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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 8  |  Issue : 1  |  Page : 29-34

Trial design: The effect of high-dose rosuvastatin on echocardiographic parameters in patients with intermediate- and high-risk pulmonary embolism – A randomized placebo-controlled trial


1 Echocardiography Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
2 Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
3 Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran

Date of Web Publication23-Apr-2019

Correspondence Address:
Dr. Parham Sadeghipour
Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Vali-Asr Ave., Hashemi Rafsanjani Exp, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/rcm.rcm_3_19

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  Abstract 


Background: It has been shown recently that a considerable burden of pulmonary embolism (PE) roots from an inflammatory response. The activated inflammatory cascade will be responsible for the final fibrotic response of pulmonary vascular bed, creating further mechanical obstruction which results in subsequent right ventricular (RV) dysfunction, influencing functional capacity and future prognosis. Although anticoagulants represent the cornerstone treatment of PE, the drug class has a minimal effect on the mentioned pathology. Study Design: The present study is a single-center randomized, double-blind, parallel group controlled trial with placebo which will evaluate the effect of high-intensity statin – rosuvastatin 20 mg daily on patients with intermediate-to-high-risk PE. Study population will be selected from patients for whom statin is not otherwise indicated. Primary end point of the present trial will be echocardiographic measures of RV function. We believe that the mentioned indexes represent an accurate surrogate for the functional capacity and prognosis. Our secondary end point will be the composites of PE recurrence and exertional capacity measured by 6-minute walk test.
Conclusions: The result of the present trial might influence the complimentary treatment of acute PE.

Keywords: Echocardiography, high-intensity statin, pulmonary embolism, right ventricular function, rosuvastatin


How to cite this article:
Asl AA, Peighambari MM, Moosavi J, Shafe O, Naghshbandi M, Farrashi M, Khansary N, Pouraliakbar HR, Kalantari KR, Bakhshandeh H, Talakoob H, Salehi MM, Naderi S, Ghourchian E, Mehrvarz F, Rafiee N, Sadeghipour P. Trial design: The effect of high-dose rosuvastatin on echocardiographic parameters in patients with intermediate- and high-risk pulmonary embolism – A randomized placebo-controlled trial. Res Cardiovasc Med 2019;8:29-34

How to cite this URL:
Asl AA, Peighambari MM, Moosavi J, Shafe O, Naghshbandi M, Farrashi M, Khansary N, Pouraliakbar HR, Kalantari KR, Bakhshandeh H, Talakoob H, Salehi MM, Naderi S, Ghourchian E, Mehrvarz F, Rafiee N, Sadeghipour P. Trial design: The effect of high-dose rosuvastatin on echocardiographic parameters in patients with intermediate- and high-risk pulmonary embolism – A randomized placebo-controlled trial. Res Cardiovasc Med [serial online] 2019 [cited 2019 Jul 23];8:29-34. Available from: http://www.rcvmonline.com/text.asp?2019/8/1/29/256879




  Introduction Top


Venous thromboembolism (VTE) constitutes one of the three most prevalent cardiovascular diseases (CVDs) worldwide, the other two being myocardial infarction and stroke. Global incidence of VTE is estimated to be 1.2–2.7 per 1000 person per year.[1] Pulmonary embolism (PE) is the third leading cause of cardiovascular death in the United States[1] with an inhospital case fatality rate of approximately 4%.[2]

Apart from the case fatality during the acute phase, PE is a disabling disease.[3] Principal midterm and chronic complications of PE include post-PE syndrome and chronic thromboembolic pulmonary hypertension.[3],[4],[5] Both conditions have considerable effect on the quality of life, functional capacity, and prognosis.[3],[4],[5] There are emerging evidences that incomplete thrombus resolution might activate an inflammatory cascade which finally translate to a fibrotic response of pulmonary vascular bed, creating a mechanical obstruction. Interestingly, the inflammatory response might act irrespective of the degree of thrombus resolution, which demonstrates that the inflammatory cascade might also be the cause and not only the consequence of the venous thrombotic event.[3] It has been shown that many of VTE risk factors such as surgery, obesity, and inflammatory bowel disease might modulate thrombosis by inflammatory mediator.[6] It is clearly obvious that anticoagulation therapy has no proved effect on this novel inflammatory pathway.

Statins are well known for their effects on the primary and secondary prevention of CVD, and exert its therapeutic benefit through various pleiotropic effects.[7] Statin by reducing platelet/inflammatory aggregate, increasing nitric oxide bioavailability and both simulating fibrinolysis and decreasing fibrin generation, might influence and modulate the inflammatory response.[7] We have evidence from a number of randomized and nonrandomized studies which prove a preventive effect of statin on the occurrence of PE.[7]

To date, no randomized controlled trial (RCT) has evaluated the effect of statins in secondary prevention of PE. We aim to evaluate the effect of statins on the secondary prevention of VTE occurrence and the echocardiographic parameters of right ventricular (RV) function in a randomized placebo-controlled trial.


  Study Objectives Top


The primary objective of the present study is to show the efficacy of rosuvastatin compared to placebo in improving the RV function echocardiographic index of patients with intermediate- and high-risk PE. The secondary objective is to show the efficacy of rosuvastatin compared to placebo in improving the composite end point of 6-minute walk test (6MWT), PE recurrence.


  Study Design Top


The present investigation is a single-center randomized, double-blind, parallel group, placebo-controlled trial which will be conducted in Rajaie Cardiovascular Medical and Research Center, Tehran, Iran. Randomization will be web based, and the concealment will be central [Figure 1]. The study protocol was approved by our Local Ethical Committee, and patients provided a written informed consent before participation the study and for all patients, a written informed consent prior to entering the study will be provided.
Figure 1: Protocol schema for the trial

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Diagnosis of pulmonary embolism

In the present study, the diagnosis of PE should be confirmed with pulmonary computed tomography angiography in each patient. After the PE confirmation, cardiac biomarkers (high-sensitive troponin, pro b-type natriuretic peptide), electrocardiogram, and a fast echocardiography examination will be obtained. Patients will be risk stratified according to the European Society of Cardiology (ESC) Guideline.[8]

Study population

We will enroll patients with intermediate- and high-risk PE according to ESC Guideline. Inclusion and exclusion criteria have been summarized in [Table 1]. Patients regardless of the type of initial treatment (systemic fibrinolytic therapy, catheter-directed thrombolysis, and anticoagulation only) will be randomized to receive 20 mg of rosuvastatin (intervention group) or placebo (control group). At 72 h of hospitalization, each patient will undergo a detailed echocardiographic examination. A baseline alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine phosphokinase (CPK), and highly sensitive C-reactive protein (hs-CRP) will be obtained on the day of discharge.
Table 1: Inclusion and exclusion of the trial

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Study drug administration

Each patient will receive allocated set of study drug. Rosuvastatin and the placebo have been provided by Abdi Co., Tehran, Iran, and the drug will only be identified by the randomization code marked on the drug box. The study drug will be started for each patient during the first 24 h of hospitalization.

Follow-up period

Patients will be followed monthly during the first 6 month of the trial. For patients on warfarin, a meticulous plan will be provided to maintain time in therapeutic range of ≥60%. On the 3rd month of follow-up, AST, ALT, CPK, and hs-CRP will be obtained from the trial population. At 6th month, each patient will undergo a detailed echocardiographic examination and 6MWT.

Echocardiography examination

The echocardiography examination can be categorized in the present study: on the admission, at 72 h of hospitalization, and the 6-month follow-up. The data obtained from the first one will only be used for risk stratification and the last two which will be detailed examinations will be compared for the efficacy end point of statin. All echocardiography examinations are going to be done by two echocardiographers who are blinded to the randomization groups. Our detailed examination will constitute of four parts.

Conventional echocardiography

All patients undergo transthoracic echocardiography using a commercially available Cardiovascular Ultrasound System (Philips EPIQ 7). The RV-to-left ventricular (LV) end-diastolic diameter ratio is calculated in the apical four-chamber view (4-C view). RV systolic pressure (RVSP) is obtained by continuous wave Doppler (CWD). Two-dimensional (2D) and color flow Doppler is used to identify the most complete TR jet followed by CWD acquisition of spectral envelopes of the greatest maximal velocity. Right atrial pressure (RAP) is estimated by visualizing the inferior vena cava (IVC) diameter from subcostal views and its response to respiration (RAP is estimated as 5 mmHg if the IVC is <2.1 cm in diameter 1–2 cm below the junction to the right atrium, 15 mmHg if the IVC is dilated and collapsed with respiration (>50%), and 20 mmHg if the IVC is dilated and does not collapse with respiration). Pulmonary arterial hypertension is classified according to the baseline RVSP as mild (35–44 mmHg), moderate (45–59 mmHg), or severe (>60 mmHg). Normalization of pressures is defined as RVSP <35 mmHg.

RVFAC is calculated using the RV-focused apical 4-C view with the following formula: RVFAC (%) = (RV end-diastolic area − RV end-systolic area)/RV end-diastolic area × 100. The measure <35% is regarded as abnormal. TAPSE is measured as the length between the end-diastolic and peak systolic points of the lateral tricuspid annulus; any value <17 mm is regarded as abnormal. Tricuspid annular S' velocity is measured by tissue Doppler application of the lateral tricuspid annulus; S' velocity <9.5 is considered abnormal. RV Tei index (myocardial performance index) is measured using tissue Doppler imaging (TDI) method ([isovolumic contraction time + isovolumic relaxation time]/E/T); the values <0.54 by DTI were considered normal [Figure 2]a.
Figure 2: (a) Tricuspid inflow deceleration time by pulse wave Doppler assessment was 162 msec, (b) assessment of right ventricular area in systole and diastole showed right ventricular fractional area change about 31%, (c) right ventricular free wall strain assessed by TomTec software was 16%, (d) three-dimensional assessment of right ventricle by TomTec software showed right ventricular ejection fraction about 60% and right ventricular end-diastolic volume about 93 cc

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Right ventricular diastolic function

From apical 4-C view, sample volume of PW Doppler is placed at the tips of the tricuspid leaflets across the tricuspid valve and TDI at the TV annulus, and E-wave DCT, E/A, E/e′, and e' velocity are measured. Measurement of trans-tricuspid flow will be at end expiration. Patients with severe TR or AF are excluded from the study. Normal E/A is 0.8–2, E/e′ is <6, and e' is <8 cm/s. A normal E-wave DCT is 180 ± 31 msec. In addition, increased diastolic hepatic vein flow and enlargement of the RA also suggest RV diastolic dysfunction. Assessment of RA pressure is also performed (as mentioned above) [Figure 2]b.

Strain echocardiography

The acquisitions are obtained successively for all patients, with analyses being performed retrospectively and offline. RV-focused views are used, and special care is taken to ensure an adequate field of view to image the entire right ventricle. 2D peak systolic RV free wall longitudinal strain is measured by TomTec software. The echo results are analyzed by an echocardiologist blinded to the clinical data [Figure 2]c.

Three-dimensional echocardiography

Three-dimensional (3D) echo is done using a wide-angle, matrix-array transducer to enable full coverage of the entire right ventricle by the pyramidal volume. Before each acquisition, the images are optimized for endocardial border visualization by increasing the overall gain and modifying the time gain and compression. Echocardiographic images are stored digitally for offline analysis using TomTec software (TomTec Imaging Systems, Germany). Within the 3D data set, three orthogonal main cut planes are selected to define the end-diastolic and end-systolic frames within the sequence as well as several landmarks. On the basis of the initial view adjustment and the landmarks, the program automatically provides 4-C, sagittal, and coronal RV views. RV end-diastolic volume and RV end-systolic volume and RV ejection fraction are measured from each 3D echo data set [Figure 2]d.

Statistical consideration

Normality of numeric variables will be assessed with one sample Kolmogorov–Smirnov test. Numeric data will be expressed as median (interquartile range) and nominal and ordinal variables will be described by frequency (%). The Mann–Whitney U-test will be used to compare differences between two groups for numeric data with nonnormal distribution. The Pearson's Chi-square test will be employed to compare differences between groups for nominal data. Statistical significance will be set at P < 0.05. Spearman's correlation coefficient (rho) will be used for correlation between numeric variables. To analyze intraobserver variability, measurements of parameters will be made in ten different patients on two different occasions (same recorded loops) without knowledge of other echocardiographic parameters. The Bland–Altman method for comparing paired measurements will be used to determine intraobserver reliability.

Based on the results of the pilot study and using sample size calculation formula by Mann–Whitney U-test (with G power 3.1 statistical software), the sample size for evaluation of the changes in 3D RV EF between two groups (intervention and control) by considering the Type I error of 0.05 (α = 0.05) and power of 90%, the sample size in each group is estimated to be 120 patients.

Additional scientific investigations

The value of the all four subcategories of echocardiographic examination, conventional, diastolic function evaluation, strain echocardiography, and 3D echocardiography will be determined in the whole study population and compared with each other.

Furthermore, the prognostic value of hs-CRP will also be examined during the study period.


  Discussion Top


In this study, we aim to assess the effect of rosuvastatin as a secondary preventive strategy in patients with acute PE and will test the hypothesis of the ability of statin in decreasing the functional burden of the disease. Furthermore, we will evaluate the basic and advanced RV echocardiographic measures of these patients to detect potential subclinical surrogates among the study population.

Acute PE induces an inflammatory response;[9] this response is seen in most patients and seems to facilitate thrombus resolution. It has been suggested that in some patients, an altered inflammatory response may inhibit thrombus resolution and cause scar formation.[10],[11] Animal and human studies have demonstrated an intense inflammatory reaction in the RV wall following acute PE.[12],[13],[14],[15],[16],[17] Myocyte stretch, decreased perfusion, and increased metabolic demand in the setting of increased afterload have been suggested as the cause of inflammation of the RV wall in this setting. This can result in myocyte necrosis, thinning, and fibrosis of the RV wall.[16] It has been shown in animal models of PE that by reducing the inflammation RV myocardial function may be preserved.[18] RV dysfunction which is reported to be present among 10%–44% of the patients at 6–12-month follow-up is also one of the determinants of the post-PE syndrome.[19],[20],[21]

Statins are well established for the primary and secondary prevention of CVD. Other than the lipid-lowering properties of this drug group, statins are also known to have pleiotropic effects that modulate coagulation and inflammation.[22] Randomized and nonrandomized studies have shown the potential role of statins to reduce the incidence of first VTE event. The Heart and Estrogen/progestin Replacement Study was the first study which reported a decrease in the incidence of PE among statin users compared to nonusers.[23] The investigators of Justification for the Use of Statins in Prevention, An Intervention Trial Evaluating Rosuvastatin study, also demonstrated that rosuvastatin decreased the incidence of first VTE.[24] Similar results were achieved regarding the risk of recurrent VTE and statin use in a meta-analysis of eight observational prospective cohort studies (no RCT).[25] Interestingly, in the same meta-analysis, Kunutsor et al. have shown the superiority of rosuvastatin compared to other statins in decreasing the occurrence of VTE events.[25] Consequently, we have chosen rosuvastatin among the other agents for the present investigation. We have used the same logic in the treatment of acute coronary syndrome and reached the conclusion to allocate our intervention group to high-intensity statin treatment.[26]

The main body of previously executed trials in this field has focused on clinical end points such as recurrence and mortality. However, we believe that the assessment should also incorporate more preliminary stages of pathophysiologic changes which eventually lead to the mentioned events. Echocardiographic evaluation of RV measures, including RV sizes and systolic and diastolic functions, seems to be a useful and yet practical way for this purpose. Apart from the sample size requirement, this is the main reason that we have focused on the echocardiographic measures as the primary end point of the trial.

Evaluation of 3D RV volumes and EF has been shown to have better correlation with magnetic resonance (MR) imaging measures than conventional 2D measures. They were also better predictors of future events. Studying longitudinal strain of RV free wall is another emerging method that has good correlation with MR findings and is known to detect subclinical changes in the myocardium.

PE also invokes RV diastolic dysfunction and its evaluation can be useful for recognizing early states of disease affecting the RV, before occurrence of abnormalities in RV systolic function and size.[27] Filali et al. assessed RV characteristics by standard echo and TDI, in asymptomatic patients 1 year after PE occurrence and compared them to a healthy control group. There were no significant differences in RV diastolic diameter, RV systolic function, MPI, S', TAPSE, and SPAP among the two groups. However, tricuspid annulus early diastolic velocities (e') was markedly reduced in PE group with lower ratio of early-to-late diastolic velocities (E/A) reflecting impaired RV diastolic function in patients with previous PE.[28]

One of our secondary end points is the 6MWT. Previous studies have reported decreased functional capacity in PE survivors compared to population controls.[29] Chow et al. examined the functional status of PE survivors without comorbidities and they reported significant functional impairment in up to 25% of them and 19% of them had below normal 6MWT compared to their predicted estimates that could not be explained by comorbidities.[30] In the study by Chow et al., the functional impairment was associated with echocardiographic evidence of RV dysfunction and raised PVR.[30]


  Conclusions Top


In the present RCT, we will evaluate the effect of high-intensity statin on RV echocardiographic parameters as a surrogate end point. We believe that the result might influence the treatment of PE and reduce its burden.

Acknowledgment

The authors would like to thank Sara Tayebi for her valuable help in the images preparation

Financial support and sponsorship

Rosuvastatin and the placebo for the present study have been provided by Abidi Co.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Wendelboe AM, Raskob GE. Global burden of thrombosis: Epidemiologic aspects. Circ Res 2016;118:1340-7.  Back to cited text no. 1
    
2.
Minges KE, Bikdeli B, Wang Y, Kim N, Curtis JP, Desai MM, et al. National trends in pulmonary embolism hospitalization rates and outcomes for adults aged ≥65 years in the United States (1999 to 2010). Am J Cardiol 2015;116:1436-42.  Back to cited text no. 2
    
3.
den Exter PL, van der Hulle T, Lankeit M, Huisman MV, Klok FA. Long-term clinical course of acute pulmonary embolism. Blood Rev 2013;27:185-92.  Back to cited text no. 3
    
4.
Sista AK, Klok FA. Late outcomes of pulmonary embolism: The post-PE syndrome. Thromb Res 2018;164:157-62.  Back to cited text no. 4
    
5.
Klok FA, van der Hulle T, den Exter PL, Lankeit M, Huisman MV, Konstantinides S, et al. The post-PE syndrome: A new concept for chronic complications of pulmonary embolism. Blood Rev 2014;28:221-6.  Back to cited text no. 5
    
6.
Branchford BR, Carpenter SL. The role of inflammation in venous thromboembolism. Front Pediatr 2018;6:142.  Back to cited text no. 6
    
7.
Ray KK. Statin treatment and the risk of recurrent pulmonary embolism. Eur Heart J 2013;34:1775-7.  Back to cited text no. 7
    
8.
Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35:3033-69, 3069a-69k.  Back to cited text no. 8
    
9.
Eagleton MJ, Henke PK, Luke CE, Hawley AE, Bedi A, Knipp BS, et al. Southern association for vascular surgery William J. Von Leibig award. Inflammation and intimal hyperplasia associated with experimental pulmonary embolism. J Vasc Surg 2002;36:581-8.  Back to cited text no. 9
    
10.
Waltham M, Burnand K, Fenske C, Modarai B, Humphries J, Smith A, et al. Vascular endothelial growth factor naked DNA gene transfer enhances thrombus recanalization and resolution. J Vasc Surg 2005;42:1183-9.  Back to cited text no. 10
    
11.
Modarai B, Burnand KG, Humphries J, Waltham M, Smith A. The role of neovascularisation in the resolution of venous thrombus. Thromb Haemost 2005;93:801-9.  Back to cited text no. 11
    
12.
Watts JA, Marchick MR, Kline JA. Right ventricular heart failure from pulmonary embolism: Key distinctions from chronic pulmonary hypertension. J Card Fail 2010;16:250-9.  Back to cited text no. 12
    
13.
Iwadate K, Doi M, Tanno K, Katsumura S, Ito H, Sato K, et al. Right ventricular damage due to pulmonary embolism: Examination of the number of infiltrating macrophages. Forensic Sci Int 2003;134:147-53.  Back to cited text no. 13
    
14.
Iwadate K, Tanno K, Doi M, Takatori T, Ito Y. Two cases of right ventricular ischemic injury due to massive pulmonary embolism. Forensic Sci Int 2001;116:189-95.  Back to cited text no. 14
    
15.
Jones AE, Watts JA, Debelak JP, Thornton LR, Younger JG, Kline JA, et al. Inhibition of prostaglandin synthesis during polystyrene microsphere-induced pulmonary embolism in the rat. Am J Physiol Lung Cell Mol Physiol 2003;284:L1072-81.  Back to cited text no. 15
    
16.
Watts JA, Gellar MA, Obraztsova M, Kline JA, Zagorski J. Role of inflammation in right ventricular damage and repair following experimental pulmonary embolism in rats. Int J Exp Pathol 2008;89:389-99.  Back to cited text no. 16
    
17.
Zagorski J, Sanapareddy N, Gellar MA, Kline JA, Watts JA. Transcriptional profile of right ventricular tissue during acute pulmonary embolism in rats. Physiol Genomics 2008;34:101-11.  Back to cited text no. 17
    
18.
Watts JA, Gellar MA, Stuart LK, Obraztsova M, Kline JA. Proinflammatory events in right ventricular damage during pulmonary embolism: Effects of treatment with ketorolac in rats. J Cardiovasc Pharmacol 2009;54:246-52.  Back to cited text no. 18
    
19.
Stevinson BG, Hernandez-Nino J, Rose G, Kline JA. Echocardiographic and functional cardiopulmonary problems 6 months after first-time pulmonary embolism in previously healthy patients. Eur Heart J 2007;28:2517-24.  Back to cited text no. 19
    
20.
Kline JA, Steuerwald MT, Marchick MR, Hernandez-Nino J, Rose GA. Prospective evaluation of right ventricular function and functional status 6 months after acute submassive pulmonary embolism: Frequency of persistent or subsequent elevation in estimated pulmonary artery pressure. Chest 2009;136:1202-10.  Back to cited text no. 20
    
21.
Ribeiro A, Lindmarker P, Johnsson H, Juhlin-Dannfelt A, Jorfeldt L. Pulmonary embolism: One-year follow-up with echocardiography Doppler and five-year survival analysis. Circulation 1999;99:1325-30.  Back to cited text no. 21
    
22.
Undas A, Brummel-Ziedins KE, Mann KG. Statins and blood coagulation. Arterioscler Thromb Vasc Biol 2005;25:287-94.  Back to cited text no. 22
    
23.
Herrington DM, Vittinghoff E, Lin F, Fong J, Harris F, Hunninghake D, et al. Statin therapy, cardiovascular events, and total mortality in the heart and estrogen/Progestin replacement study (HERS). Circulation 2002;105:2962-7.  Back to cited text no. 23
    
24.
Ridker PM. The JUPITER trial: Results, controversies, and implications for prevention. Circ Cardiovasc Qual Outcomes 2009;2:279-85.  Back to cited text no. 24
    
25.
Kunutsor SK, Seidu S, Khunti K. Statins and primary prevention of venous thromboembolism: A systematic review and meta-analysis. Lancet Haematol 2017;4:e83-93.  Back to cited text no. 25
    
26.
Lavie CJ, Milani RV. High-dose atorvastatin in acute coronary and cerebrovascular syndromes. JACC Cardiovasc Interv 2010;3:340-2.  Back to cited text no. 26
    
27.
Faludi R, Komócsi A, Bozó J, Kumánovics G, Czirják L, Papp L, et al. Isolated diastolic dysfunction of right ventricle: Stress-induced pulmonary hypertension. Eur Respir J 2008;31:475-6.  Back to cited text no. 27
    
28.
Filali T, Jedaida B, Gommidh M, Lahidheb D, Mahfoudhi H, Hajlaoui N, et al. 082: Right ventricular diastolic dysfunction in patients with previous pulmonary embolism. Arch Cardiovasc Dis Suppl 2013;5:27.  Back to cited text no. 28
    
29.
Klok FA, van Kralingen KW, van Dijk AP, Heyning FH, Vliegen HW, Kaptein AA, et al. Quality of life in long-term survivors of acute pulmonary embolism. Chest 2010;138:1432-40.  Back to cited text no. 29
    
30.
Chow V, Ng AC, Seccombe L, Chung T, Thomas L, Celermajer DS, et al. Impaired 6-min walk test, heart rate recovery and cardiac function post pulmonary embolism in long-term survivors. Respir Med 2014;108:1556-65.  Back to cited text no. 30
    


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