Abstract: Chronic total occlusion (CTO) recanalization and its effects on left ventricular function and patient outcomes has intrigued the interventional community over the last several years. Now that there is plenty of knowledge and experience on “how to treat” the lesion, another scientific effort should focus on “when to treat” the lesion. Physiologic assessment has altered the way we treat coronary artery stenosis to improve cardiovascular outcomes. We tend to assess the effects of CTO recanalization by evaluating resting parameters, although the effects of ischemia and concomitant left ventricular dysfunction manifest mainly during exercise. Physiologic assessment in CTOs by implementation of cardiopulmonary exercise testing, in order to indirectly assess the physiological effect of exercise-induced left ventricular dysfunction, could represent a novel approach to monitor the effects of CTO recanalization and hopefully to identify the responders after recanalization.
J INVASIVE CARDIOL 2019;31(12):E384-E386.
Key words: cardiopulmonary exercise test, chronic total occlusion, physiology
The pursuit of the beneficial effects of chronic total occlusion (CTO) recanalization has intrigued the interventional community for the last several years. A lot of work has already been done on “how to” treat the lesion. Now that there is plenty of knowledge, technological advances, and experience concerning the techniques, an additional scientific effort could investigate whether there are lesions that are about to alter outcomes if treated: a shift to “when to treat” the lesion.
Effects of CTO recanalization. There is a growing body of evidence showing that CTO recanalization could provide several benefits. Two meta-analyses have shown that CTO recanalization is accompanied by improvement in survival, stroke, coronary artery bypass grafting, and improvement of left ventricular (LV) function.1,2 There is also evidence that CTO recanalization might improve strong clinical endpoints as well as ventricular arrhythmias, quality of life, and functional capacity.3,4 However, fewer data are available from randomized studies.
There are four randomized studies investigating the effects of CTO recanalization. The EXPLORE trial did not find any overall benefit on cardiac function after 4 months of CTO percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) and concurrent CTO.5 However, there was a signal for cardiac function improvement depending on the location of CTO in favor of left anterior descending (LAD) coronary artery CTO. The study was not powered to detect differences in clinical endpoints such as death, MI, and stroke, and was affected by the recent STEMI, which could be a strong confounder when investigating the mechanisms of cardiac function recovery, making it difficult to extrapolate conclusions for other CTO-PCI scenarios.
The DECISION-CTO trial is the first randomized clinical trial to compare the strategy of optimal medical treatment (OMT) with CTO-PCI.6 The intention-to-treat analysis showed that OMT as an initial strategy was non-inferior to CTO-PCI with respect to the primary endpoint (composite of death, MI, stroke, or any revascularization at 3 years). However, OMT did not meet the statistical criteria for non-inferiority compared with PCI, and the trial was stopped early because of the slow enrollment. EuroCTO is another randomized study aimed to assess quality of life 12 months after CTO-PCI.7 CTO recanalization was accompanied by an improvement of health status as assessed by the Seattle Angina Questionnaire.
The recent REVASC8 randomized trial included 205 patients to assess whether CTO-PCI would improve segmental wall thickening of the ischemic LV territory as compared with OMT alone. No benefit was observed in LV contractility at 6 months after CTO-PCI, as assessed by cardiac magnetic resonance (CMR) imaging. CTO-PCI resulted in reduced major adverse events at 12 months driven by repeat intervention. It is important to mention that the baseline LV ejection fraction (LVEF) of the study population was normal (>50%), limiting the potential beneficial impact of revascularization on an ischemic ventricle, and also that there was no assessment of viability and ischemia burden of the LV, limiting the interpretation of the negative results of the study.
Ischemic cardiomyopathy resulting from ischemic LV territories might be a disease state to benefit from a successful CTO-PCI. In an observational study, Galassi et al presented a significant improvement of the LVEF by 43% (EF increased from 29% to 42%) in 66 patients with ischemic cardiomyopathy (baseline EF <35%) after successful CTO revascularization.9 Similarly, a CMR imaging study that included 29 patients with ischemic cardiomyopathy and CTO showed that successful CTO-PCI was accompanied by an increase in LVEF (from 31% to 38%) and by a decrease of LV end-systolic volume.10 Both studies provided evidence that revascularization of viable ischemic territories could induce reverse remodeling and systolic dysfunction improvement in patients with CTO and ischemic cardiomyopathy.
A subanalysis of 180 out of 302 patients from the EXPLORE trial with serial CMR imaging noted that regional systolic function of a CTO territory was improved.11 This improvement was noted mainly in the dysfunctional (but viable) segments and was associated with the development of the collateral circulation. In the same concept, previous smaller studies have shown that improvement of regional LV function after a CTO recanalization related to the viability and the extent of dysfunctional myocardium.12-14 Thus, according to current evidence, we could hypothesize that some indicative parameters for responders to a CTO recanalization therapy are the location of the CTO-PCI and the viability of the ischemic territory, indicating the role of the ischemic burden.
The FAME trial, based on physiology assessment, altered the way we treat coronary artery stenosis, to improve cardiovascular outcomes.15 Is there any physiologic-derived parameter that could cumulatively estimate the ischemic burden in a patient with a CTO?
Effect of CTO-PCI in exercise capacity. Two decades ago, Finci et al showed that patients who underwent a successful CTO-PCI had a functional benefit, in terms of exercise capacity during a stress test, compared to patients with unsuccessful CTO-PCI.16
There are two recent studies so far that have shown a significant improvement in exercise capacity after CTO-PCI, as objectively assessed by cardiopulmonary exercise test (CPET).17,18 More specifically, Abdullah et al17 enrolled 32 patients referred for CTO-PCI because of angina or symptoms of heart failure and finally assessed the 28 patients with successful CTO-PCI and clinically patent CTO target vessel at follow-up. From the 28 patients, the 25 patients who could undergo CPET at follow-up were finally evaluated. In this group of 25 patients with successful CTO revascularization, an increased maximum oxygen uptake (peak VO2) by 9% (P<.01) and oxygen uptake at anaerobic threshold (AT) by 9% (P=.06) were noted, which are both indicative of improvement in functional capacity after CTO-PCI. Improvement of AT probably supports an improved contractility of myocardium during exercise, delaying the anaerobic mechanism onset (this variable is independent of the patient’s effort and other causes of maximal exercise limitation), while improvement of peak VO2 might also be explained by prolonged exercise due to elimination of the angina. The improved functional capacity was accompanied by improvement of plasma brain natriuretic peptide levels, angina and heart failure symptoms, and quality of life parameters.
In agreement with this study, Mashayekhi et al18 investigated the role of CTO-PCI in 50 patients with a CTO as the only remaining target lesion. Patients underwent CPET 1 week before and 7 months after the CTO-PCI. Authors reported a 12% increase in peak VO2, a 28% increase in AT, and a 9% increase in oxygen pulse (supportive of reduction of the exercise-induced myocardial ischemia after the CTO-PCI).19 This interesting signal from these two elegant studies is also supported by another study that investigated the improvement of functional capacity, as assessed by 6-minute walk test (6MWT) at 6 months post CTO-PCI.20 Even though 6MWT is not a precise method to evaluate exercise capacity, the most interesting aspect of the study was that patients with higher ischemic scores presented a more pronounced improvement of functional capacity, implying a possible mechanism to identify the responders.
Dynamic tests: Role of cardiopulmonary exercise testing. Myocardial perfusion in a collateral-dependent myocardium (even dysfunctioning) can be normal or near normal at rest, while collateral flow reserve can be markedly blunted.21,22 Moreover, as known from the ischemic cascade, the more pronounced the stress level (heart rate x blood pressure), the more ischemia for a given stenosis. Studies until now have been focusing on the effects of CTO revascularization at rest, while ischemia and concomitant LV dysfunction manifest mainly during exercise, where ischemia logarithmically increases due to the inability of the collateral circulation to cover the increased demands.
Incremental exercise causes a rightward swift to the ischemia cascade (perfusion defect > diastolic dysfunction > regional wall-motion abnormalities > electrocardiographic changes > angina). Regional myocardial ischemia causes wall-motion abnormalities accompanied the following: hemodynamic changes; reduced stroke volume and cardiac output during exercise. Therefore, the increasing magnitude of ischemia during exercise diminishes/blunts the increasing rate of cardiac output during the progressively increased work rate (WR) of exercise (as in CPET), with a direct impact on CPET-derived parameters.
The physiologic effect of exercise-induced LV dysfunction is common to microvascular- and macrovascular-derived ischemia. CPET has the potential to globally identify the ischemia consequences irrespective of the underlying physiologic mechanism mediating the ischemia. Belardinelli et al19,23 have shown that the analysis of gas exchange during exercise can be used to identify decreased stroke volume during exercise and that CPET could detect the exercise-induced myocardial ischemia. More specifically, oxygen deficit of myocardium during exercise causes mechanical dysfunction, resulting in reduced stroke volume proportional to the progressively increasing workload. A compensative mechanism to maintain adequate peripheral perfusion to the exercising muscles is the up-regulation of the sympathetic nervous system that increases heart rate (HR) disproportionally higher. This link between oxygen kinetics and LV dysfunction during ischemia can be identified during CPET by oxygen kinetic parameters comparing the increased workload (ΔVO2/ΔWR, ΔHR/WR slopes).19,23,24 More specifically, CPET-derived parameters of exercise-induced decreased stroke volume because of myocardial dysfunction caused by ischemia can be the following: a reduced peak O2 pulse that gradually decreases with increasing WR; an abrupt decrease in ΔVO2/ΔWR slope; and steepening of HR-VO2 uptake slope.19,25,26 Generally, CPET parameters associated with ischemia are peak VO2, AT, O2 pulse, O2 pulse flattening duration, HR-VO2 uptake slope, and ΔVO2/ΔWR b-b´ slope.19 These parameters also supply valuable (qualitative and quantitative) information about the time onset and magnitude of ischemia.
The concept of monitoring CTO-PCI with CPET could be promising, considering the remarkable findings that successful CTO-PCI improves exercise capacity17,18 and that exercise-derived parameters from CPET have a predictive value for coronary artery disease.27 Future studies should investigate the role of CPET in assessing functional capacity and prognosis, as well as designating the responders of a CTO-PCI. The exercise physiology implementation in CTO recanalization might alter the outcomes by identifying the responders; this is a hypothesis that has to be tested.
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From the 1Unit of Cardiovascular Interventions, IRCCS San Raffaele Scientific Institute, Milan, Italy; 21st Critical Care Medicine Department, Cardiopulmonary Exercise Testing and Rehabilitation Laboratory, “Evangelismos” Hospital, National and Kapodistrian University of Athens, Athens, Greece; and the 3Interventional Cardiology Unit, GVM Care & Research Maria Cecilia Hospital, Cotignola, Italy.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted June 13, 2019, provisional acceptance given June 18, 2019, final version accepted June 24, 2019.
Address for correspondence: Georgios Tzanis, MD, PhD, Cardiopulmonary Exercise Testing and Rehabilitation Laboratory, “Evangelismos” Hospital, National and Kapodistrian University of Athens, Greece, Ypsilantoy 45-47, Athens, 106 76. Email: firstname.lastname@example.org