Independence of restrictive filling pattern and LV ejection fraction with
mortality in heart failure: An individual patient meta-analysis
Meta-analysis Research Group in Echocardiography (MeRGE) Heart Failure Collaborators⁎
Received 15 April 2008; accepted 10 June 2008
Background: The Doppler echocardiographic restrictive mitral filling pattern (RFP) is an important prognostic indicator in patients with heart
failure (HF), but the interaction between RFP, left ventricular ejection fraction (LVEF) and filling pattern remains uncertain.
Aims: To determine whether the RFP is predictive of mortality independently of LVEF in patients with HF.
Methods: Online databases were searched to identify studies assessing the relationship between prognosis and LV filling pattern in patients
with HF. Individual patient data from 18 studies (3540 patients) were extracted and collated at the MeRGE Coordinating Centre (The
University of Auckland).
Results: Overall, RFP was associated with higher all-cause mortality than the non-restrictive filling pattern: hazard ratio 2.42 (95% CI 2.06,
2.83). In multivariable analysis the RFP, LVEF, NYHA class and age were independent predictors of mortality. The prevalence of the RFP
was inversely related to LVEF but remained a predictor of mortality even in those patients with preserved LVEF.
Conclusions: The restrictive mitral filling pattern is a powerful predictor of mortality, independent of LVEF and age, in patients with HF.
Doppler-derived LV filling patterns are an accessible marker from echocardiography that can readily be incorporated in risk stratification of
all patients with HF.
© 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Restrictive filling pattern; Doppler echocardiography; Heart failure; Prognosis; LV ejection fraction
Congestive heart failure is a major clinical condition with
increasing prevalence, annual mortality rates often exceed-
ing 20% even after institution of contemporary treatment,
and more than one million hospitalisations each year .
The total cost of heart failure in the United States in 2006
was estimated at US$29.6 billion . However, the clinical
course of individual patients with heart failure is highly
variable and better understanding of the clinical, laboratory
and echocardiographic factors that are associated with poor
clinical outcome is important.
Pulsed wave Doppler echocardiography of left ventricular
(LV) filling is now widely accepted as a reliable clinical tool
in the non-invasive evaluation of diastolic function . With
severe diastolic impairment a restrictive filling pattern (RFP)
may develop, characterized by left ventricular inflow
predominantly occurring in early diastole with a large mitral
E wave, rapid deceleration and reduced atrial contribution to
filling (mitral A wave). This is associated with elevated left
atrial pressures [3–9], increased LV stiffness , higher
neurohormone levels [11,12], and higher NYHA class .
In a recent literature-based meta-analysis, involving 3024
patients with heart failure from 26 prospective studies the
unadjusted odds ratio of a RFP for all-cause mortality was
4.36 (CI: 3.60, 5.29) .
Many patients with RFP also have concomitant severe LV
systolic impairment and although in some studies RFP
remained a prognostic predictor in multivariable analyses,
none of the individual studies possessed sufficient power to
European Journal of Heart Failure 10 (2008) 786–792
⁎R.N. Doughty, Department of Medicine, The University of Auckland,
Private Bag 92019, Auckland, New Zealand. Tel.: +64 9 373 7599x89804;
fax: +64 9 3677146.
E-mail address: firstname.lastname@example.org.
1388-9842/$ - see front matter © 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
patients with chronic heart failure and atrial fibrillation. Am J Cardiol
 Traversi E, Cobelli F, Pozzoli M. Doppler echocardiography reliably
predicts pulmonary artery wedge pressure in patients with chronic
heart failure even when atrial fibrillation is present. Eur J Heart Failure
 Yamamoto T, Oki T, Yamada H, et al. Prognostic value of the atrial
systolic mitral annular motion velocity in patients with left ventricular
systolic dysfunction. J Am Soc Echocardiogr 2003;16:333–9.
 Little W, Ohno M, Kitzman D, Thomas J, Cheng C. Determination of
left ventricular chamber stiffness fromthe time for decelerationof early
left ventricular filling. Circulation 1995;92:1933–9.
 Akioka K, Takeuchi K, Yanagi S, et al. Prognostic value of Doppler
transmittal flow patterns and cardiac natriuretic peptides in patients
with chronic congestive heart failure admitted for episodes of acute
decompensation. Heart Vessels 2000;15(2):53–60.
 Margulies KB, Jaffer S, Pollack PS, Ennis KJ. Physiological sig-
nificance of early deceleration time prolongation in asymptomatic
elderly subjects. J Cardiac Fail 1999;5(2):92–9.
 Xie GY, Berk MR, Smith MD, DeMaria AN. Relation of Doppler
transmitral flow patterns to functional status in congestive heart failure.
Am Heart J 1996;131(4):766–71.
 Whalley GA, Gamble G, Doughty R. The prognostic significance of
Int J Cardiol 2006;116:70–7.
 Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational
studies in epidemiology: a proposal for reporting. JAMA 2000;283
 Whalley GA, Gamble GD, Dini FL, et al. Individual patient meta-
analyses of restrictive diastolic filling and death post acute myocardial
infarction and in patients with heart failure — MeRGE. Int J Cardiol
 Bruch C, Gotzmann M, Stypmann J, et al. Electrocardiography and
heart failure: incremental prognostic value of QRS duration and a
restrictive mitral filling pattern. J Am Coll Cardiol 2005;45(7):1072–5.
 Dini FL, Cortigiani L, Baldini U, et al. Prognostic value of left atrial
enlargement in patients with idiopathic dilated cardiomyopathy and
ischemic cardiomyopathy. Am J Cardiol 2002;89(5):518–23.
 Dini FL, Michelassi C, Micheli G, Rovai D. Prognostic value of
pulmonary venous flow Doppler signal in left ventricular dysfunction.
J Am Coll Cardiol 2000;36:1295–302.
 Doughty RN, Whalley GA, Walsh HA, et al. Effects of carvedilol on
left ventricular remodeling after acute myocardial infarction: the
CAPRICORN Echo Substudy. Circulation 2004;109(2):201–6.
 Feola M, Aspromonte N, Canali C, et al. Prognostic value of plasma
brain natriuretic peptide, urea nitrogen, and creatinine in outpatients N
70 years of age with heart failure. Am J Cardiol 2005;96(5):705–9.
 Ghio S, Recusani F, Klersy C, et al. Prognostic usefulness of the
tricuspid annular plane systolic excursion in patients with congestive
heart failure secondary to idiopathic or ischemic dilated cardiomyo-
pathy. Am J Cardiol 2000;85:837–42.
 Giannuzzi P, Temporelli PL, Bosmini E, et al. Independent and
incremental prognostic value of Doppler-derived mitral deceleration
time of early filling in both symptomatic and asymptomatic patients
with left ventricular dysfunction. J Am Coll Cardiol 1996;28:383–90.
 Hansen A, Haass M, Zugck C, et al. Prognostic value of Doppler
echocardiographic mitral inflow patterns: implications for risk
stratification in patients with congestive heart failure. J Am Coll
 Ortiz J, Matsumoto AY, Gheffer CGM, et al. Prognosis in dilated
myocardial disease: influence of diastolic dysfunction and anatomical
changes. Echocardiography 1993;10(3):247–54.
 Pinamonti B, Zecchin M, Di Lenarda A, Gregori D, Sinagra G,
Camerini F. Persistence of restrictive left ventricular filling pattern in
dilated cardiomyopathy: an ominous prognostic sign. J Am Coll
 Rossi A, Cicoira M, Zanolla L, et al. Determinants and prognostic
value of left atrial volume in patients with dilated cardiomyopathy.
J Am Coll Cardiol 2002;40(8):1425–30.
 Tabet JY, Logeart D, Geyer C, et al. Comparison of the prognostic
value of left ventricular filling and peak oxygen uptake in patients with
systolic heart failure. Eur Heart J 2000;21(22):1864–71.
 Temporelli PL, Corra U, Imparato A, Bosimini E, Scapellato F,
Giannuzzi P. Reversible restrictive left ventricular diastolic filling with
optimized oral therapy predicts a more favorable prognosis in patients
with chronic heart failure. J Am Coll Cardiol 1998;31(7):1591–7.
 Troughton RW, Prior DL, Frampton CM, et al. Usefulness of tissue
Doppler and color M-mode indexes of left ventricular diastolic
function in predicting outcomes in systolic left ventricular heart failure
(from the ADEPT study). Am J Cardiol 2005;96(2):257–62.
 Whalley GA, Doughty RN, Gamble GD, et al. Pseudonormal mitral
filling pattern predicts hospital readmission in patients with congestive
heart failure. J Am Coll Cardiol 2002;39:1787–95.
 Yu CM, Sanderson JE. Different prognostic significance of right and
left ventricular diastolic dysfunction in heart failure. Clin Cardiol
quantification: a report from the American Society of Echocardiogra-
phy's Guidelines and Standards Committee and the Chamber Quanti-
fication Writing Group, developed in conjunction with the European
Association of Echocardiography, a branch of the European Society of
Cardiology. J Am Soc Echocardiogr 2005;18:1440–63.
 Ho KKL, Anderson KM, Kannel WB. Survival after the onset of
congestive heart failure in the Framingham Heart Study subjects.
 MacIntyre K, Capewell S, Stewart S, Chalmers JWT. Evidence of
improving prognosis in heart failure: trends in case fatality in 66547
patients hospitalised between 1986 and 1995. Circulation 2000;102:
 Hunt S, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline
update for the diagnosis and management of chronic heart failure in the
adult—summary article: a report of the American College of
Cardiology/American Heart Association Task Force on practice
guidelines (writing committee to update the 2001 guidelines for the
evaluation and management of heart failure). J Am Coll Cardiol
 Cleland JGF, Swedberg K, Follath F, et al. The EuroHeart Failure
survey programme—a survey on the quality of care among patients
with heart failure in Europe: part 1: patient characteristics and
diagnosis. Eur Heart J 2003;24(5):442–63.
 Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with
preserved ejection fraction in a population-based study. N Engl J Med
 Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield
MM. Trends in prevalence and outcome of heart failure with preserved
ejection fraction. N Engl J Med 2006;355(3):251–9.
 Cleland JGF, Tendera M, Adamus J, et al. The perindopril in elderly
people with chronic heart failure (PEP-CHF) study. Eur Heart J
 Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in
patients with chronic heart failure and preserved left-ventricular
ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362
 Capomolla S, Pinna G, Febo O, et al. Echo-Doppler mitral flow
monitoring: an operative tool to evaluate day-to-day tolerance to and
effectiveness of beta-adrenergic blocking agenttherapyin patientswith
chronic heart failure. J Am Coll Cardiol 2001;38(6):1675–84.
792MeRGE Heart Failure Collaborators / European Journal of Heart Failure 10 (2008) 786–792