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Summary: Hibernating myocardium is defined as persistently impaired myocardial and left ventricular function at rest resulting from reduced myocardial blood flow. It is postulated that despite the reduced coronary blood flow, metabolic activity is sufficient to prevent tissue necrosis. Recovery of the hibernating myocardium has clearly been shown to occur with the establishment of successful revascularization either by coronary bypass surgery or by percutaneous transluminal coronary angioplasty. The differentiation of viable, hibernating myocardium from non-viable myocardium in patients with coronary artery disease and left ventricular dysfunction is a key issue in the current era of myocardial revascularization.
Ischemic myocardial dysfunction, defined as a transient impairment of
contractile function due to reduced coronary blood flow, has been well
documented (34). Persistent impairment of contractile function was initially
believed to represent irreversible myocardial damage resulting from myocardial
infarction (13). In the 1970s several studies demonstrated that chronically
dysfunctioning myocardium was able to resume contraction to some extent after
revascularization (14). Thus, some areas of myocardium exhibiting left
ventricular asynergy at rest had to be viable, since they recovered after the
restoration of coronary flow.
In 1985, Rahimtoola proposed the concept of
hibernating myocardium to describe a state of persistently impaired myocardial
and left ventricular function at rest due to reduced coronary blood flow that
can be partially or completely restored to normal if the myocardial oxygen
supply/demand relationship is favorably altered, either by improving blood flow
and/or by reducing demand (27). In his theory, based on clinical observations,
hibernating myocardium was a result of downgrading of cardiac function so that
blood flow and function were once again in equilibrium. As a result, neither
myocardial necrosis, nor ischemia symptoms were present (15). The concept of
hibernation presupposed that a reduction in coronary blood flow, i.e. the
initial or triggering event, was followed by a downregulation in cardiac
function to a point at which the limited oxygen supply enabled the maintenance
of the biochemical functions that sustained cell integrity (16,27). If the
myocardial oxygen supply/demand balance was subsequently altered either
temporarily or permanently, then sypmtoms and signs of ischemia and/or of
necrosis might occur (29).
The hibernating response of the heart, namely a
reduction of cardiac function to cope with a reduced myocardial blood flow, was
considered as an act of self-preservation (little blood, little work) and the
hibernating heart was considered to be "a smart heart" (29).
The initial investigators in the 1970s believed that persistent contractile
left ventricular dysfunction in patients with coronary heart disease represented
irreversible myocardial damage (13).
With the widespread use of coronary
bypass surgery it became apparent that successful coronary revascularization was
often associated with the return of myocardial contractility in the asynergic
regions. Thus, it was hypothesised that some areas of myocardium exhibiting
dysfunction at rest had to be viable, since they recovered after the restoration
of coronary flow (14). Investigations focused on predicting which of these areas
would recover contractile function using a variety of interventions aimed at
either increasing the contractile function with catecholamine administration or
postextrasystolic potentiation or reducing myocardial oxygen demand and/or
increasing coronary blood flow with nitroglycerin (13,34). Subsequently, with
the advent of nuclear cardiology, it became possible to gain better knowledge
about the correlation between myocardial perfusion and the contractile function
of the left ventricle. The work correlating myocardial perfusion with function
was pivotal in describing the presence of severe wall-motion abnormatilies
associated with coronary artery stenoses exceeding a 90% reduction of the
coronary intraluminal diameter. The histopathology of these areas revealed a
myocardium exhibiting an increased amount of fibrosis but with preserved
myocardial cell integrity (1).
With the introduction of stunned myocardium by
Braunwald and Kloner (4) in 1982, the interest of cardiologists focused on the
new concept of persistent ischemic dysfunction (20,22). Myocardial stunning or
postischemic left ventricular dysfunction, described a clinical state that
persisted after reperfusion despite the absence of irreversible damage and
despite the restoration of normal or near-normal coronary blood flow (2,4,10).
The two "despites" were important to distinguish stunning from other causes of
persistent ischemic dysfunction after reperfusion (such as infarction or
persistent ischemia) that had nothing to do with stunning.
The last decade
has witnessed an explosion of research effort in the area of stunned myocardium
(3,19). The substantial evidence has been obtained that myocardial stunning is a
widespread and important phenomenon readily seen in a number of clinical
situations, e.g. the occurence of stunning after myocardial infarction and, more
recently, following coronary reperfusion with thrombolysis or angioplasty
(16,22,27). Perhaps the most common and important clinical manifestation of
stunning occurs in the hearts of patients who have undergone ischemic cardiac
arrest during cardiopulmonary bypass, despite the protection offered by
hypothermia and cardioplegia. Following reperfusion many such hearts require
support with inotropic agents and/or mechanical assistance for hours or days
untill the stunning subsides (3,16). It should be noted that myocardial stunning
is a fully reversible abnormality, provided of course that sufficient time is
allowed for the myocardium to recover (4,20). It is a mild, sublethal injury
where the hallmark is the presence of a flow-function "mismatch", i.e., a
depression of function is out of proportion to a mild depresion of flow (32).
The basic mechanisms of myocardial stunning are not yet completely elucidated,
however, most probably it is not a problem of energy production, but rather of
energy utilization.
In 1985, Rahimtoola proposed the concept of hibernating
myocardium to describe a state when myocardial blood flow falls to a level
sufficient to maintain cell viability, but not myocardial contraction (26). He
considered the hibernation as a response to a chronic reduction in resting
coronary blood flow, leading to a new equilibrium where myocardial metabolism
was altered with a subsequent reduction in energy production and myocardial
contractility (27). In contrast to other forms of reversible myocardial
dysfunction, such as stunning, in hibernating myocardium flow and function were
appropriately matched (31,32). This chronic adaptation could occur in the
absence of angina (the lack of resting angina is a unique sign of chronic
hibernation) or electrocardiographic evidence of ischemia and was thought to be
a protective mechanism, reducing the oxygen demand of hypoperfused myocardium
and preserving long-term viability (11). On imaging the heart, it presented as
areas of left ventricular wall that could have been hypokinetic, akinetic or
dyskinetic (29).
Hibernating and stunned myocardium are clinically very
important conditions of contractile asynergy, since they are potentially
reversible (16). Hibernating myocardium is similar to stunned myocardium in that
both are characterized by viable myocardial cells with depressed function. More
recently, some clinical studies have suggested that when ischemia is relieved,
the hibernating myocardium exhibits nearly immediate return of function, whereas
stunned myocardium exhibits gradual recovery (27). However, hibernating
myocardium,once reperfused, may go through a phase of stunning before normal
contractile function is restored (29).
According to the role of calcium in
stunning, it has been suggested that calcium overload may play a crucial role
and therefore calcium antagonists could have a beneficial effect on recovery of
myocardial stunning (17,21,25). By contrast, in hibernation, where there is an
ongoing reduction in the contractile function of the myocardium, calcium
antagonists may further depress the inotropic state (25). The hibernating
myocardium can only recover after successful revascularization either by
coronary bypass surgery or by percutaneous transluminal coronary angioplasty
(7).
What is the clinical evidence that supports the concept of hibernating
myocardium? Several studies have shown that persistent left ventricular
wall-motion abnormalities in patients with chronic angina were reversed to
normal by successful coronary artery bypass surgery (7,14). Rankin et al. (30)
observed an improvement in regional wall-motion abnormalities in 34% of
patients, with an increase in global left ventricular ejection fraction from 53%
to 71% at 7-14 days after surgery. Breisblatt et al. (6) documented a case of
reversal of a longstanding ventricular aneurysm following coronary
revascularization supporting the concept that chronically ischemic (hibernating)
myocardium could actually mimic an infarction. Topol et al. (35) reported the
immediate improvement in dysfunctional myocardial segments after coronary
revascularization.
Regions of myocardium supplied by severely diseased
coronary arteries may develop chronic ischemia at rest and exhibit reduced
contractility, contributing to a reduction in global left ventricular function.
These regions of asynergy described as hibernating myocardium, in which normal
contractility may be restored, often coexist with areas of either infarcted or
scar tissue, supporting the hypothesis of jeopardized but viable myocardium
(7,9,30). Chatterjee et al. reported that up to 66% of myocardial segments with
wall-motion abnormalities showed improvement or a return to normal after bypass
surgery. Improvement also occured in 29% of myocardial regions with prior
infarction, implying the coexistence of scar and viable myocardium in the same
territory (14).
Recently some authors have suggested that anaerobic or
minimal but relevant preservation of oxidative metabolism may generate enough
ATP to sustain tissue viability (22,23). To maintain these metabolic conditions
it is necessary for the regional coronary blood flow to remain between 20-40% of
normal (33).
The data obtained suggest that progressive decline of oxygen
supply leads to cellular hypoxia. Anaerobiosis accelerates the transport and
utilization of exogeneous glucose as well as the breakdown of glycogen stores.
Products of anaerobic glycolysis, namely protons, reduced coenzymens and lactic
acid, can feed back to inhibit glycolysis at various levels (12). The inhibitory
effect of acidosis is one factor explaining the difference between the effect of
acute, severe ischemia, which inhibits glycolysis, and chronic, mild ischemia,
which accelerates it. These differences are reflected in the increased glucose
uptake of the mildly ischemic (hibernating) heart versus decreased glucose
uptake of the severely ischemic heart. Hypoperfused (hibernating) myocardium
retains its responsiveness to an inotropic agent that also suggests that some
dysfunctional myocardium has maintained the ability to contract
(8,36).
However, several key issues remain to be resolved. First, the length
of time the ischemic myocardium can maintain its metabolic integrity and
responsiveness to an inotropic challenge is not known. It is possible that the
metabolic status deteriorates again over time and the responsiveness is
eventually lost. In this scenario, the early lost of contractile function during
low-flow ischemia is only a temporary mechanism to prolong myocardial viability
but is inherently time limited (16). On the other hand, it is possible that the
myocardium can maintain such a state indefinitely. Second, it may be postulated
that the ability of the myocardium to adjust to the ischemia is related to the
absolute level of the ischemia present. Total ischemia, as studied
experimentally or as observed during coronary thrombosis or vasospasm in a
patient without substantial collateral vessels, is well known to produce cell
death within approximately 20 minutes, starting in the inner wall and
progressing transmurally acros the wall over time, the so-called "wave front" of
infarct formation (37). Whether there is a minimal flow requirement permitting
hibernation is still not known.
The differentiation of viable from nonviable myocardium in patients with
coronary artery disease and left ventricular dysfunction is a key issue in the
current era of myocardial revascularization (26). Reperfusion of viable,
hibernating myocardium causes a recovery of mechanical function of the left
ventricle that correlates with improvement in survival (5,7). This is in
agreement with the current understanding of left ventricular function as a
critically important determinant of long-term prognosis in patients with
coronary artery disease.
In order to fulfill the working hypothesis of
Rahimtoola that hibernation is "a state of myocardial hypocontractility during
chronic hypoperfusion, in the presence of completely viable myocardium which
recovers functionally upon revascularization" (27) - three major criteria should
be present, i.e.:
Hibernating myocardium refers to the presence of persistent myocardial and
left ventricular dysfunction at rest, associated with conditions of severely
reduced coronary blood flow. Hibernation is thought to occur as a response to a
chronic reduction in resting coronary blood flow, leading to a new equilibrium
where myocardial metabolism is altered with a subsequent reduction in energy
production and myocardial contractility.
The identification of hibernating
but still viable myocardium in regions of left ventricular dysfunction is an
increasingly relevant issue in the management of patients with severe coronary
artery disease and left ventricular dysfunction.
Revascularization of
hibernating myocardium should lead to the greatest improvement in left
ventricular function and, thus, improvement in survival.
Submitted July 1996.
Accepted September 1996.
MUDr. Jan Knap,
Hradecka 1124, 500 02 Hradec Kralove
2,
Czech Republic.