The outcome after revascularization of hibernating myocardium is still an area of debate since the results of the randomized clinical trials are not supporting the findings from previous observational studies. Furthermore, the usefulness of viability testing prior to the revascularization procedure became unclear after publishing the results from the STICH trial and REVIVED BCSI2 [104,117].

However, the follow-up of patients from the STICH trial after 20 years of enrollment showed a trend for better survival in the group of patients with viability, compared to the non-viable group, and once again assessing myocardial viability came into focus [26]. Imaging tools such as SPECT and DSE used in STICH could miss some cases of myocardial viability, and patients were wrongly included in the non-viable group. PET and cardiac MRI can detect myocardial viability in cases where DSE and SPECT are failing, but these imaging tools were not available in STICH [77,97].

Yet, what is clear is that patients with severe LV remodeling, lower ejection fraction, larger LV volume, and more extensive CAD are more likely to benefit from surgical revascularization. These patients are at the highest risk for future acute coronary events, will tolerate less a new event, and will benefit more after CABG.

It seems that improvement of the LV function is not the only mechanism, and is not the most important mechanism for improved outcomes after CABG [77]. A relatively small improvement in LV ejection fraction was observed in the early stages following revascularization in STICH. The mean improvement in LV ejection fraction was 2% at 4 months in a group with an important amount of viable myocardium [18]. There are multiple factors involved in this: viable areas are not necessarily with contractile dysfunction, the regional nature of LV dysfunction that can result from various combinations of scarred and hibernating myocardium, the completeness and durability of revascularization, and the degree of peri-operative myocardial injury [118]. On the other side, after revascularization, sometimes a longer time of recovery may be necessary [119]. In the STICH viability sub-study, improvement of LVEF at 4 months was also observed in patients with optimization of medical treatment and was not correlated with long-term outcomes [77]. A small number of patients from STICH had a significant improvement (≥10%) of ejection fraction at 24 months after randomization [120] associated with reduced mortality. This improvement of the LV ejection fraction was not correlated with the type of treatment, and this further sustains that improving of LV function is not the most important mechanism that is leading to increased survival after CABG [121]. Beyond recovery of LV function, the most important beneficial mechanism for CABG is protection from future acute coronary events, and preventing of further damage and of sudden death [122]. Other mechanisms involved in the benefit of CABG are myocardial ischemia improvement due to improvement of coronary flow reserve and restoration of electrical stability of myocytes. CABG is improving survival, but also exercise tolerance and quality of life [123,124]. An important factor that should be considered is if there is concordance between the viable segments and the suitability for revascularization of the vessels that are distributing blood to that area. If there is concordance, CABG revascularization will protect the myocardium from future ischemic and arrhythmic events. In addition, this is more relevant in patients with multi-vessel disease and LV dysfunction [125].

The risk of death from heart failure in patients with ischemic LV dysfunction is clearly correlated to LV ejection fraction, but sudden arrhythmic or ischemic deaths are not. In the Digitalis Intervention Group trial, after analyzing the connection between LV ejection fraction and mechanism of death in 7788 patients (69% of them with ischemic heart failure), a near-linear relationship was demonstrated between LV ejection fraction and death from worsening heart failure, but the risk of death due to arrhythmic events was constant across the spectrum of reduced LV ejection fraction [126]. Sudden death risk due to ventricular arrhythmic events and myocardial infarction [122,127] can be influenced by revascularization, independent of any effect on contractile function. Myocardial scar can produce electrical instability, but the relationship between the amount of scar and risk is non-linear [128,129]. The benefits of CABG in STICH probably resulted from the reduction in sudden deaths due to fatal ventricular arrhythmias, and the prevention of acute myocardial infarction. The border area between the infarcted and viable myocardium is characterized by a non-uniform conduction and varying refractoriness and has an important arrhythmogenic potential [130,131]. Arrhythmogenesis is further increased by ischemia via intracellular acidosis and membrane depolarization. Incomplete revascularization with residual ischemia and peri-procedural myocardial infarction can appear [118], and therefore the reduction of arrhythmic risk cannot be predicted precisely. The electrophysiological properties of the myocardium are influenced earlier and independent from LV function recovery after revascularization [132,133].

Reduction in LV volume and sphericity after revascularization are also important prognostic factors beyond the improvement of regional wall thickening and of LV ejection fraction [8,134].

The risk associated with CABG will determine the final decision of surgical revascularization. PCI has a lower procedural risk, but the benefits of interventional revascularization in patients with ischemic cardiomyopathy need to be further evaluated. No improvement in regional LV function was observed in the randomized studies of chronic total occlusion PCI, even in the presence of viable myocardium; however, these were not addressed to patients with severe LV systolic dysfunction [135,136]. More recently, the REVIVED-BCIS2 trial showed no additional benefit for PCI revascularization versus OMT alone, in patients with severely impaired LV function and extensive CAD [104].

Furthermore, the presence of extensive viability has been shown to predict the response to various treatment methods, such as pharmacological [137,138], and cardiac resynchronization therapy [139], and not only to revascularization.

The available data suggest that revascularization is reducing mortality in patients with ischemic heart failure that have a substantial amount of viable myocardium. The benefits of revascularization in patients without a substantial amount of viable myocardium remain unclear. The treatment effect of CABG in STICH was independent of viability status, with similar reductions in sudden cardiac death and heart failure. It is probably appropriate to recommend CABG in patients with ischemic cardiomyopathy based on the extent of their CAD, rather than on the viability testing [17]. Furthermore, no imaging method can assess viability with perfect precision, and variable accuracy is described for different imaging tests, so the HEART Team can decide on revascularization if it is clinically indicated [140].

The relationship between myocardial viability and revascularization is further studied in the ongoing trial IMAGE-HF (Imaging Modalities to Assist with Guiding and Evaluation of patients with Heart Failure): a prospective study that will compare the effect of an advanced imaging technique such as PET and cardiac MRI on clinical outcomes of patients with ischemic heart failure compared to those using standard care, including SPECT [116].

There are still many unknown elements regarding the interaction between ischemia and viability in predicting both clinical outcomes and treatment effects.

Myocardial hibernation is induced by recurrent episodes of inducible ischemia, and the reversal of hibernation depends on two factors: resolution of ischemia and a viable myocardium that is able to recover. The recovery of dysfunctional myocardium is most likely to occur in territories with both inducible ischemia and viability.

There are a few observational data that support these findings, respectively, a greater diagnostic accuracy if both contractile reserve and ischemia are demonstrated via a biphasic response on DSE, versus the demonstration of contractile reserve alone [92,110]. In addition, in the CHRISTMAS trial, a more important improvement in the LV ejection fraction was observed in patients with a larger area of hibernating myocardium or hibernating and ischemic myocardium, suggesting that the pharmacological treatment of ischemic or hibernating myocardium is contributing to the improvement of LV function [135].

Patients with ischemic LV dysfunction have, in general, a multi-vessel complex CAD, so probably they have a large ischemic burden on functional testing. Hibernating myocardium itself is an adaptive response to ischemia, but the ability to demonstrate inducible ischemic contractile dysfunction may be limited, and it is difficult to evaluate ischemia when the myocardium is thinned or partially scarred [141].

Patients with ischemic LV dysfunction and important inducible ischemia have poorer outcomes. The benefits of revascularization are greater in those with more extensive ischemia in observational studies [142]. However, it is difficult to evaluate the treatment effect from observational data, since the revascularization decision is commonly influenced by comorbidities or the frailty of patients that increase the procedural risk or reduce the chance of benefit, despite the presence of extensive ischemia.

The role of ischemia in selecting patients with ischemic LV dysfunction for revascularization is controversial. Observational studies observed that low-dose DSE allowed the risk stratification of outcome after revascularization [143]. Some studies have identified an association between the presence of inducible ischemia and better outcomes after revascularization, while others have shown that this becomes irrelevant when other clinical factors, such as scar burden and non-viable myocardium are considered [95,144]. Rizzello et al. identified that in patients already scheduled to undergo revascularization, viability was a strong predictor of long-term prognosis, but the magnitude of ischemia on DSE was not a predictor of cardiac mortality [92].

A sub-study of the ISCHEMIA trial evaluated the relation between inducible ischemia and the effect of revascularization on clinical outcomes, in patients with heart failure and a mid-range ejection fraction, and revealed improved results with revascularization vs. pharmacological treatment [145]. The value of this analysis is limited by a small sample size, interactions between ischemia and viability were not explored, and patients with severely reduced ejection fraction were excluded from the study [146].

In clinical practice, most of the patients undergo coronarography as an initial investigation, followed directly by angioplasty or they are sent to CABG, so the majority of them are not evaluated regarding myocardial viability. If the evidence for the importance of viability testing will increase, then development of viability tests that can be used as adjunctive to coronarography will improve the management of these patients [18].

Pharmacological therapy can improve the balance between myocardial oxygen consumption and demand, can diminish myocardial ischemia and restore contractile function, and can reduce the risk of recurrent ischemic and arrhythmic events. Beta-blockers are reducing heart rate and myocardial oxygen consumption; increasing diastole and improving coronary perfusion; and decreasing the risk of arrhythmia, recurrent myocardial infarction, and sudden death [147]. In the CHRISTMAS trial, the effectiveness of beta-blockers in improving LV function was related to the extent of myocardial hibernation [147].

Angiotensin converting enzyme inhibitors (ACE), angiotensin receptor blockers, and aldosterone receptor antagonists are reducing LV end-diastolic volume, LV pressure, and wall stress, and are improving subendocardial flow. These drugs can reduce mortality and the risk of heart failure hospitalization and improve symptoms [148].

Angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter-2 inhibitors reduce the worsening of heart failure, cardiovascular and all-cause mortality, and improve heart failure symptoms and quality of life [149,150,151].

Obviously, the pharmacological treatment has a key role in the management of patients with ischemic heart failure and should not be neglected even if patients are referred for revascularization. On the other hand, there is an interaction between pharmacological therapy, revascularization, and viability, so controlling for their individual effect is very difficult in clinical trials. An experimental approach to the treatment of hibernating myocardium is to consider regenerative techniques by injecting stem cells (mesenchymal stem cells and mononuclear cells) into models of myocardial ischemia, that can lead to the improvement of myocardial contractility [117].

Randomized trials are needed, which consider the scope of viability testing more broadly, not simply if there is viable myocardium or not, but also to evaluate the amount or the percentage of the myocardium that is viable and to determine a relation between the amount of viable but dysfunctional myocardium and the response to revascularization therapy.