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European Heart Journal Advance Access originally published online on August 1, 2007
European Heart Journal 2007 28(20):2517-2524; doi:10.1093/eurheartj/ehm295
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Echocardiographic and functional cardiopulmonary problems 6 months after first-time pulmonary embolism in previously healthy patients

Brad G. Stevinson1, Jackeline Hernandez-Nino2, Geoffrey Rose3 and Jeffrey A. Kline2,*

1 MS4, School of Medicine, Georgetown University, Washington DC, USA
2 Emergency Medicine Research, Department of Emergency Medicine, Carolinas Medical Center, PO Box 32861,Charlotte, NC 28323-2861, USA
3 Department of Internal Medicine, Cardiology Division, Carolinas Medical Center, Charlotte, NC, USA

Received 6 October 2006; revised 11 June 2007; accepted 14 June 2007; online publish-ahead-of-print 1 August 2007.

* Corresponding author. Tel: +1 704 355 7092; fax: +1 704 355 7047. E-mail address; jkline{at}carolinas.org

See page 2430 for the editorial comment on this article (doi:10.1093/eurheartj/ehm366)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims: We hypothesized that first-time submassive pulmonary embolism (PE) can cause persistent, significant cardiopulmonary problems, including right ventricular damage and worsened quality of life in patients with no prior cardiopulmonary disease.

Methods and results: We prospectively enrolled 205 patients without end-stage comorbidity diagnosed with submassive PE (systolic blood pressure always > 100 mmHg). Using explicit criteria, we identified a subgroup of 127 ‘previously healthy’ patients who were free of cardiopulmonary disease or other disabling process. All patients had transthoracic echocardiography (echo) at the time of diagnosis. Six months later, survivors returned for repeat echo, 6 min walk distance (6MWD), and a quality-of-life survey. We defined a significant cardiopulmonary problem as either: (i) abnormal RV on echo (RV dilation or RV hypokinesis); or (ii) NYHA score > II or a 6MWD < 330 m at 6 months. Of 127 study patients, five had inadequate echos, nine were lost to follow-up, and four died, leaving 109 with complete data. Of 109 patients, 45 (41%) had cardiopulmonary problems 6 months after PE: 18 of 109 (17%) had only an abnormal RV, 18 of 109 (17%) had only functional limitation, and nine of 109 (8%) had both. Twenty-two patients (20%) indicated at least one index of poor quality-of-life: health status worse, not currently shopping, or perceived need for oxygen at home. Patients with cardiopulmonary problems demonstrated a significant decrease in SaO2% after 6MWD (97 ± 1.3 pre-6MWD vs. 96 ± 1.8% post-6MWD, P = 0.004 by paired t-test).

Conclusion: Six months after first-time PE, 41% of previously healthy patients had either an abnormal RV on echo, an NYHA score > II or a 6MWD < 330 m. Treatment studies of PE should include these persistent cardiopulmonary problems as study endpoints.

Key Words: Prognosis • Pulmonary embolism • Echocardiography • Cardiac failure • Right ventricle • Fibrinolysis


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Pulmonary embolism (PE) hospitalizes approximately 150 000 Americans each year, making it one of the most common cardiovascular diseases in the United States.1 Submassive PE, defined as PE in the absence of systolic hypotension [systolic blood pressure (SBP) > 100 mmHg], frequently causes clinical deterioration and death shortly after diagnosis and treatment, with 5–20% of patients developing circulatory shock or respiratory failure during hospitalization2–4 and more than 15% dying within 3 months of diagnosis.5

Despite wide recognition of its short-term effects, a paucity of literature has examined the long-term course of PE,6–11 and a majority of these studies have used mortality as the study endpoint. Few PE studies have examined longer term, quality-of-life and functional endpoints akin to those used in outcome studies of congestive heart failure (CHF) and the pulmonary hypertension syndromes [e.g. scleroderma, idiopathic pulmonary hypertension, chronic thrombo-embolic pulmonary hypertension (CTEPH), chronic obstructive pulmonary disease (COPD)]. Traditional modalities for assessing these outcomes include a New York Heart Association (NYHA) heart failure score, a 6-minute walk test (6MWD), and echocardiography.12–19 In this study, we measured these outcomes 6 months after first-time submassive PE with particular focus on the subset who had no pre-existing comorbidity or other functional limitations.

The hypothesis states that first-time, submassive PE in previously healthy patients can cause clinically significant, persistent cardiopulmonary problems. Specific aims include: (i) measure the frequency of cardiopulmonary problems 6 months after submassive PE; (ii) assess the accuracy of echo for prognosing 6-month outcome. In addition, because certain non-malignant thrombophilias have been implicated in progressive cardiopulmonary damage after PE, we compare the frequency of non-malignant thrombophilias based upon outcome.20–22


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Study design
This was a prospective, cross-sectional, non-interventional study of prognosis. The study was approved by the center's Institutional Review Board (IRB), and written informed consent was obtained from each study subject. The screening process was performed under partial waiver of authorization for the release of medical records for the purpose of research. All patients in the study were enrolled through the emergency department, the medicine ward, or the intensive care unit at Carolinas Medical Center—a large, urban, academic hospital with more than 110 000 emergency department visits each year. Except for holiday breaks, patients were enrolled consecutively, 12 h per day, 6 days per week from January 2002 to February 2005.

Screening process
Patients were identified by an electronic Standard Query Language report of all chest CT angiography orders performed in the hospital, including inpatients and emergency department patients. This did not include elective CT scans done for outpatients. The report was updated and reviewed at 07:00, 11:00, and 15:00 each day. For each CT angiography, one of two study authors (J.H. or J.A.K.) reviewed the radiologist's initial interpretation as soon as practicable to identify patients with a CT angiography positive for PE. The diagnosis of PE required evidence of a filling defect on CT angiography, interpreted as acute PE by a board-certified radiologist with specialty training in body imaging.23 Patients with isolated deep venous thrombosis (DVT) and no PE were not enrolled. We then reviewed the patient's medical record, and when necessary, contacted other health care providers involved in the patient's care to determine eligibility.

Inclusion and exclusion criteria
We included only patients with acute, submassive PE, defined as the absence of two consecutive SBP measurements < 100 mmHg, measured > 15 min apart, or a SBP decrease > 40 mmHg within 12 h prior to enrolment.24 Exclusion criteria were: (i) comorbidity causing the patient's primary care physician to predict a 6-month mortality > 50% (e.g. end-stage heart or renal failure with no plan for transplantation or haemodialysis, end-stage AIDS, metastatic cancer); (ii) treatment with fibrinolytic therapy, catheter fragmentation, or surgical embolectomy; (iii) > 12 h elapsed since start of heparin therapy; (iv) presence of a ‘do not resuscitate’ order with clinical plan not to treat the patient for PE; (v) refusal of consent or voluntary withdrawal from the study; (vi) over-read of an initial positive CT angiography interpretation as negative for PE.

Study protocol
We completed a comprehensive, paper case report form at the bedside of every patient. Transthoracic Doppler-echocardiography (echo) was performed within 12 h of initiation of heparin by invoking a stat protocol designed for the study. Echos were performed with fourth generation ultrasound machines, capable of colour-enhanced continuous wave and pulse Doppler measurements; acoustic images were obtained using a 7.5 Mz small-footprint transducer by a registered diagnostic cardiac sonographer, and the results were interpreted by a board-certified cardiologist with specialty training in echo who was blinded to the clinical data. Images were obtained prior to the 6MWD with the patient in the left lateral decubitus position. The echocardiographic protocol included two- and four-chamber views, parasternal and short-axis views, subxyphoid and suprasternal notch views. Cardiologists evaluated the RV for presence or absence of two parameters: (i) RV hypokinesis—Observation of dynamic RV contraction in the apical four-chamber views to categorize the RV as exhibiting normal wall contraction, or hypokinesis, defined as asymmetrical or delayed contraction, usually in the RV base;25 (ii) RV dilatation—Measurement of RV diameter relative to LV diameter, made in the apical four-chamber view; RV diameter > 90% LV diameter was considered RV dilatation.

A qualified phlebotomist drew a sample of whole blood (0.11 mM sodium citrate VacutainerTM Tubes; Becton Dickinson, Franklin Lakes, NJ, USA) from each patient at enrollment to test for common thrombophilias known to increase the risk of venous thrombosis. Immediately after collection, a study author centrifuged the blood sample in a Beckman GS-6R centrifuge at 4000 rpm for 10 min, aliquoted the plasma, and froze the aliquots at –70°C until analysis. We used commercially available ELISA kits to measure the plasma for levels of anticardiolipin antibodies (IgA, IgG, and IgM isotypes) (BioQuant Inc., Irvine, CA, USA), ß2-glycoprotein antibodies [American Laboratory Products Company (ALPCO), Windham, NH, USA], homocysteine levels (ALPCO, Windham, NH, USA), Thrombin Activatable Fibrinolysis Inhibitor (TAFI) antigen (Affinity Biologicals Inc., Ontario, Canada), and lupus anticoagulant (STACLOT LA, Diagnostica Stago). We also performed genotyping on each sample to determine the incidence of heterogenicity or homogenicity in polymorphisms for the Factor V Leiden, prothrombin G20210A, and methylene tetrahydrofolate reductase genes.26

After discharge, a staff assistant contacted survivors by telephone approximately 5 months later, to schedule follow-up to assess cardiopulmonary disability. To encourage follow-up, the study offered free transportation, a physician's note for any missed activity, and a stipend to defray lost wages. If the staff assistant could not establish follow-up, the principal investigator called the patient or the family to attempt to facilitate follow-up. If these steps failed to secure the patient's return, a follow-up questionnaire was completed by telephone to assess functional status.

Six months after diagnosis of PE, patients returned for repeat echo, performed using the same methods as at diagnosis. Patients also completed a survey of overall functional status, including questions required to categorize the patient according to the NYHA heart failure score. Patients then walked on a horizontal, carpeted indoor path for 6 min, as fast and as far as possible, as described previously.19 Pulse rate and oximetry readings were obtained with the patient breathing room air before and after the walk test.

Study endpoints
We used a patient-oriented, composite definition of cardiopulmonary problems which comprised either overtly abnormal RV observed on the follow-up echo or functional limitation. We defined an ‘abnormal RV’ on echocardiography as RV dilatation (RV diameter > 90% LV diameter) or the presence of RV hypokinesis. We defined functional limitation as a NYHA heart failure score > II (requiring an answer of ‘yes’ to the question ‘Are you short of breath at rest on most days?’) or a 6MWD < 330 m.

Definition of previously healthy
We then selected patients who met our pre-study definition of previously healthy: (i) no prior history of cardiopulmonary disease (e.g. severe asthma, sarcoidosis, chronic obstructive pulmonary disease, coronary artery disease, or myocardial infarction); (ii) no prior history of PE or DVT; (iii) no active malignancy (i.e. metastatic disease or cancer currently under treatment); (iv) a left ventricular ejection fraction (LVEF) > 45% on their enrollment echocardiogram and no history of congestive heart failure. We excluded patients who were unable to walk secondary to orthopaedic or neurological impediment. Last, each patient had to answer ‘no’ to the question, asked by a study author (J.H. or J.K.), ‘Do you consider yourself disabled?’.

Statistical analysis
We estimated that one-half of the patients with submassive PE would meet the a priori definition of previously healthy, and at least one-third of these would have the outcome of cardiopulmonary disability at 6 months.9,27 Thus, to narrow the 95% CI to ± 10% for the primary endpoint of cardiopulmonary problems would require > 200 patients in the cohort.28 Data are shown as means ± SD, median and interquartile range, or percentages with 95% CI. Between-group means were tested with an unpaired t-test and proportions were compared with 95% CI for their differences. Within-group 6MWD data were compared with a paired t-test. We performed logistic regression to test if specific indexes derived from echocardiography at baseline had independent predictive value for cardiopulmonary problems; 95% CI odds ratios from the logistic regression were bias-corrected using the bootstrap technique over 1000 iterations. Model fit was examined with the Hosmer–Lemeshow test. Diagnostic utility of echocardiography are presented using standard 2 x 2 diagnostic table analysis. For all statistical calculations, an {alpha} < 0.05 was considered to be statistically significant. All statistical analyses were performed using StatsDirect (v. 2.6.2, Cheshire, UK).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
We screened 341 patients with PE and successfully enrolled 205 patients in accordance with our inclusion and exclusion criteria; 127 met the definition of previously healthy. Of the 78 excluded patients, 11 had a history of cardiopulmonary disease, 12 had prior DVT or PE, 14 had active malignancy, nine had CHF or an LVEF < 45%, 14 described themselves as ‘disabled’, and 18 had a combination of these factors. All 127 previously healthy patients were initially treated with unfractionated heparin.29 No acoustic echocardiographic window could be obtained at diagnosis for five of these 127 patients. These five were excluded from further analysis. Table 1 summarizes the clinical characteristics, categorized by RV findings on echocardiogram at time of diagnosis, of the remaining 122 previously healthy patients with submassive PE. The difference in mean age between the two groups was the only characteristic in Table 1 that reached statistical significance (P < 0.01, unpaired t-test). These patients were also screened for risk factors associated with thrombosis, and the results are shown in Table 2. We did not measure a statistically significant difference in any of the risk factors between the two groups.


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  		Table 1 Clinical characteristics of study population at diagnosis

 

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  		Table 2 Risk factors for thrombosis in study population at diagnosis

 
During the 6-month period between diagnosis and follow-up, four patients died (one from acute renal failure, one from sepsis, and two from recurrent PE) and nine were lost to follow-up, leaving 109 previously healthy patients for which complete follow-up data was available. Of the four fatalities, none had comorbidities that were disclosed to us at the time of enrolment. Three of the four had an abnormal RV observed on initial echo: one had RV dilation and hypokinesis, one had RV dilation with RVSP = 44 mmHg, and one had only RV dilation.

Six-month outcomes
Figure 1 shows the main study results. Of all 109 previously healthy patients with acute, submassive PE, and complete data, 45 (41%; 95% CI: 32–50%) had at least one abnormal cardiopulmonary finding at 6-month follow-up: 18 (17%) had only an abnormal RV, 18 (17%) had only functional limitation, and nine (8%) had both.


Figure 1
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  		Figure 1 Flow diagram showing the outcomes of enrolled patients. See text for definition of an abnormal RV. 6MWD, 6 min walk distance; FL, functional limitation; RV, right ventricle.

 
Echocardiographic findings
At diagnosis, 61 patients (50%) had normal RV on initial echo, whereas 61 (50%) had an abnormal RV. Of the 61 with an abnormal RV, 28 had RV dilation only, three had hypokinesis only, and 30 had both criteria (dilation and hypokinesis). One patient had a slightly dilated left ventricle but with a normal EF at diagnosis; no others had evidence of abnormal left ventricular function. On 6-month follow-up echo, 82 patients (75%) had a normal RV, whereas 27 patients (25%) had an abnormal RV. Figure 1 shows this progression. Abnormalities specific to the RV observed on follow-up echo included RV dilatation alone (n = 21), RV hypokinesis alone (n = 2), and both RV dilation and hypokinesis (n = 4). One patient had a dilated LV on follow-up but none had an LVEF < 50%.

Functional limitation
Overall, 27 patients (25%) met our definition of functional limitation: 12 with 6MWD < 330 m, six with NYHA score > II, and nine exhibiting both.

Multivariate logistic regression analysis
Table 3 shows the results of the logistic regression analysis. This analysis shows that each year of life added significant increase in risk for a cardiopulmonary problem 6 months later. However, no echocardiographic parameter at diagnosis had significant predictive value.


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  		Table 3 Results of logistic regression

 
Six-minute walk distance and quality-of-life
We found a statistically significant decrease in O2 saturation after the 6MWD in patients with cardiopulmonary problems (97 ± 1.3 pre-6MWD vs. 96 ± 1.8% post-6MWD; P = 0.004 by paired t-test), whereas the SaO2 did not change significantly in patients without cardiopulmonary problems (97 ± 1.4 pre-6MWD vs. 97 ±1.5 % post-6MWD; P = 0.238). Heart rate increased significantly in both groups but the mean post-6MWD heart rates were not different between groups (96 ± 16 vs. 97 ± 17 b.p.m.).

Table 4 lists responses to the quality-of-life questionnaire all patients answered at follow-up. Of note, 22 patients (20%) indicated at least one index of poor quality-of-life (reporting their health status being worse at 6-month follow-up than it was at the time of PE diagnosis, not currently able to shop, or needing oxygen at home).


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  		Table 4 Functional outcome at 6 months for 109 previously healthy patients

 
Diagnostic performance of echocardiography
Table 5 shows the prognostic indexes of the initial echocardiogram for the 109 patients who reached a study endpoint. Using our definition of RV dysfunction specified previously, echocardiography had 62% sensitivity and 53% specificity.


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  		Table 5 Prognostic value of the initial echocardiogram in 109 previously healthy patients with acute pulmonary embolism

 
Frequency of thrombophilia
Table 6 shows the distribution of several thrombophilias in each of the two study groups, those patients who had abnormal cardiopulmonary findings and those who did not. Lupus anticoagulant was observed more frequently in patients with cardiopulmonary problems.


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  		Table 6 Frequency of thrombophilia in 109 previously healthy patients with pulmonary embolism

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
This study prospectively examined the incidence of cardiopulmonary problems 6 months after previously healthy patients experienced first-time submassive PE. The principal finding was that submassive PE was associated with a high rate of persistent RV abnormalities on echocardiography, and functional limitations, identified by NYHA class > II and/or 6MWD < 330 m. Our definition of functional limitation—the NYHA score and the 6MWD—are well recognized and uniformly available methods of assessing severity of progressive heart and lung diseases.12–17 To our knowledge, this is the first study to assess long-term outcome of first-time PE in relatively healthy subjects using these patient-oriented, functional endpoints. Our findings suggest that PE causes permanent damage that impairs quality-of-life.

Our findings are consistent with observations by others. In 1999, Ribeiro et al.,9 and in 2000, Sharma et al.27 independently reported that ≥ 40% of PE survivors had resting RV hypertension or overt RV hypokinesis 6 months after diagnosis and even greater pulmonary hypertension induced with exercise. In 2003, Pengo et al.11 drew wider attention to the concept that PE can cause permanent cardiopulmonary damage when their group reported that seven of 223 (3.1%) patients had persistent pulmonary hypertension (RVSP > 40 mmHg) after first-time PE.

The question of whether or not RV dysfunction observed on echo at the time of PE diagnosis represents a significant pathophysiological event has been controversial. Some have postulated that RV dysfunction with PE represents a transient phenomenon that often spontaneously resolves with standard anticoagulant treatment.30 Others maintain that acute PE causes persistent RV abnormalities despite correct treatment. Ciurzynski et al.31 found that, when compared with controls, patients with acute PE manifested persistent abnormalities in RV function and morphology on echocardiography more than 1 year after their PE. We found that 41% of previously healthy patients experiencing their first acute, non-massive PE treated with heparin-warfarin anticoagulation had overt RV dysfunction on echo or functional impairment 6 months later. Nine patients (8%) had both echocardiographic evidence of RV dysfunction and functional limitation, and one in five reported a negative index of quality-of-life at follow-up. Thirty-six percentage of patients with an abnormal echo at diagnosis continued to have RV dysfunction on the 6-month follow-up echocardiogram, and 15% with a normal echo at diagnosis subsequently developed RV dysfunction on their follow-up echo. These findings suggest that first-time PE can render persistent RV injury or initiate a process that damages the RV over time.

Ciurzynski et al.31 also observed a significantly greater O2 desaturation after 6MWD in patients who had experienced an acute PE when compared with controls. Similarly, we observed a statistically significant decrease in SaO2% after 6MWD in patients with persistent cardiopulmonary problems. These results suggest the presence of exercise-induced venous admixture and exertional ventilation-perfusion mismatch that persist months after the acute embolic episode.

Work in animal models of PE has demonstrated that the immediate mechanisms for RV damage include subendocardial ischaemia and shear-mediated ultrastructural damage to myocytes.32,33 Watts et al.34 recently demonstrated a large increase in expression of the chemokine monocyte chemoattractant protein (MCP-1) in the RV (but not the left ventricle) of rats with experimental PE. Iwadate et al.35 observed large numbers of CD68-staining cells on histological examination of RV tissue from humans who died from PE. Taken together, these observations suggest that PE causes initial ischaemic and structural injury followed by an inflammatory response in the RV.

Our findings also underscore the need for cardiac-specific biomarkers to prognose the outcome of submassive PE.36 In this study, echo had very modest prognostic value with a sensitivity of 62% and an overall accuracy of 57%. At 6-month follow-up, we observed that 18 patients (38% of all patients with cardiopulmonary problems) had no overt RV dysfunction on resting echo, yet they had an NYHA heart failure score > II or a 6MWD < 330 m. One interpretation of this finding is that resting echocardiography may not detect inducible RV damage caused by PE. In addition, we performed univariate analysis to test if patients who had a poor outcome were more likely to be affected by a non-malignant thrombophilia. We observed only an increase in the frequency of the lupus anticoagulant factor. This modest observation suggests that laboratory testing for a thrombophilia will have very limited relevance in prognosing 6-month outcome of patients with submassive PE.

The absence of baseline data represents an insoluble limitation in this study. We attempted to reduce the confounding effect of pre-existing cardiopulmonary disease by excluding patients with debilitating conditions and the patient's own perception of disability. Our exclusion criteria were stringent, but it remains possible that some of the patients who were deemed ‘previously healthy’ in the study could have had other problems that would cause them to be categorized as having cardiopulmonary dysfunction, including the sum of multiple aetiologies such as chronic physical deconditioning, obesity, and cigarette smoking. In addition, to better quantify the independent impact of submassive PE on patients' subsequent quality-of-life, we excluded patients with overt, pre-existing cardiopulmonary disease. As a result we do not have evidence to conclude that submassive PE worsens heart or lung function in patients with pre-existing cardiopulmonary disease.

In addition, this study did not use conventional methodology to examine cardiopulmonary function (i.e. cardiopulmonary exercise stress test with evaluation of gas exchange). Instead, we assessed functional limitation with measures of cardiopulmonary functional capacity (i.e. NYHA and 6MWD). As such we cannot draw any direct conclusions about cardiopulmonary function (or dysfunction) in these acute PE patients, although cardiopulmonary function is one of the several factors that contributes to functional capacity. Future studies employing the conventional methodology to directly examine cardiopulmonary function after acute PE are warranted.

Finally, by excluding patients who died before follow-up in the final analysis, our study may have biased against the predictive value of echocardiography.

In summary, we observed a high frequency of cardiopulmonary problems, including an abnormal RV on echo, or functional cardiopulmonary limitations (NYHA score > II and/or 6MWD < 330 m), 6 months after submassive PE in previously healthy patients. Treatment studies of PE should include persistent RV abnormalities and functional cardiopulmonary limitations as study endpoints in addition to in-hospital mortality and complications.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
Work supported by NIH/NHLBI RO1 HL074384 and the Howard Hughes Medical Institute.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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