Heart structure and function in systemic sclerosis

ARTICLE

Systemic sclerosis (SSc) is a multisystem disorder characterised by connective tissue fibrosing with vascular abnormalities and autoimmune changes [1]. The course and prognosis are highly dependent on the clinical pattern, and the main causes of death are cardiovascular, renal and pulmonary disease [1]. Heart involvement is one of the main factors shortening the survival of SSc patients [2, 3]. Thus, diagnosis of structural changes and pathophysiology of the heart is the key factor in calculating the individual patient's prognosis and mapping out further therapy.

To date, the literature predominantly referred to conduction abnormalities and arrhythmias [4, 5], myocardial ischemia [6, 7] or contractility disturbances [8, 9] in SSc patients. However, fibrosis of the myocardium predominantly affects diastolic properties of left ventricle. The introduction of the new echocardiographic technique - Tissue Doppler Imaging (TDI) facilitates the quantitative assessment of regional left ventricle systolic and diastolic function [10, 11].

Aim of the study

The aim of the study was (1) an assessment of structural and pathophysiological changes of the heart in SSc patients in standard echocardiographic examination and (2) an evaluation of regional systolic and diastolic left ventricle disturbances in SSc patients by means of Tissue Doppler Echocardiography.

Material and methods

The study group consisted of 19 SSc women aged 22-72 years (mean age 51.7 years) diagnosed according to American Rheumatism Association [12], admitted to the Department of Dermatology of the Jagiellonian University in Cracow. According to the classification of LeRoy [13] limited SSc (lSSc) was diagnosed in 11 (58%) women, and in 8 (42%) women diffuse SSc (dSSc) was found. The existence of symptoms up to the time of enrolment in the study was 1 to 25 years (mean 13.4 years). Neither the age of the patients nor the duration of the existence of symptoms differed in lSSc and dSSc group. In 2 women arterial hypertension was diagnosed (defined as resting blood pressure above 140/90 mmHg), treated with the angiotensin converting enzyme inhibitors, and one of them manifested stenocardia requiring nitrate administration.

The control group consisted of 16 healthy women (no symptoms of any disease, normal resting ECG, resting blood pressure below 140/90 mmHg) aged 19-57 years (mean age 43.6 years). The age of the patients in SSc and the control group did not differ significantly.

In all the patients echocardiographic examination was performed. In M-Mode projection left ventricle end-diastolic and end-systolic diameter, ejection fraction, left atrial diameter, right ventricle end-diastolic diameter and left ventricular wall thickness were assessed. In conventional Continuous Doppler examination valvular pressure gradients and pulmonary systolic pressure were measured. The level of valvular insufficiency was evaluated by means of Colour Doppler examination.

On the basis of continuous Doppler mitral flow examination the E/A ratio was estimated. "E" wave represents early filling of left ventricle. "A" wave represents late filling of the left ventricle during atrial contraction. In the normal heart most of the blood inflow to the left ventricle is observed during early diastole, and the E/A ratio is greater than 1.0. In the case of diastolic dysfunction less blood inflows to the ventricle in early diastole, and the E/A ratio is below 1.0.

After the echocardiographic examination Tissue Doppler Imaging was performed. This is the method of assessing myocardial velocities. Regional (segmental) systolic and diastolic left ventricle myocardial function can be measured. Tissue Doppler myocardial velocities were evaluated in 14 myocardial segments shown in Figure 1. In each examined segment maximal systolic and maximal early diastolic velocity of myocardium was assessed according to standards [14]. The important value of Tissue Doppler Imaging is the possibility of independent estimation of the velocity of longitudinal and circumflex myocardial fibers. When myocardial velocities are measured in parasternal views (Fig. 1) the information about circumflex-placed myocardial fibers is recorded. In case of examination from apical views (Fig. 1) the information about longitudinally-placed myocardial fibers is recorded.

The echocardiographic examinations and TDI measurements were performed by means of Toshiba Power Vision equipment.

The results of echocardiographic and TDI examinations are reported as mean ± SD and the variables are compared using t-test.

Results

The echocardiographic data of ejection fraction, dimension of heart cavities, thickness of left ventricle walls, mitral E/A ratio and pulmonary systolic pressure in both examined groups are shown in Table I. In SSc women a statistically significant decrease of E/A ratio was observed. Pulmonary hypertension was observed in 9 (47.4%) SSc women: moderate pulmonary hypertension (systolic pressure > 40 mmHg) in 3 (15.8%) women, mild pulmonary hypertension (systolic pressure 30-40 mmHg) in 6 (31.6%) women. Normal pulmonary systolic pressure (< 30 mmHg) was found in 10 (52.6%) SSc women.

Mitral valve fibrosis was detected in 3 (15.8%) SSc women, and aortic valve fibrosis in 4 (21.1%) SSc women. There were no patients with valvular fibrosis in the control group. The common finding in SSc women was tricuspid insufficiency, observed in all but one patients in this group. The mild (I degree) tricuspid insufficiency was detected in 17 (89.5%) SSc women, and in 1 woman (5.3%) severe (IV degree) tricuspid insufficiency was observed. No valvular stenosis was diagnosed.

The results of Tissue Doppler Imaging are shown in Figures. 2, 3 and 4.

Figure 2 shows mean values of systolic and diastolic myocardial velocities for all assessed segments of left ventricle in SSc women and in the control group. No significant difference between the groups in systolic myocardial velocity was found. Significant decrease of diastolic velocities was found in SSc women. The detailed assessment of diastolic function in the SSc group showed severe diastolic dysfunction of longitudinal myocardial fibers (Fig. 3) with normal function of circumflex myocardial fibers (Fig. 4).

In two SSc women with arterial hypertension no left ventricle muscle hypertrophy was found, and the diastolic dysfunction was not more pronounced than in the other SSc patients.

No patients with pericardial effusion were observed.

No significant difference in assessed TDI parameters was found when the limited SSc and diffuse SSc groups were compared. The mean values of systolic myocardial velocities were 6.09 cm/sec vs. 6.55 cm/s, respectively, and the mean values of diastolic velocities 7.26 cm/sec vs. 7.58 cm/sec, respectively.

No statistically significant correlation between the age of SSc patients and TDI parameters was found, as well as no correlation between the duration of symptoms and estimated TDI parameters.

Discussion

Fibrosis of the heart is one of the most important factors shortening the survival of SSc patients [2, 3]. Fibroblastic proliferation and overproduction of collagen result from the low-grade inflammatory process [2]. The main pathophysiological change consists in the diastolic dysfunction of the heart caused by enhanced fibrosing processes in the myocardium and pericardium. To date, the diagnosis of diastolic dysfunction was based on the examination of mitral inflow [16]. This method provides the information of global left ventricle diastolic function only. Our results confirm the observation of the other authors [17, 18] that the E/A mitral inflow ratio is decreased in SSc patients.

For the quantitative assessment of the regional diastolic left ventricular function the new echocardiographic technique - TDI - was used. TDI examination showed the diastolic dysfunction only in the longitudinal myocardial fibres, but not in the circumflex fibres. Thus, the fibrosis seems to be concentrated in the subendocardial region built by longitudinal muscle layer. This is also the conclusion of Henein et al. [19], who examined 34 SSc patients by TDI technique.

However, the other factor that influences the diastolic dysfunction of the left ventricle is ischemia. Ischemia can be detected by heart scintigraphy. Gustafsson et al. [7] observed fixed defects in the myocardium of SSc patients, but even more common were cold-induced reversible defects. Ischemia apparently results from injury or spasm at the level of very small arteries, 150 to 500 mum in diameter, and capillaries are gradually obliterated [2]. The subendocardial region of the myocardium is more sensitive for ischemia than the subepicardial part. This may additionally result in a decrease of the diastolic velocity of longitudinal myocardial fibres observed in TDI examination.

The important finding in SSc patients is the coexistence of the left ventricle diastolic dysfunction with normal left ventricle wall thickness. Thus, the diastolic dysfunction in this group does not result from muscle hypertrophy.

Myocardial ischemia detected in SSc patients by heart scintigraphy does not influence systolic left ventricle function. As was mentioned above, myocardial ischemia results from cold-induced reversible arterial spasms, and usually small ischemic regions in well-perfused myocardium are seen [20]. This is why the systolic function of the myocardium is preserved in most of the cases, and left ventricle ejection fraction is normal. In our study no significant difference between both examined groups in ejection fraction as well as in systolic myocardial velocities assessed by TDI were found. The same results were obtained by other authors [17, 21]. Additionally, high ejection fraction in SSc patients may result from adrenergic overactivity. Tachycardia is common in this group and has a predictive value for patients' mortality [22].

There is evidence that the myocardial ischemia in SSc patients may influence diastolic, but not systolic properties of left ventricle. This can be due to the observation that the diastolic the function is much more sensitive for ischemia than the systolic function [23].

Pulmonary disease may shorten survival in patients affected by systemic sclerosis [1]. In our study pulmonary hypertension was observed in 47.4% of examined SSc women. In the other studies the frequency of pulmonary hypertension in SSc patients was similar: from 39% [24] to 52% [25]. The extent and severity of pulmonary involvement are not directly correlated with skin changes [25]. This is why the examination of pulmonary involvement is important, including pulmonary systolic pressure estimation and interstitial lung fibrosis assessment (high resolution computer tomography). Morelli et al. [25] reported that restrictive lung disease was more frequent in patients with diffuse SSc, while a tendency to higher prevalence of pulmonary hypertension was observed in patients with limited SSc. In our study the type of systemic sclerosis had no influence on pulmonary systolic pressure. The correlation between pulmonary hypertension and impairment of exercise performance in SSc patients has also been reported in the literature [24].

No significant structural pathology of the heart was found in women with systemic sclerosis. The interventricular septum thickness and the left ventricle posterior wall thickness were slightly higher in the SSc group, but in the normal range. The valvular fibrosis detected in SSc women was not clinically significant, and no valvular stenosis was observed. Tricuspid insufficiency was the common finding in SSc women, although it was not the consequence of tricuspid valve pathology, but of pulmonary hypertension.

The results discussed above may have important implications for the treatment of SSc patients. The existence of severe diastolic left ventricle dysfunction may lead to the symptoms of circulatory decompensation even when systolic left ventricle function is preserved. Therapy should concentrate on fibrosis process inhibition and the left ventricle preload improvement. Thus, angiotensin converting enzyme inhibitors, beta-blockers and spironolactones should be considered together with the standard treatment.

The important role of angiotensin converting enzyme inhibitors should be emphasized. The recent data show the influence of angiotensin II on fibroblasts activity and collagen synthesis [26, 27]. Angiotensin II stimulates the expression of transforming growth factor beta1 (TGFbeta1) gene, which leads to enhanced collagen synthesis in heart muscle [28]. Sun et al. [29] reported that in the myocardial regions with fibrosing process activation, a high level of local agiotensin II production was observed, together with the increase of angiotensin AT1 receptors and TGFbeta1 receptors levels. In an experimental model of arterial hypertension in rats, chronic treatment with angiotensin converting enzyme inhibitor - lisinopril - inhibited the fibrosing process of interstitial tissue of the heart [30]. The beneficial effect of angiotensin converting enzyme inhibitors on diastolic properties of left ventricle in SSc patients, the course of the disease and prognosis should be confirmed by further human trials.

CONCLUSION

1/ In SSc patients significant left ventricle diastolic dysfunction was found.

2/ Diastolic dysfunction was observed only in longitudinal myocardial fibres and was not found in circumflex myocardial fibres. Thus, myocardial fibrosing and ischemia in SSc patients seem to be concentrated in the subendocardial region built by longitudinal muscle layer.

3/ Left ventricle diameter, wall thickness and systolic function in SSc patients are preserved.

Article accepted on 12/2/02

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