Reactivity of pulmonary circulation and right ventricle function to inhaled nitric oxide in systemic sclerosis patients

Systemic sclerosis (SSc) is complicated by pulmonary hypertension and right ventricle (RV) failure in approximately 10% of the patients. Factors influencing the reactivity of pulmonary circulation to vasodilators are not established, while the examination of vasoreactivity is important in determining the treatment, because systemic administration of oral vasodilators can induce severe adverse events in nonresponders. The mechanism of RV failure in SSc is unclear and may result either from increased RV afterload or intrinsic myocardial disease. The aim of the study was to assess the reactivity of pulmonary circulation to inhaled nitric oxide (iNO) and to evaluate its influence on RV function in SSc patients with elevated right ventricle systolic pressure (RVSP). In 60 SSc patients aged 24–73 (58 females, two males; 33 patients with limited SSc and 27 with diffuse SSc), echocardiographic examination with tissue Doppler echocardiography (TDE) was performed. RV function was measured by systolic (S) and early diastolic (E) velocity of tricuspid annulus by TDE. In patients with RVSP >45 mmHg, the reactivity of pulmonary circulation was assessed by iNO test. High-resolution computerized tomography (HRCT) was performed to assess the extent of pulmonary fibrosis. Of 14 SSc subjects with elevated RVSP (13 females, one male; RVSP 47–62 mmHg), positive reaction to iNO was observed in five (RVSP decreased from 51.6 ± 3.7 to 32.24 ± 2.3 mmHg); nine patients were not reactive (RVSP 53.5 ± 5.7 mmHg before iNO vs. 49.6 ± 6.7 mmHg). RV systolic function was decreased in patients with elevated RVSP as compared to the patients with normal pulmonary pressure (S velocity 13.2 ± 1.3 vs. 14.4 ± 1.6 cm/s, respectively, p < 0.05). Significant increase of RV systolic function during iNO test was found in reactive patients only (S velocity before iNO 12.8 ± 1.2 cm/s, during iNO 14.5 ± 1.5 cm/s, p < 0.01). RVSP decrease strongly correlated with S velocity increase (r = 0.95, p < 0.0001). Response to iNO was found only in limited form of SSc; diffuse SSc patients showed no response. Pulmonary fibrosis on HRCT was more frequent in subjects nonreactive to iNO (67% of patients) than in the reactive group (40% of patients). The reactivity of pulmonary circulation to iNO in SSc patients with elevated RVSP was found predominantly in limited form of the disease. Pulmonary fibrosis typical for diffuse SSc was more frequent in nonreactive subjects. Elevated pulmonary pressure plays an important role in RV systolic dysfunction. Pulmonary pressure decrease during iNO test leads to the improvement of RV systolic function. Therapy for right-heart failure in reactive SSc patients should be directed, if possible, at the decrease in pulmonary resistance

Down-regulation of protein kinase Cdelta inhibits inducible nitric oxide synthase expression through IRF1

Peer reviewe

Identification of QTL for resistance and susceptibility to Stagonospora meliloti in autotetraploid lucerne

In eastern Australia and California, USA, one of the major lethal fungal diseases of lucerne (Medicago sativa) is Stagonospora root and crown rot, caused by Stagonospora meliloti. Quantitative trait loci (QTL) involved in resistance and susceptibility to S. meliloti were identified in an autotetraploid lucerne backcross population of 145 individuals. Using regression analysis and interval mapping, we detected one region each on linkage groups 2, 6 and 7 that were consistently associated with disease reaction to S. meliloti in two separate experiments. The largest QTL on linkage group 7, which is associated with resistance to S. meliloti, contributed up to 17% of the phenotypic variation. The QTL located on linkage group 2, which is potentially a resistance allele in repulsion to the markers for susceptibility to S. meliloti, contributed up to 8% of the phenotypic variation. The QTL located on linkage group 6, which is associated with susceptibility to S. meliloti, contributed up to 16% of the phenotypic variation. A further two unlinked markers contributed 5 and 8% of the phenotypic variation, and were detected in only one experiment. A total of 517 simple sequence repeat (SSR) markers from Medicago truncatula were screened on the parents of the mapping population. Only 27 (6%) SSR markers were polymorphic and could be incorporated into the autotetraploid map of M. sativa. This allowed alignment of our M. sativa linkage map with published M. truncatula maps. The markers linked to the QTL we have reported will be useful for marker assisted selection for partial resistance to S. meliloti in lucerne