The impairment of vascular reactivity across the spectrum of cardiometabolic health


Loader, Jordan Luke 2018. The impairment of vascular reactivity across the spectrum of cardiometabolic health. Thesis
AuthorsLoader, Jordan Luke
Qualification nameDoctor of Philosophy (PhD)

Cardiovascular disease (CVD) remains the single leading cause of mortality and is strongly associated with obesity and cardiometabolic disease (inclusive of metabolic syndrome [MetS], impaired glucose tolerance and type 2 diabetes [T2D]). Impairments in vascular reactivity, stemming from such endothelial dysfunction, as well as possible disruptions to endothelium-independent activity and maladaptation to the vascular smooth muscle, increase susceptibility to endothelial injury and, thus, promote atherosclerotic change. Several large cross-sectional studies provide evidence that chronic impairments in vascular reactivity may present early in the decline of cardiometabolic health, such as in those considered overweight. However, whether there is a pathophysiological continuum in in the impairment of vascular reactivity between early stages and diabetic complications has never been addressed. Excess sugar consumption is one of the main dietary factors driving the increased prevalence of obesity, insulin resistance and CVD, but the overall effect of acute hyperglycemia on vascular reactivity is currently unclear due to discrepant findings. Considering this, the primary aim of this research program was to examine the extent and nature of vascular impairment across the spectrum of cardiometabolic health; with a focus on the mediating effects of excess sugar consumption and the validity and accuracy of current methods used to quantify vascular reactivity in affected individuals. Study one evaluated the effect of acute hyperglycemia on vascular reactivity through a systematic review and meta-analysis; presenting evidence that excess sugar consumption may transiently impair endothelium-dependent vascular reactivity in the macrocirculation of those considered healthy or obese and of those with cardiometabolic disease (30 studies; n = 884; standardized mean difference [SMD], -1.40; 95% CI, -1.68 to -1.12; P < 0.01); while microvascular endothelium-dependent (9 studies; n = 181; SMD, -0.63; 95% CI, -1.36 to 0.11; P=0.09) and endotheliumindependent vascular reactivity (6 studies; n = 144; SMD, -0.07; 95% CI, -0.30 to 0.16; P=0.55) remain unaffected. However, these findings were ultimately inconclusive due to inadequate reporting of macrovascular data in nearly all studies included in the analyses and considerable heterogeneity in microvascular endothelial data; and due to a limited availability of endothelium-independent data. XXII Considering this, study two aimed to clarify the effect of acute hyperglycemia on vascular function, by assessing the impact of sugar-sweetened beverage (SSB) consumption, one of the most prominent sources of added sugar in the human diet. Compared to water consumption, a single 600 mL SSB impaired microvascular and macrovascular endothelial function in a healthy population, as indicated by a decrease in the vascular response to acetylcholine iontophoresis (208.3 ± 24.3 vs. 144.2 ± 15.7 %, P < 0.01) and by reduced flow-mediated dilation (0.019 ± 0.002 vs. 0.014 ± 0.002 %/s-1, P < 0.01), respectively. Similar to findings in study one, endothelium-independent vascular reactivity remained unaffected. Experimental models suggested that this SSBmediated endothelial dysfunction is partly due to an acute hyperglycemic-mediated increase in oxidative stress that reduces the bioavailability of nitric oxide, a key vasodilating agent. Combined, study one and two demonstrated that excess sugar consumption transiently impairs endothelial function in those considered healthy or obese and in those with cardiometabolic diseases; and, subsequently, that it may have a significant role in the initial and ongoing development of chronic vascular dysfunction, obesity, MetS, T2D and CVD. Despite this, whether there is a pathophysiological continuum in vascular dysfunction between early stages and diabetic complications was still unclear. Therefore, study three assessed, in a systematic review and network meta-analysis, the extent and nature of impairment in vascular reactivity across the spectrum of cardiometabolic health (i.e. overweight, obesity, impaired glucose tolerance, MetS, T2D and T2D with complications). One hundred and ninety three articles (7226 healthy subjects and 19,344 overweight or obese patients, or those with cardiometabolic diseases) were analysed, revealing a pathophysiological continuum where there is progressive impairment in endothelium-dependent and endothelium-independent vascular reactivity throughout the pathogenesis of T2D and its complications. Interestingly, meta-regressions revealed that for every 1 mmol/l increase in fasting blood glucose concentration, flow-mediated dilation decreased by 0.52 %. One of the most commonly used techniques to assess microvascular reactivity is iontophoresis of a vasoactive agent; a methodology that, within itself, presents a range of varying protocols for researchers to choose from, with no standardization of the XXIII protocols or data expression. In addition to a lack of standardization amongst the variety of techniques used to assess microvascular reactivity, the considerable heterogeneity, observed in the microvascular data from studies one and three, may have also been influenced by non-specific vasodilatory effects that can be induced by the iontophoresis technique. Indeed, there is no consensus as to which protocols of iontophoresis are free of confounding, non-specific vasodilatory effects. Considering this, study four evaluated commonly used protocols of iontophoresis finding that seven out of the ten published methods assessed in this present study induce non-specific vasodilatory effects that may confound vascular data. Providing updated methodological recommendations, this study found that iontophoresis of acetylcholine or sodium nitroprusside in sodium chloride (0.02 mA for 200 and 400 s, respectively) and acetylcholine in deionized water (0.1 mA for 30 s) mediate the least non-specific vasodilatory effects when iontophoresis is coupled with laser speckle contrast imaging; while the cutaneous microvascular responses to each tested insulin protocol were mediated mainly by non-specific effects. In conclusion, this program of research demonstrates that there is a pathophysiological continuum in vascular dysfunction; where endothelium-dependent and endothelium independent vascular reactivity are progressively impaired throughout the pathogenesis of T2D and its complications. Additionally, this research confirmed that excess sugar consumption induces transient impairments in endothelial function, which may contribute to the development of chronic vascular dysfunction, obesity, MetS, T2D and CVD. Further research is needed to assess if transient impairments in vascular function, mediated by several dietary and lifestyles factors, develop into chronic impairments, when the individual is still considered clinically healthy, or after the clinical onset of an overweight state. However, several issues within the current methodology for assessing vascular reactivity should be addressed first. Regardless, this research continues to inform public health policy that transient and chronic impairments of vascular function, which are representative of critical events in the pathogenesis of CVD and are associated with CVD mortality, occur early, long before the clinical onset of obesity, MetS and T2D. Furthermore, from a clinical perspective, the findings of this research program importantly provide further understanding of the development of vascular dysfunction, which may enhance the timing and, subsequent, effectiveness of treatment strategies that aim to improve vascular health and CVD outcomes.

PublisherACU Research Bank
Digital Object Identifier (DOI)
Research GroupMary MacKillop Institute for Health Research
Publisher's version
Publication dates01 Jan 2018
Additional information

The author acknowledges the Laboratory of Cardiovascular Pharm-Ecology, School of Sciences and Agrosciences, Université d’Avignon, where he spent 12 months during his candidature. The author has also included the abstract of his thesis in French.

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