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Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias
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JJCC-1916; No. of Pages 8 Journal of Cardiology xxx (2019) xxx–xxx
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Original article
Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias Masashi Amano (MD)a,b,*, Chisato Izumi (MD PhD FJCC)a,b, Megumi Baba (MS)c, Rie Abe (MS)c, Hayato Matsutani (MS)c, Takashi Inao (MD)d, Makoto Miyake (MD)b, Yuko Nishimoto (MD)e, Toshihiro Tamura (MD PhD)b, Satoshi Noma (MD PhD)e, Yoshio Taguchi (MD)d, Yoshihisa Nakagawa (MD PhD)b a
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan Department of Cardiology, Tenri Hospital, Tenri, Japan c Department of Clinical Laboratory, Tenri Hospital, Tenri, Japan d Department of Respiratory Medicine, Tenri Hospital, Tenri, Japan e Department of Radiology, Tenri Hospital, Tenri, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 29 April 2019 Received in revised form 24 July 2019 Accepted 15 August 2019 Available online xxx
Background: Few studies have examined the relationship between echocardiographic indices of right ventricular (RV) function and the severity of pulmonary disease, or their prognostic impact. We evaluated the RV function in patients with interstitial pneumonia and its prognostic impact at each stage of disease severity. Method: A total of 176 patients with idiopathic interstitial pneumonias (IIPs) were retrospectively enrolled and we evaluated RV function by transthoracic echocardiography. The severity of IIPs was graded according to the Goh score. The primary outcome was all-cause death. Results: There were 55 patients in mild group (31%), 66 in moderate group (38%), and 55 in severe group (31%). Regarding RV function, RV free wall longitudinal strain and tricuspid annular plane systolic excursion (TAPSE) deteriorated with increasing severity of IIPs, but fractional area change (FAC) decreased significantly only in severe group. There were 64 all-cause deaths during the follow-up period (median 908 days). In moderate group, TAPSE [hazard ratio (HR): 0.85, 95% confidence interval (CI): 0.74– 0.97, p = 0.017], FAC (HR: 0.89, 95% CI: 0.83–0.96, p = 0.001), and mean pulmonary artery pressure (PAP)/ cardiac output (HR: 1.50, 95% CI: 1.08–2.09, p = 0.015) were independent predictors of all-cause death, even after adjusting for age and log brain natriuretic peptide (BNP). On the other hand, not RV function or PAP but male sex and BNP level were associated with mortality in severe group. Conclusions: Among patients with IIPs, RV longitudinal function deteriorated with increasing severity of IIPs. Echocardiographic indices of RV function were independently associated with mortality in moderate-stage IIPs. © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Interstitial pneumonia Right ventricular dysfunction Echocardiography Mortality Brain natriuretic peptide
Introduction Tricuspid annular plane systolic excursion (TAPSE), tricuspid lateral annular systolic velocity, fractional area change (FAC), and right ventricular (RV) free wall longitudinal strain are indices of RV function measured by transthoracic echocardiography [1]. The current guideline of the American Heart Association and American
* Corresponding author at: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail address: [email protected] (M. Amano).
Thoracic Society recommend these echocardiographic indices as important follow-up tools for assessing RV function in patients with pulmonary hypertension [2]. However, this guideline is mainly based on data from patients with pulmonary arterial hypertension [2,3]. A few previous reports have shown that mean pulmonary artery pressure (PAP) plays an important role in evaluating the severity and prognosis of pulmonary diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and sarcoidosis [4,5]. Although right heart failure is known to be progressive in patients with pulmonary diseases, few studies have examined the relationship between echocardiographic indices of RV function and the severity or patient prognosis of pulmonary diseases.
https://doi.org/10.1016/j.jjcc.2019.08.010 0914-5087/© 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010
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The prevalence of pulmonary hypertension (PH) in patients with interstitial pneumonia (IP) is 14% at the initial evaluation [6] and only 60% even in end-stage patients [5], and the mean PAP rarely exceeds 40 mmHg in patients with IP [7]. It is therefore difficult to evaluate the progression of IP severity based on PAP alone. Echocardiographic indices of RV function may thus help to evaluate disease severity and/or prognostic impact in patients with IP. The present study aimed to evaluate the relationship between RV function and severity of pulmonary disease, and the prognostic impact of RV function in patients with IP. Methods Study population A total of 222 consecutive patients diagnosed with IP who underwent transthoracic echocardiography to investigate RV function between November 2013 and October 2015 were retrospectively enrolled. Patients with an underlying IP etiology of connective tissue disease (N = 27) or chronic hypersensitivity pneumonitis (N = 3) were excluded. Patients with combined pulmonary fibrosis and emphysema (N = 11), or left ventricular (LV) systolic dysfunction (ejection fraction <50%) or heart failure with preserved ejection fraction [ejection fraction 50% and early diastolic mitral inflow velocity (E)/early diastolic mitral annular tissue velocity (e’) > 15 (N = 5)] were also excluded. Finally, 176 patients with idiopathic interstitial pneumonias (IIPs) were included in the final analysis. The primary outcome was all-cause death. Follow-up data were mainly collected through review of hospital charts or corrected through contact with patients, relatives, and/or referring physicians using telephone with questions regarding survival. The study protocol was approved by the institutional ethics committee at Tenri Hospital. The written informed consent to participate in this study was obtained from all patients.
Table 1 Baseline characteristics. N = 176 Clinical variable Age (years) Sex (male) Body surface area (m2) Hypertension Diabetes Smoking habit Current smoker Atrial fibrillation Hemodynamics and respiratory function Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) FVC% predicted (%) %FEV1 predicted (%) FEV1/FVC%, (%) DLCO/VA% predicted (%)
71.4 8.2 113 (64.2) 1.62 0.27 51 (28.9) 30 (17.0) 95 (54.0) 30 (17.0) 5 (2.8) 130.6 20.0 73.9 12.4 71.3 15.2 79.3 22.8 82.5 21.6 81.5 9.4 82.5 23.8
Values are mean SD or N (%). FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; DLCO/VA, diffusing capacity for carbon monoxide/alveolar ventilation.
outflow tract and the time–velocity integral in the LV outflow tract. E and peak atrial filling velocity (A) were acquired in the apical four-chamber view, and e’ was measured in the apical fourchamber view with the sample volume positioned at the lateral mitral annulus. Longitudinal strain was measured from grey-scale images recorded in apical four-chamber, two-chamber, and longaxis views. Global longitudinal strain was calculated by averaging all segmental strain values from the apical four-chamber, twochamber, and long-axis views. To confirm the accuracy of the echocardiographic parameters, the measurements were repeated by two experienced sonographers at our institution being blinded to the clinical outcome.
High-resolution computed tomography and respiratory function test High-resolution computed tomography was performed at baseline. Each image was taken as a 1.25- or 2.0-mm-thick axial section at 1-cm intervals throughout the entire thorax, and reconstructed using a high spatial frequency algorithm. A total of 20–25 computed tomography scan images were acquired for each patient and evaluated by two expert radiologists. The total involved area due to fibrotic component, defined by reticular opacities, and inflammation, defined by ground glass opacities, was graded according to Goh scores [8]. The extent of IP was estimated as a percentage of the involved area. All patients were divided into mild (<10%), moderate (10%–30%), or severe (>30%) groups based on their Goh scores. Respiratory function data, including forced vital capacity, forced expiratory volume in 1 s, and diffusing capacity of carbon monoxide were obtained. Echocardiography Comprehensive transthoracic echocardiography was performed using a commercially available ultrasound system (a Vivid E9 ultrasonic unit; GE Healthcare, Tokyo, Japan), with a frame rate of >50/s. Images were analyzed using EchoPAC PC version 113 (GE Healthcare). Measurements and recordings were obtained according to American Society of Echocardiography recommendations [1]. The ejection fraction and left atrial volume were calculated using the modified Simpson’s method. Stroke volume was calculated as the product of the cross-sectional area of the LV
Fig. 1. Mortality in patients with idiopathic interstitial pneumonias. Kaplan–Meier curves for freedom from all-cause death in patients with mild, moderate, and severe idiopathic interstitial pneumonias.
Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010
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RV function was measured and recorded according to American Society of Echocardiography recommendations, including TAPSE and FAC [1]. To measure 2-dimensional speckle tracking longitudinal strain of RV, the RV was divided into 6 standard segments (at the basal, middle, and apical levels), and 6 corresponding timestrain curves were generated. RV free wall longitudinal strain was calculated by averaging the peak longitudinal strain of the three RV free wall segments, excluding the interventricular septum, to avoid LV interaction. Systolic PAP was calculated from the peak velocity of the tricuspid regurgitation using the modified Bernoulli equation and right atrial pressure. Right atrial pressure was estimated from the diameter of the inferior vena cava and its collapsibility [1]. Mean PAP was calculated as: 0.6 systolic PAP + 2 [9]. Mean PAP/cardiac output (CO) was used to identify abnormal pulmonary vascular response as a substitute for pulmonary vascular resistance [10,11]. Statistical analysis Statistical analyses were performed using SPSS Statistics for Windows (ver. 22.0; IBM, Armonk, NY, USA). Categorical variables are presented as numbers and percentages, and continuous variables are expressed as mean standard deviation (SD). One-way repeatedmeasures analysis of variance (ANOVA) and post hoc Tukey–Kramer tests were used to test for significance adjustment for multiple
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comparisons. The cumulative incidence of end points in each group was evaluated using Kaplan–Meier analysis and the log-rank test. Median values were used to divide patients into 2 groups for Kaplan– Meier analysis. The predictors of mortality were determined using a Cox proportional hazards model to estimate the risks associated with the following variables: age, gender, background, laboratory data, respiratory function, RV function, and LV function. Intra- and interobserver variabilities of RV free wall longitudinal strain were estimated using intraclass correlation coefficients (ICC). Statistical significance was set at a p-value of 0.05. Results Baseline characteristics of all patients The demographic characteristics of the 176 patients are presented in Table 1. The median follow-up period was 908 days (interquartile range 454–1083 days). There were 64 all-cause deaths during the follow-up period. Atrial fibrillation was revealed in five patients (2.8%), and 30 patients (17%) were current smokers. Severity of IIPs by high-resolution computed tomography Among the 176 patients, 55 patients (31%) were classified in the mild group (<10%), 66 (38%) in the moderate group, and 55 (31%) in
Table 2 Clinical background, laboratory data, respiratory function, and echocardiographic parameters in relation to severity of idiopathic interstitial pneumonias.
Clinical variable Age (years) Sex (male) Body surface area (m2) Systolic blood pressure (mm Hg) Heart rate (bpm) Cardiac output (L/min) Hypertension Diabetes Smoking habit Current smoker Atrial fibrillation Laboratory data and respiratory function KL 6 (U/mL) SP D (ng/mL) Creatinine (mg/dL) BNP (pg/mL) FVC% predicted (%) DLCO/VA% predicted (%) Right ventricular function and hemodynamics Right ventricular free wall strain (%) Tricuspid annular plane systolic excursion (mm) Fractional area change (%) Tricuspid regurgitation velocity peak (m/s) (N = 161) Mean PAP (mmHg) (N = 161) Mean PAP / CO (mm Hg/L/min) (N = 161) Left ventricular function Left ventricular end-diastolic diameter (mm) Left ventricular end-systolic diameter (mm) Interventricular septum (mm) Posterior wall thickness (mm) Ejection fraction (%) Left atrial diameter (mm) Left atrial volume index (mL/m2) E wave (cm/s) E/A ratio (N = 169) Deceleration time (ms) E/e'
All patients (N = 176)
Mild (N = 55)
Moderate (N = 66)
Severe (N = 55)
p-value
71.4 8.3 113 (64.2) 1.62 0.27 130.6 20.0 71.5 15.6 4.89 1.56 51 (29.0) 30 (17.0) 95 (54.0) 30 (17.0) 5 (2.8)
71.2 7.7 40 (72.7) 1.63 0.18 133.6 18.8 67.6 10.9 5.09 1.58 16 (29.1) 11 (20.0) 29 (52.7) 11 (20.0) 0 (0)
69.8 8.4 39 (59.1) 1.65 0.37 131.7 19.6 67.2 11.4 4.62 1.37 16 (24.2) 7 (10.6) 37 (56.1) 12 (18.2) 2 (3.0)
73.7 8.0y 34 (66.7) 1.56 0.18 126.1 20.7 80.7 19.9z 5.01 1.71 19 (34.5) 12 (21.8) 29 (52.7) 7 (12.7) 3 (5.5)
0.035 0.269 0.126 0.120 <0.001 0.207 0.461 0.206 0.912 0.570 0.205
1134.6 909.5 270.2 185.0 0.85 0.42 32.5 (14.7 61.9) 79.3 22.9 82.5 23.9
713.8 561.1 170.4 118.9 0.91 0.35 27.8 (12.9 46.8) 98.9 16.9 88.4 20.4
1225.0 961.7* 296.1 186.9* 0.79 0.21 26.3 (13.3 56.1) 74.5 17.6* 84.7 23.1
1446.9 960.8 339.0 193.2 0.87 0.62 47.5 (22.9 86.7)y 63.8 18.8z 72.3 25.4z
<0.001 <0.001 0.291 0.004 <0.001 0.002
21.0 6.3 18.8 3.8 39.8 8.5 2.61 0.46 20.7 6.6 4.68 2.19
24.2 5.4 21.1 2.9 43.1 8.2 2.38 0.24 17.7 3.1 3.77 1.32
20.7 5.6* 19.1 3.8* 40.7 7.7 2.48 0.35 18.9 4.9 4.49 1.51
18.1 6.4y 16.4 3.1y 34.8 9.1z 2.98 0.50z 25.9 7.6z 5.80 2.90z
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001
42.6 5.4 26.4 5.3 9.1 1.6 9.3 1.4 66.6 7.2 35.0 7.2 31.3 12.0 63.4 19.0 0.82 0.51 244.0 59.1 9.66 2.97
43.5 4.1 26.4 4.4 9.0 1.3 9.2 1.2 67.8 4.5 35.2 5.7 31.0 10.4 65.5 19.3 0.94 0.85 242.9 57.8 9.43 2.94
43.1 5.1 26.7 4.7 9.1 1.5 9.3 1.4 66.7 6.8 35.6 8.1 29.6 9.4 62.3 16.2 0.80 0.22 252.8 57.1 9.64 2.67
41.2 6.4 26.2 6.6 9.1 1.8 9.3 1.5 65.2 9.3 34.0 7.0 33.5 15.5 62.6 21.2 0.74 0.20 234.8 60.8 9.91 3.28
0.051 0.858 0.953 0.963 0.172 0.480 0.200 0.609 0.117 0.246 0.708
Values are mean SD, median (interquartile range), or N (%). *p < 0.01 versus mild patients; yp < 0.05 versus moderate patients; zp < 0.01 versus moderate patients. KL-6, Krebs von den Lungen-6; SP-D, surfactant protein-D; BNP, brain natriuretic peptide; FVC, forced vital capacity; DLCO/VA, diffusing capacity for carbon monoxide/alveolar ventilation; PAP, pulmonary artery pressure; CO, cardiac output; E, early diastolic mitral inflow velocity; A, atrial contraction mitral inflow velocity; e’, early diastolic mitral annular tissue velocity.
Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010
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Fig. 2. Relationship between severity of idiopathic interstitial pneumonias and measures of RV function and hemodynamics. Values under each box plot are mean SD. RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion; FAC, fractional area change; PAP, pulmonary artery pressure; CO, cardiac output.
the severe group. The 3-year freedom rate from the primary outcome measure was 92.7%, 69.1%, and 27.5% in the mild, moderate, and severe group, respectively (mild vs. moderate group: p = 0.001, moderate vs. severe group: p < 0.001) (Fig. 1). Relationship between severity of IIPs and RV function and hemodynamics Clinical background, laboratory data, respiratory function, and echocardiographic parameters in relation to severity of IIPs are shown in Table 2. There were significant differences among the three groups in terms of age (p = 0.035), heart rate (p < 0.001), Krebs von den Lungen-6 values (p < 0.001), surfactant protein-D (p < 0.001), brain natriuretic peptide (BNP) (p = 0.004), percent predicted forced vital capacity (p < 0.001), and percent predicted diffusing capacity of carbon monoxide/alveolar ventilation (p = 0.002). Regarding RV function, RV free wall longitudinal strain and TAPSE worsened with increasing severity of IIPs. There were no differences in FAC, peak tricuspid regurgitation velocity, and mean PAP/CO between the mild and moderate groups (p > 0.05, respectively), but these parameters were significantly lower in the severe compared with the moderate group (p < 0.001) (Fig. 2). There were no significant differences among the three groups in all parameters of LV function (all p > 0.05) (Table 2). The intra- and inter-observer ICCs for RV free wall longitudinal strain in our institution were 0.845 and 0.885, respectively.
Predictors of all-cause mortality in moderate-stage IIPs Among the 66 patients in the moderate group, there were 20 allcause deaths during the follow-up period. The results of univariate analysis of predictors of all-cause death in the moderate group are shown in Table 3. Regarding RV function, TAPSE, FAC, peak tricuspid regurgitation velocity, and mean PAP / CO were significant predictors of all-cause death. Regarding LV function, none of the parameters, except LV end-diastolic diameter, were significantly related to allcause death. Age and log BNP were also significantly associated with all-cause death. Even after adjusting for age and log BNP, TAPSE, FAC, peak tricuspid regurgitation velocity, and mean PAP/CO were independent predictors of all-cause death (Table 4). All-cause death was more frequent in patients with TAPSE < 18 mm (3-year-survival rate: 51% vs. 79%, p = 0.021), FAC <40% (3-year-survival rate: 54% vs. 78%, p = 0.005), and mean PAP/CO >5.0 mmHg/L/min (3-yearsurvival rate: 49% vs. 78%, p = 0.045) (Fig. 3). Predictors of all-cause mortality in severe-stage IIPs Among the 55 patients in the severe group, there were 40 allcause deaths during the follow-up period. The results of univariate analysis of predictors of all-cause death in the severe group are shown in Table 5. Although none of the indices of RV function were significant predictors of all-cause death in the severe group, gender, creatinine, and log BNP were significant predictors of the primary outcome. Multivariate analysis including these three factors and age showed that the HRs of male sex and high BNP for
Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010
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Table 3 Univariate analysis of predictors of all-cause death in the moderate group.
Clinical variable Age (per 1 year increase) Sex (male) Body surface area (per 0.1 m2 increase) Systolic blood pressure (per 10 mmHg) Heart rate (per 1 bpm) Cardiac output (per 1 L/min) Hypertension Diabetes Smoking habit Atrial fibrillation Laboratory data and respiratory function KL-6 (per 100 U/mL increase) SP-D (per 10 ng/mL increase) Creatinine (per 0.1 mg/dL increase) Log BNP (per 1 log unit increase) FVC% predicted (per 1% increase) DLCO/VA% predicted (per 1 % increase) Right ventricular function and hemodynamics Right ventricular free wall strain (per 1% increase) Tricuspid annular plane systolic excursion (per 1 mm increase) Fractional area change (per 1% increase) Tricuspid regurgitation velocity peak (N = 59) (per 0.1 m/s increase) Mean PAP / CO (N = 59) (per 1 mm Hg/L/min increase) Left ventricular function Left ventricular end-diastolic diameter (per 1 mm increase) Left ventricular end-systolic diameter (per 1 mm increase) Ejection fraction (per 1% increase) Left atrial volume index (per 1 mL/m2 increase) E wave (per 1 cm/s increase) Deceleration time (per 10 ms increase) E/e' (per 1 U increase)
HR (95% CI)
p-value
1.08 (1.02–1.15) 0.90 (0.37–2.18) 0.97 (0.83–1.14) 0.89 (0.70–1.13) 1.02 (0.99–1.06) 1.34 (0.97–1.84) 1.12 (0.41–3.09) 0.96 (0.22–4.14) 1.26 (0.52–3.10) 0.05 (0.00–80,414)
0.013 0.82 0.74 0.33 0.12 0.077 0.83 0.95 0.61 0.68
0.98 (0.93–1.03) 0.99 (0.96–1.01) 0.86 (0.68–1.08) 1.64 (1.04–2.60) 0.98 (0.95–1.01) 0.98 (0.96–1.002)
0.44 0.32 0.20 0.035 0.20 0.083
1.06 (0.99–1.14) 0.85 (0.74–0.97) 0.90 (0.85–0.97) 1.20 (1.07–1.35) 1.52 (1.10–2.11)
0.12 0.015 0.003 0.001 0.012
0.92 (0.85–0.995) 0.91 (0.83–1.01) 0.99 (0.92–1.06) 1.002 (0.95–1.06) 0.997 (0.97–1.03) 1.03 (0.95–1.10) 1.09 (0.93–1.28)
0.038 0.079 0.73 0.94 0.82 0.51 0.29
KL-6, Krebs von den Lungen-6; SP-D, surfactant protein-D; BNP, brain natriuretic peptide; FVC, forced vital capacity; DLCO/VA, diffusing capacity for carbon monoxide/ alveolar ventilation; PAP, pulmonary artery pressure; CO, cardiac output; E, early diastolic mitral inflow velocity; A, atrial contraction mitral inflow velocity; e’, early diastolic mitral annular tissue velocity.
Table 4 Adjusted excess risk in patients with moderate-stage idiopathic interstitial pneumonias. Tricuspid annular plane systolic excursion 0.85 (0.74–0.97) (per 1 mm increase) 0.89 (0.83–0.96) Fractional area change (per 1% increase) Tricuspid regurgitation velocity peak (N = 59) 1.16 (1.05–1.28) (per 0.1 m/s increase) 1.50 (1.08–2.09) Mean PAP/CO (N = 59) (per 1 mmHg/L/min increase) Adjusted for age and log brain natriuretic peptide. PAP, pulmonary artery pressure; CO, cardiac output.
0.017 0.001 0.007 0.015
all-cause mortality tended to be high, but were not significant [male sex; hazard ratio (HR): 1.97, 95% confidence interval (CI): 0.97–3.99, p = 0.061; BNP, HR: 1.42 per 1 log unit increase, 95% CI: 0.96–2.10, p = 0.081]. All-cause death was more frequent in patients with BNP >50 pg/mL compared with those with levels 50 pg/mL (3-year-survival rate: 19% vs. 36%, p = 0.029).
Discussion The results of the present study indicated that RV function worsened with progression of IIPs, with indices of RV longitudinal systolic function, such as TAPSE and RV free wall longitudinal strain, deteriorating even during the moderate stage of IIPs. Furthermore, indices of RV function were independent predictors of all-cause death in patients with moderate-stage IIPs, even after adjusting for confounders, while male sex and BNP values, but not
indices of RV function, were predictors of all-cause death in patients with severe-stage IIPs. Mechanism of PH and usefulness of PAP values in patients with IP PH is often associated with obliteration of the pulmonary vascular bed by lung destruction and fibrosis in patients with IP [12]. The mechanism of PH in IP patients may be related to hypoxia, loss of effective pulmonary vasculature as a result of lung destruction, and/or indirectly caused by pulmonary vasculopathy. Although the development of PH is linked to emerging symptoms and progression of RV dysfunction in patients with IP, the mean PAP in patients with IP is low compared to patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension [7,13]. It is therefore difficult to accurately evaluate the lower range of mean PAP values based on peak tricuspid regurgitation velocity or peak velocity of pulmonary regurgitation by echocardiography. Although right heart catheterization may be useful for detecting subtle differences, it is impossible to perform this procedure routinely in all patients. It is difficult to make prognostic impact by the subtle differences of mean PAP especially at earlier stages of IIPs. Moreover, in the current study, peak tricuspid regurgitation velocity and mean PAP was measured only at one point at rest. Exertional dyspnea is one of the specific symptoms in IP patients, thus the development of PH is also associated with increased exertional oxygen requirements regardless of PH at rest. Therefore, especially in earlier stage IP patients without PH at rest, PH may occur only at exertion due to hypoxia. Other echocardiographic markers that can be obtained in most patients should therefore be investigated to evaluate RV
Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010
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Fig. 3. Survival according to predictors of mortality in patients with moderate or severe idiopathic interstitial pneumonias. Kaplan–Meier curves for freedom from all-cause death according to cut-off points for tricuspid annular plane systolic excursion (A), fractional area change (B), tricuspid regurgitation velocity peak (C), and mean pulmonary artery pressure / cardiac output (D) in the moderate group, and brain natriuretic peptide (E) in the severe group. TAPSE, tricuspid annular plane systolic excursion; FAC, fractional area change; TRvP, tricuspid regurgitation velocity peak; PAP, pulmonary artery pressure; CO, cardiac output; BNP, brain natriuretic peptide.
Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010
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JJCC-1916; No. of Pages 8 M. Amano et al. / Journal of Cardiology xxx (2019) xxx–xxx Table 5 Univariate analysis of predictors of all-cause death in the severe group.
Clinical variable Age (per 1 year increase) Sex (male) Body surface area (per 0.1 m2 increase) Systolic blood pressure (per 10 mmHg) Heart rate (per 1 bpm) Cardiac output (per 1 L/min) Hypertension Diabetes Smoking habit Atrial fibrillation Laboratory data and respiratory function KL 6 (per 100 U/mL increase) SP D (per 10 ng/mL increase) Creatinine (per 0.1 mg/dL increase) Log BNP (per 1 log unit increase) FVC% predicted (per 1% increase) DLCO/VA% predicted (per 1% increase) Right ventricular function and hemodynamics Right ventricular free wall strain (per 1% increase) Tricuspid annular plane systolic excursion (per 1 mm increase) Fractional area change (per 1% increase) Tricuspid regurgitation velocity peak (N = 51) (per 0.1 m/s increase) mPAP/CO (N = 51) (per 1 mmHg/L/ min increase) Left ventricular function Left ventricular end-diastolic diameter (per 1 mm increase) Left ventricular end-systolic diameter (per 1 mm increase) Ejection fraction (per 1% increase) Left atrial volume index (per 1 mL/ m2 increase) E wave (per 1 cm/s increase) Deceleration time (per 10 ms increase) E/e' (per 1 U increase)
HR (95% CI)
p-value
0.998 (0.96–1.04) 2.38 (1.20–4.71) 1.05 (0.88–1.24)
0.92 0.013 0.61
0.99 (0.85–1.15)
0.91
1.01 (0.99–1.02) 1.06 (0.90–1.25) 0.64 (0.32–1.29) 0.92 (0.44–1.95) 1.48 (0.79–2.78) 1.35 (0.33–5.63)
0.31 0.46 0.21 0.83 0.22 0.68
0.995 (0.96–1.03) 1.00 (0.99–1.02) 1.09 (1.04–1.14) 1.69 (1.19–2.39) 0.995 (0.98–1.01) 1.00 (0.99–1.02)
0.77 0.72 <0.001 0.003 0.63 0.97
1.02 (0.98–1.07)
0.32
1.01 (0.82–1.11)
0.84
0.99 (0.96–1.03)
0.61
1.02 (0.95–1.08)
0.63
1.06 (0.94–1.19)
0.34
1.001 (0.94–1.06)
0.98
1.01 (0.95–1.06)
0.87
0.98 (0.95–1.02) 0.998 (0.98–1.02)
0.37 0.86
0.99 (0.97–1.003) 0.98 (0.93–1.03)
0.11 0.35
0.94 (0.85–1.05)
0.26
KL-6, Krebs von den Lungen-6; SP-D, surfactant protein-D; BNP, brain natriuretic peptide; FVC, forced vital capacity; DLCO/VA, diffusing capacity for carbon monoxide/alveolar ventilation; PAP, pulmonary artery pressure; CO, cardiac output; E, early diastolic mitral inflow velocity; A. atrial contraction mitral inflow velocity; e’, early diastolic mitral annular tissue velocity.
dysfunction in relation to IP stage, as alternatives to PAP. This is because RV dysfunction is caused by not only PH at rest but also exertional PH, thus it may be revealed at earlier stage in IP patients. Usefulness of indices of RV function in IP patients TAPSE and RV free wall longitudinal strain reflect the longitudinal components of RV systolic function, while FAC reflects both the transverse and longitudinal components, similar to RV ejection fraction [14]. Previous studies demonstrated the usefulness of these indices for detecting RV dysfunction in patients with pulmonary arterial hypertension, chronic thromboembolic PH, or chronic obstructive pulmonary disease [14–16]. However, data about RV function in patients with IP are limited [17]. The results of the present study suggest that RV longitudinal dysfunction may occur even in the moderate stage of IIPs, although transverse RV dysfunction or increased PAP was only revealed in the severe stage. This finding is consistent with previous reports that longitudinal
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shortening accounts for the majority of RV contraction in patients with PH, and longitudinal shortening is impaired previously in the early stage and transverse shortening is worsening subsequently in the severe stage [18,19]. Notably, PAP only starts to increase in the severe stage, and is therefore not a useful tool for detecting RV dysfunction at an earlier stage. Impact of RV function on prognosis in patients with IIPs PH has previously been reported as a good predictor of mortality in patients with IP [4,5,20,21]. Moreover, measures of respiratory function, including percent predicted forced vital capacity and diffusing capacity of carbon monoxide / alveolar ventilation, were also described as good predictors [5,21]. However, few studies have examined the relationship between RV function and prognosis in patients with IP. In the present study, RV longitudinal dysfunction deteriorated in patients with even moderate-stage IIPs. In addition, indices of both RV longitudinal and transverse function could be important predictors, even after adjusting for confounders in the moderate stage. Echocardiographic indices of RV function may be useful for risk stratification of patients with moderate-stage IIPs. On the other hand, among patients with severe-stage IIPs, none of the indices of RV function were significant predictors of all-cause death, although male sex and high levels of BNP had comparatively high HRs, even in multivariate analysis. According to the results of the present study, early detection of RV dysfunction can identify highrisk patients in moderate-stage IIPs. Previous studies reported the usefulness of a combination of echocardiographic parameters and BNP levels as risk-evaluation tools. Song et al. [22] showed that a combination of BNP level and echocardiographic value of PAP predicted mortality in patients with IP, while Corte et al. [23] demonstrated that BNP level and pulmonary vascular resistance were independently associated with a poor prognosis. Ruocco et al. [24] reported that BNP levels increased in patients with RV dysfunction or PH, with a cut-off value >50 pg/mL demonstrating good accuracy for identifying pulmonary disease. However, the present study evaluated prognostic factors at each stage of IIPs, and suggested that BNP levels were independently related to mortality in patients with severe IIPs. The prevalence of patients with RV dysfunction and/or PH may be high among patients with severe IIPs, and indices of RV function or PAP may thus not be independent predictors of mortality. BNP level is a combined index of RV dysfunction and degree of PH, and may therefore be the most useful parameter for predicting mortality among patients with severe IIPs. Therefore, the present study suggested the importance for evaluating prognostic factors at each stage of IIPs. Differences among indices of RV longitudinal function in patients with IIPs Among the indices of RV longitudinal function, RV free wall longitudinal strain was not a good predictor of prognosis. This apparent discrepancy between TAPSE and RV free wall longitudinal strain could be due to either intra- and/or inter-observer variability, or to the difficulty in obtaining a clear image of the RV free wall in patients with pulmonary diseases. Given its routine measurement in daily practice, the fact that strain data are not interchangeable among ultrasound vendors represents a major disadvantage [25]. In the present study, we used the same ultrasound system to analyze two-dimensional speckle-tracking images, but intra- and inter-observer variabilities were not negligible. Moreover, in a clinical setting, describing clear images of the whole of the RV free wall is more difficult in patients with IP than in normal patients. Conversely, measurement of TAPSE needs only one point at the base of the RV free wall, and is thus easy to
Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010
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obtain compared with describing the whole of the RV free wall. TAPSE may thus be a good index for confirming the progression of RV dysfunction and predicting prognosis in patients with IP, compared with RV free wall longitudinal strain. Study limitations The main limitation of the present study was its retrospective, single-center nature. However, all patients diagnosed with IP undergo echocardiography as routine practice in our institution, thus minimizing any selection bias due to echocardiography being performed according to the severity of IIPs. Because most patients in the present study did not undergo right heart catheterization, we could not obtain direct data on pulmonary vascular resistance and therefore estimated it by echocardiographic measurements. In total, in 15 patients, 7 of whom were in moderate stage and 4 of whom were in severe stage, tricuspid regurgitation velocity peak could not be measured. However, in previous studies, Doppler echocardiographic measurements of tricuspid regurgitation velocity peak are not obtained in one-third to one-half of IP patients for technical reasons [26,27]. Therefore, the measurement rate of tricuspid regurgitation velocity peak in the present study was comparatively high, and the effects on the multivariable analysis related to prognostic impact in patients with moderate-stage IIPs was minimum. Moreover, we did not evaluate pulmonary capillary wedge pressure, and therefore could not definitely exclude patients with pulmonary hypertension resulting from heart failure with preserved ejection fraction [28]. However, we did exclude subjects with more advanced dysfunction (E/e’ > 15). Conclusion RV longitudinal function worsens with increasing severity of IIPs. Echocardiographic indices of RV function are independently associated with mortality in patients with moderate IIPs, while BNP level may be an important predictor of mortality in patients with severe IIPs. Funding None. Conflict of interest The authors have no conflict of interest to disclose. References [1] Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1–39. e14. [2] Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, et al. Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation 2015;132:2037–99. [3] Forfia PR, Fisher MR, Mathai SC, Housten-Harris T, Hemnes AR, Borlaug BA, et al. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med 2006;174:1034–41. [4] Seeger W, Adir Y, Barberà JA, Champion H, Coghlan JG, Cottin V, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol 2013;62 (25 Suppl):D109–16.
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Original article
Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias Masashi Amano (MD)a,b,*, Chisato Izumi (MD PhD FJCC)a,b, Megumi Baba (MS)c, Rie Abe (MS)c, Hayato Matsutani (MS)c, Takashi Inao (MD)d, Makoto Miyake (MD)b, Yuko Nishimoto (MD)e, Toshihiro Tamura (MD PhD)b, Satoshi Noma (MD PhD)e, Yoshio Taguchi (MD)d, Yoshihisa Nakagawa (MD PhD)b a
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan Department of Cardiology, Tenri Hospital, Tenri, Japan c Department of Clinical Laboratory, Tenri Hospital, Tenri, Japan d Department of Respiratory Medicine, Tenri Hospital, Tenri, Japan e Department of Radiology, Tenri Hospital, Tenri, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 29 April 2019 Received in revised form 24 July 2019 Accepted 15 August 2019 Available online xxx
Background: Few studies have examined the relationship between echocardiographic indices of right ventricular (RV) function and the severity of pulmonary disease, or their prognostic impact. We evaluated the RV function in patients with interstitial pneumonia and its prognostic impact at each stage of disease severity. Method: A total of 176 patients with idiopathic interstitial pneumonias (IIPs) were retrospectively enrolled and we evaluated RV function by transthoracic echocardiography. The severity of IIPs was graded according to the Goh score. The primary outcome was all-cause death. Results: There were 55 patients in mild group (31%), 66 in moderate group (38%), and 55 in severe group (31%). Regarding RV function, RV free wall longitudinal strain and tricuspid annular plane systolic excursion (TAPSE) deteriorated with increasing severity of IIPs, but fractional area change (FAC) decreased significantly only in severe group. There were 64 all-cause deaths during the follow-up period (median 908 days). In moderate group, TAPSE [hazard ratio (HR): 0.85, 95% confidence interval (CI): 0.74– 0.97, p = 0.017], FAC (HR: 0.89, 95% CI: 0.83–0.96, p = 0.001), and mean pulmonary artery pressure (PAP)/ cardiac output (HR: 1.50, 95% CI: 1.08–2.09, p = 0.015) were independent predictors of all-cause death, even after adjusting for age and log brain natriuretic peptide (BNP). On the other hand, not RV function or PAP but male sex and BNP level were associated with mortality in severe group. Conclusions: Among patients with IIPs, RV longitudinal function deteriorated with increasing severity of IIPs. Echocardiographic indices of RV function were independently associated with mortality in moderate-stage IIPs. © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Interstitial pneumonia Right ventricular dysfunction Echocardiography Mortality Brain natriuretic peptide
Introduction Tricuspid annular plane systolic excursion (TAPSE), tricuspid lateral annular systolic velocity, fractional area change (FAC), and right ventricular (RV) free wall longitudinal strain are indices of RV function measured by transthoracic echocardiography [1]. The current guideline of the American Heart Association and American
* Corresponding author at: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail address: [email protected] (M. Amano).
Thoracic Society recommend these echocardiographic indices as important follow-up tools for assessing RV function in patients with pulmonary hypertension [2]. However, this guideline is mainly based on data from patients with pulmonary arterial hypertension [2,3]. A few previous reports have shown that mean pulmonary artery pressure (PAP) plays an important role in evaluating the severity and prognosis of pulmonary diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and sarcoidosis [4,5]. Although right heart failure is known to be progressive in patients with pulmonary diseases, few studies have examined the relationship between echocardiographic indices of RV function and the severity or patient prognosis of pulmonary diseases.
https://doi.org/10.1016/j.jjcc.2019.08.010 0914-5087/© 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010
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The prevalence of pulmonary hypertension (PH) in patients with interstitial pneumonia (IP) is 14% at the initial evaluation [6] and only 60% even in end-stage patients [5], and the mean PAP rarely exceeds 40 mmHg in patients with IP [7]. It is therefore difficult to evaluate the progression of IP severity based on PAP alone. Echocardiographic indices of RV function may thus help to evaluate disease severity and/or prognostic impact in patients with IP. The present study aimed to evaluate the relationship between RV function and severity of pulmonary disease, and the prognostic impact of RV function in patients with IP. Methods Study population A total of 222 consecutive patients diagnosed with IP who underwent transthoracic echocardiography to investigate RV function between November 2013 and October 2015 were retrospectively enrolled. Patients with an underlying IP etiology of connective tissue disease (N = 27) or chronic hypersensitivity pneumonitis (N = 3) were excluded. Patients with combined pulmonary fibrosis and emphysema (N = 11), or left ventricular (LV) systolic dysfunction (ejection fraction <50%) or heart failure with preserved ejection fraction [ejection fraction 50% and early diastolic mitral inflow velocity (E)/early diastolic mitral annular tissue velocity (e’) > 15 (N = 5)] were also excluded. Finally, 176 patients with idiopathic interstitial pneumonias (IIPs) were included in the final analysis. The primary outcome was all-cause death. Follow-up data were mainly collected through review of hospital charts or corrected through contact with patients, relatives, and/or referring physicians using telephone with questions regarding survival. The study protocol was approved by the institutional ethics committee at Tenri Hospital. The written informed consent to participate in this study was obtained from all patients.
Table 1 Baseline characteristics. N = 176 Clinical variable Age (years) Sex (male) Body surface area (m2) Hypertension Diabetes Smoking habit Current smoker Atrial fibrillation Hemodynamics and respiratory function Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) FVC% predicted (%) %FEV1 predicted (%) FEV1/FVC%, (%) DLCO/VA% predicted (%)
71.4 8.2 113 (64.2) 1.62 0.27 51 (28.9) 30 (17.0) 95 (54.0) 30 (17.0) 5 (2.8) 130.6 20.0 73.9 12.4 71.3 15.2 79.3 22.8 82.5 21.6 81.5 9.4 82.5 23.8
Values are mean SD or N (%). FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; DLCO/VA, diffusing capacity for carbon monoxide/alveolar ventilation.
outflow tract and the time–velocity integral in the LV outflow tract. E and peak atrial filling velocity (A) were acquired in the apical four-chamber view, and e’ was measured in the apical fourchamber view with the sample volume positioned at the lateral mitral annulus. Longitudinal strain was measured from grey-scale images recorded in apical four-chamber, two-chamber, and longaxis views. Global longitudinal strain was calculated by averaging all segmental strain values from the apical four-chamber, twochamber, and long-axis views. To confirm the accuracy of the echocardiographic parameters, the measurements were repeated by two experienced sonographers at our institution being blinded to the clinical outcome.
High-resolution computed tomography and respiratory function test High-resolution computed tomography was performed at baseline. Each image was taken as a 1.25- or 2.0-mm-thick axial section at 1-cm intervals throughout the entire thorax, and reconstructed using a high spatial frequency algorithm. A total of 20–25 computed tomography scan images were acquired for each patient and evaluated by two expert radiologists. The total involved area due to fibrotic component, defined by reticular opacities, and inflammation, defined by ground glass opacities, was graded according to Goh scores [8]. The extent of IP was estimated as a percentage of the involved area. All patients were divided into mild (<10%), moderate (10%–30%), or severe (>30%) groups based on their Goh scores. Respiratory function data, including forced vital capacity, forced expiratory volume in 1 s, and diffusing capacity of carbon monoxide were obtained. Echocardiography Comprehensive transthoracic echocardiography was performed using a commercially available ultrasound system (a Vivid E9 ultrasonic unit; GE Healthcare, Tokyo, Japan), with a frame rate of >50/s. Images were analyzed using EchoPAC PC version 113 (GE Healthcare). Measurements and recordings were obtained according to American Society of Echocardiography recommendations [1]. The ejection fraction and left atrial volume were calculated using the modified Simpson’s method. Stroke volume was calculated as the product of the cross-sectional area of the LV
Fig. 1. Mortality in patients with idiopathic interstitial pneumonias. Kaplan–Meier curves for freedom from all-cause death in patients with mild, moderate, and severe idiopathic interstitial pneumonias.
Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010
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RV function was measured and recorded according to American Society of Echocardiography recommendations, including TAPSE and FAC [1]. To measure 2-dimensional speckle tracking longitudinal strain of RV, the RV was divided into 6 standard segments (at the basal, middle, and apical levels), and 6 corresponding timestrain curves were generated. RV free wall longitudinal strain was calculated by averaging the peak longitudinal strain of the three RV free wall segments, excluding the interventricular septum, to avoid LV interaction. Systolic PAP was calculated from the peak velocity of the tricuspid regurgitation using the modified Bernoulli equation and right atrial pressure. Right atrial pressure was estimated from the diameter of the inferior vena cava and its collapsibility [1]. Mean PAP was calculated as: 0.6 systolic PAP + 2 [9]. Mean PAP/cardiac output (CO) was used to identify abnormal pulmonary vascular response as a substitute for pulmonary vascular resistance [10,11]. Statistical analysis Statistical analyses were performed using SPSS Statistics for Windows (ver. 22.0; IBM, Armonk, NY, USA). Categorical variables are presented as numbers and percentages, and continuous variables are expressed as mean standard deviation (SD). One-way repeatedmeasures analysis of variance (ANOVA) and post hoc Tukey–Kramer tests were used to test for significance adjustment for multiple
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comparisons. The cumulative incidence of end points in each group was evaluated using Kaplan–Meier analysis and the log-rank test. Median values were used to divide patients into 2 groups for Kaplan– Meier analysis. The predictors of mortality were determined using a Cox proportional hazards model to estimate the risks associated with the following variables: age, gender, background, laboratory data, respiratory function, RV function, and LV function. Intra- and interobserver variabilities of RV free wall longitudinal strain were estimated using intraclass correlation coefficients (ICC). Statistical significance was set at a p-value of 0.05. Results Baseline characteristics of all patients The demographic characteristics of the 176 patients are presented in Table 1. The median follow-up period was 908 days (interquartile range 454–1083 days). There were 64 all-cause deaths during the follow-up period. Atrial fibrillation was revealed in five patients (2.8%), and 30 patients (17%) were current smokers. Severity of IIPs by high-resolution computed tomography Among the 176 patients, 55 patients (31%) were classified in the mild group (<10%), 66 (38%) in the moderate group, and 55 (31%) in
Table 2 Clinical background, laboratory data, respiratory function, and echocardiographic parameters in relation to severity of idiopathic interstitial pneumonias.
Clinical variable Age (years) Sex (male) Body surface area (m2) Systolic blood pressure (mm Hg) Heart rate (bpm) Cardiac output (L/min) Hypertension Diabetes Smoking habit Current smoker Atrial fibrillation Laboratory data and respiratory function KL 6 (U/mL) SP D (ng/mL) Creatinine (mg/dL) BNP (pg/mL) FVC% predicted (%) DLCO/VA% predicted (%) Right ventricular function and hemodynamics Right ventricular free wall strain (%) Tricuspid annular plane systolic excursion (mm) Fractional area change (%) Tricuspid regurgitation velocity peak (m/s) (N = 161) Mean PAP (mmHg) (N = 161) Mean PAP / CO (mm Hg/L/min) (N = 161) Left ventricular function Left ventricular end-diastolic diameter (mm) Left ventricular end-systolic diameter (mm) Interventricular septum (mm) Posterior wall thickness (mm) Ejection fraction (%) Left atrial diameter (mm) Left atrial volume index (mL/m2) E wave (cm/s) E/A ratio (N = 169) Deceleration time (ms) E/e'
All patients (N = 176)
Mild (N = 55)
Moderate (N = 66)
Severe (N = 55)
p-value
71.4 8.3 113 (64.2) 1.62 0.27 130.6 20.0 71.5 15.6 4.89 1.56 51 (29.0) 30 (17.0) 95 (54.0) 30 (17.0) 5 (2.8)
71.2 7.7 40 (72.7) 1.63 0.18 133.6 18.8 67.6 10.9 5.09 1.58 16 (29.1) 11 (20.0) 29 (52.7) 11 (20.0) 0 (0)
69.8 8.4 39 (59.1) 1.65 0.37 131.7 19.6 67.2 11.4 4.62 1.37 16 (24.2) 7 (10.6) 37 (56.1) 12 (18.2) 2 (3.0)
73.7 8.0y 34 (66.7) 1.56 0.18 126.1 20.7 80.7 19.9z 5.01 1.71 19 (34.5) 12 (21.8) 29 (52.7) 7 (12.7) 3 (5.5)
0.035 0.269 0.126 0.120 <0.001 0.207 0.461 0.206 0.912 0.570 0.205
1134.6 909.5 270.2 185.0 0.85 0.42 32.5 (14.7 61.9) 79.3 22.9 82.5 23.9
713.8 561.1 170.4 118.9 0.91 0.35 27.8 (12.9 46.8) 98.9 16.9 88.4 20.4
1225.0 961.7* 296.1 186.9* 0.79 0.21 26.3 (13.3 56.1) 74.5 17.6* 84.7 23.1
1446.9 960.8 339.0 193.2 0.87 0.62 47.5 (22.9 86.7)y 63.8 18.8z 72.3 25.4z
<0.001 <0.001 0.291 0.004 <0.001 0.002
21.0 6.3 18.8 3.8 39.8 8.5 2.61 0.46 20.7 6.6 4.68 2.19
24.2 5.4 21.1 2.9 43.1 8.2 2.38 0.24 17.7 3.1 3.77 1.32
20.7 5.6* 19.1 3.8* 40.7 7.7 2.48 0.35 18.9 4.9 4.49 1.51
18.1 6.4y 16.4 3.1y 34.8 9.1z 2.98 0.50z 25.9 7.6z 5.80 2.90z
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001
42.6 5.4 26.4 5.3 9.1 1.6 9.3 1.4 66.6 7.2 35.0 7.2 31.3 12.0 63.4 19.0 0.82 0.51 244.0 59.1 9.66 2.97
43.5 4.1 26.4 4.4 9.0 1.3 9.2 1.2 67.8 4.5 35.2 5.7 31.0 10.4 65.5 19.3 0.94 0.85 242.9 57.8 9.43 2.94
43.1 5.1 26.7 4.7 9.1 1.5 9.3 1.4 66.7 6.8 35.6 8.1 29.6 9.4 62.3 16.2 0.80 0.22 252.8 57.1 9.64 2.67
41.2 6.4 26.2 6.6 9.1 1.8 9.3 1.5 65.2 9.3 34.0 7.0 33.5 15.5 62.6 21.2 0.74 0.20 234.8 60.8 9.91 3.28
0.051 0.858 0.953 0.963 0.172 0.480 0.200 0.609 0.117 0.246 0.708
Values are mean SD, median (interquartile range), or N (%). *p < 0.01 versus mild patients; yp < 0.05 versus moderate patients; zp < 0.01 versus moderate patients. KL-6, Krebs von den Lungen-6; SP-D, surfactant protein-D; BNP, brain natriuretic peptide; FVC, forced vital capacity; DLCO/VA, diffusing capacity for carbon monoxide/alveolar ventilation; PAP, pulmonary artery pressure; CO, cardiac output; E, early diastolic mitral inflow velocity; A, atrial contraction mitral inflow velocity; e’, early diastolic mitral annular tissue velocity.
Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010
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Fig. 2. Relationship between severity of idiopathic interstitial pneumonias and measures of RV function and hemodynamics. Values under each box plot are mean SD. RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion; FAC, fractional area change; PAP, pulmonary artery pressure; CO, cardiac output.
the severe group. The 3-year freedom rate from the primary outcome measure was 92.7%, 69.1%, and 27.5% in the mild, moderate, and severe group, respectively (mild vs. moderate group: p = 0.001, moderate vs. severe group: p < 0.001) (Fig. 1). Relationship between severity of IIPs and RV function and hemodynamics Clinical background, laboratory data, respiratory function, and echocardiographic parameters in relation to severity of IIPs are shown in Table 2. There were significant differences among the three groups in terms of age (p = 0.035), heart rate (p < 0.001), Krebs von den Lungen-6 values (p < 0.001), surfactant protein-D (p < 0.001), brain natriuretic peptide (BNP) (p = 0.004), percent predicted forced vital capacity (p < 0.001), and percent predicted diffusing capacity of carbon monoxide/alveolar ventilation (p = 0.002). Regarding RV function, RV free wall longitudinal strain and TAPSE worsened with increasing severity of IIPs. There were no differences in FAC, peak tricuspid regurgitation velocity, and mean PAP/CO between the mild and moderate groups (p > 0.05, respectively), but these parameters were significantly lower in the severe compared with the moderate group (p < 0.001) (Fig. 2). There were no significant differences among the three groups in all parameters of LV function (all p > 0.05) (Table 2). The intra- and inter-observer ICCs for RV free wall longitudinal strain in our institution were 0.845 and 0.885, respectively.
Predictors of all-cause mortality in moderate-stage IIPs Among the 66 patients in the moderate group, there were 20 allcause deaths during the follow-up period. The results of univariate analysis of predictors of all-cause death in the moderate group are shown in Table 3. Regarding RV function, TAPSE, FAC, peak tricuspid regurgitation velocity, and mean PAP / CO were significant predictors of all-cause death. Regarding LV function, none of the parameters, except LV end-diastolic diameter, were significantly related to allcause death. Age and log BNP were also significantly associated with all-cause death. Even after adjusting for age and log BNP, TAPSE, FAC, peak tricuspid regurgitation velocity, and mean PAP/CO were independent predictors of all-cause death (Table 4). All-cause death was more frequent in patients with TAPSE < 18 mm (3-year-survival rate: 51% vs. 79%, p = 0.021), FAC <40% (3-year-survival rate: 54% vs. 78%, p = 0.005), and mean PAP/CO >5.0 mmHg/L/min (3-yearsurvival rate: 49% vs. 78%, p = 0.045) (Fig. 3). Predictors of all-cause mortality in severe-stage IIPs Among the 55 patients in the severe group, there were 40 allcause deaths during the follow-up period. The results of univariate analysis of predictors of all-cause death in the severe group are shown in Table 5. Although none of the indices of RV function were significant predictors of all-cause death in the severe group, gender, creatinine, and log BNP were significant predictors of the primary outcome. Multivariate analysis including these three factors and age showed that the HRs of male sex and high BNP for
Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010
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Table 3 Univariate analysis of predictors of all-cause death in the moderate group.
Clinical variable Age (per 1 year increase) Sex (male) Body surface area (per 0.1 m2 increase) Systolic blood pressure (per 10 mmHg) Heart rate (per 1 bpm) Cardiac output (per 1 L/min) Hypertension Diabetes Smoking habit Atrial fibrillation Laboratory data and respiratory function KL-6 (per 100 U/mL increase) SP-D (per 10 ng/mL increase) Creatinine (per 0.1 mg/dL increase) Log BNP (per 1 log unit increase) FVC% predicted (per 1% increase) DLCO/VA% predicted (per 1 % increase) Right ventricular function and hemodynamics Right ventricular free wall strain (per 1% increase) Tricuspid annular plane systolic excursion (per 1 mm increase) Fractional area change (per 1% increase) Tricuspid regurgitation velocity peak (N = 59) (per 0.1 m/s increase) Mean PAP / CO (N = 59) (per 1 mm Hg/L/min increase) Left ventricular function Left ventricular end-diastolic diameter (per 1 mm increase) Left ventricular end-systolic diameter (per 1 mm increase) Ejection fraction (per 1% increase) Left atrial volume index (per 1 mL/m2 increase) E wave (per 1 cm/s increase) Deceleration time (per 10 ms increase) E/e' (per 1 U increase)
HR (95% CI)
p-value
1.08 (1.02–1.15) 0.90 (0.37–2.18) 0.97 (0.83–1.14) 0.89 (0.70–1.13) 1.02 (0.99–1.06) 1.34 (0.97–1.84) 1.12 (0.41–3.09) 0.96 (0.22–4.14) 1.26 (0.52–3.10) 0.05 (0.00–80,414)
0.013 0.82 0.74 0.33 0.12 0.077 0.83 0.95 0.61 0.68
0.98 (0.93–1.03) 0.99 (0.96–1.01) 0.86 (0.68–1.08) 1.64 (1.04–2.60) 0.98 (0.95–1.01) 0.98 (0.96–1.002)
0.44 0.32 0.20 0.035 0.20 0.083
1.06 (0.99–1.14) 0.85 (0.74–0.97) 0.90 (0.85–0.97) 1.20 (1.07–1.35) 1.52 (1.10–2.11)
0.12 0.015 0.003 0.001 0.012
0.92 (0.85–0.995) 0.91 (0.83–1.01) 0.99 (0.92–1.06) 1.002 (0.95–1.06) 0.997 (0.97–1.03) 1.03 (0.95–1.10) 1.09 (0.93–1.28)
0.038 0.079 0.73 0.94 0.82 0.51 0.29
KL-6, Krebs von den Lungen-6; SP-D, surfactant protein-D; BNP, brain natriuretic peptide; FVC, forced vital capacity; DLCO/VA, diffusing capacity for carbon monoxide/ alveolar ventilation; PAP, pulmonary artery pressure; CO, cardiac output; E, early diastolic mitral inflow velocity; A, atrial contraction mitral inflow velocity; e’, early diastolic mitral annular tissue velocity.
Table 4 Adjusted excess risk in patients with moderate-stage idiopathic interstitial pneumonias. Tricuspid annular plane systolic excursion 0.85 (0.74–0.97) (per 1 mm increase) 0.89 (0.83–0.96) Fractional area change (per 1% increase) Tricuspid regurgitation velocity peak (N = 59) 1.16 (1.05–1.28) (per 0.1 m/s increase) 1.50 (1.08–2.09) Mean PAP/CO (N = 59) (per 1 mmHg/L/min increase) Adjusted for age and log brain natriuretic peptide. PAP, pulmonary artery pressure; CO, cardiac output.
0.017 0.001 0.007 0.015
all-cause mortality tended to be high, but were not significant [male sex; hazard ratio (HR): 1.97, 95% confidence interval (CI): 0.97–3.99, p = 0.061; BNP, HR: 1.42 per 1 log unit increase, 95% CI: 0.96–2.10, p = 0.081]. All-cause death was more frequent in patients with BNP >50 pg/mL compared with those with levels 50 pg/mL (3-year-survival rate: 19% vs. 36%, p = 0.029).
Discussion The results of the present study indicated that RV function worsened with progression of IIPs, with indices of RV longitudinal systolic function, such as TAPSE and RV free wall longitudinal strain, deteriorating even during the moderate stage of IIPs. Furthermore, indices of RV function were independent predictors of all-cause death in patients with moderate-stage IIPs, even after adjusting for confounders, while male sex and BNP values, but not
indices of RV function, were predictors of all-cause death in patients with severe-stage IIPs. Mechanism of PH and usefulness of PAP values in patients with IP PH is often associated with obliteration of the pulmonary vascular bed by lung destruction and fibrosis in patients with IP [12]. The mechanism of PH in IP patients may be related to hypoxia, loss of effective pulmonary vasculature as a result of lung destruction, and/or indirectly caused by pulmonary vasculopathy. Although the development of PH is linked to emerging symptoms and progression of RV dysfunction in patients with IP, the mean PAP in patients with IP is low compared to patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension [7,13]. It is therefore difficult to accurately evaluate the lower range of mean PAP values based on peak tricuspid regurgitation velocity or peak velocity of pulmonary regurgitation by echocardiography. Although right heart catheterization may be useful for detecting subtle differences, it is impossible to perform this procedure routinely in all patients. It is difficult to make prognostic impact by the subtle differences of mean PAP especially at earlier stages of IIPs. Moreover, in the current study, peak tricuspid regurgitation velocity and mean PAP was measured only at one point at rest. Exertional dyspnea is one of the specific symptoms in IP patients, thus the development of PH is also associated with increased exertional oxygen requirements regardless of PH at rest. Therefore, especially in earlier stage IP patients without PH at rest, PH may occur only at exertion due to hypoxia. Other echocardiographic markers that can be obtained in most patients should therefore be investigated to evaluate RV
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Fig. 3. Survival according to predictors of mortality in patients with moderate or severe idiopathic interstitial pneumonias. Kaplan–Meier curves for freedom from all-cause death according to cut-off points for tricuspid annular plane systolic excursion (A), fractional area change (B), tricuspid regurgitation velocity peak (C), and mean pulmonary artery pressure / cardiac output (D) in the moderate group, and brain natriuretic peptide (E) in the severe group. TAPSE, tricuspid annular plane systolic excursion; FAC, fractional area change; TRvP, tricuspid regurgitation velocity peak; PAP, pulmonary artery pressure; CO, cardiac output; BNP, brain natriuretic peptide.
Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010
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JJCC-1916; No. of Pages 8 M. Amano et al. / Journal of Cardiology xxx (2019) xxx–xxx Table 5 Univariate analysis of predictors of all-cause death in the severe group.
Clinical variable Age (per 1 year increase) Sex (male) Body surface area (per 0.1 m2 increase) Systolic blood pressure (per 10 mmHg) Heart rate (per 1 bpm) Cardiac output (per 1 L/min) Hypertension Diabetes Smoking habit Atrial fibrillation Laboratory data and respiratory function KL 6 (per 100 U/mL increase) SP D (per 10 ng/mL increase) Creatinine (per 0.1 mg/dL increase) Log BNP (per 1 log unit increase) FVC% predicted (per 1% increase) DLCO/VA% predicted (per 1% increase) Right ventricular function and hemodynamics Right ventricular free wall strain (per 1% increase) Tricuspid annular plane systolic excursion (per 1 mm increase) Fractional area change (per 1% increase) Tricuspid regurgitation velocity peak (N = 51) (per 0.1 m/s increase) mPAP/CO (N = 51) (per 1 mmHg/L/ min increase) Left ventricular function Left ventricular end-diastolic diameter (per 1 mm increase) Left ventricular end-systolic diameter (per 1 mm increase) Ejection fraction (per 1% increase) Left atrial volume index (per 1 mL/ m2 increase) E wave (per 1 cm/s increase) Deceleration time (per 10 ms increase) E/e' (per 1 U increase)
HR (95% CI)
p-value
0.998 (0.96–1.04) 2.38 (1.20–4.71) 1.05 (0.88–1.24)
0.92 0.013 0.61
0.99 (0.85–1.15)
0.91
1.01 (0.99–1.02) 1.06 (0.90–1.25) 0.64 (0.32–1.29) 0.92 (0.44–1.95) 1.48 (0.79–2.78) 1.35 (0.33–5.63)
0.31 0.46 0.21 0.83 0.22 0.68
0.995 (0.96–1.03) 1.00 (0.99–1.02) 1.09 (1.04–1.14) 1.69 (1.19–2.39) 0.995 (0.98–1.01) 1.00 (0.99–1.02)
0.77 0.72 <0.001 0.003 0.63 0.97
1.02 (0.98–1.07)
0.32
1.01 (0.82–1.11)
0.84
0.99 (0.96–1.03)
0.61
1.02 (0.95–1.08)
0.63
1.06 (0.94–1.19)
0.34
1.001 (0.94–1.06)
0.98
1.01 (0.95–1.06)
0.87
0.98 (0.95–1.02) 0.998 (0.98–1.02)
0.37 0.86
0.99 (0.97–1.003) 0.98 (0.93–1.03)
0.11 0.35
0.94 (0.85–1.05)
0.26
KL-6, Krebs von den Lungen-6; SP-D, surfactant protein-D; BNP, brain natriuretic peptide; FVC, forced vital capacity; DLCO/VA, diffusing capacity for carbon monoxide/alveolar ventilation; PAP, pulmonary artery pressure; CO, cardiac output; E, early diastolic mitral inflow velocity; A. atrial contraction mitral inflow velocity; e’, early diastolic mitral annular tissue velocity.
dysfunction in relation to IP stage, as alternatives to PAP. This is because RV dysfunction is caused by not only PH at rest but also exertional PH, thus it may be revealed at earlier stage in IP patients. Usefulness of indices of RV function in IP patients TAPSE and RV free wall longitudinal strain reflect the longitudinal components of RV systolic function, while FAC reflects both the transverse and longitudinal components, similar to RV ejection fraction [14]. Previous studies demonstrated the usefulness of these indices for detecting RV dysfunction in patients with pulmonary arterial hypertension, chronic thromboembolic PH, or chronic obstructive pulmonary disease [14–16]. However, data about RV function in patients with IP are limited [17]. The results of the present study suggest that RV longitudinal dysfunction may occur even in the moderate stage of IIPs, although transverse RV dysfunction or increased PAP was only revealed in the severe stage. This finding is consistent with previous reports that longitudinal
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shortening accounts for the majority of RV contraction in patients with PH, and longitudinal shortening is impaired previously in the early stage and transverse shortening is worsening subsequently in the severe stage [18,19]. Notably, PAP only starts to increase in the severe stage, and is therefore not a useful tool for detecting RV dysfunction at an earlier stage. Impact of RV function on prognosis in patients with IIPs PH has previously been reported as a good predictor of mortality in patients with IP [4,5,20,21]. Moreover, measures of respiratory function, including percent predicted forced vital capacity and diffusing capacity of carbon monoxide / alveolar ventilation, were also described as good predictors [5,21]. However, few studies have examined the relationship between RV function and prognosis in patients with IP. In the present study, RV longitudinal dysfunction deteriorated in patients with even moderate-stage IIPs. In addition, indices of both RV longitudinal and transverse function could be important predictors, even after adjusting for confounders in the moderate stage. Echocardiographic indices of RV function may be useful for risk stratification of patients with moderate-stage IIPs. On the other hand, among patients with severe-stage IIPs, none of the indices of RV function were significant predictors of all-cause death, although male sex and high levels of BNP had comparatively high HRs, even in multivariate analysis. According to the results of the present study, early detection of RV dysfunction can identify highrisk patients in moderate-stage IIPs. Previous studies reported the usefulness of a combination of echocardiographic parameters and BNP levels as risk-evaluation tools. Song et al. [22] showed that a combination of BNP level and echocardiographic value of PAP predicted mortality in patients with IP, while Corte et al. [23] demonstrated that BNP level and pulmonary vascular resistance were independently associated with a poor prognosis. Ruocco et al. [24] reported that BNP levels increased in patients with RV dysfunction or PH, with a cut-off value >50 pg/mL demonstrating good accuracy for identifying pulmonary disease. However, the present study evaluated prognostic factors at each stage of IIPs, and suggested that BNP levels were independently related to mortality in patients with severe IIPs. The prevalence of patients with RV dysfunction and/or PH may be high among patients with severe IIPs, and indices of RV function or PAP may thus not be independent predictors of mortality. BNP level is a combined index of RV dysfunction and degree of PH, and may therefore be the most useful parameter for predicting mortality among patients with severe IIPs. Therefore, the present study suggested the importance for evaluating prognostic factors at each stage of IIPs. Differences among indices of RV longitudinal function in patients with IIPs Among the indices of RV longitudinal function, RV free wall longitudinal strain was not a good predictor of prognosis. This apparent discrepancy between TAPSE and RV free wall longitudinal strain could be due to either intra- and/or inter-observer variability, or to the difficulty in obtaining a clear image of the RV free wall in patients with pulmonary diseases. Given its routine measurement in daily practice, the fact that strain data are not interchangeable among ultrasound vendors represents a major disadvantage [25]. In the present study, we used the same ultrasound system to analyze two-dimensional speckle-tracking images, but intra- and inter-observer variabilities were not negligible. Moreover, in a clinical setting, describing clear images of the whole of the RV free wall is more difficult in patients with IP than in normal patients. Conversely, measurement of TAPSE needs only one point at the base of the RV free wall, and is thus easy to
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obtain compared with describing the whole of the RV free wall. TAPSE may thus be a good index for confirming the progression of RV dysfunction and predicting prognosis in patients with IP, compared with RV free wall longitudinal strain. Study limitations The main limitation of the present study was its retrospective, single-center nature. However, all patients diagnosed with IP undergo echocardiography as routine practice in our institution, thus minimizing any selection bias due to echocardiography being performed according to the severity of IIPs. Because most patients in the present study did not undergo right heart catheterization, we could not obtain direct data on pulmonary vascular resistance and therefore estimated it by echocardiographic measurements. In total, in 15 patients, 7 of whom were in moderate stage and 4 of whom were in severe stage, tricuspid regurgitation velocity peak could not be measured. However, in previous studies, Doppler echocardiographic measurements of tricuspid regurgitation velocity peak are not obtained in one-third to one-half of IP patients for technical reasons [26,27]. Therefore, the measurement rate of tricuspid regurgitation velocity peak in the present study was comparatively high, and the effects on the multivariable analysis related to prognostic impact in patients with moderate-stage IIPs was minimum. Moreover, we did not evaluate pulmonary capillary wedge pressure, and therefore could not definitely exclude patients with pulmonary hypertension resulting from heart failure with preserved ejection fraction [28]. However, we did exclude subjects with more advanced dysfunction (E/e’ > 15). Conclusion RV longitudinal function worsens with increasing severity of IIPs. Echocardiographic indices of RV function are independently associated with mortality in patients with moderate IIPs, while BNP level may be an important predictor of mortality in patients with severe IIPs. Funding None. Conflict of interest The authors have no conflict of interest to disclose. References [1] Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1–39. e14. [2] Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, et al. Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation 2015;132:2037–99. [3] Forfia PR, Fisher MR, Mathai SC, Housten-Harris T, Hemnes AR, Borlaug BA, et al. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med 2006;174:1034–41. [4] Seeger W, Adir Y, Barberà JA, Champion H, Coghlan JG, Cottin V, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol 2013;62 (25 Suppl):D109–16.
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Please cite this article in press as: Amano M, et al. Progression of right ventricular dysfunction and predictors of mortality in patients with idiopathic interstitial pneumonias. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.010