Tpeak-Tend ECG Marker in Obesity and Cardiovascular Diseases: A Comprehensive Review

Globally, cardiovascular diseases are still the leading cause of death. Numerous methods are used to diagnose cardiovascular pathologies; there is still a place for straightforward and noninvasive techniques, such as electrocardiogram (ECG). Depolarization and repolarization parameters, including QT interval and its derivatives, are well studied. However, the Tpeak-Tend interval is a novel and promising ECG marker with growing evidence for its potential role in predicting malignant arrhythmias. In this review, we discuss the association between the Tpeak-Tend interval and several cardiovascular diseases, including long QT syndrome, cardiomyopathies, heart failure, myocardial infarction, and obesity, which constitutes one of the risk factors for cardiovascular diseases.


Introduction
Cardiovascular diseases (CVDs) are among the most important and growing healthcare problems.Tey are the leading cause of death worldwide.In 2019, according to WHO data [1], nearly 17.9 million people died due to CVDs, and they accounted for almost 1/3 of all deaths worldwide.Due to this, research has been conducted to evaluate tools for fnding pathology early or helping prevent sudden cardiac death (SCD) and other serious events.For this reason, there is still a search for novel and noninvasive or less invasive tools to detect and eventually monitor cardiovascular pathologies efectively.
Electrocardiography is a technique that is used to visualize and assess the heart's electrical activity.Information obtained with this test is helpful in the diagnostics of heart diseases, including arrhythmias, ventricular hypertrophy, ischemia, and myocardial infarction (MI).An electrocardiogram (ECG) may also be useful in detecting asymptomatic disorders, e.g., long QT syndrome (LQTS).Moreover, ECG has an application in risk stratifcation, monitoring of cardiac conditions, and response to treatment.ECG stands out from other tests mainly due to its safety, noninvasive character, easy and quick testing, and low cost.ECG can be widely used in almost every healthcare facility.
Numerous markers have been extracted from the ECG record, which refects the various stages of the heart's function.Among them, there is a need to search for markers refecting the myocardial depolarization and repolarization associated with malignant ventricular arrhythmias or predicting sudden cardiac death [2].Some of these parameters, e.g., QT interval and calculated consistent with Bazett's formula-corrected QT interval (QTc), are commonly used to determine the risk of malignant arrhythmias.Other novel ECG markers, like Tpeak to Tend interval (Tp-e) and its derivatives, are still not used routinely.
Te novel repolarization markers include Tpeak-Tend dispersion, JTpeak/JT, Tp-e/JTpeak, and Tpeak/JT ratios [3].Te JTpeak interval refects early repolarization, while the Tp-e refects late repolarization.Despite numerous studies, there is still uncertainty regarding the clinical application of the new parameters.Furthermore, no normal reference values of Tp-e and parameters and ratios are associated with that interval [4].
Describing the physiological role of the new marker Tp-e is an index of the transmural dispersion of ventricular repolarization, and it refects the diferent durations of the action potential in the epicardium, endocardium, and M cells from the heart.As explained by Castro-Torres, the cellular mechanisms are translated to the T wave on the surface 12-lead electrocardiogram and allow the determination of an increase in the transmural dispersion of the ventricular repolarization through a measure from the peak or nadir to the end of the T wave.Te Tp-e/QTc ratio includes values of ventricular repolarization's transmural and spatial dispersion [5].
As new knowledge about QT interval, Tp-e, and other repolarization markers is still increasing, comprehensive reviews are needed to summarize the current knowledge about their role and the circumstances infuencing their variations.Tis study aims to discuss the current state of knowledge and the most recent studies regarding the meaning and application of the Tp-e interval in selected disease entities and its predictive value.It also aims to identify gaps and inaccuracies in the current knowledge regarding this parameter (Figure 1).

Search Strategy.
Te review was conducted by searching PubMed, Embase, and Cochrane Library databases using keywords: Tpeak-Tend, Tp-e, TpTe, obesity, long QT syndrome, cardiomyopathy, heart failure, and myocardial infarction.

Inclusion and Exclusion Criteria. Te inclusion criteria were (I) Tp-e-related studies; (II) disease associations with
Tp-e among studies; (III) English language; (IV) publication in peer-reviewed journals; (V) adult population; and (VI) human population.We excluded animal studies, conference proceedings, case reports, and abstracts without complete text publication.

Literature Selection.
We assessed the most relevant randomized controlled trials, case-control, cohort studies, and meta-analyses published between 2017 and 2023.Two reviewers independently evaluated three hundred seventyeight articles according to the title, abstract, text, and scientifc validity.As reported in the PRISMA fowchart, after removing duplicates (n � 163), 190 studies were initially screened, and 84 were found appropriate for a full assessment.In the end, 66 articles fulflled the inclusion criteria (Figure 2).

ECG Parameters in the Prediction of Malignant
Arrhythmias.Te parameter considered, especially in the past, useful in predicting ventricular arrhythmias, including ventricular fbrillation (VF), is QT dispersion (QTd).QTd is defned as a diference between the longest and the shortest QT in the specifc lead.Although QT interval has been confrmed to correlate with ventricular arrhythmias (VA), QT dispersion ranges vary widely between 10 and 71 ms, which may cause difculties in its proper assessment [6].QTd appears unreliable, even when appropriately measured, and is being questioned in extensive prospective studies [7].Moreover, the correct measurement of QT dispersion is difcult and time-consuming.Other parameters have not yet been sufciently researched for general use.Furthermore, it is believed that QT dispersion has been shown to refect not the extent of heterogeneity of ventricular repolarization itself but the spatial position of the vectorcardiographic T loop [8].
Other markers can be used to assess heart function.Heart rate turbulence (HRT) is used to detect the impairment of the autonomic system and barorefex, and it also has a prognostic role in assessing the risk of all-cause or sudden death [9].HRT includes two parameters: turbulence onset and turbulence slope.Turbulence onset is a percentage of the length change between the mean of 2 RR intervals before and 2 RR intervals after ventricular premature beat.Te turbulence slope is the steepest slope of the regression line of 5 consecutive RR intervals in the range of 15 RR intervals after ventricular premature beat.
Heart rate variability (HRV) is another marker used in cardiovascular risk stratifcation.It is measured as a change in the length of consecutive RR intervals.HRV is used to detect autonomic system dysfunction [10].Tis method uses 2 Scientifca two HRV types: time-domain analysis and frequency domain (spectral).Both have been widely evaluated in the last decades.However, they are not routinely used in clinical settings as diferent studies are rather diverse.Secondly, markers of HRV are very dependent on sympathetic and parasympathetic balance.However, this analysis is applied in numerous 24-hour Holter systems.It was observed that HRV in frequency domain analysis was changed toward the sympathetic predominance in people with higher values of premature ventricular contractions in Holter monitoring, simultaneously in patients with higher blood pressure [11].
In the study by Cosgun and Oren authors compared repolarization markers: T-wave peak-end interval (Tp-e), QT, corrected QT (QTc), Tp-e/QT, Tp-e/corrected QT, and heart rate variability values in healthy men and women and to investigate their daily variations [12].Tere were statistically signifcant diferences in Tp-e and cTp-e intervals at various hours of the same day in both groups (women and men).In addition, there were statistically substantial moderate negative correlations between Tp-e intervals and SDNN at various hours of the same day.Some experts propose in this view that T peak-end markers should probably be adjusted to heart rate or use ratios such as Tp-e/QTand Tp-e/QTc, which is a better tool, independent from any changes in RR cycles and heart rate.Tis question should be studied in the coming years.Additionally, it should be commented on that the Tpe/QTc ratio remains relatively constant between a heart rate of 60 and 100 beats/min.However, some researchers have recently published good outcomes after the correction of this parameter by the heart rate [13,14].Akdi et al. compared two groups of patients with higher and lower numbers of premature ventricular contractions in 24-hour Holter monitoring, and no signifcant diferences were found in HRV time-domain indices.However, the study revealed that the Tp-e interval and Tp-e/QT are associated with the frequency of PVCs.HRV refects the other type of physiological balance, that is, in the case of T peak indices and their derivatives [15].In the diferent studies by Cosgun and Oren, including 500 healthy males categorized by fve age subgroups, it occurred that there were signifcant Scientifca diferences between these groups in repolarization parameters in terms of Tp-e interval but not Tp-e/QTand Tp-e/QTc ratios.Considering the HRV parameters, there were statistically signifcant diferences between the fve male healthy groups in terms of HRV temporal parameters and no signifcant diferences in HRV frequency parameters.Te authors concluded that as the age increases, basal Tp-e interval increases and HRV temporal parameters decrease signifcantly in the male subjects aged between 30 and 79 years, but HRV frequency parameters do not change.Te relations between the markers from the repolarization group and heart rate variability seem complex and need further evaluation [16].T-wave alternans (TWA) is another marker with potential clinical use.TWA is the diference between consecutive T-wave amplitude and morphology.It may be helpful in the assessment of the risk of lethal ventricular arrhythmias and death due to cardiovascular events.Eventually, more studies are needed to confrm its usefulness, and this method requires more sophisticated equipment [17].In 2008, in the AHA/ACCF/HRS Scientifc Statement, TWA was listed as one of the potentially valuable markers of SCD risk due to a moderate amount of data.However, the measurement of TWA requires proper heart rate and regular RR interval duration.It was often inaccurate for many reasons, including failure to achieve the appropriate heart rate during gradual exercise and arrhythmias [18].In most recent ventricular arrhythmias guidelines of AHA and ESC, it has no signifcant role [19,20].In ESC Guidelines, TWA is only used in modifed LQTS diagnostic scores.Positive TWA adds 1 point to the score, requiring >3 points to diagnose LQTS [20].
Until now, QT interval has been well studied.Tere are commonly known factors infuencing its duration, such as heart rate, age, hormone concentration, time of the day of the examination, potential imbalances in water volume and electrolyte concentrations, the infuence of medications, and autonomic system nervous tension.In addition, essential QT interval changes may be observed in patients with heart failure and other heart diseases [21].In contrast to QT or JTpeak intervals, studies claim that Tp-e duration is independent of HR [22].However, it has been previously proposed that it be corrected with Bazett's formula, so it remains equivocal.Some studies reveal the Tp-e dependence of HR and suggest the Tp-e/QT ratio to be more appropriate in repolarization characteristics due to minimizing HRinfuenced alterations [14].In addition, Tp-e time may vary in diferent ECG leads [22].
Te Tpeak-Tend interval (Tp-e) can be measured in many ways.Tp-e can be measured in a single lead or from the earliest Tpeak among all leads to the latest Tend throughout all leads.Te second method is often used in research studies [23][24][25].Moreover, the measurement of Tp-e in multiple leads is preferred to measurement in single lead because it allows the calculation of Tp-e dispersion, which is a diference between the highest and the lowest value of Tp-e in all leads [26].Such an approach yields better results, especially when local changes are expected in myocardial ischemia.In one of the studies, the authors compared single-lead and multilead measurements of Tp-e and presented fndings in favor of multilead measurements.Automated measurement is the most accurate Tp-e measurement method; among the manual methods, the tangent method is the most useful.Te lead optimal for this measurement is the lead V2 [27].
Tp-e interval is the ECG parameter representing the dispersion of repolarization across the ventricles [28].Notably, the predictive role of Tp-e prolongation and occurrence of SCD have been found, for example, in Oregon Sudden Unexpected Death Study [29].Te authors proved that prolonging the Tp-e interval was independently associated with SCD, with particular utility when the QTc was normal or not measurable because of prolonged QRS duration.In another study, the Tp-e interval is associated with SCD in adults with congenital heart diseases [30].Te potential mechanisms underlying the alterations visible in ECG as a Tp-e prolongation leading to the SCD may be driven by abnormal ion channel function, pathophysiological dispersions of repolarization providing a substrate for reentrant arrhythmias or autonomic dysfunction [31].As suggested by Vehmeijer et al., various studies have demonstrated that there may be the transmural dispersion of repolarization due to prolonged repolarization of the subendocardial M cells or overall dispersion of repolarization [23,30,32].

Tp-e Interval in Overweight and Obese People.
Obesity is a disease characterized by excessive adipose tissue deposition in the body [39].Obese individuals are more susceptible to developing cardiac diseases and dying of cardiovascular disorders, including SCD.Many changes indicate heart disease found more often in ECG records of obese people than in ECG records of people with normal weight, including prolongation of QT and QTc interval, prolongation of QT or QTc dispersion, tachycardia and higher heart rate, atrial and ventricular enlargement, conduction defects, left axis deviation, features of ischemia, old infarction, and repolarization abnormalities [40][41][42].Moreover, obesity was associated with changes in the QRS complex in premenopausal women [43].In children, obesity is associated with prolonged QT interval, longer QRS complex, and leftward shifts in frontal P-wave, QRS, and T-wave axes [44].
Several studies examining the connection between obesity and repolarization markers such as Tp-e, Tp-e/QT, and Tp-e/QTc support this association.Inanir et al.'s study [45] found that previously mentioned repolarization parameters, Tp-e/JT and Tp-e/JTc, were signifcantly increased in patients with class 3 obesity (body mass index (BMI) ≥40) in comparison with patients with normal body weight.Furthermore, according to Bagcı et al.'s research [46], Tp-e, Tp-e/QT, and Tp-e/QTc increase gradually with the growth of BMI.Te association was found by examining these parameters in four groups of patients: normal weight (BMI: 18.0-24.9),overweight (BMI: 25-29.9),obese (BMI: 30.0-39.9), and class 3 obese (BMI ≥ 40).Te same study found that Tp-e length was signifcantly positively correlated with age and systolic and diastolic blood pressure.Tis study suggests that repolarization impairment occurs before reaching class 3 of obesity.
On the contrary, Al-Mosawi et al. [47] associated the prolongation in repolarization markers (Tp-e, Tp-e/QT) with pericardial fat volume measured by multidetector computer tomography.Tey found no signifcant association between them and the growth of BMI.Tey found a signifcant association only in the group of patients with coronary atherosclerosis.In contrast to other studies, the Tpe value decreased sequentially in groups of normal weight, overweight, and obese patients.Te Tp-e interval was the shortest in the group of obese people, whereas, in most other studies, the obese have the most prolonged Tp-e interval.Te result of this study may seem controversial because of this negative correlation.Some recent studies evaluated how weight loss due to bariatric surgery and sleeve gastrectomy surgery afected the change in markers of repolarization.
In trying to explain the conficting results, it should be taken into account that both cardiac and extracardiac factors matter in the case of surface ECG.Tere may be a potential efect of extracardiac factors such as subcutaneous fat, heart position, fuid overload, and body habitus on the temporal parameters, not only on voltage parameters, which cannot be excluded entirely [48].Generally, Tp-e is thought to refect dispersion of repolarization, and this is an intracardiac factor.However, it should be considered that both obesity and weight loss may involve a change in extracardiac factors.Tis consideration might account for conficting results.
It is also worth noting that values of Tp-e and its derivatives change after surgical procedures, leading to weight loss.Gul et al.'s study [49] included class 3 obesity patients and found a signifcant reduction in Tp-e, Tp-e/QT, Tp-e/ QTc, Tp-e/JT, and Tp-e/JTc after bariatric surgery (measured 1 and 6 months after operation).Te change in these parameters was also signifcantly correlated with weight loss.Ibisoglu et al. [50] also found a signifcant reduction in Tp-e, Tp-e/QT, Tp-e/QTc, Tp-e/JT, and Tp-e/JTc 6 months after bariatric surgery and stated that this change may reduce the risk of developing ventricular arrhythmia.Moreover, Inanir et al. [51] found that Tp-e interval, Tp-e/QT, Tp-e/QTc, Tp-e/ JT, and Tp-e/JTc ratios decreased signifcantly after sleeve gastrectomy surgery in class 3 obesity patients, which suggests that weight loss by this surgery also reduces the risk of arrhythmias and SCD.
In conclusion, most studies support the statement that Tp-e duration and other repolarization parameters positively correlate with BMI.Tis indicates a higher risk of developing arrhythmias, including VAs, which may result in SCD, especially in obese patients.Opposing these fndings, a study also shows the opposite trend: normal-weighted patients have the longest Tp-e, and obese patients have the shortest Tp-e.Moreover, studies agree that these parameters should be improved after weight loss due to bariatric surgery.However, only some studies examine the association between body weight and novel repolarization parameters, even though some are contradictory.

Tp-e Interval in
Long QT Syndrome.LQTS is an electrical disorder that is characterized by the prolongation of QT interval [52] (QTc >440 ms in men and QTc >460 ms in women) [53].LQTS increases the risk of polymorphic ventricular tachycardia (torsade de pointes), which might result in SCD.LQTS can be congenital or acquired.It may have an asymptomatic course in some people, and cardiac arrest may be the frst sign of this disorder.
Te length of the QT interval provides data about the time between depolarization and repolarization of cardiomyocytes.In addition to these data, the Tp-e interval includes information about the dispersion of repolarization.Te Tp-e interval may be helpful in diagnostics and risk stratifcation in this condition.
Firstly, the Tp-e interval, along with other markers, may be used to determine whether the case of LQTS is congenital or acquired, which is essential because depending on the cause of the disease, the prognosis and treatment vary.Sugrue et al. [54] investigated T-wave morphology to differentiate whether LQTS is congenital or acquired.Tey found that patients with acquired LQTS had longer Tp-e in V5 lead than those with congenital LQTS.Patients with acquired LQTS also had a shallower right slope and a smaller T-wave centre of gravity.Tey suggested that T-wave morphology may also be useful in assessing IKr ion channel (a potassium channel that takes part in cardiac repolarization) activity in drug testing, especially in association with arrhythmogenesis.Te Tp-e interval is a marker that appears to be efective in evaluating the risk of arrhythmogenesis, so the Tp-e interval could be one of the markers in this process.
Furthermore, Tardo et al.'s systematic review [55], apart from Sugrue et al.'s research, included Johannesen et al.'s [56] study, which found J-Tp and Tp-e intervals useful in the diferentiation of IKr ion channel block and multichannel block in acquired LQTS.Te block of IKr was associated with longer J-Tp and Tp-e intervals.Te multichannel block (block of both IKr and calcium or sodium channel) was associated with shorter J-Tp and longer Tp-e and QT intervals.
Apart from diferentiating congenital and acquired LQTS, Tp-e can potentially be used as a marker for assessing cardiac event risk in LQTS patients.Tse et al.'s meta-analysis [57] found that Tp-e is signifcantly longer in people with LQTS sufering from cardiac events than those without cardiac events and suggested that Tp-e may be useful in risk stratifcation.It was also found that the Tp-e/QTc ratio is also higher in high-risk patients, making it a useful risk marker.Furthermore, according to Markiewicz-Łoskot et al.'s study [58], Tp-e, combined with QTc, may have potential use in detecting afected relatives of people with congenital LQTS.Tey found that Tp-e is signifcantly longer in relatives affected by LQTS than in those unafected and associated this marker with the possibility of cardiac events.Tey also Scientifca found signifcant diferences in Tp-e in LQTS type 1, LQTS type 2, and unafected people when divided into groups based on sex.Te Tp-e interval was also longer in LQTS type 2 than in LQTS type 1 without reaching statistical signifcance.
Moreover, according to Krych et al., longer Tp-e was associated with a higher risk of arrhythmia and cardiac events in people with LQTS type 7 (Andersen-Tawil syndrome).According to the same study, the higher value of Tpe, QT, and U-wave presence in V2-V4 leads may also be related to the presence of KCNJ2 mutation [59].Additionally, the meta-analysis by Tse et al. showed that the values of Tp-e and Tp-e/QT ratio among people with acquired QT interval prolongation were higher in patients with torsade de pointes incidents than in those without them, and due to that, these markers can be used in the stratifcation of risk in acquired LQTS [60].Tp-e was longer in people with atrioventricular block-related LQTS and cardiac events than those without cardiac events, whereas Tp-e/QT was higher in people with drug-related LQTS and cardiac events than those without cardiac events.
In conclusion, the Tp-e interval may be a useful marker in diferentiating congenital and acquired LQTS and assessing risk in LQTS independently from its cause.

Tp-e in Cardiomyopathies.
According to ESC Guidelines, cardiomyopathy is a morphological and functional abnormality of the ventricular myocardium not caused by coronary artery fow limitation or abnormal loading conditions [61].
Referring to SCD among HCM patients, there is a suggestion that Tp-e does not have a signifcant prognostic value in that group.However, QTc may be an appropriate tool for risk stratifcation in patients with HCM [63].Another study revealed the utility of T-wave amplitude and traditional risk factors as an SCD marker in this group of patients.In contrast, this research did not show the statistical signifcance of Tp-e [64].Importantly, in a large cohort of patients with HCM, it has been proven that a signifcant diference between genotype-positive and genotype-negative HCM patients in spatial mean and spatial peak QRS-T angles exists, which could be a better tool in identifying patients with HCM than traditional Seattle criteria.Moreover, Tp-e was signifcantly higher among genotype-positive patients than those without genetic backgrounds [65].In addition, spatial QRS-T angle was shown to be signifcantly associated with VF and SCD in Brugada syndrome (BS) patients, who usually have structurally normal heart muscle; however, recently, the association between ARVC and BS molecular insight of pathogenesis was taken under scientifc discussion [38,66,67].Te same study revealed that Tp-e does not have a predictive value in the BS group of patients according to malignant arrhythmias and SCD.
Dinshaw et al. showed that Tp-e prolongation in HCM patients is associated with VA, such as ventricular tachycardia (VT) and ventricular fbrillation (VF).It assessed its predictive role in SCD risk stratifcation.Besides, it is underlined that Tp-e < 78 ms among HCM patients with implanted ICDs is associated with a low risk of VA [67].Tere were no signifcant diferences among patients with transthyretin cardiac amyloidosis (TTR-CA) compared to the control group referring to Tpe and Tp-e/QTc [68].
On the other hand, in the HCM population without a sarcoidosis background, Tp-e and Tp-e/QTc were signifcantly higher.Tey trended toward increased QT dispersion compared to the group without cardiac disease.Te result present in the TTR-CA group is consistent with observed low-range SCD in that group of patients due to homogenous amyloid distribution [69].Furthermore, the long-term prognostic value of ventricular repolarization dispersion in cardiac sarcoidosis patients was investigated.Endpoint was defned as the occurrence of the atrioventricular block (AVB), VT/VF, heart failure (HF) hospitalization, and all-cause death.Tat study assessed Tp-e/QT as an independent positive predictor of previously mentioned adverse events.VT/VF and SCD were observed more often in patients with greater Tp-e/QT ratios of ≥0.242 ms [70].It was also confrmed that in patients without apparent heart involvement at early-stage sarcoidosis, QTcd, Tp-e, and Tp-e/QT ratios were signifcantly higher than in the control group [71].
Cardiomyopathy in Fabry disease is the most frequently present as left ventricular hypertrophic cardiomyopathy-in that group, ECG abnormalities included shorter P-wave and T-wave peak time, what was observed as a more symmetric T wave with lower T-wave time ratio described by Tonset-Tpeak/Tp-e compared to the control group [71].Tere are contrasting results regarding the predictive value of Tp-e among HCM patients, especially its role in SCD prediction.Te issue needs more studies and meta-analyses to assess its role in that population.In addition, a study confrmed that higher Tp-e among patients with nonischemic dilated cardiomyopathy was associated with malignant ventricular arrhythmias [72].Lopez et al. investigated how ECG parameters predict SCD change after cardiac resynchronization therapy (CRT) with His bundle pacing.Tere was an improvement in QT interval, QT dispersion, and Tp-e dispersion, and Tp-e was shortened [73].
6 Scientifca Te study of Ponnusam et al. also noticed a signifcant improvement in repolarization parameters after His bundle pacing using QTc, Tp-e, and Tp-e/QTc ratio parameters.Tose results prove a reasonable option for CRT among patients with left bundle branch block (LBBB)-induced cardiomyopathy with an improvement visible as normalization of electrical and mechanical pathologies [74].However, in a group of HF patients with implantable cardioverter-defbrillator (ICD), in which 85.5% of patients (n � 272) were diagnosed with dilated cardiomyopathy, postimplantation Tp-e was revealed as an independent predictive factor of VT, VF, and all-cause mortality [75].According to ARVC, one study corresponds to this review criterion, which revealed the association in longitudinal follow-up poorer prognosis and fragmented QRS, longer Tp-e in lead V2, and defnite ARVC [76].
ESC Guidelines currently describe unclassifed cardiomyopathies in Takotsubo cardiomyopathy and left ventricular noncompaction.Tose pathologies found their association with ECG parameters.Patients with Takotsubo syndrome who sufered from major adverse cardiovascular events (MACE) (defned as acute heart failure, cardiogenic shock, sustained ventricular tachycardia, ventricular fbrillation, and death) had more often ST-segment elevation and their Tp-e/QT ratio was signifcantly higher.Tp-e/QT range >0.27, accompanied by low ejection fraction (EF), was defned as the subpopulation at higher risk of MACE [77].
When considering left ventricular noncompaction cardiomyopathies, patients compared to groups with normal cardiac ultrasound, Tp-e, and Tp-e/QT ratio were revealed as potential risk markers of that pathology presentation.Tese may be helpful markers before invasive procedures such as cardiac biopsy [78].
In conclusion, the role of Tp-e and its derivatives in assessing patients with cardiomyopathy may vary between its subtypes according to malignant ventricular arrhythmias.However, it can be an attractive parameter for monitoring a patient's prognosis after electrotherapy devices or LVAD implantation procedures.Furthermore, Tp-e can be a potential ECG marker, allowing preliminary diagnosis according to HCM genetic background and noncompaction cardiomyopathy suspicion before performing the cardiac biopsy.

Tp-e Interval in Heart
Failure.Heart failure (HF) is when the cardiac output is reduced, and the heart cannot pump enough blood to meet the body's needs.Te prevalence of HF grows rapidly in many countries because of the aging society.UpToDate shows about 64 million people worldwide sufered from this condition in 2022 [79].A report from the American Heart Association estimated that the lifetime risk of heart failure development is 20-45% of people over 45, depending on the racial and ethnic group.Many circulatory diseases, including hypertension or coronary heart disease, may cause this condition.Heart failure increases the risk of death and reduces the quality of life [80].
In recent years, Piccirillo et al. conducted several studies [81][82][83][84][85] on patients sufering from heart failure and assessed the role of repolarization markers, including Tp-e, in chronic heart failure.Tere were attempts to fnd the use of repolarization markers in predicting hospital length of stay and the mortality of patients with acute decompensated heart failure [81].It has been found that mean Tp-e was helpful as the predictor of mortality in the next 30 days, while Tp-e variance normalized and Tp-e standard deviation (Tp-eSD) was useful as the predictor of length of hospital stay and thus a predictor of severity.It was also suggested that these markers may be used to monitor both morphological and structural alterations of the heart.
It was also found that in patients with heart failure with a reduced ejection fraction (HFrEF), mean Tp-e and its standard deviation were higher than in those with heart failure with preserved ejection fraction (HFpEF) [82].However, Son et al. found no diference in Tp-e and Tp-e/QT ratio based on ejection fraction in three groups of heart failure patients (preserved, midrange, and reduced ejection fraction) [86].
Mean Tp-e was also signifcantly correlated with mortality [81].Patients who responded to the heart failure therapy had reduced Tp-eSD compared to nonresponders.Moreover, people with higher Tp-eSD died more often.In another study, mean Tp-e was related to chronic heart failure mortality, and Tp-eSD was a risk factor for aggravation and complications of this disease [83].Another Piccirillo et al. study found an association between Tp-e and mortality in acutely decompensated chronic heart failure [84].In a study including patients with decompensated heart failure and atrial fbrillation (AF), mean Tp-e was again associated with mortality, while higher Tp-eSD was associated with permanent AF [85].Te important conclusion from the last study is that Tp-e is not afected by atrial fbrillation.
Several recent studies have investigated repolarization markers in heart failure therapies.Usalp et al. investigated the length of Tp-e and T wave in cardiac resynchronization therapy.Tey found that a reduction in the duration of these markers was a signifcant predictor of a favorable response to the treatment [87].Moreover, Banavalikar et al. found that Tp-e predicts ventricular tachyarrhythmias in heart failure patients after cardiac resynchronization therapy [88].Furthermore, Li et al. investigated the association between left bundle branch area pacing (LBBAP) and echocardiographic response in heart failure patients.Tey found that Tp-e is useful as the predictor of response to the therapy, especially in patients without left bundle branch block [89].Patients with Tp-e shorter than 81.2 ms after therapy were signifcantly more likely to be responders than those with longer Tp-e.Tey also found that Tp-e interval duration and Tp-e/ QTc ratio were reduced considerably after therapy in patients with QRS >130 ms.Also, Xue et al. investigated Tp-e in patients with heart failure and ICD and its use in predicting VA and mortality [75].It was found that a longer duration of Tp-e was positively associated with VT, VF, and mortality.
In conclusion, the Tp-e interval and its derivatives may be practical in predicting mortality and severity during heart failure.Moreover, it may be used to monitor the Scientifca efectiveness of therapy.It should be kept in mind that most of the studies conducted in recent years have been carried out by one research team, and there is a need to replicate these studies in other populations.
3.6.Tpeak-Tend in Myocardial Infarction.Tpeak-Tend interval and Tpeak-Tend/QT ratio were essential predictors among patients with myocardial infarction (MI), mainly in those with ST-segment elevation myocardial infarction (STEMI).However, groups with myocardial infarction with nonobstructive coronary artery disease (MINOCA) were investigated according to repolarization parameters, including Tp-e.
Prolonged Tp-e was confrmed to be an independent risk factor of VA in STEMI patients after percutaneous coronary intervention (PCI) [90,91].In addition, the Tp-e interval measured before the procedure was found to be an independent predictor of reperfusion VF [92].One study did not confrm the Tp-e association with VF, as it was statistically insignifcant among other investigated parameters [93].Patients described with MINOCA had a signifcantly higher risk of VA, and Tp-e Tp-e/QT was longer in that group [94].According to myocardial reperfusion, Tp-e >72.5 ms and Tp-e/QT ratio >0.18 independently predicted procedure impairment, in-hospital MACEs, and poorer 6-month survival rate [93].Moreover, the 3-year survival rate among patients with prolonged Tp-e/QT in infarct-related leads corresponded with patients' higher mortality [95].
Namazi et al. retrospectively confrmed the statistical signifcance of QT dispersion, Tp-e value, and in-hospital mortality in STEMI patients with those parameters measured before PCI [96].In addition, Tp-e was revealed to be an independent predictive factor of incomplete ST-segment resolution in STEMI patients treated with PCI [97].However, there was a trial analyzing only patients with acute anterior MI.Its results contradicted those previously mentioned, revealing no statistical signifcance of Tp-e or Tp-e/QT in patients undergoing PCI [96].Moreover, Wang et al. assessed Tp-e as an independent predictive factor of 1year MACE defned as cardiac death and malignant arrhythmia event [90].
An analysis according to preinfarction angina (PIA) was conducted and revealed that STEMI patients with PIA had a lower chance of sufering from VA than those without PIA-who had longer Tp-e, Tp-e/QTratio, which independently predicted in-hospital VA [98].Interestingly, Tp-e was found to predict Intensive Care Unit (ICU) stay among patients with acute coronary syndrome (ACS) with COVID-19 [99].
Tp-e prolongation was also associated with the marker of coronary artery disease (CAD) severity [100].One of those markers is the SYNTAX score; its higher scores were associated with prolonged Tp-e and Tp-e/QT in patients with CAD [101][102][103].Tese results may be an interesting potential noninvasive predictive marker of CAD severity.
In conclusion, those fndings may help invasive cardiologists stratify the procedural and periprocedural risk, including VA, MACE, mortality, and long-term prognosis.

Tpeak-Tend in Valvular Heart
Disease.Changes in Tp-e length and derived parameters have been reported in valvular heart diseases.Most studies focus on the relationship between Tp-e and its derivatives and aortic stenosis (AS).Patients with aortic stenosis have signifcantly higher values of Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios than healthy people [104].Te more severe the AS, the more signifcant the parameter increase.Moreover, a positive correlation was found between the Tp-e/QTc ratio and the mean aortic gradient.
Furthermore, the Tp-e/QTc ratio was a signifcant and independent predictor of severe AS.Another study observed increases in Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios [105].In this study, again Tp-e/QT and Tp-e/QTc ratios were signifcantly associated with AS, and mean aortic gradient was positively correlated with Tp-e, Tp-e/Qt, Tp-e/QTc, and Tp-ed.Also, a negative correlation between aortic valve areas and Tp-e, Tp-e/Qt, Tp-e/QTc, and Tp-ed was found.
In several studies, after transcatheter aortic valve implantation (TAVI), there was a signifcant reduction in values of Tp-e, Tp-e/Qt, Tp-e/QTc, and Tp-ed, indicating that TAVI might reduce the risk of ventricular arrhythmias and mortality [105,106].Moreover, before TAVI, there was a positive correlation among Tp-e, Tp-e/QT, Tp-e/QTc, and left ventricular mass index (LVMI) [106].Tp-e was also independently associated with LVMI.
Another study found Tp-e and its derivatives useful in predicting complete atrioventricular blocks after TAVI [107].Tp-e, Tp-e/QT, Tp-e/QTc, Tp-e/JT, and Tp-e/JTc were signifcantly higher in patients requiring permanent pacemaker after TAVI and, additionally, Tp-e/QTc and Tp-e/JTc were signifcantly associated with the presence of complete atrioventricular block.Moreover, Tp-e/JTc was a potential independent predictor of complete atrioventricular block after TAVI.
Tp-e, Tp-e/QT, Tp-e/QTc, and Tp-ed also had higher values in the group of patients who died after successful treatment of AS with surgical aortic valve replacement (SAVR) in comparison with patients who survived within a mean follow-up period of 66.3 ± 42.4 months [108].Tp-e, Tp-e/QT, Tp-e/QTc, and Tp-ed were independent mortality predictors after SAVR.Higher values of Tp-e/QT and Tp-e/ QTc were associated with a lower chance of long-term survival.In another study, lower values of preprocedural Tp-e were associated with better survivability after TAVI [109].Te follow-up period in this study was one year.
Contrary to most previously mentioned studies, Chino et al.'s study showed no signifcant changes in Tp-e, Tp-e/ QT, and Tp-e/QTc after neither TAVI nor surgical aortic valve replacement [110].
Similarly to patients with aortic stenosis, the patients with severe mitral stenosis have signifcantly higher values of Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios than the healthy population [111].Moreover, after percutaneous mitral balloon valvuloplasty, the value of these parameters signifcantly decreased, revealing the benefcial efect of this procedure on the mentioned repolarization parameters.Furthermore, the Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios also had higher values in children with mitral valve 8 Scientifca prolapse when compared to healthy children [112].Moreover, the value of Tp-e/QTc correlated positively with the degree of mitral regurgitation.It is suspected that these changes might be associated with the increased risk of ventricular arrhythmias and SCD in patients with mitral valve prolapse.
In conclusion, most studies suggest that Tp-e and its derivatives have increased values in valvular heart disease, and the proper treatment of this disease might reduce the values of these parameters.Te high values of these parameters are also associated with a worse prognosis after treatment of valvular disease.
3.8.Tpeak-Tend in Brugada Syndrome.Patients with Brugada syndrome (BS) are more susceptible to ventricular arrhythmia and sudden cardiac death if the Tp-e interval is prolonged [113].In BS, the ajmaline challenge is performed to provoke BS, and there was research investigating whether prolonged Tp-e or the corrected interval can predict the positive result of the ajmaline challenge.However, its role declined [114].Other studies revealed a signifcant correlation between Tp-e prolongation and the occurrence of lifethreatening arrhythmic events among patients with BS [115,116].
Importantly, Tp-e was found to be the most promising ECG marker together with QTc interval in predicting malignant arrhythmias among BS patients.However, there is a need to assess the cut-of for the Tp-e value, which signifcantly increases the risk of life-threatening arrhythmias [117].Interestingly, when the BS typical ECG pattern was observed in precordial leads V1-V3, it was simultaneously revealed that the Tp-e interval in V1 lead was signifcantly higher among patients with malignant arrhythmias.In contrast, in the other leads, no signifcant diferences were noted [113].However, in the bigger cohort, it was observed that among BS patients in the mean follow-up of 88 months, Tp-e was not signifcantly prolonged in those with syncope or malignant arrhythmias [118].
A consistent statement on the role of the Tp-e interval in risk stratifcation in BS should be evaluated in further research.Te pathophysiological mechanism is still under debate with the considered potential mechanisms including the "depolarization hypothesis" and "early repolarization hypothesis" [119].
Similarly, as in BS, in patients with J wave syndrome who were aborted from sudden cardiac death, the Tpeak-Tend interval and Tp-Te/QT ratio are signifcantly increased [120].
3.9.Other Cardiovascular Diseases and Sleep Apnea.Te role of Tp-e has been noted concerning various clinical conditions.Importantly, acute myocarditis (AM) is one of these conditions, and prolonged Tp-e, Tp-e/QT, and Tp-e/QTc ratios have been observed in patients with AM [121].What makes an interesting insight into the AM patient's characteristics in terms of ECG changes as usually observed abnormalities are sinus tachycardia or nonspecifc ST-T wave changes [122].However, elucidating the patients' prognosis revealed in the Ucar et al. study parameters among AM patients would make a practical application of these results [121].
Tp-e characteristics in hypertension have been confrmed to be prolonged in nondipper hypertension and positively correlated with the cardio-ankle vascular index in this population [123,124].Tp-e and Tp-e/QTc parameters in patients with arterial hypertension increased in patients with subclinical myocardial dysfunction diagnosed by the echocardiography parameter, left ventricular global longitudinal strain (LV-GLS) [125].
Tp-e and its derivatives were essential parameters in patients with hypothyroidism, where they were prolonged in both overt and subclinical presentations [126,127].As the cardiovascular system is signifcantly afected in liver cirrhosis, it has been revealed that heart rate, Tp-e, Tp-e/QT, and Tp-e/QTc were considerably higher in the diseased group than in the control group [128].Moreover, the same study showed the predictive value of heart rate, Tp-e, and Tpe/QT for end-stage liver cirrhosis, although no correlation with Child stages was observed.Another study confrmed that Tp-e, QTc interval, Tp-e/QTc ratio, and fQRS are increased in liver cirrhosis, noting a parallel association of these parameter prolongations with disease severity [129].However, this contradicted the fndings of the previously mentioned study, as it showed a signifcant correlation with the Pugh-Child classifcation.
Obstructive sleep apnea (OSA) is a risk factor for ventricular arrhythmias.Assessing which patients are at a higher risk of this complication is important, as demonstrated in Yan et al.'s study [130].According to their retrospective analysis, patients who presented nocturnal premature ventricular contractions had a signifcantly higher Tp-e/QT ratio than those with OSA.Another study conducted among patients with OSA revealed a signifcant correlation between moderate and severe OSA and increased Tp-e, Tp-e/QT, and Tp-e/QTc ratios [131].However, fndings describe Tp-e, Tpe/QT, and Tp-e/QTc prolongation only during the apnea period, with a decrease in the postapnea hyperventilation period [132].
Another disease confrmed to be correlated with altered repolarization is chronic obstructive pulmonary disease (COPD), where signifcant prolongation of Tp-e, Tp-e/QT, and Tp-e/QTc ratio compared to the control group was observed [133].According to blood test results, it was revealed that low ferritin levels among female patients without anemia or history of cardiac disease, as well as vitamin B12 defciency in the healthy adult population, infuence their arrhythmogenic susceptibility, which was observed by increased Tp-e, Tp-e/QT, and Tp-e/QTc parameters [134,135].Moreover, the signifcantly higher values of Tp-e, Tp-e/QT, and Tp-e/QTc were also observed in patients with benign paroxysmal positional vertigo who were admitted to the emergency department when compared to the healthy population, suggesting that these patients might be prone to cardiac arrhythmias [136].

Conclusions
In conclusion, Tp-e and its derivatives are very promising ECG markers.Tp-e may be a potential marker in several groups of patients; in each, it may provide diferent vital clinical prognoses.It can be associated with the genetic background of certain diseases, e.g., LQTS or HCM.Moreover, its prolongation may help stratify patients' prognosis among patients with HF cardiomyopathy after several invasive management procedures and those with MI treated by PCI.
In the case of obesity, studies considering conditions from normal weight through overweight and subsequent classes of obesity would be particularly valuable.Te role of Tp-e in VA and SCD is visible, although situations should be evaluated in meta-analysis to reach a consensus on that issue.More randomized trials are needed to defne the parameters infuencing Tp-e duration and the value of its derivatives, and more studies are required to precisely evaluate the association between Tp-e and derived parameters of diseases examined in this study (Figure 3).
Tp-e in V5 in patients with acquired LQTS was longer than those with congenital LQTS Tp-e interval in LQTS patients is useful for the stratifcation of cardiac events risk Tere are significant diferences in Tp-e interval time between LQTS type 1 and type 2, and unafected patients in gender groups Tp-e prolongation was an independent risk factor of VA in STEMI patients afer PCI and of 1-year MACE in patients with MI afer PCI MINOCA patients with significantly higher risk of VA had higher values of Tp-e and Tp-e/QT Patients without PIA who had longer Tp-e interval more ofen sufered from in-hospital VA Tp-e interval may be an important parameter according to: Tp-e is a predictor of mortality in chronic and acute HF, including patients with ICD Tp-e is a potential prognostic marker of response of resynchronization therapy in HF patients Tp-e has higher values in HFrEF than HFpEF patients In genetically determined HCM patients Tp-e was more ofen signifcantly prolonged Higher Tp-e among patients with non-ischemic dilated cardiomyopathy was associated with malignant VA His-bundle pacing was associated with Tp-e shortening Tp-e and Tp-e/QT ratio are potential risk markers of lef ventricular noncompaction cardiomyopathy Tp-e in prolongation is positively correlated with BMI in general population Among class 3 obesity patients weight loss due to the bariatric surgery or sleeve gastrectomy surgery were correlated with decreased Tp-e and its derivatives

Figure 3 :
Figure 3: Tp-e interval: current state of knowledge summary.