Systemic sclerosis-associated pulmonary arterial hypertension (SScPAH) has a worse prognosis and response to pulmonary arterial hypertension (PAH) therapy than idiopathic PAH (IPAH). These differences have not yet been explained. Knowledge concerning histological pulmonary vasculopathy in SScPAH is limited in contrast to IPAH. Therefore, we explored patterns of vasculopathy in SScPAH compared with IPAH.
Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1–9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020–001236–10). Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56–73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76–1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27–0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26–1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63–1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3–13) in the imatinib group compared with 12 days (6–20) in the placebo group (p=0·0080). 91 (46%) of 197 pa...
Since systemic sclerosis (SSc) also involves the heart, the aim of the present study was to evaluate possible differences in right ventricular (RV) pump function between SScassociated pulmonary arterial hypertension (PAH; SScPAH) and idiopathic PAH (IPAH).In 13 limited cutaneous SScPAH and 17 IPAH patients, RV pump function was described using the pump function graph, which relates mean RV pressure (PRV) and stroke volume index (SVI). Differences in pump function result in shift or rotation of the pump function graph. PRV and SVI were measured using standard catheterisation. The hypothetical isovolumic PRV (PRV,iso) was estimated using a single-beat method. The pump function graph was approximated by a parabola:, where SVImax is the hypothetical maximal SVI at zero PRV, enabling calculation of SVImax. There were no differences in SVI and SVImax. Both PRV and PRV,iso were significantly lower in SScPAH than in IPAH (PRV 30.7¡8.5 versus 41.2¡9.4 mmHg; PRV,iso 43.1¡12.4 versus 53.5¡10.0 mmHg). Since higher pressures were found at similar SVI, the difference in the pump function graph results from lower contractility in SScPAH than in IPAH.Right ventricular contractility is lower in systemic sclerosis-associated pulmonary arterial hypertension than in idiopathic pulmonary arterial hypertension.
The platelet-derived growth factor receptor inhibitor imatinib has demonstrated clinical and haemodynamical improvement in both animal models of pulmonary hypertension (PH) and patients with PH. It has been suggested that anti-proliferative effects on pulmonary vascular smooth muscle cells are responsible for these beneficial effects.The current study describes a patient with pulmonary arterial hypertension associated with a suspected pulmonary veno-occlusive disease.Treatment with imatinib resulted in rapid clinical improvement and decrease of ground-glass opacities and lobular septal thickening on high-resolution computed tomography.Based on these findings and on in vitro effects of imatinib on permeability of the endothelium, the authors hypothesise that the rapid clinical outcome is partly due to effects of imatinib on vascular integrity.KEYWORDS: Imatinib, platelet-derived growth factor receptor, pulmonary arterial hypertension, pulmonary veno-occlusive disease, vascular permeability CASE REPORT A 56-yr-old female was referred to the VU University Medical Center (Amsterdam, the Netherlands) for the evaluation of pulmonary hypertension. The patient's medical history included tuberculosis at the age of 12 yrs, which was treated with para-aminosalicylate, hypothyroidism and a smoking history of 7 pack-yrs. Prior to referral, the patient had been hospitalised elsewhere and diagnosed with pneumonia. Due to her complaint of progressive dyspnoea for 15 months, and following the diagnosis of idiopathic pulmonary arterial hypertension (PAH) in her sister 1 yr earlier, an echocardiogram was performed, which demonstrated an elevated pulmonary artery systolic pressure of 50 mmHg. Pulmonary hypertension (PH) was confirmed by right heart catheterisation, revealing a pulmonary arterial systolic pressure of 102 mmHg, a pulmonary arterial diastolic pressure of 40 mmHg and a mean pulmonary arterial pressure of 69 mmHg. The mean right atrial pressure was 9 mmHg. The pulmonary capillary wedge pressure (PCWP) was 12 mmHg. There was a mixed venous saturation of 59%, a cardiac output of 3.0 L?min -1 and a pulmonary vascular resistance of 1,497 dynes?s -1 ?cm -5 . Systemic blood pressure during right heart catheterisation was AFFILIATIONS
Objective. Systemic sclerosis-associated pulmonary arterial hypertension (SScPAH) has a disturbed function of the right ventricle (RV) when compared to idiopathic PAH (IPAH). Systemic sclerosis may also affect the heart. We hypothesize that RV differences may occur at the level of interstitial inflammation and—fibrosis and compared inflammatory cell infiltrate and fibrosis between the RV of SScPAH, IPAH, and healthy controls. Methods. Paraffin-embedded tissue samples of RV and left ventricle (LV) from SScPAH (n = 5) and IPAH (n = 9) patients and controls (n = 4) were picrosirius red stained for detection of interstitial fibrosis, which was quantified semiautomatically. Neutrophilic granulocytes (MPO), macrophages (CD68), and lymphocytes (CD45) were immunohistochemically stained and only interstitial leukocytes were counted. Presence of epi- or endocardial inflammation, and of perivascular or intimal fibrosis of coronary arteries was assessed semiquantitatively (0–3: absent to extensive). Results. RV's of SScPAH showed significantly more inflammatory cells than of IPAH (cells/mm2, mean ± sd MPO 11 ± 3 versus 6 ± 1; CD68 11 ± 3 versus 6 ± 1; CD45 11 ± 1 versus 5 ± 1 , P < .05) and than of controls. RV interstitial fibrosis was similar in SScPAH and IPAH (4 ± 1 versus 5 ± 1%, P = .9), and did not differ from controls (5 ± 1%, P = .8). In 4 SScPAH and 5 IPAH RV's foci of replacement fibrosis were found. No differences were found on epi- or endocardial inflammation or on perivascular or intimal fibrosis of coronary arteries. Conclusion. SScPAH RVs display denser inflammatory infiltrates than IPAH, while they do not differ with respect to interstitial fibrosis. Whether increased inflammatory status is a contributor to altered RV function in SScPAH warrants further research.
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