Characteristics of Wellens' Syndrome in the Current PCI Era: A Single-Center Retrospective Study

Objectives The goal of this retrospective study was to reveal the prevalence, angiographic characteristics, clinical presentation, and long-term outcomes of non-ST-segment elevation myocardial infarction (NSTEMI) patients with Wellens' syndrome. Background Procedural results for percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) have improved in recent years. However, there is still a paucity of available clinical trial data for Wellens' syndrome even though it is a well-known high-risk ACS. Methods Among a total of 3528 patients with ACS who underwent angioplasty from 2017 to 2019 at the Cardiovascular Center of Beijing Friendship Hospital, 476 NSTEMI patients with culprit left anterior descending (LAD) vessels were enrolled in this study. According to electrocardiographic criteria of Wellens' syndrome, the patients were divided into a Wellens group (n = 138) and a non-Wellens group (n = 338). The primary endpoint was cardiac death; the secondary endpoints were main adverse cardiovascular and cerebrovascular events (MACCEs), a composite of all-cause death, cardiac death, heart failure, target lesion revascularization, recurrent myocardial infarction, and stroke. All of the medical and follow-up data were obtained from our institutional database. Results The incidence of Wellens' syndrome in all ACS patients was 5.7% (200 of 3528). Among the 200 patients with Wellens' syndrome, 138 had NSTEMI, for a proportion of 69%. There was a significant decrease in the percentage of preexisting coronary heart disease (CHD), prior myocardial infarction, and previous PCI (P < 0.05) in the Wellens group compared with the non-Wellens group. On coronary angiography, single-vessel lesions were more common in the Wellens group (11.6% vs. 5.3%, P=0.016), and almost all (97.1%) of these patients received drug-eluting stents. Notably, the Wellens group had a higher proportion of early PCI than the non-Wellens group (71% vs. 61.2%, P=0.044). At 24 months, there was no statistically significant difference in cardiac death (P=0.111) between the two groups, but the MACCEs were comparable (Wellens: 5.1% vs. non-Wellens: 13.3%, P=0.009). Age ≥65 years was the largest independent risk factor for adverse prognosis. Conclusions With early recognition and aggressive intervention, Wellens' syndrome is no longer a risk factor for adverse prognosis in patients with NSTEMI in the current PCI era.


Introduction
Acute coronary syndrome (ACS) is one of the leading causes of acute chest pain, requiring emergency care and eventual hospitalization [1][2][3]. An accurate assessment of the clinical setting is needed to ensure that the patient is correctly managed. Tis includes a good anamnesis, physical examination, and electrocardiographic (ECG) and cardiac biomarker evaluation. However, within the spectrum of ACS, subtle presentations cannot be overlooked. Wellens' syndrome is one such example, which in ACS patients is a catastrophic event often accompanied by extensive anterior myocardial infarction and high mortality rates. Wellens' syndrome, frst described by Wellens and his group in 1982 [4], is the characteristic ECG pattern of T waves in the precordial leads that are associated with critical stenosis in the left anterior descending (LAD) artery. Early recognition and appropriate intervention for this syndrome carry signifcant diagnostic and prognostic consequences [5]. According to the Fourth Universal Defnition of myocardial infarction [6], absence of ST-elevation in the precordial leads and the symmetrical and often deep (>2 mm) T wave inversions in the anterior precordial leads are an early sign that may precede the elevation of the ST-segment [7]. Tus, this syndrome was thought to be an acute ST-segment elevation myocardial infarction (STEMI) equivalent [8].
In previous studies [4,9], Wellens' syndrome mainly presented with unstable angina pectoris (UAP). Actually, it should be noted that with the implementation of cardiac troponin (cTn) and high-sensitivity cardiac troponin (hs-cTn) assays, the diagnosis has been revolutionized [10]. Among the patients with Wellens' syndrome, the incidence of unstable angina is decreasing, and the diagnosis of non-ST-segment elevation myocardial infarction (NSTEMI) is increasing. Prompt identifcation of patients with Wellens' syndrome is critical. Tese individuals constitute a special cohort with their own clinical characteristics, which may afect the outcomes in this population. However, only limited data have been published regarding this syndrome, in which the authors reported mostly sporadic cases and clinical experience. Sparse studies of large sample sizes are available on patients with Wellens' syndrome. Updated information on the incidence, risk factors, angiographic fndings, and prognosis of this subset of patients should be taken into consideration when taking care of these patients. Te goal of this retrospective control study was therefore to investigate the risk factor profle, angiographic and clinical characteristics, and long-term outcomes of patients with Wellens' syndrome vs. other NSTEMI patients with culprit LAD vessels who were admitted to Beijing Friendship Hospital in China between 2017 and 2019.

Study Design and Participants.
From January 2017 to December 2019, coronary angioplasty was performed in 3528 consecutive ACS patients at Cardiovascular Center, Beijing Friendship Hospital, and a total of 2621 patients with culprit LAD vessels were enrolled in this study. Te medical retrospective data were collected and recorded in CBD-BANK (Cardiovascular Center Beijing Friendship Hospital Database Bank) supported by the DHC Software system (Dong Hua Software Co., Ltd). Both 460 STEMI patients and 1651 UAP patients were excluded. In addition, 34 patients were lost to follow-up. Finally, a total of 476 NSTEMI patients were included in the fnal analysis, all of whom were shown angiographically to have signifcant LAD stenosis. Among these patients, 138 patients met the ECG criteria of Wellens' syndrome and served as the Wellens group. Te remaining 338 patients were assigned to the non-Wellens group. A fowchart of patient enrollment is shown in Figure 1.
Standard 12-lead ECGs were routinely obtained from all patients at the time of presentation to the emergency department and were reviewed by two independent cardiologists. Additional ECGs were measured during and after new episodes of chest pain. According to ECG pattern and angiography, the criteria for Wellens' syndrome are as follows [11,12]: (a) symmetric and deeply inverted T waves, in leads V2 and V3, occasionally in leads V1, V4, V5, and V6, or biphasic T waves in leads V2 and V3, (b) isoelectric or minimally elevated (1 mm) ST segment, (c) no pathological precordial Q waves, (d) no loss of precordial R waves, (e) history of angina, and (f ) angiographically signifcant LAD stenosis.

Data Collection and Follow-Up.
Baseline data, including demographic information, initial clinical presentation (waist circumference and blood pressure at admission), cardiovascular risk factors, and past medical history, such as hypertension, diabetes, dyslipidaemia, chronic kidney disease (CKD), peripheral arterial disease (PAD), heart failure (HF), smoking, preexisting coronary heart disease (CHD), and previous PCI, were collected from CBD-BANK and then analysed. Laboratory examination results including haemoglobin A1c (HbA1c), creatinine, and lipid spectra were collected from CBD-BANK and then analysed. Echocardiography (ECHO) was performed (Philips IE33) for routine parameters, such as left ventricular ejection fraction (LVEF) and end-diastolic dimension (EDD), at baseline. Te characteristics of coronary artery lesions and stent implantation information were evaluated by angiographic and PCI procedures and are presented in the medical documents.
After discharge, all patients were followed up for at least 24 months. Regular follow-up was conducted by clinic visits or phone interviews every 1-3 months. All information was recorded in the data bank.

Primary and Secondary Endpoints.
Te primary endpoint for this analysis was cardiac death, defned as previously reported, including death from myocardial infarction, heart failure, or arrhythmia, as well as unexplained sudden death [13]. A composite of major adverse cardiovascular and cerebrovascular events (MACCEs), including all-cause death, cardiac death, heart failure, target lesion revascularization, recurrent myocardial infarction, and stroke during follow-up, was defned as the secondary study endpoint. Clinically driven target lesion revascularization was defned as any repeat percutaneous intervention of the target lesion or bypass surgery of the target vessel that was performed for restenosis or other complication of the target lesion [14]. Recurrent myocardial infarction was defned by the Fourth Universal Defnition [6]. All MACCEs were confrmed by two separate cardiologists simultaneously. In addition, readmissions due to cardiogenic causes such as hypertension, angina pectoris, myocardial infarction, arrhythmia, and cardiac insufciency were included in the clinical outcomes.
All procedures performed in studies involving human participants were in accordance with the Institutional Ethics Committee of the Beijing Friendship Hospital afliated with Capital Medical University (2021-P2-096-01) and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Tis retrospective study was considered minimal risk by the Institutional Ethics Committee; therefore, formal consent was not needed.

Statistical Analysis.
Continuous variables are expressed as mean ± standard deviation or median with interquartile range, and one-way analysis of variance was used to compare diferences between continuous variables. Categorical variables are expressed as percentages and were analysed using Pearson's χ 2 test or Fisher's exact test of variance. Te cumulative incidence was estimated by the Kaplan-Meier method, and diferences between groups were assessed by the log-rank test. A two-sided P value <0.05 was considered statistically signifcant.
Cox regression was used to estimate the relative risk among groups of patients. All factors showing signifcance in the univariate analysis (P < 0.05) or an indicator clinically considered important for the outcome was then examined by multivariate analysis. All analyses were performed by using SPSS (version 25.0, Chicago, IL, USA); Kaplan-Meier survival curves were generated with GraphPad Prism software (version 5; GraphPad, Inc., San Diego, CA) [15].

Predictors of Survival.
Considering all patients, a multivariable Cox regression analysis (

Discussion
Wellens' syndrome, also known as LAD coronary T-wave syndrome or "widow maker," is observed in a subset of patients who often present with chest pain and are found to have specifc precordial T-wave changes on ECG. Its prevalence is estimated to be approximately 10-15% of acute coronary syndrome (ACS) cases. Te natural course of this pattern is potentially dangerous, with a high incidence of recurrent symptoms. It can rapidly progress to an anterior wall myocardial infarction if left untreated, causing catastrophic outcomes due to lesions in the proximal LAD artery. In Wellens' initial study group, of 145 patients admitted for UAP, 9% had the typical pattern upon presentation, with a further 9% developing T-wave changes within 24 h [9]. If they were treated medically without revascularization, approximately seventy-fve percent of these patients developed anterior myocardial infarction within 1 week, despite the temporary relief of symptoms. Generally, Wellens' T-wave changes mainly occur during a pain-free interval when other evidence of ischaemia or infarction may be absent [16]. So, the Wellens sign was often formerly overlooked at hospital visits. However, as awareness of this syndrome has increased, early recognition and aggressive intervention have become the primary choice for physicians. For Wellens' syndrome, cardiac biomarkers can be falsely reassuring, as they are typically normal or only minimally elevated. Previous data suggest that only 12% of patients with this syndrome have elevated cardiac biomarker levels, and the levels are always less than twice the upper limit of normal [9]. However, among 2127 NSTE-ACS patients with culprit LAD vessels in our study, 200 patients (9.4%) presented with Wellens' syndrome, including 138 patients with NSTEMI and 62 patients with UAP. Unlike prior studies, our research demonstrated that Wellens' syndrome more often manifests as NSTEMI than UAP (69% vs. 31%). Tis increased incidence rate of NSTEMI could be due to the adoption of the Fourth Universal Defnition of Myocardial Infarction, which was based on elevated cardiac troponin. On the other hand, the former type of patient is usually pain-free at the time of presentation, and his or her cardiac biomarker concentration returns to the normal reference range. However, most patients will immediately seek medical attention for chest pain, and in such cases, a signifcant rise in cardiac biomarkers is frequently detected.
Te mechanism of Wellens' syndrome remains unclear. In Wellens' sign, the ST segment and the frst half of the T wave are essentially normal. T-wave inversion is generally seen hours or days after myocardial ischaemic pain subsides. During pain, T waves are usually upright with STelevation or ST depression [17]. Te T-wave change is not a sign of acute coronary occlusion but rather a sign of coronary artery reperfusion that is very likely to reocclude [18,19]. Tere is also a view that the changes in the ECG account for the reperfusion of the ischaemic myocardium due to the alleviation of spasm of the proximal LAD artery [20,21]. Other views, such as the lack of adaptive response, remain to be discussed. Multiple cardiovascular risk factors are common in patients with Wellens' syndrome, and the majority of these patients are revealed to have at least one typical cardiovascular risk factor. Our study found that the proportion of DM was much lower in Wellens group, but there was no signifcant diference in other traditional risk factors between the two groups. However, in terms of past medical history, Wellens patients were much less likely than non-Wellens patients to have a history of CHD, MI, and previous PCI at admission, which reveals that Wellens' syndrome tends to occur in patients with new-onset cardiovascular disease.
Te angiographic and procedural characteristics of patients with Wellens' syndrome may difer from the presentation in other NSTEMI patients. Compared with the non-Wellens group, the Wellens group had fewer LM Values are expressed as n (%), mean ± SD, or median with interquartile range. FMC to B, frst medical contact to balloon. Bold values indicate that the diference is statistically signifcant (P < 0.05).   Emergency Medicine International patients and more single-vessel disease, with more than twice as many single-vessel patients. More Wellens than non-Wellens patients were treated with drug-eluting stents for revascularization, and fewer Wellens patients were treated with balloons only. Tis discrepancy may, to a large degree, be explained by a higher percentage of proximal and middle LAD lesions in Wellens patients. Balloon angioplasty, including both plain-old balloon angioplasty and drug-coated balloon angioplasty, is not appropriate for these critical sites [22,23].
Te prognosis of ACS patients depends on the earliest recognition of the symptoms along with subtle clues on the ECG, which would lead the physician to stratify the patients into low-risk, medium-risk, or high-risk categories and thus to act accordingly. Stabilization of the plaque by medical management in low-risk patients or revascularization by coronary angioplasty mostly in medium-risk/high-risk patients is the primary requirement. As a known high-risk group, Wellens patients had a greater proportion of early PCI than did non-Wellens patients in our study. Tese data indicate that cardiologists are more inclined to apply aggressive interventions for patients with Wellens' syndrome in clinical practice.
As previously discussed, patients with Wellens' syndrome have a substantial risk for future cardiovascular events, including extensive anterior wall infarction, malignant arrhythmias, cardiogenic shock, and sudden death. Somewhat unexpectedly, there was no statistically signifcant diference in cardiac death between the two groups during the follow-up period. Moreover, the 2-year incidence of MACCEs was much lower in the Wellens group than in the non-Wellens group (5.1% vs. 13.3%, P � 0.009). Tese results support the view that patients with Wellens' syndrome may have a favorable prognosis in the long run. A possible explanation is that this low incidence was achieved by our appropriate management, which aggressively treated Wellens patients with urgent angiography and intervention. As mentioned earlier, the proportion of early PCI was higher in the Wellens group in our study. Tis highlights the importance of timely identifcation of Wellens' syndrome and aggressive invasive strategies in this group of patients. Most patients, when identifed early and taken for cardiac catheterization, do well after appropriate intervention. Regarding the strength of the improvement in medical procedures, a small number of Wellens patients (8.7%) were readmitted within 2 years after  PCI, which was much fewer than those from the non-Wellens group (23.1%, P < 0.001). Another possible explanation for the lower cardiac readmission incidence is that more patients with Wellens' syndrome have single-vessel coronary artery disease, which allows them to achieve complete revascularization during the frst hospitalization. Recent randomized trials and meta-analyses have demonstrated the prognostic beneft of complete revascularization in NSTEMI patients by reducing unplanned repeat revascularization, allcause mortality, cardiac mortality, and recurrent infarction [24][25][26]. It is worth mentioning that age ≥65 years was the largest independent risk factor for cardiac death and MACCEs in this study, while Wellens' syndrome was a protective factor against adverse prognosis. Early PCI is currently the preferred treatment for patients with high-risk NSTE-ACS. In our real application, once a patient was diagnosed with Wellens' syndrome and enzyme elevation, he or she was admitted through the fasttrack process. After an initial evaluation, the patient would undergo cardiac catheterization as soon as possible. We presumed that an early invasive strategy could attenuate the risk of MACCE and avoid long-term adverse outcomes in patients with Wellens' syndrome.

Limitations
Various limitations of the current analysis should be acknowledged. First, it was an observational study with potential bias and unmeasured confounding factors of nonrandomized analyses. Second, we only included patients who underwent coronary angioplasty, and thus the generalizability of our fndings is limited. Moreover, the choice of therapeutic strategy refected the convention and tendency of our single center, which may have afected the objectivity of the conclusions. Further prospective multicenter studies are needed to validate our fndings.

Conclusions
First, the present study revealed that the incidence of Wellens' syndrome can reach up to 5.7% as assessed by coronary arteriography in clinical practice and 9.4% in NSTE-ACS patients with culprit LAD vessels. Second, Wellens' syndrome more often occurs in people with new-onset CHD, with NSTEMI having become the predominant clinical manifestation in these patients. Tird, single-vessel coronary artery disease is more common in patients with Wellens' syndrome than in other NSTEMI patients. Although still regarded as an ominous omen, Wellens' syndrome is no longer a risk factor for adverse prognosis in the current PCI era.

Data Availability
Access to the data is restricted because of third-party rights and patient privacy.

Conflicts of Interest
Te authors declare that they have no conficts of interest.