ABSTRACT
Right heart catheterization defines pulmonary hypertension (PH) hemodynamics, but simple markers of pulmonary vascular load remain useful. Inferior‐lead T‐wave inversion (TWI) is seen in right ventricular pressure overload; its association with pulmonary vascular resistance (PVR) and prognosis is uncertain. We retrospectively studied a cohort of 98 patients who underwent electrocardiography (ECG), echocardiography, and right heart catheterization within 48 h from 2021 to 2023. Inferior TWI amplitudes in leads II, III, and aVF were measured as absolute values and summed. Associations with PVR, performance for PVR > 5 Wood units, and all‐cause mortality were evaluated. Twenty‐five patients (26%) had PVR > 5 Wood units. The inferior TWI sum correlated with PVR (ρ = 0.326, p = 0.001) and discriminated PVR > 5 Wood units better than conventional ECG markers (area under the curve, 0.78). A cutoff > 0.10 mV yielded 72% sensitivity, 84% specificity, and an odds ratio of 13.1 (95% confidence interval [CI], 4.5–38.1; p < 0.001). During a median follow‐up of 731 days, 19 patients died. Inferior TWI sum > 0.15 mV was associated with higher mortality (log‐rank p = 0.015) and remained associated after adjustment for age and log2 N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) (hazard ratio, 3.83; 95% CI, 1.48–9.90; p = 0.007). Adding this ECG marker increased the global chi‐square from 12.0 to 19.3. Quantitative inferior‐lead TWI was associated with high PVR and all‐cause mortality in patients evaluated for PH. It may complement non‐invasive assessment and right heart catheterization but requires external validation.
Keywords: electrocardiography, prognosis, pulmonary hypertension, pulmonary vascular resistance, right heart catheterization, T‐wave inversion
Pulmonary hypertension (PH) is defined by invasive hemodynamics and encompasses a heterogeneous group of pulmonary vascular, cardiac, and respiratory disorders [1, 2]. Across PH phenotypes, the clinical consequences of pulmonary vascular disease are mediated through right ventricular (RV) afterload and RV‐pulmonary vascular interaction [3]. Among right heart catheterization (RHC)‐derived variables, pulmonary vascular resistance (PVR) provides an integrated pressure‐flow measure of the resistive component of RV afterload and is central to hemodynamic phenotyping, severity assessment, and therapeutic decision‐making [1, 2, 3]. Although contemporary diagnostic thresholds use lower PVR cutoffs, PVR > 5 Wood units has been used to identify severe pulmonary vascular involvement in selected PH settings and in previous ECG‐based diagnostic work [1, 4].
RHC remains the reference standard for PH diagnosis and classification; however, it is invasive and cannot serve as a frequent serial test in all patients. Thus, low‐cost and repeatable markers that raise suspicion for high pulmonary vascular load could be useful for triage and risk enrichment, particularly in non‐specialist settings. Standard 12‐lead electrocardiography (ECG) is attractive for this purpose because it is inexpensive, available, and routinely obtained in patients with unexplained dyspnea or suspected PH. Prior ECG studies in PH have focused mainly on right axis deviation, right atrial enlargement, RV hypertrophy criteria, or right precordial repolarization abnormalities [5, 6, 7, 8, 9]. Many conventional ECG signs show high specificity but limited sensitivity, and several have been evaluated against echocardiographic estimates, RV size, or RV mass rather than invasively measured PVR [5, 6, 7, 8]. T‐wave inversion (TWI) reflects altered ventricular repolarization and is a recognized feature of RV pressure overload. While right precordial TWI is well described, inferior‐lead TWI in leads II, III, and aVF is also encountered clinically and may reflect a frontal‐plane component of RV strain. Its direct association with catheterization‐derived PVR and prognosis in patients undergoing PH evaluation remains uncertain. The aim of this study was to determine whether the quantitative sum of inferior‐lead TWI amplitudes is associated with invasively measured PVR, discriminates high PVR, and provides prognostic information for all‐cause mortality.
1. Methods
1.1. Study Design and Population
This was a single‐center retrospective observational study evaluating associations between ECG findings, invasive hemodynamics, and prognosis in patients referred for PH assessment. Consecutive patients who underwent echocardiography and RHC within 48 h, with a standard 12‐lead ECG obtained before RHC, at the University of the Ryukyus Hospital between 2021 and 2023 were screened. The indication for RHC was evaluation of suspected or established PH. Patients were excluded for left ventricular pacing, missing thermodilution‐derived cardiac output/cardiac index, or poor‐quality ECG recordings. PH groups were assigned according to contemporary guideline‐based classification using clinical, echocardiographic, imaging, and hemodynamic data [1, 2]. Patients who did not meet invasive hemodynamic criteria for PH were categorized as non‐PH. Because both PH and non‐PH patients were included, the study population is described as patients evaluated for PH. The study protocol was approved by the Institutional Review Board of the University of the Ryukyus Hospital (approval number: 24‐2371‐00‐00‐00). The requirement for written informed consent was waived because of the retrospective design, and information about the study was disclosed on the institutional website with an opt‐out opportunity. The study was conducted in accordance with the Declaration of Helsinki.
1.2. Electrocardiographic Assessment
Standard 12‐lead ECGs were obtained before RHC using Nihon Kohden electrocardiographs (Nihon Kohden Corporation, Tokyo, Japan), recorded at a paper speed of 25 mm/s and a calibration of 10 mm/mV. Automated ECG measurements were obtained using the manufacturer‐provided measurement function. ECGs with poor recording quality and those showing left ventricular pacing were excluded. Right bundle branch block and other ECG findings were retained and analyzed as clinical ECG parameters. TWI amplitudes in leads II, III, and aVF were measured using the automated ECG analysis output generated by the recording system. TWI amplitude was defined as the absolute vertical distance from the isoelectric baseline to the nadir of an inverted T wave. If TWI was absent, the amplitude for that lead was assigned as 0 mV. The inferior TWI sum was calculated as the sum of TWI amplitudes in leads II, III, and aVF. TWI amplitudes in leads V1, V2, and V3 were also analyzed for comparison. Conventional ECG parameters for RV overload or PH were assessed as shown in Table 2, including P pulmonale, right axis deviation, S1Q3T3 pattern, S1S2S3 pattern, R in V1/V2 plus S in V5/V6, deep R wave in V1, deep S waves in V5 and V6, complete right bundle branch block, and qR in V1.
Table 2.
Diagnostic performance of electrocardiographic parameters for identifying PVR > 5 Wood units.
| Parameters | AUC | Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) | Odds Ratio (95% CI) | p value |
|---|---|---|---|---|---|---|---|
| P pulmonale (> 2.5 mm) | 0.56 | 12 | 100 | 100 | 77 | — | 0.004 |
| Right axis deviation (> 90°) | 0.56 | 60 | 29 | 22 | 68 | 0.6 (0.2–1.6) | 0.303 |
| S1Q3T3 pattern | 0.56 | 12 | 100 | 100 | 77 | — | 0.004 |
| S1S2S3 pattern | 0.53 | 8 | 97 | 50 | 76 | 3.1 (0.4–23.2) | 0.283 |
| R (V1, V2) + S (V5, V6) > 1.05 mV | 0.63 | 68 | 58 | 35 | 84 | 2.9 (1.1–7.5) | 0.026 |
| Deep R wave in V1 (> 0.6 mV) | 0.63 | 36 | 89 | 53 | 80 | 4.6 (1.5–13.7) | 0.007 |
| Deep S wave in V5 (> 1.0 mV) | 0.57 | 28 | 86 | 41 | 78 | 2.5 (0.8–7.4) | 0.117 |
| Deep S wave in V6 (> 0.3 mV) | 0.64 | 56 | 73 | 41 | 83 | 3.4 (1.3–8.7) | 0.011 |
| Complete right bundle branch block | 0.55 | 28 | 82 | 35 | 77 | 1.8 (0.6‐5.2) | 0.287 |
| qR in V1 | 0.59 | 24 | 95 | 60 | 78 | 5.4 (1.4–21.3) | 0.014 |
| Sum of TWI amplitudes in inferior leads (> 0.1 mV) | 0.78 | 72 | 84 | 60 | 90 | 13.1 (4.5–38.1) | < 0.001 |
| Sum of TWI amplitudes in inferior leads (> 0.1 mV), CAD excluded (n = 74) | 0.79 | 72 | 80 | 54 | 90 | 10.6 (3.1‐36.2) | < 0.001 |
Note: Values in the sensitivity analysis cohort (n = 74) were calculated after excluding all patients with coronary artery disease.
Abbreviations: AUC, area under the receiver operating characteristic curve; CI, confidence interval; NPV, negative predictive value; PPV, positive predictive value; PVR, pulmonary vascular resistance; TWI, T‐wave inversion. CAD, coronary artery disease.
1.3. Echocardiography and Right Heart Catheterization
Comprehensive transthoracic echocardiography was performed within 48 h of RHC by experienced sonographers or cardiologists using commercially available high‐end ultrasound systems. TRV, tricuspid annular plane systolic excursion, RV fractional area change, and tricuspid annular systolic tissue Doppler velocity were measured according to institutional practice and guideline recommendations [10, 11]. RHC was performed using a Swan‐Ganz catheter via the internal jugular or femoral vein approach. Mean right atrial pressure, mean pulmonary arterial pressure, pulmonary arterial wedge pressure, mixed venous oxygen saturation, and cardiac output were measured using standard techniques. Cardiac output was determined by thermodilution. PVR was calculated as (mean pulmonary arterial pressure ‐ pulmonary arterial wedge pressure)/cardiac output and expressed in Wood units. High PVR was defined as PVR > 5 Wood units for diagnostic‐performance analyses. This exploratory threshold was selected to identify markedly elevated pulmonary vascular resistance and was informed by its use in selected PH settings and previous ECG‐based diagnostic research [1, 4].
1.4. Outcomes and Follow‐Up
Patients received regular follow‐up at our institution or affiliated clinics from the index visit until the occurrence of an outcome event or the end of surveillance. The primary prognostic outcome was all‐cause mortality. Survival time was calculated from the date of ECG to the date of death or last follow‐up. Vital status was ascertained from medical records, and follow‐up was censored on September 30, 2025.
1.5. Statistical Analysis
Continuous variables are presented as medians with interquartile ranges and categorical variables as numbers with percentages. Between‐group comparisons were performed using the Mann‐Whitney U test for continuous variables and the chi‐square test or Fisher exact test for categorical variables, as appropriate. Correlations between PVR and ECG or clinical parameters, as well as between the inferior TWI sum and RV functional parameters, were assessed using Spearman rank correlation coefficients. Diagnostic performance for PVR > 5 Wood units was evaluated using receiver operating characteristic analysis, with sensitivity, specificity, positive predictive value, negative predictive value, and odds ratios calculated for relevant cutoffs. The diagnostic cutoff for the inferior TWI sum was determined by receiver operating characteristic analysis using the Youden index. Survival was estimated by the Kaplan‐Meier method and compared using the log‐rank test. Cox proportional hazards models were used for univariable and multivariable analyses. NT‐proBNP values were log2‐transformed before Cox regression so that hazard ratios represent the effect of a doubling of NT‐proBNP. Because of the limited number of deaths, the multivariable model was intentionally parsimonious and included age, log2 NT‐proBNP, and inferior TWI sum > 0.15 mV. The prognostic threshold of > 0.15 mV was evaluated as an exploratory, clinically interpretable cutoff and should be externally validated. Incremental prognostic value was assessed by changes in model global chi‐square statistics. A two‐sided p < 0.05 was considered statistically significant. Analyses were performed using JMP software, version 19 (SAS Institute Inc., Cary, NC, USA).
2. Results
2.1. Patient Characteristics
Among 107 screened patients, 9 were excluded because of left ventricular pacing (n = 4), missing thermodilution‐derived cardiac output/cardiac index (n = 2), or poor‐quality ECG recordings (n = 3). The final cohort included 98 patients (Figure 1). The median age was 66 [52–77] years, and 68 patients (69%) were male. The diagnostic categories were Group 1 PH/pulmonary arterial hypertension in 20 patients, Group 2 PH due to left heart disease in 33, Group 3 PH due to lung disease in 9, Group 4 chronic thromboembolic PH in 17, Group 5 PH in 1, and non‐PH in 18 (Table 1). Twenty‐five patients (26%) had PVR > 5 Wood units. Compared with patients with PVR ≤ 5 Wood units, those with PVR > 5 Wood units had worse World Health Organization functional class, shorter 6‐min walk distance, higher TRV, lower RV fractional area change, higher mean pulmonary arterial pressure, lower cardiac index, lower mixed venous oxygen saturation, and greater inferior TWI sum (Table 1). Median inferior TWI sum was 0 [0–0.082] mV in the PVR ≤ 5 group and 0.187 [0.036–0.525] mV in the PVR > 5 group (p < 0.001).
Figure 1.
Patient flow diagram. Of 107 patients who underwent echocardiography and right heart catheterization within 48 h, with electrocardiography performed before right heart catheterization between 2021 and 2023, 9 were excluded: left ventricular pacing (n = 4), missing thermodilution‐derived cardiac output/cardiac index (n = 2), and poor‐quality ECG recording (n = 3). The remaining 98 patients were included in baseline, correlation, diagnostic performance, and survival analyses. ECG, electrocardiography; RHC, right heart catheterization.
Table 1.
Baseline characteristics of patients.
| All (N = 98) | PVR ≤ 5 Group (N = 73) | PVR > 5 Group (N = 25) | p value | |
|---|---|---|---|---|
| Demographics | ||||
| Age (years) | 66 [52–77] | 66 [53–77] | 67 [50–78] | 0.990 |
| Male gender, n (%) | 68 (69) | 49 (67) | 19 (76) | 0.461 |
| BMI (kg/m2) | 23.5 [21.0–26.5] | 23.3 [21.3–26.5] | 23.6 [20.8–26.7] | 0.896 |
| Diagnosis, n (%) | < 0.001 | |||
| Group 1 (PAH) | 20 (20) | 13 (18) | 7 (28) | |
| Group 2 (PH‐LHD) | 33 (34) | 26 (36) | 7 (28) | |
| Group 3 (PH‐Lung) | 9 (9) | 3 (4) | 6 (24) | |
| Group 4 (CTEPH) | 17 (17) | 13 (18) | 4 (16) | |
| Group 5 | 1 (1) | 0 (0) | 1 (4) | |
| Non‐PH | 18 (18) | 18 (25) | 0 (0) | |
| Clinical status | ||||
| WHO‐FC, n (%) | 0.014 | |||
| Class I | 8 (8) | 8 (11) | 0 (0) | |
| Class II | 61 (64) | 48 (68) | 13 (52) | |
| Class III | 23 (24) | 12 (17) | 11 (44) | |
| Class IV | 4 (4) | 3 (4) | 1 (4) | |
| 6MWD (m) | 362 [245–455] | 413 [306–473] | 266 [160–355] | 0.004 |
| Laboratory data | ||||
| Hemoglobin (g/dL) | 13.1 [11.3–14.3] | 13.0 [11.0–14.3] | 14.0 [11.6–15.3] | 0.119 |
| eGFR (mL/min/1.73 m2) | 55.0 [37.0–71.0] | 55.5 [36.3–70.8] | 52.0 [38.5–75.0] | 0.760 |
| Total bilirubin (mg/dL) | 0.7 [0.5–1.0] | 0.7 [0.5–1.0] | 0.8 [0.6–1.1] | 0.316 |
| NT‐proBNP (pg/mL) | 902 [122–3174] | 641 [99–3474] | 1107 [420–2726] | 0.427 |
| Echocardiographic indices | ||||
| TRV (m/s) | 2.88 [2.37–3.32] | 2.64 [2.18–2.97] | 3.67 [3.05–4.13] | < 0.001 |
| TAPSE (mm) | 18.0 [14.0–20.0] | 19.0 [15.5–21.8] | 17.0 [14.0–20.0] | 0.208 |
| RV‐FAC (%) | 33.0 [23.0–39.3] | 36.0 [32.0–39.0] | 23.0 [14.0–40.0] | 0.033 |
| TV‐S’(cm/s) | 11.8 [9.8–13.0] | 11.8 [10.0–13.0] | 11.6 [9.0–12.5] | 0.583 |
| Hemodynamics | ||||
| Mean RAP (mmHg) | 7 [4–10] | 7 [4‐9] | 7 [5‐12] | 0.118 |
| Mean PAP (mmHg) | 25 [20–36] | 22 [18–29] | 39 [35–49] | < 0.001 |
| Cardiac index (L/min/m2) | 2.46 [1.91–3.07] | 2.60 [2.14–3.35] | 2.00 [1.80–2.45] | 0.002 |
| PVR (Wood units) | 3.0 [1.9–5.1] | 2.3 [1.6–3.4] | 7.1 [6.1–9.3] | < 0.001 |
| SvO2 (%) | 66.5 [60.0–72.0] | 68.5 [63.3–74.0] | 63.0 [51.3–65.0] | < 0.001 |
| Electrocardiogram | ||||
| Heart rate (bpm) | 77 [63–85] | 77 [66–86] | 76 [58–86] | 0.420 |
| Inferior TWI sum (mV) | 0 [0–0.136] | 0 [0–0.082] | 0.187 [0.036–0.525] | < 0.001 |
Note: Data are expressed as n (%) or median [interquartile range].
Abbreviations: 6MWD, 6‐min walk distance; BMI, body mass index; eGFR, estimated glomerular filtration rate; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RV FAC, right ventricular fractional area change; SvO2, mixed venous oxygen saturation; TAPSE, tricuspid annular plane systolic excursion; TWI, T‐wave inversion; WHO‐FC, World Health Organization functional class.
2.2. Association of Inferior TWi With PVR and RV Function
The inferior TWI sum was significantly correlated with PVR (ρ = 0.326, p = 0.001; Supporting Information S1: Table S1). Among individual inferior leads, TWI amplitude in lead III showed the strongest correlation with PVR (ρ = 0.378, p < 0.001), followed by lead aVF (ρ = 0.272, p = 0.007) and lead II (ρ = 0.176, p = 0.084). By comparison, right precordial TWI amplitudes showed weaker correlations with PVR: lead V1 (ρ = 0.244, p = 0.015), lead V2 (ρ = 0.187, p = 0.065), and lead V3 (ρ = 0.201, p = 0.047). In subgroup analyses, the inferior TWI sum remained positively correlated with PVR in both groups, with a moderate correlation in Group 1 PH/pulmonary arterial hypertension (ρ = 0.587, p = 0.007) and a weaker, non‐significant correlation in Group 4 chronic thromboembolic PH (ρ = 0.317, p = 0.215; Supporting Information S1: Table S2). Regarding right ventricular functional parameters, the inferior TWI sum showed a significant negative correlation with right ventricular fractional area change (Spearman ρ = −0.416, p = 0.015). Patients with an inferior TWI sum > 0.10 mV had significantly lower right ventricular fractional area change than those with an inferior TWI sum ≤ 0.10 mV (p = 0.0074), whereas TAPSE and TV‐S' showed no significant associations.
2.3. Diagnostic Performance for PVR > 5 Wood Units
The diagnostic performance of ECG parameters for identifying PVR > 5 Wood units is summarized in Table 2. Several conventional ECG findings were highly specific but insensitive. P pulmonale and the S1Q3T3 pattern each showed 12% sensitivity and 100% specificity. qR in V1 showed 24% sensitivity and 95% specificity. The inferior TWI sum showed the best overall discrimination among the assessed ECG parameters, with an area under the curve of 0.78. A cutoff > 0.10 mV yielded 72% sensitivity, 84% specificity, 60% positive predictive value, and 90% negative predictive value, with an odds ratio of 13.1 (95% CI, 4.5–38.1; p < 0.001) for PVR > 5 Wood units. In our cohort, 24 patients (25%, 24/98) had coronary artery disease. In a sensitivity analysis excluding these 24 patients (n = 74), the inferior TWI sum still correlated with PVR (Spearman ρ = 0.307, p = 0.008). For identifying PVR > 5 Wood units, the diagnostic accuracy remained high (area under the curve, 0.79; cutoff > 0.10 mV: sensitivity, 72% [13/18]; specificity, 80% [45/56]; positive predictive value, 54% (13/24); negative predictive value, 90% [45/50]; odds ratio, 10.6 [95% CI, 3.1–36.2]; p < 0.001).
2.4. Outcome Analysis
During a median follow‐up of 731 days, 19 patients died. The causes of death are summarized in Supporting Information S1: Table S3: definite or presumed PH/RV failure death (n = 6, 32%), sudden death or other cardiovascular deaths (n = 8, 42%), malignancy (n = 2, 10%), and other non‐cardiovascular deaths (n = 3, 16%). Among the 6 patients with definite or presumed PH/RV failure death, 5 (83%) had an inferior TWI sum > 0.15 mV. Kaplan‐Meier analysis demonstrated significantly higher all‐cause mortality among patients with an inferior TWI sum > 0.15 mV than among those with an inferior TWI sum ≤ 0.15 mV (log‐rank p = 0.015; Figure 2). In univariable Cox analyses, age, World Health Organization functional class, 6‐min walk distance, log2 NT‐proBNP, estimated glomerular filtration rate, PVR, and inferior TWI sum > 0.15 mV were associated with all‐cause mortality (Table 3). The univariable hazard ratio for inferior TWI sum > 0.15 mV was 2.92 (95% CI, 1.18–7.20; p = 0.025). After adjustment for age and log2 NT‐proBNP, inferior TWI sum > 0.15 mV remained independently associated with all‐cause mortality (hazard ratio, 3.83; 95% CI, 1.48–9.90; p = 0.007). Incremental model analysis showed that the global chi‐square statistic increased from 8.1 for age alone to 12.0 after adding log2 NT‐proBNP and to 19.3 after adding inferior TWI sum > 0.15 mV (Figure 3).
Figure 2.
Kaplan‐Meier curves for all‐cause mortality according to inferior TWI sum. Patients with an inferior TWI sum > 0.15 mV had significantly higher mortality than those with an inferior TWI sum ≤ 0.15 mV (log‐rank p = 0.015). TWI, T‐wave inversion.
Table 3.
Univariable and multivariable Cox proportional hazards analyses for all‐cause mortality.
| Variables | Univariate HR (95% CI) | p value | Adjusted HR (95% CI) | p value |
|---|---|---|---|---|
| Clinical characteristics | ||||
| Age (per 1 year) | 1.05 (1.02–1.09) | 0.003 | 1.04 (1.01–1.08) | 0.009 |
| WHO Functional Class | 2.41 (1.24–4.53) | 0.010 | ||
| 6MWD (per 10 m) | 0.90 (0.80–0.98) | 0.013 | ||
| Laboratory findings | ||||
| log2 NT‐proBNP (per doubling) | 1.23 (1.06–1.43) | 0.008 | 1.23 (1.01–1.51) | 0.041 |
| eGFR (per 10 mL/min/1.73 m2) | 0.83 (0.69–0.99) | 0.038 | ||
| Total bilirubin (mg/dL) | 1.34 (0.63–2.29) | 0.402 | ||
| Echocardiographic parameters | ||||
| TRV (m/s) | 1.59 (0.91–2.72) | 0.101 | ||
| TAPSE (mm) | 0.89 (0.77–1.03) | 0.119 | ||
| Hemodynamic parameters (RHC) | ||||
| Mean RAP (mmHg) | 1.00 (0.90–1.08) | 0.947 | ||
| Mean PAP (mmHg) | 1.03 (0.99–1.07) | 0.111 | ||
| Cardiac index (L/min/m2) | 0.67 (0.35–1.17) | 0.165 | ||
| SvO2 (%) | 0.97 (0.94–1.01) | 0.154 | ||
| PVR (Wood units) | 1.11 (1.00–1.20) | 0.047 | ||
| Electrocardiographic parameters | ||||
| TWI amplitudes in lead II (per 0.1 mV) | 1.43 (0.94–1.90) | 0.086 | ||
| TWI amplitudes in lead III (per 0.1 mV) | 1.32 (0.95–1.69) | 0.091 | ||
| TWI amplitudes in lead aVF (per 0.1 mV) | 1.40 (0.97–1.81) | 0.067 | ||
| TWI amplitudes in lead V1 (per 0.1 mV) | 1.11 (0.81–1.39) | 0.483 | ||
| TWI amplitudes in lead V2 (per 0.1 mV) | 0.96 (0.69–1.19) | 0.760 | ||
| TWI amplitudes in lead V3 (per 0.1 mV) | 0.84 (0.53–1.11) | 0.253 | ||
| Sum of TWI amplitudes in inferior leads (> 0.15 mV) | 2.92 (1.18–7.20) | 0.025 | 3.83 (1.48–9.90) | 0.007 |
Abbreviations: 6MWD, 6‐min walk distance; CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio; mPAP, mean pulmonary arterial pressure; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RHC, right heart catheterization; SvO2, mixed venous oxygen saturation; TAPSE, tricuspid annular plane systolic excursion; TRV, tricuspid regurgitation velocity; TWI, T‐wave inversion; WHO‐FC, World Health Organization functional class.
Figure 3.
Incremental prognostic value of the inferior TWI sum for all‐cause mortality. The global chi‐square statistic increased from 8.1 for age alone to 12.0 after adding log2 NT‐proBNP and to 19.3 after adding inferior TWI sum > 0.15 mV. Multivariable analysis was performed on 93 patients with complete data. NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; TWI, T‐wave inversion.
2.5. Representative Cases
Supporting Information S1: Figure S1 shows two representative Group 1 pulmonary arterial hypertension cases with borderline TRV and normal NT‐proBNP levels. The first patient had high PVR (5.91 Wood units), high mean pulmonary arterial pressure (38 mmHg), borderline TRV (3.16 m/s), normal NT‐proBNP (45 pg/mL), and a high inferior TWI sum (0.547 mV). The second patient had lower PVR (2.31 Wood units), lower mean pulmonary arterial pressure (22 mmHg), similar borderline TRV (2.92 m/s), normal NT‐proBNP (106 pg/mL), and no inferior TWI (0 mV). These cases illustrate how the inferior TWI sum may provide additional information when conventional non‐invasive markers are borderline or apparently reassuring.
3. Discussion
In this single‐center retrospective cohort of patients evaluated for PH, the quantitative sum of inferior‐lead TWI amplitudes was associated with catheterization‐derived PVR and all‐cause mortality. Four findings are clinically relevant. First, the inferior TWI sum showed a modest correlation with PVR, and this correlation was stronger than those observed for TWI amplitudes in leads V1 to V3. Second, the inferior TWI sum discriminated PVR > 5 Wood units with an area under the curve of 0.78, whereas conventional ECG markers were generally specific but insensitive. Third, an inferior TWI sum > 0.15 mV identified patients with higher all‐cause mortality. Fourth, this prognostic association persisted after adjustment for age and NT‐proBNP and improved the model global chi‐square. Together, these findings suggest that quantitative inferior‐lead TWI may capture a clinically meaningful component of RV‐pulmonary vascular load; however, the results should be interpreted as hypothesis‐generating until externally validated.
Existing ECG studies in PH have mostly examined whether ECG can detect PH, RV hypertrophy, or RV dilation. Al‐Naamani et al. showed that conventional ECG findings may support a diagnosis of PH but have limited sensitivity [5]. In a previous Pulmonary Circulation study, Blyth et al. reported that the ECG‐derived Butler‐Leggett score correlated with cardiac magnetic resonance‐derived RV mass in pulmonary arterial hypertension, but the score was highly specific and relatively insensitive for RV hypertrophy [6]. Other studies similarly demonstrated that ECG criteria can reflect RV pressure load or remodeling but have limited sensitivity for detecting RV structural abnormalities [7, 8]. More recently, Ley et al. evaluated the diagnostic performance of ECG parameters for PH and severe PH and proposed a modified ECG parameter [4]. Unlike previous studies that evaluated T‐wave inversion qualitatively or according to its distribution, our study quantified inferior‐lead T‐wave inversion using automated ECG measurements. Our findings are consistent with the specificity‐sensitivity tradeoff of conventional ECG criteria but extend the literature by anchoring a simple repolarization marker directly to invasively measured PVR and by showing an association with all‐cause mortality. Notably, our newly proposed inferior TWI sum provided a much more balanced diagnostic profile for identifying high PVR, achieving an area under the curve of 0.78 with optimal sensitivity and specificity.
The association between inferior TWI and high PVR is biologically plausible but should not be considered mechanistically proven by this study. PVR represents the resistive component of RV afterload, whereas RV adaptation and clinical outcome are also influenced by pulsatile load, contractile reserve, ventricular interdependence, and RV‐pulmonary vascular coupling [3]. Chronic elevation of pulmonary vascular load can increase RV wall stress, alter RV geometry, and affect ventricular depolarization and repolarization. These changes may contribute to the development of T‐wave inversion [3]. Moreover, because the normal 12‐lead ECG is dominated by left ventricular electrical activity, substantial right ventricular hypertrophy is generally required before characteristic RV‐related repolarization abnormalities become apparent on the surface ECG. Previous studies have shown that extended T‐wave inversion in pulmonary hypertension is associated with right ventricular enlargement and adverse prognosis [9]. Inferior‐lead TWI may capture a frontal‐plane manifestation of RV strain or altered repolarization, whereas right precordial leads may capture a more anterior component. The stronger association of inferior than precordial TWI with PVR in this cohort is therefore intriguing, but further studies integrating ECG with cardiac magnetic resonance imaging, echocardiographic RV strain, or vectorcardiographic analysis are needed to clarify the anatomical and electrophysiological basis of this finding. Previous longitudinal studies have shown that ECG abnormalities related to RV overload may improve after effective treatment of PAH or CTEPH, in parallel with hemodynamic and right ventricular remodeling [12, 13].
From a clinical perspective, the inferior TWI sum has several attractive features: it is derived from a standard 12‐lead ECG, is quantitative, and can be measured automatically. The diagnostic performance should be interpreted in context. A cutoff > 0.10 mV had a high negative predictive value for PVR > 5 Wood units in this cohort, which may be useful for triage or risk enrichment. Conversely, the positive predictive value was modest, so an abnormal value should not be treated as diagnostic of high PVR. The marker is not intended to replace echocardiography or RHC. Rather, it may complement symptoms, biomarkers, and echocardiographic findings when deciding whether more careful PH evaluation is warranted. The representative cases in our study illustrate this potential role: the inferior TWI sum differed markedly between two patients with borderline TRV and normal NT‐proBNP but discordant invasive PVR (Supporting Information S1: Figure S1). Although coronary artery disease can cause inferior TWI, our sensitivity analysis excluding patients with coronary artery disease showed similar associations between the inferior TWI sum and PVR, suggesting that the observed relationship was not primarily driven by coexisting coronary artery disease.
Natriuretic peptides and multiparametric risk assessment remain central to PH risk stratification, especially in pulmonary arterial hypertension [1, 14]. ECG variables are not part of standard risk models, but they may provide low‐cost information about RV‐pulmonary vascular stress. In this study, the inferior TWI sum > 0.15 mV remained independently associated with all‐cause mortality after adjustment for age and NT‐proBNP (hazard ratio, 3.83; 95% confidence interval, 1.48–9.90; p = 0.007) and significantly increased the global chi‐square statistic. Because only 19 deaths occurred, the model was intentionally parsimonious and cannot establish independence from the full range of clinical, echocardiographic, and invasive hemodynamic risk markers. In addition, our review of causes of death showed that most patients who died of PH/RV failure (83%, 5/6) had an inferior TWI sum > 0.15 mV. This finding is consistent with a potential association between inferior TWI and RV failure‐related mortality, although the small number of cause‐specific deaths precludes definitive conclusions. Future prospective cohorts should test whether the inferior TWI sum improves established PH risk models, predicts PH‐specific outcomes, or changes dynamically with treatment. Previous studies have shown that selected ECG markers may change following effective treatment in PAH and CTEPH [12, 13] and may also provide prognostic information [15].
Several limitations should be acknowledged. First, this was a retrospective, single‐center study with a modest sample size. Second, the cohort was intentionally composed of patients evaluated for PH, including non‐PH patients and multiple PH clinical groups; this design is appropriate for diagnostic triage but limits disease‐specific inference. Third, only 19 all‐cause deaths occurred, limiting the number of variables that could be included in multivariable survival models. Fourth, missing data were present for several clinical and echocardiographic variables, including 6‐min walk distance and tricuspid annular plane systolic excursion, which restricted adjustment for established risk markers. Furthermore, right ventricular global longitudinal strain was not routinely measured in this retrospective study, although conventional right ventricular functional parameters, including right ventricular fractional area change, were evaluated. Fifth, the diagnostic and prognostic thresholds for the inferior TWI sum were exploratory and require independent validation. Sixth, TWI was measured using the specific automated ECG analysis output of our institution's system, and external reproducibility across different ECG vendors, algorithms, and manual readers remains unknown. Seventh, treatment changes during follow‐up, PH‐specific causes of death, rhythm status, and other non‐ischemic causes of inferior TWI were not fully evaluated, although a sensitivity analysis excluding coronary artery disease confirmed the validity of our primary findings. Finally, because the study did not include cardiac magnetic resonance imaging or serial ECG‐hemodynamic assessment, the mechanism linking inferior TWI to high PVR could not be directly tested.
The quantitative sum of inferior‐lead TWI amplitudes was associated with invasively measured PVR and all‐cause mortality in patients evaluated for PH. This simple ECG‐derived marker may complement existing non‐invasive assessment and help identify patients with high pulmonary vascular load who warrant careful evaluation. Prospective, multicenter validation is required before routine clinical implementation.
Author Contributions
H.I. conceived and designed the study. H.I. and A.M. collected the data. H.I. performed the statistical analyses. K.K. drafted the initial manuscript, and K.K. and H.I. revised and finalized the manuscript. H.I., A.M., and all other authors contributed to patient care, interpreted the data, critically revised the manuscript, and approved the final version of the manuscript.
Ethics Statement
The study was approved by the Institutional Review Board of the University of the Ryukyus Hospital (approval number: 24‐2371‐00‐00‐00). The requirement for written informed consent was waived because of the retrospective study design, and an opt‐out approach was used in accordance with institutional policy.
Conflicts of Interest
The authors declare no conflicts of interest.
Disclosure of AI Use in Manuscript Preparation
During the preparation of this manuscript, the authors used an artificial intelligence (AI) assistant to support manuscript preparation and English language editing. The authors take full responsibility for the content of the manuscript.
Guarantor
Kenya Kusunose, MD, PhD.
Supporting information
Figure S1: Representative cases of pulmonary arterial hypertension (Group 1) with borderline tricuspid regurgitation velocity (TRV) and normal N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels. (A) A patient with high pulmonary vascular resistance (PVR: 5.91 Wood units) and high mean pulmonary arterial pressure (mPAP: 38 mmHg). Although standard non‐invasive markers were borderline or normal (TRV: 3.16 m/s, NT‐proBNP: 45 pg/mL), the inferior T‐wave inversion (TWI) sum was high (0.547 mV). (B) A patient with lower PVR (2.31 Wood units) and lower mPAP (22 mmHg). Although this patient showed similar borderline TRV (2.92 m/s) and normal NT‐proBNP (106 pg/mL), the inferior TWI sum was absent (0 mV). These cases illustrate that the inferior TWI sum may provide additional information when other non‐invasive tests are inconclusive. Pressure tracings are displayed using different vertical scales for optimal visualization.
Acknowledgments
We would like to thank all the clinical and technical staff at the University of the Ryukyus Hospital for their invaluable support in patient care and data collection. We also thank the patients who participated in this study. This study is supported by a grant from the Ministry of Education, Culture, Sports, Science, Technology (MEXT) project for the promotion of clinical research and education to K.K., Japanese Circulation Society Grant for Cardiovascular AI Research to K.K., and Japan Agency for Medical Research and Development Grant no. 26uk1024013h0001.
Data Availability Statement
Data are available from the corresponding author upon reasonable request.
References
- 1. Humbert M., Kovacs G., Hoeper M. M., et al., “2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension,” European Heart Journal 43 (2022): 3618–3731, 10.1093/eurheartj/ehac237. [DOI] [PubMed] [Google Scholar]
- 2. Kovacs G., Bartolome S., Denton C. P., et al., “Definition, Classification and Diagnosis of Pulmonary Hypertension,” European Respiratory Journal 64 (2024): 2401324, 10.1183/13993003.01324-2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Hemnes A. R., Celermajer D. S., D'Alto M., et al., “Pathophysiology of the Right Ventricle and Its Pulmonary Vascular Interaction,” European Respiratory Journal 64 (2024): 2401321, 10.1183/13993003.01321-2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Ley L., Wiedenroth C. B., Guth S., et al., “The Diagnostic Accuracy of an Electrocardiogram in Pulmonary Hypertension and the Role of “R V1, V2 + S I, aVL ‐ S V1,” Journal of Clinical Medicine 13 (2024): 7613, 10.3390/jcm13247613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Al‐Naamani K., Hijal T., Nguyen V., Andrew S., Nguyen T., and Huynh T., “Predictive Values of the Electrocardiogram in Diagnosing Pulmonary Hypertension,” International Journal of Cardiology 127 (2008): 214–218, 10.1016/j.ijcard.2007.06.005. [DOI] [PubMed] [Google Scholar]
- 6. Blyth K. G., Kinsella J., Hakacova N., et al., “Quantitative Estimation of Right Ventricular Hypertrophy Using Ecg Criteria in Patients With Pulmonary Hypertension: A Comparison With Cardiac MRI,” Pulmonary Circulation 1 (2011): 470–474, 10.4103/2045-8932.93546. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Henkens I. R., Mouchaers K. T. B., Vonk‐Noordegraaf A., et al., “Improved ECG Detection of Presence and Severity of Right Ventricular Pressure Load Validated With Cardiac Magnetic Resonance Imaging,” American Journal of Physiology‐Heart and Circulatory Physiology 294 (2008): H2150–H2157, 10.1152/ajpheart.01312.2007. [DOI] [PubMed] [Google Scholar]
- 8. Kopec G., Tyrka A., Miszalski‐Jamka T., et al., “Electrocardiogram for the Diagnosis of Right Ventricular Hypertrophy and Dilation in Idiopathic Pulmonary Arterial Hypertension,” Circulation Journal 76 (2012): 1744–1749, 10.1253/circj.CJ-11-1517. [DOI] [PubMed] [Google Scholar]
- 9. Waligóra M., Gliniak M., Bylica J., et al., “Extended Precordial T‐Wave Inversions Are Associated With Right Ventricular Enlargement and Poor Prognosis in Pulmonary Hypertension,” Journal of Clinical Medicine 10 (2021): 2147, 10.3390/jcm10102147. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Rudski L. G., Lai W. W., Afilalo J., et al., “Guidelines for the Echocardiographic Assessment of the Right Heart in Adults: A Report From the American Society of Echocardiography,” Journal of the American Society of Echocardiography 23 (2010): 685–713, 10.1016/j.echo.2010.05.010. [DOI] [PubMed] [Google Scholar]
- 11. Lang R. M., Badano L. P., Mor‐Avi V., et al., “Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update From the American Society of Echocardiography and the European Association of Cardiovascular Imaging,” European Heart Journal ‐ Cardiovascular Imaging 16 (2015): 233–271, 10.1093/ehjci/jev014. [DOI] [PubMed] [Google Scholar]
- 12. Henkens I. R., Gan C. T. J., van Wolferen S. A., et al., “ECG Monitoring of Treatment Response in Pulmonary Arterial Hypertension Patients,” Chest 134 (2008): 1250–1257, 10.1378/chest.08-0461. [DOI] [PubMed] [Google Scholar]
- 13. Nishiyama T., Takatsuki S., Kawakami T., et al., “Improvement in the Electrocardiograms Associated With Right Ventricular Hypertrophy After Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension,” IJC Heart & Vasculature 19 (2018): 75–82, 10.1016/j.ijcha.2018.05.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Hoeper M. M., Pausch C., Olsson K. M., et al., “COMPERA 2.0: A Refined Four‐Stratum Risk Assessment Model for Pulmonary Arterial Hypertension,” European Respiratory Journal 60 (2022): 2102311, 10.1183/13993003.02311-2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Sato S., Ogawa A., and Matsubara H., “Change in R Wave in Lead V1 Predicts Survival of Patients With Pulmonary Arterial Hypertension,” Pulmonary Circulation 8 (2018): 2045894018776496, 10.1177/2045894018776496. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Representative cases of pulmonary arterial hypertension (Group 1) with borderline tricuspid regurgitation velocity (TRV) and normal N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels. (A) A patient with high pulmonary vascular resistance (PVR: 5.91 Wood units) and high mean pulmonary arterial pressure (mPAP: 38 mmHg). Although standard non‐invasive markers were borderline or normal (TRV: 3.16 m/s, NT‐proBNP: 45 pg/mL), the inferior T‐wave inversion (TWI) sum was high (0.547 mV). (B) A patient with lower PVR (2.31 Wood units) and lower mPAP (22 mmHg). Although this patient showed similar borderline TRV (2.92 m/s) and normal NT‐proBNP (106 pg/mL), the inferior TWI sum was absent (0 mV). These cases illustrate that the inferior TWI sum may provide additional information when other non‐invasive tests are inconclusive. Pressure tracings are displayed using different vertical scales for optimal visualization.
Data Availability Statement
Data are available from the corresponding author upon reasonable request.