hypothesis is now refuted since a correlation between myocardial ATP levels and recovery of myocardial contractility was not observed in certain models of myocardial stunning (Haworth and Berkoff, 1986; Ambrosio et al., 1989). Furthermore, it was also shown that by administering a nucleotide precursor (adenosine) during postischemic reperfusion, causes an increase in ADP and ATP levels, but with no improvement in cardiac contractility (Ambrosio et al., 1989). This finding also suggest that a decreased availability of nucleotide precursors as the primary cause, rather than a defect in mitochondrial function, as the limiting factor for ATP recovery in stunned myocardium (Ambrosio et al., 1989). An increased phospocreatin content found in stunned myocardium further confirms that phosphorylating capability of mitochondria is not lost (Ambrosio et al., 1987).

Figure 2. Postischemic replenishment of ATP is through the slow de novo pathway since salvage precursors are washed away during reperfusion. (Abd-Elfattah and Wechsler, 1986, cited in Abd-Elfattah et al., 1995).

Impaired Energy Use by Myofibrils

Greenfield and Swain (1987) has shown that myofibrillar creatin kinase activity is decreased in stunned myocardium. A reduction of free ADP, that is used to produce ATP at the contractile site by the myofibrillar creatin kinase was also observed in the stunned myocardium (Ambrosio et al., 1989). Thus, a disruption of the myofibrillar end of the phosphocreatin shuttle was proposed as a possible mechanism of stunning (Greenfield and Swain, 1987).

This hypothesis is unlikely since inotropic stimulation causes an immediate and sustained increase in performance in the stunned myocardium (Ambrosio et al., 1989). This increase in myocardial performance suggest that the residual activity of the enzymes are still able to run the myofibrillar ATPase reaction at increased rates (Ambrosio et al., 1989).

Reduced Myofilament Responsiveness to Calcium

It has been found that both myofilament Ca2+ sensitivity and maximal Ca2+ - activated force is reduced in the stunned myocardium (Kusuoka et al., 1990; Marban, 1991; Kusuoka and Marban, 1992). Thus, it is hypothesised that a reduced responsiveness of myofilaments to Ca2+ is a mechanism for myocardial stunning. Either a decreased intracellular free Ca2+ concentration ([Ca]i) transient or a decreased sensitivity of myofilaments to calcium, could cause a reduced myofilament responsiveness to extracellular calcium in the stunned heart (Kusuoka et al., 1990; Marban, 1991). Since Kusuoka et al. (1990) and Marban (1991) have observed an increase in Ca2+ transients in the stunned heart, it is proposed that a decreased sensitivity of myofilaments to calcium as the mechanism for myocardial stunning. This decreased sensitivity could be a result of a shift in myofilament Ca2+ sensitivity and / or a reduction in the maximal Ca2+ - activated force (refer figure 3) (Marban, 1991; Kusuoka and Marban, 1992; Gao et al., 1995).

Figure 3. Possible causes of reduced responsiveness of myofilaments to Ca2+. Diagrams of Ca2+ transients (left), twitch force (right), and [Ca2+]i - activated force relation (above arrows). (A) Control; (B) decreased twitch force caused from reduced Ca2+ transient amplitude, (C) a shift to the right in myofilament Ca2+ sensitivity, and / or a decrease in maximal Ca2+ - activated force (D). (Marban, 1991)

Murphy et al. (1989) found that [Mg2+]i rises during ischemia and remains elevated during early reflow. It has been observed that as [Mg2+]i rises the [Ca2+]- activated force relation is shifted to the right (Fabiato and Fabiato, 1975, cited by Kusuoka and Marban, 1992). These observations of magnesium transients however do not explain the reduced maximal Ca2+ - activated force. Furthermore, increased [Mg2+]i reducing the sensitivity of myofilaments to calcium, do not explain the ability of the stunned myocardium to respond to inotropic stimuli with a normal contractile reserve (Ito et al., 1987; Ambrosio et al., 1989).

Recent studies by Gao et al. (1997) have found that troponin I is partially degraded in the stunned heart. Usually, the troponin-tropomyosin complex inhibits the binding of myosin and actin. A structural alteration occurs within tropomyosin when Ca2+ binds to troponin C (Gao et al., 1995). This exposes the myosin binding site on actin (Gao et al., 1995). The free energy needed to cause this structural change in the troponin-tropomyosin complex is obtained from the energy of Ca2+ binding to troponin C (Gao et al., 1995). This energy is then transduced by troponin T and troponin I (Gao et al., 1995). Since troponin I is partially degraded in the stunned myocardium by Ca2+-activated protease (see Calcium Overload) the energy obtain from Ca2+ binding to troponin C cannot be effectively transduced to cause the necessary structural change in the troponin-tropomyosin complex (Gao et al., 1995; Gao et al., 1997). Thus, a greater [Ca2+]i is required to bring about muscle contraction, or in other words myofilament responsiveness to calcium is reduced. These studies have also found a reduction of both myofilament Ca2+ sensitivity and maximal Ca2+ - activated force (Gao et al., 1995; Gao et al., 1997). Since only limited proteolysis of troponin I occurs (by calpain I) this would not affect the upstream mechanisms controlling [Ca2+]i (Gao et al., 1995) . Thus, the ability of the stunned myocardium to respond to inotropic stimuli with a normal contractile reserve is explained (Gao et al., 1995). Turnover of troponin I takes several days and this could explain the usual time of recovery of the stunned myocardium (Braunwald and Kloner, 1982; Gao et al., 1997).

Calcium Overload

Though intracellular calcium is vital for excitation-contraction coupling, it has been suggested that an increase in transient [Ca2+]i during ischemia and early reperfusion could be a mechanism for myocardial stunning (Kusuoka et al., 1990; Marban, 1991). It has been observed that the intracellular calcium concentration increases during the first 10 - 15 minutes of total ischemia and remains elevated (for at least 5 minutes) during early reperfusion (Marban et al., 1990). A similar period of ischemia is required for myocardial stunning to occur (Braunwald and Kloner, 1982). Kusuoka et al. (1987, cited by Bolli, 1990 and Opie, 1991) found that reperfusion with solutions containing low calcium concentrations after 15 minutes of ischemia, would significantly attenuate postischemic dysfunction. Furthermore, it has been shown that exposure of isolated ferret hearts to a transient calcium overload mimics several features of stunning, even in the absence of prior ischemia (Kitakaze, Weisman and Marban, 1988). Features such as decreased maximal Ca2+ - activated force and sensitivity to calcium, ATP depletion, and absence of histological evidence of irreversible injury were observed (Kitakaze, Weisman and Marban, 1988).

The precise mechanisms leading to calcium overload is not known (Tani and Neely, 1989; Bolli, 1990). However, it is proposed that during ischemia H+ are produced excessively and accumulated (Tani and Neely, 1989). These are then exchanged for extracellular Na+, slowly during ischemia and rapidly during early reperfusion, by H+-Na+ exchange (Tani and Neely, 1989). Increased intracellular Na+ are then exchanged for Ca2+ by the Na+-Ca2+ exchange, and this causes calcium overload (Tani and Neely, 1989). Based on previous findings, Kusuoka et al., (1990) proposed that an increase in [Ca2+]i during ischemia and early reperfusion could activate Ca2+ - depended protein kinases, which could then cause changes in myofilaments to decrease Ca2+ sensitivity and / or maximal Ca2+ - activated force through phosphorylation of contractile proteins. Recent studies by Gao et al. (1997) have concluded that an increase in [Ca2+]i during ischemia and early reperfusion causes Ca2+-activated protease to partially degrade troponin I in the stunned myocardium. This in turn causes myofilament responsiveness to calcium to decrease (see Reduced Myofilament Responsiveness to Calcium). An increase in [Ca2+]i could generate oxygen radicals via xanthine oxidase, which is in itself a mechanism of stunning (see Generation of Oxygen - Derived Free Radicals) (Przyklenk and Kloner, 1986).

Reduced Contractile Protein Activation Due to Sarcoplasmic Reticulum Dysfunction

The normal myocardial contraction - relaxation cycle depends on a proper functioning calcium release - uptake cycle (Krause, Jacobus and Becker, 1989; Limbruno et al., 1989). Release of Ca2+ from the sarcoplasmic reticulum stores causes the intracellular free Ca2+ concentration to rise. Through Ca2+ binding to troponin C contraction is generated. Relaxation is then achieved by sequestration of Ca2+ by the sarcoplasmic reticulum through Ca2+-ATPase activity (Chemnitius et al., 1985; Krause, Jacobus and Becker, 1989). Krause, Jacobus and Becker (1989) found that the sarcoplasmic reticulum isolated from stunned myocardium had decreased Ca2+ uptake ability and Ca2+, Mg2+-ATPase activity. This decrease in calcium uptake ability would result in less sequestration of Ca2+ and in turn less subsequent release from the sarcoplasmic reticulum stores (Krause, Jacobus and Becker, 1989). Attenuated calcium release in turn would cause reduced contractile protein activation (Krause, Jacobus and Becker, 1989). Thus, a dysfunction of the sarcoplasmic reticulum uptake ability could be a possible mechanism of myocardial stunning.

Since this hypothesis implies a decreased in [Ca]i it may explain the ability of the stunned myocardium to achieve contractile function comparable to preischemic levels with the addition of the exogenous calcium or other inotropic agents (Ambrosio et al., 1987; Ito et al., 1987; Bolli, 1990). The addition of inotropic agents would increase intracellular calcium concentration and contractile protein activation. However, this hypothesis cannot explain the increase in [Ca2+]i transients observed in the stunned myocardium by Kusuoka et al., (1990) and Gao et al., (1995).

Generation of Oxygen-Derived Free Radicals

In early 1980s, it was postulated that the generation of oxygen-derived free radicals could be a mechanism of myocardial stunning (Bolli, 1990; Hearse, 1991). These free radicals are unstable, cytotoxic and highly reactive variations of the oxygen molecule (Przyklenk and Kloner, 1986). Through the administration of free radical scavengers such as superoxide dismutase (SOD) and catalase before and during ischemia, and throughout reperfusion it has been possible to attenuate myocardial stunning in open-chest dogs (Przyklenk and Kloner, 1986). Superoxide dismutase acts by catalysing the dismutation of superoxide ions (.O2-) to hydrogen peroxide (H2O2) and O2, while catalase acts by reducing H2O2 to O2 and H2O (refer figure 4) (Przyklenk and Kloner, 1986; Bolli, 1990). It has been found that administering SOD or catalase alone does not significantly attenuate myocardial stunning (Bolli, 1990). This suggest that both .O2- and H2O2 are important contributors to stunning. Through the administration of dimethylthiourea (effective .OH scavenger) Bolli et al., (1987) were able to attenuate stunning in open-chest dogs and also implicate .OH in the pathogenesis of myocardial stunning. Thus, it appears that .O2--- and .OH are contributors to stunning by direct cytotoxicity and H2O2 as a precursor of .OH.

Figure 4. Events leading to the production of oxygen-derived free radicals (Przyklenk and Kloner, 1986)

The evidence above, to implicate oxygen-derived free radicals in the pathogenesis of stunning are inconclusive (Bolli, 1990; Hearse, 1991). It is so, as they do not directly measure free radical generation in the presence and absence of myocardial stunning. Using spin trap a-phenyl N-tert-butyl nitrone (PBN) and electron paramagnetic resonance (EPR) spectroscopy it has been possible to measure the free radical generation in the stunned heart (Bolli, 1990; Hearse, 1991). It has been shown that free radicals are generated during coronary occlusion and dramatically increase to a peak within 2-4 minutes after reperfusion (refer figure 5) (Bolli, 1990; Hearse, 1991). A linear positive relationship between free radical generation and the severity of ischemia has also been found (Bolli et al., 1988, cited by Bolli, 1990).

Figure 5. Burst of free radical generation in the isolated rat heart after 15 minutes of ischemia (Hearse, 1991).

Free radicals can be generated through xanthine oxidase and activated neutrophils (Przyklenk and Kloner, 1986; Bolli, 1990). By administering allopurinol (xanthine oxidase inhibitor) it has been possible to markedly improve contractile recovery (Headrick, Armiger and Willis, 1990). Therefore, this finding suggest that xanthine oxidase activity generates oxygen-derived free radicals (refer figure 4). However, experiments by Eddy et al., (1987) have shown that human hearts are similar to rabbit hearts in that they have undetectable levels of either xanthine oxidase or xanthine dehydrogenase activity. Thus, significant quantities of oxygen-derived free radicals cannot be generated through xanthine oxidase activity in humans. Whether neutrophils are a source of free radical generation causing myocardial stunning remains uncertain (Becker, 1991; Mullane and Engler, 1991). Studies which relied on neutrophil depletion through the use of leukocyte filters and neutrophil antisera have provided inconsistent results as to whether a beneficial effect on postischemic function is achieved (Hearse, 1991; Mullane and Engler, 1991). It is also suggested that the ischemic period required to cause myocardial stunning is not adequate to cause neutrophil activation (Becker, 1991). However, there are many other processes in which oxygen-derived free radicals could be formed. These include activation of the arachidonate cascade, autoxidation of catecholamines and damage to the electron transport chain in the mitochondria (Bolli, 1990).

The mechanism by which oxygen-derived free radicals may cause stunning is poorly understood (Gao, Liu and Marban, 1996). Oxygen-derived free radicals may bring about multiple changes to the cellular structure and function (Bolli, 1990; Hearse, 1991). They may cause structural injury in enzymes, proteins and nucleic acids (Hearse, 1991). In addition, free radicals may alter the fluidity and permeability of the cell membrane through lipid peroxidation (Hearse, 1991). However, this latter mechanism is considered unlikely by Hearse (1991) since lipid peroxidation is a relatively slow process and cannot occur in a short space of time (period in which free radicals impose their effect) after a brief period of ischemia. It is also suggested that oxygen-derived free radicals could cause an increase in permeability to Ca2+ in sarcolemma and rapidly release Ca2+ from the sarcoplasmic reticulum following damage to the release channels (Josephson et al., 1991; Opie, 1991). The Ca2+, Mg2+-ATPase activity could be impaired by free radicals as a decrease in Ca2+ uptake ability is observed in the isolated sarcoplasmic reticulum exposed to oxygen radicals (Thompson and Hess, 1986, cited by Bolli, 1990). Thus, oxygen-derived free radical may also cause stunning through calcium overload.

CLINICAL RELEVANCE OF MYOCARDIAL STUNNING

Clinical Settings of Myocardial Stunning

In percutaneous transluminal coronary angioplasty (PTCA) a coronary artery is completely occluded for a short period of time during balloon inflation (Bolli, 1992). With balloon deflation the artery is abruptly reperfused. Given that the artery is only occluded for usually less than two minutes it is unlikely that postischemic dysfunction would occur (Bolli, Hartley and Rabinovitz, 1991; Bolli, 1992). In experimental models a coronary artery occlusion of at least 5 minutes are employed to cause persistent postischemic abnormilies (Bolli, 1992). Occlusions of lesser periods result in quick recovery and any persistent occurrence of stunning is considered to be so small that it is likely to be undetectable (Bolli, Hartley and Rabinovitz, 1991). However, it is likely that myocardial stunning could be more severe in cases where PTCA-induced ischemia may be more prolonged by complications such as arterial dissection or abrupt occlusion (Bolli, Hartley and Rabinovitz, 1991; Bolli, 1992).

Unstable angina is caused by usually severe transient episodes of ischemia that do not cause irreversible damage (Bolli, 1992). Thus, it is likely that myocardial stunning would occur in patients with unstable angina. It has been found that in 5 of the 6 patients with unstable angina the wall-motion abnormalities persisted for several hours after the chest pain has ceased (Bolli, Hartley and Rabinovitz, 1991). This suggest that rest angina (a major form of unstable angina) is associated with stunning (Bolli, Hartley and Rabinovitz, 1991; Bolli, 1992). Unstable angina is considered the clinical counterpart of the experimental setting in which the animal myocardium is stunned by a completely reversible ischemic insult lasting < 20 minutes (Bolli, 1992). Variant angina is caused by ischemia due to vasospasm of an epicardial coronary artery (Bolli, 1992). Thus, variant angina is another clinical setting in which myocardial stunning could occur. Takatsu et al. (1986, cited by Bolli, 1992) observed in a patient that it took approximately 2 weeks for wall-motion abnormalities to completely normalise after the last attack of recurrent variant angina.

Patients with acute myocardial infarction could be treated with early reperfusion through thrombolytic therapy (using fibrinolytic agents) and / or PTCA to salvage myocardial cells destined to die (Bolli, 1992; Kloner, 1993). The salvaged tissue is mainly located in the subepicardial wall overlying a subendocardial infarction in the left ventricle (Kloner, 1993). Studies have found that the recovery of the left ventricular contraction after interventional recanalisation is delayed for several days (Bolli, 1992). Thus, due to myocardial stunning the benefits of reperfusion therapy are delayed.

Despite much improvement in surgical procedures the benefits of cardiac surgery are delayed due to postoperative left ventricular dysfunction (Bolli, Hartley and Rabinovitz, 1991). It is believed that the this postoperative dysfunction is due to global myocardial stunning since the heart is rendered globally ischemic during the surgical procedure (Bolli, 1992). In one study it was found that left ventricular wall thickening declined 2 to 6 hours after surgery and improved usually completely by 24 to 48 hours (Bolli, 1992). Postoperative contractile dysfunction is also observed after cardiac transplantation (Bolli, Hartley and Rabinovitz, 1991). This could be due to myocardial stunning since the heart is subjected to global ischemia and reperfusion during the course of the transplantation procedure (Bolli, 1992).

Clinical Interest of Myocardial Stunning

Myocardial stunning as defined is reversible and will resolve with time. It can also be completely reversed with inotropic agents such as calcium, dopamine and adrenaline (Ambrosio et al., 1989; Bolli, 1992). Yet, much time, effort and money is spent on studying this phenomenon. The enormous clinical interest on this phenomenon is evident with the presence of vast literature on the subject. Several reasons for this magnitude of clinical interest are stated below.

As stated above it is evident that myocardial stunning occurs in several clinical settings in humans. However, it may not cause significant problems in patients with normal left ventricular contractile function (Bolli, 1992). In patients at high risk for example with unstable angina, poor left ventricular function and left main coronary artery disease, the occurrence of myocardial stunning may cause the incidence and severity of postoperative complications to significantly increase (Bolli, Hartley and Rabinovitz, 1991; Bolli, 1992). Thus, myocardial stunning may contribute to both morbidity and mortality.

As a result of intensive investigation it has been found that this phenomenon can be reversed completely with inotropic agents and possibly prevented with the administration of free radical scavengers at the onset of reperfusion (Przyklenk and Kloner, 1986; Ambrosio et al., 1989). Prevention of myocardial stunning is preferred since the use of inotropic agents could cause arrhythmia and lengthen the stay in the intensive care unit due to the need of constant monitoring (Bolli, 1992).

Due to stunning, patients with acute myocardial infarction for example, are unable to get the benefits of reperfusion therapy immediately (Bolli, 1992). Furthermore, it is a dilemma to the clinicians since they are unable to assess the viability of tissue by contractile function after procedure such as thrombolytic therapy (Bolli, Hartley and Rabinovitz, 1991). Also due to the presence of stunning left ventricular wall motion cannot be used as a guide in deciding whether a patient requires PTCA or bypass surgery (Bolli, 1992).

CONCLUSION

The most accepted mechanisms believed to cause myocardial stunning have been discussed. However, among these mechanisms generation of oxygen-derived free radicals, calcium overload, reduced myofilament responsiveness to calcium and reduced contractile protein activation due to sarcoplasmic reticulum dysfunction could be considered the most plausible in causing stunning. As suggested by Bolli (1990) these hypothesis are not distinct from one another and infact may well be different steps of the same patho-physiological sequence. Generation of oxygen-derived free radicals could cause calcium overload both directly and indirectly through sarcoplasmic reticulum dysfunction. This increase in intracellular calcium concentration could causes Ca2+-activated protease to partially degrade troponin I and decrease myofilament responsiveness to calcium. This in turn is manifested as myocardial stunning.

It is evident that stunning occurs in clinical settings in which the myocardium is exposed to a brief period of ischemia and then followed by reperfusion. As a consequence of stunning the benefits of reperfusion therapy, cardiac surgery and transplantation are delayed. Furthermore, it may contribute to both morbidity and mortality by causing the incidence and severity of postoperative complications to significantly increase in high risk patients. Stunning poses another problem to the clinicians, in that they are unable to assess the viability of tissue by contractile function after procedure such as thrombolytic therapy. However, this phenomenon can be reversed completely with inotropic agents and possibly prevented with the administration of free radical scavengers at the onset of reperfusion. Thus, this phenomenon continues to interest cardiologists and surgeons.

REFERENCES

Abd-Elfattah, A.S.A., & Wechsler, A.S. 1995, `Myocardial stunning and preconditioning during non-cardioplegic warm intermittent aortic cross-clamping', in Purines and Myocardial Protection, eds A.S.A. Abd-Elfattah & A.S. Wechsler, Norwell, MA, USA, pp. 513-523.

Abd-Elfattah, A.S.A., Guo, J., El-Guessab, E., & Wechsler, A.S. 1995, `Physiologic and pathophysiologic significance of purine metabolism in the heart', in Purines and Myocardial Protection, eds A.S.A. Abd-Elfattah & A.S. Wechsler, Norwell, MA, USA, pp. 3-16.

Abd-Elfattah, A.S.A., Maddox, R.P., Jessen, M.E., Rebeyka, I.K. & Wechsler, A.S. 1995, `Selective nucleoside transport blocker NBMPR attenuates myocardial stunning in a rabbit model deficient of xanthine oxidase', in Purines and Myocardial Protection, eds A.S.A. Abd-Elfattah & A.S. Wechsler, Norwell, MA, USA, pp. 219-231.

Ambrosio, G., Jacobus, W.E., Bergman, C.A., Weisman, H.F. & Becker, L.C. 1987, `Preserved high energy phosphate metabolic reserve in globally "stunned" hearts despite reduction of basal ATP content and contractility', Journal of Molecular Cell Cardiology, vol. 19, pp. 953-964.

Ambrosio, G., Jacobus, W.E., Mitchell, M.C., Litt, M.R., & Becker, L.C. 1989, `Effects of ATP precursors on ATP and free ADP content and functional recovery of postischemic hearts', American Journal of Physiology, vol. 256, pp. H560-H566.

Becker, L.C. 1991, `Do neutrophils contribute to myocardial stunning?', Cardiovascular Drugs and Therapy, vol. 5, pp. 909-914.

Bolli, R. 1990, `Mechanism of myocardial "stunning" ', Circulation, vol. 82, no. 3, pp. 723-738.

Bolli, R. 1992, `Myocardial stunning in man', Circulation, vol. 86, no. 6, pp. 1671-1691.

Bolli, R., Hartley, C.J., & Rabinovitz, R.S. 1991, `Clinical relevance of myocardial "stunning" ', Cardiovascular Drugs and Therapy, vol. 5, pp. 877-890.

Bolli, R., Zhu, W., Hartley, C.J., Michael, L.H., Repine, J.E., Hess, M.L., Kukreja, R.C., & Roberts, R. 1987, `Attenuation of dysfunction in postischemic `stunned' myocardium by dimethylthiourea', Circulation, vol. 76, no. 2, pp. 458-468.

Braundwald, E., & Kloner, R.A. 1982, `The stunned myocardium: prolonged, postischemic ventricular dysfunction', Circulation, vol. 66, no. 6, pp. 1146-1149.

Braunwald, E. 1991, `Stunning of the myocardium: an update', Cardiovascular Drugs and Therapy, vol. 5, pp. 849-851.

Braunwald, E., & Kloner, R.A. 1982, `The stunned myocardium: prolonged, postischemic ventricular dysfunction', Circulation, vol. 66, no. 6, pp. 1146-1149.

Chemnitius, J.M., Sasaki, Y., Burger, W., & Bing, R.J. 1985, `The effect of ischemia and reperfusion on sarcolemmal function in perfused canine hearts', Journal of Mollecular Cell Cardiology, vol. 17, pp. 1139-1150.

Eddy, L.J., Stewart, J.R., Jones. H.P., Engerson, T.D., McCord, J.M., & Downey, J.M. 1987, `Free radical-producing enzyme xanthine oxidase is undetectable in human hearts', American Journal of Physiology, vol. 253, pp. H709-H711.

Fine, L.G., & Yellon, D.M. 1993, `Unstable angina - report of a meeting of physicians and scientists, University College London Medical School', The Lancet, vol. 341, pp. 1323-1327.

Flameng, W., Andres, J., Ferdinande, P., Mattheussen, M. & Belle, H.V. 1991, `Mitochondrial function in myocardial stunning', Journal of Molecular Cell Cardiology, vol. 23, pp. 1-11.

Gao, W.D., Atar, D., Backx, P.H., & Marban, E. 1995, `Relationship between intracellular calcium and contractile force in stunned myocardium: direct evidence for decreased myofilament Ca2+ responsiveness and altered Diastolic function in intact ventricular muscle', Circulation Research, vol. 76, no. 6, pp. 1036-1048.

Gao, W.D., Atar, D., Liu, Y., Perez, N.G., Murphy, A.N., & Marban, E. 1997, `Role troponin I proteolysis in the pathogenesis of stunned myocardium', Circulation Research, vol. 80, no. 3, pp. 393-399.

Gao, W.D., Liu, Y., & Marban, E. 1996, `Experimental myocardial ischemia / infarction / vascular regulation: Selective effects of oxygen free radicals on excitation-contraction coupling in ventricular muscle: Implications for the mechanism of stunned myocardium', Circulation, vol. 94, no. 10, pp. 2597-2604.

Greenfield, R.A., & Swain, J.L. 1987, `Disruption of myofibrillar energy use: dual mechanisms that may contribute to postischemic dysfunction in stunned myocardium', Circulation Research, vol. 60, no. 2, pp. 283-289.

Headrick, J.P., Armiger, L.C., & Willis, R.J. 1990, `Behaviour of energy metabolites and effect of allopurinol in the "stunned" isovolumic rat heart', Journal of Molecular Cell Cardiology, vol. 22, pp. 1107-1116.

Hearse, D.J. 1991, `Stunning: A radical re-view', Cardiovascular Drugs and Therapy, vol. 5, pp. 853-876.

Ito, B.R., Tate, H., Kobayshi, M., & Schaper, W. 1987, `Reversibly injured, postischemic canine myocardium retains normal contractile reserve', Circulation Research, vol. 61, no. 6, pp. 834-846.

Jeroudi, M.O., Tang, X., Abd-Elfattah, A.S.A., & Bolli, R. 1995, `Effect of adenosine on myocardial stunning', in Purines and Myocardial Protection, eds A.S.A. Abd-Elfattah & A.S. Wechsler, Norwell, MA, USA, pp. 297-313.

Josephson, R.A., Silverman, H.S., Lakatta, E.G., Stern, M.D., & Zweier, J.L. 1991, `Study of the mechanisms of hydrogen peroxide and hydroxyl free radical-induced cellular injury and calcium overload in cardiac myocytes', The Journal of Biological Chemistry, vol, 266, no. 4, pp. 2354-2361.

Kitakaze, M., Weisman, H.F., & Marban, E. 1988, `Contractile dysfunction and ATP depletion after transient calcium overload in perfused ferret hearts', Circulation, vol. 77, no. 3, pp. 685-695.

Kloner, R.A. 1993, `Myocardial stunning', The Lancet, vol. 341, pp. 1323-1325.

Krause, S.M., Jacobus, W.E., & Becker, L.C. 1989, `Alterations in cardiac sarcoplasmic reticulum calcium transport in the postischemic "stunned" myocardium', Circulation Research, vol. 65, no. 2, pp. 526-530.

Kusuoka, H., & Marban, E. 1992, `Cellular mechanisms 'of myocardial stunning', Annual Reviews in Physiology, vol. 54, pp 243-256.

Kusuoka, H., Koretsune, Y., Chacko, V.P., Weisfeldt, M.L., & Marban, E. 1989, `Excitation-contraction coupling in postischemic myocardium. Does failure of activator Ca2+ transients underlie stunning?', Circulation Research, vol. 66, no. 5, pp. 1268-1276.

Limbruno, U., Zucchi, R., Ronca-Testoni, S., Galbani, P., Ronca, G., & Marini, M. 1989, `Sarcoplasmic reticulum function in the "stunned" myocardium', Journal of Molecular Cell Cardiology, vol. 21, pp. 1063-1072.

Marban, E. 1991, `Myocardial stunning and Hibernation. The physiology bind the colloquialisms', Circulation, vol. 83, no. 2, pp. 681-688.

Mullane, K., & Engler, R. 1991, `Proclivitiy of activated neutrophils to cause postischemic cardiac dysfunction: Participation in stunning?', Cardiovascular Drugs and Therapy, vol. 5, pp. 915-924.

Murphy, E., Steenbergen, C., Levy, L.A., Raju, B., & London, R.E. 1989, `Cytosolic free magnesium levels in ischemic rat heart', The Journal of Biological Chemistry, vol, 264, no. 10, pp. 5622-5627.

Opie, L.H. 1991, `Postischemic stunning - The case for calcium as the ultimate culprit', Cardiovascular Drugs and Therapy, vol. 5, pp. 895-900.

Przyklenk, K., & Kloner, R.A. 1986, `Superoxide dismutase plus catalase improve contractile function in the canine model of the "stunned myocardium", Circulation Research, vol. 58, no. 1, pp. 148-156.

Schaper, W. 1991, `Molecular mechanisms in "stunned" myocardium', Cardiovascular Drugs and Therapy, vol. 5, pp. 925-932.

Tani, M., & Neely, J.R. 1989, `Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Possible involvement of H+- Na-+ and Na+ - Ca2+ exchange', Circulation Research, vol. 65, no. 4, pp. 1045-1056.

BACK TO THE CHAOTIC BIOMEDICAL SCIENCE PAGE

BACK TO THE MAIN PAGE

You are Visitor Number since 26/June/1998.