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Systemic sclerosis (SSc) is frequently associated with interstitial lung disease (ILD) often leading to lung fibrosis. In this study we investigated whether matrix metalloproteinase 9 (MMP-9) and its natural inhibitor; the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), would be associated with remodelling in ILD in SSc. Levels of total MMP-9, pro-MMP-9 and TIMP-1 were measured in bronchoalveolar lavage (BAL) fluid from nine SSc patients with ILD, seven SSc patients without ILD and 16 age- and sex-matched healthy controls. Total MMP-9 and pro-MMP-9 levels were significantly elevated in SSc patients with ILD, compared to levels in SSc patients without ILD and healthy controls. In SSc patients with ILD calculated active MMP-9 levels were significantly higher than in SSc patients without ILD and tended to be higher than in healthy controls. TIMP-1 levels were elevated in both patient groups compared to healthy controls. Total-, pro- and active MMP-9 levels as well as pro-MMP-TIMP-1 and active MMP-9/TIMP-1 ratios were inversely associated with total lung capacity. The present study suggests that MMP-9 plays a pathophysiological role in the remodelling in ILD and lung fibrosis associated with SSc, and may represent a new therapeutic target in this condition.

Background: Cardiopulmonary involvement in patients with systemic sclerosis (SSc) carries a poor prognosis, mainly due to pulmonary hypertension and right-heart failure. To date, right ventricular (RV) involvement has not been studied in detail. We therefore assessed RV function in patients with SSc and related the findings to the clinical features of the disease., Method: Twenty-six consecutive patients (21 women) with SSc (mean age, 56 +/- 15 years [+/- SD]) and 25 healthy, age-matched control subjects (21 women) were studied. Doppler echocardiography including Doppler tissue imaging was used to evaluate cardiac function. Pulmonary function was also studied., Results: Compared with control subjects, RV free wall thickness (5.8 +/- 1.7 mm vs 3.7 +/- 1.1 mm, p < 0.001) and right atrial (RA) systolic area (15.9 +/- 3.7 cm2 vs 13.0 +/- 2.3 cm2, p < 0.01) were increased in patients with SSc, while the global early diastolic/atrial component velocity ratio was reduced (1.2 +/- 0.4 vs 1.7 +/- 0.6, p < 0.01). The global isovolumic relaxation time (IVRT) [64 +/- 23 ms vs 39 +/- 13 ms, p < 0.001] and regional IVRT (83 +/- 40 ms vs 46 +/- 24 ms, p < 0.001) were prolonged in patients vs control subjects, whereas the RV global filling time was reduced (454 +/- 122 ms vs 548 +/- 104 ms, p < 0.01). RV systolic function and pulmonary pressures at rest were similar in the two groups, but the pulmonary artery acceleration time was reduced (119 +/- 34 ms vs 141 +/- 29 ms, p < 0.05) in patients compared to control subjects. Left ventricular function did not differ between the two groups., Conclusion: Patients with SSc exhibit altered RV diastolic function together with an increase in RV wall thickness and RA area. These findings appear to be early markers of RV disturbance, probably in response to intermittent pulmonary arterial hypertension.

Objective: To investigate the relationship between endothelium-dependent and endothelium-independent functions and the stiffness of conduit arteries as well as levels of endothelial activation markers in patients with systemic sclerosis (SSc)., Methods: Endothelium-dependent (i.e., flow-mediated) and endothelium-independent (i.e., nitroglycerin-induced) dilation of the brachial artery was measured as the percentage of change from baseline (FMD% and NTG%, respectively) in 24 SSc patients and 24 age- and sex-matched healthy controls by high-resolution ultrasound imaging. The maximum increase in systolic pressure per unit of time (dP/dt(max)), as a measure of arterial wall stiffness, was assessed in the radial artery by pulse applanation tonometry. Plasma nitrate, the most important metabolite of nitric oxide, and 24-hour urinary excretion of nitrate were measured by gas chromatography mass spectrometry. Soluble E-selectin and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured by enzyme-linked immunosorbent assay., Results: Brachial artery FMD% and NTG% did not differ between SSc patients and controls. Radial artery dP/dt(max) was significantly increased in the patients and correlated significantly with elevated levels of plasma nitrate and sVCAM-1. Twenty-four-hour urinary nitrate excretion tended to be elevated. Brachial artery NTG% was significantly inversely correlated with levels of plasma nitrate and soluble endothelial adhesion molecules., Conclusion: The ability of the brachial arteries to dilate in response to hyperemia and nitroglycerin challenge is preserved in SSc. Stiffness of the radial artery is increased, however. Endothelial activation seems to determine the extent of the brachial artery NTG% and the radial artery dP/dt(max). The data are compatible with the hypothesis that nitrate tolerance is present in the vascular smooth muscle cells of the brachial artery wall in SSc.

Objective: To determine the relationship between vascular function and the inflammatory response in systemic sclerosis (SSc), and to investigate whether production of endothelial-derived nitric oxide (NO) is disturbed in this disease., Methods: We measured plasma nitrate, urinary excretion of both nitrate and cGMP, and soluble adhesion molecules of endothelial origin in patients with SSc and in age- and sex-matched controls and compared these levels between groups. Additionally, we performed correlation analysis to determine how these variables were related to one another. Plasma nitrate and 24-hour-urinary excretion of nitrate in patients and controls were measured after a 72-hour nitrate-free-diet, using a gas chromatography/mass spectrometric method. Soluble adhesion molecules intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), and E-selectin and cytokines were measured by enzyme-linked immunosorbent assay. The expression of E-selectin was further investigated in skin biopsy specimens by immunoperoxidase staining, and the presence of inducible NO synthase by immunoblotting., Results: Plasma nitrate and 24-hour-urinary-excretion of cGMP were significantly elevated in patients compared with controls, while 24-hour-urinary-excretion of nitrate tended to be elevated in SSc patients. Levels of sICAM-1, sVCAM-1, and sE-selectin were significantly elevated in the patients. Levels of plasma nitrate in the patients correlated significantly with levels of sVCAM-1 (P = 0.020) and sE-selectin (P = 0.018) and approached a significant correlation with sICAM-1 (P = 0.055), suggesting that activated endothelial cells may produce plasma nitrate., Conclusion: NO synthesis is elevated in SSc patients, and the activated endothelial cell is a likely site of its production.

Objective: The present study was performed to measure concentrations of plasma noradrenaline and neuropeptide-Y-like immunoreactivity in relation to cardiac function in patients with systemic sclerosis (SSc)., Methods: Plasma noradrenaline was measured by high performance liquid chromatography and neuropeptide-Y by radioimmunoassay in 30 consecutive patients with SSc and 48 sex and age matched controls. Left ventricular (LV) function was evaluated by Echocardiography., Results: There were no significant differences between patients and controls in either plasma noradrenaline or plasma neuropeptide-Y. LV dysfunction and hypertrophy were common among patients. Plasma Neuropeptide-Y was related only to systolic function, while noradrenaline was related to both systolic and diastolic function as well as to LV hypertrophy., Conclusion: Patients with SSc develop different forms of myocardial dysfunction without activation of the sympathetic nervous system as evaluated by plasma noradrenaline and neuropeptide-Y; leaving vascular disease of the heart to be a main candidate.

We evaluated 30 consecutive patients and 48 age- and sex-matched controls to explore the possibility of a pathogenic contribution by plasma endothelin-1 in the cardiac expression of systemic sclerosis. Venous plasma endothelin-1 was measured by radio-immunoassay and left ventricular function by echocardiography. The patient group had elevated plasma endothelin-1 (2.6 +/- 0.2 vs. 1.8 +/- 0.1 pmol/1, P < 0.001), but endothelin-1 was not related to age, heart rate, blood pressure, total peripheral resistance, disease duration or systemic sclerosis score. Endothelin-1 was related to left ventricular hypertrophy in terms of septal thickness (r = 0.33, P < 0.01) and left ventricular mass index (r = 0.32, P < 0.01). Plasma endothelin-1 was further related to measures indicating reduced left ventricular filling; left atrial emptying index (r = -0.50, P < 0.0005), the first third filling fraction (r = -0.31, P < 0.05) and the time velocity integral of Doppler early/late filling velocity (r = -0.40, P < 0.001). Furthermore, circulating endothelin-1 was related to impaired left ventricular contractility as estimated by pre-ejection period/left ventricular ejection time (r = 0.32, P < 0.01) and end-systolic wall stress/volume index (r = -0.30, P < 0.05). We conclude that plasma endothelin-1 is elevated in relation to the degree of left ventricular hypertrophy, diastolic dysfunction and impaired contractility in systemic sclerosis. It may be of pathogenic importance to the cardiac involvement in systemic sclerosis which is not mediated via an increase in systemic blood pressure. It is not yet clear whether our findings are exclusive to systemic sclerosis patients or represent a generalized phenomenon in patients with impaired left ventricular function.

We related atrial natriuretic peptide (ANP) among 30 consecutive patients with systemic sclerosis (SScl) and 48 gender- and age-matched controls to the measurements of left ventricular (LV) function as evaluated by echocardiography and external pulse curves to determine possible causative factors for an increased level of plasma ANP. The patients had a markedly elevated plasma ANP level (239.4 +/- 59 vs. 178.2 +/- 36 pmol/l, p < 0.0005), which was not related to LV systolic function, heart rate, or blood pressure. Patients had LV hypertrophy and plasma ANP correlated directly to interventricular septal thickness (r = 0.41, p < 0.005), LV posterior wall thickness (r = 0.32, p < 0.01), and wall thickness to cavity dimension (r = 0.44, p < 0.0005), LV mass index (r = 0.40, p < 0.005). LV early filling properties were impaired, with reduction of atrial emptying index (p < 0.0005) and increased contribution of atrial contraction to LV filling. Plasma ANP correlated to atrial emptying index (r = 0.41, p < 0.0005) and to apex-cardiographic a wave (r = 0.28, p < 0.05). Plasma ANP was also related to left atrial dimension index (r = 0.27, p < 0.05), and was still related to atrial emptying index, but not to left atrial dimension, when considering the degree of LV hypertrophy in multivariate analysis. We conclude that ANP is elevated in patients with SScl. Reduced LV compliance, probably due to increased fibrosis, may cause changes in atrial pressure sufficient to stimulate ANP production without systolic dysfunction as a prerequisite.

Objectives: Were to determine whether plasma atrial natriuretic peptide (ANP) is increased in patients with systemic sclerosis (SScl) and to evaluate its relation to cardiac dimensions and function., Methods: Using radio-immunoassay, plasma ANP was determined in 30 patients with SScl and 48 age and sex matched controls. The plasma ANP level was related to cardiac structure and function as determined by two-dimensional echocardiography (2-D echo)., Results: Plasma ANP was markedly elevated among patients as compared to controls (239,4 +/- 59 vs 178.2 +/- 36 pmpl/l, p < 0.0005). The left atrial long-axis and area were increased, and ANP was directly related to both measurements (r = 0.27, p < 0.05 and r = 0.40, p < 0.005, respectively). Plasma ANP was also related to the increased right atrial long-axis (r = 0.27, p < 0.05). The ANP level was not related to LV systolic function as estimated by ejection fraction, fractional area change and end-systolic wall stress, neither did these measures differ between patients and controls. However, there was an inverse correlation between ANP level and stroke volume (r = -0.35, p < 0.05), which was lower among the patients (p < 0.005). ANP displayed also an inverse relation to LV long axis diameter (r = -0.37, p < 0.005) and area (r = -0.42, p < 0.005) as well as to LV end-diastolic volume (r = -0.42, p < 0.005). Various measurements indicated LV hypertrophy among the SScl patients in spite of a small LV cavity. ANP was directly related to measures of LV hypertrophy, as interventricular septum thickness (r = 0.44, p < 0.005), LV posterior wall thickness (r = 0.34, p < 0.05), the wall thickness to cavity dimension ratio (r = 0.36, p < 0.05), and LV myocardial area (r = 0.36, p < 0.05). There was no relationship between ANP concentration and heart rate, blood pressure or total peripheral resistance., Conclusion: These results suggest that the ANP production is not reduced in SScl. Rather, circulating ANP is elevated in relation to the degree of LV hypertrophy. This implies that ANP may be useful for the identification of cardiac involvement in patients with SScl.

Impairment of left ventricular (LV) function has previously been reported in patients with systemic sclerosis (SScl). An intermittent vasospastic process in the myocardium may contribute to the development of myocardial dysfunction. Vasodilators may therefore be potentially useful in the treatment of cardiac dysfunction in patients with SScl. This study was designed to evaluate the long-term effects of captopril on the myocardial function of patients with SScl. Twenty-two patients with SScl (15 patients with diffuse scleroderma and 7 patients with CREST syndrome, i.e. calcinosis. Raynaud's phenomenon, oesophageal hypomotility, sclerodactyly, telangiectasia) were investigated by means of Doppler and echophonocardiography before and after treatment with captopril (1.3 mg kg-1 body weight d-1) for 11-15 months. There were no significant differences in heart rate, systolic and diastolic blood pressure, end-systolic blood pressure, total peripheral resistance or LV diameters before or after treatment. However, captopril treatment exerted significant effects on LV function: the pre-ejection period (PEP) and the ratio of pre-ejection period to LV ejection time decreased significantly (P less than 0.05). Mitral E-point septal separation decreased significantly (P less than 0.01), even after adjustment for LV end-diastolic diameter (P less than 0.01). The ejection fraction increased significantly (P less than 0.05), and the isovolumic relaxation time decreased (P less than 0.01). The left atrial emptying index increased (P less than 0.01). The Doppler peak late to early ventricular filling velocity decreased (P less than 0.05), and the isovolumic index was also reduced (P less than 0.05). We conclude that both systolic and diastolic LV function indices improved in patients with SScl after captopril treatment for a mean period of 1 year. The effects of captopril might be due to vasodilation of the myocardial vessels and/or a direct effect on the renin-angiotensin system of the heart.

Systemic sclerosis is a multisystemic disorder, also affecting the heart. To evaluate its influence on systolic left ventricular (LV) function, we investigated 30 consecutive patients (age 54.5 +/- 2.4 years, 15 men and 15 women) and 48 controls matched for age and sex. All subjects were investigated by phonocardiography, pulse curve recordings, M-mode echocardiography, and by pulsed and continuous wave Doppler. Heart rate, blood pressure and peripheral resistance did not differ, but patients weighed less than controls (P less than 0.01). Systolic time intervals indicated systolic impairment, with an increased pre-ejection period to LV ejection time (LVET) ratio (0.37 +/- 0.02 vs 0.30 +/- 0.01 P less than 0.001), and also an increased isovolumic contraction time to LVET ratio (0.17 +/- 0.02 vs 0.12 +/- 0.01, P less than 0.02). The latter difference remained when LVET was adjusted for heart rate. Echocardiographic E-point to septal separation was increased in patients (8.3 +/- 1.3 vs 4.8 +/- 0.3 mm, P = 0.001), also after adjustment for LV dimension (P = 0.0001), while septal fractional thickening was decreased (P less than 0.01). End systolic wall stress (P = 0.0002) and stress to volume ratio (P = 0.03) were lower in systemic sclerosis. Peak LV emptying rate was also lower in the patient group when measured by echocardiography (P = 0.03). There was no difference between groups regarding LV dimensions, fractional shortening or mean velocity of circumferential fibre shortening. While aortic Doppler peak emptying rate did not differ between groups, it occurred later in systole in the patient group (P less than 0.01) as did peak velocity (P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

To evaluate the left ventricular filling characteristics in systemic sclerosis, we examined 30 consecutive patients, 15 men and 15 women, and related the findings to those from 48 age- and sex-matched controls. All patients were investigated by pulsed and continuous wave mitral Doppler, and M mode echocardiography. We found the A wave of the mitral flow velocity as recorded by pulsed wave Doppler to be higher in patients (0.74 +/- 0.07 vs 0.54 +/- 0.02 m/sec, P less than 0.002), while the E wave did not differ. The high A/E ratio indicating reduced distensibility, correlated to interventricular septal thickness (r = 0.53, P less than 0.001), and atrial emptying index (r = -0.55, P less than 0.001). Early filling was impaired, with a prolonged pressure half time (99 +/- 6 vs 84 +/- 4 msec, P less than 0.05), and a reduced first third filling fraction (0.41 +/- 0.02 vs 0.48 +/- 0.01, P less than 0.001). Mitral regurgitation was found in 67% of systemic sclerosis patients and in 15% of controls (P less than 0.001). Doppler measures of left ventricular filling properties were not related to the presence of mitral regurgitation or systolic blood pressure. We conclude that left ventricular distensibility and early filling properties are impaired in systemic sclerosis and not related to blood pressure, but rather to left ventricular wall thickness and therefore probably secondary to myocardial fibrosis. Mitral regurgitation is a common finding in systemic sclerosis.

To evaluate the extent of left ventricular (LV) diastolic impairment in systemic sclerosis, we examined 30 consecutive patients (15 men and 15 women) with this condition, and compared the findings with the data for 48 age- and sex-matched randomly sampled controls. All patients were investigated by phonocardiography, pulse curve recording, and M-mode echocardiography. Twenty-three of 30 (77%) patients had LV hypertrophy and/or diastolic impairment. Interventricular septum (P = 0.0001), LV posterior wall (P less than 0.05), and the wall thickness to cavity dimension ratio (P less than 0.001) were increased in patients compared to controls, as was LV mass index (P less than 0.002). Five patients had asymmetric septal hypertrophy. LV end-diastolic dimension did not differ between groups. LV distensibility was impaired, as judged from apexcardiographic a/H ratio (P less than 0.05) and from an increased left atrial index (P less than 0.005). LV early filling was impaired, with a reduced left atrial emptying index (P = 0.0001), and a reduced rate of dimension increase in digitized M-mode (P less than 0.02). We found no evidence of impaired LV relaxation. Blood pressure did not differ between patients and controls. With longer duration of the disease, left atrial dimension appeared to increase (r = 0.42, P less than 0.05), while other variables were not related to disease duration. The impaired LV filling was not secondary to systolic dysfunction. We conclude that systemic sclerosis patients have an increased LV wall thickness, with impaired early filling properties and LV distensibility.