Heart failure (HF) is a complex syndrome characterized by impaired cardiac function, leading to inadequate tissue perfusion and subsequent multiorgan dysfunction. It is a major cause of morbidity and mortality worldwide, with an increasing prevalence and economic burden. Left ventricular systolic dysfunction (LVSD), often results from coronary artery disease (CAD) and contributes significantly to the progression and clinical manifestations of HF, while the presence of LVSD is one of the strongest predictors of adverse clinical events among patients affected by CAD [1]. Despite advancements in pharmacological and device-based therapies, patients with LVSD continue to face substantial challenges and poorer long-term outcomes.

Coronary artery chronic total occlusions (CTOs), defined as complete occlusions of a coronary artery for at least three months, are a common finding in patients with CAD and LVSD, and their presence is associated with a worse prognosis [2, 3]. CTOs pose a unique therapeutic dilemma since traditional revascularization strategies, such as percutaneous coronary intervention (PCI), may be challenging owing to technical difficulties, a perceived lack of benefit [4, 5], and a possible higher incidence of stent failure, compared to non-CTO PCIs [6]. Consequently, patients with CTOs often receive medical management alone [7, 8, 9, 10], potentially limiting their prognosis and exacerbating HF symptoms.

Over the past decade, advances in interventional techniques, tools, and operator expertise have improved the success rates and safety profiles of CTO PCIs. Consequently, there has been a growing interest in exploring the potential benefits of CTO revascularization in patients with LVSD. Previous studies in this population [11, 12, 13] have focused on short-term procedural success, cardiovascular mortality, myocardial infarction, and angina relief; however, the long-term impacts of CTO PCIs on heart failure-related outcomes in this specific patient population remain largely unknown.

Understanding the effects of CTO PCI on heart failure-related outcomes in patients with LVSD is of paramount importance. Successful revascularization of CTOs has the potential to alleviate myocardial ischemia, improve left ventricular function, and subsequently, enhance HF symptoms and prognoses. However, the risks associated with CTO PCIs, including procedural complications, contrast-induced nephropathy, and potential exacerbation of HF, need to be carefully weighed against the expected benefits.

Therefore, the objective of this study was to examine the success rate and complication rate of PCIs for CTOs in patients with an LV ejection fraction $\le$40% at baseline. We also aimed to explore the clinical outcomes during the follow-up of this cohort of patients, based on the success or failure of the CTO PCI, particularly, regarding heart failure-related clinical events, such as heart failure hospitalization (HFH), occurrence of atrial fibrillation (AF), and worsening of renal function (WRF).

In this analysis, from a prospective multicenter registry of patients with reduced LV function, we showed that: (1) CTO PCI is a procedure with a high success rate (82.5%), which can be performed with an acceptable number of complications, even in patients with higher baseline risks because of reduced LV ejection fraction(s); (2) at a median follow-up of 23 months, patients in the successful CTO PCI group had a lower risk of HFH compared to patients in the unsuccessful CTO PCI group, although no significance was observed in terms of WRF and AF; (3) in the multivariate analysis, successful CTO PCI was an independent predictor of reduced risk of HFH together with a higher eGFR, whereas prior stroke and diabetes were independent predictors of a higher risk of HFH.

Severe LVSD due to ischemic heart disease is associated with high morbidity, more frequent hospitalizations for heart failure, and deterioration of renal function, which have significant consequences on the prognosis and quality of life for patients. Previous registries have shown that a significant proportion of patients with ischemic LVSD have at least one CTO, and these patients have a higher frequency of prior MI, a higher prevalence of diabetes, and a higher percentage of triple vessel disease [2]. Collectively, these data suggest that patients with LVSD and at least one CTO have a very high risk of morbidity and mortality. In our study, at a median follow-up duration of 23 months, we observed overall and cardiovascular mortality rates consistent with previously published data, whilst 16% of patients were hospitalized for heart failure and 17.7% of patients experienced significant WRF, indicating the high-risk profile of these patients (the 2-year rates of HFH and WRF in the Enalapril group of the PARADIGM-HF study were 15.6% and 2.6%, respectively) [15].

Regarding the comparison between the successful and unsuccessful CTO PCI groups, patients in the unsuccessful CTO PCI group had more adverse baseline characteristics, both clinical and angiographic, compared to patients in the successful CTO PCI group. This difference in angiographic characteristics was expected since the J-CTO score, with its variables, is a recognized and widely used predictor of successful antegrade crossing within a short time and, indirectly, of CTO PCI success or failure [14]. The unsuccessful CTO PCI group also had a higher prevalence of CKD alongside previous HFH and CRT implantation. The higher CKD rate is not unexpected because it is generally associated with older and more challenging CTOs and a higher burden of calcifications within the occlusion. The higher prevalence of these factors in the unsuccessful PCI group suggests that these patients were possibly more complex and potentially characterized by a more advanced stage of disease than the patients in the successful PCI group. This could represent a possible confounding factor, although none of these variables were identified as independent predictors of the outcome during the multivariate analysis.

In this study, no significant differences were documented between the successful and unsuccessful CTO PCI groups in terms of rates of mortality, MI, target vessel failure, and stroke during the follow-up. For cardiovascular death, a trend toward a better outcome in the successful PCI group was clearly observed but it did not reach statistical significance. Other previously published larger registries [12, 18] have documented a reduction in mortality after successful CTO PCI in patients with LVSD, yet these data have never been explored in a specific randomized clinical trial.

Regarding clinical events related to heart failure, successful CTO PCI was associated with a reduced risk of HFH compared to unsuccessful CTO PCI, although there was no significant difference in terms of WRF and AF. This observation is both interesting and intriguing. However, since it was only formed from a registry with a small number of patients, currently, it should be considered only as hypothesis generating. Other registries that have studied CTO PCI in patients with LVSD have documented a prognostic benefit in terms of overall or cardiovascular mortalities but without an effect on MIs or major adverse cardiovascular events (MACE) [12, 18]. Therefore, it is possible that, at least in part, the prognostic benefit results from the improved heart failure clinical status of the patients. Indeed, during the follow-up, we observed improvements in NYHA and CCS classes and a slight improvement in ejection fraction. These improvements were consistent in both patients with successful CTO PCI and those with unsuccessful CTO PCI. Moreover, they could be explained by the positive effect of optimal medical therapy for heart failure, the adherence to which was optimal either at the time of recruitment or during the follow-up assessment. The number of patients in our study was not sufficient to conduct a reliable statistical analysis on further echocardiographic characteristics (diastolic function, filling pressures, mitral and tricuspid regurgitation, and right ventricular function) but it is known that ischemia is an important cause of diastolic dysfunction. This could be the underlying pathophysiological mechanism involved in the reduction of HFH. Hypothetically, these lower rates of HFH that were observed in the patients with LVSD could result from even a slight reduction in the extent of ischemic territory since this could lead to a limited improvement in systolic function. Moreover, it could also lead to an improvement in diastolic function, a reduction in filling pressures, and, consequently, in mitral regurgitation and pulmonary pressures, alongside an improvement in right ventricular function. However, this hypothesis is purely speculative and requires confirmation in dedicated studies using a larger cohort.

In the multivariate analysis of clinical events, successful CTO PCI and higher eGFR remained favorably associated with a lower risk of HFH during the follow-up. Conversely, a previous stroke and diabetes were associated with an increased risk of HFH. No other factors were independently associated with a reduction or increase in the risk of HFH during the follow-up period.

CTO-PCI is a procedure with a high success rate and acceptable complication rate in patients with LVSD and an ejection fraction $\le$40%. In this cohort of patients, successful CTO PCI was associated with a reduced risk of HFH during the follow-up. Future studies with a larger patient cohort and longer follow-ups are needed to confirm these findings and further evaluate the benefits of CTO PCI in patients with LVSD.

The results from this multicenter registry are observational and hypothesis-generating. We used patients with unsuccessful CTO PCIs as a control group to understand the effect of CTO PCI. Although these patients have very similar characteristics compared to patients with successful CTO PCIs, other confounding variables may still negatively affect the comparison (e.g., radiation exposure, contrast agent volume, and post-procedural hospitalization). The patients in the unsuccessful PCI group were possibly more complex than the patients in the successful PCI group (higher prevalence of prior HFH, CKD, and CRT implantation). Even though these were not identified as independent predictors of the outcome, they could still represent potential confounding factors.

Furthermore, the high success rate of CTO PCIs significantly reduced the number of patients in the unsuccessful CTO PCI group, thereby reducing the size of the control group.

Finally, the percentage of usage of AWE in comparison to ADR, RWE, and RDR appears higher than in contemporary practice. One might speculate that a potential reason is a mid-complexity range of the CTO lesions (average J-CTO score of 2.11) combined with the operator preferences being to avoid retrograde approaches to reduce the risk of donor vessel injury/ischemia in the setting of important LVSDs. Therefore, more prolonged antegrade attempts are possibly performed.

The authors do not wish to share the complete dataset because of ongoing research on the same dataset.

PL and JB designed the research study. PL, MV, EP, and GC performed the research. KM, DC, CZ CD, PA, and JD provided help and advice on the research and manuscript. LM analyzed the data. PL and JB wrote the manuscript. All authours contributed to editorial changes in the manuscript. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work.

The CTO registries were approved by the local ethics committees and all patients provided written informed consent. The names for of the ethics committees are those of UZ Leuven (Ethische Commissie onderzoek UZ / KU Leuven, S57285), ZOL Genk (EC number is 13072016, Comité Medisch Ethiek ZOL Genk), and ZNA Antwerp (EC number is 4771, Commissie voor Medische Ethiek ZNA).

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.