The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury.

Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide1-6. Clinical studies have demonstrated that the severity of cardiac injury following myocardial infarction exhibits a circadian pattern, with larger infarct sizes and poorer outcomes in patients experiencing morning onset myocardial infarctions7-14. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL114-20, a core circadian transcription factor, orchestrates diurnal variability in myocardial injury. Unexpectedly, BMAL1 modulates circadian-dependent cardiac injury by forming a transcriptionally active heterodimer with a non-canonical partner, hypoxia-inducible factor 2 alpha (HIF2A)6,21-23, in a diurnal manner. Substantiating this finding, we determined the cryo-EM structure of the BMAL1/HIF2A/DNA complex, revealing a previously unknown capacity for structural rearrangement within BMAL1, which enables the crosstalk between circadian rhythms and hypoxia signaling. Furthermore, we identified amphiregulin (AREG) as a rhythmic transcriptional target of the BMAL1/HIF2A heterodimer, critical for regulating circadian variations of myocardial injury. Finally, pharmacologically targeting the BMAL1/HIF2A-AREG pathway provides effective cardioprotection, with maximum efficacy when aligned with the pathway's circadian trough. Our findings not only uncover a novel mechanism governing the circadian variations of myocardial injury but also pave the way for innovative circadian-based treatment strategies, potentially shifting current treatment paradigms for myocardial infarction.

The Hypoxia-Adenosine Link during Myocardial Ischemia-Reperfusion Injury.

Despite increasing availability and more successful interventional approaches to restore coronary reperfusion, myocardial ischemia-reperfusion injury is a substantial cause of morbidity and mortality worldwide. During myocardial ischemia, the myocardium becomes profoundly hypoxic, thus causing stabilization of hypoxia-inducible transcription factors (HIF). Stabilization of HIF leads to a transcriptional program that promotes adaptation to hypoxia and cellular survival. Transcriptional consequences of HIF stabilization include increases in extracellular production and signaling effects of adenosine. Extracellular adenosine functions as a signaling molecule via the activation of adenosine receptors. Several studies implicated adenosine signaling in cardioprotection, particularly through the activation of the Adora2a and Adora2b receptors. Adenosine receptor activation can lead to metabolic adaptation to enhance ischemia tolerance or dampen myocardial reperfusion injury via signaling events on immune cells. Many studies highlight that clinical strategies to target the hypoxia-adenosine link could be considered for clinical trials. This could be achieved by using pharmacologic HIF activators or by directly enhancing extracellular adenosine production or signaling as a therapy for patients with acute myocardial infarction, or undergoing cardiac surgery.

Noteworthy Literature Published in 2018 for Cardiothoracic Anesthesiologists.

The year 2018 was marked by high-quality, impactful articles spanning the basic, translational, and clinical spectrum in the field of cardiothoracic anesthesia. In this article, we present several hand-picked articles from the past year that we feel were the most significant in shaping our specialty. Large multicenter, randomized controlled trials presenting clinical outcome data dominated the publishing arena: is a restrictive red blood cell transfusion strategy superior to a liberal red blood cell transfusion strategy during cardiopulmonary bypass? Does a low mean arterial blood pressure strategy during cardiopulmonary bypass increase stroke incidence? Does the obesity paradox apply to cardiac surgery? Advancing technology continues to revolutionize our field: can the MitraClip be used to effectively treat secondary mitral regurgitation? Can stem cells improve cardiac function in patients with left ventricular assist devices? These studies allow us to shape our practice in an evidence-based manner, so that we may evolve as a specialty and deliver the best care to our patients.

Noteworthy Literature published in 2017 for Cardiothoracic Anesthesiologists.

The year 2017 was a year dominated by large-scale clinical studies reporting the outcome of various interventions in cardiac surgery and heart failure (HF) patients, relevant to all cardiothoracic anesthesiologists. Among them were studies investigating the addition of levosimendan, an alternative inotropic agent, to standard management of patients with HF undergoing cardiac surgery. Also, corticosteroids have been used for various purposes in cardiac patients. Here, a new study reports the effect of high-dose methylprednisolone on recovery and delirium. Furthermore, with increasing evidence that transfusions increase morbidity and mortality, a publication reports the use of rotational thromboelastometry to reduce transfusion requirements. In addition, several randomized controlled multicenter studies report the outcomes of patients undergoing cardiac procedures: surgical versus transcatheter aortic valve replacement in intermediate-risk patients and the use of centrifugal-flow versus axial-flow left-ventricular devices in patients with HF. These studies demonstrate the dynamic and ever-evolving state of perioperative cardiovascular medicine and show us the direction of future developments.

Severity of tricuspid regurgitation is associated with long-term mortality.

OBJECTIVES: To determine the association between intraoperative/presurgical grade of tricuspid regurgitation (TR) and mortality, and to determine whether surgical correction of TR correlated with an increased chance of survival compared with patients with uncorrected TR. METHODS: The grade of TR assessed by intraoperative transesophageal echocardiography (TEE) before surgical intervention was reviewed for 23,685 cardiac surgery patients between 1990 and 2014. Cox proportional hazard regression models were used to determine association between grade of TR and the primary endpoint of all-cause mortality. Association between tricuspid valve (TV) surgery and survival was determined with Cox proportional hazard regression models after matching for grade of TR. RESULTS: Kaplan-Meier survival curves demonstrated a relationship between all grades of TR. Multivariable analysis of the entire cohort demonstrated significantly increased mortality for moderate (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.1-1.4; P < .0001) and severe TR (HR, 2.02; 95% CI, 1.57-2.6; P < .0001). Mild TR displayed a trend for mortality (HR, 1.07; 95% CI, 0.99-1.16; P = .075). After matching for grade of TR and additional confounders, patients who underwent TV surgery had a statistically significant increased likelihood of survival (HR, 0.74; 95% CI, 0.61-0.91; P = .004). CONCLUSIONS: Our study of more than 20,000 patients demonstrates that grade of TR is associated with increased risk of mortality after cardiac surgery. In addition, all patients who underwent TV surgery had a statistically significantly increased likelihood of survival compared with those with the same degree of TR who did not undergo TV surgery.

Aortic Atheroma Increases the Risk of Long-Term Mortality in 20,000 Patients.

BACKGROUND: The association between long-term survival and aortic atheroma in cardiac surgical patients has not been comprehensively investigated. In this study we determine the relation between grade of atheroma and the risk of long-term mortality in a retrospective cohort of more than 20,000 patients undergoing cardiac operation during a 20-year period. METHODS: We included 22,304 consecutive intraoperative transesophageal and epiaortic ultrasound examinations performed at Brigham and Women's Hospital between 1995 and 2014, with long-term follow-up. The extent of atheromatous disease recorded in each examination was used for analysis. Mortality data were obtained from our institution's data registry. Mortality analyses were done using Cox proportional hazard regression models with follow-up as a time scale. We repeated the analysis in a subgroup of 14,728 patients with more detailed demographic characteristics, including postoperative stroke, queried from the institutional Society of Thoracic Surgeons database. RESULTS: A total of 7,722 mortality events and 872 stroke events occurred. Patients with atheromatous disease demonstrated a significant increase in mortality across all grades of severity, both for the ascending and descending aorta. This relation remained unchanged after adjusting for additional covariates. Adjustments for postoperative stroke resulted in only minimal attenuation in the risk of postoperative mortality related to aortic atheroma. CONCLUSIONS: Aortic atheromatous disease of any grade in the ascending and descending aorta is a significant long-term risk of long-term, all-cause mortality in cardiac operation patients. This association remains independent of other conventional risk factors and is not related to postoperative cerebrovascular accidents.

Inferring genetic causal effects on survival data with associated endo-phenotypes.

Age-at-onset phenotypes are important traits in genetic association analyses. Often, intermediate phenotypes that are related to the age-at-onset phenotype are also associated with the marker loci that are associated with the age-at-onset phenotype. In order to understand the genetic etiology of the observed associations, statistical methodology is needed to distinguish between a direct genetic effect on the age-at-onset phenotype and an indirect effect induced by the genetic association with the endo-phenotype that is correlated with the age-at-onset phenotype. In this communication, we introduce a new statistical approach to detect causal genetic effects on survival data in the presence of genetic associations with secondary phenotypes that might influence survival as well and thereby induce seemingly causal relationships. Derived using causal inference methodology, the proposed method is based on standard statistical methodology and can be implemented straight-forwardly, using standard software. Using simulation studies, the theoretical properties of the approach are verified and the power is assessed under realistic scenarios. The practical relevance of the approach is illustrated by an application to survival after cardiac surgery, where genetic components of myocardial infarctions are determined to not influence post-surgery hospital duration except through the MI-pathway.