Electrocardiographic abnormalities and NT-proBNP levels at long-term follow-up of patients with dyspnea after pulmonary embolism.

OBJECTIVES: Electrocardiogram (ECG) and measurement of plasma brain natriuretic peptides (BNP) are established markers of right ventricular dysfunction (RVD) in the setting of acute pulmonary embolism (PE) but their value at long-term follow-up is largely unknown. The purpose of this prospective study was to determine the prevalence of ECG abnormalities, describe levels of N-terminal proBNP (NT-proBNP), and establish their association with dyspnea at long-term follow-up after PE. DESIGN: All Swedish patients diagnosed with acute PE in 2005 (n = 5793) were identified through the Swedish National Patient Registry. Surviving patients in 2007 (n = 3510) were invited to participate. Of these, 2105 subjects responded to a questionnaire about dyspnea and comorbidities. Subjects with dyspnea or risk factors for development of chronic thromboembolic pulmonary hypertension were included in the study in a secondary step, which involved collection of blood samples and ECG registration. RESULTS: Altogether 49.3% had a completely normal ECG. The remaining participants had a variety of abnormalities, 7.2% had atrial fibrillation/flutter (AF). ECG with any sign of RVD was found in 7.2% of subjects. Right bundle branch block was the most common RVD sign with a prevalence of 6.4%. An abnormal ECG was associated with dyspnea. AF was associated with dyspnea, whereas ECG signs of RVD were not. 61.2% of subjects had NT-proBNP levels above clinical cut-off (>125 ng/L). The degree of dyspnea did not associate independently with NT-proBNP levels. CONCLUSIONS: We conclude that the value of ECG and NT-proBNP in long term follow-up after PE lies mostly in differential diagnostics.

Outpatient Follow-up of Pulmonary Embolism: Putting It all Together.

Many patients discharged after an acute pulmonary embolism (PE) admission have inconsistent outpatient follow-up and insufficient workup for chronic complications of PE. A structured outpatient care program is lacking for the different phenotypes of chronic PE, such as chronic thromboembolic disease, chronic thromboembolic pulmonary hypertension, and post-PE syndrome. A dedicated PE follow-up clinic extends the organized, systematic care provided to patients with PE via the PERT (Pulmonary Embolism Response Team) model in the outpatient setting. Such an initiative can standardize follow-up protocols after PE, limit unnecessary testing, and ensure adequate management of chronic complications.

Neurophysiological mechanisms of exertional dyspnea in post-pulmonary embolism syndrome.

Following pulmonary embolism (PE), a third of patients develop persistent dyspnea, which is commonly termed the post-PE syndrome. The neurophysiological underpinnings of exertional dyspnea in patients with post-PE syndrome without pulmonary hypertension (PH) are unclear. Thus, the current study determined if abnormally high inspiratory neural drive (IND) due, in part, to residual pulmonary gas-exchange abnormalities, was linked to heightened exertional dyspnea and exercise limitation, in such patients. Fourteen participants with post-PE syndrome (without resting PH) and 14 age-, sex-, and body mass index-matched healthy controls undertook pulmonary function testing and a symptom-limited cycle cardiopulmonary exercise test with measurements of IND (diaphragmatic electromyography), ventilatory requirements for CO2 (V̇e/V̇co2), and perceived dyspnea intensity (modified Borg 0-10 scale). Post-PE (vs. control) had a reduced resting transfer coefficient for carbon monoxide (KCO: 84 ± 15 vs. 104 ± 14%pred, P < 0.001) and peak oxygen uptake (V̇o2peak) (76 ± 14 vs. 124 ± 28%pred, P < 0.001). IND and V̇e/V̇co2 were higher in post-PE than controls at standardized submaximal work rates (P < 0.05). Dyspnea increased similarly in both groups as a function of increasing IND but was higher in post-PE at standardized submaximal work rates (P < 0.05). High IND was associated with low KCO (r = -0.484, P < 0.001), high V̇e/V̇co2 nadir (r = 0.453, P < 0.001), and low V̇o2peak (r = -0.523, P < 0.001). In patients with post-PE syndrome, exercise IND was higher than controls and was associated with greater dyspnea intensity. The heightened IND and dyspnea in post-PE, in turn, were strongly associated with low resting KCO and high exercise V̇e/V̇co2, which suggest important pulmonary gas-exchange abnormalities in this patient population.NEW & NOTEWORTHY This study is the first to show that increased exertional dyspnea in patients with post-pulmonary embolism (PE) syndrome, without overt pulmonary hypertension, was strongly associated with elevated inspiratory neural drive (IND) to the diaphragm during exercise, compared with healthy controls. The greater IND was associated with impairments in pulmonary gas exchange and significant deconditioning. Our results help to explain why many patients with post-PE syndrome report significant dyspnea at relatively low levels of physical activity.

Symptoms Suggestive of Postpulmonary Embolism Syndrome and Utilization of Diagnostic Testing.

Background: Persistent symptoms of chest pain, dyspnea, fatigue, lightheadedness, and/or syncope more than 3 months after an acute pulmonary embolism (PE) are collectively classified as postpulmonary embolism syndrome (PPES). Although PPES is increasingly recognized as an important long-term sequel of acute PE, its contemporary incidence is unclear. Furthermore, the utilization of diagnostic testing for further phenotypic characterization of these patients is unknown. This study aimed to define the incidence of PPES and evaluate the utilization of diagnostic tests among a national cohort of patients with PE. Methods: Retrospective cohort study was performed using the national administrative database, Clinformatics DataMart Database (Optum Insight), and included adult patients (18 years or older) with no history of acute PE or pulmonary hypertension, diagnosed with acute PE between October 1, 2016, and December 31, 2018. With acute PE event as the exposure, the incidence of symptoms consistent with PPES and diagnostic test utilization among patients with PPES were evaluated. Results: Of 21,297 incident patients with acute PE, 11,969 (56.2%) showed ≥1 symptom of PPES, which was new since their pre-PE baseline. New dyspnea was the most common and noted in 3268/15,203 (21.5%) patients, followed by new malaise or fatigue in 2894/15,643 (18.5%) patients. Among the 11,969 patients with PPES, 5128 (42.8%) received ≥1 diagnostic test, with 3242 (27%) receiving a computed tomography pulmonary angiogram, 2997 (25%) receiving an echocardiogram, and 325 (2.7%) received a ventilation-perfusion scan within 3-12 months after PE. Significantly lower use of diagnostic testing was noted in patients older than 65 years (adjusted odds ratio, 0.89; 95% CI, 0.81-0.98). Conclusions: Symptoms consistent with PPES are common after acute PE, occurring in more than half of the patients. Diagnostic imaging for further phenotypic characterization is used in less than half of such patients with PPES.

Isoprostane-8 and GDF-15 as novel markers of post-PE syndrome: Relation with prothrombotic factors.

BACKGROUND: Post-pulmonary embolism (PE) syndrome occurs in up to 50% of PE patients. The pathophysiology of this syndrome is obscure. OBJECTIVE: We investigated whether enhanced oxidative stress and prothrombotic state may be involved in post-PE syndrome. METHODS: We studied 101 normotensive noncancer PE patients (aged 56.5 ± 13.9 years) on admission, after 5-7 days and after a 3-month anticoagulation, mostly with rivaroxaban. A marker of oxidative stress, 8-isoprostane, endogenous thrombin potential, fibrinolysis proteins, clot lysis time (CLT) and fibrin clot permeability (Ks ), along with PE biomarkers, were determined. RESULTS: Patients who developed the post-PE syndrome (n = 31, 30.7%) had at baseline 77.6% higher N-terminal brain natriuretic propeptide and 46.8% higher growth differentiation factor 15, along with 14.1% longer CLT associated with 34.4% higher plasminogen activator inhibitor-1 as compared to subjects without post-PE syndrome (all P < .05). After 5-7 days, only hypofibrinolysis was noted in post-PE syndrome patients. When measured at 3 months, prolonged CLT and reduced Ks were observed in post-PE syndrome patients, accompanied by 23.8% higher growth differentiation factor 15 and 35.8% higher plasminogen activator inhibitor-1 (all P < .05). 8-isoprostane levels ≥108 pg/ml (odds ratio=4.36; 95% confidence interval 1.63-12.27) and growth differentiation factor 15 ≥ 1529 pg/ml (odds ratio=3.89; 95% confidence interval 1.29-12.16) measured at 3 months were associated with higher risk of developing post-PE syndrome. CONCLUSIONS: Enhanced oxidative stress and prothrombotic fibrin clot properties could be involved in the pathogenesis of the post-PE syndrome. Elevated growth differentiation factor 15 assessed at 3 months might be a new biomarker of this syndrome.

The impact of post-pulmonary embolism syndrome and its possible determinants.

INTRODUCTION: Recent studies suggest that up to 50% of patients surviving pulmonary embolism (PE) may suffer from post-PE syndrome, which is defined by persistent dyspnea, impaired exercise capacity and/or decreased health-related quality of life (HRQoL). The possible determinants of post-PE syndrome are however not fully established. AIMS: To describe the differences between dyspneic and non-dyspneic PE-patients and to explore determinants of dyspnea, 6-min walking test (6MWT) and HRQoL. MATERIAL AND METHODS: In this cross-sectional study, consecutive patients diagnosed with PE between 2002 and 2011 at Østfold Hospital, Norway were identified from hospital registries. Patients were scheduled for clinical examination and a 6MWT. Dyspnea was assessed by the New York Heart Association (NYHA) classification. HRQoL was assessed with PEmb-QoL questionnaire. PE severity was assessed with PESI score, mean bilateral proximal extent of the clot and right-/left ventricle-ratio (RV/LV-ratio). RESULTS: 203 patients participated in this study, of which 96 patients reported dyspnea (47%). Median time from diagnosis was 3.6 years (IQR 1.9-6.5). Patients without dyspnea performed better on 6MWT (488 m vs 413 m, p < 0.005) and had better HRQoL results (p < 0.005). None of the variables we examined, including Charlson comorbidity index, was independently associated with dyspnea. However, higher RV/LV ratio at diagnosis was significantly associated with reduced 6MWT at follow-up. Further, ongoing anticoagulation and unemployment were independently associated with impaired HRQoL. CONCLUSIONS: PE-survivors complaining of dyspnea suffer from impaired HRQoL and reduced exercise capacity. Although PE-severity factors were associated with reduced exercise capacity, none of the examined factors were found to be independent determinants of dyspnea.

Late outcomes of pulmonary embolism: The post-PE syndrome.

The post-Pulmonary Embolism (post-PE) syndrome is being increasingly recognized as a long-term consequence of PE. Its most severe manifestation, chronic thromboembolic pulmonary hypertension (CTEPH), affects a small proportion of PE survivors. However, many more with less severe post-PE syndrome have reduced quality of life and functional capacity. The pathophysiology is incompletely understood, but involves unresolved pulmonary artery thrombi, right ventricular damage, and abnormal gas exchange. Treatment has only been established for CTEPH, and further studies are required to determine how less severe forms of the post-PE syndrome should be treated and if preventive strategies can reduce its incidence.