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Dynamic Nature of Pulmonary Artery Systolic Pressure in Decompensated Heart Failure With Preserved Ejection Fraction: Role of Functional Mitral Regurgitation
Journal of Cardiac Failure Vol. 19 No. 11 2013
Dynamic Nature of Pulmonary Artery Systolic Pressure in Decompensated Heart Failure With Preserved Ejection Fraction: Role of Functional Mitral Regurgitation PIERRE VLADIMIR ENNEZAT, MD,1 SYLVESTRE MARECHAUX, MD,2 NADIA BOUABDALLAOUI, MD,3 AND THIERRY H. LE JEMTEL, MD4 Lille and Paris, France; and New Orleans, Louisiana
ABSTRACT Background: Pulmonary hypertension (PH) is prevalent in decompensated heart failure with preserved ejection fraction (HFpEF). We investigated the effect of a return to a compensated state on pulmonary artery systolic pressure (PASP) and functional mitral regurgitation (FMR). Methods and Results: Two-dimensional Doppler echocardiography was prospectively performed before initiation of standard therapy and 48 hours later in 37 patients hospitalized for HFpEF-related dyspnea and in 26 patients hospitalized for non-HFpEFerelated dyspnea. Left atrial volume index, and E/e0 ratio, and PASP were significantly greater and E-wave deceleration time significantly shorter in HFpEF than in nonHFpEF patients. Thirty-two of the 37 HFpEF had FMR on admission whereas none of the non-HFpEF patients had FMR. After 48 hours of therapy, the reduction in PASP was significantly greater in the 26 HFpEF patients who improved than in the 11 HFpEF patients who did not (24 vs 9 mm Hg, respectively; P ! .0001), whereas PASP remained unchanged in non-HFpEF patients. The decrease in PASP correlated in HFpEF patients with reductions in blood pressure, heart rate, left ventricular end-diastolic volume, inferior vena cava diameter, E/A ratio, E/e0 ratio, mitral effective regurgitant orifice area (EROA), and E-wave deceleration time. The correlation between PASP and mitral EROA was the only one that remained significant by multivariate analysis. Conclusions: Noninvasive monitoring of PASP and FMR during an episode of HFpEF decompensation reveals that the return to a compensated state is associated with a significant reduction in PASP and FMR. (J Cardiac Fail 2013;19:746e752) Key Words: Heart failure with preserved ejection fraction, pulmonary hypertension, mitral regurgitation.
Patients with heart failure with preserved ejection fraction (HFpEF) have as poor prognosis as those with heart failure due to reduced ejection fraction.1 The presence of
pulmonary hypertension (PH) identifies a subset of HFpEF patients with a specially poor prognosis.2,3 Pulmonary hypertension has been reported in HFpEF mostly during a hospitalization for symptomatic decompensation or in symptomatic ambulatory patients.2e5 To what extent relief of symptoms with standard HFpEF treatment affects PH has not been investigated.6 One expects intravenous loop diuretic therapy to lower PH by reducing pulmonary venous congestion. Combined diuretic and vasodilator therapy may also lower PH by decreasing the amount of functional mitral regurgitation (FMR), which has been shown to be a major determinant of PH in ambulatory HFpEF patients.7 The hypothesis behind the present study was that PH may significantly subside and FMR lessen when standard HFpEF treatment for decompensation results in a rapid return to a compensated state. Accordingly pulmonary artery systolic pressure (PASP) and FMR were prospectively evaluated
From the 1Institut Federatif de Recherche, Universite Lille Nord de France, Lille, France; 2Groupement Hospitalier de l’Institut Catholique Lillois, Universite Lille Nord de France, and Faculte Libre de Medecine, Universite Catholique de Lille, Lille, France; 3Cardiology Intensive Care Unit, H^ opital Europeen Georges Pompidou, Paris, France and 4Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana. Manuscript received January 24, 2013; revised manuscript received August 30, 2013; revised manuscript accepted September 30, 2013. Reprint requests: Pierre Vladimir Ennezat, MD, Department of Cardiology, Centre Hospitalier Universitaire de Grenoble, BP 217 - 38043 Grenoble cedex 09, France. Tel: þ33 4 76 76 84 66; Fax: þ33 4 76 76 53 68. E-mail: [email protected] See page 752 for disclosure information. 1071-9164/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2013.09.006
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PH and Mitral Regurgitation in Acute HFpEF
on presentation and 48 hours later in hospitalized patients for HFpEFe and non-HFpEFerelated shortness of breath. Methods Study Population The study population included patients who when presenting to the emergency department (ED) for severe shortness of breath at rest had windows that allowed acquisition of high quality 2dimensional Doppler echocardiography. The study population consisted of 2 cohorts. The first cohort included patients who were diagnosed as experiencing HFpEF decompensation on the basis of history of present illness, Framingham criteria for heart failure,8 and left ventricular (LV) ejection fraction (EF) O45% without wall motion abnormalities on 2-dimensional Doppler echocardiography. Patients with ventricular or supraventricular arrhythmias, bradycardia related to atrioventricular block or sinus node dysfunction, primary cardiac valvular disease, or cardiac valve replacement, acute coronary syndrome, infiltrative cardiomyopathy, and sleep disorder breathing were ineligible for the study. Similarly, initiation of therapy before 2-dimensional Doppler echocardiography examination and mechanical ventilation excluded patients from the study. Patients with a poor-quality 2-dimensional Doppler echocardiography examination also were ineligible for the study. Stress echocardiography or nuclear myocardial imaging and, when clinically indicated, coronary artery angiography were obtained to exclude ongoing myocardial ischemia. Standard therapy for HFpEF decompensation consisted of intravenous administration of loop diuretics and control of blood pressure, with angiotensin-converting enzyme inhibition (ACEI), angiotensin receptor blockade (ARB), calcium channel blockade, or nonspecific vasodilators, such as nitroglycerin. None of the patients with HFpEF-related shortness of breath received phosphodiesterase-5 inhibition. The patients were asked to evaluate changes in shortness of breath by marking on a box report form. Shortness of breath was assessed with a similar questionnaire to that used in the Nesiritide trials.9,10 The self designed questionnaire included the following questions: 1) Are you more short of breath than you are usually? 2) Are you much more short of breath than usually? 3) Has your shortness of breath completely resolved as much as you can tell? 4) Has your shortness of breath improved? 5) Are you still more short of breath than usual? 6) Are you as short of breath as you were on admission? 7) Is your shortness of breath only minimally improved? The patients with HFpEF who improved at 48 hours self-marked affirmative answers to questions 3 and 4, whereas those who did not improve at 48 hours marked 1, 2, 5, 6, or 7. The second cohort consisted of patients who were evaluated in the ED for severe shortness of breath and had no evidence for HFpEF by history, physical examination, and 2-dimensional Doppler echocardiography. These patients were diagnosed as having chronic obstructive pulmonary disease (COPD) exacerbation or pneumonia and treated accordingly with appropriate antibiotics and bronchodilators. Clinical and Laboratory Data Collection All data were prospectively collected. The first 2-dimensional Doppler echocardiography examination was performed in the ED before initiation of any therapy. The second 2-dimensional Doppler echocardiography examination was performed 48 hours later. Body mass index was calculated as weight/height2. Obesity was defined as
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a body mass index O30 kg/m2. Clinical data included age, sex, and medical history including hypertension, dyslipidemia, type II diabetes mellitus, and tobacco. Clinical history was obtained from patients, reviews of medical records, and primary care physician interviews. Diagnosis and severity of COPD was assessed according to Global Initiative for Chronic Obstructive Lung Disease guidelines.11 Laboratory data included serum creatinine, hemoglobin, and B-type natriuretic peptide (BNP) levels. Glomerular filtration rate (eGFR) was estimated by the Modification of Diet in Renal Disease equation.12 All study patients were white. Chest X-rays and electrocardiograms were obtained for all study patients on admission. Data were collected as part of their routine evaluation. An informed consent for access to protected health information was approved by our Institutional Review Board and was obtained from every patient. The registry was declared to the Commission Nationale de l’Informatique et des Libertes (CNIL). Echocardiographic Data Collection Two-dimensional Doppler echocardiography examinations were performed on admission and repeated 48 hours later with the use of a multiple-frequency 2e4-MHz transducer (IE33; Philips, Andover, Massachusetts) or a Vivid S5 ultrasound system (GE Medical Systems, Horten, Norway). Left ventricular volumes and EF were calculated with the use of the modified Simpson rule. Left atrial (LA) volume was obtained from the apical 4- and 2-chamber views with the use of the Simpson method. Pulsed-wave Doppler was performed in the apical 4-chamber view at end-expiration with a 3-mm sample volume to obtain mitral inflow velocities (E and A waves). Pulsed-wave tissue Doppler imaging was sequentially performed to acquire lateral and septal mitral annular early-diastolic velocities (e0 waves), and both velocities were averaged to calculate the E/e0 ratio (which correlates reasonably well with LV end-diastolic pressure) as previously described.13 The trans-tricuspid pressure gradient was recorded from any view with continuous-wave Doppler imaging and was used to determine PASP with the use of the modified Bernouilli equation (PASP 5 4 Vmax2 þ RAP), where Vmax is the peak tricuspid regurgitation velocity and RAP the right atrial pressure. Right atrial pressure was estimated from echocardiographic characteristics of the inferior vena cava and importance of inspiratory collapse during a brief sniff.14 Mitral regurgitant volume (RV) and effective regurgitant orifice area (EROA) were measured by the proximal flow convergence technique. Depth, size, and sector settings were optimized for optimal color Doppler resolution. The Doppler color flow zero baseline was shifted downward to obtain satisfactory hemispheric proximal isovelocity surface area. The proximal flow convergence was imaged and expanded in the apical 4-chamber view. The aliasing velocity (Vr) was carefully adjusted (20e40 cm/s). The midsystole radius of proximal flow convergence region (r) was measured from the point of aliasing to the leaflet tips. Maximum mitral regurgitant velocity and the regurgitant time-velocity integral were obtained from continuous-wave Doppler recordings. The regurgitant flow was measured as 2 p r2 Vr. The following parameters were calculated: mitral EROA 5 regurgitant flow/maximal regurgitant velocity; and RV 5 EROA regurgitant time-velocity integral. Statistical Considerations and Analysis Data are presented as median [25the75th percentiles] for continuous variables and as proportions for categoric variables. Median values of continuous variables for HFpEF patients and control
748 Journal of Cardiac Failure Vol. 19 No. 11 November 2013 subjects were compared with the use of Mann-Whitney U tests for independent samples. Categoric variables were compared with the use of the chi-square test. The relationships between changes in PASP and echocardiographic parameters changes were analyzed by Spearman correlation coefficients. To identify independent echocardiographic factors associated with changes in MR severity, all variables that correlated with a P value of !.05 in univariate analysis were submitted to a complete multiple linear regression analysis. A 2-tailed P value of !.05 was required for statistical significance. All analyses were conducted with the use of SPSS 11.0 software (Chicago, Illinois).
Results Clinical Characteristics of HFpEF and Non-HFpEF Cohorts
The HFpEF cohort of the study consisted of 37 patients. Forty-eight hours after admission, 26 patients were markedly improved and 11 were not or marginally improved.
The non-HFpEF cohort consisted of 26 patients. Nineteen of these 26 patients were hospitalized for COPD exacerbation and 7 for atypical or bacterial pneumonia. Steady mean forced expiratory volume in 1 second (FEV1) was 0.99 6 0.36 L and steady mean Tiffeneau-Pinelli index 38 6 16% in COPD patients. Patients with HFpEF decompensation were treated with loop diuretics and vasodilators and no antibiotics, whereas non-HFpEF patients received antibiotics and no loop diuretics or vasodilators (Table 1). The clinical and laboratory data of HFpEF patients (improved and not improved at 48 hours) and of nonHFpEF patients are detailed in Table 1. HFpEF patients had greater blood pressures, heart rate, and BNP levels and lower eGFR and hemoglobin concentration than nonHFpEF patients. Left atrial volume index, PASP, E/A ratio, and E/e0 ratio were significantly greater and E-wave deceleration time significantly shorter in HFpEF patients than in non-HFpEF patients. Mild to moderate FMR was noted in
Table 1. Clinical and Echocardiographic Parameters in HFpEF and Non-HFpEF Patients Before Initiation of Therapy
Sex (male/female) Age (y) Hypertension, n (%) Diabetes mellitus, n (%) Obesity, n (%) Chronic obstructive pulmonary disease, n (%) B-Type natriuretic peptide (pg/mL) Hemoglobin (g/dL) Estimated GFR (mL/min/1.73 m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Left ventricular ejection fraction (%) Left ventricular mass index (g/m2) Left atrial volume index (mL/m2) Left ventricular end-diastolic volume (mL) E/A ratio E-Wave deceleration time (ms) E/e0 ratio Inferior vena cava diameter (mm) Pulmonary artery systolic pressure (mm Hg) Mitral regurgitation, n (%) Mitral effective regurgitant orifice area (mm2) Mitral regurgitant volume (mL) Therapy within 48 h, n (%) Loop diuretic Furosemide Dosage (mg) Nitrates ACE inhibition/ARB Aldosterone receptor antagonist Calcium channel antagonists Beta-adrenergic blockade Antibiotics Amoxicillineclavulanate potassium Ceftriaxone Levofloxacin Bronchodilators Salbutamol/ipratropium Inhaled or systemic corticosteroids
HFpEF Improved (n 5 26)
HFpEF Not Improved (n 5 11)
Non- HFpEF (n 5 26)
P Value (HFpEF vs Non-HFpEF)
P Value (HFpEF Improved vs Not Improved)
4/22 73 [69e81] 26 (100) 11 (42) 15 (58) 3 (11) 207 [151e332] 11.1 [11.1e13] 49 [43e58] 160 [154e171] 88 [76e100] 92 [82e102] 57 [55e64] 92 [75e102] 48 [40e67] 85 [75e95] 1.4 [1.1e1.8] 135 [134e175] 20 [16e23] 20 [15e23] 58 [48e73] 21 (82) 13 [5e16] 18 [7e23]
3/8 79 [74e90] 11 (100) 5 (45) 4 (36) 0 (0) 430 [320e896] 11.0 [9.7e12.0] 43 [36e59] 150 [130e164] 88 [76e100] 75 [64e85] 55 [55e60] 111 [93e129] 43 [35e90] 95 [82e110] 1.45 [1.11e1.78] 120 [80e136] 17 [14e21] 24 [22e29] 60 [55e70] 11 (100) 11 [7e15] 14 [11e24]
4/22 68 [63e75] 26 (100) 13 (50) 18 (69) 26 (100) 78 [35e145] 12.8 [11.7e13.2] 71 [57e89] 132 [118e150] 73 [64e78] 87 [75e100] 60 [55e65] 93 [82e112] 33 [30e38] 89 [80e100] 1.0 [0.8e1.2] 204 [169e245] 10 [8e13] 18 [14e20] 32 [26e39] d d d
1.0 0.02 1.0 .58 .39 !.0001 !.0001 !.0001 !.0001 !.0001 !.0001 .23 .29 .96 !.0001 .15 !.0001 !.0001 !.0001 .08 !.0001 d d d
.403 .026 1.0 1.0 .235 .540 !.0001 .285 .384 .094 .005 .004 .832 .03 .832 .150 .508 .008 .087 .014 .909 .295 .907 .785
26 (100) 80 [40e125] 14 (54) 21 (81) 11 (42) 6 (23) 9 (35) 0 (0)
11 (100) 80 [60e120] 2 (18) 5 (45) 2 (18) 3 (27) 6 (54) 0 (0)
0 (0)
!.0001
0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0)
0 (0) 26 (100) 1 (4) 18 (69) 4 (15) 20 (76) 13 (50) 7 (27) 7 (27) 19 (73) 19 (73) 19 (73)
!.0001 .002 .003 !.0001 .03 !.0001 d d d !.0001 !.0001 !.0001
1.0 .95 .33 .05 .26 1.0 .29 d d d d d d d
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; GFR, glomerular filtration rate. Unless otherwise indicated, values are presented as median [25the75th percentiles].
PH and Mitral Regurgitation in Acute HFpEF
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Fig. 1. Doppler color flow images of mitral regurgitation (MR) proximal-flow convergence zone (left) and continuous-wave Doppler signal of MR (right) in a 75-year-old hypertensive woman with decompensated heart failure with preserved ejection fraction (HFpEF).
32 of 37 HFpEF patients (Video 1; Fig. 1). None of the nonHFpEF patients had FMR. The HFpEF patients who did not improve at 48 hours were older and had higher BNP levels, lower heart rate, shorter E-wave deceleration time, higher LV mass index, and larger inferior vena cava diameters than the HFpEF patients who did improve (Table 1).
patients. Decreases in blood pressures, heart rate, E/A ratio, E/e0 ratio, E-wave deceleration time, inferior vena cava diameter, and PASP were significantly lower in HFpEF patients without improvement than in those with improvement. After 48 hours of treatment, FMR significantly decreased in HFpEF patients (Video 2; Fig. 2), with a greater decrease in patients with improvement than in patients without improvement. Ninety-two percent of HFpEF patients who improved had a PASP O35 mm Hg on presentation. FMR was present on presentation in 83% of these HFpEF patients who had elevated PASP.
Changes in Doppler Echocardiography Parameters at 48 Hours
Mean changes in hemodynamic and Doppler echocardiography parameters in improved and nonimproved HFpEF patients and in non-HFpEF patients during the first 48 hours of hospitalization are detailed in Table 2. Decreases in blood pressures, heart rate, E/A ratio, E/e’ ratio, E-wave deceleration time, and inferior vena cava diameter were significantly greater in HFpEF patients than in nonHFpEF patients. Similarly the decrease in PASP was substantially greater in HFpEF patients than in non-HFpEF
Correlates of Doppler Echocardiography Changes
The decrease in PASP in HFpEF patients correlated with that of systolic blood pressure (R 5 0.42; P 5 .009), diastolic blood pressure (R 5 0.54; P 5 .001), heart rate (R 5 0.62; P ! .0001), inferior vena cava diameter (R 5 0.51;
Table 2. Changes (Day 2 Admission) in Hemodynamic and Doppler Echocardiography Parameters After 48 Hours of Standard Therapy
HFpEF Improved Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Diuresis (L/48 h) Left ventricular ejection fraction (%) Left ventricular end diastolic volume (mL) E/A ratio E-wave deceleration time (ms) E/e0 ratio Inferior vena cava diameter (mm) Pulmonary artery systolic pressure (mm Hg) Mitral effective regurgitant orifice area (mm2) Mitral regurgitant volume (mL)
33 17 14 6.4 5 4 0.4 þ50 5.0 5 24 8 11
[42, 22] [27, 10] [20, 9] [5.6, 7.0] [3, 7] [7, 1] [0.8, 0.3] [32, 70] [7, 4.1] [8, 3] [39, 15] [13, 4] [17, 5]
HFpEF Not Improved 10 10 5 2.4 5 3 0.1 þ10 1.1 1 9 2 2
[25, 0] [12, 5] [7, 3] [1.8, 3.0] [0, 5] [5, þ5] [0.4, 0.1] [4, 30] [3.0, 0.0] [2, 0] [10, 4.5] [3, 0] [3, 1]
Unless otherwise indicated, values are presented as median [25th, 75th percentiles].
Non-HFpEF 5 0 7 2.2 0 1 0.1 þ5 1.0 2 2
[12, þ5] [5, þ7] [14, 3] [1.8, þ2.6] [0, 5] [10, 0] [0.2 , þ0.1] [1, 36] [þ0.8, 1.8] [4, 0] [6, 0] d d
P Value (HFpEF vs Non-HFpEF)
P Value (HFpEF Improved vs Not Improved
!.0001 !.0001 .003 !.0001 .38 .38 !.0001 !.0001 !.0001 !.0001 !.0001 d d
!.0001 .012 !.0001 !.0001 .612 .181 .033 .001 !.0001 !.0001 !.0001 !.0001 !.0001
750 Journal of Cardiac Failure Vol. 19 No. 11 November 2013
Fig. 2. Apical 4-chamber view with color flow mapping (A), transmitral pulsed Doppler flow pattern (B), and continuous-wave Doppler signal of tricuspid regurgitation (C) in the same 75-year-old hypertensive woman with decompensated HFpEF as in Figure 1 before (left) and after (right) standard therapy. Functional MR reduction is associated with left ventricular filling pressure and pulmonary artery systolic pressure reduction.
P 5 .01), LV end-diastolic volume (R 5 0.49; P 5 .002), E/A ratio (R 5 0.55; P 5 .001), E/e0 ratio (R 5 0.59; P ! .0001), E-wave deceleration time (R 5 0.71; P ! .0001), and mitral EROA (R 5 0.83; P ! .0001; Fig. 3). By multivariate analysis only the correlation between decreases in PASP and mitral EROA remained significant (P ! .0001; R2 5 0.81).
Discussion Several reports have previously underscored the high prevalence of PH in HFpEF patients who seek medical attention for relief of symptoms.2e5 The present report of 37 patients with high-quality 2-dimensional Doppler echocardiography examinations during an episode of
PH and Mitral Regurgitation in Acute HFpEF
Fig. 3. Relationship between changes in pulmonary artery systolic pressure (PASP) and in mitral effective regurgitant orifice area (EROA). Red circles represent HFpEF patients who did not improve at 48 hours and open circles those who did improve.
symptomatic HFpEF decompensation indicates that the return to a compensated state is associated with significant PASP decrease and FMR lessening. The dynamic nature of PH in HFpEF has been previously reported in 32 patients who had normal PASP at rest.15 Supine cycle ergometry or outstretched arm adduction lifting of 4-lb weights increased mean pulmonary artery pressure to 43 6 7 mm Hg with 88% of patients meeting criteria for exercise-induced PH.15 Data regarding the dynamic nature of FMR during exercise are scarce in HFpEF. Handgrip exercise resulted in severe MR in 2 of 6 HFpEF patients who also had a history of myocardial infarction and hypokinesis in the segment adjacent to the papillary muscle.16 Myocardial ischemia, a common cause of inducible MR in acute settings or during stress test, was carefully excluded in our patients. We have previously reported that 28% of patients with stable HFpEF develop FMR during dynamic exercise.17 The mechanisms underlying the development/exacerbation of FMR during an episode of HFpEF decompensation are incompletely understood. Increased pulmonary venous return during exercise may raise LA pressure enough to cause FMR because the tenting of mitral valves precludes leaflets’ coaptation.7,18,19 Similarly to what has been reported with exercise, increased LA pressure during an episode of decompensation fosters pulmonary venous congestion and may beget FMR in patients with HFpEF.20,21 Thus, as previously reported, in heart failure due to LV
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systolic dysfunction, severity of LV diastolic dysfunction and FMR are also the key determinants of PH in HFpEF.22 Of note, FMR was detected during the initial 2-dimensional Doppler echocardiography examination in 84% of patients with pulmonary edema studied by Ghandi et al.23 Whether an increase in LA pressure resulting in heightened pulmonary venous congestion and FMR can fully account for PH during an episode of decompensation can not be ascertained from the present data.24e26 Independently from the passive or reactive nature of PH in HFpEF, the present data highlight the dynamic nature of PH during an episode of symptomatic decompensation. Because LV filling pressure (estimated from the E/e0 ratio) and the severity of PH are not closely related in patients with HFpEF,2,7 factors other than pulmonary venous congestion, including vascular stiffness, may account for the development of PH in HFpEF, especially in older patients.6,27,28 Changes in E/e0 and E/A ratios were related to changes in PASP only by univariate analysis in our patients. They were not related by multivariate analysis. Elevation in LA pressure secondary to fluid accumulation during an episode of HFpEF decompensation directly leads to pulmonary venous hypertension and thereby to PH. Elevation of LA pressure also leads to FMR by reducing mitral closing forces and, in association with LA enlargement, increasing systolic mitral leaflet tenting.18 To what extent FMR aggravates PH and increases pulmonary vascular resistances can not be ascertained from the present data. However, as reported in patients with heart failure due to reduced EF, FMR is likely to become with time an important determinant of PH in HFpEF.7 The therapeutic implication of the present data may be the need to measure pulmonary arterial pressure in steady symptomatic state before considering specific therapy for PH in patients with HFpEF. When PH wanes after treatment of an episode of symptomatic decompensation, therapy may mainly focus on control of fluid accumulation. When PH persists after return to a compensated state, therapy that aims specifically at lowering pulmonary vascular resistance may be warranted. The limitations of the present study are readily apparent. Besides the small patient population, the data do not permit ascertaining the factors that may predict/mediate an episode of HFpEF decompensation and a rapid symptomatic improvement after an episode of decompensation and the long-term clinical correlates of a rapid decrease in PASP. Measurement of PASP solely relied on Doppler echocardiography findings in the absence of invasive hemodynamic confirmation.2,6,27e29 Finally, patients who served as control subjects had significantly lower PASP on presentation to the hospital than did HFpEF patients. In summary, as estimated by Doppler echocardiography, PASP significantly decreases when HFpEF patients return to a compensated state within 48 hours of an episode of decompensation. The decrease in PASP is associated with lessening of FMR.
752 Journal of Cardiac Failure Vol. 19 No. 11 November 2013 Disclosures None. Supplementary Data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.cardfail.2013.09.006.
References 1. 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;355:251e9. 2. Lam CS, Roger VL, Rodeheffer MM, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction. J Am Coll Cardiol 2009;53:119e26. 3. Agarwal R, Shah SJ, Foreman AJ, Glassner C, Bartolome SD, Safdar Z, et al. Risk assessment in pulmonary hypertension associated with heart failure and preserved ejection fraction. J Heart Lung Transplant 2012;31:467e77. 4. Willens HJ, Kessler KM. Severe pulmonary hypertension associated with diastolic left ventricular dysfunction. Chest 1993;103:1877e83. 5. Klapholz M, Maurer M, Lowe AM, Messineo F, Meisner JS, Mitchell J, et al. Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction. J Am Coll Cardiol 2004;43:432e8. 6. Lewis GD. The role of the pulmonary vasculature in heart failure with preserved ejection fraction. J Am Coll Cardiol 2009;53:1127e8. 7. Marechaux S, Neicu DV, Braun S, Richardson M, Delsart P, Bouabdallaoui N, et al. Functional mitral regurgitation: a link to pulmonary hypertension in heart failure with preserved ejection fraction. J Cardiac Fail 2011;17:806e12. 8. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971;285:1441e6. 9. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002;287:1531e40. 10. Colucci WS, Elkayam U, Horton DP, Abraham WT, Bourge RC, Johnson AD, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med 2000;343:246e53. 11. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS, GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256e76. 12. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D, Modification of Diet in Renal Disease Study Group. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130:461e70. 13. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009;22:107e33.
14. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685e713. 15. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010;3:588e95. 16. Penicka M, Bartunek J, Trakalova H, Hrabakova H, Maruskova M, Karasek J, et al. Heart failure with preserved ejection fraction in outpatients with unexplained dyspnea. J Am Coll Cardiol 2010;55: 1701e10. 17. Ennezat PV, Lefetz Y, Marechaux S, Six-Carpentier M, Deklunder G, Montaigne D, et al. Left ventricular abnormal response during dynamic exercise in patients with heart failure and preserved left ventricular ejection fraction at rest. J Card Fail 2008;14:475e80. 18. Marechaux S, Pinc¸on C, Poueymidanette M, Verhaeghe M, Bellouin A, Asseman P, et al. Elevated left atrial pressure estimated by Doppler echocardiography is a key determinant of mitral valve tenting in functional mitral regurgitation. Heart 2010;96:289e97. 19. Marechaux S, Terrade J, Biausque F, Lefetz Y, Deturck R, Asseman P, et al. Exercise-induced functional mitral regurgitation in heart failure and preserved ejection fraction: a new entity. Eur J Echocardiogr 2010;11:E14. 20. Thenappan T, Shah SJ, Gomberg-Maitland M, Collander B, Vallakati A, Shroff P, et al. Clinical characteristics of pulmonary hypertension in patients with heart failure and preserved ejection fraction. Circ Heart Fail 2011;4:257e65. 21. Zile MR, Admason PB, Cho Y, Bennett TD, Bourge RC, Aaron MF, et al. Hemodynamic factors associated with acute decompensated heart failure: part 1. Insights into pathophysiology. J Cardiac Fail 2011;17:282e91. 22. Enriquez Sarano M, Rossi A, Steward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. J Am Coll Cardiol 1997;29:153e9. 23. Gandhi SK, Powers JC, Nomeir AM, Fowle K, Kitzman DW, Rankin KM, et al. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344:17e22. 24. Aronson D, Eitan A, Dragu R, Burger AJ. Relationship between reactive pulmonary hypertension and mortality in patients with acutely decompensated heart failure. Circ Heart Fail 2011;4:644e50. 25. Hill NS, Preston J, Roberts K. Defining the phenotypes for pulmonary hypertension associated with diastolic heart failure. Circ Heart Fail 2011;4:238e40. 26. Borlaug BA. Discerning pulmonary venous from pulmonary arterial hypertension without the help of a catheter. Circ Heart Fail 2011;4: 235e7. 27. Lam CS, Borlaug BA, Kane GC, Enders FT, Rodeheffer RJ, Redfield MM. Age-associated increases in pulmonary artery systolic pressure in the general population. Circulation 2009;119:2663e70. 28. Gomberg-Maitland M. Something subtle about death: isolated systolic pulmonary pressure. Circulation 2009;119:2647e9. 29. Arcasoy SM, Christie JD, Ferrari VA, Sutton MS, Zisman DA, Blumenthal N, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 2003;167:735e40.
Dynamic Nature of Pulmonary Artery Systolic Pressure in Decompensated Heart Failure With Preserved Ejection Fraction: Role of Functional Mitral Regurgitation PIERRE VLADIMIR ENNEZAT, MD,1 SYLVESTRE MARECHAUX, MD,2 NADIA BOUABDALLAOUI, MD,3 AND THIERRY H. LE JEMTEL, MD4 Lille and Paris, France; and New Orleans, Louisiana
ABSTRACT Background: Pulmonary hypertension (PH) is prevalent in decompensated heart failure with preserved ejection fraction (HFpEF). We investigated the effect of a return to a compensated state on pulmonary artery systolic pressure (PASP) and functional mitral regurgitation (FMR). Methods and Results: Two-dimensional Doppler echocardiography was prospectively performed before initiation of standard therapy and 48 hours later in 37 patients hospitalized for HFpEF-related dyspnea and in 26 patients hospitalized for non-HFpEFerelated dyspnea. Left atrial volume index, and E/e0 ratio, and PASP were significantly greater and E-wave deceleration time significantly shorter in HFpEF than in nonHFpEF patients. Thirty-two of the 37 HFpEF had FMR on admission whereas none of the non-HFpEF patients had FMR. After 48 hours of therapy, the reduction in PASP was significantly greater in the 26 HFpEF patients who improved than in the 11 HFpEF patients who did not (24 vs 9 mm Hg, respectively; P ! .0001), whereas PASP remained unchanged in non-HFpEF patients. The decrease in PASP correlated in HFpEF patients with reductions in blood pressure, heart rate, left ventricular end-diastolic volume, inferior vena cava diameter, E/A ratio, E/e0 ratio, mitral effective regurgitant orifice area (EROA), and E-wave deceleration time. The correlation between PASP and mitral EROA was the only one that remained significant by multivariate analysis. Conclusions: Noninvasive monitoring of PASP and FMR during an episode of HFpEF decompensation reveals that the return to a compensated state is associated with a significant reduction in PASP and FMR. (J Cardiac Fail 2013;19:746e752) Key Words: Heart failure with preserved ejection fraction, pulmonary hypertension, mitral regurgitation.
Patients with heart failure with preserved ejection fraction (HFpEF) have as poor prognosis as those with heart failure due to reduced ejection fraction.1 The presence of
pulmonary hypertension (PH) identifies a subset of HFpEF patients with a specially poor prognosis.2,3 Pulmonary hypertension has been reported in HFpEF mostly during a hospitalization for symptomatic decompensation or in symptomatic ambulatory patients.2e5 To what extent relief of symptoms with standard HFpEF treatment affects PH has not been investigated.6 One expects intravenous loop diuretic therapy to lower PH by reducing pulmonary venous congestion. Combined diuretic and vasodilator therapy may also lower PH by decreasing the amount of functional mitral regurgitation (FMR), which has been shown to be a major determinant of PH in ambulatory HFpEF patients.7 The hypothesis behind the present study was that PH may significantly subside and FMR lessen when standard HFpEF treatment for decompensation results in a rapid return to a compensated state. Accordingly pulmonary artery systolic pressure (PASP) and FMR were prospectively evaluated
From the 1Institut Federatif de Recherche, Universite Lille Nord de France, Lille, France; 2Groupement Hospitalier de l’Institut Catholique Lillois, Universite Lille Nord de France, and Faculte Libre de Medecine, Universite Catholique de Lille, Lille, France; 3Cardiology Intensive Care Unit, H^ opital Europeen Georges Pompidou, Paris, France and 4Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana. Manuscript received January 24, 2013; revised manuscript received August 30, 2013; revised manuscript accepted September 30, 2013. Reprint requests: Pierre Vladimir Ennezat, MD, Department of Cardiology, Centre Hospitalier Universitaire de Grenoble, BP 217 - 38043 Grenoble cedex 09, France. Tel: þ33 4 76 76 84 66; Fax: þ33 4 76 76 53 68. E-mail: [email protected] See page 752 for disclosure information. 1071-9164/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2013.09.006
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PH and Mitral Regurgitation in Acute HFpEF
on presentation and 48 hours later in hospitalized patients for HFpEFe and non-HFpEFerelated shortness of breath. Methods Study Population The study population included patients who when presenting to the emergency department (ED) for severe shortness of breath at rest had windows that allowed acquisition of high quality 2dimensional Doppler echocardiography. The study population consisted of 2 cohorts. The first cohort included patients who were diagnosed as experiencing HFpEF decompensation on the basis of history of present illness, Framingham criteria for heart failure,8 and left ventricular (LV) ejection fraction (EF) O45% without wall motion abnormalities on 2-dimensional Doppler echocardiography. Patients with ventricular or supraventricular arrhythmias, bradycardia related to atrioventricular block or sinus node dysfunction, primary cardiac valvular disease, or cardiac valve replacement, acute coronary syndrome, infiltrative cardiomyopathy, and sleep disorder breathing were ineligible for the study. Similarly, initiation of therapy before 2-dimensional Doppler echocardiography examination and mechanical ventilation excluded patients from the study. Patients with a poor-quality 2-dimensional Doppler echocardiography examination also were ineligible for the study. Stress echocardiography or nuclear myocardial imaging and, when clinically indicated, coronary artery angiography were obtained to exclude ongoing myocardial ischemia. Standard therapy for HFpEF decompensation consisted of intravenous administration of loop diuretics and control of blood pressure, with angiotensin-converting enzyme inhibition (ACEI), angiotensin receptor blockade (ARB), calcium channel blockade, or nonspecific vasodilators, such as nitroglycerin. None of the patients with HFpEF-related shortness of breath received phosphodiesterase-5 inhibition. The patients were asked to evaluate changes in shortness of breath by marking on a box report form. Shortness of breath was assessed with a similar questionnaire to that used in the Nesiritide trials.9,10 The self designed questionnaire included the following questions: 1) Are you more short of breath than you are usually? 2) Are you much more short of breath than usually? 3) Has your shortness of breath completely resolved as much as you can tell? 4) Has your shortness of breath improved? 5) Are you still more short of breath than usual? 6) Are you as short of breath as you were on admission? 7) Is your shortness of breath only minimally improved? The patients with HFpEF who improved at 48 hours self-marked affirmative answers to questions 3 and 4, whereas those who did not improve at 48 hours marked 1, 2, 5, 6, or 7. The second cohort consisted of patients who were evaluated in the ED for severe shortness of breath and had no evidence for HFpEF by history, physical examination, and 2-dimensional Doppler echocardiography. These patients were diagnosed as having chronic obstructive pulmonary disease (COPD) exacerbation or pneumonia and treated accordingly with appropriate antibiotics and bronchodilators. Clinical and Laboratory Data Collection All data were prospectively collected. The first 2-dimensional Doppler echocardiography examination was performed in the ED before initiation of any therapy. The second 2-dimensional Doppler echocardiography examination was performed 48 hours later. Body mass index was calculated as weight/height2. Obesity was defined as
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a body mass index O30 kg/m2. Clinical data included age, sex, and medical history including hypertension, dyslipidemia, type II diabetes mellitus, and tobacco. Clinical history was obtained from patients, reviews of medical records, and primary care physician interviews. Diagnosis and severity of COPD was assessed according to Global Initiative for Chronic Obstructive Lung Disease guidelines.11 Laboratory data included serum creatinine, hemoglobin, and B-type natriuretic peptide (BNP) levels. Glomerular filtration rate (eGFR) was estimated by the Modification of Diet in Renal Disease equation.12 All study patients were white. Chest X-rays and electrocardiograms were obtained for all study patients on admission. Data were collected as part of their routine evaluation. An informed consent for access to protected health information was approved by our Institutional Review Board and was obtained from every patient. The registry was declared to the Commission Nationale de l’Informatique et des Libertes (CNIL). Echocardiographic Data Collection Two-dimensional Doppler echocardiography examinations were performed on admission and repeated 48 hours later with the use of a multiple-frequency 2e4-MHz transducer (IE33; Philips, Andover, Massachusetts) or a Vivid S5 ultrasound system (GE Medical Systems, Horten, Norway). Left ventricular volumes and EF were calculated with the use of the modified Simpson rule. Left atrial (LA) volume was obtained from the apical 4- and 2-chamber views with the use of the Simpson method. Pulsed-wave Doppler was performed in the apical 4-chamber view at end-expiration with a 3-mm sample volume to obtain mitral inflow velocities (E and A waves). Pulsed-wave tissue Doppler imaging was sequentially performed to acquire lateral and septal mitral annular early-diastolic velocities (e0 waves), and both velocities were averaged to calculate the E/e0 ratio (which correlates reasonably well with LV end-diastolic pressure) as previously described.13 The trans-tricuspid pressure gradient was recorded from any view with continuous-wave Doppler imaging and was used to determine PASP with the use of the modified Bernouilli equation (PASP 5 4 Vmax2 þ RAP), where Vmax is the peak tricuspid regurgitation velocity and RAP the right atrial pressure. Right atrial pressure was estimated from echocardiographic characteristics of the inferior vena cava and importance of inspiratory collapse during a brief sniff.14 Mitral regurgitant volume (RV) and effective regurgitant orifice area (EROA) were measured by the proximal flow convergence technique. Depth, size, and sector settings were optimized for optimal color Doppler resolution. The Doppler color flow zero baseline was shifted downward to obtain satisfactory hemispheric proximal isovelocity surface area. The proximal flow convergence was imaged and expanded in the apical 4-chamber view. The aliasing velocity (Vr) was carefully adjusted (20e40 cm/s). The midsystole radius of proximal flow convergence region (r) was measured from the point of aliasing to the leaflet tips. Maximum mitral regurgitant velocity and the regurgitant time-velocity integral were obtained from continuous-wave Doppler recordings. The regurgitant flow was measured as 2 p r2 Vr. The following parameters were calculated: mitral EROA 5 regurgitant flow/maximal regurgitant velocity; and RV 5 EROA regurgitant time-velocity integral. Statistical Considerations and Analysis Data are presented as median [25the75th percentiles] for continuous variables and as proportions for categoric variables. Median values of continuous variables for HFpEF patients and control
748 Journal of Cardiac Failure Vol. 19 No. 11 November 2013 subjects were compared with the use of Mann-Whitney U tests for independent samples. Categoric variables were compared with the use of the chi-square test. The relationships between changes in PASP and echocardiographic parameters changes were analyzed by Spearman correlation coefficients. To identify independent echocardiographic factors associated with changes in MR severity, all variables that correlated with a P value of !.05 in univariate analysis were submitted to a complete multiple linear regression analysis. A 2-tailed P value of !.05 was required for statistical significance. All analyses were conducted with the use of SPSS 11.0 software (Chicago, Illinois).
Results Clinical Characteristics of HFpEF and Non-HFpEF Cohorts
The HFpEF cohort of the study consisted of 37 patients. Forty-eight hours after admission, 26 patients were markedly improved and 11 were not or marginally improved.
The non-HFpEF cohort consisted of 26 patients. Nineteen of these 26 patients were hospitalized for COPD exacerbation and 7 for atypical or bacterial pneumonia. Steady mean forced expiratory volume in 1 second (FEV1) was 0.99 6 0.36 L and steady mean Tiffeneau-Pinelli index 38 6 16% in COPD patients. Patients with HFpEF decompensation were treated with loop diuretics and vasodilators and no antibiotics, whereas non-HFpEF patients received antibiotics and no loop diuretics or vasodilators (Table 1). The clinical and laboratory data of HFpEF patients (improved and not improved at 48 hours) and of nonHFpEF patients are detailed in Table 1. HFpEF patients had greater blood pressures, heart rate, and BNP levels and lower eGFR and hemoglobin concentration than nonHFpEF patients. Left atrial volume index, PASP, E/A ratio, and E/e0 ratio were significantly greater and E-wave deceleration time significantly shorter in HFpEF patients than in non-HFpEF patients. Mild to moderate FMR was noted in
Table 1. Clinical and Echocardiographic Parameters in HFpEF and Non-HFpEF Patients Before Initiation of Therapy
Sex (male/female) Age (y) Hypertension, n (%) Diabetes mellitus, n (%) Obesity, n (%) Chronic obstructive pulmonary disease, n (%) B-Type natriuretic peptide (pg/mL) Hemoglobin (g/dL) Estimated GFR (mL/min/1.73 m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Left ventricular ejection fraction (%) Left ventricular mass index (g/m2) Left atrial volume index (mL/m2) Left ventricular end-diastolic volume (mL) E/A ratio E-Wave deceleration time (ms) E/e0 ratio Inferior vena cava diameter (mm) Pulmonary artery systolic pressure (mm Hg) Mitral regurgitation, n (%) Mitral effective regurgitant orifice area (mm2) Mitral regurgitant volume (mL) Therapy within 48 h, n (%) Loop diuretic Furosemide Dosage (mg) Nitrates ACE inhibition/ARB Aldosterone receptor antagonist Calcium channel antagonists Beta-adrenergic blockade Antibiotics Amoxicillineclavulanate potassium Ceftriaxone Levofloxacin Bronchodilators Salbutamol/ipratropium Inhaled or systemic corticosteroids
HFpEF Improved (n 5 26)
HFpEF Not Improved (n 5 11)
Non- HFpEF (n 5 26)
P Value (HFpEF vs Non-HFpEF)
P Value (HFpEF Improved vs Not Improved)
4/22 73 [69e81] 26 (100) 11 (42) 15 (58) 3 (11) 207 [151e332] 11.1 [11.1e13] 49 [43e58] 160 [154e171] 88 [76e100] 92 [82e102] 57 [55e64] 92 [75e102] 48 [40e67] 85 [75e95] 1.4 [1.1e1.8] 135 [134e175] 20 [16e23] 20 [15e23] 58 [48e73] 21 (82) 13 [5e16] 18 [7e23]
3/8 79 [74e90] 11 (100) 5 (45) 4 (36) 0 (0) 430 [320e896] 11.0 [9.7e12.0] 43 [36e59] 150 [130e164] 88 [76e100] 75 [64e85] 55 [55e60] 111 [93e129] 43 [35e90] 95 [82e110] 1.45 [1.11e1.78] 120 [80e136] 17 [14e21] 24 [22e29] 60 [55e70] 11 (100) 11 [7e15] 14 [11e24]
4/22 68 [63e75] 26 (100) 13 (50) 18 (69) 26 (100) 78 [35e145] 12.8 [11.7e13.2] 71 [57e89] 132 [118e150] 73 [64e78] 87 [75e100] 60 [55e65] 93 [82e112] 33 [30e38] 89 [80e100] 1.0 [0.8e1.2] 204 [169e245] 10 [8e13] 18 [14e20] 32 [26e39] d d d
1.0 0.02 1.0 .58 .39 !.0001 !.0001 !.0001 !.0001 !.0001 !.0001 .23 .29 .96 !.0001 .15 !.0001 !.0001 !.0001 .08 !.0001 d d d
.403 .026 1.0 1.0 .235 .540 !.0001 .285 .384 .094 .005 .004 .832 .03 .832 .150 .508 .008 .087 .014 .909 .295 .907 .785
26 (100) 80 [40e125] 14 (54) 21 (81) 11 (42) 6 (23) 9 (35) 0 (0)
11 (100) 80 [60e120] 2 (18) 5 (45) 2 (18) 3 (27) 6 (54) 0 (0)
0 (0)
!.0001
0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0)
0 (0) 26 (100) 1 (4) 18 (69) 4 (15) 20 (76) 13 (50) 7 (27) 7 (27) 19 (73) 19 (73) 19 (73)
!.0001 .002 .003 !.0001 .03 !.0001 d d d !.0001 !.0001 !.0001
1.0 .95 .33 .05 .26 1.0 .29 d d d d d d d
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; GFR, glomerular filtration rate. Unless otherwise indicated, values are presented as median [25the75th percentiles].
PH and Mitral Regurgitation in Acute HFpEF
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Fig. 1. Doppler color flow images of mitral regurgitation (MR) proximal-flow convergence zone (left) and continuous-wave Doppler signal of MR (right) in a 75-year-old hypertensive woman with decompensated heart failure with preserved ejection fraction (HFpEF).
32 of 37 HFpEF patients (Video 1; Fig. 1). None of the nonHFpEF patients had FMR. The HFpEF patients who did not improve at 48 hours were older and had higher BNP levels, lower heart rate, shorter E-wave deceleration time, higher LV mass index, and larger inferior vena cava diameters than the HFpEF patients who did improve (Table 1).
patients. Decreases in blood pressures, heart rate, E/A ratio, E/e0 ratio, E-wave deceleration time, inferior vena cava diameter, and PASP were significantly lower in HFpEF patients without improvement than in those with improvement. After 48 hours of treatment, FMR significantly decreased in HFpEF patients (Video 2; Fig. 2), with a greater decrease in patients with improvement than in patients without improvement. Ninety-two percent of HFpEF patients who improved had a PASP O35 mm Hg on presentation. FMR was present on presentation in 83% of these HFpEF patients who had elevated PASP.
Changes in Doppler Echocardiography Parameters at 48 Hours
Mean changes in hemodynamic and Doppler echocardiography parameters in improved and nonimproved HFpEF patients and in non-HFpEF patients during the first 48 hours of hospitalization are detailed in Table 2. Decreases in blood pressures, heart rate, E/A ratio, E/e’ ratio, E-wave deceleration time, and inferior vena cava diameter were significantly greater in HFpEF patients than in nonHFpEF patients. Similarly the decrease in PASP was substantially greater in HFpEF patients than in non-HFpEF
Correlates of Doppler Echocardiography Changes
The decrease in PASP in HFpEF patients correlated with that of systolic blood pressure (R 5 0.42; P 5 .009), diastolic blood pressure (R 5 0.54; P 5 .001), heart rate (R 5 0.62; P ! .0001), inferior vena cava diameter (R 5 0.51;
Table 2. Changes (Day 2 Admission) in Hemodynamic and Doppler Echocardiography Parameters After 48 Hours of Standard Therapy
HFpEF Improved Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Diuresis (L/48 h) Left ventricular ejection fraction (%) Left ventricular end diastolic volume (mL) E/A ratio E-wave deceleration time (ms) E/e0 ratio Inferior vena cava diameter (mm) Pulmonary artery systolic pressure (mm Hg) Mitral effective regurgitant orifice area (mm2) Mitral regurgitant volume (mL)
33 17 14 6.4 5 4 0.4 þ50 5.0 5 24 8 11
[42, 22] [27, 10] [20, 9] [5.6, 7.0] [3, 7] [7, 1] [0.8, 0.3] [32, 70] [7, 4.1] [8, 3] [39, 15] [13, 4] [17, 5]
HFpEF Not Improved 10 10 5 2.4 5 3 0.1 þ10 1.1 1 9 2 2
[25, 0] [12, 5] [7, 3] [1.8, 3.0] [0, 5] [5, þ5] [0.4, 0.1] [4, 30] [3.0, 0.0] [2, 0] [10, 4.5] [3, 0] [3, 1]
Unless otherwise indicated, values are presented as median [25th, 75th percentiles].
Non-HFpEF 5 0 7 2.2 0 1 0.1 þ5 1.0 2 2
[12, þ5] [5, þ7] [14, 3] [1.8, þ2.6] [0, 5] [10, 0] [0.2 , þ0.1] [1, 36] [þ0.8, 1.8] [4, 0] [6, 0] d d
P Value (HFpEF vs Non-HFpEF)
P Value (HFpEF Improved vs Not Improved
!.0001 !.0001 .003 !.0001 .38 .38 !.0001 !.0001 !.0001 !.0001 !.0001 d d
!.0001 .012 !.0001 !.0001 .612 .181 .033 .001 !.0001 !.0001 !.0001 !.0001 !.0001
750 Journal of Cardiac Failure Vol. 19 No. 11 November 2013
Fig. 2. Apical 4-chamber view with color flow mapping (A), transmitral pulsed Doppler flow pattern (B), and continuous-wave Doppler signal of tricuspid regurgitation (C) in the same 75-year-old hypertensive woman with decompensated HFpEF as in Figure 1 before (left) and after (right) standard therapy. Functional MR reduction is associated with left ventricular filling pressure and pulmonary artery systolic pressure reduction.
P 5 .01), LV end-diastolic volume (R 5 0.49; P 5 .002), E/A ratio (R 5 0.55; P 5 .001), E/e0 ratio (R 5 0.59; P ! .0001), E-wave deceleration time (R 5 0.71; P ! .0001), and mitral EROA (R 5 0.83; P ! .0001; Fig. 3). By multivariate analysis only the correlation between decreases in PASP and mitral EROA remained significant (P ! .0001; R2 5 0.81).
Discussion Several reports have previously underscored the high prevalence of PH in HFpEF patients who seek medical attention for relief of symptoms.2e5 The present report of 37 patients with high-quality 2-dimensional Doppler echocardiography examinations during an episode of
PH and Mitral Regurgitation in Acute HFpEF
Fig. 3. Relationship between changes in pulmonary artery systolic pressure (PASP) and in mitral effective regurgitant orifice area (EROA). Red circles represent HFpEF patients who did not improve at 48 hours and open circles those who did improve.
symptomatic HFpEF decompensation indicates that the return to a compensated state is associated with significant PASP decrease and FMR lessening. The dynamic nature of PH in HFpEF has been previously reported in 32 patients who had normal PASP at rest.15 Supine cycle ergometry or outstretched arm adduction lifting of 4-lb weights increased mean pulmonary artery pressure to 43 6 7 mm Hg with 88% of patients meeting criteria for exercise-induced PH.15 Data regarding the dynamic nature of FMR during exercise are scarce in HFpEF. Handgrip exercise resulted in severe MR in 2 of 6 HFpEF patients who also had a history of myocardial infarction and hypokinesis in the segment adjacent to the papillary muscle.16 Myocardial ischemia, a common cause of inducible MR in acute settings or during stress test, was carefully excluded in our patients. We have previously reported that 28% of patients with stable HFpEF develop FMR during dynamic exercise.17 The mechanisms underlying the development/exacerbation of FMR during an episode of HFpEF decompensation are incompletely understood. Increased pulmonary venous return during exercise may raise LA pressure enough to cause FMR because the tenting of mitral valves precludes leaflets’ coaptation.7,18,19 Similarly to what has been reported with exercise, increased LA pressure during an episode of decompensation fosters pulmonary venous congestion and may beget FMR in patients with HFpEF.20,21 Thus, as previously reported, in heart failure due to LV
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systolic dysfunction, severity of LV diastolic dysfunction and FMR are also the key determinants of PH in HFpEF.22 Of note, FMR was detected during the initial 2-dimensional Doppler echocardiography examination in 84% of patients with pulmonary edema studied by Ghandi et al.23 Whether an increase in LA pressure resulting in heightened pulmonary venous congestion and FMR can fully account for PH during an episode of decompensation can not be ascertained from the present data.24e26 Independently from the passive or reactive nature of PH in HFpEF, the present data highlight the dynamic nature of PH during an episode of symptomatic decompensation. Because LV filling pressure (estimated from the E/e0 ratio) and the severity of PH are not closely related in patients with HFpEF,2,7 factors other than pulmonary venous congestion, including vascular stiffness, may account for the development of PH in HFpEF, especially in older patients.6,27,28 Changes in E/e0 and E/A ratios were related to changes in PASP only by univariate analysis in our patients. They were not related by multivariate analysis. Elevation in LA pressure secondary to fluid accumulation during an episode of HFpEF decompensation directly leads to pulmonary venous hypertension and thereby to PH. Elevation of LA pressure also leads to FMR by reducing mitral closing forces and, in association with LA enlargement, increasing systolic mitral leaflet tenting.18 To what extent FMR aggravates PH and increases pulmonary vascular resistances can not be ascertained from the present data. However, as reported in patients with heart failure due to reduced EF, FMR is likely to become with time an important determinant of PH in HFpEF.7 The therapeutic implication of the present data may be the need to measure pulmonary arterial pressure in steady symptomatic state before considering specific therapy for PH in patients with HFpEF. When PH wanes after treatment of an episode of symptomatic decompensation, therapy may mainly focus on control of fluid accumulation. When PH persists after return to a compensated state, therapy that aims specifically at lowering pulmonary vascular resistance may be warranted. The limitations of the present study are readily apparent. Besides the small patient population, the data do not permit ascertaining the factors that may predict/mediate an episode of HFpEF decompensation and a rapid symptomatic improvement after an episode of decompensation and the long-term clinical correlates of a rapid decrease in PASP. Measurement of PASP solely relied on Doppler echocardiography findings in the absence of invasive hemodynamic confirmation.2,6,27e29 Finally, patients who served as control subjects had significantly lower PASP on presentation to the hospital than did HFpEF patients. In summary, as estimated by Doppler echocardiography, PASP significantly decreases when HFpEF patients return to a compensated state within 48 hours of an episode of decompensation. The decrease in PASP is associated with lessening of FMR.
752 Journal of Cardiac Failure Vol. 19 No. 11 November 2013 Disclosures None. Supplementary Data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.cardfail.2013.09.006.
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