Heart and Metabolism

Number 20, 2003
Hibernation preconditioning
New therapeutic approaches for myocardial viability: selecting who will benefit

Thomas H. Marwick
University of Queensland, Brisbane, Australia
Correspondence: Professor Thomas H. Marwick, University of Queensland Department of Medicine, Building 1, C Wing, Level 4, Princess Alexandra Hospital, Ipswich Road,
Brisbane, Queensland 4102, Australia.
Tel: +61 7 32405340; fax: +61 7 32405399; e-mail: tmarwick@medicine.pa.uq.edu.au

Abstract

New interventional therapies for myocardial viability include the use of metabolic interventions, cell transplantation, or revascularization to improve the status of patients with left ventricular dysfunction. Each of these new therapies has a different mechanism of effect, therefore preintervention testing needs to supply information regarding a number of pathophysiologic processes including nontransmural scar, damage to the contractile apparatus of the cell, recurrent stunning from ischemia, and perfusion. In order to appropriately select patients for the promising new technologies discussed in this review, we will need to become much more particular about the contribution of these processes within individual patients. However, the clinical application of these techniques is currently limited and the following discussion is based on pathophysiologic principles rather than on evidence per se. n Heart Metab. 2003;20:23–28.

Keywords: Myocardial viability, myocardial metabolism, cell transplantation

Introduction
Although it may seem obvious, a fundamental and often neglected principle of testing for myocardial viability is to know the eventual goal in the care of the patient. The detection of viable myocardium is important in two circumstances: following myocardial infarction, and in congestive heart failure. In the postinfarct patient, the detection of viability may justify the performance of target-vessel angioplasty; its absence, however, usually restricts the therapeutic options towards measures that should be used in all patients, directed towards preventing the progression of atherosclerosis. In the patient with heart failure, the absence of viable myocardium would generally lead to the patient being treated with medical management only, apart from those undergoing transplantation or an assist device.
The presence of extensive viability identifies patients whose functional state is likely to improve and whose outcome is likely to be helped by revascularization.
New interventional therapies can be categorized as those involving revascularization, cell transplantation, or metabolic interventions (Table I).

Table I. Interventions for viable myocardium.

Generally, these would be considered to improve the status of patients with left ventricular dysfunction. In this situation, a critical first step is that we confirm the presence of left ventricular dysfunction and that it is the cause of the patient’s symptoms; this will not be discussed further. Following this, each of the new therapies has a different mechanism of effect, so preintervention testing needs to supply different information. Three components are important: measurement of the extent of scar, measurement of the residual perfusion, and evaluation of myocardial viability — recognizing that not all tests identify these in the same way. Reports of the clinical application of these techniques are limited and the following discussion is based on pathophysiologic principles rather than on evidence per se.

Medical therapy
It would be very attractive to have an effective medical therapy to improve left ventricular dysfunction in patients with viable myocardium who are unsuitable for revascularization because of poor targets or comorbidities. At present these options are limited, but they could be divided into therapies that influence intermediary metabolism and those that may protect the heart from ischemia.

Metabolic interventions
Infusion of glucose, insulin, and potassium (GIK) has been studied during acute ischemia and infarction, where it has been associated with reduction of infarct size and enhancement of functional recovery [1, 2]. Cottin et al [3] examined the effects of GIK in 12 stable patients with ischemic dysfunction (ejection fraction <45%). The authors found a significant improvement of wall motion score index at the end of the infusion, with ejection fraction improving at 20 and 40 minutes after infusion, but they did not characterize the association with viability. We recently reported that GIK improves wall motion score, myocardial velocity, and end-systolic volume in patients with viable myocardium and chronic left ventricular dysfunction, independent of effects on hemodynamics or catecholamines. These effects correlated with the response to dobutamine, implying that contractile reserve is a prerequisite for a GIK response [4]. Similarly, Yetkin et al [5] performed low-dose dobutamine stress echo and GIK therapy in 21 patients with chronic coronary artery disease and myocardial dysfunction. Of the asynergic segments at baseline, viability was detected in 19% with GIK and 16% with low-dose dobutamine; the agreement between the glucose and dobutamine stimulation was 95%. While this therapy has limited feasibility for ambulatory care, the results suggest that it may help in sick patients with viable myocardium, and the studies provide proof of concept that viable tissue is responsive to metabolic modulation.
Two oral agents with similar metabolic effects are currently available. Trimetazidine is a metabolic agent that works by inhibition of long-chain 3-ketoacyl-CoA-thiolase activity, resulting in a reduction in fatty acid oxidation and a stimulation of glucose oxidation [6]. Brottier et al [7] showed an improvement of dyspnea and ejection fraction with trimetazidine in a 6-month, double-blind, placebo-controlled study of 20 patients with severe ischemic cardiomyopathy, confirmed by coronary angiography. Similarly, in a blinded crossover study of 15 patients with chronic coronary artery disease undergoing dobutamine echocardiography, Lu et al [8] showed that trimetazidine improved resting left ventricular function and reduced the severity of dobutamine-induced ischemia. However, from the standpoint of viability testing, the most important study was performed by Ciavolella et al [9], who studied 12 patients with previous infarction who underwent 99mTc sestamibi SPECT and echocardiography before revascularization. Patients taking trimetazidine showed a significant increase in tracer uptake, mainly in viable segments that improved function postoperatively. These results suggest that viable segments, perhaps predominantly those with ischemia (hence perhaps best studied with a test for both viability and ischemia such as dobutamine echo or stress-redistribution-reinjection thallium SPECT), benefit from therapy with trimetazidine.
Perhexilene has also been shown to inhibit myocardial utilization of long-chain fatty acids and to inhibit the mitochondrial enzyme carnitine palmitoyltransferase [10], which has been shown to have favorable effects on cardiac function in ischemia. However, its use has not been studied in patients with viable myocardium.
In general, when metabolic interventions are being considered, the presence of preserved contractile reserve and an ischemic component may be critical determinants of whether the patient will respond to therapy. In situations where chronic dysfunction is due to recurrent stunning [11, 12], metabolic agents may be useful to prevent or attenuate ischemia. Moreover, some severely damaged tissue may have lost contractile elements [13], making it unresponsive to dobutamine even if it is apparent by FDG PET or thallium SPECT. In these situations, metabolic agents are unlikely to show short-term effects, and perhaps dobutamine echo will be the best means of selecting patients.

Carvedilol
The first large-scale trial of a medical therapy for hibernating myocardium was the CHRISTMAS trial (Carvedilol Hibernation Reversible Ischaemia Trial: a Marker of Success). This study was a randomized double-blind trial of carvedilol (n = 142) vs placebo (n = 163) in patients with coronary artery disease, chronic stable heart failure (mainly functional class II) of at least 3 months’ duration, and left ventricular ejection fraction <40% [14]. Most patients were already taking ACE inhibitors, and patients were on a stable dose of carvedilol for 4 months before retesting. Viability was defined as a function-perfusion mismatch by MIBI SPECT, and the average amount of viability was almost 30% of left ventricular mass. Carvedilol therapy was found to give a 3% greater increase in left ventricular ejection fraction than placebo (P = 0.0001) in patients with and without viable myocardium (Figure 1), but the amount of jeopardized (ischemic and viable) tissue and more severe dysfunction at baseline were predictive of a greater response.

Figure1. Comparative pharmacokinetic profile of modified-release trimetazidine bid and trimetazidine immediate release tid. After [14].

Although the details are as yet unpublished, it is interesting that the authors used jeopardized extent, which suggests that perhaps the substrate for the b-blocker effect is ischemia. To select patients for this therapy, we therefore need to have a test showing left ventricular dysfunction, viable myocardium, and ischemia: stress-rest SPECT was used in the trial, but full-dose dobutamine echo could be expected to offer the same information. The problem with this approach, however, is that carvedilol would be considered to be standard therapy for our population with left ventricular dysfunction and heart failure [15].

Cell proliferation
Myoblast transplants
The initial clinical experience of myoblast transplantation [16] involved engraftment of skeletal muscle myoblasts within scar tissue. This and a number of animal studies demonstrated improved global left ventricular function after the procedure. Recent work has confirmed that myocytes colonize fibrotic areas and demonstrate some characteristics of cardiac rather than skeletal muscle [17]. Some initial work involved intracoronary injection of the myoblasts, which might have led to the use of perfusion imaging as a selection tool for areas with some preservation of perfusion. However, arrhythmias have been associated with this delivery method, and recent work has involved direct engraftment. As the technique has been successfully performed into scar tissue, it is difficult to mount an argument for the use of viability testing. Although it seems less likely that engraftment would be effective if encased in extensive scar, the impact of the extent and transmurality of scar on the results of myoblast transplantation remain to be defined.

Stem cell transplantation
An alternative approach to myoblast transplantation is the engraftment of stem cells. An early report of this in postinfarct patients [18, 19] and patients with chronic ischemic heart disease [20] showed improvement of global left ventricular function. However, the results from both groups showed that regional perfusion appeared to improve more than regional function. This led the authors to hypothesize that this approach induces angiogenesis more than local myocytes, and, if this is true, it would more resemble a treatment for viability than a transplant procedure for cardiac muscle. Indeed, the Hong Kong group used the NOGA mapping system to target engraftment into areas of viability, evidenced by preserved electrical and reduced mechanical activity [20]. The impact of baseline flow has yet to be defined; perhaps this procedure will be more effective in the setting of reduced function with relatively preserved perfusion. However, on the appearance of SPECT images published to date, the technique appears to be quite effective in the presence of rather profound reductions in flow (Figure 2) [19].

Figure 2. Paired vertical (A and D), horizontal (B and E) and short axis (C and F) images before and after stem cell transplantation, showing changes of perfusion. Reproduced with permission from [19].

Tissue factors
The goal of regrowing muscle or vessels might be attainable with local delivery of cytokines. Unfortunately, despite initial promise of angiogenic cytokines (eg, fibroblast or vascular endothelial growth factors) using protein or gene therapy in in-vitro and small clinical studies, a subsequent randomized double-blind study showed no benefit over placebo [21]. Several explanations have been offered for the failure of cytokine-based approaches, including the difficulties posed by using a single angiogenic cytokine to stimulate such a complex process, the inability to detect small benefits with current technologies, and suboptimal delivery strategies [22]. In any event, it does not appear that imaging strategies for the detection of viability are currently needed.

Hemodynamic support
The spectrum of viable myocardium stretches from postischemic stunning to the picture of short-term hibernation (metabolism-perfusion mismatch but preserved contractile reserve and intact contractile apparatus) and long-term hibernation. In the latter situation, despite metabolism-perfusion mismatch, contractile reserve is lost, corresponding to damage of the cell’s contractile apparatus [23]. Given the high risks of revascularization surgery in severe left ventricular dysfunction, and the prolonged recovery time of tissue in this situation, an approach that enabled preoperative improvement of severely damaged tissue might be of value.
Various devices have now been described for the support of patients with heart failure in circumstances where transplantation is not an option. While these may not immediately appear to pertain to therapy for viable myocardium, they could be used to prepare high-risk patients for revascularization. Such a device would not need to be implanted; for example, enhanced external counterpulsation could be of value [24]. If such a regimen were to be developed, the appropriate selection of patients would be those with evidence of viability on metabolic grounds (FDG PET, thallium SPECT) with loss of contractile reserve at dobutamine echo.

Inhibitors of cell death
Viable myocardium is characterized by apoptosis. A number of new markers of myocyte injury and death have been developed, including 99mTc-labeled annexin V and contrast-enhanced magnetic resonance imaging, which have replaced their rather insensitive predecessors 99mTc pyrophosphate and 111In-labeled antimyosin. It is possible in the future that we will use these markers to identify the amount of ongoing destruction, in order to justify the use of a specific therapy against apoptosis.

Transmyocardial laser revascularization (TMR)
Transmyocardial laser revascularization (TMR), both operative and percutaneous, is primarily a procedure for myocardial revascularization for the patient with no conduits or an artery incompatible with percutaneous intervention. Indeed, despite relief of angina (which may relate to a placebo effect or even myocardial denervation), the efficacy of this therapy for improving regional perfusion by SPECT appears limited [25]. This may be a shortcoming of the current techniques; other studies have shown improvement of regional function during dobutamine stress echo [26], and a recent study even showed improved thickening by MRI at rest [27]. Indeed, there is a significant evidence base that TMR stimulates angiogenesis (after a delay of a few months), and it may be useful for treating viability in situations of both chronically reduced blood flow and intermittent stunning. Extensive myocardial scar has been perceived as a scenario where the development of channels carries risk, so testing for wall thickness and scar thickness by MRI would be of value, as would demonstration of reduced perfusion with preserved contractile reserve. However, the early experience of performing TMR in high-risk patients was exceedingly unfavorable, with 30-day mortality as high as 20% [28]. Thus for the group under discussion with heart failure, this would not be a good option.

Conclusions
The phenomenon of “viability” encapsulates a number of pathophysiologic processes, including nontransmural scar, damage to the contractile apparatus of the cell, recurrent stunning from ischemia, and perfusion. In order to appropriately select patients for the promising new technologies discussed in this review, we will need to become much more particular about the contribution of these processes within individual patients.

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REFERENCES

24. Michaels AD, Accad M, Ports TA, Grossman W.
Left ventricular systolic unloading and augmentation of intracoronary pressure and Doppler flow during enhanced external counterpulsation.
Circulation. 2002 Sep 3;106(10):1237-42.
PMID: 12208799 [PubMed - indexed for MEDLINE]

25. Saririan M, Eisenberg MJ.
Myocardial laser revascularization for the treatment of end-stage coronary artery disease.
J Am Coll Cardiol. 2003 Jan 15;41(2):173-83. Review.
PMID: 12535804 [PubMed - indexed for MEDLINE]

26. Donovan CL, Landolfo KP, Lowe JE, Clements F, Coleman RB, Ryan T.
Improvement in inducible ischemia during dobutamine stress echocardiography after transmyocardial laser revascularization in patients with refractory angina pectoris.
J Am Coll Cardiol. 1997 Sep;30(3):607-12.
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27. Laham RJ, Simons M, Pearlman JD, Ho KK, Baim DS.
Magnetic resonance imaging demonstrates improved regional systolic wall motion and thickening and myocardial perfusion of myocardial territories treated by laser myocardial revascularization.
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28. Horvath KA, Mannting F, Cummings N, Shernan SK, Cohn LH.
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J Thorac Cardiovasc Surg. 1996 May;111(5):1047-53.
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Number 20, 2003Hibernation preconditioning New therapeutic approaches for myocardial viability: selecting who will benefit

Number 20, 2003Hibernation preconditioning

Number 20, 2003
Hibernation preconditioning
New therapeutic approaches for myocardial viability: selecting who will benefit

Number 20, 2003
Hibernation preconditioning