The authors have declared that no competing interests exist.
Right Atrial Volume Index (RAVI) measured by echocardiography is an independent predictor of morbidity in patients with heart failure (HF) with reduced ejection fraction (HFrEF). The aim of this study is to evaluate the predictive value of RAVI assessed by cardiac magnetic resonance (CMR) for all-cause mortality in patients with HFrEF and to assess its additive contribution to the validated Meta-Analysis Global Group in Chronic heart failure (MAGGIC) score.
We identified 243 patients (mean age 60 ± 15; 33% women) with left ventricular ejection fraction (LVEF) ≤ 35% measured by CMR. Right atrial volume was calculated based on area in two- and four -chamber views using validated equation, followed by indexing to body surface area. MAGGIC score was calculated using online calculator. During mean period of 2.4 years 33 patients (14%) died. The mean RAVI was 53 ± 26 ml/m2; significantly larger in patients with than without an event (78.7±29 ml/m2 vs. 48±22 ml/m2, p<0.001). RAVI (per ml/m2) was an independent predictor of mortality [HR = 1.03 (1.01–1.04), p = 0.001]. RAVI has a greater discriminatory ability than LVEF, left atrial volume index and right ventricular ejection fraction (RVEF) (C-statistic 0.8±0.08 vs 0.55±0.1, 0.62±0.11, 0.68±0.11, respectively, all p<0.02). The addition of RAVI to the MAGGIC score significantly improves risk stratification (integrated discrimination improvement 13%, and category-free net reclassification improvement 73%, both p<0.001).
RAVI by CMR is an independent predictor of mortality in patients with HFrEF. The addition of RAVI to MAGGIC score improves mortality risk stratification.
An estimated 5.7 million Americans have heart failure (HF). The foreseen increase in the prevalence of HF will top 8 million by 2030. Approximately 870, 000 new cases of HF are diagnosed annually [
Right atrium volume index (RAVI) measured by trans-thoracic echocardiography (TTE) was identified as an independent predictor of adverse outcome in patients with HF with reduced ejection fraction (HFrEF) [
This study is part of an ongoing outcomes registry of patients undergoing CMR imaging at the New York Methodist Hospital. Our study was approved by the institutional review board. Every patient enrolled in this study provided written informed consent for inclusion of CMR, demographic, and outcomes data to the registry. There was no external funding used to support this work. The authors are fully responsible for the design and conduct of this study, all data analysis, drafting, editing of the paper and its final content.
We systematically obtained clinical, demographic, electrocardiographic (baseline rhythm, PR, QRS, QT, QTc intervals as well as presence of LBBB/RBBB) and laboratory data (Na,Creatinine, C-reactive protein and Pro-BNP-NT) via direct patient interview at the time of enrollment in the registry, and review of notes from referring physicians and electronic medical record at the time of CMR scan. Vital status was followed at regular intervals after initial CMR. Data were collected at regular intervals by cardiovascular research associates blinded to the CMR results through either standardized telephone interview with the patients or, if deceased, with family members or contact with the referring physician; review of inpatient and outpatient medical records. Vital status and date of death was additionally confirmed using Social Security Death Index. The primary outcome was all-cause mortality. Cause of death was adjudicated using electronic health records, death certificate, telephone interview with a relative or with a physician involved in care. We defined cause of death as cardiac or non-cardiac.
Patients referred for CMR from June 2006 to December 2014, older than 18 years of age, with severely reduced left ventricular systolic function defined as an ejection fraction (EF) ≤ 35% at index CMR exam were and enrolled in the registry were enrolled in this study. We excluded patients with complex congenital heart disease, prior valve surgery, severe valvular disease by CMR, those scheduled for open heart surgery or patients with inadequate/incomplete imaging.
CMR studies were performed with a 1.5-T CMR system Magnetom Avanto™(Siemens Healthcare®) using standard pulse sequences. Before contrast administration, short-axis steady-state free precession (SSFP) images covering the left ventricle (LV) from the mitral valve annulus to the apex were obtained for the evaluation of LV function. Three chamber, four chamber and two (both right and left sided) chamber SSFP images were also acquired according to the American Heart Association imaging recommendation [
Two physicians blinded to patient clinical data performed area measurements of the right atrium in the 4-chamber view and right-sided-2 -chamber view at the end systole utilizing retrospectively gated SSFP images. Precession™ software (Heart Imaging Technologies®) was used for area measurements. The right atrial appendage was not included in the measurements. The equation(RA volume = 3.08*(2C area) +3.36*(4C area) -44.4) published elsewhere was utilized to calculate right atrial volume (7). Body surface area (BSA) was calculated according to the Mosteller formula[
Both left and right ventricular volumes were measured during diastole and systole using PRECESSION software™. For the volumetric assessment of the both ventricles and calculation of ejection fraction we utilized technique described by Bourantas et al [
MAGGIC score was calculated using an on-line calculator (available at
We present continuous data as mean, and standard deviation (SD) for normally distributed variables, or median and interquartile range (IQR) for non-gaussian distributed variables. We present categorical data as frequencies. Continuous variables were compared using Mann-Whitney test. The Wilcoxon rank sum-test test was performed for categorical variables. Spearman’s and Pearsons correlation coefficients were used to show a correlation between RAVI and tested variables. The primary outcome was assessed using Cox proportional hazard model controlled for MAGGIC (Integer) risk and right ventricular ejection fraction (RVEF). The proportional hazard assumption was confirmed using Schoenfeld residuals (p for RAVI = 0.847, p for global test = 0.879) and by the scaled Schoenfeld residuals plot. Kaplan–Meier curves with the log-rank statistic were used to illustrate outcome. Receiver operating characteristic (ROC) analysis was used to compare area under the curve (AUC) of RAVI to volumetric CMR parameters (right ventricular ejection fraction, left ventricular ejection fraction and left atrium volume index) and MAGGIC risk for the prediction of mortality [
We included 243 patients in our analysis (
Parameter | Allpatients | RAVI ≤44.5 ml/m2 | RAVI >44.5 ml/m2 | P |
---|---|---|---|---|
Age-yr |
60±15.6 | 58.1±14.9 | 61.7±16.1 | 0.0632 |
FemaleGender | 79(33%) | 38(31.2%) | 41(33.9%) | 0.65 |
BMI (kg/m2) | 28.6±6.4 | 28.9±6.4 | 28.2±6.4 | 0.3 |
Hypertension | 181(75%) | 88(74%) | 93(77%) | 0.6 |
Hyperlipidemia | 142(59%) | 75(62%) | 67(55%) | 0.3 |
Diabetes | 81(34%) | 46(38%) | 35(29%) | 0.12 |
CAD | 103(43%) | 54(45%) | 49(41%) | 0.52 |
PriorMI | 71(29%) | 38(32%) | 33(27%) | 0.49 |
NYHAIclass | 54(22%) | 29(24%) | 25(21%) | 0.0213 |
IIclass | 105(43%) | 63(51.6%) | 43(35.3%) | |
III class | 74(31%) | 24(19.7%) | 50(41%) | |
IVclass | 10(4%) | 6(5%) | 4(3.3%) | |
HistoryofAF | 38(16%) | 8(7%) | 30(25%) | 0.0001 |
PAD | 11(5%) | 6(5%) | 5(4%) | 0.74 |
Activesmoking | 31(13%) | 26(22%) | 5(4%) | 0.0001 |
COPD | 20(8%) | 10(9%) | 10(8%) | 0.94 |
Cancer | 22(9%) | 10(8%) | 12(10%) | 0.64 |
PriorCVA | 18(7%) | 6(45%) | 12(10%) | 0.15 |
RASblocker | 154(66%) | 83(68%) | 89(72.9%) | 0.4 |
Beta-blockers | 180(76%) | 90(74%) | 111(91%) | 0.003 |
MRA | 46(20%) | 20(17%) | 32(26%) | 0.1 |
Otherdiuretics | 112(48%) | 47(39.2%) | 65(54.1%) | 0.055 |
Digoxin | 24(10%) | 10(9%) | 14(12%) | 0.5 |
Statins | 125(53%) | 63(56%) | 62(51%) | 0.5 |
Aspirin | 124(53%) | 66(58%) | 59(48.4%) | 0.13 |
ProBNP-NT,pg/dl |
2139(472;6138) | 660(268;2862) | 4894(1763;11360) | 0.0001 |
Creatinine,mg/dl | 1.22±0.8 | 1.1±0.6 | 1.2±0.9 | 0.004 |
Na | 139.1±3.9 | 139±4 | 139±4 | 0.11 |
CRP |
3.3(1.6;10.7) | 2.9(1;6.4) | 4.1(2.4;17.1) | 0.017 |
Sinusrhythm | 183(87%) | 101(98%) | 83(78%) | 0.0001 |
Atrialfibrillation | 26(13%) | 2(2%) | 24(22%) | |
PR,ms | 170.4±37.4 | 163.8±32.7 | 178.6±4.6 | 0.0008 |
QRS,ms | 104.7±24.1 | 104.3±25.6 | 105±22.7 | 0.5971 |
QT | 411±47.6 | 407±45 | 415.2±49.8 | 0.1237 |
QTc | 466.3±40.4 | 458.9±39.7 | 473.6±39.7 | 0.0097 |
RBBB | 12(6%) | 4(4%) | 8(8%) | 0.263 |
LBBB | 26(12%) | 16(16%) | 10(10%) | 0.175 |
0.054 | ||||
Cardiomyopathy | 183(75%) | 86(70%) | 97(80%) | |
StressTest- | 37(15%) | 25(21%) | 12(10%) | |
Mass/thrombus | 19(8%) | 7(6%) | 12(10%) | |
Arrythmia/syncope | 5(2%) | 4(3%) | 1(1%) | |
NICM | 152(63%) | 67(55%) | 86(70.5%) | 0.014 |
ICM | 87(36%) | 52(43%) | 35(29%) | 0.026 |
Combined | 4(2%) | 3(2%) | 1(1%) | 0.32 |
AmyloidosisDx | 12(5%) | 0 | 12(10.%) | 0.0001 |
LVEF,% | 25(20;32) | 26(20;33) | 23(18;30) | 0.006 |
LVEDVi | 86±36 | 79±36 | 94±34 | 0.0001 |
LVESVi | 66±31 | 60±33 | 72±27 | 0.0001 |
LVSVi | 21±9 | 20±6 | 22±11 | 0.32 |
RVEF,% | 33±11 | 36±10 | 29±11 | 0.0001 |
RVEDVi | 72±26 | 60±19 | 84±26 | 0.0001 |
RVESVi | 50±23 | 40±17 | 61±25 | 0.0001 |
RVSVi | 22±8 | 21±7 | 23±9 | 0.04 |
LAVI | 54±24 | 41±16 | 67±23 | 0.0001 |
None | 128(52%) | 86(70%) | 42(34%) | 0.0001 |
Present | 116(48%) | 37(30%) | 79(66%) | 0.0001 |
Integerscore | 19.9±6.5 | 19±6.1 | 20.8±6.7 | 0.03 |
BMI = Body mass index, CAD = coronary artery disease, Prior MI = prior myocardial infarction, AF = atrial fibrilation, PAD = peripheral artery disease, COPD = chronic obstructive pulmonary disease, CVA = cerebrovascular accident, RAS = renin angiotensin system, MRA = mineralocorticoid antagonist, Pro BNP = pro–B-type natriuretic peptide, RBBB = right bundle brunch block, LBBB = left bundle brunch block, Stress Test = regadenosin perfusion imaging, HF = heart failure, NICM = non-ischemic cardiomyopathy, ICM = ischemic cardiomyopathy, Dx = diagnosis, LVEF = left ventricular ejection fraction, LVEDVi = left ventricular end diastolic volume indexed (ml/m2), LVSVi = left ventricular stroke volume indexed, RVEF = right ventricular ejection fraction, RVEDVi = right ventricular end diastolic volume indexed, RVSVi = right ventricular stroke volume indexed, LAVI = left atrial volume indexed, TR = tricuspid regurgitation, CMR = Cardiovascular Magnetic Resonance, MAGGIC = Meta-analysis Global Group in Chronic Heart Failure
*Plus-minus values are means ± SD, nominal variables presented as N (%)
# Variables are presented as median (interquartile range)
There were 33 deaths (13.6%) over a median follow-up of 2.2 years (interquartile range 1–3.4), and mean follow-up of 2.4 ± 2 years. Of those, seventeen patients (51%) had a cardiac, eight patients (24.5%)- non-cardiac and eight patients (24.5%) had unknown cause of death. There were four and 29 deaths in patients with RAVI ≤ than median and > than median, respectively, P<0.001, corresponding to annual mortality of 9.2% vs. 1.4%, respectively (
Predictor | HR | 95% CI | P |
---|---|---|---|
RAVI | 1.03 | 1.01–1.04 | 0.001 |
RVEF | 1.02 | 0.98–1.05 | 0.3 |
MAGGIC |
1.13 | 1.06–1.2 | 0.001 |
RAVI- right atrium volume index
RVEF- right ventricular ejection fraction
MAGGIC- Meta-analysis Global Group in Chronic Heart Failure (Integer score)
Further analysis showed that RAVI has greater C statistics (AUC 0.79 (CI 0.72–0.88) than RVEF (AUC 0.62 (CI 0.50–0.73), p<0.03), LAVI (AUC 0.68 (CI 0.57–0.78), p<0.02) and LVEF (AUC 0.55 (CI 0.45–0.66), p<0.01). There was no difference in C statistic between RAVI and MAGGIC score (AUC 0.77 (CI 0.67–0.86), p = 0.61,
Outcome | ROC | SD | P |
IDI | P |
NRI | P |
---|---|---|---|---|---|---|---|
RAVI | 0.80 | 0.72–0.88 | |||||
LAVI | 0.68 | 0.57–0.78 | 0.018 | 0.55 | <0.0001 | 0.71 | <0.0001 |
RVEF | 0.62 | 0.50–0.73 | 0. 027 | 0.17 | <0.0001 | 0.71 | <0.0001 |
LVEF | 0.55 | 0.45–0.66 | 0.001 | 0.16 | <0.0001 | 0.89 | <0.0001 |
MAGGIC | 0.77 | 0.67–0.86 | 0.61 | 0.13 | 0.001 | 0.73 | 0.0002 |
*- when compared to RAVI ROC for mortality
^- integrated discrimination improvement when RAVI added
#- category free net reclassification improvement when RAVI added
RAVI- right atrium volume index
LAVI-left atrium volume index
RVEF- right ventricular ejection fraction
LVEF-left ventricular ejection fraction
MAGGIC- Meta-analysis Global Group in Chronic Heart Failure (Integer score)
Twenty-five RAVI measurements were randomly selected and measured separately by two operators blinded to each other’s results (A.I. and A.M.).There was a excellent reproducibility of RAVI measurements for both observers: 1.9 ml/m2 (95% CI (-3.2)-4.9) for observer I and 1.5 ml/m2 ((-1.9)- 4.1) for observer II, with mean interobserver RAVI difference assessed by Bland-Altman method was -1.7 ml/m2 (95% CI -2.5–4.4).Spearman correlation coefficient for interobserver variability of RAVI was 0.951 (p<0.001)
We report several findings emphasizing the prognostic importance of RAVI in our cohort of patients with severely reduced left ventricular systolic function referred for CMR imaging. First, RAVI was an independent predictor of mortality even after adjusting for MAGGIC score and right ventricular ejection fraction. Second, RAVI is a stronger predictor of mortality than LVEF and LAVI. Thirdly, addition of RAVI increased mortality discrimination of MAGGIC score when assessed by IDI and NRI. These findings make RAVI an important predictor of mortality in patients with HFrEF and suggest that it provides more important prognostic data when compared to conventionally used predictors.
MAGGIC score is a result of a patient level meta-analysis of 39,372 patients from 30 studies with a median follow-up of 2.5 years—the largest dataset published for score derivation (2). Median and mean integer score were 19 and 20, respectively, in our cohort, consistent with the observed mortality of 12.8% at a median follow-up of 1.6 years. RAVI and MAGGIC score were predictors of mortality in the multivariable analysis, independent of each other. MAGGIC score has excellent discrimination ability for mortality, with AUC of 0.76± 0.1. The addition of RAVI to this well calibrated risk score leads to significant risk reclassification when assessed by IDI and NRI.
Sallach et al.(3) assessed RAVI as a surrogate of right ventricular function by TTE in 192 patients. They found RAVI to be an independent predictor of primary outcome that consisted of mortality, cardiac transplant and repeated hospitalization for HF. In our analysis RVEF was a predictor of mortality only in univariate analysis, and RAVI remains to be an independent predictor in multivariate analysis even after controlling for RVEF and other variables. Moreover RAVI has a greater C statistics than RVEF for predicting mortality. These findings suggest that right atrial volume is a more sensitive parameter than right ventricular systolic function to identify higher risk patients. Their reported mean RAVI was 28 ml/m2, much smaller than in our analysis (53 ml/m2). This difference might be explained by several factors: CMR has a greater precision with higher spatial resolution of endocardial borders, use of slightly different anatomical views to measure right atrium by echocardiography and absence of geometric assumptions in retrospectively gated CMR images in contrast to echocardiography. Whitlock et al. reported a significant underestimation of RA volume by echocardiographic area length method when compared to CMR imaging[
There are only a few peer-review articles addressing right atrial dimensions by CMR [
The underlying pathophysiologic mechanism linking RAVI with mortality is not fully understood. One of the possible explanation maybe the fact that right atrium has thin walls, and it is influenced by the same factors that are affecting right ventricular diastolic filling and increase in RAVI may serve as an early manifestation of right ventricular diastolic dysfunction even when RVEF is still relatively preserved. Further investigation of RAVI’s dynamic changes in patients with heart failure and their correlation with adverse clinical outcomes is warranted.
There were multiple publication elaborating on utilization of transthoracic echocardiography for an evaluation of right ventricular function in patients with HfrEF [
We recognize several limitations of our study. There is, probably, some degree of referral and selection bias for patients undergoing cardiac MRI in our center. However the external validity of our findings was supported by MAGGIC score—predicted mortality rate is in line with observed one. The total number of patients was significantly affected by our inclusion/exclusion criteria, however our sample size is comparable or exceeding number of patients with LVEF<35% in recent publications[
Despite these limitations, we conclude that right atrium volume index measured by cardiac magnetic resonance imaging is an independent predictor of mortality in patients with heart failure with reduced ejection fraction. The addition of right atrium volume to the MAGGIC score significantly improves mortality risk stratification.
Contains Fig A, Fig B.
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