Myocardial hibernation: adaptation to ischaemia

824

Clinical Perspectives

[7] Wiggers CJ. Are ventricular conduction changes of importance in the dynamics of ventricular contraction? Am J Physiol 1927; 12-30. [8] Xiao HB, Roy C, Gibson DG. Nature of ventricular activation in patients with dilated cardiomyopathy: evidence for bilateral bundle branch block. Br Heart J 1994; 72: 167-74. [9] Ng KSK, Gibson DG. Impairment of diastolic function by shortened filling period m severe left ventricular disease. Br Heart J 1989; 62: 246-52. [10] Oldershaw PJ, Dawkins K.D, Ward DE, Gibson DG. Diastolic mechanisms of impaired exercise tolerance in aortic valve disease. Br Heart J 1983; 49: 568-73. [11] Mahaim I, Winston MR. Recherches d'anatomie comparee et de pathologie experimentale sur les connexions hautes du fasiceau de His-Tawara. Cardiologia 1941; 5: 189-90. [12] Xiao HB, Brecker SJD, Gibson DG. Differing effects of right ventricular pacing and left bundle branch block on left ventricular function. Br Heart J 1993; 69: 166-73. [13] Curfman GD. Inotropic therapy for heart failure — an unfulfilled promise. N Engl J Med 1993; 325. 1509-10.

[14] Brecker SJD, Xiao HB, Sparrow J, Gibson DH. Effects of dual-chamber pacmg with short atrioventricular delay in dilated cardiomyopathy. Lancet 1992; 340: 1308-12. [15] Gold MR, Feliciano Z, Gottlieb SS, Fisher ML. Dualchamber pacmg with a short atrioventricular delay in congestive heart failure: a randomized study. J Am Coll Cardiol 1995; 26: 967-73. [16] Nishimura RA, Hayes DL, Holmes DR Jr, Tajik AJ. Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction, an acute Doppler and catheterization study. J Am Coll Cardiol 1995; 25: 281-8. [17] Linde C, Gadler F, Edner M, Norlander R, Rosenqvist M, Ryden L. Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure. Am J Cardiol 1995; 75: 919-23. [18] Xiao HB, Gibson DG. Natural history of abnormal conduction and its relation to prognosis in patients with dilated cardiomyopathy Int J Cardiol 1996; 53: 163-70.

Myocardial hibernation: adaptation to ischaemia The concept of hibernation When severely reduced coronary blood flow persists for more than 20 min, myocardial necrosis begins to develop and contractile function is eventually irreversibly lost. When myocardial ischaemia is more moderate, the myocardium can remain viable for a longer period of time, and although contractile function is reduced, it recovers upon reperfusion. In patients with coronary artery disease, chronic contractile dysfunction, which is reversible upon reperfusion, is termed myocardial hibernation1'1. The term hibernation has been borrowed from zoology and implies that the observed reduction in contractile function is an adaptive and regulatory event acting to preserve viability. The concept of hibernation was developed entirely on clinical grounds, but quickly gained support from experimental studies.

Mechanisms of acute ischaemic contractile dysfunction

(within a few cardiac cycles) ceases. However, reduction in myocardial ATP as the underlying mechanism for the rapid reduction in contractile function has been ruled out, since (1) contractile dysfunction occurs prior to changes in myocardial ATP, and (2) the result of myocardial ATP loss should be rigor of the myofibril rather than the observed loss of wall tension. Mechanisms which have been proposed, but not unequivocally proven, include a reduction in the free energy change in ATP hydrolysis, a decreased rephosphorylation rate of cytosolic ADP from creatine phosphate, the development of intracellular acidosis, accumulation of inorganic phosphate or impairment of sarcoplasmic calcium transport kinetics, which again may be pH- or ATP-dependent (for review see[2]).

Transition from an imbalance between supply and demand towards myocardial hibernation

Within the first few seconds following acute reduction of myocardial blood flow, energy demand by the hypoperfused myocardium clearly exceeds the reduced energy supply. However, this imbalance Correspondence: Gerd Heusch, MD, FESC, FACC, Department of Pathophysiology, Centre of Internal Medicine, University Essen, between energy supply and demand is an inherently School of Medicine, HufelandstraBe 55, 45122 Essen, Germany. unstable condition since contractile function and

Following acute reduction of coronary blood flow, contractile function in the ischaemic region rapidly

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 6, 2012

European Heart Journal (1996) 17, 824-828

Clinical Perspectives 825

Table 1 Characterization of short-term hibernating myocardium Balance between the reduced regional myocardial blood flow and the reduced contractile function (perfusion-contraction-matching)13-4' Recovery of contractile function during reperfusion'41 Recovery of metabolic parameters (creatine phosphate, lactate) during persistent ischaemia15"71 Recniitable inotropic reserve at the expense of metabolic recovery17-81

Table 2 Characterization of long-term hibernating myocardium Decrease in the number of myofibrils and increased collagen network Recovery of contractile function during reperfusion'1'

myocardium Metabolism of short-term hibernating myocardium

The mechanisms responsible for the development of short-term myocardial hibernation remain unclear at present, but suggestions that alterations in Within the first 5 min of ischaemia, the myocardial /?-adrenoceptor density or affinity are the underlying creatine phosphate concentration is reduced, and mechanism of such an adaptive process have been lactate consumption is reversed to net lactate produc- excluded'81. Ischaemia-induced activation of ATPtion. When ischaemia is prolonged to 60-90 min, however, the myocardial creatine phosphate concen- dependent potassium channels might increase potasstration recovers to near control values (Fig. l)'6-7), ium efflux, thereby reducing action potential duration lactate production is attenuated15'71, and regional and subsequently calcium influx into the myocyte. contractile function is persistently reduced'5"71. Such decreased intracellular calcium concentration Apparently, the reduction in regional contractile could then reduce contractile function and ATP confunction during moderate ischaemia permits the sumption, thus finally allowing the development of partial recovery of ischaemia-induced metabolic myocardial hibernation. Indeed, monophasic action potential duration shortens during ischaemia, and alterations. this shortening is inhibited by blockade of ATPdependent potassium channels with glibenclamide. Recruitment of an inotropic reserve at However, blockade of ATP-dependent potassium channels neither alters contractile function, metabolic the expense of metabolic recovery in parameters nor myocardial viability. Activation of short-term hibernating myocardium ATP-dependent potassium channels is therefore Although baseline contractile function is depressed, not involved in the development of short-term the hypoperfused myocardium retains its responsive- myocardial hibernation'101. Increased levels of endogenous adenosine durness to an inotropic challenge (Fig. I)'71. When, after 85 min of ischaemia, dobutamine is infused selectively ing ischaemia might, through a number of secondary into the ischaemic myocardium of anaesthetized pigs, mechanisms, such as inhibition of adenylate cyclase contractile function increases, although regional activity, inhibition of norepinephrine release from blood flow remains reduced. Thus, energy is available sympathetic nerve endings or inhibition of L-type in the ischaemic myocardium which is not used to calcium channels, attenuate the decrease in myosupport baseline function, but permits the increase in cardial energy-rich phosphates and the increase in Eur Heart J, Vol. 17, June 1996

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 6, 2012

thus energy demand rapidly decrease following the contractile function upon an inotropic challenge. onset of ischaemia. In the subsequent steady state However, the increase in contractile function during condition, the reduction of contractile function is inotropic stimulation again decreases the myocardial in proportion to the reduction in myocardial creatine phosphate concentration and increases blood flow. This situation has been termed perfusion- lactate production (Fig. 1), indicating a renewed contraction matching by Ross'31; perfusion- supply-demand imbalance. contraction matching, reflecting a balance between energy supply and demand, is a key feature of short-term myocardial hibernation (Tables 1 and 2). Mechanisms of short-term hibernating

826

Clinical Perspectives

(ml x min

X

Myocardial creatine phosphate

Subendocardiai blood flow

0.8 0.6 0.4

0.2

"

\

-V

*

1

n r\

1

*

1

1

1 Myocardial lactate consumption

Work index

85 +DOB - Ischaemia-

Figure 1 Reduction in subendocardiai blood flow of the anterior myocardium after 5 min of ischaemia is associated with decreased regional contractile function. The creatine phosphate concentration falls and lactate consumption is reversed to net lactate production. With ischaemia extended to 85 min at a constant subendocardiai blood flow, there is a tendency for a further decrease in regional contractile function. In contrast, lactate production is attenuated and the creatine phosphate concentration recovers to a value no longer significantly different from control (C). Infusion of dobutamine (+DOB) after 90 min of ischaemia increases regional contractile function at an unchanged subendocardiai blood flow. This increase in contractile function, however, is again associated with increased lactate production and decreased creatine phosphate concentration. */ >