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Introduction: We have recently reported that ALN-AGT, a subcutaneous (SC) investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, reduced BP and was generally well tolerated in a single ascending dose study of hypertensive patients. To further assess its safety profile, additional studies have been initiated to test the effects of peak ALN-AGT pharmacology during salt depletion or irbesartan add-on treatment. Methods: As part of a Phase 1 program, hypertensive patients (mean seated SBP of >130 and ≤165 mm Hg after washout of antihypertensive medication) were given a single dose of ALN-AGT 800 mg SC that has been shown to reduce serum AGT by ≥95%. At Day 43 (corresponding to expected peak serum AGT reduction), these ALN-AGT-treated patients were admitted to receive interventions of a 7-day sodium restricted diet (10 mmol sodium day) or a 14-day add-on treatment regimen with the angiotensin receptor blocker irbesartan 300 mg by oral administration daily. Results: In the salt depletion cohort, 12 patients (mean age 56 years, 75% male, 25% black, mean baseline 24-h SBP 141+/- 8 mm Hg) have been dosed 2:1 with ALN-AGT or placebo SC in advance of the sodium restricted diet. In the irbesartan add-on cohort, 10 patients (mean age 55 years, 30% male, 30% black, mean baseline 24-h SBP 147 +/- 8 mm Hg) have received ALN-AGT in advance of irbesartan add-on. The study has completed patient enrollment and interventions with no patient discontinuations due to AEs. The data analysis is ongoing at the time of abstract submission. Conclusions: This ongoing study will provide insight into ALN-AGT tolerability during potential augmented pharmacology, using salt restriction to test ALN-AGT’s effects during reduced extracellular fluid volume and irbesartan coadministration to assess the effects of ALN-AGT’s liver-specific AGT silencing during angiotensin II receptor blockade. Data on tolerability, laboratory safety monitoring, serum AGT reduction, RAAS-related biomarkers, and blood pressure will be presented.

Introduction: ALN-AGT, a subcutaneous (SC) investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, is being evaluated as a novel treatment for hypertension in a multicenter, randomized, placebo-controlled single ascending dose study. Here we present new data on the long-term pharmacodynamic and antihypertensive effects of ALN-AGT six months after single-dose administration. Methods: As part of a Phase 1 program to assess the safety and tolerability of ALN-AGT, hypertensive patients (mean seated systolic blood pressure [SBP] of >130 and ≤165 mmHg after a washout of antihypertensive medications) were randomized 2:1 to ascending single doses of ALN-AGT (10-800 mg) or placebo. Change from baseline BP was measured by ambulatory BP monitoring (ABPM) at Week 8, Week 12, and Month 6. Interim results as of May 28, 2021 are reported. Results: 84 hypertensive patients (mean age 53 years, 61% male, 26% black, mean (SD) baseline 24-h SBP 140 (9) mm Hg) were enrolled in ascending single dose cohorts of ALN-AGT up to 800 mg SC. Dose-dependent and durable reductions in serum AGT levels were observed, with single doses ≥100 mg achieving serum AGT reductions >90% and 24-h SBP reductions >10 mm Hg (17 mm Hg in the 800 mg cohort) through Week 12. The 24-hour ABPM profile of ALN-AGT-treated patients showed sustained reductions of daytime BP with equally marked nighttime BP reduction. Notably, new data from follow-up visits show that all patients who received a single dose of 800 mg maintained serum AGT reductions >90% from Week 3 to Month 6, with a mean (SD) 24-h SBP reduction of 22 (15) mm Hg at Month 6 (5 of 8 patients without add-on antihypertensive treatment). There were no treatment-related serious adverse events or clinically significant elevations in blood creatinine or potassium. No patient required intervention for hypotension. Conclusions: Single dose administration of ALN-AGT to hypertensive patients was generally well tolerated and resulted in profound reductions in serum AGT and BP through Month 6. The durable reduction of serum AGT >90% with sustained 24-hour BP reduction over a period of 6 months after single dose SC administration of ALN-AGT 800 mg supports further evaluation of both quarterly and biannual dose administration.

Bedside cardiac output (CO) measurement is an important part of routine hemodynamic monitoring in the differential diagnosis of circulatory shock and fluid management. Different choices of CO measurement devices are available. The purpose of this review is to review the importance of CO [or stroke volume (SV)] measurement and to discuss the various methods (devices) used in determination of CO.CO measurement devices can be classified into two types: those use simple physical principles with minimal assumptions, and those predicting CO via mathematical modelling with a number of assumptions. Both have pros and cons, with the former being more accurate but with limited continuous monitoring capability whereas the latter less accurate but usually equipped with continuous monitoring functionality. With frequent updates in mathematical models, research data constantly become outdated in this area. Recent data suggest devices based on mathematical modelling have limited accuracies and poor precisions.Measurement of CO or SV is important in critically ill patients. Most devices have accuracy and reliability issues. The choice of device should depend on the purpose of measurement. For diagnostic purposes, devices based on simple physical principles, especially thermodilution and transthoracic echocardiography are more reliable due to accuracy.

Background: Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides and plays a key role in hypertension pathogenesis. We evaluated the effect of ALN-AGT01, a subcutaneous investigational RNAi therapeutic targeting hepatic AGT synthesis, on blood pressure in hypertensive patients. Methods: As part of a phase 1 program designed to assess the safety and tolerability of ALN-AGT01, we conducted a multicenter study randomizing patients aged 18-65 years with mild to moderate hypertension (mean seated systolic blood pressure [SBP] of >130 and ≤165 mmHg after washout of antihypertensive medication) 2:1 to ascending single doses of ALN-AGT01 or placebo. Change from baseline in BP at 8 weeks was measured by ambulatory BP monitoring (ABPM). We report interim results as of May 14, 2020. Results: Sixty patients (mean age 52 years, 45% female, mean baseline 24h SBP 139 +/- 7 mm Hg) were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg. Dose-related reductions in serum AGT levels were observed (figure), with reductions >90% in the 100 and 200 mg dose cohorts. AGT remained durably reduced through 12 weeks after single dose administration. Concomitant reductions in BP from baseline were observed with AGT knockdown, with an over 10 mm Hg reduction of mean 24-hour SBP observed at Week 8 after single doses of 100 mg or 200 mg. No symptomatic hypotension, treatment-related serious adverse events, or clinically significant elevations in blood creatinine or potassium were seen. Conclusions: Single dose administration of ALN-AGT01 to hypertensive patients resulted in dose-related reductions in serum AGT and BP over 8 weeks without hypotension or other related serious adverse events. Durable AGT knockdown to 12 weeks supports further evaluation of once quarterly or potentially less frequent dose administration.

Objectives Competence in point-of-care ultrasound is recommended/mandated by several critical care specialties. Although doctors commonly attend point-of-care ultrasound short-courses for introductory training, there is little follow-up data on whether they eventually attain competence. This study was done to determine the impact of point-of-care ultrasound short-courses on point-of-care ultrasound competence. Design Web-based survey. Setting Follow-up after point-of-care ultrasound short-courses in the Asia-Pacific region. Subjects Doctors who attended a point-of-care ultrasound short-course between December 2015 and February 2018. Interventions Each subject was emailed a questionnaire on or after 6 months following their short-course. They were asked if they had performed at least 30 structured point-of-care ultrasound scans and/or reached point-of-care ultrasound competence and their perceived reasons/challenges/barriers. They were also asked if they used point-of-care ultrasound as a clinical diagnostic aid. Measurements and main results The response rate was 74.9% (182/243). Among the 182 respondents, only 12 (6.6%) had attained competence in their chosen point-of-care ultrasound modality, attributing their success to self-motivation and time management. For the remaining doctors who did not attain competence (170/182, 93.4%), the common reasons were lack of time, change of priorities, and less commonly, difficulties in accessing an ultrasound machine/supervisor. Common suggestions to improve short-courses included requests for scanning practice on acutely ill ICU patients and prior information on the challenges regarding point-of-care ultrasound competence. Suggestions to improve competence pathways included regular supervision and protected learning time. All 12 credentialled doctors regularly used point-of-care ultrasound as a clinical diagnostic aid. Of the 170 noncredentialled doctors, 123 (72.4%) reported performing unsupervised point-of-care ultrasound for clinical management, either sporadically (42/170, 24.7%) or regularly (81/170, 47.7%). Conclusions In this survey of doctors attending point-of-care ultrasound short-courses in Australasia, the majority of doctors did not attain competence. However, the practice of unsupervised point-of-care ultrasound use by noncredentialled doctors was common. Further research into effective strategies to improve point-of-care ultrasound competence is required.

A single dose of small interfering ribonucleic acids (siRNA) targeting angiotensinogen (AGT) provides a strong and sustained antihypertensive effect, lasting weeks to months in preclinical models. It is not known whether conventional vasopressors are effective to reverse RNAi-mediated blood pressure lowering. Here, we investigated whether conventional vasopressors can elevate arterial pressure under conditions of AGT depletion. Spontaneously hypertensive rats on a low-salt diet (

Deoxycorticosterone acetate (DOCA)-salt is suggested to increase blood pressure via selective upregulation of the brain renin-angiotensin system (RAS), while suppressing the circulating RAS. Yet, we have observed parallel downregulation of plasma and brain renin in mice. Here, we quantified brainstem angiotensinogen (AGT) and angiotensin (Ang) levels in rats exposed to DOCA (200mg; 60-day release) and 0.9% NaCl as drinking water for 7 weeks. To determine the contribution of AGT (liver vs. kidney/brain), Ang II type 1 receptors (AT1R) and blood pressure to tissue Ang II content, rats received vehicle, liver-targeted AGT siRNA (10 mg/kg fortnightly; s.c.), valsartan (31 mg/kg/day; s.c.) or spironolactone (80 mg/kg/day; s.c.) during the final 3 weeks, the latter fully normalizing blood pressure (n=3-9 per group). Plasma renin and AGT were determined by enzyme-kinetic assay, tissue AGT by western blotting, and Ang I and II by LC-MS/MS. Plasma renin, AGT, Ang I and II in rats not exposed to DOCA-salt were 24±8ng Ang I/mL per h, 731±51nM, 123±38pM and 109±43pM. AGT was present in liver, kidney and brainstem. Kidney Ang I and II were 540±135and 510±97fmol/g, while brainstem Ang I and II were undetectable in all and 50% of the rats, respectively (

There is currently no reliable tool available to measure immune dysfunction in septic patients in the clinical setting. This proof-of-concept study assesses the potential of gene expression profiling of whole blood as a tool to monitor immune dysfunction in critically ill septic patients. Whole-blood samples were collected daily for up to 5 days from patients admitted to the intensive care unit with sepsis. RNA isolated from whole-blood samples was assayed on Illumina HT-12 gene expression microarrays consisting of 48,804 probes. Microarray analysis identified 3,677 genes as differentially expressed across 5 days between septic patients and healthy controls. Of the 3,677 genes, biological pathway analysis identified 86 genes significantly downregulated in the sepsis patients were present in pathways relating to immune response. These 86 genes correspond to known immune pathways implicated in sepsis, including lymphocyte depletion, reduced T-lymphocyte activation, and deficient antigen presentation. Furthermore, expression levels of these genes correlated with clinical severity, with a significantly greater degree of downregulation found in nonsurvivors compared with survivors. The results show that whole-blood gene expression analysis can capture systemic immune dysfunctions in septic patients. Our study provides an experimental basis to support further study on the use of a gene expression-based assay, to assess immunosuppression, and to guide immunotherapy in future clinical trials.

PURPOSE OF REVIEW: Plasma B-type natriuretic peptide levels are used to screen for cardiac dysfunction in the emergency department and outpatient population. However, in the critically ill patient elevated plasma B-type natriuretic peptide levels do not necessarily reflect just ventricular dysfunction, as there are important confounding factors to consider. This review summarizes the recent advances in the application of B-type natriuretic peptide measurement in the intensive care unit. RECENT FINDINGS: B-Type natriuretic peptide levels are very useful in identifying cardiac dysfunction but not the specific pathology, whether it is right or left ventricular failure, diastolic or systolic dysfunction. Elevated serum B-type natriuretic peptide levels also occur in severe sepsis or septic shock. It also predicts cardiac dysfunction in sepsis. The lack of correlation of B-type natriuretic peptide concentrations with filling pressures in the intensive care unit precludes its use for monitoring cardiac therapy. Some studies involving patients with sepsis or septic shock demonstrate a positive correlation with mortality, while others failed to establish such a relation. The prognostic value of B-type natriuretic peptide in predicting mortality and morbidity remains controversial, partly due to different study designs. SUMMARY: B-Type natriuretic peptide is potentially a very useful diagnostic tool in the intensive care unit. To date there have been few studies and the results are often contradictory, mainly due to the special setting of the intensive care unit, which is constantly exposed to hemodynamically unstable patients, different case mixes as well as vigorous treatments. All of these are potential confounders to B-type natriuretic peptide levels and make interpretations of B-type natriuretic peptide difficult. We need more research on these confounding factors to accentuate the positive value of B-type natriuretic peptide in the intensive care unit.

Background —The purpose of this study was to evaluate the safety and efficacy of a temperature-controlled radiofrequency catheter ablation system. Methods and Results —The patient population included 1050 patients who had undergone ablation of atrioventricular nodal reentrant tachycardia (AVNRT), an accessory pathway (AP), or the atrioventricular junction (AVJ). Ablation was successful in 996 patients. The probability of success was highest among patients who had undergone ablation of the AVJ, lowest in patients who had undergone ablation of an AP, and in between for patients who had undergone ablation of AVNRT. A major complication occurred in 32 patients. Four variables predicted ablation success (AVJ, AVNRT, or left free wall AP ablation and an experienced center). Four factors predicted arrhythmia recurrence (right free wall, posteroseptal, septal, and multiple APs). Two variables predicted development of a complication (structural heart disease and the presence of multiple targets), and 3 variables predicted an increased risk of death (heart disease, lower ejection fraction, and AVJ ablation). Conclusions —These findings may serve as a guide to clinicians considering therapeutic options in patients who are candidates for ablation.

Catheter ablation of left-sided atrioventricular accessory pathways through the coronary sinus by direct-current shock may be complicated by rupture and thrombosis of the coronary sinus and injury to the coronary arteries. This study examined short and long-term effects of radiofrequency catheter ablation of the coronary sinus in 20 closed-chest dogs to determine whether this technique is feasible for potential interruption of left-sided accessory pathways. Single-pulsed radiofrequency energy (750 kHz, 85-293 J) was delivered to three sites in the distal and middle coronary sinus between the distal (1) or the proximal electrodes (2 or 3) of a standard 6 French quadripolar catheter and a chest-wall patch electrode. Single-pulsed radiofrequency energy (78-293 J) was also applied to two sites near the ostium of the coronary sinus with the proximal (4) or the distal (1) electrode of the same catheter. Coronary artery and levophase coronary sinus angiograms obtained before and immediately after ablation, as well as before killing, showed intact vascular structures in all dogs. Right atrial, pulmonary arterial, and aortic pressures measured in three dogs did not change significantly at the time of energy delivery. No significant changes were found in atrioventricular nodal refractoriness and conduction. None of the dogs had significant rhythm disturbances during and after ablation as evaluated by ambulatory electrocardiographic monitoring and periodic rhythm strips at follow-up. Ten dogs were killed 1-7 days after ablation, three dogs were killed at 4 weeks, three dogs at 6 weeks, two dogs at 8 weeks, and two dogs at 12 weeks. Discrete lesions ranging in size from 3 x 3 to 8 x 10 mm2 in surface area and 0.5-4.5 mm in depth were found in the coronary sinus with most of the lesions extending to the left atrial and left ventricular myocardium. There was neither rupture of the coronary sinus nor occlusion of the coronary arteries. Mural thrombus was found in the coronary sinus on five acute lesions in two dogs, but none was noted on the chronic lesions, which was characterized by chronic granulation tissue and fibrosis. Two dogs in the study during chronic conditions had damage to branches of the underlying coronary artery that showed necrotizing arteritis and arterial sclerosis. Conduction system studies in four dogs showed some chronic inflammatory and fibrotic changes. Similar discrete lesions were found in situ in the coronary sinus of four postmortem human hearts with radiofrequency catheter ablation.(ABSTRACT TRUNCATED AT 400 WORDS)