Study to Explore the Association of the Renin-Angiotensin System and Right Ventricular Function in Mechanically Ventilated Patients

Abstract

Background: Right ventricular (RV) dysfunction is associated with pulmonary vasoconstriction in mechanically ventilated patients. Enhancing the activity of angiotensin-converting enzyme 2 (ACE2), a key enzyme of the renin-angiotensin system (RAS), using recombinant human ACE2 (rhACE2) could alleviate RAS-mediated vasoconstriction and vascular remodeling.

Methods: This prospective observational study investigated the association between concentrations of RAS peptides (Ang II or Ang(1-7)) and markers of RV function, as assessed by echocardiography (ratio of RV to left ventricular end-diastolic area, interventricular septal motion, and pulmonary arterial systolic pressure (PASP)).

Results: Fifty-seven mechanically ventilated patients were enrolled. Incidence rates of acute cor pulmonale (ACP) and pulmonary circulatory dysfunction (PCD) were consistent with previous studies. In the 45 evaluable participants, no notable or consistent changes in RAS peptides concentration were observed over the observation period, and there was no correlation between Ang II concentration and either PASP or RV size. The model of the predicted posterior distributions for the pre- and post-dose values of Ang II demonstrated no change in the likelihood of PCD after hypothetical dosing with rhACE2, thus meeting the futility criteria. Similar results were observed with the other RAS peptides evaluated.

Conclusions: Pre-defined success criteria for an association between PCD and the plasma RAS peptides were not met in the mechanically ventilated unselected patients.

Keywords: acute cor pulmonale; acute respiratory distress syndrome; angiotensin (1–7); angiotensin II; angiotensin-converting enzyme 2; echocardiography; pulmonary circulatory dysfunction; renin-angiotensin system; right ventricular function.

Figure 1

Study design and key study features. h, hours; RAS, renin-angiotensin system.

Figure 2

Participant flow. * Patients were pre-screened for eligibility; however, the number of pre-screened patients is unavailable. ^a Screened population: all participants who were screened. Safety population: all participants for whom at least one echocardiograph and/or blood sample was taken. At-risk population: participants for whom PASP and RV size ratio were recorded for all three study days and/or had a databased PCD and/or ARDS assessment during the study period. ^b Evaluable population: all participants for whom PASP, RV size ratio, Ang II, and Ang(1–7) data were recorded for at least one study time point. ^c Completed population: all participants for whom PASP, RV size ratio, Ang II, and Ang(1–7) data were recorded for all three study days. ACP, acute cor pulmonale; Ang, angiotensin; ARDS, acute respiratory distress syndrome; PASP, pulmonary arterial systolic pressure; PCD, pulmonary circulatory dysfunction; RV, right ventricle.

Figure 3

Individual time profile of (A) Ang II and (B) Ang(1–7) concentrations by time point. Ang angiotensin.

Figure 4

Scatterplots of PASP (A) and RV size ratio (B) versus Ang II concentrations, with posterior prediction regions for RV function. Data are median PASP and RV size and 95% equal-tailed credibility intervals for the corresponding ‘pre-dose’ 30 pg/mL and ‘post-dose’ 8 pg/mL Ang II. One measurement was databased per day, per participant. The horizontal reference line corresponds to the defined threshold value associated with PCD. Ang, angiotensin; CrI, credible interval; PASP, pulmonary arterial systolic pressure; RV, right ventricular.

Figure 5

PCD measurements for hypothetical ‘pre-‘ and ‘post-‘dose Ang II concentrations (A); scatterplot of PASP versus RV size ratio, marked by interventricular septal motion status (B) and colored by Ang II concentration (C), with posterior prediction regions (D). Data are for ‘pre-dose’ 30 pg/mL and ‘post-dose’ 8 pg/mL Ang II concentrations. The horizontal reference lines correspond to the defined threshold value for PCD. Figure 4A contains additional sampling points that did not have an associated Ang II concentration value. Ang, angiotensin; N, no; ND, not done; PASP, pulmonary arterial systolic pressure; PCD, pulmonary circulatory dysfunction; Pr, probability; Y, yes.

Figure 6

Scatterplot of PASP versus RV size ratio, marked by interventricular septal motion status and colored by Ang(1–7) concentration, with posterior prediction regions for PCD measurements for hypothetical ‘pre-‘ and ‘post-‘dose Ang(1–7) concentrations. Data are for ‘pre-dose’ 2 pg/mL and ‘post-dose’ 30 pg/mL Ang II concentrations. The horizontal reference lines correspond to the defined threshold value for PCD. Ang, angiotensin; PASP, pulmonary arterial systolic pressure; Pr, probability; RV, right ventricular.