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Functional Mitral Regurgitation Predicts Short-Term Adverse Events in Patients With Acute Heart Failure and Reduced Left Ventricular Ejection Fraction
Functional Mitral Regurgitation Predicts Short-Term Adverse Events in Patients With Acute Heart Failure and Reduced Left Ventricular Ejection Fraction Rafael De la Espriella, MDa, Enrique Santas, PhDb,c,d, Gema Miñana, PhDb,c,d, Vicent Bodí, PhDb,c,d, Ernesto Valero, MDb,c,d, Rafael Payá, PhDa, Eduardo Núñez, PhDb,c,d, Ana Payá, MDb,c,d, Francisco J. Chorro, PhDb,c,d, Antoni Bayés-Genis, PhDd,e,f, Juan Sanchis, PhDb,c,d, and Julio Núñez, PhDb,c,d,* Functional mitral regurgitation (FMR) is a common finding in patients with acute heart failure (AHF) and reduced left ventricular ejection fraction (heart failure and reduced ejection fraction [HFrEF]). However, its clinical impact remains unclear. We aimed to evaluate the association between the severity of FMR after clinical stabilization and short-term adverse outcomes after a hospitalization for AHF. We prospectively included 938 consecutive patients with HFrEF discharged after a hospitalization for AHF, after excluding those with organic valve disease, congenital heart disease, or aortic valve disease. FMR was assessed semiquantitatively by color Doppler analysis of the regurgitant jet area, and its severity was categorized as none or mild (grade 0 or 1), moderate (grade 2), or severe (grade 3 or 4). FMR was assessed at 120 ± 24 hours after admission. The primary end point was the composite of all-cause mortality and rehospitalization at 90 days. At discharge, 533 (56.8%), 253 (26.9%), and 152 (16.2%) patients showed none-mild, moderate, and severe FMR. At the 90-day follow-up, 161 patients (17.2%) either died (n = 49) or were readmitted (n = 112). Compared with patients with none or mild FMR, rates of the composite end point were higher for patients with moderate and severe FMRs (p <0.001). After the multivariable adjustment, those with moderate and severe FMRs had a significantly higher risk of reaching the end point (hazard ratio = 1.50, 95% confidence interval 1.04 to 2.17, p = 0.027; and hazard ratio = 1.63, 95% confidence interval 1.07 to 2.48, p = 0.023, respectively). In conclusion, FMR is a common finding in patients with HFrEF, and its presence, when moderate or severe, identifies a subgroup at higher risk of adverse clinical outcomes at short term. © 2017 Elsevier Inc. All rights reserved. (Am J Cardiol 2017;120:1344–1348) In patients with heart failure (HF) and reduced ejection fraction, functional mitral regurgitation (FMR) is a common condition (reported prevalence of about 50%)1; however, its clinical implications remain not well clarified.1–3 Although some previous studies showed that FMR was associated with worse long-term survival rates in chronic HF,4,5 others failed to show a prognostic role.6 The evidence in patients with acute heart failure (AHF) is scarcer.7,8 In this scenario of in-
a Cardiology Department, Hospital General Universitario de Valencia, Valencia, Spain; bCardiology Department, Hospital Clínico Universitario, Valencia, Spain; cINCLIVA Instituto de Investigación Sanitaria, Universitat de València, Valencia, Spain; dCentro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, España; eCardiology Service and Heart Failure Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; and fDepartment of Medicine, Autonomous University of Barcelona, Barcelona, Spain. Manuscript received March 23, 2017; revised manuscript received and accepted July 3, 2017. This work was supported in part by grants 16/11/00420 and 16/11/ 00403 from Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, and by grant PIE15/00013 from Fondo Europeo de Desarrollo Regional, Spain. See page 1347 for disclosure information. *Corresponding author: Tel: +34961973500; fax: +34961973500. E-mail address: [email protected] (J. Núñez).
0002-9149/© 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2017.07.023
creased ventricular loading, we postulate that FMR could play a determinant prognostic role. The aim of the present study was to evaluate the association between the severity of FMR after clinical stabilization and short-term adverse outcomes after a hospitalization for AHF. Methods We prospectively included a consecutive cohort of 1,180 patients with HF and reduced ejection fraction discharged with the diagnosis of AHF from 2009 to 2015. AHF was defined according to current European Clinical Practice Guidelines.9 Patients with new-onset or acutely decompensated HF were included in the registry. By design, patients who died during the index hospitalization (n = 51) were not included in the final analysis. To properly define mitral regurgitation as functional, patients with organic mitral valve disease, congenital heart disease, aortic valve disease, and prosthetic heart valves were excluded (n = 242), leaving the study sample with 938 patients (Figure 1). FMR evaluation was performed by 2 expert sonographers who were blinded to clinical follow-up, and its severity was assessed semiquantitatively by color Doppler analysis of the regurgitant jet area after clinical stabilization was reached (120 ± 24 hours after admission). Clinical stabilization was www.ajconline.org
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respectively. The cumulative probability of the clinical end point was estimated by the Kaplan-Meier method and curves were compared by the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards models. For the multivariate regression model, candidate covariates were chosen based on previous medical knowledge and independent of their p value. A reduced and parsimonious model was derived using backward stepwise selection. The covariates included in the final multivariable model for the primary end point were as follows: age, gender, previous AHF hospitalization, length of stay, systolic blood pressure, the interaction between atrial fibrillation and heart rate, N-terminal pro b-type natriuretic peptide (NT-proBNP), urea, hemoglobin, and tricuspid annular plane systolic excursion. The discriminative ability (Harrell C-statistics) and the calibration (Groennesby and Borgan test) of the final model were 0.783 and 0.102, respectively. A 2-sided p value of <0.05 was considered statistically significant for all analyses. All analyses were performed using STATA 14.1 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). Figure 1. Flowchart.
Results defined as a cessation of intravenous therapy, a reinstitution of oral diuretics, and hemodynamic stability without the need for mechanical ventilation or ventilator support (other than for sleep apnea, if required). FMR severity was categorized as: none or mild (grade 0 or 1), moderate (grade 2), or severe (grade 3 or 4). Left ventricular ejection fraction (LVEF) was calculated by the biplane Simpson method. Reduced LVEF was defined as an LVEF of ≤40%, based on previously established thresholds.9 Two commercially available systems were used throughout the study, Agilent Sonos 5500 and ie33 (Philips, Andover, Massachusetts). During the index hospitalization, data on demographics, medical history, vital signs, 12-lead electrocardiogram, laboratory and echocardiographic parameters, and drug use were routinely recorded using preestablished registry questionnaires. Treatment and other therapeutic strategies were individualized after established guidelines that were operating at the time the patient was included in the registry.9 The primary end point of the present study was a composite end point (all-cause mortality and/or all-cause readmission) at the 90-day follow-up after discharge. Patients’ follow-up was censored if death, cardiac transplantation, or valve replacement occurred. End points were ascertained by a physician blinded to the exposure through a review of hospital and/or outpatient electronic medical records. The study was prospectively designed, conformed to the principles outlined in the Declaration of Helsinki, and was approved by the institutional local review ethical committee. All patients gave informed consent. Continuous variables were expressed as mean ± standard deviation or median (interquartile range), as appropriate. Discrete variables were presented as percentages. Comparisons across FMR groups were performed by chi-square test for categorical variables. For continuous variables, 1-way analysis of variance and Kruskal-Wallis test were used for those variables with parametric and nonparametric distributions,
The mean age was 70.4 ± 12.2 years, 634 patients (67.7%) were male, the underlying etiology of HF was ischemic in 445 patients (47.4%), and 448 patients (47.7%) had a previous admission for AHF. The mean LVEF was 28.8 ± 1.3% and the median NT-proBNP was 5,206 (6,909) ng/ml. After clinical stabilization, 533 (56.8%), 253 (27.0%), and 152 (16.2%) patients showed none or mild (grade 0 or 1), moderate (grade 2), and severe (grade 3 or 4) FMRs, respectively. The baseline characteristics according to FMR categories are shown in Table 1. The composite end point was reached by 161 (17.1%) patients: 49 patients died and 112 were readmitted at 90 days. Patients with a higher degree of FMR showed higher rates of 90-day mortality (none-mild: 16/533 [3.0%], moderate 17/ 253 [6.7%], and severe 16/152 [10.5%]) and the composite of 90-day death and readmission (none-mild: 71/533 [13.3%], moderate 54/253 [21.3%], and severe 36/152 [23.6%]). KaplanMeier curves revealed substantial divergent risk trajectories among FMR groups since the first days after discharge (Figure 2). In the univariate analysis, compared with patients with none or mild FMR, those with FMR grade 2 and grade 3 or 4 showed an almost twofold increased risk of reaching the composite end point at 90 days (unadjusted hazard ratio [HR] = 1.73, 95% confidence interval [CI] 1.22 to 2.47, p = 0.002; and HR = 1.89, 95% CI 1.26 to 2.85, p = 0.002, respectively). After the multivariate adjustment, including wellestablished prognosticators and potential confounders, a more than mild FMR remained significantly associated with an increased risk of reaching the composite end point (p <0.05). Adjusted HRs for FMR grades 2 and 3 or 4 were 1.50 (95% CI 1.04 to 2.17, p = 0.027 and 1.63; 95% CI 1.07 to 2.48 p = 0.023, respectively. A subgroup analysis revealed a nonsignificant differential prognostic effect across age (>75 vs ≤75 years: p value for interaction = 0.149), gender (p value for interaction = 0.635), ischemic etiology (p value for interaction = 0.774), previous AHF admission (p value for interaction = 0.418), and LVEF
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Table 1 Baseline characteristics stratified according to functional mitral regurgitation severity after clinical stabilization Variables
Age (years) Men Hypertension Diabetes Mellitus Dyslipidemia Current smoker Former smoker Chronic obstructive pulmonary disease Peripheral artery disease Ischemic heart failure etiology Prior admission for acute heart failure Atrial fibrillation Implantable cardioverter-defibrillator Cardiac resynchronization therapy New York Heart Association class† class I class II class III or IV Heart rate (bpm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Hemoglobin (g/dL)‡ Creatinine (mg/dL)‡ Estimated glomerular filtration rate (mL/min/1.73 m2)‡,§ Serum sodium (mEq/L)‡ NT-proBNP on admission* NT-proBNP (pg/mL)*,‡ Echocardiographic findings after clinical stabilization Left ventricular ejection fraction (%) Left ventricle end-diastolic diameter (mm) Left atrial dimension (mm) Estimated pulmonary artery systolic pressure (mmHg) ¶ Tricuspid annular plane systolic excursion (mm) Medication at discharge Loop Diuretics Spironolactone Hydrochlorothiazide Beta-blockers Angiotensin converter enzyme inhibitor Angiotensin receptor antagonist Digoxin Nitrates Amiodarone Statins Platelet inhibitors Oral anticoagulants
Functional Mitral Regurgitation
p-Value
None/mild (n = 533)
Moderate (n = 253)
Severe (n = 152)
70.3 ± 12.2 383 (71.8%) 434 (81.4%) 275 (51.6%) 305 (57.2%) 103 (19.3%) 173 (32.4%) 120 (22.5%) 71 (13.3%) 273 (51.2%) 242 (45.4%) 175 (32.9%) 28 (5.2%) 7 (1.3%)
71.1 ± 12.3 148 (58.5%) 189 (74.7%) 125 (49.4%) 139 (54.9%) 41 (16.2%) 76 (30.0%) 54 (21.3%) 22 (8.7%) 107 (42.3%) 125 (49.4%) 100 (39.5%) 10 (3.9%) 5 (1.9%)
69.4 ± 12.0 103 (67.7%) 111 (73.0%) 67 (44.1%) 84 (55.2%) 24 (15.8%) 57 (37.5%) 42 (27.6%) 14 (9.2%) 65 (42.7%) 81 (53.3%) 39 (32.2%) 10 (6.6%) 5 (3.3%)
186 (34.9%) 272 (51.0%) 75 (14.0%) 103 ± 27 151 ± 34 86 ± 20 13.0 ± 1.9 1.3 ± 0.5 63 ± 26 139 ± 4 5936 (6876) 4871 (6302)
82 (32.4%) 133 (52.5%) 38 (15.0%) 101 ± 26 141 ± 33 82 ± 19 12.9 ± 1.8 1.3 ± 0.5 62 ± 25 138 ± 4 7934 (9933) 5825 (7271)
47 (30.9%) 72 (47.3%) 33 (21.7%) 99 ± 25 134 ± 32 79 ± 19 12.5 ± 1.9 1.4 ± 0.7 59 ± 25 138 ± 4 6333 (9134) 5901 (10389)
34 ± 6 60 ± 8 42 ± 7 40 ± 9 18 ± 3 527 (98.8%) 135 (25.3%) 27 (5.4%) 378 (70.9%) 253 (47.4%) 157 (29.4%) 99 (18.6%) 110 (20.6%) 42 (7.9%) 300 (56.3%) 288 (54.0%) 176 (33.0%)
33 ± 7 62 ± 8 42 ± 5 42 ± 10 17 ± 3 251 (99.2%) 93 (36.7%) 11 (4.4%) 193 (76.2%) 137 (54.1) 57 (22.5%) 39 (15.6%) 49 (19.3%) 22 (10.7%) 142 (56.1%) 114 (45.0%) 100 (39.5%)
32 ± 6 65 ± 7 46 ± 7 46 ± 9 16 ± 2 149 (98.0%) 54 (35.5%) 13 (8.7%) 116 (76.3%) 68 (44.7) 38 (25.0%) 36 (23.7%) 31 (20.3%) 18 (11.9%) 76 (50%) 71 (46.7%) 52 (34.0%)
0.41 <0.01 0.024 0.26 0.80 0.43 0.29 0.31 0.10 0.10 0.19 0.15 0.49 0.70 0.22
0.37 <0.01 <0.01 <0.01 0.06 0.33 0.10 0.06 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 0.55 <0.01 0.15 0.18 0.11 0.10 0.13 0.91 0.22 0.36 0.04 0.19
Continuous variables are expressed as mean ± 1 standard deviation, unless otherwise specified. * Variable expressed as median (interquartile range). † Last New York Heart Association (NYHA) functional class, prior to admission. ‡ Laboratory data were assessed during admission, median 4 days (interquartile range: 3–6) after admission. § Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease (MDRD) Study equation. ¶ Data available in 486 patients.
above vs below or equal median (>36% vs ≤36%: p value for interaction = 0.111). Discussion In the present study, we found that an FMR grade 2 or higher, assessed at late hospitalization, was a frequent finding
in a cohort of consecutive patients with AHF and reduced ejection fraction. In addition, and most importantly, FMR grade 2 or higher was related with a short-term risk of adverse events. Previous authors have reported that FMR is present in about 50% of patients with chronic HF with reduced LVEF,1,10 with
Heart Failure/FMR in Acute Heart Failure
Figure 2. Kaplan-Meier estimates of the composite end point (all-cause mortality and/or all-cause readmission at the 90-day follow-up) in the 3 groups stratified by the severity of the functional mitral regurgitation.
conflicting results regarding its prognostic significance.4,6,10–13 In AHF, the evidence is scarcer, with only few studies available evaluating the clinical impact of FMR severity at discharge. Wada et al7 reported a prevalence of moderate or severe FMR of 36% in patients with AHF on admission, but lower rates at discharge (22%), suggesting a relevant dynamic behavior. Interestingly, in this study, those who had a persistent moderate or severe FMR at discharge had a 1.7-fold increased risk of reaching the composite end point (allcause death and HF hospitalization). Along the same line, Kajimoto et al8 also found that hemodynamically significant (moderate or severe) FMR at discharge was present in about one-third of patients with AHF with reduced LVEF and its presence was associated with a significantly increased risk of adverse events. In the present study, up to 43.2% of patients showed a more than mild FMR at the moment of echocardiographic evaluation. Two main reasons could explain this higher prevalence. First, our patient population exhibited features of a more advanced disease compared with those reported by Kajimoto et al, where up to 92.5% of patients were in NYHA functional class I or II. Second, the timing of echocardiography evaluation was different in our study group, where FMR was graded at mid-late hospitalization (after clinical stabilization) and not exactly at discharge. We consider this a relevant matter because it resembles daily clinical practice, where most diagnostic tests are performed once initial stabilization was reached and not on the day of discharge. From a pathophysiologic point of view, FMR is the result of a complex interaction among increased tethering forces (annular and left ventricular [LV] remodeling, segmental or global LV dysfunction with papillary muscle displacement or dysfunction), decreased closing forces (reduced LV contractility or synchrony), and LV end-diastolic pressures.14–16 However, given the reported dynamic profile of FMR in patients with AHF,8 loading LV conditions appears to play a crucial role in this clinical scenario. In this sense, it is reasonable to think that a residual hemodynamically significant FMR after clinical stabilization could be an epiphenomenon of a more advanced disease in which LV loading pressures remain persistently elevated despite a clinical con-
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gestion resolution. In fact, patients with residual grade 2 or more FMR exhibited higher levels NT-proBNP, worse LVEF, and larger LV and LA diameters. According to our findings, and regardless of whether there is a causal relation between FMR and adverse prognosis, we postulate that the presence of a higher degree of FMR at late hospitalization may act as an easily recognizable surrogate of persistent higher loading pressures despite the intensive treatment administered during the first days of admission. Along this line of thought, important clinical messages could be extracted. First, in the setting of AHF, FMR grade 2, classically considered as a nonrelevant echocardiographic finding, appears to be related with a higher risk of short-term events independent of traditional prognosticators, including surrogates of LV pressures, such as natriuretic peptides. Second, FMR emerges as a potential useful tool for monitoring and, maybe, tailored depletive and vasodilator therapy during hospitalization for AHF. We speculate that FMR grade 2 or greater might identify patients in whom a close follow-up and/or a therapy intensification could be recommended. Third, after discharge, a close monitoring of the evolution of FMR might help clinicians to stratify the risk during the transition phase and to identify those in which a progressive increase of FMR may be considered as a therapeutic target. In this regard, transcatheter edge-to-edge mitral valve repair using the MitraClip device (Abbott Vascular, Abbott Laboratories, Abbott Park, Illinois, United States) has emerged. Although the only randomized clinical trial to date supporting the effectiveness of this procedure is the Endovascular Valve Edge-to-Edge Repair Study (EVEREST II), which mainly included organic mitral regurgitation,17 real-world registries showed that it is predominantly used in high-risk, elderly patients mainly affected by FMR18 with encouraging results.19 There are several limitations in our study that need to be acknowledged. First, this is a single-center observational study in which some circumstances and hidden bias influencing the pattern of hospitalizations might be operating. Second, we graded the severity of FMR in a semiquantitative manner, and it has been reported that quantitative grading allows more accurate and reproducible stratification.20 Third, data regarding diastolic function and pulmonary hypertension estimation, which are reported to be prognostic factors in AHF,21–24 were not available in a considerable number of patients. In conclusion, a more than mild FMR present at late hospitalization for AHF identified a subgroup of higher risk of adverse clinical outcomes at short term. Further studies are warranted to confirm these findings and to elucidate the exact clinical role of FMR during the transitional phase. Disclosure The authors have no other funding, financial relations, or conflicts of interest to disclose. 1. Robbins JD, Maniar PB, Cotts W, Parker MA, Bonow RO, Gheorghiade M. Prevalence and severity of mitral regurgitation in chronic systolic heart failure. Am J Cardiol 2003;91:360–362. 2. Bursi F, Barbieri A, Grigioni F, Reggianini L, Zanasi V, Leuzzi C, Ricci C, Piovaccari G, Branzi A, Modena MG. Prognostic implications of functional mitral regurgitation according to the severity of the underlying chronic heart failure: a long-term outcome study. Eur J Hear Fail 2010;12:382–388.
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3. Cioffi G, Tarantini L, De Feo S, Pulignano G, Del Sindaco D, Stefenelli C, Di Lenarda A, Opasich C. Functional mitral regurgitation predicts 1-year mortality in elderly patients with systolic chronic heart failure. Eur J Heart Fail 2005;7:1112–1117. 4. Trichon BH, Felker GM, Shaw LK, Cabell CH, O’Connor CM. Relation of frequency and severity of mitral regurgitation to survival among patients with left ventricular systolic dysfunction and heart failure. Am J Cardiol 2003;91:538–543. 5. Koelling TM, Aaronson KD, Cody RJ, Bach DS, Armstrong WF, Arbor A. Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction. Am Heart J 2002;144:524–529. 6. Patel JB, Borgeson DD, Barnes ME, Rihal CS, Daly RC, Redfield MM. Mitral regurgitation in patients with advanced systolic heart failure. J Card Fail 2004;10:8–11. 7. Wada Y, Ohara T, Funada A, Hasegawa T, Sugano Y, Kanzaki H, Tokoyama H, Yasuda S, Ogawa H, Anzai T. Prognostic impact of functional mitral regurgitation in patients admitted with acute decompensated heart failure. Circ J 2015;80:139–147. 8. Kajimoto K, Sato N, Takano T. investigators of the Acute Decompensated Heart Failure Syndromes (ATTEND) registry. Functional mitral regurgitation at discharge and outcomes in patients hospitalized for acute decompensated heart failure with a preserved or reduced ejection fraction. Eur J Heart Fail 2016;18:1051–1059. 9. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland J, Coats A, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129–2200. 10. Pu M. The frequency, impact, and management of mitral regurgitation in patients with heart failure. Curr Cardiol Rep 2006;8:226–231. 11. Agricola E, Ielasi A, Oppizzi M, Faggiano P, Ferri L, Calabrese A, Vizzardi E, Alfieri O, Margonato A. Long-term prognosis of medically treated patients with functional mitral regurgitation and left ventricular dysfunction. Eur J Heart Fail 2009;11:581–587. 12. Rossi A, Dini FL, Faggiano P, Agricola E, Cicoira M, Frattini S, Simioniuc A, Gullace M, Ghio S, Enriquez-Sarano M, Temporelli PL. Independent prognostic value of functional mitral regurgitation in patients with heart failure. A quantitative analysis of 1256 patients with ischaemic and non-ischaemic dilated cardiomyopathy. Heart 2011;97:1675–1680. 13. García-Cosío Carmena MD, Roig Minguell E, Ferrero-Gregori A, Vázquez García R, Delgado Jiménez J, Cinca J. Impacto de la insuficiencia mitral funcional en el pronóstico de pacientes con
14.
15. 16. 17.
18.
19.
20.
21. 22.
23. 24.
insuficiencia cardiaca y fracción de eyección reducida. Rev Esp Cardiol 2016;doi:10.1016/j.recesp.2016.10.005. Yiu S, Enriquez-Sarano M, Triboilloy C, Seward J, Tajik J. Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction: a quantitative clinical study. Circulation 2000;94:1099–1110. Dwivedi A, Vainrib A, Saric M. Functional mitral regurgitation in patients with heart failure and depressed ejection fraction. Curr Opin Cardiol 2016;31:483–492. Bertrand PB, Schwammenthal E, Levine RA, Vandervoort PM. Exercise dynamics in secondary mitral regurgitation. Circulation 2017;135:297–314. Feldman T, Foster E, Glower DD, Kar S, Rinaldi M, Fail P, Smalling R, Siegel R, Rose GA, Engeron E, Loghin C, Trento A, Skipper ER, Fudge T, Letsou GV, Massaro JM, Mauri L. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364:1395–1406. Maisano F, Franzen O, Baldus S, Shafer U, Hausleiter J, Butter C, Ussia GP, Sievert H. Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, A prospective, multicenter, nonrandomized post-approval study of the Mitraclip therapy in Europe. J Am Coll Cardiol 2013;62:1052–1061. D’Ascenzo F, Moretti C, Marra WG, Montefusco A, Omede P, Taha S, Castagno D, Gaemperli O, Taramasso M, Frea S, Pidello S, Rudolph V, Franzen O, Braun D, Giannini C, Ince H, Perl L, Zoccai G, Marra S, D’Amico M, Maisano F, Rinaldi M, Gaita F. Meta-Analysis of the usefulness of Mitraclip in patients with functional mitral regurgitation. Am J Cardiol 2015;116:325–331. Lancellotti P, Moura L, Pierard LA, Agricola E, Popescu B, Triboilloy C, Hagendorff A, Monin JL, Badano L, Zamorano JL. European association of echocardiography recommendations for the assessment of valvular regurgitation. Part 2: Mitral and tricuspid regurgitation (native valve disease). Eur J Echocardiogr 2010;11:307–332. Harinstein ME, Filippatos GS, Gheorghiade M. Acute heart failure syndromes: epidemiology, risk stratification and prognostic factors. Acute Card Care 2009;11:77–82. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Kitzman D. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: The Cardiovascular Health Study. J Am Coll Cardiol 2001;37:1042–1048. Choudhary G, Jankowich M, Wu WC. Elevated pulmonary artery systolic pressure predicts heart failure admissions in African Americans: Jackson Heart Study. Circ Heart Fail 2014;7:558–564. Kane GC, Karon BL, Mahoney DW, Redfield MM, Roger VL, Burnett JC, Jacobsen SJ, Rodeheffer RJ. Progression of left ventricular diastolic dysfunction and risk of heart failure. JAMA 2011;306:856–863.
a Cardiology Department, Hospital General Universitario de Valencia, Valencia, Spain; bCardiology Department, Hospital Clínico Universitario, Valencia, Spain; cINCLIVA Instituto de Investigación Sanitaria, Universitat de València, Valencia, Spain; dCentro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, España; eCardiology Service and Heart Failure Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; and fDepartment of Medicine, Autonomous University of Barcelona, Barcelona, Spain. Manuscript received March 23, 2017; revised manuscript received and accepted July 3, 2017. This work was supported in part by grants 16/11/00420 and 16/11/ 00403 from Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, and by grant PIE15/00013 from Fondo Europeo de Desarrollo Regional, Spain. See page 1347 for disclosure information. *Corresponding author: Tel: +34961973500; fax: +34961973500. E-mail address: [email protected] (J. Núñez).
0002-9149/© 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2017.07.023
creased ventricular loading, we postulate that FMR could play a determinant prognostic role. The aim of the present study was to evaluate the association between the severity of FMR after clinical stabilization and short-term adverse outcomes after a hospitalization for AHF. Methods We prospectively included a consecutive cohort of 1,180 patients with HF and reduced ejection fraction discharged with the diagnosis of AHF from 2009 to 2015. AHF was defined according to current European Clinical Practice Guidelines.9 Patients with new-onset or acutely decompensated HF were included in the registry. By design, patients who died during the index hospitalization (n = 51) were not included in the final analysis. To properly define mitral regurgitation as functional, patients with organic mitral valve disease, congenital heart disease, aortic valve disease, and prosthetic heart valves were excluded (n = 242), leaving the study sample with 938 patients (Figure 1). FMR evaluation was performed by 2 expert sonographers who were blinded to clinical follow-up, and its severity was assessed semiquantitatively by color Doppler analysis of the regurgitant jet area after clinical stabilization was reached (120 ± 24 hours after admission). Clinical stabilization was www.ajconline.org
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respectively. The cumulative probability of the clinical end point was estimated by the Kaplan-Meier method and curves were compared by the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards models. For the multivariate regression model, candidate covariates were chosen based on previous medical knowledge and independent of their p value. A reduced and parsimonious model was derived using backward stepwise selection. The covariates included in the final multivariable model for the primary end point were as follows: age, gender, previous AHF hospitalization, length of stay, systolic blood pressure, the interaction between atrial fibrillation and heart rate, N-terminal pro b-type natriuretic peptide (NT-proBNP), urea, hemoglobin, and tricuspid annular plane systolic excursion. The discriminative ability (Harrell C-statistics) and the calibration (Groennesby and Borgan test) of the final model were 0.783 and 0.102, respectively. A 2-sided p value of <0.05 was considered statistically significant for all analyses. All analyses were performed using STATA 14.1 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). Figure 1. Flowchart.
Results defined as a cessation of intravenous therapy, a reinstitution of oral diuretics, and hemodynamic stability without the need for mechanical ventilation or ventilator support (other than for sleep apnea, if required). FMR severity was categorized as: none or mild (grade 0 or 1), moderate (grade 2), or severe (grade 3 or 4). Left ventricular ejection fraction (LVEF) was calculated by the biplane Simpson method. Reduced LVEF was defined as an LVEF of ≤40%, based on previously established thresholds.9 Two commercially available systems were used throughout the study, Agilent Sonos 5500 and ie33 (Philips, Andover, Massachusetts). During the index hospitalization, data on demographics, medical history, vital signs, 12-lead electrocardiogram, laboratory and echocardiographic parameters, and drug use were routinely recorded using preestablished registry questionnaires. Treatment and other therapeutic strategies were individualized after established guidelines that were operating at the time the patient was included in the registry.9 The primary end point of the present study was a composite end point (all-cause mortality and/or all-cause readmission) at the 90-day follow-up after discharge. Patients’ follow-up was censored if death, cardiac transplantation, or valve replacement occurred. End points were ascertained by a physician blinded to the exposure through a review of hospital and/or outpatient electronic medical records. The study was prospectively designed, conformed to the principles outlined in the Declaration of Helsinki, and was approved by the institutional local review ethical committee. All patients gave informed consent. Continuous variables were expressed as mean ± standard deviation or median (interquartile range), as appropriate. Discrete variables were presented as percentages. Comparisons across FMR groups were performed by chi-square test for categorical variables. For continuous variables, 1-way analysis of variance and Kruskal-Wallis test were used for those variables with parametric and nonparametric distributions,
The mean age was 70.4 ± 12.2 years, 634 patients (67.7%) were male, the underlying etiology of HF was ischemic in 445 patients (47.4%), and 448 patients (47.7%) had a previous admission for AHF. The mean LVEF was 28.8 ± 1.3% and the median NT-proBNP was 5,206 (6,909) ng/ml. After clinical stabilization, 533 (56.8%), 253 (27.0%), and 152 (16.2%) patients showed none or mild (grade 0 or 1), moderate (grade 2), and severe (grade 3 or 4) FMRs, respectively. The baseline characteristics according to FMR categories are shown in Table 1. The composite end point was reached by 161 (17.1%) patients: 49 patients died and 112 were readmitted at 90 days. Patients with a higher degree of FMR showed higher rates of 90-day mortality (none-mild: 16/533 [3.0%], moderate 17/ 253 [6.7%], and severe 16/152 [10.5%]) and the composite of 90-day death and readmission (none-mild: 71/533 [13.3%], moderate 54/253 [21.3%], and severe 36/152 [23.6%]). KaplanMeier curves revealed substantial divergent risk trajectories among FMR groups since the first days after discharge (Figure 2). In the univariate analysis, compared with patients with none or mild FMR, those with FMR grade 2 and grade 3 or 4 showed an almost twofold increased risk of reaching the composite end point at 90 days (unadjusted hazard ratio [HR] = 1.73, 95% confidence interval [CI] 1.22 to 2.47, p = 0.002; and HR = 1.89, 95% CI 1.26 to 2.85, p = 0.002, respectively). After the multivariate adjustment, including wellestablished prognosticators and potential confounders, a more than mild FMR remained significantly associated with an increased risk of reaching the composite end point (p <0.05). Adjusted HRs for FMR grades 2 and 3 or 4 were 1.50 (95% CI 1.04 to 2.17, p = 0.027 and 1.63; 95% CI 1.07 to 2.48 p = 0.023, respectively. A subgroup analysis revealed a nonsignificant differential prognostic effect across age (>75 vs ≤75 years: p value for interaction = 0.149), gender (p value for interaction = 0.635), ischemic etiology (p value for interaction = 0.774), previous AHF admission (p value for interaction = 0.418), and LVEF
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Table 1 Baseline characteristics stratified according to functional mitral regurgitation severity after clinical stabilization Variables
Age (years) Men Hypertension Diabetes Mellitus Dyslipidemia Current smoker Former smoker Chronic obstructive pulmonary disease Peripheral artery disease Ischemic heart failure etiology Prior admission for acute heart failure Atrial fibrillation Implantable cardioverter-defibrillator Cardiac resynchronization therapy New York Heart Association class† class I class II class III or IV Heart rate (bpm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Hemoglobin (g/dL)‡ Creatinine (mg/dL)‡ Estimated glomerular filtration rate (mL/min/1.73 m2)‡,§ Serum sodium (mEq/L)‡ NT-proBNP on admission* NT-proBNP (pg/mL)*,‡ Echocardiographic findings after clinical stabilization Left ventricular ejection fraction (%) Left ventricle end-diastolic diameter (mm) Left atrial dimension (mm) Estimated pulmonary artery systolic pressure (mmHg) ¶ Tricuspid annular plane systolic excursion (mm) Medication at discharge Loop Diuretics Spironolactone Hydrochlorothiazide Beta-blockers Angiotensin converter enzyme inhibitor Angiotensin receptor antagonist Digoxin Nitrates Amiodarone Statins Platelet inhibitors Oral anticoagulants
Functional Mitral Regurgitation
p-Value
None/mild (n = 533)
Moderate (n = 253)
Severe (n = 152)
70.3 ± 12.2 383 (71.8%) 434 (81.4%) 275 (51.6%) 305 (57.2%) 103 (19.3%) 173 (32.4%) 120 (22.5%) 71 (13.3%) 273 (51.2%) 242 (45.4%) 175 (32.9%) 28 (5.2%) 7 (1.3%)
71.1 ± 12.3 148 (58.5%) 189 (74.7%) 125 (49.4%) 139 (54.9%) 41 (16.2%) 76 (30.0%) 54 (21.3%) 22 (8.7%) 107 (42.3%) 125 (49.4%) 100 (39.5%) 10 (3.9%) 5 (1.9%)
69.4 ± 12.0 103 (67.7%) 111 (73.0%) 67 (44.1%) 84 (55.2%) 24 (15.8%) 57 (37.5%) 42 (27.6%) 14 (9.2%) 65 (42.7%) 81 (53.3%) 39 (32.2%) 10 (6.6%) 5 (3.3%)
186 (34.9%) 272 (51.0%) 75 (14.0%) 103 ± 27 151 ± 34 86 ± 20 13.0 ± 1.9 1.3 ± 0.5 63 ± 26 139 ± 4 5936 (6876) 4871 (6302)
82 (32.4%) 133 (52.5%) 38 (15.0%) 101 ± 26 141 ± 33 82 ± 19 12.9 ± 1.8 1.3 ± 0.5 62 ± 25 138 ± 4 7934 (9933) 5825 (7271)
47 (30.9%) 72 (47.3%) 33 (21.7%) 99 ± 25 134 ± 32 79 ± 19 12.5 ± 1.9 1.4 ± 0.7 59 ± 25 138 ± 4 6333 (9134) 5901 (10389)
34 ± 6 60 ± 8 42 ± 7 40 ± 9 18 ± 3 527 (98.8%) 135 (25.3%) 27 (5.4%) 378 (70.9%) 253 (47.4%) 157 (29.4%) 99 (18.6%) 110 (20.6%) 42 (7.9%) 300 (56.3%) 288 (54.0%) 176 (33.0%)
33 ± 7 62 ± 8 42 ± 5 42 ± 10 17 ± 3 251 (99.2%) 93 (36.7%) 11 (4.4%) 193 (76.2%) 137 (54.1) 57 (22.5%) 39 (15.6%) 49 (19.3%) 22 (10.7%) 142 (56.1%) 114 (45.0%) 100 (39.5%)
32 ± 6 65 ± 7 46 ± 7 46 ± 9 16 ± 2 149 (98.0%) 54 (35.5%) 13 (8.7%) 116 (76.3%) 68 (44.7) 38 (25.0%) 36 (23.7%) 31 (20.3%) 18 (11.9%) 76 (50%) 71 (46.7%) 52 (34.0%)
0.41 <0.01 0.024 0.26 0.80 0.43 0.29 0.31 0.10 0.10 0.19 0.15 0.49 0.70 0.22
0.37 <0.01 <0.01 <0.01 0.06 0.33 0.10 0.06 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 0.55 <0.01 0.15 0.18 0.11 0.10 0.13 0.91 0.22 0.36 0.04 0.19
Continuous variables are expressed as mean ± 1 standard deviation, unless otherwise specified. * Variable expressed as median (interquartile range). † Last New York Heart Association (NYHA) functional class, prior to admission. ‡ Laboratory data were assessed during admission, median 4 days (interquartile range: 3–6) after admission. § Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease (MDRD) Study equation. ¶ Data available in 486 patients.
above vs below or equal median (>36% vs ≤36%: p value for interaction = 0.111). Discussion In the present study, we found that an FMR grade 2 or higher, assessed at late hospitalization, was a frequent finding
in a cohort of consecutive patients with AHF and reduced ejection fraction. In addition, and most importantly, FMR grade 2 or higher was related with a short-term risk of adverse events. Previous authors have reported that FMR is present in about 50% of patients with chronic HF with reduced LVEF,1,10 with
Heart Failure/FMR in Acute Heart Failure
Figure 2. Kaplan-Meier estimates of the composite end point (all-cause mortality and/or all-cause readmission at the 90-day follow-up) in the 3 groups stratified by the severity of the functional mitral regurgitation.
conflicting results regarding its prognostic significance.4,6,10–13 In AHF, the evidence is scarcer, with only few studies available evaluating the clinical impact of FMR severity at discharge. Wada et al7 reported a prevalence of moderate or severe FMR of 36% in patients with AHF on admission, but lower rates at discharge (22%), suggesting a relevant dynamic behavior. Interestingly, in this study, those who had a persistent moderate or severe FMR at discharge had a 1.7-fold increased risk of reaching the composite end point (allcause death and HF hospitalization). Along the same line, Kajimoto et al8 also found that hemodynamically significant (moderate or severe) FMR at discharge was present in about one-third of patients with AHF with reduced LVEF and its presence was associated with a significantly increased risk of adverse events. In the present study, up to 43.2% of patients showed a more than mild FMR at the moment of echocardiographic evaluation. Two main reasons could explain this higher prevalence. First, our patient population exhibited features of a more advanced disease compared with those reported by Kajimoto et al, where up to 92.5% of patients were in NYHA functional class I or II. Second, the timing of echocardiography evaluation was different in our study group, where FMR was graded at mid-late hospitalization (after clinical stabilization) and not exactly at discharge. We consider this a relevant matter because it resembles daily clinical practice, where most diagnostic tests are performed once initial stabilization was reached and not on the day of discharge. From a pathophysiologic point of view, FMR is the result of a complex interaction among increased tethering forces (annular and left ventricular [LV] remodeling, segmental or global LV dysfunction with papillary muscle displacement or dysfunction), decreased closing forces (reduced LV contractility or synchrony), and LV end-diastolic pressures.14–16 However, given the reported dynamic profile of FMR in patients with AHF,8 loading LV conditions appears to play a crucial role in this clinical scenario. In this sense, it is reasonable to think that a residual hemodynamically significant FMR after clinical stabilization could be an epiphenomenon of a more advanced disease in which LV loading pressures remain persistently elevated despite a clinical con-
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gestion resolution. In fact, patients with residual grade 2 or more FMR exhibited higher levels NT-proBNP, worse LVEF, and larger LV and LA diameters. According to our findings, and regardless of whether there is a causal relation between FMR and adverse prognosis, we postulate that the presence of a higher degree of FMR at late hospitalization may act as an easily recognizable surrogate of persistent higher loading pressures despite the intensive treatment administered during the first days of admission. Along this line of thought, important clinical messages could be extracted. First, in the setting of AHF, FMR grade 2, classically considered as a nonrelevant echocardiographic finding, appears to be related with a higher risk of short-term events independent of traditional prognosticators, including surrogates of LV pressures, such as natriuretic peptides. Second, FMR emerges as a potential useful tool for monitoring and, maybe, tailored depletive and vasodilator therapy during hospitalization for AHF. We speculate that FMR grade 2 or greater might identify patients in whom a close follow-up and/or a therapy intensification could be recommended. Third, after discharge, a close monitoring of the evolution of FMR might help clinicians to stratify the risk during the transition phase and to identify those in which a progressive increase of FMR may be considered as a therapeutic target. In this regard, transcatheter edge-to-edge mitral valve repair using the MitraClip device (Abbott Vascular, Abbott Laboratories, Abbott Park, Illinois, United States) has emerged. Although the only randomized clinical trial to date supporting the effectiveness of this procedure is the Endovascular Valve Edge-to-Edge Repair Study (EVEREST II), which mainly included organic mitral regurgitation,17 real-world registries showed that it is predominantly used in high-risk, elderly patients mainly affected by FMR18 with encouraging results.19 There are several limitations in our study that need to be acknowledged. First, this is a single-center observational study in which some circumstances and hidden bias influencing the pattern of hospitalizations might be operating. Second, we graded the severity of FMR in a semiquantitative manner, and it has been reported that quantitative grading allows more accurate and reproducible stratification.20 Third, data regarding diastolic function and pulmonary hypertension estimation, which are reported to be prognostic factors in AHF,21–24 were not available in a considerable number of patients. In conclusion, a more than mild FMR present at late hospitalization for AHF identified a subgroup of higher risk of adverse clinical outcomes at short term. Further studies are warranted to confirm these findings and to elucidate the exact clinical role of FMR during the transitional phase. Disclosure The authors have no other funding, financial relations, or conflicts of interest to disclose. 1. Robbins JD, Maniar PB, Cotts W, Parker MA, Bonow RO, Gheorghiade M. Prevalence and severity of mitral regurgitation in chronic systolic heart failure. Am J Cardiol 2003;91:360–362. 2. Bursi F, Barbieri A, Grigioni F, Reggianini L, Zanasi V, Leuzzi C, Ricci C, Piovaccari G, Branzi A, Modena MG. Prognostic implications of functional mitral regurgitation according to the severity of the underlying chronic heart failure: a long-term outcome study. Eur J Hear Fail 2010;12:382–388.
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3. Cioffi G, Tarantini L, De Feo S, Pulignano G, Del Sindaco D, Stefenelli C, Di Lenarda A, Opasich C. Functional mitral regurgitation predicts 1-year mortality in elderly patients with systolic chronic heart failure. Eur J Heart Fail 2005;7:1112–1117. 4. Trichon BH, Felker GM, Shaw LK, Cabell CH, O’Connor CM. Relation of frequency and severity of mitral regurgitation to survival among patients with left ventricular systolic dysfunction and heart failure. Am J Cardiol 2003;91:538–543. 5. Koelling TM, Aaronson KD, Cody RJ, Bach DS, Armstrong WF, Arbor A. Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction. Am Heart J 2002;144:524–529. 6. Patel JB, Borgeson DD, Barnes ME, Rihal CS, Daly RC, Redfield MM. Mitral regurgitation in patients with advanced systolic heart failure. J Card Fail 2004;10:8–11. 7. Wada Y, Ohara T, Funada A, Hasegawa T, Sugano Y, Kanzaki H, Tokoyama H, Yasuda S, Ogawa H, Anzai T. Prognostic impact of functional mitral regurgitation in patients admitted with acute decompensated heart failure. Circ J 2015;80:139–147. 8. Kajimoto K, Sato N, Takano T. investigators of the Acute Decompensated Heart Failure Syndromes (ATTEND) registry. Functional mitral regurgitation at discharge and outcomes in patients hospitalized for acute decompensated heart failure with a preserved or reduced ejection fraction. Eur J Heart Fail 2016;18:1051–1059. 9. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland J, Coats A, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129–2200. 10. Pu M. The frequency, impact, and management of mitral regurgitation in patients with heart failure. Curr Cardiol Rep 2006;8:226–231. 11. Agricola E, Ielasi A, Oppizzi M, Faggiano P, Ferri L, Calabrese A, Vizzardi E, Alfieri O, Margonato A. Long-term prognosis of medically treated patients with functional mitral regurgitation and left ventricular dysfunction. Eur J Heart Fail 2009;11:581–587. 12. Rossi A, Dini FL, Faggiano P, Agricola E, Cicoira M, Frattini S, Simioniuc A, Gullace M, Ghio S, Enriquez-Sarano M, Temporelli PL. Independent prognostic value of functional mitral regurgitation in patients with heart failure. A quantitative analysis of 1256 patients with ischaemic and non-ischaemic dilated cardiomyopathy. Heart 2011;97:1675–1680. 13. García-Cosío Carmena MD, Roig Minguell E, Ferrero-Gregori A, Vázquez García R, Delgado Jiménez J, Cinca J. Impacto de la insuficiencia mitral funcional en el pronóstico de pacientes con
14.
15. 16. 17.
18.
19.
20.
21. 22.
23. 24.
insuficiencia cardiaca y fracción de eyección reducida. Rev Esp Cardiol 2016;doi:10.1016/j.recesp.2016.10.005. Yiu S, Enriquez-Sarano M, Triboilloy C, Seward J, Tajik J. Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction: a quantitative clinical study. Circulation 2000;94:1099–1110. Dwivedi A, Vainrib A, Saric M. Functional mitral regurgitation in patients with heart failure and depressed ejection fraction. Curr Opin Cardiol 2016;31:483–492. Bertrand PB, Schwammenthal E, Levine RA, Vandervoort PM. Exercise dynamics in secondary mitral regurgitation. Circulation 2017;135:297–314. Feldman T, Foster E, Glower DD, Kar S, Rinaldi M, Fail P, Smalling R, Siegel R, Rose GA, Engeron E, Loghin C, Trento A, Skipper ER, Fudge T, Letsou GV, Massaro JM, Mauri L. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364:1395–1406. Maisano F, Franzen O, Baldus S, Shafer U, Hausleiter J, Butter C, Ussia GP, Sievert H. Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, A prospective, multicenter, nonrandomized post-approval study of the Mitraclip therapy in Europe. J Am Coll Cardiol 2013;62:1052–1061. D’Ascenzo F, Moretti C, Marra WG, Montefusco A, Omede P, Taha S, Castagno D, Gaemperli O, Taramasso M, Frea S, Pidello S, Rudolph V, Franzen O, Braun D, Giannini C, Ince H, Perl L, Zoccai G, Marra S, D’Amico M, Maisano F, Rinaldi M, Gaita F. Meta-Analysis of the usefulness of Mitraclip in patients with functional mitral regurgitation. Am J Cardiol 2015;116:325–331. Lancellotti P, Moura L, Pierard LA, Agricola E, Popescu B, Triboilloy C, Hagendorff A, Monin JL, Badano L, Zamorano JL. European association of echocardiography recommendations for the assessment of valvular regurgitation. Part 2: Mitral and tricuspid regurgitation (native valve disease). Eur J Echocardiogr 2010;11:307–332. Harinstein ME, Filippatos GS, Gheorghiade M. Acute heart failure syndromes: epidemiology, risk stratification and prognostic factors. Acute Card Care 2009;11:77–82. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Kitzman D. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: The Cardiovascular Health Study. J Am Coll Cardiol 2001;37:1042–1048. Choudhary G, Jankowich M, Wu WC. Elevated pulmonary artery systolic pressure predicts heart failure admissions in African Americans: Jackson Heart Study. Circ Heart Fail 2014;7:558–564. Kane GC, Karon BL, Mahoney DW, Redfield MM, Roger VL, Burnett JC, Jacobsen SJ, Rodeheffer RJ. Progression of left ventricular diastolic dysfunction and risk of heart failure. JAMA 2011;306:856–863.