Wellens Syndrome: Single Centre Study and Literature Review

Wellens syndrome (WS) is correlated with a critical left anterior descendent artery (LAD) stenosis due to acute plaque rupture resulting in temporary obstruction of the blood flow, subsequently followed by spontaneous reperfusion before extensive myocardial infarction (MI) develops [1]. This sequence of events initially determines a minimal ST segment elevation on the ECG, then ST segment resolution and T wave inversion (biphasic or negative) once the blood flow is restored [2, 3]. The electrocardiographic and angiographic picture of Wellens syndrome suggests an “abortive” form of ST segment elevation myocardial infarction (STEMI) [4].

In 1982 Chris de Zwaan and Hein J.J Wellens described in patients with unstable angina (UA) the eponymous ECG pattern Wellens’ sign, identifying a subgroup of patients with unfavorable outcomes on conservative management and critical LAD stenosis on coronary angiography [5]. Wellens syndrome was characterised 20 years later, when Rinehardt J et al introduced a set of diagnostic criteria: –

symmetric and deeply inverted T waves in leads V2 and V3 (occasionally in leads V1, V4, V5, and V6) – also known as type B,

We conducted a prospective analysis of 64 consecutive patients with WS who underwent coronary angiography, and we compared them with an age- and sex-matched cohort of patients with non-ST segment elevation acute coronary syndrome (NSTEACS) who underwent coronary angiography within the same period of time.

Inclusion criteria were: chest pain or equivalent; ischemic changes on ECG (horizontal or down-sloping ST-segment depression ≥ 0.05 mV or +/− biphasic/negative T-waves in two or more contiguous leads) or absence of ST-T changes on ECG; and coronary angiography performed during the reference hospitalization. Wellens syndrome has been defined as: chest pain or equivalents; +/− biphasic or negative T-waves in two or more contiguous leads; and normal myocardial necrosis enzymes (CK, CK-MB). Exclusion criteria were: ST segment elevation on ECG; pathological Q waves in leads V2 sand V3; left ventricular hypertrophy; complete left bundle branch block; ventricular paced rhythm; and alternative diagnoses (acute myocarditis, acute pericarditis, acute pulmonary embolism, hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, central nervous system injury). We screened 483 patients, of whom 127 were included in the final analysis.

Patients’ follow-up visits were at one month and at six months from the index event. The primary endpoints of our study were the rate of cardiovascular rehospitalizations, the rate of ischaemic recurrences, the rate of subsequent or recurrent revascularization, and the rate of mortality at the end of the follow-up period.

The mean age of the study group was 62.38 years. The proportion of men was 67%. Baseline cardiovascular risk profile was similar across the 2 groups, except for a larger proportion of patients with diabetes mellitus (DM) in the control group (65,1% in the control group vs 48,4% in the WS group, p = 0,07).

The ECG at presentation showed mostly T-wave anomalies in patients with WS and ST segment depression in patients in the control group. The rest of the patients in the WS group developed the typical ECG pattern during hospitalization. Within the WS group, the prevalence of type A was 43,9%, the rest accounting for type B.

High sensitive troponin I had significantly higher values in the control group, both at presentation (321,62 ng/l in the WS group vs 1567,39 ng/l in the control group, p = 0,049) and at peak (553,91 ng/l in the WS group vs 4029,12 ng/l in the control group, p = 0,002), reflecting a larger area of myocardial necrosis. In contrast, the NT-proBNP value did not differ between the two groups (1204,43 pg/ml in the WS group vs 1286,84 pg/ml in the control group, p = 0,808), meaning that the severity of heart failure was similar.

At cardiac ultrasound, the patients in the WS group exhibited wall motion abnormalities mostly in the anterior segments (59,4% vs 33,3% in the control group), and those in the control group had wall motion abnormalities mostly in the inferior segments (20,6% vs 12,5% in the WS group), global p=0,03. The severity of mitral regurgitation (MR) was similar across the two groups (global p = 0,565). However, there were more patients with mild MR in the Wellens group (6,3% vs 3,2%) and more patients with severe MR in the control group (6,3% față de 3,2%). The systolic left ventricular (LV) performance did not differ between the two groups; the mean LV ejection fraction (EF) was 47,48% in the WS group and 48,19% in the control group (p = 0,63), and the mean LV wall motion score index (LVWMSi) was 1,34 in the WS group and 1,27 in the control group (p = 0,272).

At coronary angiography, most of the patients in the WS group had single-vessel disease, with a statistically significant difference from the control group (46,9% vs 20,6%, p = 0,02), while the patients in the control group had mostly three-vessel disease (34,9% vs 10,%, p = 0,02). The proportion of patients with two-vessel disease was similar between the two groups (21,9% in the WS group vs 23,8% in the control group).

Regarding the culprit artery, the proportion of left main (LM) and LAD disease was significantly higher in the WS group compared to the control group (15,3% vs 9,8%, p = 0,002, for LM disease; 66,1% vs 44,3%, p = 0,002, for LAD disease). Although WS was classically described in the anterior territory, we report a significantly higher proportion of RCA as the culprit vessel in the WS group (13,6% vs 6,5%). In the control group, there were significantly more cases that had the circumflex artery (Cx) as culprit vessel (27,9% vs 1,7%, p = 0,002).

The overall treatment indication did not differ between the two groups (global p = 0,09), although the patients in the control group had a slightly higher proportion of surgical indication. 65.62% of the patients in the WS group and 53.96% of patients in the control group were treated by ad-hoc PCI, achieving complete interventional revascularization in 88,1% of patients in the WS group and in a similar proportion of patients in the control group (81,1%, p = 0,53).

Within six months of follow-up, the rate of cardiovascular rehospitalizations was higher across the control group (41,9% vs. 21,9%, p = 0,016). The rate of ischaemic recurrences was similar between the two groups (18% in the WS group vs 22,2% in the control group, p = 0,56), as were other interventional end-points: subsequent interventional revascularization regardless of the treatment at the beginning of the study (14,8% in the WS group vs 17,5% in the control group, p = 0,31), repeat interventional revascularization in patients treated by PCI during the index hospitalization (11,9% in the WS group vs 17,6% in the control group, p = 0,52), and repeat target vessel revascularization (TVR) (4,9% in the WS group vs 5,9% in the control group, p = 1). At the end of the six-month follow-up period there was no significant difference with respect to global mortality (6,3% in the WS group vs 7.9% in the control group, p = 0.74).

The prevalence and prognostic implications of Wellens’ sign in a contemporary cohort of patients with acute coronary syndromes (ACS) have not yet been elucidated [7]. Systematic review of available data in the literature showed plenty of case reports of WS with particular etiology (in-stent neoatherosclerosis [8], noncritical plaque coronary artery vasospasm [3, 9], coronary vasospasm due to illicit drugs use [10], spontaneous coronary artery dissection [11], myocardial bridging [12], coronary fistulae [13], stress cardiomyopathy [14]), or atypical ECG and angiographic localization (inferior [15] or posterior [16] localization), but very few studies. The inventory of the studies published so far in are shown in Table 1. The main caveats and limitations of these studies are: –

Limited sample size. This is partly explained by the rarity of this pathology. The study with the longest period of enrollment (five and a half years) gathered 180 patients [17].

The prevalence of Wellens’ sign in patients with UA in the first study of de Zwaan and Wellens was 18% (26 of 145 patients) [5]. In their subsequent study, the prevalence was 14% (180 of 1260 patients) [17]. Another study conducted in the same period identified a prevalence of 40% of new negative T waves in patients with UA, with no clear mention if patients with biphasic T waves were also included [19]. We emphasize the fact that these studies were made before the widespread use of cardiac biomarkers such as troponins [7]. Thus, we can speculate that some of the patients included in these pioneer studies would have been diagnosed with non-ST segment elevation myocardial infarction (NSTEMI) if troponin dosing had been available [7]. The first study in the era of troponin dosing (2007) was conducted by a group of Norwegian researchers, who found that Wellens’ sign had a prevalence of 22% in a group of patients with NSTEACS [22]. The studies published after 2015 reported different levels of prevalence depending on the study population (Wellens’ sign or Wellens syndrome) and the reference population (UA or NSTEMI or NSTEACS). The first study from Kobayashi et al., published in 2015, included 424 consecutive patients with NSTEMI who underwent coronary angiography within 5 days of admission, of which 18 patients (4,2%) had Wellens’ sign [20]. The second study belonging to the same group of researchers, published in 2019, included 274 patients with NSTEMI who underwent coronary angiography and found a prevalence of 8% (24 patients) with Wellens’ sign [23]. Other studies reported either the prevalence of WS from a group of patients with UA [24], or the prevalence of Wellens’ sign from a group of consecutive patients who underwent urgent or elective coronary angioplasty [25]. We highlight the fact that these studies included an unselected population of patients with UA/NSTEMI/NSTEACS. Instead, the design of the current study involves the comparison of patients with WS with a selected control group, age and sex matched, therefore the prevalence of WS could not be determined.

According to the initial description, the most frequent ECG type is type B, identified in 75% of the cases [5]. This dominance of type B is also reported in the subsequent studies, but with a higher proportion of type A, accounting for one third of cases. In Liu's study 34,3% of the patients presented type A and the rest presented type B [24]. In our study, the distribution of the ECG type of WS was almost equivalent (43,9% type A and 56,1% type B).

Regarding the culprit artery, our study showed that in the WS group it was mainly LAD (66,1% vs 44,3%), followed by LM (15,3% vs 9,8%), the distribution of the culprit lesion being significantly different between the two groups (global p= 0,002). In the first study of de Zwaan and Wellens, of 11 patients with WS who underwent coronary angiography, 10 had a ≥ 90% LAD stenosis [5]. In the extended study of the same researchers, 180 patients benefited of coronary angiography and all of them had LAD culprit lesions; none of the patients had the LM as culprit artery [17]. In another study, 61% of the patients with Wellens’ sign had a ≥ 50% stenosis of LAD as culprit lesion (85% of the patients with type A WS and 44% of the patients with type B WS), resulting a sensitivity (Sen) of 76%, a specificity (Spe) of 89%, a positive predictive value (PPV) of 61% and a negative predictive value (NPV) of 94% of Wellens’ sign for the detection of proximal LAD stenosis in patients with NSTEACS [22]. In the first study of Kobayashi et al., patients with Wellens’ sign had a higher prevalence of LAD culprit lesion compared to the control group in patients with NSTEMI (50% vs 22,9%, p = 0,008) [20]. In his subsequent study, 66,7% of the patients with Wellens’ sign had LAD culprit artery, similarly to in our study, and the Sen and Spe of Wellens’ sign for predicting LAD culprit lesion were 24,6% and 96,2% respectively [23]. In our study, the Sen, the Spe, the PPV and the NPV of WS in the anterior leads for predicting a significant LAD/LM stenosis were 94,12%, 38,46%, 85,71% and 62,5%, respectively.

Although WS has been classically described in the anterior leads, in our study we observed a higher proportion of RCA as culprit artery in the WS group (13,6% vs 6,5%, p = 0,002) [7]. In our study, the predictive value of WS in the inferior leads for detecting a significant lesion of the RCA was correlated by a Sen of 25%, a Spe of 100%, a PPV of 100% and a NPV of 90,62%. Liu and collaborators studied the correlation between WS in DII, DIII and aVF leads and a significant stenosis of the dominant artery that supplies the inferior LV wall. Of the 20 patients that had a Wellens’ sign in the inferior leads (7,3%), 16 had a ≥ stenosis of the dominant artery. The Sen of Wellens’ sign in DII, DII and aVF for predicting a severe RCA/Cx stenosis was 9,5%, and the Spe was 96,3% [24].

In our study, 56,4% of the patients with Wellens’ sign had proximal LAD culprit lesions, 38,5% had middle LAD culprit lesions, and 5,15% had distal LAD culprit lesions. Globally, there were no statistical differences regarding the LAD segment having the culprit lesion (global p = 0,375), but we noticed that the proportion with middle LAD as the culprit lesion was higher in the WS group (38,5% vs 22,2%). In the extended study of de Zwaan and Wellens, the localization of the stenosis/occlusion was proximal to the first perforator septal branch in 29% of patients and between the first and the second septal branch in 54% of patients [17]. In a more recent study, Kobayashi et al. found that, of the 24 patients with Wellens’ sign, 8 had proximal LAD culprit lesions and 8 had middle LAD culprit lesions [23].

The current study showed a distribution of the lesional inventory in the WS group as it follows: 46,9% of the patients had single vessel disease, 21,9% had two-vessel disease and 10,9% had three-vessel disease. The results are similar to those found by de Zwaan and Wellens, who reported in 1989 that 42% of patients had single vessel disease (LAD stenosis), 37% had two-vessel disease and 21% had three-vessel disease [17], and to those found more recently by Bandara et al., who reported in 2018 that 50% of the patients had single vessel disease, 16,6% had two-vessel disease and 20% had three-vessel disease [26]. In our study the patients in the WS group had a higher probability of single vessel disease (46,9% vs 20,6%), while the patients in the control group had a higher probability of having three-vessel disease (34,9% vs 10,9%), p = 0,027. In contrast, in Kobayashi's more recent study, the patients with Wellens’ sign had a higher probability of having three-vessel or LM disease (4,2% vs. 20,4%, p = 0,057) [23].

In the present study, the treatment indication did not differ between the two groups (p global = 0,09). The rate of interventional revascularization was similar (65,62% in the WS group and 53,96% in the control group), as well as the rate of complete interventional revascularization (88,1% in Wellens group vs 81,1% in the control group, p = 0,53). The comparison of the treatment strategy adopted in our study with the treatment applied in older studies is inappropriate due to the advances in the field of interventional cardiology. In the pioneer studies from de Zwaan and Wellens, as well as in Heines’ study conducted in the same time period, coronary angiography had only a diagnostic role, with patients being further revascularized surgically [5, 17, 19]. The advancement of technical progress and the experience gained by operators along the years in the field of interventional cardiology have made even the most difficult coronary lesions suitable for interventional treatment. In a similar study published more recently, the rate of interventional or surgical revascularization procedures was similar between the two groups, and the rate of coronary angioplasty was comparable to our observations (66,7% vs 63.6%, p = 0,77) [23].

The rate of in-hospital mortality in our study was 0%, both in the WS group and in the control group. In Kobayashi's study conducted in the current era of modern treatment of coronary lesions, none of the patients in the WS group died and none had recurrent myocardial infarction during the initial hospitalization [23].

To our knowledge, this is the first prospective study with mid-term follow-up (six months) that compared a consecutive cohort of patients with Wellens syndrome who underwent coronary angiography with an age- and sex-matched cohort of patients with NSTEACS. As previously stated, the longest follow-up periods belong to the pioneer studies published 40 years ago, but they represent an inadequate term of comparison due to the diagnostic and treatment limitations. On the other hand, the studies published within the last 10 years, in the contemporary era of diagnostic and treatment of NSTEACS, had follow-up periods that were too short. In Kobayashi's study published in 2015, at the end of the 30-day follow-up period, there were no significant differences regarding the rate of major cardiovascular events (composite index including death, recurrent myocardial infarction and repeat target vessel revascularization) between the two groups (0% in the Wellens’ sign group vs 4,2% in the control group, p = 0,38). The authors concluded that Wellens’ sign did not have short term prognostic value in patients with NSTEMI [20]. In their study, Bandara et al. followed a group of 30 patients with WS that underwent coronary angiography for 90 days. The authors reported that at 30 days and at 90 days postangioplasty, none of the patients had residual angina or reinfarction, and none of the patients died [26]. In our study, throughout 6 months the patients in the control group had a significantly higher rate of repeat cardiovascular hospitalization (41,9% vs. 21,9%, p = 0,016), although the rate of ischaemic recurrences was similar between the two groups. Other interventional endpoints, such as subsequent interventional revascularization, repeat interventional revascularization, and repeat target vessel revascularization (TVR) were comparable between the two groups at the six-month follow-up mark. Also, there was no significant difference regarding global mortality (6.3% in the WS group vs 7.9% in the control group, p = 0.74).

This study intends to define and refine the place of Wellens syndrome across the large spectrum of acute coronary syndromes. Physiopathologically and angiographically, Wellens syndrome is an abortive form of ST segment elevation myocardial infarction, but electrocardiographically and prognostically it evolves similar to a non-ST segment elevation acute coronary syndrome.