Angiotensin II Formation in Human Vasculature after Chronic ACE Inhibition: A Prospective, Randomized, Placebo-Controlled Study

The QUO VADIS (the effects of QUinapril On Vascular Ace and Determinants of ISchemia) study was a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of long-term angiotensin-converting enzyme (ACE) inhibition on angiotensin II formation in human vasculature. Patients (n < 187) scheduled for coronary artery bypass surgery used study medication 27 ± 1 days before surgery. Segments of internal mammary arteries were exposed to increasing doses (0.1 nM-1 µM) of angiotensin I and II in organ baths. The rate of local angiotensin II formation is a function of the reciprocal of the difference between the pEC₅₀'s of the dose response curves to angiotensin I and II (–log/mol) and of the area between the curves (units). Quinapril (40 mg) and captopril (3×50 mg) similarly and significantly reduced mean blood pressure compared with placebo (p = 0.04). Difference between pEC₅₀'s was 0.90 ± 0.08 in quinapril patients compared with 0.60 ± 0.08 for placebo (p <5 0.01); the area between curves was 91 ± 8 for quinapril patients compared with 67 ± 8 for placebo (p = 0.03). Angiotensin II formation was decreased to a lesser extent with captopril and was not statistically different from placebo (p = 0.3); the difference between pEC₅₀'s was 0.83 ± 0.15; the area between curves was 84 ± 12. This is the first randomized study to demonstrate that long-term oral treatment with an ACE inhibitor reduces vascular angiotensin II formation in humans.     

Zur toxikologischen Bewertung der Lokalan?sthetika Lidocain und Tetracain bei Drogentodesf?llen

In Berlin traten in den letzten Jahren vermehrt Drogentodesf?lle mit Blutkonzentrationen an Lidocain bis 33 μg/ml oder dem Tetracainmetaboliten 4-n-Butylaminobenzoes?ure bis 8,6 μg/ml auf, die auf die Injektion der Lokalan?sthetika als Beimischungen zu Cocain, Heroin oder Cocain-Heroin-Zubereitungen zurückzuführen sind. Der Vergleich der in 46 F?llen festgestellten Lidocainkonzentrationen mit denen von 38 andersartigen Todesf?llen, bei denen dieser Wirkstoff als Antiarrhythmikum bei Reanimationsversuchen diente (0,1 bis 24 μg/ml), und mit Literaturdaten von An?sthesieunf?llen ergab, da? in vielen dieser F?lle hochtoxische bis komat?s-letale Werte erreicht wurden, die allein oder in Kombination mit anderen Bet?ubungsmitteln den Todeseintritt durch L?hmung des ZNS oder Blockade des kardialen Reizleitungssystems erkl?ren. In 7 F?llen wurde eine 4-n-Butylaminobenzoes?ure-Konzentration oberhalb 4 μg/ml (entspr. > 5,5 μg/ml Tetracain) festgestellt. Hier kann die Tetracainapplikation als todesurs?chlich angesehen werden. Diese Werte best?tigen die aus der Literatur bekannte h?here systemische Toxizit?t des Tetracains im Vergleich zum Lidocain.     

Fungal endophytes limit pathogen damage in a tropical tree

Every plant species examined to date harbors endophytic fungi within its asymptomatic aerial tissues, such that endophytes represent a ubiquitous, yet cryptic, component of terrestrial plant communities. Fungal endophytes associated with leaves of woody angiosperms are especially diverse; yet, fundamental aspects of their interactions with hosts are unknown. In contrast to the relatively species-poor endophytes that are vertically transmitted and act as defensive mutualists of some temperate grasses, the diverse, horizontally transmitted endophytes of woody angiosperms are thought to contribute little to host defense. Here, we document high diversity, spatial structure, and host affinity among foliar endophytes associated with a tropical tree (Theobroma cacao, Malvaceae) across lowland Panama. We then show that inoculation of endophyte-free leaves with endophytes isolated frequently from naturally infected, asymptomatic hosts significantly decreases both leaf necrosis and leaf mortality when T. cacao seedlings are challenged with a major pathogen (Phytophthora sp.). In contrast to reports of fungal inoculation inducing systemic defense, we found that protection was primarily localized to endophyte-infected tissues. Further, endophyte-mediated protection was greater in mature leaves, which bear less intrinsic defense against fungal pathogens than do young leaves. In vitro studies suggest that host affinity is mediated by leaf chemistry, and that protection may be mediated by direct interactions of endophytes with foliar pathogens. Together, these data demonstrate the capacity of diverse, horizontally transmitted endophytes of woody angiosperms to play an important but previously unappreciated role in host defense.     

Catheter ablation of accessory pathways using radiofrequency energy in the canine coronary sinus

Ablation of a left-sided accessory pathway with high energy direct-current shocks delivered by an electrode catheter in the coronary sinus is associated with the risk of coronary sinus rupture. The safety and effectiveness of closed chest catheter desiccation in the coronary sinus with use of radiofrequency energy was studied. Radiofrequency energy (174 +/- 74 J) was applied between the distal electrode of a standard electrode catheter placed 3 to 6 cm inside the coronary sinus and a large posterior chest wall patch in 16 dogs. No arrhythmias or hemodynamic changes were observed. Three dogs were killed approximately 1 h after ablation and 13 after 2 to 4 weeks. Lesions in the atrioventricular (AV) sulcus were observed in 14 of 16 dogs. Lesions were 11.6 +/- 6 mm in length, 4.3 +/- 2.3 mm in width and 2.8 +/- 1.4 mm in depth. Microscopic examination showed well circumscribed areas of necrosis and fibrosis in the fat of the AV sulcus. The media and intima of the circumflex coronary artery were not involved nor was the endocardium or mitral apparatus damaged in any dog. Coronary sinus thrombus was present in 3 of 16 dogs. Large amounts of radiofrequency energy can be safely applied to the coronary sinus. The size and location of the lesions produced suggest that this technique may be useful for the interruption of left-sided accessory AV connections in humans.     

Hemodynamic and clinical correlates of endothelin-1 in chronic thromboembolic pulmonary hypertension.

BACKGROUND: In non-thromboembolic pulmonary hypertension, endothelin (ET)-1 levels are increased and correlate with the hemodynamic severity of the disease. Whether such correlations exist in chronic thromboembolic pulmonary hypertension (CTEPH) is unknown, nor whether ET-1 levels correlate with hemodynamic outcome after pulmonary endarterectomy (PEA). METHODS AND RESULTS: ET-1 levels were determined by ELISA. ET-levels were increased in 35 CTEPH patients (1.62+/-0.21 pg/ml) compared with healthy controls (n=11: 0.75+/-0.06 pg/ml, p<0.02). ET-1 levels correlated (all p<0.0001) with mean pulmonary artery pressure (mPAP) (r=0.70), cardiac index (r=-0.76), total pulmonary resistance (r=0.72), mixed venous oxygen saturation (r=-0.87), and the distance walked in the 6-min walk test (r=-0.59; p<0.005; n=23). Three months after PEA, ET-1 levels had decreased (p<0.002), and were similar between patients with and without residual pulmonary hypertension (p=0.4). Preoperative ET-1 levels, however, were higher in patients with bad postoperative outcome; that is, patients who either died because of persistent pulmonary hypertension or had residual pulmonary hypertension after PEA (2.68+/-0.48 pg/ml, and 1.13+/-0.15 pg/ml, respectively; p<0.002). The levels also correlated with hemodynamic outcome after PEA (mPAP: r=0.67, p<0.0001). By receiver-operator characteristic curve analysis, ET-1>1.77 pg/ml detected a bad postoperative outcome with a sensitivity and specificity of 79% and 85%, respectively, and a likelihood ratio of 5.2. CONCLUSION: ET-1 levels in CTEPH closely correlated with the hemodynamic and clinical severity of disease in a large cohort of patients. Preoperative ET-1 levels may be useful for better identification of patients at risk for persistent pulmonary hypertension after PEA.     

Abnormal conduction increases risk of adverse outcomes from right ventricular pacing.

OBJECTIVES: The purpose of this study was to determine whether QRS duration or morphology increased the risk of adverse outcome in the DAVID (Dual Chamber and VVI Implantable Defibrillator) trial. BACKGROUND: The DAVID trial found an increased risk of the combined end point of death and new or worsening congestive heart failure (CHF) in defibrillator recipients who were paced DDDR-70 versus VVI-40. METHODS: We analyzed the combined end point in patients with abnormal QRS duration (AbQRS) (> or =110 ms) compared with those with normal QRS duration (NQRS) (<110 ms). RESULTS: The QRS data were available for 496 of the 506 patients enrolled in the trial, including 223 patients with NQRS (45%) and 273 patients with AbQRS (55%). In patients in whom defibrillators were programmed to pace infrequently (VVI-40), having an NQRS or AbQRS was not an indicator of increased risk of adverse outcome. However, among patients in whom defibrillators were programmed in a manner that promoted more frequent ventricular pacing (DDDR-70), there was a significant adverse interaction with AbQRS; this combination was independently associated with a higher risk for developing CHF or death (p = 0.017). CONCLUSIONS: Although patients with AbQRS tended to have other risk factors associated with poor outcome, the interaction of QRS duration with ventricular pacing (DDDR-70) independently contributed to a worse outcome and therefore, was a marker of patients in whom such treatment may be harmful. This should not imply that right ventricular pacing in NQRS patients is safe but rather that pacing in the context of an AbQRS is probably best avoided.     

High flow nasal cannula for acute respiratory failure due to COVID‐19 in patients with a ‘do‐not‐intubate’ order: A survival analysis

IntroductionHigh flow nasal cannula (HFNC) reduces the need for intubation in patients with hypoxaemic acute respiratory failure (ARF), but its added value in patients with severe coronavirus disease 2019 (COVID‐19) and a do‐not‐intubate (DNI) order is unknown. We aimed to assess (variables associated with) survival in these patients.Materials and methodsWe described a multicentre retrospective observational cohort study in five hospitals in the Netherlands and assessed the survival in COVID‐19 patients with severe acute respiratory failure and a DNI order who were treated with high flow nasal cannula. We also studied variables associated with survival.Results and discussionOne‐third of patients survived after 30 days. Survival was 43.9% in the subgroup of patients with a good WHO performance status and only 16.1% in patients with a poor WHO performance status. Patients who were admitted to the hospital for a longer period prior to HFNC initiation were less likely to survive. HFNC resulted in an increase in ROX values, reflective of improved oxygenation and/or decreased respiratory rate.ConclusionOur data suggest that a trial of HFNC could be considered to increase chances of survival in patients with ARF due to COVID‐19 pneumonitis and a DNI order, especially in those with a good WHO performance status.