ABSTRACT
PURPOSE: Peripheral vascular abnormalities contribute to compromised functional status in heart failure (HF) patients. The purpose of the present study was to test whether the intervention of moderate-intensity, resistance training could improve peripheral vascular responsiveness, that is, flow-mediated dilation (FMD) in HF. METHODS: Baseline brachial artery FMD analysis (2 minutes of cuff occlusion and 5 minutes of reperfusion) was measured in HF patients on intravenous inotropic support (n = 9) awaiting cardiac transplantation. Unilateral, upper-body resistance exercises (moderate intensity, combination of isometric and isotonic exercises at 60%-80% of maximum) were performed 3 d/wk for 4 weeks. Follow-up FMD analysis was conducted after training. Central hemodynamics were defined via right-side-heart catheterization. RESULTS: At baseline prior to training, HF patients elicited a significant hyperemic response 10 seconds following cuff occlusion (mean increase in blood flow: 194 ± 44 mL/min, P < .05). Despite this significant hyperemic response, HF patients demonstrated a mild, but paradoxical vasoconstriction of nearly 3% at 1-minute after cuff release. Four weeks of resistance training corrected the paradoxical vasoconstriction observed at baseline and resulted in vasodilatation (a positive increase in brachial artery diameter of 0.04 ± 0.04 mm, at 1 minute after cuff release; P < .05). Conversely, in a subset of 3 HF patients, studies in the untrained contralateral arm revealed no change in the FMD response. CONCLUSION: Moderate-intensity upper-body resistance training improved brachial artery FMD in end-stage HF patients on inotropic support. The reversal of the paradoxical vasoconstrictive response to reactive hyperemia following 4 weeks of training may be secondary to local improvements in vascular endothelial function rather than a quantitative change in the reactive hyperemic stimulus.
Subject(s)
Heart Failure/rehabilitation , Peripheral Vascular Diseases/rehabilitation , Resistance Training , Vasodilation , Adult , Cardiotonic Agents/administration & dosage , Chronic Disease , Combined Modality Therapy , Endothelium, Vascular , Female , Heart Failure/complications , Heart Transplantation , Hemodynamics , Humans , Male , Middle Aged , Peripheral Vascular Diseases/complicationsABSTRACT
After a meal, insulin suppresses lipolysis through the activation of its downstream kinase, Akt, resulting in the inhibition of protein kinase A (PKA), the main positive effector of lipolysis. During insulin resistance, this process is ineffective, leading to a characteristic dyslipidemia and the worsening of impaired insulin action and obesity. Here, we describe a noncanonical Akt-independent, phosphoinositide-3 kinase (PI3K)-dependent pathway that regulates adipocyte lipolysis using restricted subcellular signaling. This pathway selectively alters the PKA phosphorylation of its major lipid droplet-associated substrate, perilipin. In contrast, the phosphorylation of another PKA substrate, hormone-sensitive lipase (HSL), remains Akt dependent. Furthermore, insulin regulates total PKA activity in an Akt-dependent manner. These findings indicate that localized changes in insulin action are responsible for the differential phosphorylation of PKA substrates. Thus, we identify a pathway by which insulin regulates lipolysis through the spatially compartmentalized modulation of PKA.
Subject(s)
Adipocytes/drug effects , Adipocytes/metabolism , Insulin/metabolism , Insulin/pharmacology , Lipolysis/drug effects , 3T3-L1 Cells , Animals , Base Sequence , Cells, Cultured , Cyclic AMP-Dependent Protein Kinases/metabolism , Gene Knockdown Techniques , Insulin Resistance , Lipolysis/physiology , Mice , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA, Small Interfering/genetics , Signal TransductionABSTRACT
BACKGROUND: Vasoreactivity is known to be impaired in heart failure patients; however, it has not been determined whether standard medical therapy for end-stage heart failure patients (ES-HF) ameliorates this impairment. Therefore, we sought to investigate flow-mediated dilation (FMD) responses in ES-HF with normal or near normal cardiac indices from continuous inotropic support. METHODS AND RESULTS: Vascular ultrasound was used to assess FMD responses to isometric exercise and cuff occlusion in 15 ES-HF patients and 5 control subjects (C). ES-HF patients had significant hyperemic response to maximal exercise (P < .05), which was blunted relative to C (ES-HF; 84 +/- 21 mL/min versus C; 299 +/- 85 mL/min, P < .05). ES-HF patients did not show a significant hyperemic response to submaximal exercise. C had a significant increase in arterial diameter that exceeded ES-HF after both maximal (C; 8 +/- 1% versus. ES-HF; -0.9 +/- 0.86%, P < .05) and submaximal exercise (C; 6 +/- 1% versus ES-HF; 0.57 +/- 1%, P < .05). FMD responses at similar absolute workloads showed that both the mean hyperemic response and the change in arterial diameter were significantly greater in C. After cuff occlusion, the mean hyperemic response for ES-HF was again significantly blunted compared with C (ES-HF; 117 +/- 26% versus C; 352 +/- 86%, P < .05). After cuff occlusion, arterial diameter in C significantly increased in response to hyperemia, whereas ES-HF patients had a paradoxical vasoconstrictive response (C; 10.7 +/- 1.1% versus ES-HF; -5.3 +/- 1.5%, P < .05). CONCLUSION: Peripheral vasoreactivity in response to either maximal exercise, submaximal exercise, or hyperemic stimuli is impaired in ES-HF patients with normal resting cardiac outputs.