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ORIGINAL ARTICLE
Pulmonary Hypertension in Heart Failure Epidemiology, Right Ventricular Function, and Survival Mario Gerges1, Christian Gerges1, Anna-Maria Pistritto2, Marie B. Lang1, Pia Trip3, Johannes Jakowitsch1, Thomas Binder1, and Irene M. Lang1 1 Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Vienna, Austria; 2Division of Cardiology, Department of Internal Medicine, Ferrarotto Hospital, University of Catania, Catania, Italy; and 3Department of Pulmonary Medicine, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands
ORCID ID: 0000-0003-3295-4565 (M.G.).
Abstract Rationale: Patients with pulmonary hypertension due to left heart
disease (PH-LHD) and a diastolic pulmonary vascular pressure gradient >7 mm Hg, representing PH out of proportion to pulmonary arterial wedge pressure, have pulmonary vascular disease and increased mortality. Little information exists on this condition, recently labeled as “combined pre- and post-capillary PH” (Cpc-PH). Objectives: To investigate epidemiology, risk factors, right ventricular function, and outcomes in patients with chronic heart failure and Cpc-PH. Methods: The study population was identified from a retrospective
chart review of a clinical database of 3,107 stable patients who underwent first diagnostic right heart catheterization and from a prospective cohort of 800 consecutive patients at a national university-affiliated tertiary center. Measurements and Main Results: The retrospective cohort had 664 patients with systolic heart failure (SHF) and 399 patients with diastolic heart failure (DHF), 12% of whom were classified as
Cpc-PH. The prospective cohort had 172 patients with SHF (14% Cpc-PH) and 219 patients with DHF (12% Cpc-PH). Chronic obstructive pulmonary disease (P = 0.034) and the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio (P = 0.015) predicted Cpc-PH in SHF. Younger age (P = 0.004), valvular heart disease (P = 0.046), and the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio predicted Cpc-PH in DHF (P = 0.016). Right ventricular–pulmonary vascular coupling was worse in Cpc-PH patients (end-systolic elastance to effective arterial elastance [Ees/Ea]: SHF: 1.05 6 0.25; P = 0.002; DHF: 1.17 6 0.27; P = 0.027) than in those with isolated post-capillary PH (Ees/Ea: SHF: 1.52 6 0.51; DHF: 1.45 6 0.29). Conclusions: Cpc-PH is rare in chronic heart failure. Right
ventricular–pulmonary vascular coupling is poor in Cpc-PH and could be one explanation for dismal outcomes. Keywords: heart failure; hemodynamics; pulmonary heart disease; pulmonary hypertension
( Received in original form March 16, 2015; accepted in final form July 15, 2015 ) Supported by educational grants from Actelion Pharmaceuticals Ltd., Bayer (grant no. 15662), and United Therapeutics Corporation (grant no. REG-NC-002). M.G. holds an educational grant from United Therapeutics Corporation (grant no. REG-NC-002), and C.G. holds an educational grant from Bayer (grant no. 15662). Author Contributions: Study concept and design: M.G., C.G., and I.M.L. Acquisition of data, analysis and interpretation of data, and statistical analysis: M.G., C.G., A.-M.P., M.B.L., P.T., J.J., T.B., and I.M.L. Drafting of the manuscript: M.G., C.G., and I.M.L. Critical revision of the manuscript and final approval of the version to be published: M.G., C.G., A.-M.P., M.B.L., P.T., J.J., T.B., and I.M.L. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The corresponding author, I.M.L., had full access to all the data in the study and had final responsibility for the decision to submit for publication. Correspondence and requests for reprints should be addressed to Irene M. Lang, M.D., Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Wahringer ¨ Gurtel ¨ 18-20, 1090 Vienna, Austria. E-mail:
[email protected] This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 192, Iss 10, pp 1234–1246, Nov 15, 2015 Copyright © 2015 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201503-0529OC on July 16, 2015 Internet address: www.atsjournals.org
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American Journal of Respiratory and Critical Care Medicine Volume 192 Number 10 | November 15 2015
ORIGINAL ARTICLE
At a Glance Commentary Scientific Knowledge on the Subject: Patients with pulmonary
hypertension due to left heart disease (PH-LHD) and a diastolic pulmonary vascular pressure gradient (DPG) > 7 mm Hg have a poor survival rate. However, little information exists on this condition, recently labeled as “combined pre- and post-capillary PH” (Cpc-PH). What This Study Adds to the Field: Cpc-PH in chronic left heart
failure is present in 12% of patients with chronic left heart failure. Right ventricular to pulmonary vascular coupling is poor in Cpc-PH and might serve as one explanation for the poor survival in this subset. Pulmonary hypertension (PH) due to left heart disease (PH-LHD) is a growing health problem with high morbidity and mortality (1). PH-LHD is the most frequent subset of PH, resulting from left ventricular (LV) dysfunction (systolic and/or diastolic) and/or valvular heart disease (VHD) (1). PH-LHD has a significant negative impact on prognosis (2–4), but its prevalence is poorly defined. Right ventricular (RV) function plays a key role in patients with systolic heart failure (SHF) (4, 5) and
diastolic heart failure (DHF) (6). Individual risk assessment in patients with heart failure (HF) has to integrate hemodynamics and RV function (4, 7). Pulmonary arterial compliance (CPA) is a predictor of prognosis in patients with SHF, irrespective of pulmonary vascular resistance (PVR) (8). Although previous research has demonstrated the prognostic value of a variety of clinical characteristics and parameters in patients with HF, the RV in PH-LHD has not been sufficiently explored. Recently, at the fifth World Symposium on Pulmonary Hypertension in Nice, France, in 2013, two subsets of PH-LHD (post-capillary PH) were defined as isolated post-capillary PH (Ipc-PH; diastolic pulmonary vascular pressure gradient [DPG] , 7 mm Hg, previously labeled as “passive” PH-LHD) and combined pre- and post-capillary PH (Cpc-PH; DPG > 7 mm Hg, previously labeled as “out-ofproportion” or “reactive” PH-LHD [1]) because of pulmonary pressures higher than expected from increased pulmonary artery wedge pressure (PAWP). HF therapies such as b-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and spironolactone improve LV function and reduce LV filling pressures, but have not been convincingly shown to improve RV function in humans (9). In contrast, pulmonary vasodilators that have been approved for the treatment of pulmonary arterial hypertension (PAH) have never demonstrated a benefit in HF
populations, including recent randomized trials (10–12). As a first step in the direction of resolving an unmet need of targeted treatments of PH-LHD, a better understanding of this condition is needed. Therefore, the goal of this study was to define the prevalence of Cpc-PH using a DGP > 7 mm Hg (1, 13), and to characterize steady and pulsatile RV afterload and estimates of RV contractility by right heart catheterization and echocardiography in a well-defined study population with stable chronic HF. Some of the results of this study have been previously reported in the form of abstracts (14–17).
Methods Study Population
Our study population consisted of patients with HF and PH who underwent first diagnostic right heart catheterization at the Medical University of Vienna (Vienna, Austria), a tertiary care center. A retrospective cohort was included between May 1996 and March 2003 (n = 3,107), and a prospective cohort was included between January 2012 and September 2013 (n = 800). In 2,524 (81.2%) of 3,107 retrospective patients and in 742 (92.8%) of 800 prospective patients, the procedure was combined with a left heart catheterization for coronary angiography. Catheterizations were performed for various indications, mostly for the diagnosis
Table 1. Clinical Characteristics of Patients with Heart Failure Retrospective HF Cohort (n = 1,063) SHF (n = 664) DHF (n = 399) Age, yr Sex, no. (%) Male Female Body mass index, kg/m2 NYHA functional class, no. (%) I II III IV Arterial hypertension, no. (%) Stable ischemic heart disease, no. (%) Atrial fibrillation, no. (%) Valvular heart disease, no. (%) Creatinine clearance ,60 ml/min, no. (%)
Prospective HF Cohort (n = 391) SHF (n = 172) DHF (n = 219)
60.9 6 11.9
66.5 6 11.3
66.1 6 15.1
72.2 6 12.4
511 (77.0) 153 (23.0) 26.4 6 4.3
199 (49.9) 200 (50.1) 26.9 6 4.7
128 (74.4) 44 (25.6) 27.2 6 4.8
105 (61.0) 114 (52.1) 28.2 6 5.8
32 284 213 135 246 337 205 313 249
(4.8) (42.8) (32.1) (20.3) (37.0) (50.8) (30.9) (47.1) (37.5)
12 225 130 32 204 168 133 209 202
(3.0) (56.4) (32.6) (8.0) (51.1) (42.1) (33.3) (52.4) (50.6)
2 8 85 77 122 85 67 108 74
(1.2) (4.7) (49.4) (44.8) (70.9) (49.4) (39.0) (62.8) (43.0)
14 44 115 46 171 76 90 116 119
(6.4) (20.1) (52.5) (21.0) (78.1) (34.7) (41.1) (53.0) (54.3)
Definition of abbreviations: DHF = diastolic heart failure; HF = heart failure; NYHA = New York Heart Association; SHF = systolic heart failure.
Gerges, Gerges, Pistritto, et al.: Pulmonary Hypertension in Heart Failure
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ORIGINAL ARTICLE of elevated systolic pulmonary arterial pressure (sPAP) on echocardiography in patients with chronic HF and in patients with suspected PH, but also before valve replacements, percutaneous interventions, and surgical procedures. Diagnoses were validated on the grounds of patient histories, comorbidities, imaging, clinical data, and pathoanatomical evidence. Patients were on various specific and optimized HF treatments, but not on PAH-specific treatments at the time of hemodynamic measurements. A total of 756 (24.3%) incomplete data sets were excluded from statistical analyses in the retrospective cohort. Incomplete data were from patients with atrial septal defects or persistent foramen ovale without PH who underwent interventional catheter-guided closure.
A
Hemodynamic Assessment
For hemodynamic assessment, a 7F SwanGanz catheter (Baxter, Irvine, CA) was inserted from a femoral or jugular approach. Mean pulmonary arterial pressure (mPAP), mean right atrial pressure (mRAP), mean pulmonary arterial wedge pressure (mPAWP), and respective oxygen saturations, including the inferior and superior vena cava, were measured. All pressures were recorded as averages of eight time–pressure integral derivations during several respiratory cycles (18, 19) using CathCorLX (Siemens AG, Berlin and Munich, Germany). A zero reference level was obtained at the midthoracic level (19, 20). Cardiac output (CO) was assessed by thermodilution. The Fick method was applied in the presence of systemic-topulmonary shunts. The transpulmonary
B
3107 patients (05/1996–03/2003)
pressure gradient (TPG) was calculated by subtracting mPAWP from mPAP; PVR was calculated by dividing TPG by CO and expressed in Wood units. CPA was computed as the ratio of stroke volume (SV) to pulmonary pulse pressure (the difference between sPAP and diastolic pulmonary artery pressure [dPAP]). DPG was calculated as the difference between dPAP and mPAWP (13, 21, 22). The PVR–compliance time (RC-time; product of resistance [PVR] and compliance [CPA]) was calculated as previously described (23) and expressed in seconds. Diagnosis of Heart Failure
A diagnosis of HF was independently adjudicated by cardiologists at the outpatient clinical department of cardiology according to current HF guidelines of the
800 patients (01/2012–09/2013)
756 incomplete data sets 409 cases without HF 1288 cases without HF
391 cases with HF
1063 cases with HF
664 cases with SHF
207 cases without PH “Non-PH”
399 cases with DHF
162 cases without PH “Non-PH”
457 cases with SHF and PH “Multiple PH” -SHF n=6
237 cases with DHF and PH “Multiple PH” -DHF n=20
PH-LHD with SHF n=451
PH-LHD with DHF n=217
Ipc-PH-SHF Ipc-PH-DHF Cpc-PH-SHF Cpc-PH-DHF (DPG 25 mm Hg, mPAWP . 15 mm Hg, and DPG , 7 mm Hg (Ipc-PH); and (2) mPAP > 25 mm Hg, mPAWP . 15 mm Hg, and DPG > 7 mm Hg (Cpc-PH) (1, 13). Moderate and highgrade left-sided echocardiographic ventricular heart disease and VHD were rated as probable causes of PH. Ventilation-perfusion lung scintigraphies, multidetector computed tomographies, lung function tests (including spirometry and diffusion capacity measurement), and pulmonary angiographies were performed to differentiate chronic thromboembolic PH (CTEPH), chronic obstructive pulmonary disease (COPD), and interstitial lung disease. Creatinine clearance was calculated according to the method by Cockcroft and Gault (27). PAH associated with congenital heart disease, connective tissue disease, or portal hypertension as well as CTEPH or PH due to interstitial lung disease (moderate to severe) and/or COPD (Global Initiative of Obstructive Lung Disease [GOLD] score 3 or 4), and/or obstructive sleep apnea syndrome and simultaneous left heart disease were classified as “combinations of diagnoses” or
“multiple PH.” Patients with “multiple PH” were excluded from the analyses. Assessment of Right Ventricular to Pulmonary Vascular Coupling
The simplified single-beat approach, which does not require pressure–volume loops and vena cava occlusion, was used to assess endsystolic elastance (Ees) as previously demonstrated for the LV (28, 29) and the RV (30, 31). To assess RV isovolumetric pressure (Piso), an inverted cosine wave was laid over the RV pressure curve using the isovolumetric contraction period (from end-diastole to the point of maximal rate of pressure rise [dP/dtmax]) and the isovolumetric relaxation period (from minimal dP/dt to the beginning of diastole) by a semi-automatic toolbox (Hemolab Cardiovascular Engineering, Lifetec Group, Eindhoven, the Netherlands) for MATLAB R2008a (The MathWorks, Natick, MA) (31). The point of end-diastole was identified using the R-wave of the ECG, and when needed, was shifted manually to the point before the upslope of the ascending limb (32). Calculated Piso was averaged over at least 5 beats. Beats with significant catheter artifacts were excluded. Ees was assessed as (Piso 2 mPAP)/SV (31). Effective arterial elastance (Ea) was estimated as mPAP/SV (31). In addition to right ventricular to pulmonary vascular (RV–PV) coupling, the ratio of echo-derived
Table 2. Hemodynamic Characteristics of the Retrospective Cohort PH in SHF (n = 451) PH in DHF (n = 217) Ipc-PH in SHF Cpc-PH in SHF Ipc-PH in DHF Cpc-PH in DHF (n = 371) (n = 80) (n = 168) (n = 49) Heart rate, beats/min Cardiac output, L/min Cardiac index, L/min/m2 Mixed venous oxygen saturation, % Systemic vascular resistance, Wood units Pulmonary vascular resistance, Wood units Pulmonary arterial compliance, ml/mm Hg Systemic vascular resistance–compliance time, s Pulmonary vascular resistance–compliance time, s Mean right atrial pressure, mm Hg Mean pulmonary arterial pressure, mm Hg Mean pulmonary arterial wedge pressure, mm Hg Transpulmonary gradient, mm Hg Diastolic pulmonary vascular pressure gradient, mm Hg
77.9 6 16.0 4.6 6 1.2 2.4 6 0.6 60.6 6 10.1 19.0 6 5.6 2.5 6 1.3 2.2 6 1.0 1.28 6 0.39 0.31 6 0.15 10.1 6 4.7 36.7 6 7.8 25.7 6 7.4 11.2 6 4.8 20.7 6 4.8
83.5 6 15.8* 4.5 6 1.2 2.4 6 0.5 58.5 6 9.7 20.5 6 6.6 5.1 6 2.2* 2.2 6 1.6 1.32 6 0.41 0.55 6 0.22* 11.6 6 6.4* 43.2 6 11.9* 22.6 6 6.7 21.6 6 7.5* 11.3 6 5.2*
75.6 6 15.0 5.2 6 1.7 2.8 6 0.8 65.6 6 10.1 20.7 6 6.4 2.8 6 1.4 2.6 6 1.3 1.03 6 0.27 0.36 6 0.15 10.3 6 5.1 36.4 6 8.1 23.4 6 7.9 13.2 6 5.1 20.2 6 4.9
77.8 6 16.5 5.1 6 1.7 2.8 6 0.9 63.8 6 10.2 18.4 6 7.2 6.3 6 3.6† 2.0 6 1.2† 1.03 6 0.28 0.58 6 0.16† 11.0 6 4.9 45.6 6 12.8† 21.8 6 5.9 27.8 6 9.9† 12.7 6 5.6†
iPAH (n = 23) 78.1 6 15.3 3.8 6 1.0 2.2 6 0.5 58.0 6 11.0 23.2 6 5.1 12.5 6 5.7 1.1 6 0.6 1.45 6 0.36 0.76 6 0.26 7.8 6 5.9 55.9 6 14.4 6.1 6 2.5 46.0 6 15.7 25.8 6 14.1
Definition of abbreviations: Cpc-PH = combined pre- and post-capillary pulmonary hypertension; DHF = diastolic heart failure; iPAH = idiopathic pulmonary arterial hypertension; Ipc-PH = isolated post-capillary pulmonary hypertension; PH = pulmonary hypertension; SHF = systolic heart failure. *P , 0.05, Cpc-PH versus Ipc-PH in SHF. † P , 0.05, Cpc-PH versus Ipc-PH in DHF.
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ORIGINAL ARTICLE Multivariate analysis
Univariate analysis
A
OR
p-value
Age
0.992
0.592
Female sex
1.528
0.371
Arterial hypertension
2.870
0.102
Stable ischemic heart disease
1.420
0.433
Atrial fibrillation
0.884
0.787
Valvular heart disease
1.008
0.986
COPD GOLD score 1 – 2
3.579
0.034
Creatinine clearance
0.998
0.833
NT-proBNP
1.000
0.764
RV/LV-ratio
0.521
0.656
Tricuspid regurgitation velocity
1.708
0.197
0.001
0.017
OR
p-value
2.107
0.343
3.598
0.202
0.001
0.015
Baseline characteristics:
Echocardiographic parameters:
TAPSE/sPAP 0.001 0.01 0.1
1
(Favors “Non-PH”/ Ipc-PH)
10 100 1000
0.001 0.01 0.1
(Favors Cpc-PH)
(Favors “Non-PH”/ Ipc-PH)
10 100 1000 (Favors Cpc-PH)
Multivariate analysis
Univariate analysis
B
1
OR
p-value
OR
p-value
Age
0.966
0.035
0.894
0.004
Female sex
1.691
0.234
Arterial hypertension
0.712
0.506
Stable ischemic heart disease
0.567
0.242
Atrial fibrillation
1.134
0.767
Valvular heart disease
2.118
0.110
5.797
0.046
COPD GOLD score 1 – 2
1.446
0.469
Creatinine clearance
1.004
0.421
NT-proBNP
1.000
0.504
RV/LV-ratio
65.655
