Lipidomics Detection of Brain Cardiolipins in Plasma Is Associated With Outcome After Cardiac Arrest.

OBJECTIVES: Brain mitochondrial dysfunction limits neurologic recovery after cardiac arrest. Brain polyunsaturated cardiolipins, mitochondria-unique and functionally essential phospholipids, have unprecedented diversification. Since brain cardiolipins are not present in plasma normally, we hypothesized their appearance would correlate with brain injury severity early after cardiac arrest and return of spontaneous circulation. DESIGN: Observational case-control study. SETTING: Two medical centers within one city. PARTICIPANTS (SUBJECTS): We enrolled 41 adult cardiac arrest patients in whom blood could be obtained within 6 hours of resuscitation. Two subjects were excluded following outlier analysis. Ten healthy subjects were controls. Sprague-Dawley rats were used in asphyxial cardiac arrest studies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We developed a high-resolution liquid chromatography/mass spectrometry method and determined cardiolipins speciation in human brain, heart, and plasma within 6 hours of (return of spontaneous circulation) from 39 patients with cardiac arrest, 5 with myocardial infarction, and 10 healthy controls. Cerebral score was derived from brain-specific cardiolipins identified in plasma of patients with varying neurologic injury and outcome. Using a rat model of cardiac arrest, cardiolipins were quantified in plasma, brain, and heart. Human brain exhibited a highly diverse cardiolipinome compared with heart that allowed the identification of brain-specific cardiolipins. Nine of 26 brain-specific cardiolipins were detected in plasma and correlated with brain injury. The cerebral score correlated with early neurologic injury and predicted discharge neurologic/functional outcome. Cardiolipin (70:5) emerged as a potential point-of-care marker predicting injury severity and outcome. In rat cardiac arrest, a significant reduction in hippocampal cardiolipins corresponded to their release from the brain into systemic circulation. Cerebral score was significantly increased in 10 minutes versus 5 minutes no-flow cardiac arrest and naïve controls. CONCLUSIONS: Brain-specific cardiolipins accumulate in plasma early after return of spontaneous circulation and proportional to neurologic injury representing a promising novel biomarker.

Early coronary angiography and percutaneous coronary intervention are associated with improved outcomes after out of hospital cardiac arrest.

AIM: Early coronary angiography (CAG) and percutaneous coronary intervention (PCI) are associated with better outcomes in subjects resuscitated from out-of-hospital cardiac arrest (OHCA). We sought to determine the relative contributions of early CAG and PCI to outcomes and adverse events after OHCA. METHODS: We analyzed 599 OHCA subjects from a prospective two-center registry. Hospital survival, functional outcomes and adverse events were compared between subjects undergoing early CAG (within 24h) with or without PCI and subjects not undergoing early CAG. We adjusted for propensity to perform early CAG and PCI and for post-resuscitation illness severity and care. RESULTS: Early CAG subjects had improved rates of hospital survival (56.2% versus 31.0%, OR 2.85 [95% CI 2.04-4.00]; p<0.0001) and better functional outcomes compared to no early CAG. Early PCI was associated with improved survival compared to early CAG without PCI (65.6% versus 45.5%, OR 2.29 [95% CI 1.41-3.69]; p<0.001). After multivariate adjustment and propensity matching, early PCI remained significantly associated with improved survival compared with early CAG without PCI and no early CAG, but early CAG without PCI was no longer significantly associated with improved outcome compared with no early CAG. Early CAG and early PCI were not associated with an increase in transfusions or acute kidney injury. CONCLUSIONS: Early CAG and PCI are associated with improved survival and functional outcomes after OHCA, but only early PCI was associated with a significant benefit after statistical adjustment. Our analysis supports the performance of immediate CAG to determine the need for PCI in selected patients following resuscitation from OHCA.

Biochemical signaling by remote ischemic conditioning of the arm versus thigh: Is one raise of the cuff enough?

Remote Ischemic Conditioning (RIC), induced by brief cycles of ischemia and reperfusion, protects vital organs from a prolonged ischemic insult. While several biochemical mediators have been implicated in RIC's mechanism of action, it remains unclear whether the localization or "dose" of RIC affects the extent of protective signaling. In this randomized crossover study of healthy individuals, we tested whether the number of cycles of RIC and its localization (arm versus thigh) determines biochemical signaling and cytoprotection. Subjects received either arm or thigh RIC and then were crossed over to receive RIC in the other extremity. Blood flow, tissue perfusion, concentrations of the circulating protective mediator nitrite, and platelet mitochondrial function were measured after each RIC cycle. We found that plasma nitrite concentration peaked after the first RIC cycle and remained elevated throughout RIC. This plasma nitrite conferred cytoprotection in an in vitro myocyte model of hypoxia/reoxygenation. Notably, though plasma nitrite returned to baseline at 24h, RIC conditioned plasma still mediated protection. Additionally, no difference in endpoints between RIC in thigh versus arm was found. These data demonstrate that localization and "dose" of RIC does not affect cytoprotection and further elucidate the mechanisms by which nitrite contributes to RIC-dependent protection.

Mechanistic characterization of nitrite-mediated neuroprotection after experimental cardiac arrest.

Nitrite acts as an ischemic reservoir of nitric oxide (NO) and a potent S-nitrosating agent which reduced histologic brain injury after rat asphyxial cardiac arrest (ACA). The mechanism(s) of nitrite-mediated neuroprotection remain to be defined. We hypothesized that nitrite-mediated brain mitochondrial S-nitrosation accounts for neuroprotection by reducing reperfusion reactive oxygen species (ROS) generation. Nitrite (4 µmol) or placebo was infused IV after normothermic (37°C) ACA in randomized, blinded fashion with evaluation of neurologic function, survival, brain mitochondrial function, and ROS. Blood and CSF nitrite were quantified using reductive chemiluminescence and S-nitrosation by biotin switch. Direct neuroprotection was verified in vitro after 1 and 4 h neuronal oxygen glucose deprivation measuring neuronal death with inhibition studies to examine mechanism. Mitochondrial ROS generation was quantified by live neuronal imaging using mitoSOX. Nitrite significantly reduced neurologic disability after ACA. ROS generation was reduced in brain mitochondria from nitrite- versus placebo-treated rats after ACA with congruent preservation of brain ascorbate and reduction of ROS in brain sections using immuno-spin trapping. ATP generation was maintained with nitrite up to 24 h after ACA. Nitrite rapidly entered CSF and increased brain mitochondrial S-nitrosation. Nitrite reduced in vitro mitochondrial superoxide generation and improved survival of neurons after oxygen glucose deprivation. Protection was maintained with inhibition of soluble guanylate cyclase but lost with NO scavenging and ultraviolet irradiation. Nitrite therapy results in direct neuroprotection from ACA mediated by reductions in brain mitochondrial ROS in association with protein S-nitrosation. Neuroprotection is dependent on NO and S-nitrosothiol generation, not soluble guanylate cyclase.