Cardiovascular Interoceptive Accuracy Correlates with Piezo 1 Mediated Baroreceptor Sensitivity and State Anxiety: Implications for Hypoglycemic Awareness

CARDIOVASCULAR INTEROCEPTIVE ACCURACY CORRELATES WITH PIEZO 1 MEDIATED BARORE- CEPTOR SENSITIVITY AND STATE ANXIETY: IMPLICATIONS FOR HYPOGLYCEMIC AWARENESS. Jack Summers, B.S., Zachary Miklja, M.D., Warren Lockette, M.D., Wayne State University School of Medicine, Detroit, Ml, USA. Background: There is a brisk, reflex autonomic response to low blood glucose in which surges of catecholamines are released to enhance glycogenolysis, gluconeogenesis, and lipolysis. In addition to providing metabolic substrates, the cardiovascular responses to this surge in norepinephrine and epinephrine include an increase in heart rate and cardiac contractility. How these changes in heart rate and contractility are subjectively sensed and perceived as hypoglycemia is unknown. Exteroceptive sensors (e.g. visual and auditory receptors) allow us to respond to external threats from the environment. Interoceptive sensory receptors allow us to identify threats within the internal milieu, but their nature is unknown. Teleologically, interoceptive cues can serve as a warning as humans perceive changes in their heart rate or rhythm (“my heart skipped a beat”) brought about by stressors such as hypoglycemia or pain. Hypothesis: We propose that Piezo 1 channels in the heart of men and women are responsible for cardiac interoception. Because Piezo 1 channels mediate baroreceptor sensitivity, we postulated awareness of stress-induced increases in heart rate (i.e. cardiac interoceptive accuracy, “IA”) would correlate with changes in an individual’s heart rate and pulse pressure. Furthermore, those individuals with greater IA would have greater behavioral state anxiety. Finally, we expected that ex vivo measurements of Piezo 1 sensitivity could be used to predict an individual’s IA and state anxiety levels. Methods: We recruited 21 healthy men and women in whom IA was measured with a heartbeat detection task. We used the cold pressor test as our surrogate stressor to obviate the need to induce untoward hypoglycemia. Hemodynamics were measured non- invasively before and during a cold (1o C) pressor test over three minutes. State anxiety was assessed with a validated questionnaire. Piezo 1 channel activity was measured using a hypotonicity lysis assay on erythrocytes from our volunteers. Results: An increase in IA was inversely correlated with baroreceptor sensitivity as determined by the change in heart rate induced by cold pressor test-induced increases in pulse pressure, Spearman’s r = -0.58, p = 0.0056. IA also correlated positively with state anxiety, Spearman’s r = 0.52, p = 0. 042. Finally, our ex vivo assay demonstrated that erythrocyte Piezo1 channel sensitivity also correlated with state anxiety, Spearman’s r = 0.72, p = 0.016. Conclusions: Individual variations in Piezo 1 channel activity could explain individual differences in the subjective sensing of cardiovascular and subjective behavioral responses to physiological stressors such as hypoglycemia. Our ex vivo assay of Piezo1 sensitivity could identify those individuals predisposed to impaired awareness of hypoglycemia.