Diminished exercise capacity with increased shortness of breath and fatigue are major causes of morbidity in cardiomyopathic patients. Studies suggest that the exaggerated cardiovascular responses to exercise in heart failure patients are mediated, in part, by an over active exercise presser reflex (EPR). The EPR is a mechanism where blood pressure and heart rate increase in response to contraction-induced activation of primary afferent neurons and reflexive changes in autonomic outflow. The existence of an over active EPR in heart failure is also supported by the cardioprotective effects of sympathetic blockade in cardiomyopathic disease. In spite of these compelling clinical findings, however, the lack of an animal model in which the EPR and heart failure can be studied simultaneously has limited our understanding of the mechanisms involved in the evolution of reduced exercise capacity and abnormal circulatory control in heart failure. We have described a novel rat model in which significant increases in blood pressure and heart rate are reliably observed in response to static muscle contraction and passive stretch. Additionally, the EPR is exaggerated in rats with cardiomyopathy following coronary artery ligation. Finally, we demonstrate a molecular dysregulation of skeletal muscle afferent neurons during cardiomyopathy in the rat.
The specific aims of this proposal are:
Specific Aim #1 : Compare the effect of activation of skeletal muscle primary afferent neurons on the EPR in normal animals and in ligated animals at defined intervals during cardiomyopathy.
Specific Aim #2 : To determine the differential contribution of metabolically vs. mechanically-sensitive skeletal muscle afferent neurons to the EPR in the normal and cardiomyopathic states.
Specific Aim #3 : Evaluate the spinal pharmacology and molecular dysregulation of the exaggerated EPR. With this model, we will evaluate the contribution of the EPR to circulatory control during cardiomyopathy and provide a multidisciplinary evaluation of circulatory regulation during exercise in cardiovascular disease.
| Garry, Mary G; Garry, Daniel J (2015) Go to the Mattresses: A New Method for Human-Induced Pluripotent Stem Cell-Derived Cardiomyocyte Maturation. Circ Res 117:982-3 |
| Garry, Mary G (2011) Abnormalities of the exercise pressor reflex in heart failure. Exerc Sport Sci Rev 39:167-76 |
