53 Critical Reviews ™ in Biomedical Engineering, 46(1):53–82 (2018) 0278-940X/18/$35.00 © 2018 by Begell House, Inc. www.begellhouse.com Author Proof Facilitating Earlier Diagnosis of Cardiovascular Disease through Point-of-Care Biosensors: A Review Mackenzie M. Honikel, Chi-En Lin, David Probst, & Jefrey T. La Belle * School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona *Address all correspondence to: Dr. Jefrey T. La Belle, Ph.D., 501 E. Tyler Mall St. Tempe, AZ 85287; Tel.: (480) 727-9061, E-mail: Jefrey. Labelle@asu.edu ABSTRACT: Cardiovascular disease (CVD) accounts for 30% of all global deaths and is predicted to dominate in the coming years, despite vast improvements in medical technology. Current clinical methods of assessing an individual’s cardiovascular health include blood tests to monitor relevant biomarker levels as well as varying imaging modalities such as electrocardiograms, computed tomography, and angiograms to assess vasculature. As informative as these tools are, they each require lengthy scheduling, preparation, and highly trained personnel to interpret the results before any information is accessible to patients, often leading to delayed treatment, which can be fatal. A point-of-care (POC) sensor platform is thus paramount in rapid and early diagnosis of CVD. Among the many POC detection platforms, including established optical and mechanical methods, electrochemical-based detection mechanisms have become increasingly desirable because of their superior sensitivity, low cost, and label- free detection. Specifcally, electrochemical impedance spectroscopy (EIS) has demonstrated remarkable abilities in low-level (femtomolar) detection of several clinically useful biomarkers and has been reported in CVD diagnostic applications. In this review, we provide an in-depth overview of prevalent CVD diseases and clinically relevant pro- teomic biomarkers for assessing them. Subsequently, we discuss the ongoing development of POC sensors for CVD, highlighting the current clinical gold standard, potential alternative modalities, and electrochemical methodologies previously successful in quantifying specifc biomarkers approved by the Food and Drug Administration (FDA). A discussion of EIS highlighting the attributes and capabilities of novel analysis algorithms is included to showcase the possibility of simultaneous dual-marker detection. KEY WORDS: cardiovascular disease, early detection, biomarker, electrochemical impedance spectroscopy, label- free detection, imaginary impedance, optimal frequency algorithm ABBREVIATIONS: ApoB, apolipoprotein B; ApoA-I, apolipoprotein A-I; BNP, B-type natriuretic peptide; CK-MB, creatine kinase-muscle/brain; CRP, C-reactive protein; cTnI, Troponin I; cTnT, Troponin T; cTnC, Troponin C; CVD, cardiovascular disease; EIS, electrochemical impedance spectroscopy; FET, feld efect transistor; HAS, human serum albumin; HDL, high- density lipoprotein; IMA, ischemia-modifed albumin; LDL, low-density lipoprotein; MPO, myeloperoxidase; NT-proBNP, N-terminal prohormone of B-type natriuretic peptide; POC, point of care; RSQ, R-square; SAM, self-assembled monolayer; SOTA, state of the art; Z, impedance I. INTRODUCTION Despite advancements in medical technology and increasing trends toward a more health-conscious public, cardiovascular disease (CVD) remains the leading global killer. 1 In the year 2015 alone, of 56 million recorded deaths, CVD was identifed as the cause for over 25% of cases. 2 Unfortunately, death tolls have increased worldwide since the year 2000, and despite preventative eforts CVD is predicted to continue its global dominance in mortality in the coming years. 3 Because the physiological underpinnings of CVD vary with respect to the presented condition, diferent treatment approaches are required. However, symp- toms are often not mutually exclusive, complicating clinical diagnosis and delaying treatment. The direct efects are costs associated with unnecessary tests, misdiagnosis, and often improper treatment. 4 The devastating trends of CVD mandate the development of more efcient clinical diagnostic tools to facilitate earlier diagnosis. The pathophysiology of CVD results in the release of specifc molecular species that are indica-