α‐Adrenergic regulation of blood flow in HFpEF: too much and not enough

Patients with heart failure with preserved ejection fraction (HFpEF) have debilitating exercise intolerance that compromises functional independence and quality of life. Exercise performance is dependent upon the transport and utilization of oxygen quantified as V̇O2 during exercise testing. The transport of oxygen from the lungs to the mitochondria, referred to as the oxygen transport cascade, is an integrative, multi-step process involving several organ systems. Because cardiac dysfunction is inherent to the disease, initial investigations focused on deficiencies in cardiac output as the primary limitation to exercise capacity. However, mounting evidence indicates that non-cardiac or 'peripheral abnormalities' in skeletal muscle blood flow and muscle oxygen utilization play a primary role in exercise intolerance in many patients with HFpEF (Bunsawat et al., 2023). The importance of the mechanistic contribution of the periphery to exercise intolerance is underscored by the observation that the peripheral determinants of exercise capacity often have greater plasticity in response to exercise and lifestyle interventions than the heart. Exercise training improves several steps along the peripheral oxygen transport cascade in patients with HFpEF including blood flow, diffusion of oxygen in the muscle and mitochondrial function; whereas cardiac output tends to be more difficult to improve. In addition, evidence suggests that correcting deficiencies in skeletal muscle oxygen diffusion and utilization is predicted to be a more efficient strategy to improve peak V̇O2 than strategies solely targeting increases in cardiac output (Houstis et al., 2018). As such, unravelling the specific mechanisms responsible for regulation of skeletal muscle blood flow, diffusive capacity and oxidative capacity is an important step towards the development of efficient therapies for exercise intolerance in patients with HFpEF. The first step along the peripheral oxygen cascade after blood leaves the heart is the appropriate distribution of blood flow between skeletal muscle and other less metabolically active tissues (macro-distribution), and further spatial refinement of blood flow within exercising skeletal muscle to the areas of highest metabolic demand (micro-distribution). This is accomplished through the integration of sympathetic vasoconstriction and local vasodilatory factors within skeletal muscle. Activation of the sympathetic nervous system causes vasoconstriction that limits overperfusion in inactive tissues and helps divert blood flow to areas of higher metabolic demand. At the same time, sympathetic nervous system activity is also directed towards skeletal muscle where it competes with local metabolic vasodilatory signals. In healthy adults, local vascular signals attenuate sympathetic vasoconstriction, a process referred to as 'functional sympatholysis', to ensure adequate perfusion of metabolically active muscle. Without robust vasoconstriction in inactive tissues, blood pressure regulation and blood flow distribution are compromised and without appropriate functional sympatholysis, malperfusion of skeletal muscle reduces aerobic capacity (Saltin & Mortensen, 2012). Patients with HFpEF have documented increases in muscle sympathetic nervous system activity at rest. However, whether sympathetic dysregulation compromises blood flow regulation and aerobic capacity in patients with HFpEF is not clear. In this issue of the Journal of Physiology, Alpenglow and colleagues present a comprehensive series of experiments that investigate the role of α-adrenergic signalling, the primary effector of sympathetic vasoconstriction, on the regulation of skeletal muscle blood flow in patients with HFpEF. Two strengths of their experimental approach deserve special consideration. First, the authors utilize small muscle mass exercise combined with measurements of local V̇O2 across the leg, which isolates the peripheral steps of the oxygen cascade independent of any cardiac or pulmonary limitations to exercise performance that the patients may harbour (Andersen & Saltin, 1985). Second, the use of localized intra-arterial infusions of α-adrenergic agonists and antagonists enable strict control of the vasoconstrictor stimulus and direct assessment of local vascular signalling mechanisms, as opposed to generalized reflex sympathetic activation (e.g. cold pressor, lower body negative pressure). While in a smaller sample size of relatively lean patients, the high-resolution measures of blood flow responses, mechanistic pharmacological approaches and assessment of muscle V̇O2 provide fundamental insight regarding α-adrenergic control of blood flow at rest and during exercise in patients with HFpEF. The first set of experiments confirms that patients with HFpEF have reduced α-adrenergic responsiveness at rest. While this finding is not particularly surprising, adrenergic receptor sensitivity is often downregulated in proportion to sympathoexcitation, the observation is fundamental to our understanding of sympathetic vascular control. Vasoconstriction of vascular beds in less metabolically active tissues is the essential counterpart to functional sympatholysis, without which macro-distribution of blood flow and blood pressure regulation is severely compromised. While beyond the focus of this investigation, future investigations are needed to determine the functional impact of reduced α-adrenergic sensitivity on exercise haemodynamics and functional capacity in patients with HFpEF. Regarding the regulation of blood flow during exercise, the authors report that tonic levels of endogenous α-adrenergic signalling restrain the hyperaemic response to exercise and limit muscle oxygen utilization. While both groups experienced an increase in blood flow during exercise after blockade of α-adrenergic receptors, only patients with HFpEF showed an increase in oxygen utilization. This result provides the critical link between aberrant endogenous α-adrenergic signalling and reduced skeletal muscle aerobic capacity in patients with HFpEF. Finally, the authors utilized a classic experimental paradigm to test functional sympatholysis whereby the vasoconstrictor responsive to an infusion of an exogenous α-adrenergic agonist is assessed at rest and during exercise to quantify the ability of the muscle to attenuate α-adrenergic vasoconstriction. In healthy adults, the vasoconstrictor response was robust at rest and attenuated in a graded manner with increasing exercise intensity. In patients with HFpEF, the vasoconstrictor response was markedly diminished at rest and was attenuated to a lesser degree during exercise than in healthy controls. Altogether, it seems that tonic sympathetic activity in patients with HFpEF restrains blood flow and V̇O2 during exercise, and that a combination of poor adrenergic sensitivity and a reduced capacity of muscle to attenuate what little adrenergic vasoconstrictor reserve remains, limits muscle oxygen utilization and may contribute to exercise intolerance. There are a variety of therapeutic interventions designed to target sympathetic nervous system activity (e.g. renal or splanchnic denervation) or its downstream vasoconstrictor properties (α-adrenergic antagonist). However, to date, no therapies directly targeting the sympathetic nervous system have been approved for the treatment of HFpEF. While therapies that aim to reduce sympathetic vasoconstriction globally or in large vascular beds (e.g. splanchnic circulation) have the potential to lower blood pressure and cardiac filling pressures, special attention should be given to their effect on peripheral haemodynamics and exercise tolerance. In addition to therapies directly targeting sympathetic signalling, therapies with the potential to improve endothelial function may have the added benefit of improving sympathetic regulation of blood flow. Functional sympatholysis is an endothelium dependent process (Hearon et al., 2016); therefore, developing therapies and evaluating current therapies (e.g. GLP-1 agonists) for their effects on peripheral micro-vascular endothelial function may be essential for tailoring therapies to patients with excessive sympathetic activation and severe peripheral decrements in exercise capacity. Finally, the demonstrated benefit of exercise interventions on blood flow and oxygen utilization (Hearon et al., 2022) may be due in part to improved sympathetic regulation of muscle blood flow; therefore, additional research is needed to develop lifestyle interventions that effectively target these important signalling pathways. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. Sole author. None.