Abstract
Aims
Abnormally low right ventricular ejection fraction (RVEF) is a predictor of poor outcomes in chronic heart failure (HF) patients with low left ventricular ejection fraction (LVEF). However, little is known about the relationship between LVEF and RVEF in these patients.
Methods and results
Of the 2707 Beta-blocker Evaluation of Survival Trial (BEST) participants with ambulatory chronic HF, New York Heart Association class III–IV symptoms, and LVEF ≤35%, 2008 patients had gated-equilibrium radionuclide angiographic data on baseline LVEF and RVEF. Patients were categorized into quartiles by LVEF ≥29% (n= 507), 23–28% (n= 513), 17–22% (n= 538), and <17% (n= 450). Logistic regression models were used to determine the association of LVEF quartiles (reference, ≥29%) with abnormally low RVEF (<20%). The prevalence of RVEF <20% for patients with LVEF quartiles ≥29, 23–28, 17–22, and <17% were 3, 6, 15, and 32%, respectively. Unadjusted odds ratios [95% confidence intervals (CIs)] for RVEF <20% (vs. ≥20%) associated with LVEF quartiles 23–28, 17–22, and <17% (reference, ≥29%) were 2.18 (1.14–4.17; P= 0.018), 6.32 (3.54–11.30; P< 0.001), and 16.67 (9.46–29.39; P< 0.001), respectively. Respective multivariable-adjusted odds ratios (95% CIs) were 1.82 (0.94–3.54; P= 0.076), 4.55 (2.48–8.35; P< 0.001), and 10.53 (5.70–19.44; P< 0.001), respectively. Heart failure symptoms and signs had unadjusted associations with low RVEF, but lacked intrinsic associations.
Conclusion
In patients with advanced systolic HF, LVEF has a strong dose-dependent relationship with RVEF which is independent of other characteristics, and low LVEF is useful as a surrogate marker of abnormally low RVEF in these patients.
Keywords: Chronic heart failure, Right ventricular ejection fraction, Left ventricular ejection fraction
Introduction
An abnormally low right ventricular ejection fraction (RVEF) is an independent predictor of morbidity and mortality in chronic advanced heart failure (HF) patients with a low left ventricular ejection fraction (LVEF).1–5 However, routine accurate measurement of RVEF is technically difficult and not widely available.6 Although a low LVEF is considered an important determinant of a low RVEF in patients with systolic HF, studies of their relationship are limited by small sample size.7–9 Therefore, the purpose of the current study was to determine if LVEF and other patient characteristics may predict an abnormally low RVEF in patients with chronic systolic HF.
Methods
Study design and patients
The Beta-Blocker Evaluation of Survival Trial (BEST) was a National Heart, Lung, and Blood Institute (NHLBI)-sponsored randomized clinical trial of bucindolol in patients with chronic advanced systolic HF. The rationale, design, and results of BEST have been previously reported.10,11 Briefly, 2708 chronic HF patients with LVEF <35% and NYHA class III or IV symptoms, were randomly assigned to bucindolol or placebo between May 1995 and December 1998 at 90 clinical sites in the USA and Canada. Over 90% of these patients were receiving angiotensin-converting enzyme inhibitor, diuretics, and digitalis. The current study is based on a public-use copy of the BEST data set obtained from the NHLBI. All but one participant consented to be included in the public-use copy of the data set. After excluding patients without data on LVEF and RVEF, a total of 2008 patients were included in the current analysis.
Measurement of left ventricular ejection fraction and right ventricular ejection fraction
Data on baseline LVEF and RVEF were collected before randomization by gated-equilibrium radionuclide ventriculography using standard techniques at each of the sites. If a patient did not have a LVEF and RVEF by radionuclide ventriculography at a BEST site during the 60 days before randomization, a study was performed at the time of randomization. For quality control purposes, the first two examinations at each site were sent for re-reading at a core laboratory. Thereafter, a random sample of 5% of all the examinations was sent to the core laboratory for quality control. Valid measurements of LVEF and RVEF were available for 2008 patients. The lower limit of normal RVEF by gated-equilibrium radionuclide ventriculography is 40%.12,13 We defined abnormally low RVEF as RVEF <20% based on its association with poor outcomes.2 For the current analysis, we categorized patients into four LVEF quartiles; ≥29% (n= 507), 23–28% (n= 513), 17–22% (n= 538), and <17% (n= 450).
Statistical analysis
We used χ2 tests and analysis of variance tests, as appropriate, for descriptive analyses to compare baseline characteristics between the four LVEF quartiles. We determined the odds ratios for RVEF <20% among various LVEF quartiles using a stepwise multivariable logistic regression model. In the model, LVEF ≥29% was used as the reference category and dummy variables were used for LVEF categories 23–28, 17–22, and <17%. Variables were entered into the model in multiple steps in the following order: step 1 (unadjusted), and step 2 (step 1 plus demographics), step 3 (step 2 plus medical history), step 4 (step 3 plus medications), step 5 (step 4 plus clinical findings), and step 6 (step 5 plus laboratory findings). The final model included 33 baseline characteristics and was also used to determine the relationship of other covariates with low RVEF. We then examined the relationship of lowest LVEF quartile (<17 vs. ≥17%) with RVEF <20% among various subgroups of patients. We also constructed a receiver operating characteristic (ROC) curve for LVEF to predict low RVEF (<20 vs. ≥40%) and also determined the area under curve (AUC) with 95% CIs. All statistical tests were evaluated using two-tailed 95% confidence levels and tests with P-value <0.05 were considered significant. Data analyses were performed using SPSS for Windows (Rel. 15, 2006, Chicago, IL, USA: SPSS, Inc).
Results
Compared with patients with LVEF ≥29%, those with LVEF <17% were younger and had a higher prevalence of men and African Americans (Table 1). They also had longer mean HF duration, lower systolic and diastolic blood pressure, and higher symptom prevalence of NYHA functional class IV (Table 1).
Table 1.
Baseline patient characteristics by left ventricular ejection fraction
| n (%) or mean (±SD) | LVEF ≥29% (n= 507) | LVEF 23–28% (n= 513) | LVEF 17–22% (n= 538) | LVEF <17% (n= 450) | P-value |
|---|---|---|---|---|---|
| Age, years | 61 (±12) | 62 (±12) | 60 (±12) | 59 (±12) | 0.002 |
| Female | 126 (25) | 119 (23) | 101 (19) | 68 (15) | 0.001 |
| African American | 102 (20) | 95 (19) | 120 (22) | 111 (25) | 0.104 |
| Current smoker | 96 (19) | 79 (15) | 96 (18) | 69 (15) | 0.329 |
| New York Heart Association class IV | 30 (6) | 35 (7) | 54 (10) | 61 (14) | <0.0001 |
| Body mass index, kg/m2 | 38 (±9) | 37 (±9) | 36 (±8) | 36 (±8) | 0.002 |
| Heart rate, b.p.m. | 79 (±13) | 81 (±13) | 82 (±13) | 85 (±14) | <0.0001 |
| Systolic blood pressure, mmHg | 124 (±19) | 118 (±17) | 115 (±17) | 109 (±16) | <0.0001 |
| Diastolic blood pressure, mmHg | 73 (±12) | 71 (±11) | 70 (±11) | 69 (±11) | <0.0001 |
| Left ventricular ejection fraction, % | 32 (±2) | 25 (±2) | 20 (±2) | 13 (±3) | <0.0001 |
| Past medical history | |||||
| Duration of heart failure, months | 42 (±44) | 50 (±50) | 53 (±51) | 55 (±49) | <0.0001 |
| Idiopathic dilated cardiomyopathy | 148 (29) | 140 (27) | 152 (28) | 124 (28) | 0.911 |
| Coronary artery disease | 289 (57) | 314 (61) | 324 (60) | 271 (60) | 0.546 |
| Prior inferior/posterior myocardial infarction by electrocardiogram | 89 (18) | 87 (17) | 65 (12) | 49 (11) | 0.003 |
| Coronary artery bypass surgery | 155 (31) | 159 (31) | 175 (33) | 115 (26) | 0.103 |
| Percutaneous coronary intervention | 72 (14) | 82 (16) | 85 (16) | 69 (15) | 0.860 |
| Hypertension | 325 (64) | 302 (59) | 288 (54) | 243 (54) | 0.002 |
| Diabetes mellitus | 173 (34) | 201 (39) | 191 (36) | 136 (30) | 0.034 |
| Hyperlipidaemia | 218 (43) | 230 (45) | 237 (44) | 184 (41) | 0.637 |
| Atrial fibrillation | 131 (26) | 131 (26) | 129 (24) | 98 (22) | 0.447 |
| Peripheral vascular disease | 84 (17) | 97 (19) | 85 (16) | 70 (16) | 0.469 |
| Chronic kidney diseasea | 183 (36) | 207 (40) | 213 (40) | 160 (36) | 0.295 |
| Clinical Examination | |||||
| Jugular venous distension | 220 (43) | 212 (41) | 267 (50) | 259 (58) | <0.0001 |
| S3 gallop | 161 (32) | 212 (41) | 272 (51) | 274 (61) | <0.0001 |
| Râles | 66 (13) | 74 (14) | 91 (17) | 75 (17) | 0.253 |
| Hepatomegaly | 46 (9) | 63 (12) | 76 (14) | 71 (16) | 0.012 |
| Oedema | 135 (27) | 128 (25) | 152 (28) | 131 (29) | 0.471 |
| Pulmonary oedema | 25 (5) | 48 (9) | 84 (16) | 73 (16) | <0.0001 |
| Medications | |||||
| Bucindolol | 248 (49) | 253 (49) | 283 (53) | 233 (52) | 0.567 |
| Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers | 487 (96) | 491 (96) | 520 (97) | 433 (96) | 0.884 |
| Digitalis | 455 (90) | 467 (91) | 510 (95) | 432 (96) | <0.0001 |
| Diuretics | 467 (92) | 464 (90) | 515 (96) | 431 (96) | 0.001 |
| Vasodilators | 221 (44) | 249 (49) | 257 (48) | 195 (43) | 0.214 |
| Anticoagulants | 266 (53) | 288 (56) | 338 (63) | 294 (65) | <0.0001 |
| Radiology and laboratory findings | |||||
| Cardiothoracic ratio | 53 (±7) | 55 (±7) | 56 (±7) | 59 (±7) | <0.0001 |
| Albumin, g/dL | 4.1 (±0.4) | 4.1 (±0.4) | 4.1 (±0.4) | 4.0 (±0.4) | 0.167 |
| Total cholesterol, mg/dL | 197 (±46) | 200 (±53) | 193 (±52) | 183 (±46) | <0.0001 |
| Plasma norepinephrine, pg/dL | 468 (±253) | 491 (±244) | 535 (±311) | 570 (±325) | <0.0001 |
aEstimated glomerular filtration rate <60 mL/min/1.73 m2 of body surface area.
Relationship between left ventricular ejection fraction and right ventricular ejection fraction
The overall correlation between LVEF and RVEF is displayed in Figure 1. Abnormally low RVEF was present in 2.8, 5.8, 15.2, and 32.2% of patients with LVEF ≥29, 23–28, 17–22, and <17%, respectively (Table 2). When compared with patients with LVEF ≥29%, unadjusted odds ratios and 95% CIs for RVEF <20% among those with LVEF 23–28, 17–22, and <17% were 2.18 (1.14–4.17; P= 0.018), 6.32 (3.54–11.30; P< 0.001), and 16.67 (9.46–29.39; P< 0.001), respectively. Multivariable-adjusted odds ratios [95% confidence interval (CI)] for RVEF <20% among those with LVEF 23–28, 17–22, and <17% were 1.82 (0.94–3.54; P= 0.076), 4.55 (2.48–8.35; P< 0.001), and 10.53 (5.70–19.44; P< 0.001), respectively. The association between LVEF and RVEF appeared homogeneous across various subgroups of patients (Figure 2). The ROC curve for LVEF to predict low RVEF (<20 vs. ≥40%) had an AUC of 0.77 (95% CI, 0.74–0.80; P< 0.001), which improved to 0.83 (95% CI, 0.80–0.86; P< 0.001) when RVEF <20% was compared with RVEF ≥20% (Figure 3).
Figure 1.
Association of left ventricular ejection fraction with right ventricular ejection fraction <20% for all participants in the Beta-Blocker Evaluation of Survival Trial.
Table 2.
Relationship of left ventricular ejection fraction with right ventricular ejection fraction <20%
| Odds ratio (95% confidence interval); P-value | ||||
|---|---|---|---|---|
| LVEF ≥29% (n= 507) | LVEF 23–28% (n= 513) | LVEF 17–22% (n= 538) | LVEF <17% (n= 450) | |
| RVEF (%), mean (±SD) ANOVA P< 0.0001 | 42 (±12) | 38 (±12) | 32 (±12) | 27 (±13) |
| RVEF <20% χ2P< 0.001 | 2.8% | 5.8% | 15.2% | 32.2% |
| Step 1: Unadjusted | 1.00 (Reference) | 2.18 (1.14–4.17); P= 0.018 | 6.32 (3.54–11.3); P< 0.001 | 16.67 (9.46–29.39); P< 0.001 |
| Step 2: Step 1 + demographicsa | 1.00 (Reference) | 2.20 (1.15–4.20); P= 0.017 | 6.12 (3.42–10.96); P< 0.001 | 15.72 (8.90–27.79); P< 0.0001 |
| Step 3: Step 2 + medical historyb | 1.00 (Reference) | 2.17 (1.13–4.16); P= 0.020 | 6.22 (3.45–11.19); P< 0.001 | 16.15 (9.06–28.78); P< 0.001 |
| Step 4: Step 3 + medicationsc | 1.00 (Reference) | 2.19 (1.14–4.19); P= 0.019 | 6.26 (3.47–11.30); P < 0.001 | 16.33 (9.14–29.18); P < 0.001 |
| Step 5: Step 4 + clinical findingsd | 1.00 (Reference) | 1.90 (0.98–3.68); P= 0.056 | 4.92 (2.69–9.00); P< 0.001 | 11.40 (6.19–21.00); P< 0.001 |
| Step 6: Step 5 + laboratory findingse | 1.00 (Reference) | 1.82 (0.94–3.54); P= 0.076 | 4.55 (2.48–8.35); P< 0.001 | 10.53 (5.70–19.44); P< 0.001 |
aDemographics: age, sex, and race.
bMedical history: smoking status, duration of heart failure, New York Heart Association class, coronary artery disease, idiopathic cardiomyopathy as aetiology, diabetes mellitus, hypertension, hyperlipidaemia, and electrocardiographic evidence of inferior-posterior myocardial infarction.
cMedications: bucindolol, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, digitalis, diuretics, and anticoagulants.
dClinical findings: heart rate, systolic blood pressure, S3 gallop, jugular venous distension, pulmonary râles, hepatomegaly, and X-ray findings of cardiothoracic ratio and pulmonary oedema.
eLaboratory findings: potassium, uric acid, total cholesterol, albumin, and plasma norepinephrine.
Figure 2.
Association of left ventricular ejection fraction with right ventricular ejection fraction <20% in participants in the Beta-Blocker Evaluation of Survival Trial (confidence interval; odds ratio).
Figure 3.
Receiver operating characteristic curve for prediction of low right ventricular ejection fraction by left ventricular ejection fraction.
Other markers of abnormally low right ventricular ejection fraction
Men and African Americans had higher unadjusted odds of having abnormally low RVEF, associations that persisted despite multivariable adjustment for other covariates (Table 3). Several HF symptoms and signs such as elevated jugular venous pressure, an S3 gallop, hepatomegaly and lower extremity oedema had unadjusted associations with RVEF <20%. However, none had intrinsic associations with low RVEF. Although coronary artery disease and idiopathic cardiomyopathy had no unadjusted associations with low RVEF, both had independent associations with low RVEF. Unadjusted and multivariable-adjusted associations of other key baseline covariates with low RVEF are displayed in Table 3.
Table 3.
Relationship of other baseline characteristics with right ventricular ejection fraction <20%
| Covariates | Unadjusted odds ratio (95% confidence interval); P-value | Adjusteda odd ratio (95% confidence interval); P-value |
|---|---|---|
| Age, years | 0.98 (0.97–0.99); P= 0.002 | 0.99 (0.97–1.00); P= 0.069 |
| Female | 0.59 (0.41–0.85); P= 0.004 | 0.57 (0.37–0.88); P= 0.012 |
| African American | 1.98 (1.49–2.62); P< 0.001 | 1.54 (1.07–2.21); P= 0.020 |
| Idiopathic cardiomyopathy | 1.15 (0.87–1.52); P= 0.318 | 2.03 (1.19–3.46); P= 0.010 |
| Coronary artery disease | 0.99 (0.76–1.28); P= 0.928 | 1.80 (1.04–3.13); P= 0.035 |
| New York Heart Association class IV | 2.13 (1.47–3.08); P< 0.001 | 1.20 (0.76–1.89); P= 0.432 |
| Systolic blood pressure | 0.98 (0.98–0.99); P< 0.001 | 0.99 (0.99–1.01); P= 0.904 |
| Jugular venous distension | 1.41 (1.24–1.60); P< 0.001 | 1.01 (0.86–1.20); P= 0.894 |
| S3 gallop | 1.67 (1.29–2.16); P< 0.001 | 0.84 (0.62–1.16); P= 0.296 |
| Pulmonary râles | 1.35 (0.97–1.88); P= 0.079 | 0.94 (0.63–1.40); P= 0.759 |
| Hepatomegaly | 2.06 (1.48–2.86); P< 0.001 | 1.33 (0.88–2.01); P= 0.171 |
| Lower extremity oedema | 1.45 (1.11–1.91); P= 0.007 | 1.01 (0.72–1.42); P= 0.947 |
| Serum albumin | 0.57 (0.42–0.77); P< 0.001 | 0.76 (0.53–1.10); P= 0.142 |
| Cardiothoracic ratio by chest X-ray | 1.07 (1.05–1.09); P< 0.001 | 1.03 (1.01–1.06); P= 0.018 |
| Pulmonary oedema by chest X-ray | 3.00 (2.18–4.15); P< 0.001 | 1.99 (1.36–2.90); P< 0.001 |
aModel adjusted for all the variables in the step 6 in Table 2.
Discussion
Findings from the current study demonstrate that in patients with chronic advanced systolic HF there is a strong and dose-dependent relationship between baseline LVEF and RVEF, which was independent of other measured baseline characteristics, and that the odds of having an abnormally low RVEF increased exponentially with decreasing LVEF. We also observed that while several HF symptoms and signs were markers of abnormally low RVEF, they lacked intrinsic associations. An abnormally low RVEF is an independent predictor of poor outcomes in patients with chronic advanced systolic HF, and the findings from the current study, the largest of its kind to the best of our knowledge, suggest that a low LVEF is the strongest predictor of an abnormally low RVEF in these patients. These findings also suggest that the profile of advanced systolic HF patient who may have an abnormally low RVEF is that of a man with pulmonary oedema and a very low LVEF.
The strong relationship between LVEF and RVEF is not surprising as both ventricles are connected in series and work in tandem. Although the cross-sectional nature of our data precludes a causal inference, because LVEF impairment is considered to precede low RVEF in patients with systolic HF, low LVEF may in part explain the pathogenesis of low RVEF. An increased LV end-diastolic pressure in HF often leads to increased pulmonary venous and arterial pressure, in turn increasing RV afterload. However, the degree of pulmonary hypertension often does not fully explain the extent of RV failure in HF.14 A low RVEF in HF patients with low LVEF may also be attributed in part to the failure of the shared ventricular septum.15,16 In addition to passive back-pressure, with time, there is also development of occlusive intimal and medial changes and thrombotic occlusion of small pulmonary vessels that also contributes to increased RV afterload.14 Within the limits of the pericardial restraint, progressive RV dilatation impairs LV filling through ventricular interdependence that may in turn further lower the overall cardiac output.17
While low RVEF is associated with poor outcomes in patients with advanced systolic HF, abnormally low RVEF, as defined by RVEF <20%, has been shown to have an intrinsic association with increased mortality and hospitalization. Therefore, estimation of RVEF should ideally be performed as a part of comprehensive assessment of these patients. However, when logistically constrained, LVEF may be useful as surrogate markers of low RVEF. Findings from our ROC curve analysis suggest that an LVEF of 15% is 88% sensitive and an LVEF of 25% is 88% specific. As the profile of a patient with diastolic HF is that of an elderly woman with a history of hypertension, findings from our study suggest that the profile of an advanced systolic HF patient with an abnormally low RVEF is that of a man with pulmonary oedema and very low LVEF.
Several limitations of our study need to be considered. These findings are based on cross-sectional data, thus lack temporal association. Right ventricular ejection fraction in our study was estimated using gated-equilibrium radionuclide ventriculography, which may not be as accurate as first-pass radionuclide ventriculography or magnetic resonance imaging particularly in the setting of a dilated RV.13 Therefore, future studies are needed to prospectively study the association between LVEF and RVEF in contemporary systolic and diastolic HF using newer imaging modalities such as tomographic-gated-equilibrium radionuclide angiography, three-dimensional echocardiography, computed tomography, and magnetic resonance imaging. Finally, the findings of our study may not be generalizable to patients with diastolic HF and those with mild systolic HF.
In conclusion, LVEF has a strong dose-dependent intrinsic relationship with RVEF in patients with advanced systolic HF, in whom a low LVEF may be used as a marker of abnormally low RVEF. Future studies need to prospectively examine this relationship using newer imaging modalities.
Funding
A.A. is supported by grants (R01-HL085561 and R01-HL097047) from the National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD, USA and a generous gift from Ms. Jean B. Morris of Birmingham, AL, USA.
Conflict of interest: none declared.
Acknowledgements
The Beta-Blocker Evaluation of Survival Trial (BEST) is conducted and supported by the NHLBI in collaboration with the BEST Study Investigators. This Manuscript was prepared using a limited access data set obtained from the NHLBI and does not necessarily reflect the opinions or views of the BEST or the NHLBI.
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