Introduction

Nowadays, worldwide, Xylella fastidiosa is widely recognized as responsible for the devastation of large territories through the destruction of millions of centuries-old olive trees, as occurred in Salento (Southeastern Italy). Over several decades, the memory of extraordinary landscapes and of an olive oil of unparalleled quality has almost been lost. With a metaphorical leap, from environmental memory to cardiac physiology, the concept of cardiac memory (CM) has become increasingly familiar to cardiologists. CM generally refers to persistent T wave changes—most commonly T wave inversion—that appear after a period of abnormal ventricular activation, once normal ventricular depolarisation is restored [1]. This phenomenon was first described in 1969 by Chatterjee et al. [2], who observed T wave inversion following transient periods of artificial ventricular pacing. Nearly a decade later, Denes et al. [3] reported deep T waves inversion in the right precordial leads during normal conduction in patients with intermittent left bundle branch block (ILBBB). However, the mechanisms and clinical implications of these and other electrocardiographic findings associated with ILBBB remained poorly understood until Rosenbaum and colleagues [4] introduced the concept of CM in their seminal work. In that landmark study, two fundamental principles were established: 1) during normal conduction, the direction of the T wave reflects (remembers) the direction of the QRS complex during a preceding period of abnormal ventricular activation; and 2) both the amplitude and persistence of memory-related T wave abnormalities are proportional to the duration of the preceding abnormal activation [4]. This conceptual framework clarified several previously unexplained electrocardiographic phenomena and subsequently became the subject of extensive investigation [5]. Despite these significant advances, important aspects of ILBBB—particularly when idiopathic—remain unresolved. These include its complex electrocardiographic manifestations, its relationship with CM, its clinical significance, and its long-term evolution. In particular, the interpretation of repolarization abnormalities associated with ILBBB continues to pose diagnostic challenges, as memory-related changes may closely mimic a primary ischemic or cardiomyopathic pattern. In this retrospective study, drawing on more than four decades of clinical and electrophysiological experience, we aim to contribute further insight into CM associated with idiopathic ILBBB. Specifically, we describe a distinctive electrocardiographic pattern characterized by memory-related T wave inversion during normal conduction and concordant (homophasic) T waves during left bundle branch block (LBBB), which we propose represents a recognizable electrocardiographic phenotype.

Materials and methods

Results

Table 1 summarizes the main clinical and electrocardiographic characteristics of the 14 patients included in the study. Ages ranged from 27 to 58 years (mean 46 ± 8.4 years); eight were male and six female. Ten patients were referred for atypical chest pain, usually described as precordial and stabbing in nature, whereas four were asymptomatic and underwent evaluation for a routine check-up. At first observation, the initial electrocardiographic diagnosis was ILBBB associated with suspected myocardial ischemia in six patients, isolated myocardial ischemia in five, and ILBBB associated with anteroseptal myocardial infarction in three. ILBBB was exclusively tachycardia-dependent in eight patients, whereas in the remaining six, it was both tachycardia- and bradycardia-dependent. In all 14 patients, homophasic T waves were observed during LBBB, defined as concordance between the polarity of the QRS complex and that of the T wave. In addition, all patients exhibited negative, pseudo-ischemic T waves in the right precordial leads during phases of normal conduction. In six patients (five with exclusively tachycardia-dependent ILBBB and one with both tachycardia and bradycardia-dependent ILBBB), electrophysiological study demonstrated the presence of a narrow conduction zone interrupting the tachycardia-dependent block zone. This conduction zone lasted no more than 150 ms and was consistent with supernormal conduction (Figure 1). In all these six cases, atrial pacing readily produced 2:1 conduction through the left bundle branch.

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Figure 1. Premature atrial stimulation during sinus rhythm in a case with tachycardia-dependent left bundle branch block. The bundle branch block is evident during sinus rhythm and disappears when the cardiac cycle exceeds 840 ms during vagal stimulation, as shown in the diagram in the lower right, where black bars indicate cycles conducted with left bundle branch block and white bars indicate normally conducted cycles. Premature atrial stimulation (panels A–E) shows that the tachycardia-dependent block zone is interrupted by a narrow window of supernormal conduction (panels C and D). H: potential of His bundle; St: premature atrial stimulation during sinus rhythm.

Figure 2 illustrates a representative case from the study population. At the first evaluation, the patient was diagnosed with ILBBB and suspected myocardial ischemia. The electrocardiogram shows: 1) ischemic-like negative T waves in the right precordial leads up to V4, concordant with the negative QRS complexes in the same leads during LBBB; 2) concordance between QRS and T waves in the left precordial leads during LBBB, consistent with homophasic LBBB.

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Figure 2. The figure illustrates a representative case from the study population, showing intermittent tachycardia-dependent left bundle branch block. In the left portion of the figure, intraventricular conduction is characterized by left bundle branch block; note the concordant T wave morphology (lead V6) in the presence of left bundle block. When the cardiac cycle lengthens from 560 to 640 ms, left bundle branch conduction resumes. In the presence of normal conduction, symmetric negative T waves are evident in the precordial leads until V4. In the right portion of the figure, shortening of the cardiac cycle from 600 to 560 ms is associated with reappearance of left bundle branch block. For further details, see the text.

Figure 3 depicts the relationship between intraventricular conduction patterns and cardiac cycle length in the 14 patients, based on a representative recording period for each case. Black bars indicate cycles conducted with complete LBBB, white bars indicate cycles with normal conduction, and dashed bars (cases 10, 12, and 13) represent cycles with incomplete LBBB [6]. A partial overlap between conduction and block zones within the left bundle branch was observed. As noted above, eight patients exhibited exclusively tachycardia-dependent LBBB, whereas six showed both tachycardia- and bradycardia-dependent conduction disturbances. In only two of the eight patients with apparently isolated tachycardia-dependent LBBB were the diastolic pauses sufficiently long to reliably exclude the presence of a bradycardia-dependent block. In the remaining cases, the pauses obtained were too short to definitively rule out bradycardia-dependent LBBB.

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Figure 3. The diagram depicts the relationship between intraventricular conduction and cardiac cycle length in 14 patients. Black bars indicate cycles conducted with left bundle branch block, white bars indicate normally conducted cycles, and dashed bars represent cycles with incomplete left bundle branch block. For further details, see the text.

A strong relationship emerged between the width of the conduction zone and the degree of repolarization abnormalities in the right precordial leads. Specifically, the narrower the conduction zone, the more pronounced was T wave inversion during normal conduction, and vice versa. This singular variability is also observable in the same subject, in relation to the variation over time of the areas of blockage and conductivity across the left bundle branch.

Coronary angiography revealed no significant coronary artery disease in any patient. Right and left ventriculography demonstrated normal chamber size and morphology, with preserved and homogeneous segmental contraction in all cases.

Transthoracic echocardiography showed mild left ventricular hypertrophy in three patients; no other relevant abnormalities were detected. Exercise stress testing did not reveal clinical or electrocardiographic evidence of inducible myocardial ischemia in any patient. Among the ten patients presenting with chest pain, no temporal relationship was observed between the occurrence of symptoms and the presence or absence of LBBB.

Clinical and electrocardiographic follow-up was available only in 11 of the 14 patients, with a duration ranging from 12 to 65 months. Throughout follow-up, variability in temporal zones of conduction and block within the left bundle branch was documented. Figure 4 illustrates a representative example of this variability (case 2 in Figure 3) showing a relatively wide conduction zone between tachycardia- and bradycardia-dependent block zones at the initial evaluation, which narrows in a non-progressive way and eventually disappeared during subsequent follow-up examinations.

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Figure 4. This figure depicts the variability in the temporal zones of conduction and block within the left bundle branch during follow-up. Black bars indicate cycles conducted with left bundle branch block and white bars indicate normally conducted cycles. For further details, see the text.

For analytical purposes, the 11 patients with follow-up were divided into two groups (Table 2): those followed for 12 to 30 months (n = 6) and those followed for 31 to 65 months (n = 5). Among patients with longer follow-up, all but one progressed to permanent LBBB. In the shorter follow-up group, LBBB became permanent in one patient, remained intermittent in three, and was no longer detectable in two. No definite arrhythmic events or progressive cardiac functional deterioration were observed in ten patients, whereas one patient developed echocardiographic features suggestive of dilated cardiomyopathy.

Discussion

In this study, we report a case series of 14 patients with idiopathic ILBBB characterized by memory-related repolarization abnormalities, with the aim of better defining a distinctive electrocardiographic behavior. Accordingly, the present discussion focuses specifically on these aspects and does not address other electrophysiological features of intermittent tachycardia-dependent (phase 3) and/or bradycardia-dependent (phase 4) bundle branch block, such as mechanisms of intermittence, supernormal conduction, alternating conduction, or overlap between conduction and block zones which have been extensively examined in previous reports, including in similar patient populations [9–11]. It should be briefly noted here that although, based on our experience, the presence or absence of supernormal conduction does not appear to influence the electrocardiographic phenotype described, this possibility cannot be completely ruled out and warrants further investigation.

Transient alterations in the sequence of ventricular activation are well known to induce apparent worsening or, in some circumstances, apparent improvement of ventricular repolarization. Such pseudo-worsening phenomena have been described in the setting of rate-dependent bundle branch block, rate-dependent fascicular block, wide-QRS tachycardia, ventricular ectopy, intermittent ventricular pre-excitation, ablation of accessory atrioventricular (AV) pathway, and temporary or intermittent ventricular pacing [1]. In all these conditions, a change in the direction of ventricular activation may give rise to CM-related repolarization changes, manifesting not only as the classic inverted T waves, but also as positive T waves or pseudo-normalization of previously abnormal T waves [1]. Among the various manifestations of CM, the occurrence of deep negative T waves during normal conduction in patients with ILBBB is of particular clinical relevance. In this setting, memory-induced T wave inversion in the right precordial leads may closely mimic “primary repolarization abnormalities” [8], such as those observed in Wellens’ syndrome, which reflects transient proximal left anterior descending coronary artery occlusion and requires urgent intervention [12]. Similarly, right precordial T waves inversion may also be an expression of underlying myocardial disease, including arrhythmogenic cardiomyopathy [13]. Therefore, distinguishing memory-related repolarization changes from primary pathological T wave abnormalities is of crucial diagnostic importance. Beyond the clinical context, an important electrocardiographic clue supporting a memory-related mechanism is the concordance between the polarity of the T waves during normal conduction and the polarity of the QRS complex during LBBB. When such concordance is present, a memory phenomenon is strongly suggested, whereas a lack of coherence between these polarities should raise suspicion of a primary repolarization abnormality [14]. In this regard, our series consistently demonstrated memory-related negative T waves during normal conduction in all patients.

In addition to this well-recognized manifestation of CM, our study highlights another distinctive and previously underappreciated electrocardiographic feature: the presence of homophasic T waves during LBBB. This finding clearly differentiates our patients from typical cases of LBBB, in which heterophasism—namely, discordance between QRS and T wave polarity—is usually observed [6, 15]. Although for many years CM was thought to become evident only after restoration of normal QRS duration, accumulating evidence suggests that memory-related changes in repolarization may, under certain conditions, become apparent even in the presence of abnormal depolarization. From a pathophysiological perspective, the surface ECG represents the summation of the cardiac myocyte action potentials, which display regional heterogeneity in duration. An inverse relationship between activation time and action potential duration (APD) is well established: myocardial regions activated early exhibit longer APD, whereas later-activated regions show progressively shorter durations [16, 17]. This relationship, attributed to electrotonic interactions through gap junctions [17–19], intrinsic heterogeneity of APD [17], and ephaptic coupling [20], allows ventricular repolarization to proceed in a direction opposite to that of depolarization [1, 4], resulting in an upright T wave on the normal ECG.

Any alteration in the activation sequence produces immediate secondary changes in repolarization, typically oriented opposite to the direction of abnormal depolarization, thus explaining the usual discordance between QRS and T waves during LBBB [1, 4]. However, during sustained abnormal activation, additional non-secondary repolarization changes gradually develop. These changes remain masked by secondary repolarization abnormalities and become evident only when normal ventricular activation is restored, constituting the classical CM phenomenon [1, 4]. Importantly, experimental and clinical data indicate that, in some circumstances, memory-related repolarization changes may overcome secondary changes and manifest even during ongoing abnormal depolarization [21]. As proposed by Shvilkin and colleagues [21, 22], memory-related recovery changes may supersede secondary repolarization changes in the presence of wide QRS complexes. This mechanism offers a plausible explanation for the homophasic T wave observed during LBBB in our patients. Why this unusual phenomenon was consistently present in our series remains uncertain; however, it is noteworthy that none of our patients had demonstrable structural heart disease at the time of first observation. Although LBBB is not traditionally regarded as a heritable disorder, several studies have implicated genetic abnormalities involving ion channel genes (including SCN5A, PRKAG2, and HCN4), gap junction proteins, desmosomal components, and cardiac transcription factors in the development of bundle branch block [23–28]. In particular, SCN5A mutations have been shown to produce progressive impairment of intraventricular conduction [27], consistent with idiopathic progressive cardiac conduction disease originally described by Lenegre and Moreau [29, 30]. It cannot be excluded that, in idiopathic LBBB of presumed genetic origin, non-secondary repolarization changes may overlap with secondary ones, thereby accounting for both T wave homophasism during LBBB and the T wave inversion during normal conduction. However, it is worth highlighting here some subtle differences between Lenegre disease and the phenotype we described. Scientific evidence suggests that the pathophysiology of the hereditary Lenegre disease is related to SCN5A and involves haploinsufficiency of the cardiac Na⁺ channel gene, together with an additional, yet unidentified, mechanism that alters cardiac conduction in an age-dependent manner [30]. Classically, in Lenegre disease, a chronic conduction defect progressively develops over decades, leading to complete AV block [29, 30]. Surprisingly, in our case series, we never observed AV block, nor any involvement of the right bundle branch in the disease, despite the fact that, theoretically, the right bundle branch should be more vulnerable than the left [23].

Regarding clinical evolution, the development of echocardiographic features suggestive of dilated cardiomyopathy in one patient during long-term follow-up deserves consideration. Experimental and clinical studies [23] have demonstrated that LBBB is associated with electromechanical dyssynchrony, which may promote adverse ventricular remodeling over time [23, 31, 32]. Accordingly, patients with LBBB and initially preserved ventricular function may subsequently develop systolic dysfunction [23, 31], although it cannot be excluded that, in our specific case, the electrocardiographic phenotype described was initially an expression of a subclinical cardiomyopathy.

Finally, our observations do not support a consistent relationship between the occurrence of chest pain and the presence of LBBB, in contrast to reports describing the so-called “painful LBBB syndrome” [33, 34]. In our series, no temporal association between symptoms and conduction changes was observed.

At a broader level, the mechanisms underlying CM likely extend beyond purely electrotonic interactions. Rosen and colleagues [5, 35, 36] have suggested that CM reflects a form of electrical remodeling induced by altered activation patterns, involving ion channels, proteins, second messengers, and gene expression, and displaying features reminiscent of short- and long-term memory in the neural system. CM is therefore increasingly regarded as a universal adaptive property of the heart, reflecting dynamic adjustment of repolarization to changes in activation sequence [22]. Whether CM or the associated pseudo-primary repolarization abnormalities have clinical implications beyond their diagnostic relevance remains to be fully clarified. Some studies have suggested a potential proarrhythmic role of CM under specific conditions [37, 38], underscoring the need for further investigation. Additional studies are warranted to confirm our findings and to better define the characteristics and clinical significance of the electrocardiographic phenotype described here, which we have designated with the acronym homophasic idiopathic intermittent left bundle branch block and cardiac memory (OIL-CAME). According to this spirit, we hope that both this electrocardiographic pattern and the centuries-old olive trees of Salento will not remain merely a faint memory.