Chronic statin therapy is associated with enhanced cutaneous vascular responsiveness to sympathetic outflow during passive heat stress

Abstract

Key points Impairments in both central sympathetic and peripheral microvascular function contribute to blunted reflex cutaneous vasodilatation during heat stress in healthy older adults. Hypercholesterolaemia is associated with decrements in neurovascular function; however, little is known about the impact of hypercholesterolaemia on the integrated responses to heat stress. Further, whether chronic statin therapy alters skin sympathetic outflow or its relation to cutaneous vascular conductance during heat stress is unknown. We demonstrate that reflex cutaneous vasodilatation is impaired in older hypercholesterolaemic adults but not in formerly hypercholesterolaemic adults currently treated with a statin compared to age‐matched controls. Additionally, chronic statin treatment‐induced improvements in reflex vasodilatation are mediated, in part, by increases in end‐organ responsiveness to efferent sympathetic outflow during whole‐body heating. These data add to the growing body of literature substantiating the beneficial pleiotropic neurovascular effects of chronic statin treatment and provide further support for the use of statins to confer additional cardioprotective benefits in older adults. Abstract Attenuated reflex cutaneous vasodilatation in healthy human ageing is mediated by alterations in both central (sympathetic outflow) and peripheral (microvascular endothelial) function. Hypercholesterolaemia is associated with further impairments in neurovascular function. HMG‐CoA reductase inhibitors (statins) improve cutaneous endothelium‐dependent dilatation; however, whether statin therapy alters skin sympathetic nervous system activity (SSNA) or its relation to cutaneous vascular conductance (CVC) during passive heat stress is unknown. We hypothesized that (1) hypercholesterolaemic older adults would demonstrate blunted increases in both SSNA and CVC during passive heating and (2) chronic statin treatment would improve the response range and sensitivity of the SSNA:CVC relation. Reflex vasodilatation in response to a 1.0°C rise in oral temperature (Tor; water perfused suit) was induced in 13 healthy normocholesterolaemic adults (62 ± 2 years; LDL = 113 ± 7 mg/dl), 10 hypercholesterolaemic adults (60 ± 1 years; LDL = 183 ± 2 mg/dl), and 10 previously hypercholesterolaemic adults (64 ± 1 years; LDL = 102 ± 2 mg/dl) treated with lipophilic statin (10–40 mg daily). SSNA (peroneal microneurography) and red cell flux (laser‐Doppler flowmetry) in the innervated dermatome (dorsum of foot) were continuously measured. Reflex vasodilatation was blunted in hypercholesterolaemic adults, but not in statin‐treated adults, compared to normocholesterolaemic adults (at ∆Tor = 1.0°C: normal = 36 ± 1%CVCmax, high = 32 ± 1%CVCmax, statin = 38 ± 1%CVCmax; P < 0.01). ∆SSNA was not different (at ∆Tor = 1.0°C: normal: ∆ = 393 ± 96%, high: ∆ = 311 ± 120%, statin: ∆ = 256 ± 90%; P = 0.11). The slope of the SSNA:CVC relation was blunted in hypercholesterolaemic adults (0.02 ± 0.03%CVCmax/%baseline) compared to both normocholesterolaemic (...

Thermoregulatory reflex control of cutaneous vasodilation in healthy aging

“…Once activated, the gain (or sensitivity of the response) is a proportional value that reflects the relation between the magnitude of the input signal (in this case, mean body temperature, � T b ) and the magnitude of the output signal (SSNA and CVC/sweat rate). Retrospectively applying this control theory approach, we tested the hypothesis that the � T b threshold for activation of SSNA would be increased, but, consistent with our previous studies [8,12,13], the sensitivity of the response (gain) would be reduced, in healthy older compared to young adults.…”

“…The resultant afferent neural signals are relayed to brainstem regions, primarily the preoptic anterior hypothalamus; central integration of this thermosensory input results in an increase in efferent skin sympathetic nervous system activity (SSNA) to activate eccrine sweating and cutaneous vasodilation -the primary thermoeffector mechanisms for heat dissipation [10,11]. A series of studies from our laboratory [8,[11][12][13] has demonstrated significant functional deficits at multiple points along the efferent thermoregulatory reflex axis in healthy older adults. First, the increase in SSNA during whole-body heating is markedly blunted [8,12], a central neural limitation that appears to be specific to thermoregulatory stimuli [8,14].…”

“…A series of studies from our laboratory [8,[11][12][13] has demonstrated significant functional deficits at multiple points along the efferent thermoregulatory reflex axis in healthy older adults. First, the increase in SSNA during whole-body heating is markedly blunted [8,12], a central neural limitation that appears to be specific to thermoregulatory stimuli [8,14]. Second, this attenuated efferent sympathetic response to heating is related to impaired reflex cutaneous vasodilation [8,12,13] and, presumably, sweating [15].…”

“…First, the increase in SSNA during whole-body heating is markedly blunted [8,12], a central neural limitation that appears to be specific to thermoregulatory stimuli [8,14]. Second, this attenuated efferent sympathetic response to heating is related to impaired reflex cutaneous vasodilation [8,12,13] and, presumably, sweating [15]. Further, sympathetic transduction to the cutaneous microvasculature during heat stress, estimated from the slope of the linear relation between increases in efferent SSNA and increases in microvascular cutaneous vascular conductance (CVC), is reduced in healthy older adults [8,12,13], owing to reductions in both the sensitivity and the range of end-organ thermoeffector responsiveness.…”

“…Second, this attenuated efferent sympathetic response to heating is related to impaired reflex cutaneous vasodilation [8,12,13] and, presumably, sweating [15]. Further, sympathetic transduction to the cutaneous microvasculature during heat stress, estimated from the slope of the linear relation between increases in efferent SSNA and increases in microvascular cutaneous vascular conductance (CVC), is reduced in healthy older adults [8,12,13], owing to reductions in both the sensitivity and the range of end-organ thermoeffector responsiveness. Finally, age-related impairments in both microvascular endothelial and sweat gland function during whole-body heat exposure are well established [15][16][17][18] and contribute to compromised thermoregulatory function in older adults.…”