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Micro- and Macrocirculation Coupling: a cross sectional investigation of the cross-talk between the two circuits in insulin resistance states

Final Report Summary - MMC (Micro- and Macrocirculation Coupling: a cross sectional investigation of the cross-talk between the two circuits in insulin resistance states)

The human microcirculation and macrocirculation have distinct vital roles in the homeostasis of the cardiovascular (CV) system. Although in great extend they have separate autoregulatory mechanisms, they are closely coupled in terms of anatomy and physiology. There is a constant cross-talk (i.e. signal transduction) between them by haemodynamic (pressure and flow) and neurohumoral factors. Via this cross-talk adequate vascular adaptations take place and the optimal haemodynamic coupling of the two circuits is maintained. Multiple and different adaptive/maladaptive mechanisms exist in each vascular circuit in response to “ill” signal transduction/stimuli. When these mechanisms fail arterial dysfunction and damage starts. Early dysfunction in any of the two circuits may lead to reciprocal transduction of ill signals between the microcirculation and macrocirculation, generating a vicious circle and leading to further impairment of their coupling and acceleration of the arterial disease.

The objective of the Microcirculation-Macrocirculation Coupling (MMC) project was: (i) to detect vascular and haemodynamic signs of the cross-talk between the microcirculation and macrocirculation in different human tissues; (ii) to define adaptive mechanisms in both vascular circuits. We focused on individuals without and with insulin resistance (type 2 diabetes mellitus, T2DM), the latter condition presenting vascular dysfunction and damage in both circuits via specific pathological pathways (hyperglycemia and/or hyperinsulinemia) that leads to multiple organ diseases.

The basic hypothesis and concepts that were investigated in the MMC project concern: (i) the role of increased pressure pulsatility - due to normal senescence or accelerated large artery stiffenning - as a potential generalized “ill/deleterious” signal that propagates from the macrocirculation into the microcirculation; (ii) the potentially differential contribution of central and peripheral pulsatility in the organ specific damage of the microcirculation; (iii) the role of increased pressure wave reflections as a potential protective mechanism that hampers the propagation of pulsitile energy from penetrating and damaging the microcirculation; (iv) the role of novel methodologies, such as 24-hour stiffness monitoring of the macrocirculation, to provide evidence on the status of the microcirculation, beyond the current state-of-the-art.

From the beginning of MMC project more than 1,500 individuals (without and with T2DM) aged between 40 and 75 years and living in the southern part of the Netherlands were recruited in a observational prospective population-based cohort study (“The Maastricht Study”) and extensive phenotyping of both the microcirculation (by skin flow/vasomotion, skin resting and recruitment capillary density, retina vessel caliber, kidney-microalbuminuria) and the macrocirculation (by multiple local pulse pressure/flow patterns assessed at the brachial, radial, femoral, aortic level; local and regional stiffness and pressure wave reflections mapping throughout the elastic and muscular arterial tree). We further extended our investigation and further tested the MMC project’s observations and hypothesis by organizing and/or analyzing other European cohorts (“SUVIMAX” study, “Hoorn” study, and “Safar” study), as well as, by performing extensive review and meta-analysis of the available data regarding the association between the microcirculation and the macrocirculation.

The results of the MMC project, although overall corroborate at large the hypothesis regarding the linear coupling between the two arterial beds (both in the absence and presence of T2DM), demonstrated that there are tissue-specific and T2DM-specific particularities regarding the coupling of the two vascular beds.

The performed review and meta-analysis of the preexisting data supports the notion that increased pressure pulsatility should be regarded as a deleterious sign, generated by early accelerated (e.g. in the presence of T2DM) or normal vascular aging of the macrocirculation, which is associated with damaged microcirculation of the brain, kidney and retina, as well as, with overt clinical disease such as cognitive and renal impairement. Results from the Maastricht study, the SUVIMAX study and Hoorn study did not detect any differences between central (aortic, carotid, femoral) and peripheral (brachial) pulsatility regarding their association with the microvascular dysfunction of the skin and of the kidney.

Of note, in the observational population-based cohort derived from the south part of the Netherlands (“The Maastricht study”) no association between large arteries stiffness and skin microvascular function (resting capillary density, capillary recruitment capacity and skin laser doppler flow and vasomotion) neither between pulse pressure (brachial or aortic) and skin microvascular function, irrespective of the presence of T2DM, were detected. These observations were replicated in a smaller cohort derived from the Paris region (SUVIMAX study). Taken together, these data indicated that unlike other tissues the skin microcirculation has unique protective mechanisms against increased pressure pulsatility, at least within the herein studied range of pressure pulsatility. Since at extreme pressure pulsatility the skin microcirculation would be expected (at least theoretically) to remain vulnerable, a non-linear phenotype of association between the two arterial beds is insinuated, that contradicts the so far known linear phenotype of the microcirculation-macrocirculation coupling.

“The Maastricht Study” data indicated that individuals with T2DM, compared to non-T2DM, have distinct characteristics both at the macrocirculation (greater pressure wave reflections) and the skin microcirculation (greater resting capillary density and lower recruitment capillary capacity). Only in non-T2DM an association between pressure wave reflections and skin microcirculation was found. This association implies the presence of a protective role of pressure wave reflections against the penetration pulsatile energy in the fragile skin capillary bed. In T2DM this association, might be masked by other local factors e.g. tissue hyperglycemia and the potentially associated tissue hyperperfusion or abolished.

Data from the Greek cohort (Safar study) on the interaction of the macrocirculation with the retinal microcirculation showed that for the first time evidence that a novel methodology of 24-hour arterial stiffness monitoring can provide additional information on this cross-talk, beyond the current state-of-the-art techniques and methods.

The results of the MMC project establish the presence of a close, but not per se linear association, between the microcirculation and macrocirculation and identified particularities in the skin microcirculation. In the presence of T2DM increased resting capillary density, lower capillary recruitment capacity and increased pressure wave reflections represent ealry signs of the cross-talk between the two vascular beds, representing adaptive or maladaptive mechanism to greater arterial stiffness and pressure pulsatility; however other local metabolic factors may have major influence. Further understanding of the pathophysiology of these mechanisms, with the use of novel methods - such as the 24-hour ambulatory monitoring of the macrocirculation, is required in order to establish the optimal balance of forward and backward propagating signals between the 2 vascular beds, in order to improved early clinical prevention and management of the cardiovascular disease within the micro-macrovascular continuum.