The European Society of Cardiology
Plasma brain natriuretic peptide is a marker of right ventricular overload in pulmonary hypertension associated to HIV infection
a Division of Cardiology, Policlinico S Matteo Hospital, Piazza Golgi 1, 27100 Pavia, Italy
b Institute of Infectious Diseases, IRCCS S Matteo Hospital, Pavia, Italy
c Biometry and Clinical Epidemiology, IRCCS S Matteo Hospital, Pavia, Italy
* Correspondence: Stefano Ghio, Division of Cardiology, Policlinico S Matteo Hospital, Piazza Golgi 1, 27100 Pavia, Italy, Tel.: +39 382 503713; fax: +39 382 503159 (E-mail: s.ghio{at}smatteo.pv.it).
Abstract
AIMS: The levels of plasma brain natriuretic peptide (BNP) are known to be elevated in patients with primary pulmonary hypertension (PH). We sought to verify the sensitivity and specificity of plasma BNP levels for the diagnosis of PH in HIV infected patients.
METHODS AND RESULTS: Plasma N-terminal proBNP levels were measured in 16 patients with HIV disease and a confirmed diagnosis of PH and in 77 control HIV patients with no cardiac or pulmonary disease. All patients underwent an echocardiographic and Doppler examination focused on the evaluation of right ventricular (RV) geometry and function. An abnormal value of N-terminal proBNP (>153 pg/ml in males and >88 pg/ml in females) yielded a 91% specificity and a 81% sensitivity for the diagnosis of PH. Three PH patients with normal N-terminal but similar transtricuspidal and transpulmonary gradients in comparison to those with abnormal N-terminal pro-BNP had normal indices of RV function.
CONCLUSIONS: Abnormal plasma N-terminal proBNP levels are associated with good sensitivity and specificity to the diagnosis of PH in HIV patients. Normal values of N-terminal proBNP may be observed in PH patients with HIV infection, in the case the right ventricle is not dilated and has a normal systolic function.
Keywords Primary pulmonary hypertension; HIV infection; BNP; Echocardiography
Introduction
The natriuretic peptides are cardiac hormones which have been shown to increase in proportion to the degree of cardiac overload.1 Brain natriuretic peptide (BNP) shares with atrial natriuretic peptide (ANP) a high degree of structural homology and a profile of diuretic, natriuretic and vasodilator properties; however, it is secreted predominantly by ventricular tissue.2 Most studies have been performed in patients with left ventricular (LV) failure or LV hypertrophy. Nowadays it is well known that BNP is an important biochemical marker in heart failure: it can be used to diagnose LV systolic and diastolic dysfunction, to monitor the efficacy of therapy, to stratify prognosis.3–7 However, BNP messenger ribonucleid acid can be detected at autopsy not only in the human left ventricle but also in the right ventricle8 and natriuretic peptide receptors are widely represented in the right ventricle.9 This observation prompted to investigate the influence of right ventricular (RV) hemodynamics and function on the secretion of BNP in patients with isolated RV overload. In a series of 26 patients with either primary or chronic thromboembolic pulmonary hypertension (PH), plasma BNP levels turned out to be elevated and significantly correlated with pulmonary artery pressure while inversely related with RV ejection fraction.10 The same investigators demonstrated that BNP levels may be independently associated with increased mortality rates in patients with primary PH.11 Primary PH is a rare condition characterized by extensive remodeling of the pulmonary artery vessels (mainly medial hypertrophy and intimal proliferation of arteriolar vessels) leading to elevations in the pulmonary artery pressure and vascular resistances.12 The prevalence of this disease has been reported to be about 2 per million in the general population but it has been found to be much higher (about 0.5–1%) among subjects infected with the human immunodeficiency virus (HIV).13–15 It is still debated whether the pathogenesis of such susceptibility is genetically determined or it is acquired. Nonetheless, the possibility of early diagnosis could have important clinical and public health implications.
Accordingly, the aim of the present study was to verify the hypothesis that plasma BNP concentration could be a simple and useful marker of RV overload in patients with HIV infection and PH. In particular, we sought to assess the sensitivity and specificity of plasma BNP levels for the diagnosis of PH and to verify whether the relationship between plasma BNP levels and the severity of pulmonary hypertension holds true even in PH patients with associated HIV infection.
Methods
Patients
Blood samples were obtained in 93 HIV-positive patients. Sixteen patients had a diagnosis of HIV infection at various stages plus a confirmed diagnosis of PH. The clinical characteristics of the patients are shown in Table 1. The remaining 77 sera were obtained in 77 patients with HIV infection at various stages without symptoms or signs of cardiovascular diseases.
|
Blood sampling and assay
Blood samples were drawn from a peripheral vein while the patients were in stable hemodynamic conditions. Blood was immediately transferred into a chilled glass tube containing sodium EDTA and centrifuged at 4°C; sera were then stored at –70°C. The measurement of natriuretic peptide in sera was then performed by a commercially available ELECSYS® ProBNP assay (Roche Diagnostic). These assay quantitatively determines the N-terminal fragment of proBNP by using a immunochemiluminescence technique. The assay was performed according to the manifacturer's instructions on sera freshly thawed once. It was decided to measure the cleavage fragment of proBNP since it has, over BNP, the advantage of more stable plasma concentrations and therefore it better reflects the patient's chronic conditions.
Echocardiographic and Doppler study
A complete M-mode, 2-D and Doppler study was performed using standard parasternal, apical and subcostal approaches, according to a protocol previously described in details.16 Left ventricular end-diastolic and end-systolic volumes and left ventricular ejection fraction were calculated using the area–length method. The eccentricity index of the left ventricle was calculated in diastole and in systole. The right ventricular end-diastolic diameter and the thickness of the right ventricle free wall were determined in the parasternal view.17 End-diastolic and end-systolic right ventricular areas were measured in the apical view and the fractional area change was calculated as (end-diastolic area minus end-systolic area) divided by end-diastolic area, x100. The systolic displacement of the lateral portion of the tricuspid annular plane was measured on the M-mode tracing under the 2D-echo guidance.18 Tricuspid regurgitation was graded using the jet area method.19 The diameter of the inferior vena cava was measured from the subcostal approach and its inspiratory collapsibility evaluated.20 All echocardiographic data were averaged over 3 beats. All Doppler measurements were evaluated in 5 consecutive beats obtained during quiet respiration.
Statistical analysis
The data are shown as mean values±SD for continuous variables (or median and inter-quartile ranges (IQR) for skewed distributions) and as absolute or relative frequencies for categorical variables. For the purpose of analysis, N-terminal proBNP was dichotomized according to normality cut-off values reported for male and female patients (>153 pg/ml in male patients and >88 pg/ml in female patients below 50 years old).21 Sensitivity, specificity and predictive values were calculated to assess the diagnostic ability of proBNP in identifying pulmonary hypertension in HIV positive patients. Echocardiographic parameters were compared in patients with normal or abnormal proBNP levels by means of logistic regression. Log-transformed values of proBNP were correlated with the echocardiographic parameters by means of linear regression; the corresponding Pearson correlation coefficiency and their 95% confidence intervals were calculated. A two sided P value <0.05 was retained for statistical significance. The computations were made using Stata 7 (Stata Corp, College Station, TX).
Results
N-terminal proBNP levels and the diagnosis of PH
The plasma N-terminal proBNP levels (median and IQR) were 1412 (574–2326) pg/ml in PH patients and 29 (7–48) pg/ml in HIV control patients (P<0.001). Abnormal N-terminal proBNP levels were observed in 3 male and in 4 female control HIV patients, all with a normal echocardiographic examination; in these patients the median N-terminal proBNP levels was 238 pg/ml in males and 150 pg/ml in females. Normal N-terminal proBNP levels were observed in 3 PH patients who were symptom free under medical treatment. Sensitivity and specificity of an abnormal N-terminal proBNP level for the diagnosis of PH were 81% (95% CI=73–89) and 91% (95% CI=85–97); based on a estimated prevalence of PH of 20%, the positive and negative predictive values were 65% (95% CI=55–75) and 96% (95% CI=92–100).
N-terminal proBNP levels and the severity of PH
The log-transformed N-terminal proBNP levels was significantly correlated with several echocardiographic indices of RV geometry and function, but they did not correlate with the systolic or diastolic pulmonary artery pressure estimates (Table 2). PH patients with normal N-terminal proBNP levels had a normal RV end diastolic diameter, a slightly enlarged RV end diastolic area and a normal tricuspid annular plane systolic excursion (Table 3).
|
|
Discussion
Cardiovascular complications are becoming more and more common among patients infected with HIV, most likely as a consequence of their increased survival due to the new therapies with protease inhibitors. Dilated cardiomyopathy has been reported to be the most common life threatening cardiovascular complication of HIV infection.22,23 In addition, many studies point out that pulmonary hypertension is a severe disease associated with HIV. Although the prevalence of PH is much higher in patients infected with HIV than in the general population, the pathogenesis of this susceptibility is still debated.14,15 At present, there is no reliable method of screening for such severe cardiovascular complications other than echocardiography; however, repeated echocardiographic examinations in all HIV infected patients would be costly and time-consuming. It has recently been suggested that plasma levels of BNP may be useful to identify patients with HIV related cardiomyopathy.24 In the present study we demonstrate that abnormal plasma N-terminal BNP levels are associated with a good specificity and a fairly good sensitivity to the diagnosis of PH in HIV patients.
N-terminal BNP levels in HIV infected patients with right ventricular overload
A large number of studies have been published concerning plasma BNP levels in patients with left ventricular dysfunction or left ventricular overload. Nowadays, physicians know how to use the plasma BNP levels in the differential diagnosis of acute heart failure, to guide therapeutic adjustments during the follow-up of patients with chronic congestive heart failure, in the prognostic stratification of patients with left ventricular dysfunction. In contrast, less information is available regarding plasma N-terminal BNP levels in patients with isolated right ventricular overload.10,11 In HIV infected patients a most important problem is the screening of patients for the early diagnosis of cardiovascular complications. In the present study abnormal N-terminal BNP levels turned out to have a good sensitivity and specificity for the diagnosis of PH. In the present series N-terminal BNP levels showed a better correlation with the indices of right ventricular function rather than with pulmonary artery pressure. In fact, normal N-terminal BNP levels were observed in 3 PH patients who had a substantially normal RV geometry and function. This observation is slightly at variance with the previous observation by Nagaya who found good a direct relationship between BNP and pulmonary artery pressures.10 However, it fits with the observation that BNP is secreted predominantly in response to ventricular wall stress, which is not a simple function of the pulmonary artery pressure level; rather, wall stress depends on the capability of the right ventricle to cope with the degree of pulmonary hypertension.
Limitations of the study
Since none of the patients in the present study had left ventricular dysfunction, we have no data on the relative accuracy of plasma N-terminal proBNP levels in identifying left ventricular rather than right ventricular dysfunction in HIV infected patients. Actually, only a large-scale observational study may answer this question; a larger scale trial would also clarify the prognostic significance of plasma N-terminal proBNP levels in such patients.
Conclusions
The measurement of plasma N-terminal proBNP levels is a simple method to screen HIV infected patients for a pre-clinical diagnosis of pulmonary hypertension.
References
- Levin ER, Gardner DG, Samson WK. Natriuretic peptides N Engl J Med 1998;339:321-328.
[Free Full Text] - Yasue H, Yoshimura M, Sumida H, et al. Localization and mechanism of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and in patients with heart failure Circulation 1994;90:195-203.
[Abstract/Free Full Text] - Cowier MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care Lancet 1997;350:1349-1353.[CrossRef][Web of Science][Medline]
- Mcdonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left-ventricular systolic dysfunction Lancet 1998;351:9-13.[CrossRef][Web of Science][Medline]
- Lubien E, DeMaria A, Krishnaswamy P, et al. Utility of B natriuretic peptide in detecting diastolic dysfunction. Comparison with Doppler velocity recordings Circulation 2002;105:595-601.
[Abstract/Free Full Text] - Nicholls MG, Lainchbury JG, Richards AM, et al. Brain natriuretic pepdtide-guided therapy for heart failure Ann Med 2001;33(6):422-427.[Web of Science][Medline]
- Tsutamoto T, Wada A, Maeda K. Attenuation of compensation of endegenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with symptomatic left ventricular dysfunction Circulation 1997;96:509-516.
[Abstract/Free Full Text] - Hosoda K, Nakao K, Mukoyama M, et al. Expression of brain natriuretic peptide gene in human heart: production in the ventricle Hypertension 1991;17:1151-1156.
- AdachiS, Ito H, Ohta Y, et al. Distribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial banding Am J Physiol 1995;268:162-169.
- Nagaya N, Nishikimi T, Okano Y, et al. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension J Am Coll Cardiol 1998;31:202-208.
[Abstract/Free Full Text] - Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension Circulation 2000;102:865-870.
[Abstract/Free Full Text] - Rubin LJ. Primary pulmonary hypertension N Engl J Med 1997;336:111-117.
[Free Full Text] - Petitretz P, Brenot F, Azarian R, et al. Pulmonary hypertension in Patients with HIV infection: comparison with primary pulmonary hypertension Circulation 1994;89:2722.
[Abstract/Free Full Text] - Golpe R, Fernandez-Infante B, Fernandez-Rosaz S. Primary pulmonary hypertension associated with human immunodeficiency virus infection Postgrad Med J 1998;74:400-404.
[Abstract/Free Full Text] - Mesa RA, Edel ES, Dunn WF, et al. Human immunodeficiency virus infection and pulmonary hypertension: two new cases and a review of 86 reported cases Mayo Clin Proc 1998;73:37.[Abstract]
- Ghio S, Raineri C, Scelsi L, et al. Usefulness and limits of transthoracic echocardiography in the evaluation of patients with primary and chronic thromboembolic pulmonary hypertension J Am Soc Echo 2002;15:1374-1380.[CrossRef][Web of Science][Medline]
- Baker BJ, Scovil JA, Kane JJ, et al. Echocardiographic detection of right ventricular hypertrophy Am Heart J 1983;105:611-614.[CrossRef][Web of Science][Medline]
- Ghio S, Recusani F, Klersy C, et al. Prognostic usefulness of the tricuspid annular plane systolic excursion in patients with congestive heart failure secondary to idiopathic or ischemic cardiomyopathy Am J Cardiol 2000;85:837-842.[CrossRef][Web of Science][Medline]
- Suzuki Y, Kambara H, Kadota K, et al. Detection and evaluation of tricuspid regurgitation using a real time, two dimensional, color-coded, Doppler flow imaging system: comparison with contrast two-dimensional echocardiography and right ventriculography Am J Cardiol 1986;57:811-815.[CrossRef][Web of Science][Medline]
- Kircher BJ, Himelman RB, Schiller NB. Noninvasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava Am J Cardiol 1990;66:493-496.[CrossRef][Web of Science][Medline]
- Palladini G, Campana C, Klersy C, et al. Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis Circulation 2003;107:2440-2445.
[Abstract/Free Full Text] - Lewis W. Cardiomyopathy in AIDS: a pathophysiological perspective Progr Cardiovasc Dis 2000;43:151-170.[CrossRef][Web of Science][Medline]
- Herskowitz A. Cardiomyopathy and other symptomatic heart diseases associated with HIV infection Curr Opinion Cardiol 1996;11:325-331.[Web of Science][Medline]
- Carrillo-Jimenez R, Treadwell TL, Goldfine H, et al. Brain natriuretic peptide and HIV-related cardiomyopathy AIDS Reader 2001;12:501-508.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||