Prognostic Value of Systolic Pulmonary Artery Pressure Determined by Echocardiography in Patients with Pulmonary Hypertension

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1 Prognostic Value of Systolic Pulmonary Artery Pressure Determined by Echocardiography in Patients with Pulmonary Hypertension FLAVIA CORCIOVĂ 1, CĂLIN CORCIOVĂ 2, CĂTĂLINA ARSENESCU GEORGESCU 1 1. Faculty of General Medicine, Institute of Cardiovascular Diseases Prof. Dr. George Georgescu 2. Faculty of Medical Bioengineering University of Medicine and Pharmacy Grigore T. Popa - Iaşi Institute of Cardiovascular Diseases, Carol I Boulevard, no 50 ROMANIA flaviaantoniu@yahoo.com Abstract: Pulmonary hypertension is a hemodynamic and pathophysiological condition defined as an increase in mean pulmonary pressure more than or equal to 25 mm Hg. Risk stratification and prognostic evaluation in patients with pulmonary hypertension are complex and require multiple investigations. There is a lack of consensus on factors that predict mortality and prognosis in patients with pulmonary arterial hypertension. The aim of our study was to identify the prognostic value of the systolic pulmonary artery pressure, determined by echocardiography, in patients with pulmonary hypertension. We performed a prospective study that included 553 patients diagnosed with pulmonary hypertension in the Institute of Cardiovascular Diseases of Iasi between 2008 and We found that severe pulmonary hypertension (defined as systolic pulmonary artery pressure above 70 mm Hg) is closely related to increased mortality, survival duration, number of hospitalizations for clinical worsening and heart failure phenomena and longer hospitalization duration. We also found a statistically higher risk of patients with systolic pulmonary artery pressure > 70 mm Hg for mechanical ventilation and renal, hepatic and pericardial complications. We found no association between the systolic pulmonary artery pressure value and need for inotropic support or pleural complications. Conclusions: Echocardiography provides very useful prognostic tools in patients with pulmonary hypertension. Echocardiography is very accurate in assessing systolic pulmonary artery pressure. Systolic pulmonary artery pressure can be used as an indicator of severity and prognosis in these patients. Key words: echocardiography, pulmonary hypertension, prognosis, systolic pulmonary artery pressure, mortality, survival 1 Introduction Pulmonary hypertension (PH) is a hemodynamic and pathophysiological condition defined as an increase in mean pulmonary pressure more than or equal to 25 mm Hg. Pulmonary hypertension is a complex pathology, which is at the crossroads of numerous medical specialties (cardiology, pulmonology, rheumatology, genetics, pediatrics, cardiovascular surgery). PH is a disease which recently has seen a continuous and revolutionary development of knowledge, involving teams of clinicians, pathologists, geneticists and pharmacological studies. Interest in the subject is justified by the high frequency of disease, the diversity of clinical entities in which it occurs as a complication and the severe prognosis of the disease. PH is a progressive disease with severe evolution and dramatic natural history. In 1980, the NIH register (National Institutes of Health) established the natural history of idiopathic pulmonary arterial hypertension for a period of five years. Average survival was 2.8 years, survival rates at 1, 3 and 5 years of 68%, 48% and 34% [1, 2]. Modern therapy has led to a significant improvement in symptoms and reduced the rate of clinical worsening, but despite therapeutic advances, pulmonary hypertension remains today an incurable disease even nowadays and survival rates at 5 years are still very low [2-7] (figure 1) [2] 1997 [3] 2002 [4] 2002 [5] 2003 [6] 20 [7] 1 year 3 years 5 years Fig. 1 - Survival rates in patients with PH over time Risk stratification and prognostic evaluation in patients with PH are complex and require multiple investigations. There is a lack of consensus on factors that predict mortality and prognosis in patients with pulmonary arterial hypertension. A recent meta-analysis addressing idiopathic pulmonary arterial hypertension identified no less than 7 ISBN:

2 factors that have been associated with mortality in different studies. There are conflicting reports on the prognostic value of many of them. The first ten identified as prognostic factors were functional class, heart rate, six minutes walking distance, pericardial effusion, mpap, right atrial pressure, cardiac index, stroke volume index, PVR, mixed venous pressure of oxygen or saturations [8]. The systolic pulmonary artery pressure (spap), determined by echocardiography, has not classically been seen as a prognostic factor [1, 9]. The pulmonary artery pressure determined by cardiac catheterization is prognostic, but towards the final stages of the disease, when the right ventricle becomes insufficient, it may decrease [1]. However, recent studies show that, at least in some subsets of patients, as pulmonary hypertension due to left heart diseases, the pulmonary artery systolic pressure, determined by echocardiography, significantly influence prognosis. Systolic PAP above 50 mm Hg in patients with chronic organic mitral regurgitation was an independent predictor of mortality after cardiac surgery []. In other studies, systolic PAP above 60 mm Hg correlated with a composite end point of cardiac death, readmission for heart failure or fatal arrhythmia in a group of patients undergoing restrictive mitral annuloplasty for severe functional mitral regurgitation secondary to advanced cardiomyopathy and lower rates of survival [11, 12]. 2 Problem formulation The aim of our study was to identify the prognostic value of the systolic pulmonary artery pressure, determined by echocardiography, in patients with pulmonary hypertension. We performed a prospective study that included 553 patients diagnosed with pulmonary hypertension in the Institute of Cardiovascular Diseases of Iasi between 2008 and The classification of patients in clinical classes was performed according to the Dana Point classification of PH (2008) [1]. The transthoracic echocardiographic examination was conducted using a Vivid E9 (GE Healthcare) ultrasound system or an Acuson Sequoia C512 (Siemens) system. The clinical examination aimed to establish the WHO class [1]. The echocardiographic exam included the assessment of the left ventricular volume and ejection fraction using the biplane Simpson's method; the determination of the systolic pressure in the pulmonary artery (spap) using the maximum tricuspid regurgitation velocity measured by continuous-wave Doppler; determination of the right ventricular end-diastolic diameter; calculation of the right atrium area indexed for the body surface area (measured in the apical four-chamber view); TAPSE assessment. The right heart catheterization determined the systolic, diastolic and mean pulmonary artery pressures, pulmonary vascular resistance, cardiac index and right atrium pressure. We monitored the following parameters: WHO functional class deterioration; hospitalizations for heart failure phenomena; number of days of hospitalization; need for inotropic support or mechanical ventilation; need of treatment modification; non- cardiac complications (pleural, pericardial, hepatic, renal). We defined renal complications as a rise in serum creatinine of 0.3 mg/dl or 50% in less than 48 hours; hepatic complications as hepatic cytolysis syndrome and/or spontaneous INR > 1,5; pleural complications as significant pleurisy, which necessitated thoracentesis; pericardial complications as significant amount of pericardial fluid with signs of compression and/or need for pericardiocentesis. Patient monitoring was carried out over 34 months. Patients were examined every 6 months. We used STATISTICA (a dedicated program for medical research) for statistical processing of data. Continuous variables were described as mean SD. The χ 2 test was used to compare categorial variables. ANOVA and Kruskal- Wallis tests were used to compare means of continuous variables. Pearson linear correlation test was used to establish correlation between variables. Survival was calculated using Kaplan- Meier analysis. We performed multivariable analysis for mortality. 3 Problem solution Demographic and clinical features of patients are shown in table 1. Table 1 Demographical and clinical characteristics Class Class Class Class Total No (28 (75 (46 (61 (79 (36 (57 Male gender [n (] Age (yrs) WHO III - IV [n (] ( ( ( ( ( ( (59 ISBN:

3 Idiopathic pulmonary artery hypertension (IPAH) represented 1.26% of the total group. The majority of our group was represented by PH due to left heart diseases (class 2). Most patients had severe symptoms (WHO class III and IV). Systolic pulmonary artery pressure was determined by echocardiography and right heart catheterization. Average spap obtained by echocardiography was mm Hg; average spap obtained by cardiac catheterization was mm Hg. We obtained a very strong positive correlation between the two methods (r 0.847, p <0.0001). We recorded 25 deaths in the studied group (4.52% mortality). There were no significant differences between genders (13 male patients and 12 female) (p 0.27). Age was not an independent risk factor for death (p 0.24). The highest mortality was recorded for IPAH and the lowest in patients with congenital heart diseases, but the difference is not statistically significant (χ , p 0.1). The average systolic pulmonary artery pressure determined by echocardiography (spap) in the deceased patients group was of mm Hg. In survivors, the mean spap was of mm Hg. The ANOVA test for comparing mean values of spap depending on the patient's vital status shows that there was a statistically significant difference between the two groups p<0.001 (fig. 2). the cut off value found in our study, and this value is statistically significant (χ 2 = , p 0.01). Statistic test 95%CI (Confidence interval) Log-Rank test χ 2 = p = Cox s F Test χ 2 = p = Fig. 3 - Kaplan Meier survival curve according to the cut off value of spap Prognostic value of spap remained significant in a multivariable analysis which included clinical (WHO class), echocardiographic (spap, left ventricle ejection fraction, TAPSE, right ventricle end diastolic diameter and body indexed ri.ght atrium area) and hemodynamic (right atrium pressure and cardiac index) parameters (table 2). Only right atrial pressure (RAP) (p 0.017) and spap (p 0.028) reached statistical significance. Fig. 2 - spap value according to the vital status In order to determine the influence of spap on survival we can set a "cut off" value function of the quartiles of the variable, then setting the corresponding survival rates. For spap the value of 70 mm Hg represents a "cut off" value. Fig. 3 shows the Kaplan Meier survival curve according to Table 2 - Multivariable analysis of mortality DEATH Param DEATH Std.Err t -95% CI +95% CI Intercept spap LVEF TAPSE RVEDD Indexed RA area RAP CI WHO WHO WHO p ISBN:

4 Figure 4 shows the regression analysis for the correlation between spap and the months of survival. spap value is strongly correlated with survival duration (r 0.52, p<0.001). The average duration of hospitalization was days in the first group, respectively days in the second group (p < 0.001). The impact of PH severity on the need for mechanical ventilation, inotropic support and non- cardiac complications is presented in table 3. Patients with severe PH had a significantly higher need for mechanical ventilation and higher rates of renal, liver and pericardial complications. In our study we found that severe PH (defined as spap > 70 mm Hg) is closely related to increased mortality, survival duration, number of hospitalizations for clinical worsening and heart failure phenomena and longer hospitalization duration. We also found a statistically higher risk of patients with spap > 70 mm Hg for mechanical ventilation and renal, hepatic and pericardial complications. We found no association between spap value and need for inotropic support or pleural complications. Fig. 4 - Regression analysis for the correlation between spap and survival In order to see if spap value has other prognostic implications, we divided patients into two groups (spap lower, respectively higher than 70 mm Hg) and we analyzed the need for hospitalization due to heart failure phenomena and the average period of hospitalization for each group. For patients with spap lower than 70 mm Hg, the average number of hospitalizations for clinical worsening and heart failure phenomena during the monitoring period was vs hospitalizations for patients with severe PH (p<0.001). Table 3 Rate of complications according to spap spap<70 spap>70 χ p mm Hg mm Hg 95% 95% N = 376 N = 177 CI CI Compli cation Mechanical ventilation, n ( Inotropic support, n ( Renal, n ( Hepatic, n ( Pleural, n ( Pericardial, n ( 2 ( ( ( ( ( ( (3.39 (5.65 ( ( (3.95 ( Conclusion Severe PH (defined as systolic pulmonary artery pressure above 70 mm Hg) correlated with increased mortality, shorter duration of survival, number of hospitalizations for clinical deterioration and heart failure phenomena, increased length of stay and increased rate of complications. Echocardiography provides very useful prognostic tools in patients with pulmonary hypertension. The echocardiographic examination is very accurate in assessing systolic pulmonary artery pressure. Systolic pulmonary artery pressure can be used as an indicator of severity and prognosis in these patients. References [1] Galié N, Hoeper M, Humbert M et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009; 30: [2] D'Alonzo GE, Barst RJ, Ayres SM et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med Sep 1;115 (5): [3] Shapiro SM, Oudiz RJ, Cao T et al. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol. 1997; 30 (2): [4] Sitbon O, Humbert M, Nunes H et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002; 40: [5] McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact ISBN:

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