Ann Nucl Med DOI 10.1007/s12149-014-0861-6
ORIGINAL ARTICLE
The usefulness of gated blood pool scintigraphy for right ventricular function evaluation in pulmonary embolism patients Konstantin V. Zavadovsky • Nikolay G. Krivonogov Yuri B. Lishmanov
•
Received: 25 November 2013 / Accepted: 2 May 2014 Ó The Japanese Society of Nuclear Medicine 2014
Abstract Objective According to the international registry ICOPER, right ventricular (RV) dysfunction is the most significant predictor of mortality in patients with pulmonary embolism (PE). Aim To identify the most informative indicators of gated blood pool single photon emission computer tomography (GBP-SPECT) for evaluation of RV function in patients with PE. Methods A total of 52 patients were included in the study. The main group (n = 37) comprised patients with PE, and the comparison group (n = 15) patients suffering from coronary heart disease (NYHA class I-II). All patients received GBP-SPECT, and assessment of plasma levels of endothelin1, stable nitric oxide (NO) metabolites, and 6-keto-PG F1a. Results In patients with PE, RV end-systolic volume, stroke volume, ejection fraction, peak ejection rate, peak filling rate, and mean filling rate were significantly lower in comparison with patients without PE. In patients with PE, the levels of endothelin-1, 6-keto-PG F1a, and stable NO metabolites were increased in comparison with patients without PE. Conclusions GBP-SPECT facilitates verification of RV dysfunction in patients without massive PE or severe pulmonary hypertension. Dissociation between the volume of
K. V. Zavadovsky (&) N. G. Krivonogov Y. B. Lishmanov Nuclear Medicine Department, Federal State Budgetary Institution ‘‘Research Institute for Cardiology’’ of Siberian Branch under the Russian Academy of Medical Science, 111a Kievskaya Str., Tomsk 634012, Russia e-mail: [email protected] Y. B. Lishmanov National Research Tomsk Polytechnic University, Russian Federation, 30 Lenina Avenue, Tomsk 634050, Russia
PE and degree of RV dysfunction may be caused by an unbalance between humoral vasoactive factors. Keywords Right ventricular dysfunction Gated blood pool SPECT Pulmonary embolism
Introduction According to the World health organization, pulmonary embolism (PE) is the third leading cause of death from cardiovascular diseases after acute coronary syndrome and stroke [1, 2]. Pulmonary embolism most often occurs as a complication of a primary thrombotic process in the veins of the lower limbs and, rarely, in the superior vena cava, pelvic veins, and right chambers of the heart [3, 4]. Reduced capacity of the pulmonary arterial bed caused by PE leads to an increase in the vascular resistance, hypertension in the pulmonary circulation, and development of right ventricular (RV) failure. According to the International cooperative pulmonary embolism registry (ICOPER), RV dysfunction is the most significant predictor of in-hospital mortality [1]. Dutch researchers from the group of Rutger Van der Meer [5] believe that the absence of signs of RV dysfunction has a 100 % negative predictive value of PE adverse outcomes within 3-month observation. Therefore, the assessment of RV contractile function plays a significant role in the diagnostic examination algorithm in patients with suspected PE [2]. Along with such conventional methods as two-dimensional echocardiography and MRI [6, 7], an evaluation of RV function can be performed by using the radionuclide gated blood pool single photon emission computer tomography (GBP-SPECT) [8]. This method makes it possible to obtain three-dimensional images of the
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cardiac ventricles and to calculate the basic hemodynamic parameters: ejection fraction, end-systolic and end-diastolic volumes, stroke volume, peak ejection rate, peak filling rate, mean filling rate of one-third of diastole of the left and right ventricles, etc. [9]. At the same time, there is evidence that the degree of RV dysfunction is not always proportional to the volume of PE. The aim of the study was to investigate whether GBPSPECT is useful for RV function evaluation in PE patients and to investigate the possible causes of the dissociation between PE volume and RV dysfunction severity.
Materials and methods Patient population A total of 56 patients were examined in the study. All patients gave their informed consent before their inclusion in the study. The study comprised 37 patients with PE (mean age of 60.3 ± 12.1 years; 21 men and 16 women; NYHA classes I and II) hospitalized in the clinic of the Federal State Budgetary Institution ‘‘Research Institute for Cardiology’’ of Siberian branch under the Russian academy of medical sciences from 2006 to 2010. In PE group, RV systolic pressure measured by echocardiography was 51.88 ± 25.49 mmHg. The diagnosis of PE was verified by means of ventilation– perfusion scintigraphy and/or X-ray multislice computed tomography of pulmonary vessels. The functional state of the right ventricle was assessed by GBP-SPECT within 2 days after establishing the diagnosis of PE. A comparison group comprised 15 patients with NYHA functional class I and II coronary heart disease (mean age of 56.3 ± 8.3 years; 10 men and 5 women). Exclusion criteria were as follows: atrial fibrillation, orthopnea, cardiomyopathy, chronic obstructive pulmonary disease, congenital and valvular heart diseases, myocardial infarction and other pathological conditions (except PE) that can cause RV failure. Lung ventilation/perfusion SPECT The V/Q lung scintigraphy was performed via the SPECT technique using a double-head c-camera equipped with low-energy general purpose collimators (Forte, Philips). Ventilation scans were acquired 4 min after inhalation of 500 MBq 99mTc-diethylenetriaminepentaacetic acid aerosol. For preparation of the ultrafine aerosol, Radioaerosol Administration System (Biodex Venti-ScanTM IV) was used. Perfusion scintigraphy was performed immediately after the acquisition of the ventilation scan with a mean activity of 200 mBq for 99mTc-labeled macroaggregated albumin (99mTc-MAA). All patients remained in a supine position throughout the examination. A 360° SPECT
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acquisition (180° rotation per head was done in 32 steps of 15 s each) of the pulmonary ventilation and perfusion was performed using a 64 9 64 matrix. Reconstruction of coronal and transversal slices was done according to 3DOSEM algorithm. Based on V/Q lung scintigraphy data, we measured the volume of pulmonary embolism as the number of lung segments with normal ventilation and decreased perfusion. Equilibrium radionuclide GBP-SPECT Equilibrium radionuclide GBP-SPECT was performed with erythrocytes, labeled with 99mTc-pyrophosphate. Intravenous infusion of sterile ‘‘Pirfoteh’’ solution (Diamed, Russia) was performed followed by the administration of 1–1.5 mL of sodium 99mTc-pertechnetate with activity of 13–15 MBq/kg 30 min after the Pirfoteh infusion. The gamma-camera detectors were installed at right angles to each other; the revolution orbit of the camera allowed its rotation by 180° around the left side of the patient’s body. The gamma-camera detectors rotated in an automatic step mode with the angular displacement of 2.8° along the noncircular trajectory with the closest approach of the detectors to the surface of the patient’s body. Data were acquired using a 64 9 64 matrix in 128 projections with an exposure of 30 s per frame. A representative cardiac cycle was divided into 16 frames. Processing of the tomo-ventriculograms consisted of acquisition of the axial slices of the study area (from a series of native images) with the subsequent reconstruction of sections of the heart along the short axis (AutoSPECT ? ver: 3.5). Information was analyzed using a specialized program, Quantitative Blood Pool SPECT (QBS) 2.0. The software package allowed calculation of the main parameters of intracardiac hemodynamics based on three algorithms: (a) surface-based (SB) algorithm for determination of the surface area of the ventricles; (b) count-based (CB) algorithm to measure the counts in the chambers of the heart; and (c) volume-based (VB) algorithm for analysis of the number of voxels for each heart chamber during systole and diastole. The following hemodynamic parameters were determined: RV ejection fraction (RVEF), end-diastolic volume (RVEDV), end-systolic volume (RVESV), stroke volume (RVSV), peak emptying rate (RVPER), peak filling rate (RVPFR), and mean filling rate for one-third of diastole (RVMFR/3). All scintigraphic studies were performed using a tomographic two-head gamma-camera (Philips Forte) with high-resolution parallel collimators (Rembrandt) and the window setting of the differential discriminator for photopeak at 140 keV ± 10 %. Radiation exposure to the whole body was 0.006 mSv/MBq.
Ann Nucl Med Table 1 The values of gated blood pool SPECT in patients with PE and in comparison group (M ± SD) 1 PE group RVEF (%)
2 Comparison group
Mann–Whitney (U test) p1–2
42.80 ± 12.53
53.84 ± 8.63
0.001
RVEDV (mL)
201.43 ± 76.98
175.76 ± 27.79
0.98
RVESV (mL)
122.22 ± 72.72
107.25 ± 55.63
0.01
RVSV (mL)
79.17 ± 20.96
93.38 ± 15.66
0.01
RVPER (EDV/s)
-1.86 ± 0.72
-2.78 ± 0.79
0.0003
RVPFR (EDV/s)
1.45 ± 0.66
2.02 ± 0.74
0.007
RVMFR/3 (EDV/s)
0.85 ± 0.45
1.41 ± 0.52
0.0002
PE pulmonary embolism group, RVEF right ventricular ejection fraction, RVEDV right ventricular end-diastolic volume, RVESV right ventricular end-systolic volume, RVSV right ventricular stroke volume, RVPER right ventricular peak ejection rate, RVPFR right ventricular peak filling rate, RVMFR/3 right ventricular mean filling rate in 1/3 of diastole
Biochemical analysis The changes in the humoral regulation of pulmonary vascular tone were evaluated by measuring the levels of stable nitric oxide (NO) metabolites (NO2, NO3), endothelin-1 (ET-1), and 6-keto-prostaglandin F1a (6-keto-PG F1a) in blood plasma. Plasma levels of ET-1 were measured by noncompetitive enzyme immunoassay (BioMedica, Austria). The levels of total NO, nitrites (NO2), and nitrates (NO3) in blood plasma were assessed using R & P System kits (US). The contents of the stable degradation products of nitric monoxide in blood plasma were determined calorimetrically by Griess method. The concentration of 6-keto-PG F1a was determined using ELISA kits (Enzo). Plasma level of prohormone forms of atrial natriuretic peptide (pro-ANP) and stable N-terminal prohormone forms of brain natriuretic peptide (NT-pro-BNP) were measured by enzyme immunoassay (Biomedica, Austria). Statistical analysis Data are presented as arithmetic mean ± standard deviation (M ± SD). Distributions of the variables were evaluated for normality by the Kolmogorov–Smirnov test, which showed that data were not normally distributed. To evaluate the significance of differences between the values in the compared groups, non-parametric Mann–Whitney test was applied. Pearson’s criterion was used to determine if there were nonrandom associations between the variables. Values were considered statistically significant when p was \0.05. The study was approved by the local ethics committee of the authors’ institution (#3 from 10.09.2006).
Results Patients with PE as opposed to the comparison group had significantly lower RVEF and RVSV values. Right
Fig. 1 Relationship between right ventricular systolic pressure and pulmonary embolism volume (according to the number of lung segments with perfusion defects)
ventricular ESV was significantly higher in patients with PE. Patients with PE had decreased values of RVPFR and RVMFR/3 and increased value of RVPER in comparison with patients without PE (Table 1). Average volume of PE, defined by the number of lung segments with perfusion defects, was 4.87 ± 2.86 (minimum 1 lung segment; maximum 11 lung segments). The volume of PE had a weak positive correlation with RVEDV (r = 0.23) and RVESV (r = 0.3) and negative correlation with RVEF (r = 0.29). We found a correlation (Fig. 1) between the number of lung segments with perfusion defects and right ventricular systolic pressure (r = 0.46; p = 0.001). In patients with PE in comparison with the control group plasma levels of pro-ANP (4.51 ± 0.56 nmol/L and 0.82 ± 0.04 nmol/L; p = 0.000005) and NT-proBNP (82.01 ± 20.08 and 0.95 ± 0.21 pmol/liter; p = 0.003) were significantly higher. There were significant correlations between RV systolic pressure and RVEDV (r = 0.4; p = 0.006), RVESV (r = 0.5; p = 0.0004), RVPER (0.57; p = 0.01), RVEF (r = -0.53; p = 0.0001), and RVSV
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Fig. 2 Differences in endothelin-1 (a), total concentration of the stable metabolite of nitric oxide (b), and plasma level of the stable metabolite of prostacyclin, 6-keto-prostaglandin F1a (c), in patients
with pulmonary embolism and in comparison group. fmol femtomole, mmol millimole, ng nanogram, mL milliliter, p statistical significance level
(r = -0.33; p = 0.02). Moreover, RV systolic pressure correlated with pro-ANP (r = 0.59; p = 0.0004) and NTpro-BNP (r = 0.59; p = 0.004) concentrations. In patients with PE, correlation analysis of embolism volume from 3 to 7 lung segments did not reveal statistically significant relationships between the number of lung perfusion defects and RV functional indices (RVEDV, RVESV, and RVEF); correlation coefficients were: r = -0.07; r = 0.02; and r = -0.18, respectively. Thus, in these patients, we discovered a dissociation between RV contractility and PE volume. In the present study, the plasma levels of ET-1, NO, and prostacyclin (prostaglandin I2 [PGI2]) in patients with PE were significantly higher compared with the control group (Fig. 2a–c). The concentrations of stable NO metabolites negatively correlated with the values of RVEF (r = -0.25) and RVSV (r = -0.25). The ET-1 concentration significantly negatively correlated with RVEF (r = -0.22). The concentrations of stable NO metabolites negatively correlated with the values of RVEF (r = -0.25) and RVSV (r = -0.25). In this study, we did not find any correlation between the RV function indices and the levels of stable PGI2 metabolite, 6-keto-PGF-1a.
The level of BNP in the blood is increased in patients with heart disease, chronic obstructive pulmonary hypertension, and chronic right ventricular dysfunction [10]. A meta-analysis of 13 studies [11] suggests that elevated levels of pro-ANP and NT-pro-BNP in patients with pulmonary embolism are associated with an increased risk of early death and the occurrence of in-hospital complications. Importantly, NT-pro-BNP, similarly to its precursor, is characterized by extremely high prognostic sensitivity and negative predictive value in patients with PE, significantly outperforming the cardiac troponins [12]. Correlations between RV systolic pressure and functional indices may be explained by the increased RV afterload. Elevated levels of natriuretic peptides in the blood plasma of surveyed patients confirm the increased afterload on the right heart in patients with PE and indirectly suggest specificity of the radionuclide blood pool SPECT indices in identifying RV dysfunction. Analysis of the relationship between the PE volume and main indicators of RV contractility showed that, in the case of moderate PE volume (from 3 to 7 lung segments), the indices of RV contractility may vary greatly. In the cases of small or large PE volumes, the contractility parameters had normal or reduced values, respectively. This phenomenon may be associated with pulmonary vasoconstriction of the arterioles, which did not undergo embolization [13, 14]. Moreover, it has been clarified that pulmonary vascular vasoconstriction can occur not only immediately after PE, but can also persist during the subacute phase [15]. One of the causes of pulmonary arterial constriction in PE may be the imbalance between humoral vasoactive substances [14, 15] such as vasoconstrictor, ET-1, and vasodilators, NO and prostacyclin. In this regard, our data are consistent with the results of Gutte et al. [21] who discovered that plasma ET-1 levels in patients with PE well correlate with the pressure in the pulmonary artery. Andeas Kjaer’s scientific group from Copenhagen [22] discovered that plasma ET-1 level increases in response to increased RV volume and pressure overload. The studies performed by Lee et al. [16]
Discussion Decreased values of RVEF, RVSV, RVPFR, RVMFR/3, and increased values of ESV, RVPER in comparison with patients without PE, suggest RV filling and ejection slowdown. These data can be explained by the increased RV afterload caused by pulmonary hypertension in patients with PE. Doppler echocardiography showed an increase in RV systolic pressure to 51.88 ± 25.49 mmHg. The scintigraphic findings as well as the changes in RVEF and volume indicators provided evidence of RV dysfunction in patients with PE. Thus, the increase in PE volume caused RV dilation and decreased global contractile function of the right ventricle.
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revealed that, in experimental animal models of PE, the level of ET-1 in plasma was significantly higher than in control groups. Experimental studies of ET-1 gene expression in lung tissue confirm the role of vasoactive substances in pulmonary hypertension pathogenesis in cases of PE. However, it is not well understood whether the high ET-1 plasma level is a cause or consequence of the increased pulmonary arterial pressure [17]. At the same time, the vasoconstrictor effect of ET-1 is limited by extraction of its components by pulmonary tissue and the release of endogenous vasodilators, NO, and prostacyclin (prostaglandin I2 [PGI2]) [18], whose levels in the present study were also significantly higher in PE patients than in the control group. Prostacyclin is an arachidonic acid metabolite with potent vasodilatory effect. The level of PGI2 in the blood plasma is evaluated via measuring the concentration of its stable metabolite, 6-keto-PG F1a. Prostacyclin inhibits the release of serotonin from platelets and also reduces its uptake by lung tissue [14]. Endogenous NO is generated from L-arginine and molecular oxygen by NO-synthase [19]. Nitric oxide is a potent vasodilator with selective effect on the blood vessels of the pulmonary circulation [20]. Moreover, NO can stimulate endothelial prostacyclin release and inhibit the synthesis of thromboxane A2. Both these mechanisms potentiate pulmonary vasodilatation [20]. It should be noted that RV dysfunction in patients with PE worsens the prognosis and also leads to increased mortality compared with patients who have normal RV function [1]. In our opinion, the increased concentration of NO in patients with PE can be considered as a marker of pulmonary hypertension because this increase in NO content results from the inducible and/or endothelial NO-synthase activation triggered by pulmonary hypertension and hypoxia [23, 24]. The absence of any correlation between RV function indices and the levels of stable PGI2 metabolite, 6-keto-PGF-1a, may be explained by the fact that normal levels of this marker can be observed both in patients without acute imbalance of humoral factors of vasoconstriction and in patients with impaired synthesis of PGI2 by pulmonary endothelium [15].
Conclusions The most informative scintigraphic indicators of RV dysfunction in patients with PE were low ejection fraction, stroke volume, peak ejection rate, and mean filling rate of the right ventricle. These findings support our hypothesis that the severity of RV dysfunction is not always proportional to the volume of PE especially in case of moderate embolism. One of the reasons for this dissociation may be vasoconstriction of the pulmonary arterioles, which did not
undergo embolization. The correlation noted between the scintigraphic indices of RV contractile dysfunction and the levels of vasoactive substances contributes to the validation of GBP-SPECT for the identification of RV dysfunction in patients with PE. Acknowledgments ence Foundation.
This work was supported by the Russian Sci-
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ORIGINAL ARTICLE
The usefulness of gated blood pool scintigraphy for right ventricular function evaluation in pulmonary embolism patients Konstantin V. Zavadovsky • Nikolay G. Krivonogov Yuri B. Lishmanov
•
Received: 25 November 2013 / Accepted: 2 May 2014 Ó The Japanese Society of Nuclear Medicine 2014
Abstract Objective According to the international registry ICOPER, right ventricular (RV) dysfunction is the most significant predictor of mortality in patients with pulmonary embolism (PE). Aim To identify the most informative indicators of gated blood pool single photon emission computer tomography (GBP-SPECT) for evaluation of RV function in patients with PE. Methods A total of 52 patients were included in the study. The main group (n = 37) comprised patients with PE, and the comparison group (n = 15) patients suffering from coronary heart disease (NYHA class I-II). All patients received GBP-SPECT, and assessment of plasma levels of endothelin1, stable nitric oxide (NO) metabolites, and 6-keto-PG F1a. Results In patients with PE, RV end-systolic volume, stroke volume, ejection fraction, peak ejection rate, peak filling rate, and mean filling rate were significantly lower in comparison with patients without PE. In patients with PE, the levels of endothelin-1, 6-keto-PG F1a, and stable NO metabolites were increased in comparison with patients without PE. Conclusions GBP-SPECT facilitates verification of RV dysfunction in patients without massive PE or severe pulmonary hypertension. Dissociation between the volume of
K. V. Zavadovsky (&) N. G. Krivonogov Y. B. Lishmanov Nuclear Medicine Department, Federal State Budgetary Institution ‘‘Research Institute for Cardiology’’ of Siberian Branch under the Russian Academy of Medical Science, 111a Kievskaya Str., Tomsk 634012, Russia e-mail: [email protected] Y. B. Lishmanov National Research Tomsk Polytechnic University, Russian Federation, 30 Lenina Avenue, Tomsk 634050, Russia
PE and degree of RV dysfunction may be caused by an unbalance between humoral vasoactive factors. Keywords Right ventricular dysfunction Gated blood pool SPECT Pulmonary embolism
Introduction According to the World health organization, pulmonary embolism (PE) is the third leading cause of death from cardiovascular diseases after acute coronary syndrome and stroke [1, 2]. Pulmonary embolism most often occurs as a complication of a primary thrombotic process in the veins of the lower limbs and, rarely, in the superior vena cava, pelvic veins, and right chambers of the heart [3, 4]. Reduced capacity of the pulmonary arterial bed caused by PE leads to an increase in the vascular resistance, hypertension in the pulmonary circulation, and development of right ventricular (RV) failure. According to the International cooperative pulmonary embolism registry (ICOPER), RV dysfunction is the most significant predictor of in-hospital mortality [1]. Dutch researchers from the group of Rutger Van der Meer [5] believe that the absence of signs of RV dysfunction has a 100 % negative predictive value of PE adverse outcomes within 3-month observation. Therefore, the assessment of RV contractile function plays a significant role in the diagnostic examination algorithm in patients with suspected PE [2]. Along with such conventional methods as two-dimensional echocardiography and MRI [6, 7], an evaluation of RV function can be performed by using the radionuclide gated blood pool single photon emission computer tomography (GBP-SPECT) [8]. This method makes it possible to obtain three-dimensional images of the
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cardiac ventricles and to calculate the basic hemodynamic parameters: ejection fraction, end-systolic and end-diastolic volumes, stroke volume, peak ejection rate, peak filling rate, mean filling rate of one-third of diastole of the left and right ventricles, etc. [9]. At the same time, there is evidence that the degree of RV dysfunction is not always proportional to the volume of PE. The aim of the study was to investigate whether GBPSPECT is useful for RV function evaluation in PE patients and to investigate the possible causes of the dissociation between PE volume and RV dysfunction severity.
Materials and methods Patient population A total of 56 patients were examined in the study. All patients gave their informed consent before their inclusion in the study. The study comprised 37 patients with PE (mean age of 60.3 ± 12.1 years; 21 men and 16 women; NYHA classes I and II) hospitalized in the clinic of the Federal State Budgetary Institution ‘‘Research Institute for Cardiology’’ of Siberian branch under the Russian academy of medical sciences from 2006 to 2010. In PE group, RV systolic pressure measured by echocardiography was 51.88 ± 25.49 mmHg. The diagnosis of PE was verified by means of ventilation– perfusion scintigraphy and/or X-ray multislice computed tomography of pulmonary vessels. The functional state of the right ventricle was assessed by GBP-SPECT within 2 days after establishing the diagnosis of PE. A comparison group comprised 15 patients with NYHA functional class I and II coronary heart disease (mean age of 56.3 ± 8.3 years; 10 men and 5 women). Exclusion criteria were as follows: atrial fibrillation, orthopnea, cardiomyopathy, chronic obstructive pulmonary disease, congenital and valvular heart diseases, myocardial infarction and other pathological conditions (except PE) that can cause RV failure. Lung ventilation/perfusion SPECT The V/Q lung scintigraphy was performed via the SPECT technique using a double-head c-camera equipped with low-energy general purpose collimators (Forte, Philips). Ventilation scans were acquired 4 min after inhalation of 500 MBq 99mTc-diethylenetriaminepentaacetic acid aerosol. For preparation of the ultrafine aerosol, Radioaerosol Administration System (Biodex Venti-ScanTM IV) was used. Perfusion scintigraphy was performed immediately after the acquisition of the ventilation scan with a mean activity of 200 mBq for 99mTc-labeled macroaggregated albumin (99mTc-MAA). All patients remained in a supine position throughout the examination. A 360° SPECT
123
acquisition (180° rotation per head was done in 32 steps of 15 s each) of the pulmonary ventilation and perfusion was performed using a 64 9 64 matrix. Reconstruction of coronal and transversal slices was done according to 3DOSEM algorithm. Based on V/Q lung scintigraphy data, we measured the volume of pulmonary embolism as the number of lung segments with normal ventilation and decreased perfusion. Equilibrium radionuclide GBP-SPECT Equilibrium radionuclide GBP-SPECT was performed with erythrocytes, labeled with 99mTc-pyrophosphate. Intravenous infusion of sterile ‘‘Pirfoteh’’ solution (Diamed, Russia) was performed followed by the administration of 1–1.5 mL of sodium 99mTc-pertechnetate with activity of 13–15 MBq/kg 30 min after the Pirfoteh infusion. The gamma-camera detectors were installed at right angles to each other; the revolution orbit of the camera allowed its rotation by 180° around the left side of the patient’s body. The gamma-camera detectors rotated in an automatic step mode with the angular displacement of 2.8° along the noncircular trajectory with the closest approach of the detectors to the surface of the patient’s body. Data were acquired using a 64 9 64 matrix in 128 projections with an exposure of 30 s per frame. A representative cardiac cycle was divided into 16 frames. Processing of the tomo-ventriculograms consisted of acquisition of the axial slices of the study area (from a series of native images) with the subsequent reconstruction of sections of the heart along the short axis (AutoSPECT ? ver: 3.5). Information was analyzed using a specialized program, Quantitative Blood Pool SPECT (QBS) 2.0. The software package allowed calculation of the main parameters of intracardiac hemodynamics based on three algorithms: (a) surface-based (SB) algorithm for determination of the surface area of the ventricles; (b) count-based (CB) algorithm to measure the counts in the chambers of the heart; and (c) volume-based (VB) algorithm for analysis of the number of voxels for each heart chamber during systole and diastole. The following hemodynamic parameters were determined: RV ejection fraction (RVEF), end-diastolic volume (RVEDV), end-systolic volume (RVESV), stroke volume (RVSV), peak emptying rate (RVPER), peak filling rate (RVPFR), and mean filling rate for one-third of diastole (RVMFR/3). All scintigraphic studies were performed using a tomographic two-head gamma-camera (Philips Forte) with high-resolution parallel collimators (Rembrandt) and the window setting of the differential discriminator for photopeak at 140 keV ± 10 %. Radiation exposure to the whole body was 0.006 mSv/MBq.
Ann Nucl Med Table 1 The values of gated blood pool SPECT in patients with PE and in comparison group (M ± SD) 1 PE group RVEF (%)
2 Comparison group
Mann–Whitney (U test) p1–2
42.80 ± 12.53
53.84 ± 8.63
0.001
RVEDV (mL)
201.43 ± 76.98
175.76 ± 27.79
0.98
RVESV (mL)
122.22 ± 72.72
107.25 ± 55.63
0.01
RVSV (mL)
79.17 ± 20.96
93.38 ± 15.66
0.01
RVPER (EDV/s)
-1.86 ± 0.72
-2.78 ± 0.79
0.0003
RVPFR (EDV/s)
1.45 ± 0.66
2.02 ± 0.74
0.007
RVMFR/3 (EDV/s)
0.85 ± 0.45
1.41 ± 0.52
0.0002
PE pulmonary embolism group, RVEF right ventricular ejection fraction, RVEDV right ventricular end-diastolic volume, RVESV right ventricular end-systolic volume, RVSV right ventricular stroke volume, RVPER right ventricular peak ejection rate, RVPFR right ventricular peak filling rate, RVMFR/3 right ventricular mean filling rate in 1/3 of diastole
Biochemical analysis The changes in the humoral regulation of pulmonary vascular tone were evaluated by measuring the levels of stable nitric oxide (NO) metabolites (NO2, NO3), endothelin-1 (ET-1), and 6-keto-prostaglandin F1a (6-keto-PG F1a) in blood plasma. Plasma levels of ET-1 were measured by noncompetitive enzyme immunoassay (BioMedica, Austria). The levels of total NO, nitrites (NO2), and nitrates (NO3) in blood plasma were assessed using R & P System kits (US). The contents of the stable degradation products of nitric monoxide in blood plasma were determined calorimetrically by Griess method. The concentration of 6-keto-PG F1a was determined using ELISA kits (Enzo). Plasma level of prohormone forms of atrial natriuretic peptide (pro-ANP) and stable N-terminal prohormone forms of brain natriuretic peptide (NT-pro-BNP) were measured by enzyme immunoassay (Biomedica, Austria). Statistical analysis Data are presented as arithmetic mean ± standard deviation (M ± SD). Distributions of the variables were evaluated for normality by the Kolmogorov–Smirnov test, which showed that data were not normally distributed. To evaluate the significance of differences between the values in the compared groups, non-parametric Mann–Whitney test was applied. Pearson’s criterion was used to determine if there were nonrandom associations between the variables. Values were considered statistically significant when p was \0.05. The study was approved by the local ethics committee of the authors’ institution (#3 from 10.09.2006).
Results Patients with PE as opposed to the comparison group had significantly lower RVEF and RVSV values. Right
Fig. 1 Relationship between right ventricular systolic pressure and pulmonary embolism volume (according to the number of lung segments with perfusion defects)
ventricular ESV was significantly higher in patients with PE. Patients with PE had decreased values of RVPFR and RVMFR/3 and increased value of RVPER in comparison with patients without PE (Table 1). Average volume of PE, defined by the number of lung segments with perfusion defects, was 4.87 ± 2.86 (minimum 1 lung segment; maximum 11 lung segments). The volume of PE had a weak positive correlation with RVEDV (r = 0.23) and RVESV (r = 0.3) and negative correlation with RVEF (r = 0.29). We found a correlation (Fig. 1) between the number of lung segments with perfusion defects and right ventricular systolic pressure (r = 0.46; p = 0.001). In patients with PE in comparison with the control group plasma levels of pro-ANP (4.51 ± 0.56 nmol/L and 0.82 ± 0.04 nmol/L; p = 0.000005) and NT-proBNP (82.01 ± 20.08 and 0.95 ± 0.21 pmol/liter; p = 0.003) were significantly higher. There were significant correlations between RV systolic pressure and RVEDV (r = 0.4; p = 0.006), RVESV (r = 0.5; p = 0.0004), RVPER (0.57; p = 0.01), RVEF (r = -0.53; p = 0.0001), and RVSV
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Fig. 2 Differences in endothelin-1 (a), total concentration of the stable metabolite of nitric oxide (b), and plasma level of the stable metabolite of prostacyclin, 6-keto-prostaglandin F1a (c), in patients
with pulmonary embolism and in comparison group. fmol femtomole, mmol millimole, ng nanogram, mL milliliter, p statistical significance level
(r = -0.33; p = 0.02). Moreover, RV systolic pressure correlated with pro-ANP (r = 0.59; p = 0.0004) and NTpro-BNP (r = 0.59; p = 0.004) concentrations. In patients with PE, correlation analysis of embolism volume from 3 to 7 lung segments did not reveal statistically significant relationships between the number of lung perfusion defects and RV functional indices (RVEDV, RVESV, and RVEF); correlation coefficients were: r = -0.07; r = 0.02; and r = -0.18, respectively. Thus, in these patients, we discovered a dissociation between RV contractility and PE volume. In the present study, the plasma levels of ET-1, NO, and prostacyclin (prostaglandin I2 [PGI2]) in patients with PE were significantly higher compared with the control group (Fig. 2a–c). The concentrations of stable NO metabolites negatively correlated with the values of RVEF (r = -0.25) and RVSV (r = -0.25). The ET-1 concentration significantly negatively correlated with RVEF (r = -0.22). The concentrations of stable NO metabolites negatively correlated with the values of RVEF (r = -0.25) and RVSV (r = -0.25). In this study, we did not find any correlation between the RV function indices and the levels of stable PGI2 metabolite, 6-keto-PGF-1a.
The level of BNP in the blood is increased in patients with heart disease, chronic obstructive pulmonary hypertension, and chronic right ventricular dysfunction [10]. A meta-analysis of 13 studies [11] suggests that elevated levels of pro-ANP and NT-pro-BNP in patients with pulmonary embolism are associated with an increased risk of early death and the occurrence of in-hospital complications. Importantly, NT-pro-BNP, similarly to its precursor, is characterized by extremely high prognostic sensitivity and negative predictive value in patients with PE, significantly outperforming the cardiac troponins [12]. Correlations between RV systolic pressure and functional indices may be explained by the increased RV afterload. Elevated levels of natriuretic peptides in the blood plasma of surveyed patients confirm the increased afterload on the right heart in patients with PE and indirectly suggest specificity of the radionuclide blood pool SPECT indices in identifying RV dysfunction. Analysis of the relationship between the PE volume and main indicators of RV contractility showed that, in the case of moderate PE volume (from 3 to 7 lung segments), the indices of RV contractility may vary greatly. In the cases of small or large PE volumes, the contractility parameters had normal or reduced values, respectively. This phenomenon may be associated with pulmonary vasoconstriction of the arterioles, which did not undergo embolization [13, 14]. Moreover, it has been clarified that pulmonary vascular vasoconstriction can occur not only immediately after PE, but can also persist during the subacute phase [15]. One of the causes of pulmonary arterial constriction in PE may be the imbalance between humoral vasoactive substances [14, 15] such as vasoconstrictor, ET-1, and vasodilators, NO and prostacyclin. In this regard, our data are consistent with the results of Gutte et al. [21] who discovered that plasma ET-1 levels in patients with PE well correlate with the pressure in the pulmonary artery. Andeas Kjaer’s scientific group from Copenhagen [22] discovered that plasma ET-1 level increases in response to increased RV volume and pressure overload. The studies performed by Lee et al. [16]
Discussion Decreased values of RVEF, RVSV, RVPFR, RVMFR/3, and increased values of ESV, RVPER in comparison with patients without PE, suggest RV filling and ejection slowdown. These data can be explained by the increased RV afterload caused by pulmonary hypertension in patients with PE. Doppler echocardiography showed an increase in RV systolic pressure to 51.88 ± 25.49 mmHg. The scintigraphic findings as well as the changes in RVEF and volume indicators provided evidence of RV dysfunction in patients with PE. Thus, the increase in PE volume caused RV dilation and decreased global contractile function of the right ventricle.
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revealed that, in experimental animal models of PE, the level of ET-1 in plasma was significantly higher than in control groups. Experimental studies of ET-1 gene expression in lung tissue confirm the role of vasoactive substances in pulmonary hypertension pathogenesis in cases of PE. However, it is not well understood whether the high ET-1 plasma level is a cause or consequence of the increased pulmonary arterial pressure [17]. At the same time, the vasoconstrictor effect of ET-1 is limited by extraction of its components by pulmonary tissue and the release of endogenous vasodilators, NO, and prostacyclin (prostaglandin I2 [PGI2]) [18], whose levels in the present study were also significantly higher in PE patients than in the control group. Prostacyclin is an arachidonic acid metabolite with potent vasodilatory effect. The level of PGI2 in the blood plasma is evaluated via measuring the concentration of its stable metabolite, 6-keto-PG F1a. Prostacyclin inhibits the release of serotonin from platelets and also reduces its uptake by lung tissue [14]. Endogenous NO is generated from L-arginine and molecular oxygen by NO-synthase [19]. Nitric oxide is a potent vasodilator with selective effect on the blood vessels of the pulmonary circulation [20]. Moreover, NO can stimulate endothelial prostacyclin release and inhibit the synthesis of thromboxane A2. Both these mechanisms potentiate pulmonary vasodilatation [20]. It should be noted that RV dysfunction in patients with PE worsens the prognosis and also leads to increased mortality compared with patients who have normal RV function [1]. In our opinion, the increased concentration of NO in patients with PE can be considered as a marker of pulmonary hypertension because this increase in NO content results from the inducible and/or endothelial NO-synthase activation triggered by pulmonary hypertension and hypoxia [23, 24]. The absence of any correlation between RV function indices and the levels of stable PGI2 metabolite, 6-keto-PGF-1a, may be explained by the fact that normal levels of this marker can be observed both in patients without acute imbalance of humoral factors of vasoconstriction and in patients with impaired synthesis of PGI2 by pulmonary endothelium [15].
Conclusions The most informative scintigraphic indicators of RV dysfunction in patients with PE were low ejection fraction, stroke volume, peak ejection rate, and mean filling rate of the right ventricle. These findings support our hypothesis that the severity of RV dysfunction is not always proportional to the volume of PE especially in case of moderate embolism. One of the reasons for this dissociation may be vasoconstriction of the pulmonary arterioles, which did not
undergo embolization. The correlation noted between the scintigraphic indices of RV contractile dysfunction and the levels of vasoactive substances contributes to the validation of GBP-SPECT for the identification of RV dysfunction in patients with PE. Acknowledgments ence Foundation.
This work was supported by the Russian Sci-
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