Whether a normal electrocardiogram excludes left ventricular (LV) diastolic dysfunction (DD) and whether electrocardiographic parameters are associated with DD is unknown. We therefore sought to investigate the relation between electrocardiographic parameters and DD. We first evaluated 75 consecutive patients referred for echocardiography for clinical suspicion of heart failure (phase 1). Electrocardiography and comprehensive echocardiography were performed on all patients and were analyzed separately in a blinded fashion. Receiver operating characteristic curves and multivariate regression analyses were used to determine which electrocardiographic parameters were most closely associated with DD. Next, we prospectively validated our results in 100 consecutive, unselected patients undergoing echocardiography (phase 2). In phase 1 of our study, the mean age was 59 ± 14 years, 41% were women, 31% had coronary disease, 53% had hypertension, and 25% had diabetes. The mean ejection fraction was 54 ± 15%, and 64% had DD. Of all the electrocardiographic parameters, the QTc interval was most closely associated with DD. QTc was inversely associated with E′ velocity (r = −0.54, p <0.0001), and the area under the receiver operating characteristic curve for QTc as a predictor of DD was 0.82. QTc prolongation was independently associated with reduced E′ velocity (p = 0.021 after adjustment for age, gender, medications, QRS duration, and ejection fraction). In phase 2 of our study QTc was the electrocardiographic parameter most associated with reduced E′ velocity (435 ± 31 vs 419 ± 24 ms; p = 0.004), confirming our phase 1 study findings. In conclusion, QTc prolongation was the electrocardiographic marker most predictive of DD and was independently associated with DD.
It is now apparent that the diagnostic and prognostic significance of left ventricular (LV) diastolic dysfunction (DD) is as important as systolic dysfunction. When diagnosed using comprehensive echocardiography, DD can help diagnose the heart failure (HF) syndrome and is associated with a markedly increased all-cause mortality. Despite the importance of diagnosing DD, there has been little study of the ability of electrocardiography to evaluate the presence or absence of DD. In addition, whether a normal electrocardiogram excludes DD is unknown. We therefore sought to evaluate whether electrocardiographic parameters can provide clues to the presence of DD. We hypothesized that the QT interval would be most closely associated with DD, given the temporal alignment of electrical repolarization and mechanical relaxation in diastole. We also hypothesized that a normal electrocardiogram would exclude a reduced ejection fraction (EF) but would not exclude DD on echocardiography.
Methods
Our study consisted of 2 phases. In the first phase of the study, we performed a retrospective analysis of 75 consecutive patients referred for outpatient echocardiography at the Bluhm Cardiovascular Institute (Northwestern Memorial Hospital) from January 1, 2008 to March 1, 2008. Only patients referred for echocardiography for a clinical suspicion of HF were studied. Clinical suspicion of HF was defined as any signs or symptoms of HF (e.g., dyspnea, orthopnea, lower extremity edema) that led to the ordering of an echocardiogram by the referring physician. Patients with atrial fibrillation or an irregular underlying rhythm during cardiac testing were excluded. In the second phase of the study, we prospectively validated our phase 1 findings in a convenience sample of 100 consecutive patients who were in normal sinus rhythm and who were referred for outpatient stress echocardiography from June 1, 2009 to July 15, 2009. Only the baseline echocardiograms (before exercise) were analyzed for the purposes of our study. The institutional review board at Northwestern University Feinberg School of Medicine approved both phase 1 and phase 2 study protocols. Informed consent was waived for phase 1 because the study involved only the review of existing records. All the phase 2 study participants provided written informed consent.
All subjects underwent 12-lead electrocardiography (Marquette MAC 5000 Resting ECG System, GE Healthcare, Boston, Massachusetts). In phase 2 of the study, we analyzed the baseline electrocardiographic study at rest, which was recorded with the patient in the supine position before stress testing. All electrocardiograms were analyzed by a single trained reader who was unaware of the echocardiographic findings. We documented the rhythm and measured the PR interval, QRS duration, and QT interval according to the published guidelines. The lead with the longest QT duration was used for the QT interval. The corrected QT interval was calculated using Bazett’s formula (QTc), Fridericia’s formula (QTf), and a regression-based approach developed by Sagie et al (QTs). Left atrial abnormality was defined using previously described criteria. We used the limb lead voltage or precordial lead voltage, or a combination of the 2, to define LV hypertrophy. A normal electrocardiogram was defined as: heart rate 50 to 100 beats/min, normal sinus rhythm, normal axis, PR 120 to 200 ms, QRS <120 ms, QTc <450 ms, and no abnormalities in the P-wave, QRS, ST, or T-wave morphology.
For phase 1 of the study, all subjects underwent a complete M-mode, 2-dimensional, Doppler, and tissue Doppler echocardiographic examination using a Sonos 7500 or iE33 system (Philips Medical Systems, Andover, Massachusetts) within 48 hours of their electrocardiogram. For phase 2 of the study, all patients underwent M-mode and 2-dimensional echocardiography using a Sonos 7500 or iE33 system, with additional dedicated imaging of mitral inflow using pulse wave Doppler echocardiography and pulse wave tissue Doppler echocardiography of the septal and lateral mitral annulus. For both phases of the study, 2-dimensional echocardiography, Doppler, and tissue Doppler imaging were performed according to published guidelines.
All echocardiograms were reviewed by a single trained reader who was unaware of the electrocardiographic data. The LV diastolic function was analyzed using the following indexes: mitral inflow early (E) and late (A) velocities; mitral E deceleration time; tissue Doppler early (E′) and late (A′) velocities of the septal and lateral mitral annulus; pulmonary venous flow characteristics; and left atrial volume. In addition, the E/E′ ratio (an estimate of LV filling pressure) was calculated. We graded diastolic function as follows: normal diastolic function = septal E′ >8 cm/s; grade I DD = septal E′ <8 cm/s and E/A ratio <0.8; grade II DD = septal E′ <8 cm/s and E/A ratio 0.8 to 1.5; and grade III DD = septal E′ <8 cm/s and E/A ratio >1.5 or if the E deceleration time was <150 ms. The pulmonary venous flow characteristics and left atrial volume were used as supporting evidence for the classification of diastolic function.
For descriptive purposes, we first divided our phase 1 patients into those with normal (>8 cm/s) and abnormal (<8 cm/s) values of septal E′. We then compared the demographic, clinical, electrocardiographic, and echocardiographic data between those with normal and reduced septal E′ using t tests for continuous variables and chi-square (or Fisher’s exact) tests for categorical variables. The p values were additionally adjusted for age, given the close association between age and tissue Doppler E′ velocity. Next, we used receiver operating characteristic analysis to determine which electrocardiographic parameters were most closely associated with a decreased septal E′. We then used multivariate linear and logistic regression analyses to examine the independent association between QTc and various indexes of DD. Finally, we also examined the association between the QRS interval, JTc interval, and DD using univariate and multivariate linear regression analyses (JTc interval defined as [QT − QRS]/√RR).
In phase 2 of the study, we again compared the clinical characteristics between those with E′ >8 cm/s and E′ <8 cm/s, and we analyzed the association between the QTc interval and septal E′ velocity using receiver operating characteristic analyses. All statistical analyses were performed using Stata, version 10.1 (StataCorp, College Station, Texas).
Results
In the phase 1 study of 75 study consecutive patients referred for echocardiography for clinical suspicion of HF, the mean age was 59 ± 14 years, 41% were women, co-morbidities were common, and 36% had normal diastolic function, 20% had grade I DD, 29% had grade II DD, and 15% had grade III DD. The differences in the demographic and clinical characteristics between those with normal and reduced septal E′ are listed in Table 1 . After simple age-adjustment, β-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were the only clinical/demographic parameters that differed between those with normal and reduced septal E′ velocity. However, several electrocardiographic and echocardiographic parameters differed between those with normal and reduced septal E′, even after age adjustment ( Table 1 ). A prolonged QRS duration, increased QT interval, and left bundle branch block were more likely in the subjects with septal E′ <8 cm/s.
| Characteristic | All Subjects (n = 75) | Septal E′ >8 cm/s (n = 27) | Septal E′ <8 cm/s (n = 48) | P-value |
|---|---|---|---|---|
| Age (years) | 59 ± 14 | 52 ± 16 | 63 ± 10 | 0.0002 |
| Women | 31 (41%) | 13 (48%) | 19 (40%) | 0.47 |
| European American ethnicity | 36 (48%) | 11 (41%) | 25 (52%) | 0.35 |
| African-American ethnicity | 17 (23%) | 3 (11%) | 14 (29%) | 0.09 |
| Other ethnicity | 22 (29%) | 13 (48%) | 9 (19%) | 0.007 ⁎ |
| Systemic hypertension † | 40 (53%) | 9 (33%) | 31 (65%) | 0.009 |
| Diabetes mellitus | 19 (25%) | 3 (11%) | 16 (33%) | 0.034 |
| Coronary artery disease † | 23 (31%) | 4 (15%) | 19 (40%) | 0.02 |
| Hyperlipidemia † | 39 (52%) | 11 (41%) | 28 (53%) | 0.14 |
| Medications | ||||
| Diuretic | 31 (41%) | 6 (22%) | 25 (52%) | 0.01 |
| Calcium channel blocker | 10 (14%) | 3 (12%) | 7 (15%) | 0.72 |
| β Blocker | 45 (60%) | 8 (30%) | 37 (77%) | <0.0001 ⁎ |
| Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker | 44 (59%) | 10 (37%) | 34 (71%) | 0.004 ⁎ |
| Statin | 36 (48%) | 11 (41%) | 25 (52%) | 0.35 |
| Systolic blood pressure (mm Hg) | 125 ± 21 | 124 ± 18 | 126 ± 21 | 0.81 |
| Diastolic blood pressure (mm Hg) | 74 ± 14 | 76 ± 13 | 73 ± 14 | 0.40 |
| Pulse pressure (mm Hg) | 51 ± 14 | 48 ± 13 | 52 ± 15 | 0.25 |
| Heart rate (beats/min) | 70 ± 13 | 70 ± 10 | 70 ± 15 | 0.95 |
| Electrocardiographic parameters | ||||
| PR interval (ms) | 164 ± 29 | 152 ± 24 | 170 ± 29 | 0.01 |
| QRS interval (ms) | 114 ± 34 | 95 ± 15 | 124 ± 37 | 0.0002 ⁎ |
| QT interval (ms) | 417 ± 46 | 393 ± 24 | 431 ± 50 | 0.0004 ⁎ |
| QTc interval (ms) | 444 ± 36 | 421 ± 25 | 458 ± 31 | <0.0001 ⁎ |
| R-wave axis (°) | 1 ± 6 | 25 ± 47 | −13 ± 53 | 0.003 |
| Left atrial abnormality | 24 (32%) | 6 (22%) | 18 (38%) | 0.17 |
| Left ventricular hypertrophy | 13 (17%) | 5 (19%) | 8 (17%) | 0.84 |
| Left bundle branch block | 15 (20%) | 0 | 15 (31%) | 0.001 ⁎ |
| Right bundle branch block | 4 (5%) | 2 (7%) | 2 (4%) | 0.62 |
| Normal electrocardiographic findings | 18 (24%) | 13 (48%) | 5 (10%) | <0.0001 ⁎ |
| Echocardiographic parameters | ||||
| Left ventricular end-diastolic volume index (ml/m 2 ) | 59 ± 25 | 48 ± 14 | 65 ± 14 | 0.005 ⁎ |
| Left ventricular end-systolic volume index (ml/m 2 ) | 29 ± 23 | 20 ± 11 | 35 ± 26 | 0.004 ⁎ |
| Ejection fraction (%) | 54 ± 15 | 61 ± 10 | 50 ± 17 | 0.003 ⁎ |
| Left ventricular mass index (g/m 2 ) | 63 ± 24 | 55 ± 23 | 69 ± 24 | 0.02 |
| Left atrial volume index (ml/m 2 ) | 31 ± 14 | 25 ± 10 | 34 ± 14 | 0.008 |
| Transmitral E velocity (cm/s) | 87 ± 29 | 86 ± 19 | 88 ± 33 | 0.71 |
| Transmitral A velocity (cm/s) | 75 ± 24 | 68 ± 23 | 79 ± 23 | 0.09 |
| E/A ratio | 1.24 ± 0.59 | 1.31 ± 0.44 | 1.20 ± 0.66 | 0.46 |
| E deceleration time (ms) | 205 ± 57 | 195 ± 38 | 211 ± 65 | 0.25 |
| Septal E′ (cm/s) | 7 ± 3 | 10 ± 2 | 5 ± 1 | <0.0001 ⁎ |
| Lateral E′ (cm/s) | 9 ± 4 | 13 ± 4 | 7 ± 3 | <0.0001 ⁎ |
| Septal E/E′ ratio | 15 ± 8 | 9 ± 2 | 19 ± 8 | <0.0001 ⁎ |
| Lateral E/E′ ratio | 11 ± 6 | 8 ± 4 | 13 ± 6 | <0.0001 ⁎ |
| Left ventricular diastolic function | <0.0001 ⁎ | |||
| Normal | 27 (36%) | 27 (100%) | 0 | |
| Grade 1 | 15 (20%) | 0 | 15 (31%) | |
| Grade 2 | 22 (29%) | 0 | 22 (46%) | |
| Grade 3 | 11 (15%) | 0 | 11 (23%) |
⁎ P-value <0.05 after adjustment for age.
† Systemic hypertension defined as systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg or treatment with antihypertensive drugs; coronary artery disease defined as history of abnormal stress test consistent with ischemia, documented coronary stenosis >50%, or history of percutaneous coronary intervention, coronary artery bypass grafting, or myocardial infarction; hyperlipidemia defined as history of hyperlipidemia in the medical record or treatment with cholesterol-lowering medication.
Figure 1 displays sample tissue Doppler images and corresponding electrocardiographic tracings from 2 patients in our study, 1 with normal E′ velocity and a comparison patient with abnormally reduced E′ velocity. As shown in Figure 1 , the patient with reduced E′ velocity (signifying DD) had a greater QTc duration compared to the patient with normal E′ velocity. In the entire phase 1 study sample, there was a modest, but highly statistically significant, correlation between the QTc interval and the E′ velocity (r = −0.54, p <0.0001). There was also a graded increase in the QTc interval with worsening diastolic function ( Figure 2 ). Of all the electrocardiographic parameters (including QTf and QTs), the QTc interval was most closely associated with DD. The c-statistic (area under the receiver operating characteristic curve) for QTc as a predictor of abnormal LV diastolic function was 0.82 compared to 0.58 for electrocardiographic left atrial abnormality and 0.49 for electrocardiographic LV hypertrophy. A QTc interval of ≥435 ms had a sensitivity of 73% and specificity of 74% for the detection of overall DD (septal E′ velocity <8 cm/s). Given the greater clinical significance of moderate or severe (grade 2 or 3) DD, we also calculated the optimal QTc interval cutpoint for more significant DD. A QTc interval of ≥449 ms had a 61% sensitivity and 76% specificity for the detection of more advanced (grade 2 or greater) DD. Accordingly, patients with moderate or greater DD had a more prolonged QTc compared to patients with no or mild (grade 1) DD (QTc 461 ± 34 vs 432 ± 32 ms, respectively; p = 0.0003).
On multivariate analysis, QTc was independently associated with the E′ velocity, E/E′ ratio, and DD grade after adjusting for age, gender, β-blocker use, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, QRS duration, and EF ( Table 2 ). Per each standard deviation increase in the QTc interval, there was a 4-fold increase in the odds of septal E′ <8 cm/s (95% confidence interval 1.2 to 13.4, p = 0.026), and a 3.7-fold increased odds of an increased E/E′ ratio >15 (95% confidence interval 1.3 to 10.5, p = 0.013). Of the entire phase 1 cohort, 18 (24%) of 75 had a normal electrocardiogram. A normal electrocardiogram excluded an EF <50%. However, of the 18 subjects with normal electrocardiographic findings, 5/18 (28%) had septal E′ <8 cm/s (2 patients had grade 1 DD, 2 patients had grade 2 DD, and 1 patient had grade 3 DD). Therefore, a normal electrocardiogram did not exclude DD.
| Dependent Variable | Odds Ratio † (95% CI) | β-Coefficient † (95% CI) | P-value |
|---|---|---|---|
| E′ <8 cm/s (dichotomous) | 4.0 (1.2, 13.4) | 0.026 | |
| E/E′ >15 (dichotomous) | 3.7 (1.3, 10.5) | 0.013 | |
| E′ (continuous) (cm/s) | −1.0 (−1.8, −0.2) | 0.021 | |
| E/E′ (continuous) | 3.9 (1.4, 6.5) | 0.003 | |
| Diastolic function grade | 0.5 (0.1, 0.8) | 0.010 |
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