Severe Pulmonary Hypertension in Acute Pulmonary Thromboembolism: More Common than Expected?

Background: Pulmonary embolism (PE) is a relatively common health problem and the third most common cause of cardiovascular death with a 15-20 percent mortality rate. Severe pulmonary arterial hypertension is not common in acute forms of the disease, and we usually expect only mild to moderate degrees of PAH in these patients. However, we have encountered numerous cases of severe pulmonary hypertension after acute PE in our practice. In this study, we aimed to evaluate the echocardiographic ndings of patients admitted with documented PE in a 5 years study of two heart centers of Urmia. Methods: In this retrospective study, the data of 183 patients with a denitive diagnosis of acute pulmonary embolism based on pulmonary CT angiography have entered the study. Results: Of the 183 cases diagnosed with pulmonary embolism with an average age of 61.15 years, 45.4% were male and 54.6% were female. Shortness of breath, chest pain, and hemoptysis were seen in 88%, 49.2%, and 13.1% of patients, respectively. Tachypnea and tachycardia were the most common clinical ndings with a frequency of 54.1%. Echocardiographic ndings of right ventricular enlargement and right ventricular dysfunction were observed in 66.7% and 67.8% of patients, respectively and 42.1% of patients had severe pulmonary hypertension. We found a signicant relationship between pulmonary artery pressure severity and shock state as well as in-hospital mortality. While only 3 patients out of 64 cases (4%) with normal or mildly elevated pulmonary artery pressure died in their hospital stay period, the mortality rate was 28.5% in patients with moderate or severe pulmonary artery hypertension (p-value=0.002). Conclusion: we found a relatively high frequency of severe pulmonary artery hypertension in patients admitted with the denite diagnosis of acute pulmonary embolism and there was a signicant correlation between pulmonary artery pressure severity and shock state, as well as in-hospital mortality. So, echocardiographic ndings including right ventricular systolic pressure and TR velocity may have additional prognostic value in the decision making of acute PE patients and could be helpful in reducing in-hospital mortality of this complex illness provided being included in prognostic models of acute PE, based on future studies.


Introduction
Pulmonary embolism (PE) is the third most common cause of cardiovascular death (after myocardial infarction and stroke) that mostly originates from deep vein thrombosis of the lower limbs. [1][2][3] Genetic and acquired factors are involved in the development of venous thromboembolism. Obesity, smoking, oral contraceptives, postmenopausal hormone replacement therapy, surgery, cancer, systemic arterial hypertension, and chronic obstructive pulmonary disease are among the most common acquired underlying factors. 3,4 The incidence of pulmonary embolism in the United States is estimated at 1 in 1,000 people, although actual rate appears to be higher as many patients remain undiagnosed in some conditions. The mortality rate from pulmonary embolism in the rst 3 months after diagnosis reaches more than 15% and is usually resulting from right ventricular failure. [5][6][7] Patients with pulmonary embolism present with various symptoms. According to some studies, 73% of these patients suffer from dyspnea, whereas chest pain, cough, and hemoptysis are present in 66, 37 and 13 percent, respectively. 8 In physical examination, tachypnea is reported to be the most clinical nding with the prevalence of 70%, followed by tachycardia which is seen in 30% of patients. In severe cases of pulmonary embolism, patients may present with shock state or hemodynamic instability. 9 Because of these nonspeci c clinical manifestations, diagnostic tests play an essential role in clinical decision makings. Helpful initial work up besides history and physical examination, includes chest X ray, electrocardiography, echocardiography, plasma D-dimer level (high sensitivity but low speci city) evaluation, lung computed tomography angiography scan (sensitivity 53%-100%, speci city 83%-100%) and perfusion ventilation lung scintigraphy. However, pulmonary angiography remains the gold standard tool of the diagnosis of PE in the ambiguous cases. [8][9][10][11] It is believed that patients with systolic blood pressure less than 90 mm Hg, blood pressure drop more than or equal to 40 mm Hg for more than 15 minutes, or shock state resulting from overt right ventricular failure are at the highest risk of early mortality. 12 Besides, Right ventricular function is an important prognostic factor for pulmonary embolism. 3,12,13 In patients with stable hemodynamics and normal blood pressure, presence of moderate to severe right ventricular dysfunction in bedside echocardiography is a potential sign of increased short-term and long-term mortality. 14,15 However the appropriate strategy for the management of these patients is still controversial. 16,17 Echocardiography is a useful tool in the assessment of right ventricular pressure and function with the sensitivity of 90% in detecting massive PEs with elevated pulmonary artery pressure (PAP). In these patients, right ventricular dilatation and McConnell's sign (midfree wall akinesis but normal apical motion) as well as D-shaped left ventricle due to the displacement and attening of inter-ventricular septum, are among the most common diagnostic echocardiographic clues for signi cant PE. 18,19 Although at least 4 percent of cases presented by acute episode of PE have been reported to show symptomatic chronic pulmonary hypertension at 2 years follow up, 20 but the prevalence of acute severe pulmonary hypertension following acute PE is assumed to be low because of the right ventricle geometry, which cannot tolerate acute severe pressure rise and becomes dilated and dysfunctional before additional rise of the pulmonary artery pressure (PAP) beyond moderate degrees.
While chronic pulmonary hypertension stimulates adaptive changes in the RV myocardium that help maintain RV stroke volume, this does not occur in the acute setting and in normal individuals, the RV is unable to acutely generate a mean pressure > 40 mmHg (which is equal to systolic PAP of 60 mmhg ), and stroke volume decreases linearly as RV afterload increases. 21 Despite these facts, we have encountered numerous cases of severe pulmonary hypertension after acute PE with or without hemodynamic instability in our practice. Besides, systolic pulmonary artery pressure (sPAP) measured in transthoracic echocardiography is not a well established marker of risk strati cation in acute PE in multiple prognostic models. Hence we decided to design this study with the aim of evaluating the clinical features and echocardiographic ndings (with more focus on the parameter of sPAP for prediction of mortality) of our patient population who were admitted to our general educational hospitals with the de nite diagnosis of PE during 2014-2019.

Methods
In this descriptive-analytical cross-sectional study, 321 patients who were admitted to Urmia educational hospitals between 2014 and 2019 with the nal diagnosis of PE were collected, of which 113 were excluded due to the absence of recent pulmonary CT angiographic data, 7 due to the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) according to the patients previous admission information, and 18 due to secondary diagnosis of PAH (8 with decompensated heart failure, 6 with severe left heart valvulopathy and 4 with underling collagen vascular disease). Finally, 183 patients with a de nitive diagnosis of pulmonary embolism based on pulmonary CT angiography were eligible for our study. Clinical history and initial vital signs, echocardiographic ndings regarding right ventricular size and function, tricuspid regurgitation (TR) severity and pulmonary artery systolic pressure, as well as the nal status of the patients (discharge or death) were extracted from each patient's hospital record.
Systolic PAP below 30 mmhg was considered normal, while severe PAH was de ned as sPAP above 60 mmhg . Finally, gathered data were analyzed to verify any correlation between various echocardiographic ndings and in-hospital mortality.

Data analysis
Descriptive statistics for the relevant baseline characterization of PE patients were provided with mean and standard deviation or corresponding frequency. Continuous variables, which did not follow a normal Gaussian's distribution, were compared with the help of Wilcoxon-Whitney-U-test. Normal distributed continuous variables were compared using Stu-dents' T-test, as appropriate. Data analysis was performed using SPSS22 software and P values less than 0.05 were considered signi cant.

Clinical features
In this study 45.4% (83)  were female. Multiple previous studies were consistent with ours regarding the highest percentage of patients being female and in their middle-age. [22][23][24] We found the mortality rate of 20.2% in our pulmonary embolism patients during hospitalization which was relatively the same as other large studies to date. [5][6][7]22 The most common clinical symptoms and signs of our patients were dyspnea (88%), tachycardia (54.1%), tachypnea (54.1%), chest pain (49.2%), and shock state (37.2%). The initial presentation of syncope and hemoptysis were less common (7.1% and 13.1%, respectively). Almost in line with our study, Bajaj et al reported the most common clinical symptoms of their patients as dyspnea (72%), tachypnea (39%), chest pain (38%), tachycardia (32.6%), cough (19%), syncope (6%), and hemoptysis (4%). 25 In the study of Grifoni et al 26 patients with late hemodynamic dysfunction following PE had 10% shock and 5% in hospital mortality, which was lower than our statistics possibly due to the relatively older age and smaller sample size of our study.
In our echocardiographic ndings right ventricular enlargement and right ventricular dysfunction were seen in 66.7% and 67.8% of patients, respectively. While 75.4% of our cases (138 patients) had elevated PAP (more than 30 mm Hg) during their acute episode of PE, we found 77 patients (42.1%) with severe pulmonary hypertension (sPAP above 60 mmhg ). In the study of Kurnicka et al 24 in Poland in 2016, the echocardiographic results of their PE patients revealed right ventricular enlargement in 27.4% and sPAP > 30 mmHg in 46.6% of patients which was less common compared to our study, may be due to the differences in the study sample size or even baseline characteristics of the patients.
Based on Jennifer Mathieu's 2008 study, the normal right ventricle could not produce an average pressure above 40 mmHg in acute conditions, and stroke volume decreases linearly as RV afterload increases. 21 Also, according to the study of Wood KE in 2002, TR velocity greater than 3.7 (equivalent to 55 mmHg systolic PAP) in acute PE indicates previous underlying pulmonary disease such as chronic thromboembolism 28 . Based on another meta-analysis, risk of severe PAH and CTEPH following pulmonary embolism was reported to be between 0.5-2.3percent. 29 Nevertheless, in 42.1% of our patients who presented with acute symptoms of PE, we found systolic pulmonary pressure of ≥ 60 mmHg , which is inconsistent with the previously mentioned studies. We thought this discrepancy could be resulted from the occurrence of recurrent sub-acute pulmonary embolism or even presence of the underlying pulmonary disease in some patients, despite reviewing all patients' old documents. Following echocardiography examination of these patients at least three months after effective treatments as well as lung perfusion scans (if pulmonary hypertension persists) should be done in order to detect any underlying CTEPH and con rm these hypothesis in the future studies. Therefore gathering all these data together, we suggest large cohort studies with multi logistic regression models to investigate whether systolic PAP and TR velocity could be important markers of increased mortality in patients suffering from acute pulmonary embolism and be included in risk strati cation models of this complex illness.

Conclusion
We found relatively high frequency of severe pulmonary hypertension in patients admitted with the de nite diagnosis of acute pulmonary embolism and there were a signi cant correlation between pulmonary artery pressure severity and shock state, as well as in-hospital mortality. So, echocardiographic ndings including right ventricular systolic pressure and TR velocity may have additional prognostic value in decision making of acute PE patients and could be helpful in reducing inhospital mortality of this complex illness provided being included in prognostic models of acute PE based on future studies.

Ethical considerations
All information was con dential and was extracted without mentioning identi able details, and ethical issues regarding the observance of patients 'rights and the con dentiality of patients' information were observed, and patients entered the software based on identi cation codes.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
All of authors report no kind of con ict of interests in this study.

Funding
This study was funded by Urmia University of Medical Sciences and there is no other organizational or governmental funding.

Authors' Contributions
All of the authors in this study have contributed equally in design, performance, data collection, analysis, and writing and review of the manuscript.