Project Grant R01HL175086

PERIPHERAL MECHANISMS OF EXERCISE INTOLERANCE IN HFPEF - PROJECT SUMMARY/ABSTRACT: THE HALLMARK FEATURES OF HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF) ARE EXERCISE INTOLERANCE AND EXERTIONAL SYMPTOMOLOGY. IT IS NOW CLEAR THAT THE PATHOPHYSIOLOGY OF EXERCISE INTOLERANCE INVOLVES MULTIPLE PHYSIOLOGICAL SYSTEMS IN HFPEF WITH PERIPHERAL ('NON-CARDIAC') ABNORMALITIES HAVING A CRITICAL ROLE. LOCOMOTOR MUSCLE AFFERENT FEEDBACK REFLEXES ARE NECESSARY FOR THE NORMAL LOCOMOTOR MUSCLE BLOOD FLOW AND VENTILATORY RESPONSES TO EXERCISE IN HEALTHY ADULTS. HOWEVER, THESE LOCOMOTOR MUSCLE AFFERENT REFLEXES APPEAR TO BE 'OVERACTIVE' WITH HFPEF IMPAIRING LOCOMOTOR BLOOD FLOW AND EXAGGERATING THE VENTILATORY RESPONSE. ADDITIONALLY, PULMONARY SYSTEM ALTERATIONS AND INSPIRATORY MUSCLE METABOLIC INEFFICIENCY IN HFPEF NECESSITATE AN EXAGGERATED INSPIRATORY MUSCLE BLOOD FLOW DEMAND DURING EXERCISE. IMPORTANTLY, HFPEF PATIENTS ARE UNABLE TO MEET THIS EXAGGERATED INSPIRATORY MUSCLE BLOOD FLOW DEMAND DURING EXERCISE. THIS EXAGGERATED DEFICIT BETWEEN INSPIRATORY MUSCLE BLOOD FLOW DEMAND AND BLOOD FLOW RESPONSE TO EXERCISE IN HFPEF MAY PREDISPOSE THEM TO EXERCISE INTOLERANCE AND EXERTIONAL DYSPNEA. OUR SCIENTIFIC PREMISE IS THAT LOCOMOTOR AND INSPIRATORY MUSCLE PATHOPHYSIOLOGIC MECHANISMS CONTRIBUTE TO THE WELL DESCRIBED EXERCISE INTOLERANCE AND EXERTIONAL SYMPTOMS IN HFPEF PATIENTS. THE SPECIFIC AIMS THAT WILL BE EXPLORED IN THIS PROPOSAL INCLUDE: 1) TO TEST IF LOCOMOTOR SKELETAL MUSCLE AFFERENT FEEDBACK REFLEXES CONTRIBUTE TO THE ABNORMAL CARDIOVASCULAR AND VENTILATORY FUNCTION DURING EXERCISE IN HFPEF, AND 2) TO TEST IF INSPIRATORY MUSCLE TRAINING REDUCES THE EXAGGERATED INSPIRATORY MUSCLE BLOOD FLOW DEMAND IN HFPEF AND IMPROVES EXERCISE TOLERANCE AND EXERTIONAL SYMPTOMOLOGY IN THESE PATIENTS. BOTH AIMS ARE FRAMED WITH TESTABLE HYPOTHESES AND CLEARLY ASSOCIATED WITH THE EXPERIMENTAL PROTOCOL AND STATISTICAL ANALYSIS PLAN. OUR INTEGRATIVE, HIGHLY COLLABORATIVE RESEARCH TEAM HAS THE INTELLECTUAL AND TECHNICAL EXPERTISE, ESTABLISHED INFRASTRUCTURE, AND CLEARLY DEMONSTRATE HIGH FEASIBILITY IN PERFORMING ALL FACETS OF THESE STUDIES TO ADDRESS AND INTERPRET THE AIMS WE HAVE PROPOSED. OUR PROPOSAL ADDRESSES AN IMPORTANT PROBLEM BY FOCUSING ON IDEAS THAT ARE A SIGNIFICANT DEPARTURE FROM CURRENT PARADIGMS ON EXERCISE INTOLERANCE AND EXERTIONAL SYMPTOMOLOGY IN HFPEF PATIENTS. OUR PRELIMINARY DATA AND REVIEW OF THE RIGOR OF PRIOR RESEARCH SUPPORTING OUR AIMS PROVIDE STRONG JUSTIFICATION FOR OUR INNOVATIVE EXPERIMENTAL DESIGN, GOLD STANDARD TECHNIQUES, AND INSPIRATORY MUSCLE TRAINING (AN INTERVENTION WITH HIGH CLINICAL UTILITY) TO REVEAL HOW LOCOMOTOR AND INSPIRATORY MUSCLE DYSFUNCTION IMPAIR EXERCISE TOLERANCE AND EXERTIONAL DYSPNEA IN PATIENTS WITH HFPEF. FINALLY, WE HAVE ALIGNED OUR SCIENTIFIC PREMISE, AIMS, AND ASSOCIATED HYPOTHESES WITH THE NHLBI RESEARCH PRIORITIES AND THE CURRENT NIH REVIEW CRITERIA THAT EMPHASIZES SIGNIFICANCE, IMPACT, AND INNOVATION FOR R01 APPLICATIONS.