†These authors contributed equally.
Academic Editors: Giovanna Gallo and Giuseppe Boriani
Background: The QRS fraction is the ratio of the total amplitude of R
waves to the total amplitude of QRS complexes (
Heart failure is a growing public health problem that is an important cause of death and disability globally and a source of increasing health care costs year after year [1, 2, 3]. Current reports estimate that more than 26 million people worldwide have the burden of heart failure [4, 5, 6]. Studies in several countries have shown that survival in patients with heart failure improved markedly between 1980 and 2000 [7, 8, 9, 10, 11]. However, since then, this positive trend has levelled off [12]. In the ESC Heart Failure Long-Term Registry (ESC-HF-LT) [3], the rate of all-cause mortality at 1 year has been reported to be 8.1% (including heart failure with reduced ejection fraction [HFrEF], heart failure with mid-range ejection fraction [HFmrEF], and heart failure with preserved ejection fraction [HFpEF]), and 52.1% of deaths have been attributed to cardiovascular causes [3]. In the Italian Heart Failure Registry (IN-HF, Italian Network on Heart Failure) [13], the cumulative total mortality rate at 1 year has been reported to be 24% in acute heart failure (19.2% in 797 patients with heart failure de novo and 27.7% in 1058 with worsening heart failure) and 5.9% in chronic heart failure (CHF). Therefore, cardiovascular deaths account for 73.1% and 65.3% of total mortality in acute heart failure and chronic heart failure, respectively.
Changes in cardiac structure and function often precede clinical manifestations,
and certain alterations are shown on the electrocardiogram (ECG) [14, 15]. The
standard 12-lead ECG is a low-cost, convenient, rapid, and widely used method.
Changes in electrical activity cause changes in mechanical activity, resulting in
changes in hemodynamics, with the result being a decrease in cardiac pumping
function and an increased risk of death. Several ECG markers, including QRS
duration, fragmented QRS (fQRS), and the QRS-T angle, have been identified to
have the potential to predict the risk of adverse events [16, 17]. QRS
prolongation (
Based on previous studies, our group proposed a simple method for estimation of
left ventricular ejection fraction (LVEF) whereby the ratio of the total
amplitude of R waves to the total amplitude of QRS complexes
(
The study participants were 1715 consecutive patients (male, 61.28%; female,
38.72%) with heart failure who were hospitalized in the
Department of Cardiology at the Second Hospital of Hebei Medical University
between January 2017 and December 2018. Heart failure was diagnosed by at least
two experienced cardiologists and in accordance with the 2016 European Society of
Cardiology guidelines for the diagnosis and management of acute heart failure and
CHF [27, 28]. The study inclusion criteria were as follows: aged
Flow-diagram.
Data were collected for this study using a case report form specifically designed by our research group for patients with heart failure. Basic patient information was recorded, including demographic characteristics, time of admission, time of discharge, clinical diagnosis, comorbidities, underlying etiology, findings on physical examination, ECG findings, laboratory results, imaging findings (including ECG and echocardiogram), and medication. All patients were followed up by telephone every 3 months after discharge. Follow-up included supervision of medication, health education, and lifestyle guidance. Follow-up data, including mortality and time of death, were collected up to January 2020. Deaths were classified as all-cause, cardiovascular, non-cardiovascular, and unexplained.
Transthoracic echocardiography was performed by trained sonographers using a Vivid E95 ultrasound machine (GE Healthcare, Little Chalfont, United Kingdom). On most occasions, LVEF was assessed on two-dimensional images using the modified Simpson’s method of discs.
Cardiovascular death was defined as death caused by ischemic heart disease, sudden cardiac death, heart failure, or other disease affecting the cardiovascular system.
Heart failure is a clinical syndrome characterized by typical symptoms (e.g., breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g., elevated jugular venous pressure, pulmonary crackles, and peripheral edema) of a structural and/or functional cardiac abnormality, resulting in reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.
HFpEF was defined as an ejection fraction
A 12-lead surface ECG was obtained for all patients at the time of admission
(standard calibration, 10 mm/1 mV; paper speed, 25 mm/s; filters, 0.05 to
0.15–100 Hz). The QRS fraction was calculated as the ratio of the total
amplitude of R waves to the absolute total amplitude of QRS complexes
(
Variables of the QRS fraction. In this figure, the amplitude of
Q wave is 3.5 mm, that of R wave is 10 mm, and that of S wave is 3.5 mm. Therefore,
the total amplitude of QRS wave is 3.5 + 10 + 3.5 = 17 mm. Note: the amplitudes of Q, R
and S waves are absolute, regardless of the positive and negative directions. QRS
fraction =
Continuous variables are reported as the median and interquartile range. Groups
were compared using a non-parametric (Kruskal-Wallis) test. Categorical variables
are reported as the number (percentage). Intergroup comparisons were made using
the chi-squared test. Survival curves were plotted using the Kaplan-Meier method
and log-rank test to determine the significance of differences in survival
according to the QRS fraction. Baseline variables that were considered clinically
relevant or showed a univariate relationship with cardiovascular mortality were
entered into a multivariate Cox proportional hazards regression model. Given the
number of events available, the variables included were chosen carefully to
ensure parsimony of the final model. Hazard ratios for
cardiovascular mortality were calculated according to QRS
fraction subgroup and further significant covariables with 95% confidence
intervals (CIs). All statistical analyses were performed using SPSS statistical
software version 24.0 (IBM Corp., Armonk, NY, USA). A p-value
Four of 1828 patients who met the study inclusion criteria were excluded for being younger than 18 years, and 109 were excluded because of missing data, leaving 1715 study participants (Fig. 1); 431 patients (25.13%) in the Q1 group, 850 (49.56%) in the Q2 group, and 434 (25.31%) in the Q3 group. In total, 1051 (61.28%) of the 1715 study participants were male. The median patient age was 66 years (56, 73); 68.75% had class III–IV heart failure, the main cause of which was coronary artery disease (54.75%). Past medical history included hypertension in 62.45% of cases. The patient background characteristics are shown in Table 1. Patients in the Q1 group were younger and contained a relatively large proportion of men. The patients in this group had a relatively low systolic blood pressure and relatively rapid heart rate, and the majority had New York Heart Association class III–IV heart failure (82.6%). The BNP level and left atrial and left ventricular inner diameters were larger in the Q1 group than in the Q2 and Q3 groups. Furthermore, chronic renal insufficiency was common in the Q1 group (detected in 59.63% of patients). The main etiology of heart failure was coronary heart disease (53.83%) followed by dilated cardiomyopathy (22.74%). There was no significant difference in the use of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB), beta-blockers, or aldosterone receptor antagonists among the three groups. However, use of oral diuretic agents was more common in the Q1 group.
Variable | Total (n = 1715) | Q1 (n = 431) | Q2 (n = 850) | Q3 (n = 434) | p | |
Male gender [n (%)] | 1051 (61.28) | 293 (67.98) | 529 (62.24) | 229 (52.76) | 0.000 | |
SBP (mmHg) | 126 (113, 142) | 122 (107, 134) | 126 (113, 142) | 129 (116, 146) | 0.000 | |
DBP (mmHg) | 78 (70, 87) | 78 (68, 86) | 78 (70, 87) | 77 (70, 86) | 0.231 | |
HR (b.p.m.) | 81 (70, 97) | 83 (72, 98) | 81 (70, 97) | 78 (68, 94) | 0.004 | |
Hb (g/L) | 133 (119, 145) | 135 (123, 146) | 133 (119, 145) | 131 (117, 142) | 0.004 | |
WBC (×10 |
7.1 (5.8, 8.9) | 7 (5.82, 8.9) | 7.29 (5.9, 9.2) | 7.1 (5.7, 8.4) | 0.026 | |
HsCRP (mg/L) | 3.8 (0.9, 12.03) | 5.9 (2.31, 15.4) | 5.3 (1.9, 15.8) | 4.8 (1.9, 13.75) | 0.153 | |
FBG (mmol/L) | 5.5 (4.73, 7.09) | 5.3 (4.52, 6.7) | 5.66 (4.87, 7.32) | 5.39 (4.73, 6.63) | 0.000 | |
TC (mmol/L) | 3.91 (3.22, 4.69) | 3.79 (3.18, 4.59) | 3.91 (3.22, 4.69) | 4.03 (3.27, 4.77) | 0.165 | |
LDL-C (mmol/L) | 2.48 (1.94, 3.09) | 2.44 (1.86, 3.02) | 2.47 (1.96, 3.06) | 2.55 (2, 3.17) | 0.198 | |
Serum sodium (mmol/L) | 140 (137, 142.3) | 140 (137.1, 142.6) | 139.45 (137, 142) | 140.6 (138, 142.7) | 0.000 | |
Serum potassium (mmol/L) | 4.04 (3.71, 4.37) | 4.05 (3.67, 4.41) | 4.05 (3.71, 4.36) | 4.02 (3.73, 4.36) | 0.956 | |
Serum calcium (mmol/L) | 2.25 (2.16, 2.34) | 2.24 (2.14, 2.34) | 2.24 (2.16, 2.34) | 2.26 (2.15, 2.34) | 0.595 | |
Creatinine (umol/L) | 81 (65, 101) | 87 (72, 110) | 79 (63.9, 100) | 77 (63, 94.48) | 0.000 | |
AST (U/L) | 25.1 (18.7, 45) | 25.6 (18.7, 46.7) | 26 (19, 47.45) | 23 (17.88, 36.05) | 0.000 | |
ALT (U/L) | 22.6 (14.8, 39.9) | 23.3 (15.7, 42.8) | 23.7 (15, 40.75) | 19.35 (13.4, 34.03) | 0.001 | |
GGT (U/L) | 31 (20, 56) | 35 (23, 65) | 32 (19, 58) | 27 (18, 47.05) | 0.000 | |
BNP (pg/mL) | 961.9 (527, 1283.64) | 1080 (674, 1581.56) | 956.29 (630.22, 1249.91) | 841.5 (352.5, 1150) | 0.000 | |
LAD (mm) | 41 (36, 46) | 42 (37, 47) | 41.62 (37, 45) | 40 (36, 45) | 0.005 | |
LVEDD (mm) | 55 (48, 64) | 60 (52, 69) | 54 (48, 62) | 52 (46, 62) | 0.000 | |
EF (%) | 45 (35, 58.82) | 37.28 (30.56, 45.92) | 46 (36, 58.52) | 55 (40.88, 61.7) | 0.000 | |
Age (years) | 0.036 | |||||
541 (31.55) | 154 (35.73) | 272 (32) | 115 (26.5) | |||
60–69 | 536 (31.25) | 134 (31.09) | 264 (31.06) | 138 (31.8) | ||
638 (37.2) | 143 (33.18) | 314 (36.94) | 181 (41.71) | |||
BMI (kg/m |
0.784 | |||||
672 (39.25) | 164 (38.14) | 340 (40.05) | 168 (38.8) | |||
24–27.99 | 768 (44.86) | 202 (46.98) | 376 (44.29) | 190 (43.88) | ||
272 (15.89) | 64 (14.88) | 133 (15.67) | 75 (17.32) | |||
Cardiac function classification III–IV [n (%)] | 1179 (68.75) | 356 (82.6) | 560 (65.88) | 263 (60.6) | 0.000 | |
Medical history [n (%)] | ||||||
Coronary heart disease | 943 (54.99) | 236 (54.76) | 487 (57.29) | 220 (50.69) | 0.079 | |
Myocardial infarction | 499 (29.1) | 126 (29.23) | 270 (31.76) | 103 (23.73) | 0.011 | |
Hypertension | 1071 (62.45) | 255 (59.16) | 524 (61.65) | 292 (67.28) | 0.038 | |
Diabetes | 588 (34.29) | 134 (31.09) | 321 (37.76) | 133 (30.65) | 0.011 | |
Stroke and TIA | 261 (15.22) | 56 (12.99) | 132 (15.53) | 73 (16.82) | 0.275 | |
Chronic renal insufficiency with intervention | 860 (50.15) | 257 (59.63) | 411 (48.35) | 192 (44.24) | 0.000 | |
Etiological diagnosis of heart failure [n (%)] | ||||||
Coronary disease | 939 (54.75) | 232 (53.83) | 491 (57.76) | 216 (49.77) | 0.022 | |
Hypertension | 191 (11.14) | 60 (13.92) | 77 (9.06) | 54 (12.44) | 0.020 | |
Valvular disease | 272 (15.86) | 60 (13.92) | 140 (16.47) | 72 (16.59) | 0.444 | |
Dilated cardiomyopathy | 265 (15.45) | 98 (22.74) | 117 (13.76) | 50 (11.52) | 0.000 | |
Hypertrophic cardiomyopathy | 20 (1.17) | 3 (0.7) | 10 (1.18) | 7 (1.61) | 0.454 | |
Pericardial disease | 5 (0.29) | 1 (0.23) | 2 (0.24) | 2 (0.46) | 0.751 | |
other | 369 (21.52) | 79 (18.33) | 181 (21.29) | 109 (25.12) | 0.051 | |
Drug treatment [n (%)] | ||||||
Diuretics, oral | 1606 (93.64) | 423 (98.14) | 789 (92.82) | 394 (90.78) | 0.000 | |
ACE inibitors/ARBs | 986 (57.49) | 241 (55.92) | 500 (58.82) | 245 (56.45) | 0.536 | |
Beta-blockers | 1311 (76.44) | 322 (74.71) | 663 (78) | 326 (75.12) | 0.319 | |
Aldosterone receptor antagonist | 1451 (84.61) | 373 (86.54) | 721 (84.82) | 357 (82.26) | 0.211 | |
ACEI, angiotensin-converting enzyme inhibitors; ALT, alanine aminotransferase; ARB, angiotensin receptor blockers; AST, aspartate aminotransferase; BNP, brain natriuretic peptide; CV, cardiovascular; DBP, diastolic pressure; FBS, fasting blood glucose; GGT, glutamyl transferase; Hb, hemoglobin; HR, heart rate; HsCRP, high-sensitivity C-reactive protein; LAD, left atrial diameter; LDL-C, low-density lipoprotein cholesterol; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; SBP, systolic pressure; TC, total cholesterol; TIA, transient ischemic attack; WBC, white blood cells. 1 mmHg = 0.133 kPa. |
The median duration of follow-up in the 1715 patients (93.8% of the study
cohort) was 261 (39, 502) days. In total, there were 341 deaths (19.88%), which
included 282 (16.44%) cardiovascular, 33 (1.92%) non-cardiovascular, and 26
(1.52%) unexplained deaths. An inverse relationship between
cardiovascular mortality and QRS fraction subgroup was observed:
mortality was highest in group Q1 (20.42%) followed by group Q2 (15.41%) and
was lowest in group Q3 (14.52%) (p
Total (n = 1715) | Q1 (n = 431) | Q2 (n = 850) | Q3 (n = 434) | p | |
All causes of death | 341 (19.88) | 95 (22.04) | 161 (18.94) | 85 (19.59) | 0.415 |
CV death | 282 (16.44) | 88 (20.42) | 131 (15.41) | 63 (14.52) | 0.034 |
Non-CV death | 33 (1.92) | 3 (0.7) | 16 (1.88) | 14 (3.23) | 0.025 |
Unknown | 26 (1.52) | 4 (0.93) | 14 (1.65) | 8 (1.84) | 0.495 |
CV, cardiovascular; Q, QRS fraction subgroup. |
Variables that were considered clinically meaningful (sex, age, body mass index, etiology of coronary disease, myocardial infarction, stroke and transient ischemic attack, hypertension, chronic renal insufficiency, hemoglobin, aspartate aminotransferase, alanine aminotransferase, total cholesterol, low-density lipoprotein cholesterol, fasting blood glucose, BNP, serum sodium, left atrial diameter, left ventricular end-diastolic diameter, and use of diuretics and ACEIs/ARBs) (Table 3) were examined in univariate analysis and subsequently in a multivariate Cox regression model to identify independent predictors of cardiovascular causes of mortality. Multiple variables, including age, myocardial infarction, hemoglobin, serum sodium, left atrial diameter, BNP on admission, QRS fraction, and use of ACEIs/ARBs were significantly and independently associated with cardiovascular mortality (Table 4). The risk of cardiovascular death was lower in the Q2 and Q3 groups than in the Q1 group, with hazard ratios of 0.668 (95% CI 0.457–0.974, p = 0.036) and 0.538 (95% CI 0.341–0.849, p = 0.008), respectively (Table 4). Kaplan-Meier survival curves of patients with heart failure at different QRS levels was shown in Fig. 3 (p = 0.025, log-rank test).
Variable | HR (95% CI) | p | |
Age (years) |
|||
60–69 | 1.65 (1.149–2.368) | 0.007 | |
3.569 (2.586–4.926) | 0.000 | ||
QRS (%) |
|||
Q2 | 0.803 (0.612–1.052) | 0.111 | |
Q3 | 0.695 (0.503–0.961) | 0.028 | |
BMI (kg/m |
|||
24–27.9 | 0.734 (0.575–0.936) | 0.013 | |
0.364 (0.232–0.571) | 0.000 | ||
Hb (g/L) | 0.983 (0.978–0.988) | 0.000 | |
FBG (mmol/L) | 1.006 (1.003–1.010) | 0.000 | |
TC (mmol/L) | 0.880 (0.788–0.982) | 0.022 | |
LDL-C (mmol/L) | 0.776 (0.670–0.899) | 0.001 | |
Serum Sodium (mmol/L) | 0.981 (0.974–0.988) | 0.000 | |
AST (U/L) | 1.000 (1.000–1.001) | 0.004 | |
ALT (U/L) | 1.000 (1.000–1.001) | 0.022 | |
Coronary heart disease | 1.296 (1.022–1.644) | 0.033 | |
Hypertension | 0.771 (0.609–0.975) | 0.030 | |
Chronic renal insufficiency with intervention | 1.802 (1.414–2.297) | 0.000 | |
Myocardial infarction | 1.495 (1.172–1.908) | 0.001 | |
Stroke and TIA | 1.646 (1.237–2.189) | 0.001 | |
BNP (pg/mL) | 1.000 (1.000–1.000) | 0.000 | |
LAD (mm) | 1.021 (1.009–1.033) | 0.001 | |
LVEDD (mm) | 1.003 (1.001–1.005) | 0.007 | |
Diuretics, oral | 3.741 (1.545–9.06) | 0.003 | |
ACE inhibitors/ARBs | 0.611 (0.483–0.772) | 0.000 | |
Cardiac function classification III–IV | 2.528 (1.832–3.487) | 0.000 | |
LVEF (%) | 0.987 (0.978–0.995) | 0.003 | |
ACEI, angiotensin-converting enzyme inhibitors; ALT, alanine aminotransferase; ARB, angiotensin receptor blockers; AST, aspartate aminotransferase; BMI, body mass index; FBG, fasting blood glucose; Hb, hemoglobin; LAD, left atrial diameter; LDL-C, low-density lipoprotein cholesterol; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; TC, total cholesterol. 1 mmHg = 0.133 kPa. |
Variable | HR (95% CI) | p | |
QRS (%) |
|||
Q2 | 0.668 (0.457–0.974) | 0.036 | |
Q3 | 0.538 (0.341–0.849) | 0.008 | |
Age (years) |
|||
60–69 | 1.315 (0.800–2.161) | 0.280 | |
2.514 (1.594–3.966) | 0.000 | ||
Myocardial infarction | 1.457 (1.018–2.086) | 0.040 | |
ACE inhibitors/ARBs | 0.670 (0.477–0.942) | 0.021 | |
Hypertension | 0.713 (0.503–1.009) | 0.056 | |
Hb (g/L) | 0.983 (0.976–0.990) | 0.000 | |
Serum Sodium (mmol/L) | 0.985 (0.972–0.997) | 0.017 | |
BNP (pg/mL) | 1.000 (1.000–1.000) | 0.000 | |
LAD (mm) | 1.026 (1.012–1.041) | 0.000 | |
Kaplan-Meier curves of patients with heart failure at different
QRS fraction levels (log-rank test p = 0.025). Q1, QRS fraction
The overall study population was then stratified according to type of heart
failure, and the respective proportions of HFrEF, HFmEF, and HFpEF were 697
(40.6%), 395 (23%), and 623 (36.3%); Figs. 4,5,6 show the respective survival
curves for these three groups (p = 0.634, 0.354, and 0.031, log-rank
test). In the HFpEF subgroup, the cumulative survival rate was significantly
higher in the Q2 and Q3 groups than in the Q1 group, with no significant
difference in survival between the Q2 and Q3 groups. However, in the HFrEF and
HFmEF groups, there was no significant difference in cumulative survival
according to the QRS fraction (p
Kaplan-Meier curves of patients with reduced ejection fraction
at different QRS levels (log-rank test p = 0.634). Q1, QRS fraction
Kaplan-Meier curves of patients with mid-range ejection fraction
at different QRS levels (log-rank test p = 0.354). Q1, QRS fraction
Kaplan-Meier curves of patients with preserved ejection fraction
at different QRS levels (log-rank test p = 0.031). Q1, QRS fraction
A significant correlation between the sum of the R wave amplitudes on the
orthogonal ECG and LVEF, meaning that the ejection fraction could be estimated on
the ECG, was first reported by Gottwlk et al. [29] in 1978. However, in
1983, Luweart et al. [30] advised against use of the
In recent years, significant advances have been made in the diagnosis and
treatment of heart failure, and the management of patients with this condition
has become increasingly sophisticated. However, 70% of patients with heart
failure are aged
The role of the QRS fraction in patients with HFpEF is not well understood. On the one hand, the QRS fraction mainly reflects the amplitude of each component of the QRS wave and is the ratio of a comprehensive 12-lead vector. Therefore, we consider that the QRS fraction has an advantage over other ECG markers of heart failure. Moreover, it is not population-specific. On the other hand, it is clear that the mechanisms underlying HFpEF are related to intermittent pressure overload, coronary microvascular dysfunction, tissue ischemia, and fibrosis [37, 45], which may affect findings on a routine ECG and be closely related to the QRS fraction.
ECG markers are now recognized as important predictors of the prognosis in patients with heart failure. After more extensive and in-depth validation in clinical trials, the QRS fraction should become an easily accessible clinical measurement on the 12-lead ECG and make it possible to identify patients with high-risk HFpEF. The QRS fraction is a simple, convenient, and practical index with the potential to be useful in clinical practice and will hopefully be used widely.
Compared with biomarkers and echocardiography, the QRS fraction is a simple and non-invasive parameter that may serve as a prognostic indicator of the long-term risk of cardiovascular death in patients with heart failure, especially those with HFpEF.
This study had some limitations. First, it had a prospective cohort design and was conducted at a single center. Multicenter studies are needed to increase the credibility of our present findings by expanding the sample size. Second, the mean follow-up duration was short and should be extended in future studies of the long-term prognosis in patients with heart failure. Finally, we did not record continuous changes in the QRS fraction, and the next step is to include ECG examinations during follow-up of patients to observe the relationship between continuous changes in the QRS fraction and the prognosis.
XC and DL contributed equally in the data collection and statistical analysis. XG, QW, RL and WZ participated in data collection and patient follow-up. WC was responsible for the study design and manuscript revision. XC wrote the original draft. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
The study was approved by the Ethics Committee of The Second Hospital of Hebei Medical University (No. 2015110).
We would like to express our gratitude to all those who helped us during the writing of this manuscript. We would like to thank patients participation and thank to all the peer reviewers for their opinions and suggestions. We thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
This study was supported by S&T Program of Hebei (No. 16277738D).
The authors declare no conflict of interest.
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