Apelin and APJ orchestrate complex tissue-specific control of cardiomyocyte hypertrophy and contractility in the hypertrophy-heart failure transition.

The G protein-coupled receptor APJ is a promising therapeutic target for heart failure. Constitutive deletion of APJ in the mouse is protective against the hypertrophy-heart failure transition via elimination of ligand-independent, ß-arrestin-dependent stretch transduction. However, the cellular origin of this stretch transduction and the details of its interaction with apelin signaling remain unknown. We generated mice with conditional elimination of APJ in the endothelium (APJendo-/-) and myocardium (APJmyo-/-). No baseline difference was observed in left ventricular function in APJendo-/-, APJmyo-/-, or control (APJendo+/+, APJmyo+/+) mice. After exposure to transaortic constriction, APJendo-/- mice displayed decreased left ventricular systolic function and increased wall thickness, whereas APJmyo-/- mice were protected. At the cellular level, carbon fiber stretch of freshly isolated single cardiomyocytes demonstrated decreased contractile responses to stretch in APJ-/- cardiomyocytes compared with APJ+/+ cardiomyocytes. Ca2+ transients did not change with stretch in either APJ-/- or APJ+/+ cardiomyocytes. Application of apelin to APJ+/+ cardiomyocytes resulted in decreased Ca2+ transients. Furthermore, hearts of mice treated with apelin exhibited decreased phosphorylation in cardiac troponin I NH2-terminal residues (Ser22 and Ser23) consistent with increased Ca2+ sensitivity. These data establish that APJ stretch transduction is mediated specifically by myocardial APJ, that APJ is necessary for stretch-induced increases in contractility, and that apelin opposes APJ's stretch-mediated hypertrophy signaling by lowering Ca2+ transients while maintaining contractility through myofilament Ca2+ sensitization. These findings underscore apelin's unique potential as a therapeutic agent that can simultaneously support cardiac function and protect against the hypertrophy-heart failure transition. NEW & NOTEWORTHY These data address fundamental gaps in our understanding of apelin-APJ signaling in heart failure by localizing APJ's ligand-independent stretch sensing to the myocardium, identifying a novel mechanism of apelin-APJ inotropy via myofilament Ca2+ sensitization, and identifying potential mitigating effects of apelin in APJ stretch-induced hypertrophic signaling.

In Vivo Post-Cardiac Arrest Myocardial Dysfunction Is Supported by Ca2+/Calmodulin-Dependent Protein Kinase II-Mediated Calcium Long-Term Potentiation and Mitigated by Alda-1, an Agonist of Aldehyde Dehydrogenase Type 2.

BACKGROUND: Survival after sudden cardiac arrest is limited by postarrest myocardial dysfunction, but understanding of this phenomenon is constrained by a lack of data from a physiological model of disease. In this study, we established an in vivo model of cardiac arrest and resuscitation, characterized the biology of the associated myocardial dysfunction, and tested novel therapeutic strategies. METHODS: We developed rodent models of in vivo postarrest myocardial dysfunction using extracorporeal membrane oxygenation resuscitation followed by invasive hemodynamics measurement. In postarrest isolated cardiomyocytes, we assessed mechanical load and Ca(2) (+)-induced Ca(2+) release (CICR) simultaneously using the microcarbon fiber technique and observed reduced function and myofilament calcium sensitivity. We used a novel fiberoptic catheter imaging system and a genetically encoded calcium sensor, GCaMP6f, to image CICR in vivo. RESULTS: We found potentiation of CICR in isolated cells from this extracorporeal membrane oxygenation model and in cells isolated from an ischemia/reperfusion Langendorff model perfused with oxygenated blood from an arrested animal but not when reperfused in saline. We established that CICR potentiation begins in vivo. The augmented CICR observed after arrest was mediated by the activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Increased phosphorylation of CaMKII, phospholamban, and ryanodine receptor 2 was detected in the postarrest period. Exogenous adrenergic activation in vivo recapitulated Ca(2+) potentiation but was associated with lesser CaMKII activation. Because oxidative stress and aldehydic adduct formation were high after arrest, we tested a small-molecule activator of aldehyde dehydrogenase type 2, Alda-1, which reduced oxidative stress, restored calcium and CaMKII homeostasis, and improved cardiac function and postarrest outcome in vivo. CONCLUSIONS: Cardiac arrest and reperfusion lead to CaMKII activation and calcium long-term potentiation, which support cardiomyocyte contractility in the face of impaired postarrest myofilament calcium sensitivity. Alda-1 mitigates these effects, normalizes calcium cycling, and improves outcome.

Perihematomal Edema Expansion Rates and Patient Outcomes in Deep and Lobar Intracerebral Hemorrhage.

BACKGROUND: Perihematomal edema (PHE) expansion rate may predict functional outcome following spontaneous intracerebral hemorrhage (ICH). We hypothesized that the effect of PHE expansion rate on outcome is greater for deep versus lobar ICH. METHODS: Subjects (n = 115) were retrospectively identified from a prospective ICH cohort enrolled from 2000 to 2013. Inclusion criteria were age ≥ 18 years, spontaneous supratentorial ICH, and known onset time. Exclusion criteria were primary intraventricular hemorrhage (IVH), trauma, subsequent surgery, or warfarin-related ICH. ICH and PHE volumes were measured from CT scans and used to calculate expansion rates. Logistic regression assessed the association between PHE expansion rates and 90-day mortality or poor functional outcome (modified Rankin Scale > 2). Odds ratios are per 0.04 mL/h. RESULTS: PHE expansion rate from baseline to 24 h (PHE24) was associated with mortality for deep (p = 0.03, OR 1.13[1.02-1.26]) and lobar ICH (p = 0.02, OR 1.03[1.00-1.06]) in unadjusted regression and in models adjusted for age (deep p = 0.02, OR 1.15[1.02-1.28]; lobar p = 0.03, OR 1.03[1.00-1.06]), Glasgow Coma Scale (deep p = 0.03, OR 1.13[1.01-1.27]; lobar p = 0.02, OR 1.03[1.01-1.06]), or time to baseline CT (deep p = 0.046, OR 1.12[1.00-1.25]; lobar p = 0.047, OR 1.03[1.00-1.06]). PHE expansion rate from baseline to 72 h (PHE72) was associated with mRS > 2 for deep ICH in models that were unadjusted (p = 0.02, OR 4.04[1.25-13.04]) or adjusted for ICH volume (p = 0.02, OR 4.3[1.25-14.98]), age (p = 0.03, OR 5.4[1.21-24.11]), GCS (p = 0.02, OR 4.19[1.2-14.55]), or time to first CT (p = 0.03, OR 4.02[1.19-13.56]). CONCLUSIONS: PHE72 was associated with poor functional outcomes after deep ICH, whereas PHE24 was associated with mortality for deep and lobar ICH.

Decompressive Craniectomy in Neurocritical Care.

Neurosurgeons increasingly use decompressive craniectomy (DC) in neurocritical care. In this review, the authors summarize the topic of DC for the neurointensivist. Following a brief overview of the procedure, the major indications for the procedure are described. This includes a review of the literature regarding well-established indications, such as infarction and traumatic brain injury, as well as lesser known indications, including intracerebral hemorrhage, ruptured cerebrovascular malformations, sinus thrombosis, and infection. Complications unique to DC, specifically syndrome of the trephined, hygroma, and hydrocephalus, also are reviewed with a discussion of their management, both in the immediate and the postoperative period.

Increased Sensitivity of Focused Cardiac Ultrasound for Pulmonary Embolism in Emergency Department Patients With Abnormal Vital Signs.

BACKGROUND: Focused cardiac ultrasound (FOCUS) is insensitive for pulmonary embolism (PE). Theoretically, when a clot is large enough to cause vital sign abnormalities, it is more likely to show signs of right ventricular dysfunction on FOCUS, although this has not been well quantified. A rapid bedside test that could quickly and reliably exclude PE in patients with abnormal vital signs could be of high utility in emergency department (ED) patients. We hypothesized that in patients with tachycardia or hypotension, the sensitivity of FOCUS for PE would increase substantially. METHODS: We performed a prospective observational multicenter cohort study involving a convenience sample of patients from six urban academic EDs. Patients suspected to have PE with tachycardia (heart rate [HR] ≥ 100 beats/min) or hypotension (systolic blood pressure [sBP] < 90 mm Hg) underwent FOCUS before computed tomography angiography (CTA). FOCUS included assessment for right ventricular dilation, McConnell's sign, septal flattening, tricuspid regurgitation, and tricuspid annular plane systolic excursion. If any of these were abnormal, FOCUS was considered positive, while if all were normal, FOCUS was considered negative. We a priori planned a subgroup analysis of all patients with a HR ≥ 110 beats/min (regardless of their sBP). We then determined the diagnostic test characteristics of FOCUS for PE in the entire patient population and in the predefined subgroup, based on CTA as the criterion standard. Inter-rater reliability of FOCUS was determined by blinded review of images by an emergency physician with fellowship training in ultrasound. RESULTS: A total of 143 subjects were assessed for enrollment and 136 were enrolled; four were excluded because they were non-English-speaking and three because of inability to obtain any FOCUS windows. The mean (±SD) age of enrolled subjects was 56 (±7) years, mean (±SD) HR was 114 (±12) beats/min, and 37 (27.2%) subjects were diagnosed with PE on CTA. In all subjects, FOCUS was 92% (95% confidence interval [CI] = 78% to 98%) sensitive and 64% specific (95% CI = 53% to 73%) for PE. In the subgroup of 98 subjects with a HR ≥ 110 beats/min, FOCUS was 100% sensitive (95% CI = 88% to 100%) and 63% specific (95% CI = 51% to 74%) for PE. There was substantial interobserver agreement for FOCUS (κ = 1.0, 95% CI = 0.31 to 1.0). CONCLUSIONS: A negative FOCUS examination may significantly lower the likelihood of the diagnosis of PE in most patients who are suspected of PE and have abnormal vital signs. This was especially true in those patients with a HR ≥ 110 beats/min. Our results suggest that FOCUS can be an important tool in the initial evaluation of ED patients with suspected PE and abnormal vital signs.