Microvascular perfusion heterogeneity contributes to peripheral vascular disease in metabolic syndrome

Abstract

A major challenge facing public health is the increased incidence and prevalence of the metabolic syndrome, a clinical condition characterized by excess adiposity, impaired glycaemic control, dyslipidaemia and moderate hypertension. The greatest concern for this syndrome is the profound increase in risk for development of peripheral vascular disease (PVD) in afflicted persons. However, ongoing studies suggest that reductions in bulk blood flow to skeletal muscle may not be the primary contributor to the premature muscle fatigue that is a hallmark of PVD. Compelling evidence has been provided suggesting that an increasingly spatially heterogeneous and temporally stable distribution of blood flow at successive arteriolar bifurcations in metabolic syndrome creates an environment where a large number of the pre-capillary arterioles have low perfusion, low haematocrit, and are increasingly confined to this state, with limited ability to adapt perfusion in response to a challenged environment. Single pharmacological interventions are unable to significantly restore function owing to a divergence in their spatial effectiveness, although combined therapeutic approaches to correct adrenergic dysfunction, elevated oxidant stress and increased thromboxane A 2 improve perfusion-based outcomes. Integrated, multi-target therapeutic interventions designed to restore healthy network function and flexibility may provide for superior outcomes in subjects with metabolic syndrome-associated PVD.

Dissociation of local and global skeletal muscle oxygen transport metrics in type 2 diabetes

“…Distribution of blood flow is more spatially heterogeneous in the obese Zucker rat model of type 2 diabetes, and this perfusion heterogeneity is associated with impaired oxygen uptake. 14,15,24,25 Simulation studies reveal that heterogeneous perfusion results in impaired muscle oxygenation on average, because over-perfused vessels cannot fully compensate for under-perfused vessels. 15,26–28 By definition, heterogeneous perfusion not resulting from heterogeneous tissue demand would result in flow/VO 2 mismatch.…”

Cardiovascular consequences of metabolic syndrome

“…(95) In contrast, diminished vasodilator responsiveness and increased myogenic activation is evident in isolated middle cerebral arteries and gracilis arterioles from obese Zucker rats. (77, 96, 97) This skeletal muscle microvasculopathy is associated with an enhanced rate of fatigue and decreased maximal force development of skeletal muscle,(79, 97, 98) which can be largely corrected through pharmacologic enhancement of perfusion. (98, 99) Renal, cerebral, and skeletal muscle circulations have also been shown to be adversely affected by obesity and the MetS, which produce diminish microvascular-capillary density.…”

“…(77, 96, 97) This skeletal muscle microvasculopathy is associated with an enhanced rate of fatigue and decreased maximal force development of skeletal muscle,(79, 97, 98) which can be largely corrected through pharmacologic enhancement of perfusion. (98, 99) Renal, cerebral, and skeletal muscle circulations have also been shown to be adversely affected by obesity and the MetS, which produce diminish microvascular-capillary density. (9-13, 100, 101) Significant coronary vascular remodeling and altered vascular wall mechanics have also been documented in obese swine with MetS.…”

“…(9-13, 100, 101) Significant coronary vascular remodeling and altered vascular wall mechanics have also been documented in obese swine with MetS. (85) Aside from impaired oxygenation and tissue hypoxia, microvascular dysfunction in MetS has also been suggested to play a role in the development of glomerular injury, tubular atrophy, interstitial fibrosis,(76, 95) and exacerbation of injury in the setting of peripheral vascular disease(98) or stroke. (77)…”

Impact of physical activity, ageing, obesity and metabolic syndrome on muscle microvascular perfusion and endothelial metabolism

“…The third review (Frisbee et al . ) addresses the problem of premature muscle fatigue that is experienced by patients with metabolic syndrome and subsequent progression into peripheral vascular disease. The obese Zucker rat (OZR) was used as a model of metabolic syndrome.…”