Upstream pressure for systemic to pulmonary flow from bronchial circulation in dogs

Systemic to pulmonary flow from bronchial circulation, important in perfusing potentially ischemic regions distal to pulmonary vascular obstructions, depends on driving pressure between an upstream site in intrathoracic systemic arterial network and pulmonary vascular bed. The reported increase of pulmonary infarctions in heart failure may be due to a reduction of this driving pressure. We measured upstream element for driving pressure for systemic to pulmonary flow from bronchial circulation by raising pulmonary venous pressure (Ppv) until the systemic to pulmonary flow from bronchial circulation ceased. We assumed that this was the same as upstream pressure when there was flow. Systemic to pulmonary flow from bronchial circulation was measured in left lower lobes (LLL) of 21 anesthetized open-chest dogs from volume of blood that overflowed from pump-perfused (90-110 ml/min) pulmonary vascular circuit of LLL and was corrected by any changes of LLL fluid volume (wt). Systemic to pulmonary flow from bronchial circulation upstream pressure was linearly related to systemic arterial pressure (slope = 0.24, R = 0.845). Increasing Ppv caused a progressive reduction of systemic to pulmonary flow from bronchial circulation, which stopped when Ppv was 44 +/- 6 cmH2O and pulmonary arterial pressure was 46 +/- 7 cmH2O. A further increase in Ppv reversed systemic to pulmonary flow from bronchial circulation with blood flowing back into the dog. When net systemic to pulmonary flow from bronchial circulation by the overflow and weight change technique was zero a small bidirectional flow (3.7 +/- 2.9 ml.min-1 X 100 g dry lobe wt-1) was detected by dispersion of tagged red blood cells that had been injected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Temperature alters bronchial blood flow response to pulmonary arterial obstruction

Lobar bronchial blood flow has been reported to increase and decrease acutely after pulmonary arterial obstruction (PAO). Because bronchial blood flow (Qbr) to the trachea and bronchi is influenced by inspired air temperature, we investigated whether temperature differences could explain these disparate results. In 10 open-chested dogs the left lower lobe (LLL) was isolated and perfused in situ with autologous blood at a controlled temperature with an independent vascular circuit. The abdomen and the chest of the dog were enclosed in a Plexiglas box in which air was fully humidified and temperature could be regulated. Qbr, determined by the reference flow technique using 16 micron microspheres, was measured before and 30 min after onset of PAO with the air in the box being either at 27 or 39 degrees C and with warmed LLL blood (37 degrees C) in the latter condition. Anastomotic bronchial blood flow [Qbr(s-p), determined as overflow from the closed LLL vascular circuit and measured in ml X min-1 X 100 g dry lung wt-1 X 100 Torr mean systemic pressure-1] was measured continuously at both temperatures. Both before and after PAO, Qbr and Qbr(s-p) were closely correlated: Qbr (ml/min) = 1.12 + 0.978Qbr(s-p); R = 0.912. This was true regardless of the presence or the absence of pulmonary flow, showing that the distribution of bronchial blood flow between the anastomotic and the nonanastomotic portion does not change acutely during PAO. When the air in the box was 27 degrees C, Qbr(s-p) was 19.5 +/- 5.2 (SE) and increased to 38.6 +/- 8.1 with PAO (P less than 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)     

Detection of rat Pneumocystis carinii proteinases and elastase and antipneumocystis activity of proteinase inhibitors in vitro

Proteinases play an important role in survival of microorganisms and in pathogenicity of diseases. By using a modified SDS-gelatin-polyacrylamide gel system, proteinases of rat-P.carinii were detected as bands of proteolytic digestion after electrophoresis. P.carinii organisms obtained from dexamethasone immunosuppressed transtracheally infected rats were cultured in spinner flask suspension cultures to minimize host cell contamination. At pH 8.3, seven Pc-specific proteolytic bands were detected in three clusters of different molecular weights clearly different from host cell patterns. By using a range of pH, various preparations of organisms and both infected and uninfected culture media, proteolytic activities have been partially characterized. Elastase secretion has been assessed based on elastin digestion model. Proteinase inhibitors have been tested for their ability to inhibit P.carinii growth in HEL299 short-term monolayer cultures. Results indicate that proteolytic activities are involved in the proliferation of microorganisms since leupeptin exerted in vitro antipneumocystis activity while aprotinin enhanced P.carinii growth.     

A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors

Angiotensin I-converting enzyme inhibitors (ACEi), which are used to treat common cardiovascular diseases, are associated with a potentially life-threatening adverse reaction known as angioedema (AE-ACEi). We have previously documented a significant association between AE-ACEi and low plasma aminopeptidase P (APP) activity. With eight large pedigrees, we hereby demonstrate that this quantitative trait is partially regulated by genetic factors. We tested APP activity using a variance-component QTL analysis of a 10-cM genomewide microsatellite scan enriched with seven markers over two candidate regions. We found significant linkage (LOD = 3.75) to a locus that includes the XPNPEP2 candidate gene encoding membrane-bound APP. Mutation screening of this QTL identified a large coding deletion segregating in one pedigree and an upstream single-nucleotide polymorphism (C-2399A SNP), which segregates in the remaining seven pedigrees. Measured genotype analysis strongly suggests that the linkage signal for APP activity at this locus is accounted for predominantly by the SNP association. In a separate case-control study (20 cases and 60 controls), we found significant association of this SNP to ACEi-induced AE (P=.0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in XPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi.     

Direct comparison of predictive performance of PRECISE-DAPT versus PARIS versus CREDO-Kyoto: a subanalysis of the ReCre8 trial

BackgroundMultiple scores have been proposed to guide risk stratification after percutaneous coronary intervention. This study assessed the performance of the PRECISE-DAPT, PARIS and CREDO-Kyoto risk scores to predict post-discharge ischaemic or bleeding events.MethodsA total of 1491 patients treated with latest-generation drug-eluting stent implantation were evaluated. Risk scores for post-discharge ischaemic or bleeding events were calculated and directly compared. Prognostic performance of both risk scores was assessed with calibration, Harrell’s c‑statistics net reclassification index and decision curve analyses.ResultsPost-discharge ischaemic events occurred in 56 patients (3.8%) and post-discharge bleeding events in 34 patients (2.3%) within the first year after the invasive procedure. C‑statistics for the PARIS ischaemic risk score was marginal (0.59, 95% confidence interval (CI) 0.51–0.68), whereas the CREDO-Kyoto ischaemic risk score was moderate (0.68, 95% CI 0.60–0.75). With regard to post-discharge bleeding events, CREDO-Kyoto displayed moderate discrimination (c-statistic 0.67, 95% CI 0.56–0.77), whereas PRECISE-DAPT (0.59, 95% CI 0.48–0.69) and PARIS (0.55, 95% CI 0.44–0.65) had a marginal discriminative capacity. Net reclassification index and decision curve analysis favoured CREDO-Kyoto-derived bleeding risk assessment.ConclusionIn this contemporary all-comer population, PARIS and PRECISE-DAPT risk scores were not resilient to independent testing for post-discharge bleeding events. CREDO-Kyoto-derived risk stratification was associated with a moderate predictive capability for post-discharge ischaemic or bleeding events. Future studies are warranted to improve risk stratification with more focus on robustness and rigorous testing.Electronic supplementary materialThe online version of this article (10.1007/s12471-020-01486-y) contains supplementary material, which is available to authorized users.