The concept that exercise limitation in patients with chronic heart failure (HF) is directly due to elevated filling pressures or inadequate cardiac output during exercise has been revised. It is now recognized that the skeletal myopathy of HF is an important contributor exercise limitation in HF. The skeletal myopathy of HF is a predictable sequela to chronic cardiac dysfunction. Oxygen transport is a multi-step pathway, and according to the concept of """"""""coordinated adaptation,"""""""" the development of an abnormality in one step of a multi-step pathway initiates a readjustment of all other steps in the pathway to achieve a new equilibrium, so that all capacities are matched However, the mechanism(s) of """"""""matching capacities,"""""""" in this case the down- regulation of skeletal muscle capacity and the development of a skeletal myopathy in the setting of severe cardiac disease, remain unknown. We hypothesize that muscle sympathetic activation mediates the skeletal myopathy of HF. This may in part explain why cardiac resynchronization therapy (CRT), a therapy that improves abnormalities of cardiac function, which are not directly related to exercise dysfunction, nonetheless produces an irrefutable increase in exercise capacity. We have preliminary evidence that CRT significantly decreases muscle sympathetic nerve activity (MSNA). The overall goal of this project is to investigate the role of MSNA as the instigator of the skeletal myopathy of chronic HF.
Aim 1. To determine the mechanisms of chronic sympathoinhibiton with CRT in HF, and the effect of this sympathoinhibition on the skeletal myopathy. 1.1 Does CRT reduce resting MSNA chronically in advanced HF? 1.2 Is the skeletal myopathy reversed in HF patients in whom MSNA is decreased following CRT? 1.3 Does an increase in baroreceptor gain underlie this decrease in MSNA following CRT? 1.4 Does reversal of the augmented muscle mechanoreceptor sensitivity in HF contribute to the decrease in MSNA following CRT? Aim 2. To determine if another sympatholytic therapy, clonidine, reverses the skeletal myopathy of HF. 2.1 Is the sympatholysis with clonidine associated with a reversal of the skeletal myopathy in HF? 2.2 What is the effect of the improved skeletal myopathy on muscle mechanoreceptor sensitivity in HF? ? ? ?
|Nobre, Thais S; Antunes-Correa, Ligia M; Groehs, Raphaela V et al. (2016) Exercise training improves neurovascular control and calcium cycling gene expression in patients with heart failure with cardiac resynchronization therapy. Am J Physiol Heart Circ Physiol 311:H1180-H1188|
|Lobo, Denise M L; Trevizan, Patricia F; Toschi-Dias, Edgar et al. (2016) Sleep-Disordered Breathing Exacerbates Muscle Vasoconstriction and Sympathetic Neural Activation in Patients with Systolic Heart Failure. Circ Heart Fail 9:|
|Negrao, Carlos E; Middlekauff, Holly R; Gomes-Santos, Igor L et al. (2015) Effects of exercise training on neurovascular control and skeletal myopathy in systolic heart failure. Am J Physiol Heart Circ Physiol 308:H792-802|
|Groehs, Raphaela V; Toschi-Dias, Edgar; Antunes-Correa, Ligia M et al. (2015) Exercise training prevents the deterioration in the arterial baroreflex control of sympathetic nerve activity in chronic heart failure patients. Am J Physiol Heart Circ Physiol 308:H1096-102|
|Middlekauff, Holly R; Verity, M Anthony; Horwich, Tamara B et al. (2013) Intact skeletal muscle mitochondrial enzyme activity but diminished exercise capacity in advanced heart failure patients on optimal medical and device therapy. Clin Res Cardiol 102:547-54|
|Middlekauff, Holly R; Vigna, Chris; Verity, M Anthony et al. (2012) Abnormalities of calcium handling proteins in skeletal muscle mirror those of the heart in humans with heart failure: a shared mechanism? J Card Fail 18:724-33|
|Antunes-Correa, Ligia M; Kanamura, Bianca Y; Melo, Ruth C et al. (2012) Exercise training improves neurovascular control and functional capacity in heart failure patients regardless of age. Eur J Prev Cardiol 19:822-9|
|Martinez, Daniel G; Nicolau, José C; Lage, Rony L et al. (2011) Effects of long-term exercise training on autonomic control in myocardial infarction patients. Hypertension 58:1049-56|
|Horwich, Tamara B; Middlekauff, Holly R; Maclellan, W Robb et al. (2011) Statins do not significantly affect muscle sympathetic nerve activity in humans with nonischemic heart failure: a double-blind placebo-controlled trial. J Card Fail 17:879-86|
|Soares-Miranda, Luisa; Franco, Fabio G M; Roveda, Fabiana et al. (2011) Effects of exercise training on neurovascular responses during handgrip exercise in heart failure patients. Int J Cardiol 146:122-5|
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