Project Grant F30HL180059

ELECTROCHEMICAL BIOSENSORS FOR CONTINUOUS MONITORING OF INFLAMMATION IN HEART FAILURE WITH PRESERVED EJECTION FRACTION - PROJECT SUMMARY HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF) IS A LEADING CAUSE OF MORBIDITY AND MORTALITY. ACUTE DECOMPENSATIONS OF CHRONIC HFPEF CAUSE MOST OF THE MORTALITY IN THESE PATIENTS, BUT ARE DIFFICULT TO IDENTIFY. DURING AN ACUTE DECOMPENSATION, SIGNIFICANT CARDIAC DAMAGE OCCURS BEFORE ACCURATE DIAGNOSIS AND INTERVENTION ARE POSSIBLE. THERE IS AN URGENT UNMET NEED FOR EARLY DETECTION AND PREVENTION OF HFPEF DECOMPENSATIONS. CONTINUOUS BIOMOLECULAR MONITORING WITH WEARABLE OR POINT-OF-CARE SENSORS OFFERS AN EXCITING NEW PARADIGM FOR PREVENTING COMPLICATIONS IN CHRONIC DISEASES. THE CLASSIC EXAMPLE OF THIS STRATEGY IS CONTINUOUS GLUCOSE MONITORING (CGM), WHICH HAS REVOLUTIONIZED DIABETES CARE BY ALLOWING EARLY DETECTION OF HYPER- OR HYPOGLYCEMIA. THE SUCCESS OF THE CGM PARADIGM HIGHLIGHTS A POTENTIAL AVENUE FOR HFPEF CARE: CONTINUOUS MONITORING OF RELEVANT BIOMARKERS COULD ENABLE EARLY DETECTION AND PREVENTION OF HFPEF DECOMPENSATIONS. CONTINUOUS MONITORING FOR HFPEF REQUIRES TWO INNOVATIONS: TECHNOLOGY THAT ALLOWS REAL-TIME PROTEIN MONITORING AND A VALIDATED PANEL OF BIOMARKERS THAT FLUCTUATE SIGNIFICANTLY DURING EARLY-STAGE, SUB-CLINICAL DECOMPENSATION. THE FOUNDATION FOR EACH OF THESE INNOVATIONS ALREADY EXISTS: ELECTROCHEMICAL BIOSENSING (SPECIFICALLY, THE MOLECULAR PENDULUM TECHNIQUE) FOR SENSING TECHNOLOGY, AND PROTEIN DRIVERS OF NEUTROPHIL INFLAMMATION FOR BIOMARKERS. TRADITIONAL PROTEIN DETECTION TECHNIQUES, SUCH AS ELISA, REQUIRE MULTIPLE STEPS AND ADDITION OF EXTERNAL REAGENTS - AS SUCH, THEY ARE NOT SUITABLE FOR CONTINUOUS MEASUREMENTS. IN CONTRAST, THE MOLECULAR PENDULUM (MP) IS A REAGENTLESS ELECTROCHEMICAL SENSING PLATFORM FOR ULTRASENSITIVE PROTEIN DETECTION. THE MP OFFERS A UNIVERSAL PLATFORM FOR PROTEIN MONITORING IN HFPEF; IT NEEDS ONLY TO BE APPLIED TO NEUTROPHIL INFLAMMATION MARKERS, AND TO BE OPTIMIZED FOR FREQUENT CLINICAL MONITORING IN WEARABLE OR POINT-OF-CARE DEVICES. IN AIM 1, I PLAN TO ADAPT AND OPTIMIZE MP SENSORS TO TARGET MARKERS OF NEUTROPHIL-MEDIATED INFLAMMATION. INFLAMMATION IS A KEY DRIVER OF HFPEF DEVELOPMENT AND EXACERBATION. SPECIFICALLY, ELEVATED CIRCULATING LEVELS OF NEUTROPHIL-MEDIATED INFLAMMATION MARKERS ARE SIGNIFICANTLY ASSOCIATED WITH WORSE OUTCOMES FOR HFPEF PATIENTS. THUS, NEUTROPHIL INFLAMMATION ALREADY SERVES AS A USEFUL BIOMARKER SET FOR HFPEF CLINICAL STATUS, BUT MORE WORK IS REQUIRED TO ESTABLISH THE TIME-COURSE RELATIONSHIP BETWEEN THESE BIOMARKER FLUCTUATIONS AND SUB-CLINICAL CARDIAC FUNCTIONAL DECLINE. IN AIM 2, I PLAN TO ADDRESS THIS GAP BY PROFILING THE DYNAMIC FLUCTUATIONS IN NEUTROPHIL INFLAMMATION THROUGHOUT THE DEVELOPMENT AND EXACERBATION OF HFPEF, BOTH IN PATIENT SAMPLES AND A HFPEF MURINE MODEL. AS A WHOLE, THIS PROJECT WILL PROVIDE TECHNOLOGICAL INNOVATION IN THE FIRST FULLY REAGENTLESS SENSOR FOR CONTINUOUS MONITORING OF NEUTROPHIL INFLAMMATION PROTEIN MARKERS (AIM 1), AS WELL AS BIOLOGICAL NOVELTY IN THE FIRST DYNAMIC PROFILE OF NEUTROPHIL BIOMARKER FLUCTUATIONS IN HFPEF (AIM 2). IN DOING SO, I AIM BOTH TO ESTABLISH THE UNDERLYING TECHNOLOGY AND TO IDENTIFY THE RELEVANT BIOMARKER INSIGHT THAT WOULD BE NEEDED FOR A FUTURE CLINICAL MONITORING DEVICE FOR HFPEF PATIENTS.