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Cardiovascular Research 2003 57(2):302-311; doi:10.1016/S0008-6363(02)00716-2
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Copyright © 2003, European Society of Cardiology

Myocardial blood flow in patients with hibernating myocardium

Paolo G Camici* and Ornella E Rimoldi

MRC Clinical Sciences Centre and National Heart and Lung Institute, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK

* Corresponding author. Tel.: +44-208-383-3186; fax: +44-208-383-3742. paolo.camici{at}csc.mrc.ac.uk

Received 27 June 2002; accepted 9 October 2002


   Abstract
Top
 Abstract
1. Introduction
 2. The initial hypothesis
 3. Positron emission tomography...
 4. MBF assessed with...
 5. Technical considerations on...
 6. PET studies of...
 7. Transmural distribution of...
 8. Coronary flow reserve...
 9. Concluding remarks
 References
 
The debate on whether resting myocardial blood flow (MBF) to hibernating myocardium is reduced or not has attracted a lot of interest and has contributed to stimulate new research on heart failure in patients with coronary artery disease (CAD). Positron emission tomography with oxygen-15 labeled water (H215O) or nitrogen-13 labeled ammonia (13NH3) has been used for the absolute quantification of regional MBF in human hibernating myocardium. When hibernating myocardium is properly identified, i.e. a dysfunctional segment subtended by a stenotic coronary artery that improves function upon reperfusion, the following conclusions can be reached based on the available literature: (a) in the majority of these studies resting MBF in hibernating myocardium is not different from either flow in remote tissue in the same patient or MBF in normal healthy volunteers; (b) a reduction in MBF of ~20% compared to MBF in remote myocardium or age matched normal subjects has been demonstrated in a minority of truly hibernating segments; (c) hibernating myocardium is characterized by a severely impaired coronary flow reserve which improves after revascularization in parallel with contractile function. Thus, the pathophysiology of hibernation in humans is more complex than initially postulated. The recent evidence that repetitive ischemia in patients with coronary artery disease can be cumulative and lead to more severe and prolonged stunning, lends further support to the hypothesis that, at least initially, stunning and hibernation are two facets of the same coin.

KEYWORDS Blood flow; Coronary circulation; Hibernation


   1. Introduction
Top
 Abstract
 1. Introduction
2. The initial hypothesis
 3. Positron emission tomography...
 4. MBF assessed with...
 5. Technical considerations on...
 6. PET studies of...
 7. Transmural distribution of...
 8. Coronary flow reserve...
 9. Concluding remarks
 References
 
The debate on whether resting myocardial blood flow (MBF) to hibernating myocardium is reduced or not has attracted a lot of interest and, undoubtedly, has contributed significantly to stimulate new research on heart failure in patients with coronary artery disease (CAD). Although the debate is not over yet, some of the initial paradigms have been proven incorrect while new pathophysiological concepts have emerged.


   2. The initial hypothesis
Top
 Abstract
 1. Introduction
 2. The initial hypothesis
3. Positron emission tomography...
 4. MBF assessed with...
 5. Technical considerations on...
 6. PET studies of...
 7. Transmural distribution of...
 8. Coronary flow reserve...
 9. Concluding remarks
 References
 
There are a number of techniques available for measuring coronary blood flow in man [1], most of which involve cardiac catheterization procedures. These measurements are usually performed using Doppler catheter [2,3], quantitative coronary arteriography [4] and thermodilution [5]. Although multiple regional measurements can theoretically be made in the different coronary arteries in real time using Doppler catheter and quantitative coronary arteriography, these methods measure epicardial coronary flow velocity or coronary blood flow as opposed to tissue perfusion as the mass of myocardium supplied by the artery under study cannot be defined. The same limitations apply to coronary sinus thermodilution.

A number of radionuclide imaging techniques have emerged for the assessment of regional MBF [6]. Their non-invasive nature and the ability to provide simultaneous information on the three different coronary beds have contributed to their widespread application in patients with coronary artery disease. The initial hypothesis that hibernation is due to a down-regulation of myocardial function secondary to a reduction of resting MBF [7] was supported by a series of studies in which semiquantitative measurements of MBF were performed using different radioactive flow tracers with single photon emission tomography (SPET) (see Ref. [8]). Although radionuclide imaging techniques like thallium-201 SPET enable the assessment of nutritive tissue perfusion, they can only provide images that reflect relative regional radioactivity concentration rather than enabling measurement of absolute MBF (i.e. ml/min/g) [9]. The definition of abnormal regional uptake is based on the demonstration of a contrast between two ventricular segments and not an absolute reduction in uptake compared to normal reference values. Therefore, an apparent reduction of radioactivity concentration in one region may reflect higher uptake in the reference region rather than an absolute reduction in the ‘defect’ itself. In addition, the fact that chronically dysfunctional segments are generally thinner than remote normally contracting myocardium will contribute to increase artificially the difference between hibernating and remote myocardium as a consequence of the partial volume effect [10]. This occurs whenever the dimension of the object to be imaged (in our case the thickness of the left ventricular wall) is comparable or smaller than the camera's spatial resolution. Although the detector will accurately record the total activity in the object, it will distribute it over an area larger than the actual size of the object. Hence, the detected radioactivity concentration per unit volume will be less than the actual value [11].


   3. Positron emission tomography (PET) and absolute myocardial blood flow
Top
 Abstract
 1. Introduction
 2. The initial hypothesis
 3. Positron emission tomography...
4. MBF assessed with...
 5. Technical considerations on...
 6. PET studies of...
 7. Transmural distribution of...
 8. Coronary flow reserve...
 9. Concluding remarks
 References
 
PET overcomes the physical limitations of previously available imaging systems by providing the means for accurate attenuation correction, thus enabling accurate quantification of the concentration of radiolabeled tracer in the organ of interest [12]. Photons traveling through a composite medium such as the thorax will be scattered by interaction with atomic electrons and undergo change of direction and loss of energy. If a photon is scattered it is ‘lost’ to the original line of response (the line joining the two PET detectors in coincidence) and the apparent radioactivity measured along that line of response will be less than the truth. This effect is known as attenuation. Scatter and attenuation are problems common to all radionuclide imaging techniques and are responsible for most of the artifacts associated with SPET, particularly when low energy isotopes (e.g. thallium-201) are used. In contrast to SPET, correction for attenuation is relatively straightforward in PET because of the mechanism of coincidence detection [11].

As PET technology has advanced and rapid dynamic imaging has become possible, quantification of MBF has been achieved following the development of suitable tracer kinetic models. Oxygen-15 labeled water (H215O) [13–16] and nitrogen-13 labeled ammonia (13NH3) [17–20] are the tracers most widely used for the quantification of regional MBF with PET. Tracer kinetic models have been successfully validated in animals against the radiolabeled microsphere method for both H215O [13–16] and 13NH3 [19,20]. Both H215O and 13NH3 have short physical half lives (2 and 10 min, respectively) which allow repeated measurements of MBF in the same session [21].


   4. MBF assessed with PET in healthy human subjects
Top
 Abstract
 1. Introduction
 2. The initial hypothesis
 3. Positron emission tomography...
 4. MBF assessed with...
5. Technical considerations on...
 6. PET studies of...
 7. Transmural distribution of...
 8. Coronary flow reserve...
 9. Concluding remarks
 References
 
The non-invasive nature of PET and the low radiation dose administered (5–10 times lower than that for SPET) allows the study of healthy human volunteers. The values of MBF determined using H215O and 13NH3, both at rest and during pharmacologically-induced coronary vasodilatation, are similar [22–25]. Similarly to previous studies in animals (Fig. 1) [26,27], PET has highlighted the heterogeneity of both resting and hyperemic MBF in normal human beings [28]. The latter issue has been recently investigated by our group in a large cohort (n=160) of healthy volunteers of both sexes aged between 21 and 86 years [29] (Fig. 2). The results of this study can be summarized as follows: (i) In this population, baseline and hyperemic MBF are heterogeneous both within and between individuals; Baseline and hyperemic MBF exhibit a similar degree of spatial heterogeneity which appears to be temporally stable. (ii) Baseline, but not hyperemic, MBF is significantly higher in females than in males. (iii) There is a significant linear association between age and baseline MBF that is in part related to changes in external cardiac workload. (iv) Hyperemic MBF declines over 55 years of age. Notwithstanding the inter subjects variability, the short term repeatability of PET assessment of MBF within subjects has been well documented both under resting and hyperemic conditions [21,30]. These data, taken together, have important implications for the interpretation of myocardial perfusion studies in patients with hibernating myocardium.


Figure 1
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  		Fig. 1 Distribution of regional myocardial blood flow measured with radioactive microspheres in an anestethized dog at control and during maximal hyperemia induced by intracoronary adenosine. Although mean control flow was 1.58 ml/g/min, the extremes of flow ranged more than threefold (From Austin et al. [26] with permission).

 

Figure 2
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  		Fig. 2 Distribution of regional myocardial blood flow measured with PET and H215O at baseline and during near maximal hyperemia induced by either adenosine or dipyridamole in normal human subjects. It is worth noting the similarities in flow distributions with the example shown in Fig. 1. The heterogeneity in flow distribution across species both at baseline and during hyperemia highlights the difficulty of setting threshold values for normal myocardial blood flow. Adapted from Ref. [29].

 

   5. Technical considerations on PET MBF measurements
Top
 Abstract
 1. Introduction
 2. The initial hypothesis
 3. Positron emission tomography...
 4. MBF assessed with...
 5. Technical considerations on...
6. PET studies of...
 7. Transmural distribution of...
 8. Coronary flow reserve...
 9. Concluding remarks
 References
 
5.1 The concept of flow per gram of perfusable tissue
In patients with previous myocardial infarction (a very common finding in patients with hibernating myocardium), the presence and amount of scar tissue within a dysfunctional region may affect the flow estimates made with PET particularly when liquid deposit tracers such as 13NH3 are used whereas freely diffusible tracers such as H215O are less affected by this problem [16,31].

H215O is a metabolically inert and freely diffusible tracer [31] that has a virtually complete myocardial extraction that is independent of both flow rate [32] and myocardial metabolism [15,33]. 13NH3 is extracted from blood with an extraction fraction <100%, that is inversely related to the flow rate, and is then trapped in myocardial cells after conversion to 13N-labeled glutamine, a process mediated by adenosine triphosphate (ATP) and glutamine synthetase [19,33]. Thus, the extent of 13NH3 metabolism depends on myocardial ATP stores. When H215O is used, MBF is estimated from the tracer's washout from the myocardium while in the case of 13NH3, MBF is calculated from the tracer's uptake by myocardium. These differences are of little relevance when the measurements of MBF are performed in normal myocardium as proven by the comparable flow estimates obtained with the two tracers in normal human subjects [22,34]. However, if the tissue composition is highly heterogeneous, as in jeopardized myocardium of patients with previous infarction, the flow estimates obtained with these two tracers can show discrepancies. In a highly heterogeneous tissue, the diffusion/extraction and final uptake of H215O and 13NH3 are determined by the flow rates in each tissue compartment, i.e. higher in viable tissue and lower in scar tissue. 13NH3 uptake in a given region of interest will reflect the average uptake and hence average flow in this mixture of viable and fibrotic tissue. On the other hand, since the uptake of H215O in scar tissue is negligible, washout of H215O will mainly reflect activity in better perfused segments and the resulting flow can therefore be higher than that obtained with 13NH3 in the same region [35–37]. Recent refinements of the H215O technique have permitted incorporation of an estimate of the fraction of tissue (perfusable tissue fraction, PTF) within the volume of interest that is exchanging the freely diffusible tracer into the kinetic model [38]. This technique provides values of flow per gram of perfusable tissue and not per gram of region of interest [35,36]. A further accomplishment is the calculation of the perfusable tissue index (PTI), i.e. the ratio of the perfusable tissue fraction to the total tissue mass (anatomic tissue fraction) in the region of interest [35]. Gerber et al. [39] in a parallel assessment of MBF with H215O and 13NH3 showed that in normal and reversibly dysfunctional myocardium the two techniques yield similar results whereas discordant findings were observed in persistently dysfunctional segments. These latter are characterized by a significant decrease of PTI and the discrepancies between H215O and 13NH3 MBF estimates are smoothed when H215O MBF is corrected for PTI [39].

5.2 The partial volume effect
The loss of systolic wall thickening and presence of scar with wall thinning result in a ‘partial volume effect’ (discussed in more detail previously) that can lead to a 15–25% underestimation of regional radioactivity counts and therefore contribute to the lower MBF computed in these dysfunctional regions. The rectification of the underestimation of myocardial radioactivity due to the partial volume effect and cardiac wall motion is essential for an accurate measure of MBF in cardiac PET studies [40]. However, the correction for ‘partial volume effect’ has not been undertaken in all PET studies in patients with heart failure and hibernating myocardium (see Tables 1–3GoGo) [10].


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  		Table 1 PET studies of MBF (13NH3) without demonstration of recovery of function at follow-up

 

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  		Table 2 PET studies of MBF using H215O in patients with hibernating myocardium

 

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  		Table 3 PET studies of MBF using 13NH3 in patients with hibernating myocardium

 

   6. PET studies of MBF in patients with hibernating myocardium
Top
 Abstract
 1. Introduction
 2. The initial hypothesis
 3. Positron emission tomography...
 4. MBF assessed with...
 5. Technical considerations on...
 6. PET studies of...
7. Transmural distribution of...
 8. Coronary flow reserve...
 9. Concluding remarks
 References
 
The literature can on occasion appear confused, as variable results have been reported in different PET studies [8,41]. There are a number of technical reasons (see above) that affect the various PET studies to different extents and can explain, at least in part, this apparent discrepancy. Moreover, one has to consider the issue of whether flow in hibernating segments should be compared with flow in normally contracting, remote segments in the same patients or with the data obtained in matched normal volunteers.

Therefore, direct comparison of different PET studies must be carefully weighed considering a number of factors: (a) demonstration of functional recovery after revascularization, the latter being the definitive criterion to define a dysfunctional segment subtended by a stenotic artery as ‘hibernating’, (b) the characteristics of the tracer and kinetic model used, and (c) whether appropriate corrections for the calculation of MBF have been applied.

For instance, all the five studies summarized in Table 1 did not include demonstration of functional recovery of dysfunctional myocardium and in most cases correction for partial volume was not applied. The demonstration of viability, i.e. flow/metabolism mismatch assessed with 13NH3 and 18F-fluorodeoxyglucose (FDG) and PET was taken as indirect evidence of hibernation. It must be pointed out that the presence of flow/metabolism mismatch is not necessarily associated with functional recovery after revascularization, the latter being mainly dictated by the amount of fibrotic tissue within the region of interest [42,43]. On the other hand, when demonstration of functional recovery after revascularization is used for the definition of hibernation, both H215O and 13NH3 give comparable results. In nine of 15 studies reported in Tables 2 and 3Go, MBF in hibernating segments was not significantly different from MBF in remote, normally contracting myocardium whereas in six studies a ~20% lower MBF was found in hibernating segments compared to remote myocardium. Although the paired comparison of flow in dysfunctional and remote areas is statistically more powerful than comparing patients with a normal matched population, the data need to be carefully weighed and regional differences in cardiac workload considered. The difference observed might be explained, at least in part, by a higher MBF in the remote normally contracting regions rather than by an absolute reduction in hibernating segments. The latter would be consistent with the higher oxygen consumption reported in regions remote from segments with severe wall motion abnormalities [44].


   7. Transmural distribution of myocardial blood flow
Top
 Abstract
 1. Introduction
 2. The initial hypothesis
 3. Positron emission tomography...
 4. MBF assessed with...
 5. Technical considerations on...
 6. PET studies of...
 7. Transmural distribution of...
8. Coronary flow reserve...
 9. Concluding remarks
 References
 
In the presence of marked spatial tissue heterogeneity, such as occurs in patients with coronary artery disease and chronic left ventricular dysfunction, the measured flow value may represent a transmural average between several values ranging from very low in necrotic subendocardial areas to normal in well perfused subepicardial regions. In fact, it must be recognized that MBF rates <0.60 ml/min/g, compatible with a reduced resting perfusion, have been found in a small fraction (about 10%) of hibernating segments [9,37]. Admittedly, the limited spatial resolution of the PET scanners used in most studies allows only measurement of average transmural (i.e. full thickness) MBF. In the presence of flow restriction, subendocardial layers tend to have less flow than subepicardial layers. Therefore, a small reduction in average flow across the wall may still correspond to a more severe reduction in subendocardial blood flow. Whether or not subendocardial blood flow is reduced in patients with hibernating myocardium awaits verification by direct measurement [45]. However, using the worst case scenario (zero reduction in subepicardial blood flow with ischemia), a 20% reduction in transmural flow results in a 40% reduction in subendocardial blood flow and accounts for less functional impairment then seen in most patients with hibernating myocardium [46–48].


   8. Coronary flow reserve and hibernation
Top
 Abstract
 1. Introduction
 2. The initial hypothesis
 3. Positron emission tomography...
 4. MBF assessed with...
 5. Technical considerations on...
 6. PET studies of...
 7. Transmural distribution of...
 8. Coronary flow reserve...
9. Concluding remarks
 References
 
The coronary flow reserve is the ratio of MBF during near maximal vasodilatation (pharmacologically-induced) to resting MBF and is an index of the functional significance of coronary stenoses. In patients with coronary artery disease, flow reserve decreases in proportion to the degree of stenosis severity and is abolished (i.e. hyperemic MBF=resting MBF) for stenoses=80% of the luminal diameter [49,50]. Under these circumstances, any increase in cardiac workload above baseline conditions cannot be met by an adequate increase in MBF, leading to ischemia. Therefore, in patients with severe coronary artery disease the limited flow reserve leads to the development of myocardial ischemia, which is often asymptomatic [51] even for small increases of oxygen demand such as those associated with ordinary daily activities [52]. Regardless of the blood flow level under baseline conditions, these patients will develop ischemia when oxygen demand is increased (demand ischemia).

Myocardial ischemia is invariably associated with the development of post-ischemic contractile dysfunction that persists following reperfusion despite the restoration of normal or near-normal coronary blood flow. In the mid-1970s, this phenomenon, later on known as myocardial stunning [53], was initially described by Heyndrickx et al. [54] as a sustained, but eventually completely reversible post-ischemic contractile dysfunction in a conscious healthy dog model subjected to a 15-min coronary occlusion. Two decades later it has been shown that patients with chronic coronary artery disease and absence of contractile dysfunction at rest may also develop myocardial stunning after induction of ischemia with exercise or dobutamine [55–57]. MBF was measured using PET and H215O in patients with CAD and normal LV function. Global (EF) and regional LV systolic function (SF) were measured using quantitative echocardiography during and after dobutamine-induced ischaemia [57]. The results of this study show that EF and SF were reduced 30 min after dobutamine, but recovered by 120 min. MBF (ml/min/g) to regions with reversible LV dysfunction was normal at baseline and during dysfunction (0.88 and 1.09 ml/min/g, respectively, P = NS). In conclusions, in patients with CAD, dobutamine produces prolonged, but reversible LV dysfunction when MBF is normal, thus confirming the occurrence of stunning.

In addition, we have recently demonstrated that in patients with stable exercise-inducible ischemia and normal ventricular function, repeated episodes of ischemia may be cumulative and culminate in more prolonged and severe post ischemic stunning [58] (Fig. 3).


Figure 3
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  		Fig. 3 (A) Regional left ventricular function assessed by transthoracic echocardiography in regions subtended by an artery with <70% diameter stenosis in patients with coronary artery disease and stable stress-inducible ischemia. Data are expressed as the percentage change from baseline values [mean (S.E.)]. Zero and 60 are time in minutes after the first dobutamine infusion; times followed by (2) are times after the second infusion of dobutamine. * P<0.05; {dagger} P<0.001 versus baseline prior to first infusion. (B) Myocardial blood flow (MBF, ml/min/g) in the same regions shown in panel A, at baseline, at the peak [Peak (1)] of the first dobutamine infusion and in the recovery period after the first dobutamine infusion [Recovery (1)] and at the peak and in recovery after the second infusion [Peak (2)] and [Recovery (2)], respectively. * P<0.05 vs. baseline. From Barnes et al. [58] with permission.

 
Thus, in the long term, intermittent episodes of ischemia followed by stunning might induce regional alterations in the myocytes thus contributing to the development of persistent, but still reversible left ventricular dysfunction [44,59]. Clearly, under these conditions, coronary revascularization by restoring flow reserve could interrupt the vicious circle that has led to chronic ischemic dysfunction [60,61] (Fig. 4).


Figure 4
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  		Fig. 4 Schematic illustration of some factors contributing to the natural history of hibernating myocardium. CVR: coronary vasodilator reserve.

 
Preoperative resting flow values are not the best predictors of functional improvement after revascularization [62,63]. The prognosis depends more on ultrastructural [63,64] and metabolic [62] integrity of the myocytes. The presence and extent of functional recovery is inversely related to the amount of fibrosis [42,63]. Concurrently, the processes of transcription and translation aimed at repairing nuclear and mitochondrial abnormalities, loss of contractile material and disorganization of cytoskeleton all affect the time course of functional recovery [43,64].

In a recent study, Vanoverschelde et al. [43] showed that adequate revascularization is not always sufficient for subsequent complete recovery; successful revascularization was achieved in all patients, but only 19/32 had an improved function at 6 months. In those patients the extent of recovery was determined by a combination of several independent factors such as: MBF (13NH3), end-diastolic volume, glucose uptake and the proportion of extracellular matrix.


   9. Concluding remarks
Top
 Abstract
 1. Introduction
 2. The initial hypothesis
 3. Positron emission tomography...
 4. MBF assessed with...
 5. Technical considerations on...
 6. PET studies of...
 7. Transmural distribution of...
 8. Coronary flow reserve...
 9. Concluding remarks
References
 
If one considers the PET MBF studies in patients with hibernating myocardium based on the criteria discussed in the present review article, the following conclusions can be reached: (a) in the majority of these studies resting MBF in hibernating myocardium is not different from either flow in remote tissue in the same patient or MBF in normal healthy volunteers; (b) a reduction in MBF of ~20% compared to MBF in remote myocardium or age matched normal subjects has been demonstrated in a minority of truly hibernating segments; (c) hibernating myocardium is characterized by a severely impaired coronary flow reserve which improves after revascularization in parallel with contractile function.

Altogether, the available studies indicate that the pathophysiology of hibernation is more complex than initially postulated [7]. The recent evidence that repetitive ischemia in patients with coronary artery disease can be cumulative and lead to more severe and prolonged stunning, lends further support to the hypothesis that, at least initially, stunning and hibernation are two facets of the same coin (functional hibernation) while later on the condition becomes associated with a different phenotype (structural hibernation) [65]. This would explain the speed with which functional improvement takes place in different patients that correlates with the degree of tissue degeneration [43]. In addition, a similar pattern of ventricular dysfunction and tissue alteration have been recently reported in a porcine model with a chronic fixed coronary stenosis which is characterized by an initial impairment of flow reserve followed by a slightly reduced (~20%) resting flow [66].

Finally, because of the tight link between myocardial function and MBF, simultaneous accurate determination of regional myocardial function would be important to gain further insight into the heterogeneity of regional MBF. In addition, further studies with higher sensitivity/resolution PET scanners [67] are needed to ascertain whether hibernating myocardium is characterized by a selective reduction of MBF in the subendocardial layers of the left ventricle.

Time for primary review 27 days.


   References
Top
 Abstract
 1. Introduction
 2. The initial hypothesis
 3. Positron emission tomography...
 4. MBF assessed with...
 5. Technical considerations on...
 6. PET studies of...
 7. Transmural distribution of...
 8. Coronary flow reserve...
 9. Concluding remarks
 References
 

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