Evaluation of Plasma Adenosine as a Marker of Cardiovascular Risk: Analytical and Biological Considerations.

Background Adenosine is a ubiquitous regulatory molecule known to modulate signaling in many cells and processes vital to vascular homeostasis. While studies of adenosine receptors have dominated research in the field, quantification of adenosine systemically and locally remains limited owing largely to technical restrictions. Given the potential clinical implications of adenosine biology, there is a need for adequately powered studies examining the role of plasma adenosine in vascular health. We sought to describe the analytical and biological factors that affect quantification of adenosine in humans in a large, real-world cohort of patients undergoing evaluation for coronary artery disease. Methods and Results Between November 2016 and April 2018, we assessed 1141 patients undergoing angiography for evaluation of coronary artery disease. High-performance liquid chromatography was used for quantification of plasma adenosine concentration, yielding an analytical coefficient of variance (CVa) of 3.2%, intra-subject variance (CVi) 35.8% and inter-subject variance (CVg) 56.7%. Traditional cardiovascular risk factors, medications, and clinical presentation had no significant impact on adenosine levels. Conversely, increasing age (P=0.027) and the presence of obstructive coronary artery disease (P=0.026) were associated with lower adenosine levels. Adjusted multivariable analysis supported only age being inversely associated with adenosine levels (P=0.039). Conclusions Plasma adenosine is not significantly impacted by traditional cardiovascular risk factors; however, advancing age and presence of obstructive coronary artery disease may be associated with lower adenosine levels. The degree of intra- and inter-subject variance of adenosine has important implications for biomarker use as a prognosticator of cardiovascular outcomes and as an end point in clinical studies.

Left Ventricular Unloading During Extracorporeal Membrane Oxygenation in Patients With Cardiogenic Shock.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a widely used form of mechanical circulatory support in patients with refractory cardiogenic shock. A common drawback of this modality is a resultant increase in left ventricular afterload. OBJECTIVES: The purpose of this meta-analysis was to examine the efficacy and safety of left ventricular unloading strategies during VA-ECMO in adult patients with cardiogenic shock. METHODS: The authors performed a systematic search of studies examining left ventricular unloading during VA-ECMO in Medline, EMBASE, and the Cochrane library. The primary outcome was all-cause mortality. Secondary outcomes included limb ischemia, bleeding, need for renal replacement therapy, multiorgan failure, stroke or transient ischemic attack, and hemolysis. RESULTS: Of 2,221 publications identified, 17 observational studies met the inclusion criteria. In total, outcomes in 3,997 patients were included with 1,696 (42%) receiving a concomitant left ventricular unloading strategy while on VA-ECMO (intra-aortic balloon pump 91.7%, percutaneous ventricular assist device 5.5%, pulmonary vein or transseptal left atrial cannulation 2.8%). There were 2,412 deaths (60%) in the total cohort. Mortality was lower in patients with (54%) versus without (65%) left ventricular unloading while on VA-ECMO (risk ratio: 0.79; 95% confidence interval: 0.72 to 0.87; p < 0.00001). Hemolysis was higher in patients who underwent VA-ECMO with left ventricular unloading. Otherwise, secondary outcomes were not demonstrably different in patients treated with VA-ECMO with versus without left ventricular unloading. CONCLUSIONS: In observational studies, left ventricular unloading was associated with decreased mortality in adult patients with cardiogenic shock treated with VA-ECMO. In the absence of prospective randomized data, left ventricular unloading may be considered for appropriately selected patients undergoing VA-ECMO support.

Adenosine as a Marker and Mediator of Cardiovascular Homeostasis: A Translational Perspective.

Adenosine, a purine nucleoside, is produced broadly and implicated in the homeostasis of many cells and tissues. It signals predominantly via 4 purinergic adenosine receptors (ADORs) - ADORA1, ADORA2A, ADORA2B and ADOosine signaling, both through design as specific ADOR agonists and antagonists and as offtarget effects of existing anti-platelet medications. Despite this, adenosine has yet to be firmly established as either a therapeutic or a prognostic tool in clinical medicine to date. Herein, we provide a bench-to-bedside review of adenosine biology, highlighting the key considerations for further translational development of this proRA3 in addition to non-ADOR mediated effects. Through these signaling mechanisms, adenosine exerts effects on numerous cell types crucial to maintaining vascular homeostasis, especially following vascular injury. Both in vitro and in vivo models have provided considerable insights into adenosine signaling and identified targets for therapeutic intervention. Numerous pharmacologic agents have been developed that modulate adenmising molecule.

Prevalence and Associated Clinical Characteristics of Exercise-Induced ST-Segment Elevation in Lead aVR.

BACKGROUND: Exercise-induced ST-segment elevation (STE) in lead aVR may be an important indicator of prognostically important coronary artery disease (CAD). However, the prevalence and associated clinical features of exercise-induced STE in lead aVR among consecutive patients referred for exercise stress electrocardiography (ExECG) is unknown. METHODS: All consecutive patients receiving a Bruce protocol ExECG for the diagnosis of CAD at a tertiary care academic center were included over a two-year period. Clinical characteristics, including results of coronary angiography, were compared between patients with and without exercise-induced STE in lead aVR. RESULTS: Among 2227 patients undergoing ExECG, exercise-induced STE ≥1.0mm in lead aVR occurred in 3.4% of patients. Patients with STE in lead aVR had significantly lower Duke Treadmill Scores (DTS) (-0.5 vs. 7.0, p<0.01) and a higher frequency of positive test results (60.2% vs. 7.3%, p<0.01). Furthermore, patients with STE in lead aVR were more likely to undergo subsequent cardiac catheterization than those without STE in lead aVR (p<0.01, odds ratio = 4.2). CONCLUSIONS: Among patients referred for ExECG for suspected CAD, exercise-induced STE in lead aVR was associated with a higher risk DTS, an increased likelihood of a positive ExECG, and referral for subsequent coronary angiography. These results suggest that exercise-induced STE in lead aVR may represent a useful ECG feature among patients undergoing ExECG in the risk stratification of patients.