Predictors of exacerbation in Japanese patients with severe asthma: Analysis of the severe asthma research program (Okayama-SARP) cohort.

BACKGROUND: Because exacerbation of severe asthma decreases patients' quality of life, this study aimed to identify predictive factors for asthma exacerbation. METHODS: Japanese patients with severe asthma requiring treatment according to the Global Initiative for Asthma (GINA) guidelines ≥ Step 4 between January 2018 and August 2021 were prospectively enrolled and followed up for one year at facilities participating in the Okayama Respiratory Disease Study Group (Okayama Severe Asthma Research Program). RESULTS: A total of 85 patients (29 men and 56 women) were included. The median age was 64 (interquartile range [IQR], 51-72) years. Treatment according to GINA Steps 4 and 5 was required in 29 and 56 patients, respectively, and 44 patients (51.8%) were treated with biologics. The median peripheral-blood eosinophil count, fractional exhaled nitric oxide, IgE level, and percent predicted FEV1 (%FEV1) at enrollment were 204 (IQR, 49-436)/µL, 28 (IQR, 15-43) ppb, 172 (IQR, 56-473) IU/mL, and 80.0 (IQR, 61.1-96.1) %, respectively. Exacerbation during the previous year, asthma control test (ACT) score <20, %FEV1 <60%, and serum IL-10 level >6.7 pg/mL were associated with exacerbation during the observation period. CONCLUSIONS: Exacerbation during the previous year, low ACT score, and low %FEV1 were predictive factors of future exacerbation, even in a cohort with >50% of patients treated with biologics. Furthermore, high serum IL-10 levels might be a new predictive factor.

Solitary pulmonary nodules caused by Mycobacterium avium complex.

BACKGROUND: The prevalence of Mycobacterium avium complex (MAC) pulmonary disease (PD) is increasing significantly in Japan. Among the patterns of MAC-PD, a solitary pulmonary nodule (SPN) is less common and often resembles lung cancer. The aim of this study was to identify the clinical features of MAC-SPN. METHODS: SPNs culture-positive for MAC (definite cases) and culture-negative SPNs showing nucleic acid amplification test (NAAT)-positive status (probable cases) that presented between January 2007 and December 2017 were enrolled. The patients' clinical, laboratory, radiological, and microbiological findings and outcomes were investigated. RESULTS: This study included 28 patients (median age, 66 years; 16 men, 12 women). All patients were asymptomatic when the disease was detected. Median SPN size was 23.5 mm. Twenty-six patients underwent video-assisted thoracoscopic surgery, while the others underwent percutaneous needle biopsy for diagnosis. Granulomatous inflammation was confirmed in all cases. Microbiologically, the 28 cases were divided into 17 in the definite group and 11 in the probable group. In both groups, M. avium was predominant. There were no significant differences in clinical and radiological findings and follow-up periods between the 2 groups. After diagnosis, 6 patients received medical treatment, while the others did not. The median follow-up period was 42 months, and no recurrence was observed in both groups. CONCLUSIONS: MAC should be considered in the differential diagnosis of SPNs in asymptomatic patients. To overcome the difficulties in diagnosing MAC-SPN, this study underscores the importance of diagnostic interventions and identification of MAC by culture and/or NAAT in biopsied specimens.

Effects of glycoprotein IIb/IIIa inhibition on microvascular flow after coronary reperfusion. A quantitative myocardial contrast echocardiography study.

OBJECTIVES: We assessed the effect of glycoprotein IIb/IIIa inhibition (GPI) on microvascular flow after coronary occlusion/reperfusion using quantitative myocardial contrast echocardiography (QMCE). BACKGROUND: Platelets may play a major role in the dissociation of epicardial artery recanalization and tissue-level reperfusion, referred to as the "no-reflow phenomenon." Therefore, GPI might improve myocardial reperfusion, distinct from its effects on epicardial patency.T METHOD: hree-hour occlusion of the left anterior descending coronary artery (LAD) was followed by 3-h reperfusion in 16 open-chest dogs: 8 controls and 8 given a continuous infusion of the GPI tirofiban, starting 45 min before LAD reopening. Perfusion of the LAD bed was quantified by the rate of intensity rise (b) by QMCE; myocardial blood flow (MBF) was assessed by fluorescent microspheres. RESULTS: No differences in b or MBF were observed within the risk area between the control and GPI groups at baseline or occlusion. However, b and MBF were higher in GPI dogs than in controls during reperfusion, despite similar epicardial flow (p < 0.05 at 30, 60, and 90 min; p = NS at 180 min). Infarct area size was significantly reduced in GPI dogs compared with non-treated dogs (26.9 +/- 10.5% vs. 49.0 +/- 11.1% of at-risk area, respectively). CONCLUSIONS: As demonstrated by QMCE, GPI improves microvascular flow and reduces the infarct area after coronary occlusion/reperfusion, independent of epicardial flow. These data demonstrate the usefulness of QMCE in assessing microvascular flow, provide novel evidence for the role of platelets in the early phase of reperfusion injury, and show that GPI is of value in preserving microvascular perfusion after coronary reperfusion.

Visualization of risk-area myocardium as a high-intensity, hyperenhanced "hot spot" by myocardial contrast echocardiography following coronary reperfusion: quantitative analysis.

OBJECTIVES: We examined whether delayed post-injection imaging of a new ultrasound contrast agent (BR-14) could produce prolonged opacification and hyperenhancement of myocardium subjected to coronary occlusion/reperfusion. BACKGROUND: We hypothesized that ultrasound exposure destroyed BR-14 and eliminated visualization of sustained myocardial opacification from retained microbubbles. METHODS: We studied eight open-chest dogs with 3 h of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Myocardial contrast echocardiography (MCE) was performed before occlusion and 120 min after the onset of both occlusion and reperfusion. Ultrasound imaging was initiated 15 min after injection. Myocardial blood flow (MBF) was assessed by microspheres. RESULTS: Pre-occlusion images revealed uniform opacification of left ventricular myocardium greater than that of the cavity, with a mean intensity of the LAD bed of 8.66 +/- 1.38 dB. During occlusion, MCE resulted in the appearance of a perfusion defect in the LAD risk area (intensity 2.08 +/- 1.10 dB). After 120 min of reperfusion, the LAD risk-area myocardium manifested dense opacification of a higher intensity ("hot spot") than baseline (13.7 vs. 8.7 dB), but with reduced MBF consistent with accumulation of a high concentration of microbubbles. Increased MCE intensity was associated with a greater myeloperoxidase score. CONCLUSIONS: These data establish that contrast opacification by BR-14 may be selectively retained within the perfusion bed of a coronary artery subjected to occlusion/reperfusion. Such opacification exhibits defects with occlusion, manifests hyperenhanced intensity (hot spot) with reperfusion, is associated with the level of myeloperoxidase activity, and conforms to the area of myocardium subjected to altered flow.

Respiratory variation in superior vena cava flow in patients with chronic obstructive pulmonary disease: estimation of pulmonary hypertension using Doppler flow index.

Patients with chronic obstructive pulmonary disease (COPD) are difficult to assess by conventional transthoracic echocardiography (TTE) because of emphysematous lungs or mediastinal deviation. We hypothesized that superior vena cava (SVC) flow is related to pulmonary circulation and may be useful for the detection of pulmonary hypertension (PH) in patients with COPD that cannot been assessed by direct evaluation using the tricuspid regurgitant Doppler velocity. SVC Doppler flow velocities were examined in 46 patients with COPD and the pressure gradient between the right ventricular and right atrial pressure (RV-RADeltaP) was calculated by tricuspid regurgitant Doppler velocities. The patients were divided into 2 groups: 11 patients with PH (RV-RADeltaP > 25 mm Hg) were compared with 35 without PH. There was no significant difference in the maximal SVC peak systolic forward flow velocity during inspiration (INS) between these 2 groups. However, the minimal SVC peak systolic forward flow velocity during expiration (EXP) in the group with PH was significantly higher than that in the group without PH (37.4 +/- 20.0 cm/s vs 26.4 +/- 8.5 cm/s, P =.01). Linear regression analysis revealed a significant correlation between RV-RADeltaP and the EXP/INS ratio (r = 0.61, P <.001). In COPD patients with PH, the increased expiratory SVC systolic flow supplemented the preload for the impaired right ventricular filling flow caused by PH, thereby maintaining the transtricuspid driving pressure. Our observation suggests that respiratory variation in SVC systolic forward flow may be a sensitive Doppler flow index for evaluating severity of PH in patients with COPD that cannot been assessed by conventional TTE.

Overexpression of TRPC1 enhances pulmonary vasoconstriction induced by capacitative Ca2+ entry.

Transient receptor potential (TRP) cation channels are a critical pathway for Ca2+ entry during pulmonary artery (PA) smooth muscle contraction. However, whether canonical TRP (TRPC) subunits and which TRP channel isoforms are involved in store depletion-induced pulmonary vasoconstriction in vivo remain unclear. This study was designed to test whether overexpression of the human TRPC1 gene (hTRPC1) in rat PA enhances pulmonary vasoconstriction due to store depletion-mediated Ca2+ influx. The hTRPC1 was infected into rat PA rings with an adenoviral vector. RT-PCR and Western blot analyses confirmed the mRNA and protein expression of hTRPC1 in the arterial rings. The amplitude of active tension induced by 40 mM K+ (40K) in PA rings infected with an empty adenoviral vector (647 +/- 88 mg/mg) was similar to that in PA rings infected with hTRPC1 (703 +/- 123 mg/mg, P = 0.3). However, the active tension due to capacitative Ca2+ entry (CCE) induced by cyclopiazonic acid was significantly enhanced in PA rings overexpressing hTRPC1 (91 +/- 13% of 40K-induced contraction) compared with rings infected with an empty adenoviral vector (61 +/- 14%, P < 0.001). Endothelial expression of hTRPC1 was not involved since the CCE-induced vasoconstriction was also enhanced in endothelium-denuded PA rings infected with the adenoviral vector carrying hTRPC1. These observations demonstrate that hTRPC1 is an important Ca(2+)-permeable channel that mediates pulmonary vasoconstriction when PA smooth muscle cell intracellular Ca2+ stores are depleted.

Bosentan inhibits transient receptor potential channel expression in pulmonary vascular myocytes.

Bosentan, a dual endothelin receptor blocker, has been used clinically to treat idiopathic pulmonary arterial hypertension (IPAH). However, the mechanism of its antiproliferative effect on pulmonary artery smooth muscle cells (PASMCs) remains unclear. A rise in cytoplasmic Ca2+ stimulates PASMC proliferation and the canonical transient receptor potential (TRPC) channels are an important pathway for Ca2+ entry during PASMC proliferation. Bosentan (20-50 microM) significantly inhibited endothelin-1- or platelet-derived growth factor (PDGF)-mediated PASMC growth and [3H]thymidine uptake. In PASMCs, endothelin-1 (1 microM) and PDGF (10 ng/ml) both upregulated protein expression of TRPC6, whereas bosentan markedly downregulated TRPC6 protein levels. Furthermore, TRPC6 expression in PASMCs from patients with IPAH was greater than in normal PASMCs, and the antiproliferative effect of bosentan was significantly enhanced in IPAH-PASMCs in comparison with normal PASMCs. These observations demonstrate that the antiproliferative effect of bosentan on PASMCs involves the downregulation of TRPC6 channels via a mechanism possibly independent of endothelin receptor blockade. The greater effect of bosentan on IPAH-PASMCs than on normal PASMCs suggests that increased TRPC6 expression and function may be involved in the overgrowth of PASMCs in patients with IPAH.

Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension.

Pulmonary vascular medial hypertrophy caused by excessive pulmonary artery smooth muscle cell (PASMC) proliferation is a major cause for the elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Increased Ca(2+) influx is an important stimulus for PASMC proliferation. Transient receptor potential (TRP) channel genes encode Ca(2+) channels that are responsible for Ca(2+) entry during cell proliferation. Normal human PASMC expressed multiple canonical TRP (TRPC) isoforms; TRPC6 was highly expressed and TRPC3 was minimally expressed. The protein expression of TRPC6 in normal PASMC closely correlated with the expression of Ki67, suggesting that TRPC6 expression is involved in the transition of PASMC from quiescent phase to mitosis. In lung tissues and PASMC from IPAH patients, the mRNA and protein expression of TRPC3 and -6 were much higher than in those from normotensive or secondary pulmonary hypertension patients. Inhibition of TRPC6 expression with TRPC6 small interfering RNA markedly attenuated IPAH-PASMC proliferation. These results demonstrate that expression of TRPC channels correlates with the progression of the cell cycle in PASMC. TRPC channel overexpression may be partially responsible for the increased PASMC proliferation and pulmonary vascular medial hypertrophy in IPAH patients.