Chronic total occlusion (CTO) of coronary arteries represents an advanced form of atherosclerotic coronary artery disease, which is currently prevalent in circa one-fifth of patients presenting for diagnostic coronary angiography [1]. CTO is defined as a chronic occlusion of the artery for longer than 3 months with a TIMI 0 flow and is associated with the development of collateral conduits from donor vessels that maintain a certain perfusion level to the CTO-related myocardial segments ^[2][3][2,3]. However, these collaterals are very often insufficient to provide adequate myocardial perfusion, which often leads to the typical manifestation of ischemic heart disease [2]. A growing body of evidence suggests that the revascularization of CTO using coronary artery bypass grafting or percutaneous coronary intervention (PCI) has several clinical benefits, including ischemic symptom relief and quality of life improvement. These findings are supported to date by limited randomized controlled studies assessing the effects of CTO PCI upon clinical indication ^[4][5][6][7][4,5,6,7] (Table 1). Yet it is still unclear whether revascularization of CTO provides a survival benefit or long-term freedom from cardiac events, compared to receiving optimal medical therapy alone–indeed, the few available randomized controlled trials have reported no benefit in this context ^[5][7][5,7]. However, large observational studies on CTO patients have concordantly been reporting positive effects of CTO PCI on long-term survival and freedom from cardiac events. Of note, most of these studies compared patients that underwent successful vs. unsuccessful revascularization attempts on CTO vessels ^[8][9][10][8,9,10].

Due to the lack of randomized trials, the hard-outcome benefits of CTO PCI are not yet fully elaborated. However, the HORIZONS-AMI trial observed that the presence of a CTO in patients undergoing PCI for ST-elevation myocardial infarction was associated with worse early and late clinical outcomes [11].

CTO PCI is a challenging procedure with increased technical complexity and a need for appropriate operator experience. Through recent advancements and the development of dedicated methods and devices in the last few years, success rates of CTO PCI have increased significantly. However, they remain lower than non-CTO PCI–#, with successful revascularization of CTO vessels ranging from 60–70% of patients in inexperienced operating centers and 90–95% in some highly experienced centers ^{[10][12][13][14]}[10,12,13,14]. Moreover, these patients are characterized by a higher interventional complication risk compared to non-CTO PCI, suggesting the need for a careful patient selection and benefit-risk evaluation before attempting CTO PCI, adapted to operator experience and expected symptom and prognostic benefits ^[3][15][16][3,15,16].

The European Society of Cardiology (ESC) guidelines on myocardial revascularization suggest choosing patients for CTO PCI in a similar manner to those who need treatment for non-CTO lesions, and explain that clinical benefits are analogous among these patient groups–hence, the rationale and criteria for decision-making in the revascularization of stable CAD should apply to the CTO subset [16]. As stated in the guidelines, prognostic benefits of revascularization may be granted to patients with a significant left main and/or left anterior descending artery (LAD) stenosis, multi-vessel disease or in patients with an ischemic territory exceeding 10% of the left ventricle. For this reason, they suggest an objective quantification of ischemia using non-invasive diagnostic imaging as a first-line test before revascularization. In left ventricular dysfunction, guidelines recommend viability testing to be performed appropriately for the detection of stunned or hibernating myocardium causing heart failure with the potential of functional recovery [16].

Most importantly, CTO PCI is currently recommended by the ESC in selected patients with angina symptoms resistant to medical therapy (class of recommendation II-a, level of evidence B) [16] (Table 2). However, the 2017 American College of Cardiology/American Heart Association guidelines on myocardial revascularization recommend CTO PCI only upon clinical indication and in the hands of appropriately experienced operators, as a class II-a of recommendation and level of evidence B [15]. The recent 2021 American guidelines downgraded the clinical recommendation for CTO PCI to a class II-b level of evidence B due to equivocal evidence based on randomized trials: “In patients with suitable anatomy who have refractory angina on medical therapy, after treatment of non-CTO lesions, the benefit of PCI of a CTO to improve symptoms is uncertain”. They also encourage CTO PCI after shared-decision and potential benefits [17] (Table 2). Of note, no randomized trials comparing CTO PCI and CABG are available to date.

Pre-interventional evaluation of CTO lesions has indeed to be well elaborated as the main characteristics of this specific lesion subset, such as collateral vessels and complete antegrade flow impairment, restrict diagnostic availability or alter the interpretations for clinical indication. For example, the use of the broadly recommended FFR or the novel CT-FFR measurements is not routinely possible in CTO vessels [16]. Thus, non-invasive imaging takes on greater significance and the choice of techniques and interpretation of imaging-derived information require special attention.

In this context, suitable candidates to undergo CTO PCI should be carefully identified and selected taking into consideration diverse clinical factors and supported by appropriate cardiac imaging techniques evaluating viability and ischemia.

Guided by current recommendations and clinical practice, rwesearchers opted to review the available evidence on benefits of CTO PCI and shed light on pre-interventional requirements for the consideration of revascularization. researchers Throughout our review, we used the term revascularization to reference PCI as theour primary focus, if not stated otherwise. Furthermore, researchers swe summarised the available non-invasive imaging methods that support the physician to guide the patient selection process.

In patients with coronary artery disease and normal ventricular function without regional wall motion abnormalities assessed by echocardiography, intact myocardial viability can be presumed [18]. In these patients, several benefits of revascularization have been reported. In patients with preserved systolic left ventricular function and one single vessel disease randomized in the ORBITA trial, revascularization improved the stress wall motion score index as assessed by cardiac echocardiography after 6 weeks as a secondary endpoint [19]. Furthermore, a large meta-analysis described better outcomes of revascularization in patients with viable myocardium and normal left ventricular function, as compared to medical therapy [20].

On the other hand, the clinical benefit of revascularization in patients with left ventricular dysfunction is still ambivalent. A considerable proportion of CTO patients manifest heart failure with a reduction of left ventricular function [10] but it is unclear still whether CTO PCI is able to induce recovery. One large randomized controlled trial (n = 205) investigated the left ventricular recovery in terms of wall thickness and ejection fraction and found no differences between CTO patients who underwent revascularization and those who received optimal medical therapy alone. However, the results were limited by the low rates of ventricular dysfunction at baseline and the revascularization of diseased donor vessels in the control group [6]. However, previous studies have reported positive results in the general CAD population. A large meta-analysis of 3088 patients studied the role of myocardial viability in the revascularization of CAD patients with severe left ventricular dysfunction (as assessed by the left ventricular ejection fraction) [21]. ReThisearchers  study underlined that viable myocardium benefits immensely from revascularization as compared to medical therapy and paved the way for further research and clinical applications. Its implications may have a slightly different meaning nowadays, as, during the few past years, medical therapy for heart failure has witnessed massive improvements; patients treated medically in the current era have a better prognosis with the new heart failure therapies, as reported in large randomized controlled studies ^[22][23][22,23]. However, the interpretation for clinical practice was limited by the observational nature of the study and the lack of information on the method of revascularization. Later on, most solid data came from randomized trials on patients receiving coronary artery bypass grafting (CABG), suggesting that ischemic but viable myocardium with left ventricular dysfunction has a better long-term prognosis after CABG [24]. A viability sub-study of the STICH trial on patients with reduced left ventricular function receiving CABG reported at first less cardiac mortality and cardiac hospitalization within 5 years when myocardial viability was preserved. However, in the multivariable analysis, the correlation was lost [25]. On the other hand, in an extended 10-year follow-up, freedom from cardiac death and hospitalization was significantly higher in the STICH trial patients when myocardial viability was preserved [26].

It seems that revascularization in ventricular dysfunction has prognostic benefits, but it has been long debated if this implication depends on the revascularization method. Indeed, in the general CAD population, the recent FAME-3 trial reported a non-inferiority of functionally-guided PCI vs. CABG in 1-year follow-up. However, patients with left ventricular dysfunction were underrepresented with ca. 18% in both treatment arms [27].

Recently, one randomized trial recently addressed the evidence gap. The REVIVED trial investigated patients with viable dysfunctional left ventricles undergoing PCI and reported no benefit in survival or cardiac events in 3 years compared to the control group which received optimal medical therapy alone. Moreover, the trial showed no improvement in left ventricular ejection fraction after PCI [28]. However, the clinical endpoint observation time might have been too early in the REVIVED trial: As seen in the STICH trial, prognostic benefits of revascularization may be detected only after a longer observational period. Another issue might be the non-adequate selection of patients with left ventricular dysfunction for myocardial revascularization. In the PARR-2 randomized trial, patients identified using PET before undergoing PCI had better hard outcomes than those selected using the standard of care protocol [29]. Despite studying a smaller cohort than REVIVED, rethisearchers study emphasizeds the need for a more careful clinical indication by highly sensitive methods of non-invasive cardiac imaging.

On the other hand, non-randomized data suggest PCI survival benefits in left ventricular dysfunction: Gerber et al., reported a higher 3-year survival in patients with severe left ventricular dysfunction and viable myocardium who received revascularization. Overall, the study reported similar 3-year mortality as the REVIVED trial [30]. Although emerging data may lead to discussions in the next guidelines, current practices and indications for patients with myocardial dysfunction undergoing revascularization (including CTO patients) will most probably remain unaltered [31].

In patients with ventricular dysfunction, PCI benefits may be found mostly in the presence of hibernation. An observational study on 648 patients reported that an extent of hibernating myocardium exceeding 10% was associated with the benefits of revascularization [32]. Physiologically, improvement in left ventricular function may be physiologically explained by reversed myocardial hibernation after restored perfusion, with enhanced reversibility in those patients who have less fibrotic tissue ^[33][34][33,34]. When left untreated, hibernation can be a progressive condition with subsequent development of fibrosis, myocardial thinning and akinesia [35]. A prospective trial found progressive loss of myocardial viability in patients with ventricular dysfunction receiving neither revascularization nor medical treatment, resulting in scar formation in former hibernating myocardial segments [36]. Of note, revascularization of hibernating myocardium has been associated with improved long-term prognosis in viable areas larger than 10% of the left ventricle [32]. As such, quantification of viability has prognostic value, but is only possible non-invasively.

Revascularization of ischemic but viable myocardium aims to minimize residual ischemia and subsequently improves symptoms and prognosis. Patients with a large ischemic burden (more than 10%) are considered to benefit the most from PCI [37]. This statement is supported mainly by the randomized COURAGE trial, which reported a survival benefit and reduced myocardial infarction rates in patients with an ischemic burden of more than 10% at the baseline and less than 5% after revascularization [38]. In this study, ischemia was evaluated non-invasively using SPECT. On the other hand, a sub-study of the PARR-2 trial using PET reported fewer cardiac events after revascularization in CAD patients with an ischemic but viable myocardial area of more than 7% of the left ventricle [39]. However, the threshold of ischemia in 10% of the myocardium remains standard of care, as this amount of ischemic burden is associated with prognostic benefits of revascularization in the general CAD population [16].

Nowadays, invasive functional assessment of coronary artery stenoses can derive information related to the extent of ischemia in the distal supply region. Treatment of functionally significant stenoses, as assessed by fractional flow reserve, has been proven to be superior to revascularization guided by anatomical evaluation alone. The FAME trial reported better 2-year MACE rates after revascularization of ischemic myocardium, as assessed invasively with FFR [40]. However, for quantitative measurement of myocardial ischemia, coronary flow reserve using PET represents the most reliable parameter due to the detection of ischemia in the whole myocardium, which surpasses the invasive tool of FFR measuring the pressure drop solely [41]. In fact, invasive functional measurement does not apply to CTO lesions, as collateral vessels rather than CTO vessels themselves supply the corresponding myocardial regions.

Indeed, CTO-related myocardium can be an ischemic area even in well-developed collaterals. Werner et al., reported a sufficient collateral flow in only 5% of CTO patients with preserved left ventricular function [42]. When patients report typical symptoms, ischemia is mostly present. A quantitative correlation between ischemic burden and clinical benefits in CTO patients is not specifically stated. The IMPACTOR-CTO trial aimed to stratify patients according to their ischemic burden, guided by the belief that large ischemic CTO-related areas will benefit most from revascularization [43]. This was the only randomized study to report a significant myocardial ischemia reduction in patients undergoing CTO PCI. However, myocardial ischemia reduction remains the primary benefit of CTO PCI.