Pediatric Cardiology

, Volume 27, Issue 4, pp 440–446

Right Ventricular and Pulmonary Function in Sickle Cell Disease Patients with Pulmonary Hypertension

Authors

    • Department of CardiologyFaculty of Medicine, Mustafa Kemal University
  • Fatih Yalçin
    • Department of CardiologyFaculty of Medicine, Mustafa Kemal University
  • Cenk Babayiğit
    • Department of Respiratory DiseasesFaculty of Medicine, Mustafa Kemal University
  • Ergün Seyfeli
    • Department of CardiologyFaculty of Medicine, Mustafa Kemal University
  • Tunzale Seydaliyeva
    • Department of CardiologyFaculty of Medicine, Mustafa Kemal University
  • Edip Gali
    • Department of PaediatricsAntakya State Hospital
Article

DOI: 10.1007/s00246-006-1257-8

Cite this article as:
Akgül, F., Yalçin, F., Babayiğit, C. et al. Pediatr Cardiol (2006) 27: 440. doi:10.1007/s00246-006-1257-8

Abstract

The effects of sickle cell disease (SCD) on right ventricular (RV) and pulmonary function in SCD patients with pulmonary hypertension is not well-known. The aim of this study was to investigate RV and pulmonary functions in patients suffering from SCD with or without pulmonary hypertension using color tissue Doppler imaging and spirometry. We evaluated 48 asymptomatic patients with SCD. All patients underwent echocardiography with tissue Doppler imaging and pulmonary function test. Patients were divided into two groups: Group 1 consisted of 27 patients (age, 18.1 ± 7.1 years) with normal pulmonary artery pressure, and group 2 consisted of 21 patients (age, 21.4 ± 7.4 years) with pulmonary hypertension. Both groups were compared with a sex- and age-matched control group including 24 normal healthy subjects (age, 19.8 ± 9.2 years). Tricuspid lateral annular systolic (Sm) and early diastolic velocity (Em) were higher in group 1 than group 2 and the control group (p < 0.05). Tricuspid lateral annular late diastolic velocities (Am), isovolumetric contraction time, and myocardial performance index (MPI) were higher and the Em/Am ratio was lower in group 2 than group 1 and the control group (p < 0.05). However, no differences were found in the tricuspid lateral annular Em deceleration time, ejection time, and isovolumetric relaxation time between group 1, group 2, and the control group. Tricuspid lateral annular Sm and Em were similar in group 2 and the control group. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and the diffusion capacity of the lung for carbon monoxide were decreased in both groups of patients compared to the control group (p < 0.05). However, there was no difference in respiratory rate, FEV1/FVC ratio, peak expiratory flow, and total lung capacity between group 1, group 2, and the control group. There were no differences in any indices of lung function between the two groups of patients. MPI is useful index to evaluate RV function in patients with SCD. RV diastolic function was disturbed in only SCD patients with pulmonary hypertension. On the other hand, the restrictive pattern of pulmonary function abnormalities had developed in both groups of patients.

Keywords

Sickle cellAnemiaPulmonary hypertensionRight ventricular functionPulmonaryEchocardiographyTissue Doppler imaging

Introduction

Sickle cell disease (SCD) is an inherited hemoglobin disorder of childhood [6]. Lung involvement is frequent in adult patients with SCD [33]. It is known that lung disease may affect cardiac function and contribute to the development of pulmonary hypertension [8, 21]. There are many echocardiography studies reporting the varying degree of left ventricular (LV) systolic and diastolic functional abnormalities in patients with SCD [1, 17, 30, 32]. However, studies related to right ventricular (RV) and lung functions in these patients are scarce [4, 18, 22, 38]. Higher morbidity and mortality rates were reported in SCD patients with RV dysfunction or lung disease [8, 15]. Therefore, early recognition of cardiopulmonary abnormalities in these patients is very important for modifying their therapy and improving morbidity and mortality. Doppler tissue imaging (DTI) is a new technique that assesses myocardial velocities during the cardiac cycle [11]. The DTI-derived myocardial performance index (MPI), defined as the sum of the isovolumetric relaxation time (IVRT) and isovolumetric contraction time (IVCT) divided by ejection time (ET), was reported to reflect combined systolic and diastolic cardiac function [14, 35]. Since MPI does not require dimensional measurements and is independent of heart rate, age, sex, and weight, it may be a good tool for measuring RV function in young patients with anemia, where the complex geometrical shape has limited accurate assessment of function by noninvasive means [15, 28, 36]. We evaluated LV and RV function in SCD patients with or without pulmonary hypertension by MPI calculation obtained with DTI. We also investigated the pulmonary function tests of these patients.

Materials and Methods

A total of 48 patients with SCD admitted to the Hematology Clinic of Antakya State Hospital for routine control were included in the study. Each patient was stable and not suffering from a sickle cell crisis and was not experiencing an episode of acute chest syndrome in the preceding 6 weeks. Twenty-four age- and sex-matched normal subjects served as controls. All patients and controls underwent hematological tests, echocardiography, and pulmonary function tests. The study was approved by the institutional review board of Mustafa Kemal University. Informed consent was obtained from the subjects, the parent(s), or both before the study.

Transthoracic echocardiography was performed with a GE Vingmed Vivid 7 scanner (GE Vingmed Ultrasound, Horten, Norway). All measurements were performed by the same cardiologist on frozen images from three to five cardiac cycles using the software package of the ultrasound system. All measurements were taken according to the American Society of Echocardiographists’ recommendations [29]. DTI was performed using the apical four-chamber view. Myocardial velocity profiles of the lateral mitral annulus were obtained by placing a 2-mm sample volume at the junction of the mitral valve annulus and lateral myocardial wall. Myocardial velocities of the lateral tricuspid annulus were obtained similarly by placing the sample volume at the junction of the tricuspid annulus and RV free wall. Peak mitral annular systolic (Sm), early diastolic (Em), and late diastolic velocities (Am) were measured and the ratio of early to late diastolic mitral annular velocities (Em/Am) was calculated. Similar measurements were made for the tricuspid annulus, and the tricuspid annular Em/Am ratio was calculated. Mitral annular Em wave deceleration time, IVRT, IVCT, and Sm wave duration (ejection time) were measured. Then, DTI-derived LV MPI was calculated according to previously validated formula in Figure 1 [14]. Similar measurements were made for the tricuspid annulus and RV DTI-derived MPI was calculated. Tricuspid valve continuous-wave Doppler tracing of the tricuspid regurgitation flow was obtained to measure the pulmonary artery systolic pressure (PPA,syst). Pulmonary hypertension was diagnosed if PPA,syst exceeded the upper limits of normal for age- and body mass index-adjusted reference ranges [23].
https://static-content.springer.com/image/art%3A10.1007%2Fs00246-006-1257-8/MediaObjects/246_2006_1257_f1.jpg
Fig. 1

Time intervals of the myocardial performance index (MPI) derived with pulsed wave tissue Doppler echocardiography. MPI was calculated as the sum of isovolumic contraction time (IVCT) and isovolumic relaxation time (IVRT) divided by ejection time (ET)

Transcutaneous arterial oxygen saturation (SaO2%) was determined by pulse oxymeter (Planar PL 1500, Beaverton, USA) in the sitting position with the oxygen saturation sensor on the right index finger. Pulmonary function was measured in the sitting position using spirometry (Sensormedics Vmax, California, USA). Each patient completed at least three acceptable trials in accordance with American Thoracic Society guidelines [2]. The measured variables included forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), the ratio of FEV1/FVC, peak expiratory flow (PEF), total lung capacity, and diffusion capacity of lung for carbon monoxide (DLCO). The pulmonary function results were expressed as percentages of predicted normal values [16].

Patients were divided into two groups based on the presence of pulmonary hypertension. Group 1 consisted of 27 patients without pulmonary hypertension, and group 2 consisted of 21 patients with pulmonary hypertension.

Categorical variables were presented numerically, and for statistical analysis the chi-square test was used. All clinical, echocardiographic, and pulmonary function continuous variables are presented as mean ± SD. The values for group 1, group 2, and the control group were compared using the Bonferroni test. A p value < 0.05 was considered significant. All statistical analyses were performed using commercially available SPSS version 10.0 software.

Results

Clinical Findings

The clinical and demographic features of both groups of patients and the control group are shown in Table 1. SCD patients in group 1 (patients without pulmonary hypertension), group 2 (patients with pulmonary hypertension), and control subjects were well matched for age, sex, and body mass index. Systolic and diastolic blood pressures of both groups were similar to those of the control group. However, resting heart rate was significantly higher in both groups of patients compared to controls (p < 0.05). Although patients with pulmonary hypertension had lower systolic blood pressure than those without pulmonary hypertension (p < 0.05), acute chest syndrome episodes, diastolic blood pressure, resting heart rate, and hematocrit level were similar in both groups of patients.
Table 1

Clinical and demographic data (mean ± SD)

 

Controls

Group 1

p valuea

Group 2

p valuea

Age (years)

19.8 ± 9.2

18.1 ± 7.1

0.5

21.4 ± 7.4

0.6

Men/women

14:10

15:12

0.8

13:8

0.8

Prior acute chest syndrome (%)

28

34

Body mass index (kg/m2)

19.4 ± 3.9

18.1 ± 2.6

0.2

20.0 ± 2.5

0.5

SBP (mmHg)

103.4 ± 8.6

106.8 ± 9.3

0.8

99.3 ± 10.1

0.7

DBF (mmHg)

63.7 ± 9.0

63.5 ± 9.8

0.8

64.0 ± 10.8

0.9

Heart rate (bpm)

77.4 ± 13.1

86.8 ± 17.8

0.01

85.9 ± 11.9

0.03

Hemoglobin (g/dl)

13.8 ± 1.1

9.1 ± 1.1

0.000

10.6 ± 2.6

0.000

Haematocrit (%)

38.7 ± 2.1

25.1 ± 2.3

0.000

26.7 ± 4.2

0.000

aVersus controls

SBD, systolic blood pressure; DBP, Diastolic blood pressure

Echocardiography

Both groups of patients had larger left artrial diameter, RV diastolic dimension (RVDD), LV end diastolic dimension (LVEDD), LV end systolic dimension (LVESD), and LV wall thickness than the control group (Table 2). However, LV fractional shortening and ejection fraction were similar in both groups of patients and the control group. Patients in group 2 had larger RVDD, LVEDD, and LV wall thickness compared to patients in group 1 (p < 0.05). However, left atrial diameter and LVESD were similar in both groups of the patients.
Table 2

Comparison of echocardiographic parameters of patients and controls (mean ± SD)

 

Group 1

Group 2

Controls

Left atrium (cm)

3.3 ± 0.4*

3.5 ± 0.7†

2.9 ± 0.4

LVEDD (cm)

4.7 ± 0.6*

5.3 ± 0.6‡

4.3 ± 0.5

LVESD (cm)

2.9 ± 0.5†

3.1 ± 0.5†

2.5 ± 0.4

RVDD (cm)

2.3 ± 0.4*

2.6 ± 0.5*

1.9 ± 0.6

Septum (cm)

0.74 ± 0.2*

0.88 ± 0.3‡

0.64 ± 0.1

LV fractional shortening (%)

38.3 ± 4.6

41.3 ± 4.4

42.0 ± 8.2

LV ejection fraction (%)

71.5 ± 4.3

71.7 ± 4.6

72.6 ± 3. 8

PPA,syst (mmHg)

18.4 ± 5.4

35.8 ± 4.6‡

18.8 ± 4.4

LV, left ventricular; LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter; RVDD, right ventricular diameter at diastole; PPA,syst, pulmonary artery systolic pressure

*p ≤ 0.05 vs controls

p ≤ 0.01 vs controls

p ≤ 0.001 vs controls

The mitral lateral annular Sm, Em, Am, the Em/Am ratio, Em deceleration time, IVRT, ejection time, and MPI were statistically similar among groups 1 and 2 and the control group (Table 3). However, IVCT was prolonged in group 2 compared to group 1 and the control group (p < 0.05)
Table 3

Comparisons of mitral annular tissue Doppler velocities among patients and controls (mean ± SD)

 

Group 1

Group 2

Controls

Sm (cm/sec)

8.8 ± 2.3

9.1 ± 2.2

9.1 ± 2.0

Em (cm/sec)

15.4 ± 4.9

17.2 ± 3.1

15.6 ± 2.5

Am (cm/sec)

6.0 ± 1.7

5.4 ± 1.5

5.9 ± 1.8

Em/Am

2.63 ± 1.2

3.07 ± 1.0

2.78 ± 1.0

Em deceleration time (msec)

138.0 ± 12.0

146.8 ± 16.2

144.6 ± 15.9

IVRT (msec)

56.1 ± 14.8

49.0 ± 13.0

54.4 ± 6.2

IVCT (msec)

68.9 ± 18.4

79 .4 ± 12.6*

68.5 ± 17.6

Ejection time (msec)

280.9 ± 20.1

286.0 ± 23.5

279.4 ± 20.2

MPI

0.45 ± 0.09

0.44 ± 0.06

0.43 ± 0.06

Sm, peak mitral annular systolic velocity; Em, peak early diastolic mitral annular velocity; Am, peak late diastolic mitral annular velocity; IVRT, isovolumetric relaxation time; IVCT, isovolumetric contraction time; MPI myocardial performance index

* p ≤ 0.05 vs controls

In the right ventricle, DTI assessement at the tricuspid annulus showed an increase in Sm and Em in group 1 compared to the control group (p < 0.05) (Table 4). However, tricuspid lateral annular Am, the Em/Am ratio, Em deceleration time, IVRT, IVCT, ejection time, and MPI were similar for group 1 and the control group. In patients with pulmonary hypertension (group 2), tricuspid lateral annular DTI analysis showed increased Am and IVCT with decreased Em/Am ratio compared to the control group (p < 0.05), indicating impaired RV diastolic function. However, there was no difference in tricuspid lateral annular Sm, Em, Em deceleration time, IVRT, and ejection time between group 2 and the control group. The MPI of the right ventricle was prolonged in group 2 compared to the control group (p < 0.05), indicating impaired RV function. Among SCD patients, in patients with pulmonary hypertension tricuspid lateral annular Sm, Em, and the Em/Am ratio were lower than in those patients without pulmonary hypertension (p < 0.05). However, Am was increased and IVCT and MPI were prolonged in patients with pulmonary hypertension compared to patients without pulmonary hypertension (p < 0.05). The Em deceleration time, IVRT, and ejection time were similar in both groups of patients.
Table 4

Comparisons of tricuspid annular tissue Doppler velocities among patients and controls (mean ± SD)

 

Group 1

Group 2

Controls

Sm (cm/sec)

15.3 ± 3.6†

12.4 ± 2.3

11.9 ± 1.4

Em (cm/sec)

16.8 ± 3.3*

13.4 ± 3.4

14.1 ± 3.0

Am (cm/sec)

10.7 ± 2.1

13.9 ± 5.4*

11.3 ± 5.1

Em/Am

1.54 ± 0.3

1.02 ± 0.4*

1.31 ± 0.5

Em deceleration time (msec)

144.7 ± 28.6

137.4 ± 20.1

128.3 ± 15.2

IVRT (msec)

60.9 ± 12.1

59.3 ± 21.2

64.1 ± 20.4

IVCT (msec)

62.4 ± 16.0

74.3 ± 13.9†

58.1 ± 6.9

Ejection time (msec)

287.6 ± 34.7

278.8 ± 29.8

281.0 ± 13.6

MPI

0.42 ± 0.09

0.48 ± 0.07*

0.43 ± 0.08

Sm, peak tricuspid annular systolic velocity; Em, peak early diastolic tricuspid annular velocity; Am, peak late diastolic tricuspid annular velocity; IVRT, isovolumetric relaxation time; IVCT, isovolumetric contraction time; MPI,myocardial performance index

* p ≤ 0.05 vs controls

p ≤ 0.01 vs controls

Pulmonary Function

Transcutaneous oxygen saturation was significantly lower in group 2 than in the control group (p < 0.05) (Table 5). Although oxygen saturation was lower in group 1 than in the control group, the difference was not statistically significant FEV1, FVC, and DLCO were decreased in both groups of patients compared to the control group. However, there was no difference in respiratory rate, FEV1/FVC ratio, PEF, and total lung capacity between the three groups. There were no differences in the various indexes of lung function between the two groups of patients.
Table 5

Indices of pulmonary function among patients and controls (mean ± SD)

 

Group 1

Group 2

Controls

Respiratory rate (breaths/min)

20 ± 3

22 ± 2

17 ± 2

Oxygen saturation (%)

94 ± 1

92 ± 1*

97 ± 1

FEV1 (% predicted)

82 ± 12*

77 ± 13†

95 ± 14

FVC (% predicted)

83 ± 12*

84 ± 12*

93 ± 13

FEV1/FVC (% predicted)

98 ± 7.2

93 ± 7.3

101 ± 8.4

PEF (% predicted)

79 ± 18

73 ± 17

78 ± 15

Total lung capacity (% predicted)

96 ± 10

93 ± 11

98 ± 9.4

DLCO (% predicted)

87 ± 16*

84 ± 15†

102 ± 19

FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second; PEF, peak expiratory flow; DLCO, diffusion capacity of lung for carbon monoxide

* p ≤ 0.05 vs controls

p ≤ 0.01 vs controls

Discussion

Pulmonary hypertension is a frequent complication of SCD [1, 3, 12]. Elevated pulmonary arterial pressure is an important marker of disease severity and cause of morbidity in patients with SCD [8, 15]. We found that 40% of young adults with SCD had pulmonary hypertension, most had mild pulmonary hypertension. These results were consistent with other published studies [1, 3, 12].

Echocardiography

Previous studies reported enlargement of the left and right heart chambers and normal LV systolic function in patients with SCD [17, 32]. In accordance with previous studies, we observed that left and right heart chambers were dilated and LV function was preserved in patients with SCD (with and without pulmonary hypertension). The increase in left and right heart chambers observed in the groups of SCD patients can probably be explained by the presence of chronic anemia. Some authors suggested that chronic anemia could enhance LV performance by volume overload and mask the detection of impaired LV systolic function [13].

Tisssue Doppler Echocardiography

Left Ventricle

There are only a few reports in the literature related to LV diastolic function in SCD patients, and these reports are somewhat conflicting [17, 32, 37]. Different findings, including a restrictive or constrictive pattern of transmitral flow, have been reported. In contrast, no alteration in LV compliance was reported in the early stage of the disease by Wali et al. [37]. Because patients with SCD are volume overloaded, conventional echocardiographic indices may not reveal the true intrinsic diastolic function in these studies.

In the current study, we evaluated the LV function using DTI and we calculated DTI-derived MPI in SCD patients with or without pulmonary hypertension. We demonstrated that LV systolic and diastolic functions are preserved in all SCD patients with or without pulmonary hypertension, as indicated by normal mitral annular systolic and diastolic myocardial velocities and normal ratio of early to late mitral annular diastolic velocities. We confirmed the presence of normal combined systolic and diastolic performance with normal MPI in patients with SCD irrespective of the presence of pulmonary hypertension.

Right Ventricle

In our study, we showed preserved RV systolic function in all SCD patients with or without pulmonary hypertension, as indicated by normal tricuspid annular systolic myocardial velocities. However, RV diastolic function was impaired in SCD patients with pulmonary hypertension, as indicated by increased late tricuspid annular velocity and a reduced ratio of early to late tricuspid annular velocities. We confirmed this RV diastolic dysfunction with assessment of RV MPI. The prolongation of IVCT resulted in the increase in RV MPI values in SCD patients with pulmonary hypertension. Since RV systolic function was found to be preserved in SCD patients with pulmonary hypertension, the elevated RV MPI is most likely explained by decreased diastolic function. Similar RV MPI measurements of SCD patients without pulmonary hypertension and control subjects indicate that SCD patients without pulmonary hypertension have normal combined systolic and diastolic functions.

To our knowledge, there are no reports in the literature of RV function evaluated by MPI in SCD patients with pulmonary hypertension. However, several studies have evaluated RV function using MPI in patients with pulmonary hypertension secondary to different diseases. Lopez-Candales et al. [20] reported that patients with pulmonary hypertension secondary to a heterogeneous group of diseases had worse RV MPI than healthy volunteers. Menzel et al. [24] demonstrated that the reduction in mean pulmonary artery pressure was accompanied by a reduction in RV MPI after thromboendarterectomy surgery in patients with pulmonary hypertension secondary to thromboemboli. Özdemir et al. [26] showed that DTI-derived RV MPI correlates well with pulmonary arterial pressure in patients with mitral stenosis.

The diastolic dysfunction of the right ventricle in SCD patients with pulmonary hypertension seems to be an early subclinical manifestation of myocardial diastolic derangement, similar to that previously reported in other cardiac disease, including systemic hypertension, hypertrophic cardiomyopathy, and systemic lupus erythematosus [5, 7, 27].

This abnormal diastolic pattern may be due to an increase in RV afterload secondary to pulmonary hypertension. Myocyte degeneration caused by myocardial microemboli may also lead to diastolic abnormalities in patients with SCD. In addition, anemia-induced neurohormonal activation and tachycardia may contribute to the progression of cardiac disease in these patients.

Pulmonary Function

There are only a few studies in the literature on pulmonary function in patients with SCD. Conflicting data regarding ventilatory defects were reported in those studies. Some authors reported restrictive ventilatory defects and reduced diffusion capacity of alveolar membrane in adults with SCD [31, 34]. On the other hand, some other authors reported obstructive lung disease [19, 39]. Koumbourlis et al. [18] demonstrated that lower airway obstruction may occur even in infants with SCD. Nevertheless, no alteration in lung function tests was found in the early stage of the disease by Wall et al. [38].

We show in this study that compared with healthy subjects of a similar age, young adult with SCD, irrespective of the presence of pulmonary hypertension, had significantly lower mean values of FEV1 and FVC, suggesting mild restrictive defects. In both groups of patients, DLCO was substantially reduced, indicating that lung diffusing capacity is lower than normal. In this study, the presence of restrictive disease was also supported by the transcutaneous SaO2 values, which were lower than controls. This is consistent with the presence of restrictive disease that has reduced the surface of the alveolar capillary membrane because of limited expansion of the airspaces and/or has increased the thickness of the alveolar capillary membrane due to fibrosis.

Study Limitations

There are some potential limitations to this study. There may be some load dependence to the DTI. DTI is preload dependent in cases of normal diastolic function [10]. However, DTI is relatively preload independent in the presence of abnormal diastolic function [25]. Furthermore, hemoglobin levels, which were an important determinant of preload, were similar in both groups of SCD patients. Another important issue is that right heart catheterization remains the gold standard for measuring pulmonary artery pressure, which was not performed in this study. However, cardiac catheterization is an invasive procedure and it cannot be performed routinely during clinical use in patients with SCD. As alternative to cardiac catheterization, Doppler echocardiography is a noninvasive method and Doppler echocardiography-derived pulmonary artery systolic pressures are similar to that obtained at cardiac catheterization [11].

Conclusions

MPI is useful index to evaluate RV function in patients with SCD. Young adult patients with SCD irrespective of the development of pulmonary hypertension have normal RV systolic function. RV diastolic function is preserved in SCD patients without pulmonary hypertension. However, RV diastolic function is disturbed in those patients with pulmonary hypertension. The restrictive pattern of pulmonary function abnormalities has developed in patients with or without pulmonary hypertension.

Copyright information

© Springer Science+Business Media, Inc. 2006