A total of 83 patients with severe AS were enrolled into the study. Mean age of the study subjects was 66.5 ± 8.6 years (range: 45–84 years), and 58% were females. The main reasons for non-eligibility were significant CAD, renal dysfunction, and other valvular abnormalities. The vast majority of patients had high-gradient severe AS: the median AVA index was 0.45 cm2/m2 (0.35–0.53), and the median mean transvalvular gradient was 54.9 mm Hg (44.4–70.0). Further, 89% of patients had preserved LV ejection fraction (LVEF): mean LVEF 66.7 ± 12.8%. Of the 83 participants, 79 underwent surgical AVR and 4 postponed surgeries due to the COVID-19 epidemiologic situation. Out of 83 patients with severe AS, 43.4% had the strain pattern on their ECGs at baseline assessment. Patients were divided into 2 groups according to the presence of ECG strain. Both groups were balanced in terms of their age and comorbidities. ECG strain-positive patients were more frequently male (p = 0.002) and had lower systolic (p < 0.001) and diastolic blood pressures (p < 0.001). When ECG parameters were examined, LV hypertrophy by Sokolow-Lyon criterion was more prevalent (63.2% vs. 25.0%, p < 0.001); QRS voltage (p < 0.001) and QRS duration (p = 0.016) were greater in the ECG strain-positive group. Strain-positive patients also had several times higher BNP (p < 0.001) and Hs-Tn-I (p < 0.001) levels. The baseline clinical characteristics of the patients according to the presence of ECG strain are summarized in Table 1.
Table 1
Baseline characteristics of the study cohort and patient groups stratified by the presence of the ECG strain.
Variable | All patients (n = 83) | No ECG strain (n = 47) | ECG strain (n = 36) | P-value |
Age, yrs | 66.5 ± 8.6 | 67.2 ± 8.3 | 65.4 ± 9.1 | 0.357 |
Male gender | 35 (42.2) | 13 (27.7) | 22 (61.1) | 0.002 |
BSA, m2 | 1.9 ± 0.2 | 1.9 ± 0.2 | 2 ± 0.2 | 0.165 |
Systolic BP, mm Hg | 149.6 ± 24.8 | 157.7 ± 23.7 | 139.0 ± 22.3 | < 0.001 |
Diastolic BP, mm Hg | 84.0 ± 11.7 | 88.4 ± 10.1 | 78.2 ± 11.2 | < 0.001 |
Comorbidities |
Hypertension | 73 (88) | 42 (89.4) | 31 (86.1) | 0.740 |
Dyslipidemia | 67 (80.7) | 40 (85.1) | 27 (75) | 0.247 |
Unobstructive CAD | 39 (47) | 20 (42.6) | 19 (52.8) | 0.355 |
Diabetes mellitus | 15 (18.1) | 10 (21.3) | 5 (13.9) | 0.389 |
Risk scores |
STS-PROM, % | 1.6 (1.2–2.4) | 1.8 (1.4–2.5) | 1.3 (1.0-1.9) | 0.004 |
EuroSCORE II, % | 1 (0.7–1.6) | 1.1 (0.8–1.6) | 1 (0.7–1.7) | 0.695 |
Functional status |
NYHA f. cl.* |
I-II | 40 (48.2) | 26 (55.3) | 14 (38.9) | 0.138* |
III-IV | 43 (51.8) | 21 (44.7) | 22 (61.1) |
MLHFQ score | 32.5 (18.5–52.8) | 40.5 (19–56) | 30 (17-40.8) | 0.306 |
6 MWT, m | 369 (300–420) | 360 (294.8–420) | 388.5 (322.5–420) | 0.489 |
Blood tests |
eGFR, ml/min/1.73 m2 | 85 (69–90) | 85 (69–90) | 85 (67.5–90) | 0.875 |
Hs-Tn-I, pg/l | 9.1 (5-18.7) | 6 (4–13) | 15.5 (9–29) | < 0.001 |
BNP, pg/l | 130 (65.2-361.9) | 80.2 (46.5-163.2) | 297.2 (117.7-812.8) | < 0.001 |
ECG parameters |
Heart rate, beats/min | 75 (65–86) | 75 (68–86) | 75.5 (64.3–87.5) | 0.890 |
PQ duration, ms | 165 (153.5–180) | 162 (150–176) | 168 (160–184) | 0.067 |
QRS duration, ms | 94 (86–102) | 90 (85–98) | 96 (90.3-108.5) | 0.016 |
S-L, mm | 30.9 ± 9.9 | 25.3 ± 7.3 | 38.1 ± 8.1 | < 0.001 |
S-L ≥ 35 mm, % | 28 (33.7) | 6 (12.8) | 22 (61.1) | < 0.001 |
The boldface values indicate statistical significance.
Continuous variables are presented as mean ± SD or median (IQR). Categorical variables are expressed as n (%).
6 MWT, 6-min walking test; BMI, body mass index; BNP, brain natriuretic peptide; BP, blood pressure; BSA, body surface area; CAD, coronary artery disease; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; EuroScoreII, European System for Cardiac Operative Risk Evaluation II score; hs-Tn-I, high-sensitivity troponin I; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NYHA, New York Heart Association; S-L, Sokolow Lyon voltage criteria; STS, Society of Thoracic Surgeons’ risk model score.
*P-value for comparison among NYHA I and II vs III and IV.
ECG strain and LV remodeling
Comparative analysis revealed that ECG strain-positive patients had more advanced AS, as evident by the higher peak AV velocity (p = 0.008) and higher mean transvalvular gradient (p = 0.003). Patients with strain pattern on ECG had more advanced LV remodeling: significantly thicker LV walls (p < 0.001), larger LV dimensions (p < 0.001), greater LV mass index (p < 0.001), and larger LV end-systolic (p < 0.001) and end-diastolic (p < 0.001) volume indexes. This group of patients also showed signs of more advanced diastolic dysfunction and elevated LV filling pressures, as evident by higher septal E/e‘(p = 0.011) and larger left atrial volume index (p < 0.001). Furthermore, these patients showed worse LV systolic function, as they had lower GLS (p < 0.001), lower LVEF (p < 0.001), and higher prevalence of reduced LVEF (p = 0.009). The imaging characteristics of the patients according to the presence of ECG strain are summarized in Table 2.
Table 2
Cardiovascular imaging and histology data of the study cohort and patient groups stratified by the presence of ECG strain.
| All patients (n = 83) | No ECG strain (n = 47) | ECG strain (n = 36) | P-value |
Echocardiography data |
AVA, cm2 | 0.84 ± 0.2 | 0.85 ± 0.2 | 0.83 ± 0.2 | 0.612 |
AVA index, cm2/m2 | 0.45 (0.35–0.53) | 0.47 (0.4–0.53) | 0.41 (0.33–0.53) | 0.230 |
Peak AV velocity, m/s | 4.9 (4.4–5.3) | 4.5 (4.2–5.2) | 5.0 (4.7–5.5) | 0.008 |
Mean AV gradient, mm Hg | 54.9 (44.4–70.0) | 49 (42.0–64.0) | 60.5 (52.5–77.9) | 0.003 |
IVSd, mm | 13 (12–14) | 12 (11–13) | 13.5 (13–15) | < 0.001 |
PWd, mm | 11.5 (10–12) | 11 (10–12) | 12 (11–13) | < 0.001 |
LVdd, mm | 51.2 ± 5.4 | 49.4 ± 4.2 | 53.6 ± 5.9 | < 0.001 |
LVsd, mm | 32.7 ± 5.9 | 30.5 ± 4.5 | 35.7 ± 6.3 | < 0.001 |
LV mass, g | 130.2 ± 30.7 | 116.4 ± 20.7 | 148.3 ± 32.4 | < 0.001 |
E/A | 1.1 ± 0.4 | 1.2 ± 0.4 | 1.1 ± 0.5 | 0.132 |
E/e’ septal | 16.4 (12.7–20.9) | 15 (11.6–18.3) | 17 (13.4–25) | 0.011 |
E/e’ lateral | 13 (10.3–17) | 12.5 (9.7–17.6) | 13.4 (10.4–16.5) | 0.388 |
E/e’ mean | 14.4 (11.6–18.3) | 14 (10.8–18.3) | 15 (12.2–19) | 0.107 |
LA volume index, ml/m2 | 47.3 (40.6–55.3) | 43.5 (38.3–53) | 51.4 (44.8–56.9) | 0.004 |
Estimated PASP, mm Hg | 33 (29–43) | 33 (29.3–39.5) | 35 (29–65) | 0.272 |
GLS, %* | -18 ± 5 | -20.1 ± 3.8 | -15.2 ± 4.9 | < 0.001 |
CMR data |
IVSd, mm | 13.3 ± 2 | 12.7 ± 1.9 | 14.2 ± 1.9 | < 0.001 |
PWd, mm | 10.5 ± 1.9 | 9.8 ± 1.7 | 11.5 ± 1.8 | < 0.001 |
LVdd, mm | 50.4 ± 6.1 | 48.8 ± 5.2 | 52.4 ± 6.7 | 0.008 |
LVsd, mm | 33.7 ± 8.1 | 30.9 ± 6.6 | 37.2 ± 8.6 | < 0.001 |
LVEDV index, ml/m2 | 70.6 (61.5–80.6) | 63.1 (54.9–74.6) | 78.9 (70.4–99.8) | < 0.001 |
LVESV index, ml/m2 | 20.6 (14.9–30.8) | 16 (12.9–21.7) | 29.8 (18.4–45.3) | < 0.001 |
LVEF, % | 66.7 ± 12.8 | 71.5 ± 7.7 | 60.6 ± 15.4 | < 0.001 |
LVEF < 50%, n (%) | 9 (10.8) | 1 (2.1) | 8 (22.2) | 0.009 |
LV mass, g | 189.9 ± 68.1 | 152.3 ± 45.1 | 237.9 ± 62.2 | < 0.001 |
LV mass index, g/m2 | 92.5 (76.8-119.3) | 79.3 (61.8–90.9) | 119.8 (109.7-137.3) | < 0.001 |
LGE prevalence | 61 (73.5) | 31 (66) | 30 (83.3) | 0.075 |
Native T1, ms# | 959.6 ± 33.7 | 946.5 ± 28.2 | 974.8 ± 33.6 | < 0.001 |
ECV, %# | 23.1 (20.8–24.9) | 23 (20.7–24.9) | 23.3 (21.2–25.2) | 0.821 |
Histology data (n = 71) |
CVF total, %& | 16.1 ± 9.4 | 15.7 ± 8.7 | 16.6 ± 10.2 | 0.679 |
CVF midmyocardial, %& | 7 (3.8–11.9) | 5.9 (3.6–9.1) | 8.8 (4-12.6) | 0.155 |
CVF subendocardial, %& | 21.6 ± 12.3 | 21.4 ± 10.9 | 21.8 ± 13.8 | 0.872 |
The boldface values indicate statistical significance.
Continuous variables are presented as mean ± SD or median (IQR). Categorical variables are expressed as n (%).
AV, aortic valve; AVA, aortic valve area; E, peak early velocity of the transmitral flow; CMR, cardiovascular magnetic resonance; CVF, collagen volume fraction; e’, peak early diastolic velocity of the mitral annulus displacement; GLS, global longitudinal strain; ECV, extracellular volume; IVSd, interventricular septum diastolic diameter; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; LVEF, left ventricular ejection fraction; LA, left atrium; LGE, late gadolinium enhancement; PASP, pulmonary artery systolic pressure measured by echocardiography; PCWP, pulmonary capillary wedge pressure measured by echocardiography; *value based on the data analysis in 77 patients; #values based on the data analysis in 67 patients; &values based on the data analysis in 70 patients.
ECG strain and myocardial fibrosis
The mean native T1 was 959.6 ± 33.7 ms (range: 897–1044 ms), and the median ECV was 23.1% (20.8–24.9) (range: 15.7–34.4%). We found that patients with ECG strain had higher native T1 (p < 0.001); however, no significant differences in the mean ECV values were noted between the study groups (p = 0.821). Focal myocardial fibrosis detected by LGE-CMR was present in 74% of patients. There was a tendency of higher prevalence of LGE in patients with ECG strain; however, it did not reach statistical significance (83% vs. 66%, p = 0.075). In regard to histological analysis, we found no significant differences in histologically measured myocardial fibrosis (mean CVF values) between the patient groups with and without ECG strain (16.6 ± 10.2% vs 15.7 ± 8.7%, p = 0.679). Representative images of patients with and without ECG strain are shown in Fig. 1.
Analysis of associations
We observed significant correlations between QRS voltage and QRS duration and imaging parameters of LV remodeling: LV end-diastolic diameter (r = 0.508, p < 0.001 and r = 0.220, p = 0.046, respectively), LV end-systolic diameter (r = 0.439, p < 0.001 and r = 0.371, p = 0.001, respectively), LV end-diastolic (r = 0.364, p = 0.001 and r = 0.549, p < 0.001, respectively) and LV end-systolic volume indexes (r = 0.337, p = 0.002 and r = 0.552, p < 0.001, respectively), and LV mass index (r = 0.389, p < 0.001 and r = 0.525, p < 0.001, respectively). QRS duration and QRS voltage negatively correlated with parameters of LV systolic function: LVEF (r=-0.230, p = 0.037 and r=-0.445, p < 0.001, respectively) and GLS (r=-0.301, p = 0.008 and r=-0.381, p = 0.001, respectively) (Fig. 2). QRS duration weakly but significantly correlated with parameters related to LV diastolic dysfunction and elevated filling pressures: E wave deceleration time (r=-0.246, p = 0.035), LA volume index (r = 0.246, p = 0.027,) and estimated pulmonary artery systolic pressure (r = 0.369, p = 0.021).
In regard to serum biomarkers, QRS duration and QRS voltage also correlated with Tn-I (r = 0.367, p = 0.001 and r = 0.344, p = 0.002, respectively) and BNP (r = 0.251, p = 0.023 and r = 0.438, p < 0.001, respectively). When analyzing associations between ECG and parametric imaging data, QRS voltage correlated with native T1 (r = 0.388, p = 0.001). No correlations were found between selected ECG variables (QRS duration and QRS voltage) and histological myocardial fibrosis (CVF) or ECV.
ECG parameters as independent prognostic factors
The univariate logistic regression analysis revealed that male sex, higher levels of BNP, increased QRS voltage, lower LVEF, reduced GLS, and ECG strain were statistically significant predictors for increased LV mass index (Table 3). Only ECG strain remained a significant predictor of increased LV mass index in a multivariate regression analysis. Analysis of the predictors of diffuse myocardial fibrosis revealed that ECG strain, increased QRS voltage, and reduced LVEF and GLS were predictive of increased native T1; however, no significant associations were noted on multivariate regression analysis (Table 3).
Table 3
The univariate and multivariate regression analysis to identify prognostic factors for increased LV mass index and elevated native T1
Variable | LV mass index | Native T1 |
Univariate Analysis | Multivariate Analysis | Univariate Analysis | Multivariate Analysis |
OR (95% CI) | P-value | OR (95% CI) | P-value | OR (95% CI) | P-value | OR (95% CI) | P-value |
Male sex | 3.67 (1.39–9.69) | 0.009 | 2.91 (0.89–9.56) | 0.078 | 1.07 (0.33–3.45) | 0.914 | - | - |
Age, yrs | 0.95 (0.90-1.00) | 0.053 | - | - | 0.96 (0.90–1.03) | 0.268 | - | - |
Hs-Tn-I, pg/l | 1.00 (0.99-1.00) | 0.497 | - | - | 1.00 (0.99-1.00) | 0.697 | - | - |
BNP, pg/l | 1.00 (1.00-1.01) | 0.009 | 1.00 (1.00-1.01) | 0.309 | 1.00 (1.00–1.00) | 0.600 | - | - |
LVEF, % | 0.91 (0.86–0.97) | 0.001 | 0.94 (0.87–1.02) | 0.110 | 0.945 (0.90–0.99) | 0.016 | 1.00 (0.92–1.08) | 0.931 |
GLS, % | 0.73 (0.62–0.87) | < 0.001 | - | - | 0.86 (0.75–0.99) | 0.036 | 0.93 (0.74–1.17) | 0.546 |
QRS voltage | 1.09 (1.03–1.15) | 0.002 | 0.98 (0.91–1.06) | 0.679 | 1.10 (1.03–1.18) | 0.006 | 1.08 (0.99–1.18) | 0.093 |
PQ duration, ms | 1.01 (0.99–1.03) | 0.262 | - | - | 1.00 (0.98–1.02) | 0.885 | - | - |
QRS duration, ms | 1.02 (0.99–1.05) | 0.296 | - | - | 1.03 (0.99–1.07) | 0.129 | - | - |
ECG strain | 12.89 (3.90-42.55) | < 0.001 | 7.10 (1.46–34.48) | 0.015 | 4.40 (1.23–15.72) | 0.023 | 1.34 (0.26–7.03) | 0.726 |
The boldface values indicate statistical significance.
CI confidence interval, OR odds ratio. Abbreviations as in Tables 1 and 2.
ECG changes at follow-up
The data of 76 and 59 patients were available at 3- and 12-month follow-up visits, respectively. ECG parameters before and after surgical AVR are shown in Table 4. Comparative analysis of ECG parameters included postoperative ECGs with a new first-degree AV block (5 patients), left bundle branch block (8 patients), and right bundle branch block (2 patients). Two patients were excluded from further analysis due to cardiac pacemaker activity seen on the ECG. Our results demonstrated that QRS voltage had significantly decreased at 3 and 12 months after the surgery [30 mm (23–39) vs 23 mm (18.5–27) vs 19.5 mm (16–24), respectively, p < 0.001]. Furthermore, the prevalence of ECG strain gradually decreased from 43–17% at 1 year (p = 0.001). We also observed a significant increase in QRS duration at 3 months following AVR (p < 0.05); the result likely related to newly developed intraventricular conduction abnormalities soon after the surgery (left and right bundle branch blocks).
Further analysis revealed that patients with persistent ECG strain at 1 year following AVR had lower systolic and diastolic blood pressures (p = 0.017 and p = 0.040, respectively), greater QRS duration [102 ms (94-106.3) vs 92 ms (86–101), p = 0.042], and more advanced heart failure, as evident by higher levels of BNP (p = 0.005) at baseline. These patients also had more advanced baseline LV remodeling, as they had greater LV mass (p = 0.023) and larger indexed LV end-systolic (p = 0.003) and LV end-diastolic (p = 0.010) volumes (Table 5). Furthermore, this group of patients showed worse baseline LV and right ventricle systolic functions, as they had significantly reduced GLS (p < 0.001), lower LVEF (p < 0.001), and lower right ventricle ejection fraction (p < 0.002). In regard to histological analysis, patients with persistent ECG strain had significantly more fibrosis in the midmyocardial layer on histological analysis (12.5 ± 9.9% vs 7.3 ± 4.7%, p = 0.009).
Table 4
ECG parameters before and at 3 and 12 months after surgical AVR
Variables | Baseline (n = 83) | 3-month follow-up (n = 76) | 12-month follow-up (n = 59) |
PQ duration, ms | 165 (153.5–180) | 164 (145.5–184) | 163 (144.5-191.5) |
QRS duration, ms | 94 (86–102) | 98.5 (88-115.5)* | 96 (86–108) |
S-L, mm | 30 (23–39) | 23 (18.5–27)* | 19.5 (16–24)* |
ECG strain, n (%) | 36 (43.4) | 26 (34.2) | 10 (16.9)* |
*p < 0.05 vs baseline |
Continuous variables are presented as mean ± SD or median (IQR). Categorical variables are expressed as n (%). Abbreviations as in Table 1.
Table 5
The comparison of baseline cardiovascular imaging and histology data of the study cohort, stratified by the presence of ECG strain at 1 year following AVR
Variable | Patients without persistent ECG strain (n = 73) | Patients with persistent ECG strain (n = 10) | P-value |
Blood tests |
eGFR, ml/min/1.73 m2 | 86 (73.5–90) | 67.5 (60.3–80.8) | 0.019 |
Hs-Tn-I, pg/l | 9 (5–16) | 17 (11.3–36.3) | 0.065 |
BNP, pg/l | 118.8 (60.7–285) | 772.4 (148.3-1128.9) | 0.005 |
Echocardiography data |
AVA, cm2 | 0.9 ± 0.2 | 0.7 ± 0.1 | 0.069 |
AVA index, cm2/m2 | 0.45 ± 0.1 | 0.40 ± 0.1 | 0.220 |
Peak AV velocity, m/s | 4.9 ± 0.6 | 4.6 ± 0.6 | 0.122 |
Mean AV gradient, mm Hg | 59.2 ± 17.4 | 52.6 ± 13.4 | 0.249 |
IVSd, mm | 13 (12–15) | 13 (11-14.3) | 0.949 |
PWd, mm | 11 (10–12) | 12 (10.5–13.5) | 0.553 |
LVdd, mm | 50 (47–53) | 56.5 (51.3–58) | 0.014 |
LVsd, mm | 31.8 ± 5 | 39.1 ± 8.3 | < 0.001 |
LV mass, g | 127.7 ± 29.6 | 153.4 ± 32.1 | 0.023 |
E/A | 1.2 ± 0.4 | 1 ± 0.6 | 0.299 |
E/e’ septal | 16.3 (12.7–20.4) | 16.7 (11.7–23.2) | 0.994 |
E/e’ lateral | 13.3 (10.4–17.1) | 10.8 (9-22.2) | 0.558 |
E/e’ mean | 14.5 (11.8–18.3) | 12.7 (11.1–22) | 0.716 |
LA volume index, ml/m2 | 46.2 (29.6–55) | 54.5 (48.6–56.8) | 0.118 |
Estimated PASP, mm Hg | 33 (29.5–40.5) | 54 (26–70) | 0.250 |
GLS, %* | 18.6 ± 4.4 | 12.8 ± 6.7 | < 0.001 |
CMR data |
IVSd, mm | 13.3 ± 2.1 | 13.6 ± 1.9 | 0.648 |
PWd, mm | 10 (9–12) | 10 (9.5–11.4) | 0.861 |
LVdd, mm | 49 (46-52.5) | 55.5 (50.8–58.8) | 0.013 |
LVsd, mm | 32.6 ± 7.5 | 41.4 ± 8.8 | < 0.001 |
LVEDV index, ml/m2 | 70.5 (61.1–78.2) | 99.2 (63.7–129) | 0.010 |
LVESV index, ml/m2 | 18.7 (14.7–28.5) | 52.7 (18.9–83.8) | 0.003 |
LVEF, % | 68.9 ± 10.3 | 51 ± 18.2 | < 0.001 |
LVEF < 50%, n (%) | 4 (5.5) | 5 (50) | < 0.001 |
LV mass, g | 167 (138.3–239) | 236 (185.8–255) | 0.072 |
LV mass index, g/m2 | 86.4 (75.5-118.5) | 119.8 (101.5-131.9) | 0.052 |
RVEDV, ml | 124.3 ± 31.5 | 132.5 ± 28.6 | 0.440 |
RVESV, ml | 43.5 (35-58.6) | 57.7 (50.2–71.5) | 0.020 |
RVEF, % | 62.1 ± 7.5 | 52.5 ± 16.3 | 0.002 |
LGE prevalence | 53 (72.6) | 8 (80) | 1.000 |
Native T1, ms# | 955 (934.5–976) | 965 (943-1004.3) | 0.374 |
ECV, %# | 22.6 ± 3.7 | 23.7 ± 2.6 | 0.401 |
Histology data (n = 71) |
CVF total, %& | 15.6 ± 8.4 | 19 ± 14.2 | 0.293 |
CVF midmyocardial, %& | 7.3 ± 4.7 | 12.5 ± 9.9 | 0.009 |
CVF subendocardial, %& | 21.4 ± 11.5 | 22.6 ± 16.6 | 0.770 |
The boldface values indicate statistical significance.
Continuous variables are presented as mean ± SD or median (IQR). Categorical variables are expressed as n (%). Abbreviations as in Tables 1 and 2.