Assessment of Right Ventricular Function With CT and Echocardiography in Patients With Severe Acute Respiratory Distress Syndrome on Extracorporeal Membrane Oxygenation.

OBJECTIVES: Changes in right ventricular size and function are frequently observed in patients with severe acute respiratory distress syndrome. The majority of patients who receive venovenous extracorporeal membrane oxygenation undergo chest CT and transthoracic echocardiography. The aims of this study were to compare the use of CT and transthoracic echocardiography to evaluate the right ventricular function and to determine the prevalence of acute cor pulmonale in this patient population. DESIGN: Observational, retrospective, single-center, cohort study. SETTING: Severe respiratory failure and extracorporeal membrane oxygenation center. PATIENTS: About 107 patients with severe acute respiratory distress syndrome managed with venovenous extracorporeal membrane oxygenation. INTERVENTIONS: Chest CT to evaluate right ventricular size and transthoracic echocardiography to evaluate right ventricular size and function. MEASUREMENTS AND MAIN RESULTS: All 107 patients had a qualitative assessment of right ventricular size and function on transthoracic echocardiography. Quantitative measurements were available in 54 patients (50%) who underwent transthoracic echocardiography and in 107 of patients (100%) who received CT. Right ventricular dilatation was defined as a right ventricle end-diastolic diameter greater than left ventricular end-diastolic diameter upon visual assessment or an right ventricle end-diastolic diameter/left ventricular end-diastolic diameter and/or right ventricle cavity area/left ventricular cavity area of greater than 0.9. Right ventricle systolic function was visually estimated as being normal or impaired (visual right ventricular systolic impairment). The right ventricle was found to be dilated in 38/107 patients (36%) and in 58/107 patients (54%), using transthoracic echocardiography or CT right ventricle end-diastolic diameter/left ventricular end-diastolic diameter, respectively. When the CT right ventricle cavity/left ventricular cavity area criterion was used, the right ventricle was dilated in 19/107 patients (18%). About 33/107 patients (31%) exhibited visual right ventricular systolic impairment. Transthoracic echocardiography right ventricle end-diastolic diameter/left ventricular end-diastolic diameter showed good agreement with CT right ventricle cavity/left ventricular cavity area (R 2 = 0.57; p < 0.01). A CT right ventricle cavity/left ventricular cavity area greater than 0.9 provided the optimal cutoff for acute cor pulmonale on transthoracic echocardiography with an AUC of 0.78. Acute cor pulmonale was defined by the presence of a right ventricle "D-shape" and quantitative right ventricle dilatation on transthoracic echocardiography or a right ventricle cavity/left ventricular cavity area greater than 0.9 on CT. A diagnosis of acute cor pulmonale was made in 9/54 (14% patients) on transthoracic echocardiography and in 19/107 (18%) on CT. CONCLUSIONS: Changes in right ventricular size and function are common in patients with severe acute respiratory distress syndrome requiring venovenous extracorporeal membrane oxygenation with up to 18% showing imaging evidence of acute cor pulmonale. A CT right ventricular cavity /left ventricular cavity area greater than 0.9 is indicative of impaired right ventricular systolic function.

Perioperative management of patients with pulmonary hypertension undergoing non-cardiothoracic, non-obstetric surgery: a systematic review and expert consensus statement.

BACKGROUND: The risk of complications, including death, is substantially increased in patients with pulmonary hypertension (PH) undergoing anaesthesia for surgical procedures, especially in those with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). Sedation also poses a risk to patients with PH. Physiological changes including tachycardia, hypotension, fluid shifts, and an increase in pulmonary vascular resistance (PH crisis) can precipitate acute right ventricular decompensation and death. METHODS: A systematic literature review was performed of studies in patients with PH undergoing non-cardiac and non-obstetric surgery. The management of patients with PH requiring sedation for endoscopy was also reviewed. Using a framework of relevant clinical questions, we review the available evidence guiding operative risk, risk assessment, preoperative optimisation, and perioperative management, and identifying areas for future research. RESULTS: Reported 30 day mortality after non-cardiac and non-obstetric surgery ranges between 2% and 18% in patients with PH undergoing elective procedures, and increases to 15-50% for emergency surgery, with complications and death usually relating to acute right ventricular failure. Risk factors for mortality include procedure-specific and patient-related factors, especially markers of PH severity (e.g. pulmonary haemodynamics, poor exercise performance, and right ventricular dysfunction). Most studies highlight the importance of individualised preoperative risk assessment and optimisation and advanced perioperative planning. CONCLUSIONS: With an increasing number of patients requiring surgery in specialist and non-specialist PH centres, a systematic, evidence-based, multidisciplinary approach is required to minimise complications. Adequate risk stratification and a tailored-individualised perioperative plan is paramount.

[Pyr1]Apelin-13(1-12) Is a Biologically Active ACE2 Metabolite of the Endogenous Cardiovascular Peptide [Pyr1]Apelin-13.

Aims: Apelin is a predicted substrate for ACE2, a novel therapeutic target. Our aim was to demonstrate the endogenous presence of the putative ACE2 product [Pyr1]apelin-13(1-12) in human cardiovascular tissues and to confirm it retains significant biological activity for the apelin receptor in vitro and in vivo. The minimum active apelin fragment was also investigated. Methods and Results: [Pyr1]apelin-13 incubated with recombinant human ACE2 resulted in de novo generation of [Pyr1]apelin-13(1-12) identified by mass spectrometry. Endogenous [Pyr1]apelin-13(1-12) was detected by immunostaining in human heart and lung localized to the endothelium. Expression was undetectable in lung from patients with pulmonary arterial hypertension. In human heart [Pyr1]apelin-13(1-12) (pKi = 8.04 ± 0.06) and apelin-13(F13A) (pKi = 8.07 ± 0.24) competed with [125I]apelin-13 binding with nanomolar affinity, 4-fold lower than for [Pyr1]apelin-13 (pKi = 8.83 ± 0.06) whereas apelin-17 exhibited highest affinity (pKi = 9.63 ± 0.17). The rank order of potency of peptides to inhibit forskolin-stimulated cAMP was apelin-17 (pD2 = 10.31 ± 0.28) > [Pyr1]apelin-13 (pD2 = 9.67 ± 0.04) ≥ apelin-13(F13A) (pD2 = 9.54 ± 0.05) > [Pyr1]apelin-13(1-12) (pD2 = 9.30 ± 0.06). The truncated peptide apelin-13(R10M) retained nanomolar potency (pD2 = 8.70 ± 0.04) but shorter fragments exhibited low micromolar potency. In a ß-arrestin recruitment assay the rank order of potency was apelin-17 (pD2 = 10.26 ± 0.09) >> [Pyr1]apelin-13 (pD2 = 8.43 ± 0.08) > apelin-13(R10M) (pD2 = 8.26 ± 0.17) > apelin-13(F13A) (pD2 = 7.98 ± 0.04) ≥ [Pyr1]apelin-13(1-12) (pD2 = 7.84 ± 0.06) >> shorter fragments (pD2 < 6). [Pyr1]apelin-13(1-12) and apelin-13(F13A) contracted human saphenous vein with similar sub-nanomolar potencies and [Pyr1]apelin-13(1-12) was a potent inotrope in paced mouse right ventricle and human atria. [Pyr1]apelin-13(1-12) elicited a dose-dependent decrease in blood pressure in anesthetized rat and dose-dependent increase in forearm blood flow in human volunteers. Conclusions: We provide evidence that ACE2 cleaves [Pyr1]apelin-13 to [Pyr1]apelin-13(1-12) and this cleavage product is expressed in human cardiovascular tissues. We have demonstrated biological activity of [Pyr1]apelin-13(1-12) at the human and rodent apelin receptor in vitro and in vivo. Our data show that reported enhanced ACE2 activity in cardiovascular disease should not significantly compromise the beneficial effects of apelin based therapies for example in PAH.

Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist.

[Pyr(1)]apelin-13 is an endogenous vasodilator and inotrope but is downregulated in pulmonary hypertension and heart failure, making the apelin receptor an attractive therapeutic target. Agonists acting at the same G-protein-coupled receptor can be engineered to stabilize different conformational states and function as biased ligands, selectively stimulating either G-protein or ß-arrestin pathways. We used molecular dynamics simulations of apelin/receptor interactions to design cyclic analogues and identified MM07 as a biased agonist. In ß-arrestin and internalization assays (G-protein-independent), MM07 was 2 orders of magnitude less potent than [Pyr(1)]apelin-13. In a G-protein-dependent saphenous vein contraction assay, both peptides had comparable potency (pD2:[Pyr(1)]apelin-13 9.93±0.24; MM07 9.54±0.42) and maximum responses with a resulting bias for MM07 of ≈350- to 1300-fold for the G-protein pathway. In rats, systemic infusions of MM07 (10-100nmol) caused a dose-dependent increase in cardiac output that was significantly greater than the response to [Pyr(1)]apelin-13. Similarly, in human volunteers, MM07 produced a significant dose-dependent increase in forearm blood flow with a maximum dilatation double that is seen with [Pyr(1)]apelin-13. Additionally, repeated doses of MM07 produced reproducible increases in forearm blood flow. These responses are consistent with a more efficacious action of the biased agonist. In human hand vein, both peptides reversed an established norepinephrine constrictor response and significantly increased venous flow. Our results suggest that MM07 acting as a biased agonist at the apelin receptor can preferentially stimulate the G-protein pathway, which could translate to improved efficacy in the clinic by selectively stimulating vasodilatation and inotropic actions but avoiding activating detrimental ß-arrestin-dependent pathways.

Stressing the obvious? An allostatic look at critical illness.

Stress plays a crucial role in coping with extrinsic insults through modulating the autonomic nervous system, the hypothalamic-pituitary-adrenal axis and the cardiovascular, metabolic, and immune systems. The allostatic model of maintaining "stability through change" allows the body to respond to a challenge by adjusting to a new steady-state and terminating it once the danger has passed. However, unrelenting stress can lead to decompensation with development of pathologic illness. With sufficient activation the response may become more damaging than the stressor itself. Two types of "allostatic overload" are described: type 1 is an essentially protective response triggered by changes in environment, food supply, or physiologic status where energy demand exceeds supply. The response aims to reduce this imbalance by modifying behavior and intrinsic body systems to direct the animal into a survival mode. Type 2 overload occurs when there is sufficient or excess energy consumption; however, this situation does not trigger an escape or survival response. A clear analogy may be made to critical care where excess stress affects metabolic, hormonal, and immunoinflammatory responses and contributes to the development of organ failure. Ongoing stress also compromises recovery so it is incumbent upon caregivers to reduce stress, be it induced by tissue hypoxia, catecholamine infusion, sleep deprivation, pain, anxiety, and/or excess noise.