Patients and methods: Between July 2009 and February 2023, a total of 33 patients (8 males, 25 females; median age: 61 years; range, 55 to 70 years) with chronic thromboembolic pulmonary hypertension (CTEPH) who underwent electrocardiographic (ECG) examination were retrospectively analyzed. The fQRS-T angle was calculated from surface ECGs. Functional class, 6-min walk distance, and brain natriuretic peptide values were recorded. Two-dimensional echocardiographic data including comprehensive right ventricular (RV) functions, right atrial area (RAA), tricuspid annular systolic plane excursion (TAPSE), systolic pulmonary artery pressure (sPAP), and TAPSE/sPAP ratio were noted. Among invasive hemodynamic variables, sPAP, mean PAP (mPAP), pulmonary vascular resistance (PVR), and cardiac index (CI) were obtained. The correlations between clinical, echocardiographic, and hemodynamic variables were analyzed.

Results: There was no significant correlation between clinical variables and fQRS-T angle. The TAPSE and TAPSE/sPAP ratio were negatively correlated with fQRS/T angle (r=-0.37, p=0.02, r=-0.35, and p=0.03, respectively), whereas RV Tei index and RAA were positively correlated with the fQRS-T angle (r=0.53, p=0.014, r=0.47, and p=0.007, respectively). The hemodynamic data including sPAP, mPAP, and PVR were positively correlated with the fQRS-T angle (r=0.32, p=0.048, r=0.34, p=0.034, r=0.35, and p=0.02, respectively) and CI was negatively correlated with the fQRS-T angle (r=-0.30, p=0.048).

Conclusion: Our study results suggest that the fQRS/T angle is correlated with poor prognostic echocardiographic and hemodynamic variables in CTEPH patients.

Various clinical, echocardiographic, and hemodynamic variables are currently been used in risk stratification in Group 1 PH.[4] It has been demonstrated that European Society of Cardiology (ESC)/European Respiratory Society (ERS) risk stratification tool is also appropriate in CTEPH patients.[5] Nevertheless, additional more simplified risk assessment tools are warranted in patients with PH.

Electrocardiography (ECG) is a basic, readily accessible diagnostic modality in patients with cardiovascular disease and can mirror the cardiac anatomical and hemodynamic changes induced by PH in terms of cardiac electrical activity in CTEPH patients.

The frontal QRS-T (fQRS-T) angle is expressed as a manifestation of myocardial repolarization and depolarization diversity and is computed by the difference between ventricular depolarization (QRS axis in ECG) and repolarization (T wave).[6] It has been shown that alterations in QRS-T angle correlate with echocardiographic systolic PA pressure (sPAP), right atrial (RA) and right ventricular (RV) size, and impaired RV functions in CTEPH patients.[7]

In the present study, we aimed to examine the relationships between fQRS-T angle prognostic risk factors outlined in the current PH guidelines and to demonstrate whether the fQRS-T could detect patients with unfavorable echocardiographic and hemodynamic data.

Data collection
Institutional medical records were used for demographic, anthropometric, laboratory, ECG, echocardiographic, and hemodynamic data. The laboratory parameters including baseline serum glucose, creatinine, estimated glomerular filtration rate (eGFR), and brain natriuretic peptide (BNP) were recorded.

Electrocardiography
Utilizing a paper rate of 25 mm/sec and a standard deviation of 0.1 mV/mm, a 12-lead ECG was obtained from each patient. Heart rate (HR), PR interval, QRS duration, QT and QTc interval, QRS axis, and T axis were all automatically computed by the ECG machine and examined by a cardiologist. Using the T and QRS axis, the fQRS-T angle was computed. If the computed angle was more than 180 degrees, 360 - [obtained angle] was determined as the fQRS-T angle (Figure 1).

Figure 1. An ECG example showing the measurement of the QRS-T angle. The QRS axis and T axis were all automatically computed by the ECG (arrowheads). Using the T and QRS aqis, the fQRS-T angle was computed. If the computed angle was more than 180 degrees, 360 - [obtained angle] was determined as the fQRS-T angle. For this ECG example, the QRS-T angle is 7° (QRS angle= 58°, T angle= 51°).
ECG: Electrocardiographic; fQRS-T: Frontal fQRS-T.

Echocardiography
A Philips HD 11 XE ultrasound system (Philips, Andover, MA, USA) with a 3.2 MHz transducer was used for echocardiographic examination. The RV-focused apical four-chamber (4C) view was used for the linear longitudinal end-diastolic dimension of RV (RVd). The RV fractional area change (RVFAC) was computed as (area at end of diastole - area at the end of systole)/area at end of diastole ¥ 100%.[8] In the apical 4C view, an M-mode cursor was set along the lateral RV wall to the tricuspid annulus. The maximum length of tricuspid annulus movement along systole was specified as tricuspid annular systolic plane excursion (TAPSE). The RA area (RAA) was calculated at the end of the systole from the apical 4C view.

Tissue Doppler imaging was utilized to record the RV systolic (RV S’) rate and RV Tei index. The RV Tei index was determined by dividing the ejection period by the summation of the contraction duration and isovolumetric relaxation duration.[8] Continuous-wave Doppler was used for recording tricuspid regurgitation velocity (TRV). The peak TR gradient was computed by the modified Bernoulli equation [4 x TRV2]. The inferior vena cava (IVC) was visualized from the subcostal view, and patients were advised to quickly inhale or “sniff” throughout the procedure. The RA pressure was estimated using the inspiratory magnitude of IVC collapse and the size of the IVC.[9] The sum of RA pressure and anticipated peak TR gradient was recorded as sPAP.

Right heart catheterization
An expert cardiologist conducted RHC using femoral access, while the patient was at rest and without anesthesia. The RA pressure, PCWP, mPAP, diastolic, and systolic PA pressures (dPAP, and sPAP, respectively) were recorded. Blood gas analyses were obtained. The indirect Fick method was used to evaluate cardiac output (CO). Cardiac index (CI) was calculated as CO/body surface area and the pulmonary vascular resistance (PVR) was determined as [mPAP-PCWP]/CO.

Statistical analysis
Statistical analysis was performed using the IBM SPSS version 26.0 software (IBM Corp., Armonk, NY, USA). The normality of the continuous data was checked with histograms and the Kolmogorov-Smirnov test. Continuous data were expressed in mean ± standard deviation (SD) or median (min-max), while categorical data were expressed in number and frequency. The Pearson and Spearman correlation analyses were used to identify the associations between the fQRS-T angle and clinical, laboratory, echocardiographic, and hemodynamic variables. A p value of <0.05 was considered statistically significant.

Table 1 Baseline characteristics of patients

Electrocardiographic, echocardiographic, and hemodynamic data of the patients are presented in Table 2. The mean HR was 84±14 bpm and the median fQRS-T angle was 47° (range, 20 to 93.5°) degrees. The mean echocardiographic RAA was 22.1±3.9 cm² and the median TAPSE/sPAP ratio was 0.25 (range, 0.14 to 0.39) mm/mmHg. Only three patients (9.1%) had pericardial effusion. The RHC data revealed that the mean RA pressure was 11.9±6.9 mmHg, the mean CI was 2.1±0.6 L/min/m2, and the mean mixed venous oxygen saturation was 57.8±8.3%.

Table 2 Electrocardiographic, echocardiographic, and hemodynamic data of the patients (n=33)

The correlations between the fQRS-T angle and clinical, laboratory, echocardiographic, and hemodynamic variables are given in Table 3 and Figure 2. Accordingly, there was no significant correlation between the fQRS-T angle and clinical and laboratory characteristics of the patients. Among echocardiographic data, however, TAPSE and TAPSE/sPAP ratio were negatively correlated with fQRS/T angle (r=-0.37, p=0.02, and r=-0.35, p=0.03, respectively), whereas the RV Tei index and RAA were positively correlated with fQRS-T angle (r=0.53, p=0.014, and r=0.47, p=0.007, respectively). The hemodynamic data including sPAP, mPAP, and PVR were positively correlated with fQRS-T angle (r=0.32, p=0.048, r=0.34, p=0.034, and r=0.35, p=0.02, respectively) and CI was negatively correlated with the fQRS-T angle (r=-0.30, p=0.048).

Table 3 The bivariate correlations between the fQRS-T angle and clinical, laboratory, echocardiographic, and hemodynamic parameters

Figure 2. The correlations between the fQRS-T angle and echocardiographic and hemodynamic variables. fQRS-T: Frontal QRS-T.

Under normal circumstances, the left ventricular (LV) mass is higher than the RV mass, and RV electrical activity is concealed by LV.[10] Pulmonary hypertension results in RV pressure overload and RV hypertrophy. As RV mass increases, RV contributes to ventricular depolarization and QRS axis changes. The course of the T-axis becomes divergent to QRS-axis and the spatial QRS-T (sQRS-T) angle increase with elevated PH.[11] It was previously shown that, even in the very early phases of PH, the sQRS-T angle was elevated in rats.[10] Henkens et al.[12] also demonstrated that the sQRS-T angle was greater in patients with chronically elevated RV pressure compared with controls.

In the current study, we investigated the clinical, echocardiographic, and invasive hemodynamic correlates of fQRS-T angle CTEPH patients. We were unable to demonstrate a correlation between clinical variables and fQRS-T angle in patients with CTEPH. The inadequate significance can be attributed to the small sample size used in our study. However, we were able to find significant associations between echocardiographic variables including TAPSE, TAPSE/sPAP ratio, RV Tei index, and RAA and fQRS-T angle. Previously, similar to our findings, the QRS-T angle was demonstrated to be linked to echocardiographic variables such as SPAP, dimension of RA and RV, and RV systolic dysfunction and impaired diastolic function in patients with CTEPH.[7] We showed that the fQRS-T angle was negatively associated with TAPSE and TAPSE/sPAP ratio. As TAPSE estimates RV contractile function, an increase in fQRS-T angle CTEPH patients may correspond to RV systolic dysfunction. Recently, a new prognostic parameter was included in the current PH guidelines. The TAPSE/sPAP ratio, which is a surrogate non-invasive marker of RV-PA coupling and provides information about RV diastolic function, was demonstrated to be a significant prognostic variable in PH patients.[13,14] An increase in the fQRS-T angle was also found to be linked to a reduction in TAPSE/sPAP ratio in our study. Therefore, we can speculate that an increase in fQRS-T angle in patients with CTEPH may correspond to impaired both RV diastolic and systolic function. Another parameter that reflects the overall function of the RV is the RV Tei index. The RV Tei index has been shown to be increased in patients with connective tissue-associated-PAH due to RV diastolic dysfunction and decreased myocardial contractility of RV.[15] Similarly, we showed that the RV Tei index was elevated in CTEPH patients and an elevation in the fQRS-T angle corresponded to an increase in RV Tei index of CTEPH patients. Additionally, RAA has been shown to be a valuable prognostic factor in PH patients. The mortality of PH patients increases in patients with elevated values of RAA.[4] In the current study, an increase in fQRS-T angle was linked to an increase in RAA. Our results are consistent with the findings of Sakhnova et al.[7] showing that the QRS-T angle is related to elevated RA size.

In this study, we also examined the correlations between the fQRS-T angle and invasive hemodynamic data in CTEPH patients. The sPAP, mPAP, and PVR correlated positively, whereas CI was negatively correlated with the fQRS-T angle. The positive correlation between sPAP, mPAP, and PVR and fQRS-T angle is comprehensible as an increase in PA pressures and PVR results in an increase in RV mass and a change in QRS and T-axis, resulting in an increased QRS-T angle.[11] Chronic pressure and volume overload on RV in patients with PH modify the geometry of RV. As a result, RV occupies more space in the pericardium and causes paradoxical interventricular septum movement, thereby leading to a decrease in LV volume at end-diastole.[16] The decrease in LV diastolic volume at end-diastole results in altered LV stroke volume as explained by the Frank- Starling mechanism.[17] This may explain the negative correlation between CI and fQRS-T angle.

Nonetheless, this study has several limitations. First, our study has a single-center, retrospective design. Second, since CTEPH is a rare condition, the number of patients is limited. Although multi-center studies involving more patients on this subject are needed, we believe that our study may be a pioneer for further studies on this subject. In addition, although we have long-term follow-up data, the impact of the fQRS-T angle on prognosis in CTEPH patients is unclear due to the small number of subjects. Another limitation of our study was the utilization of an fQRS-T angle instead of an sQRS-T angle. However, the fQRS-T angle has been used instead of the sQRS-T angle in studies on cardiovascular diseases. The main reason for this is that sQRS-T angle measurement is complicated and necessitates sophisticated computer programs. On the contrary, the fQRS-T angle can be simply calculated from the automatic description of the ECG machine.

In conclusion, ECG seems to be a tool that should not be ignored in the evaluation of CTEPH patients. In these patients, the fQRS-T angle, which can be computed simply by ECG, is negatively correlated with TAPSE, TAPSE/sPAP ratio, and CI, while it is positively correlated with RV Tei index, RAA, sPAP, mPAP, and PVR, which are important prognostic factors in patients with PH.

Ethics Committee Approval: The study protocol was approved by the Dokuz Eylül University Faculty of Medicine Ethics Committee (date: 29.03.2023, no: 2023/10-14). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Patient Consent for Publication: A written informed consent was obtained from each patient.

Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions: Idea/concept, writing the article: A.Ç., M.K.; Design: M.K., B.A.; Control/supervision: B.A.; Data collection and/or processing: Z.K., D.S.; Analysis and/or interpretation, materials: A.Ç., Z.K.; Critical review: B.A., B.Ş.; References and fundings: A.Ç., B.Ş.

Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding: The authors received no financial support for the research and/or authorship of this article.

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