Coronary atherosclerosis: Un-altered physiology

Background End-stage coronary artery atherosclerosis has been studied extensively but the exact mechanisms of initiation and progression have not been defined fully. The aim of this study was to mathematically describe luminal change in relation to coronary vessel wall thickness in its progression from normal to atherosclerotic to establish whether these explain the pathophysiology. Methods One hundred coronary artery sections were graded histologically as ‘normal’ to ‘highly atherosclerotic’. Random systemic sampling by image analysis yielded 32 measurements (lumen radius and intima, medial, and adventitial thickness) from each section along 32 evenly spaced radii. Results The raw data follow an undulating course in relation to successive segments in all sections analyzed, pointing to a dynamic and well-ordered system. The calculated values, studied in triplets, followed a non-synchronized parabolic course, which was converted to linearity by taking the change in numbers (n-(n-1)=Δ) into account. The course and sign of ‘Δvessel wall’ (resulting from summed Δintima, Δmedia, Δadventitia) and ‘Δlumen radius’ values were unique for each triplet. Triplets order according to ‘Δlumen radius minus Δvessel wall’ and its course given by the trendline a-value presented stages in which increased Δvessel wall resulted in increased Δlumen radius in stages 1 and 3 and decreased Δlumen radius in stage 2. This phenomenon was found in all sections regardless of histological indication and independent of vessel wall constituent parts (intima, media, adventitia). Conclusions Similar basic processes are defined in all sections regardless of histological rating, indicating un-altered physiology. As such, coronary atherosclerosis can only be defined by a large to small shift of the triplets Δvessel wall trendline a-value. Consequently, no parameter of vessel wall pathology exists in absolute terms. Vessel wall composition has no importance for Δlumen radius.


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The anatomy and pathology of the coronary arteries are widely studied, especially by 43 histological means. However, basic knowledge is lacking regarding, for example, the 44 mechanism of arterial tapering, which corresponds to deficient knowledge of vessel 45 wall/lumen interactions and, even more fundamentally, the intimal, medial, adventitial 46 interplay. 47 Research has traditionally focused on the histopathology of plaque formation, the end-stage 48 atherosclerotic process. The process from initiation to plaque formation has often been studied 49 in a retrograde manner [1-3], which may lead to cause/effect reversal. An enlarged intima was 50 considered a characteristic and regarded as a key player in atherosclerotic pathology [4,5]. 51 Consequently, the limits of normality, the thickness of the media and adventitia, and their role 52 in atherosclerosis remain elusive. 53 We hypothesized that mathematical differences in the cross-sectional dimensions of normal 54 and atherosclerotic arteries between stages could be used to help explain the pathophysiology 55 of coronary artery atherosclerosis. This study aims to bridge the knowledge gap between the 56 physiology of vessel morphology and the pathogenesis of atherosclerosis by mathematically 57 defining both processes. Using a specially designed morphometric method termed 'random  100 The center point is located by the best fit circle procedure. Thirty-two radii differing by 11.25 101 degrees defined 32 measurement units of the lumen radius and intima, media, and adventitia 102 dimensions. 105 INTd, MEDd, and ADVd were highly variable, even between two consecutive measurement 106 units and regardless of the originating section. As the three vessel wall layer dimensions were 107 not usually independent, they were defined as a single functional unit (FU-1). Similarly, Rlu-   change (∆values 1.1-1.0 … n-(n-1)), which transformed the parabolic relationship into a linear 147 one (trendline formula: y = ax + b, R 2 =1).

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After data conversion to linear courses (∆), various triplets showed that ∆T-FU2 and ∆Rlu-VWd (R 2 always > 0.95) alternated from increasing to decreasing order. Regardless of a 180 section's histological rating, nine triplets showed a decrease and seven triplets an increase.

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Increasing and decreasing triplets were not always successive.

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increase or decrease of one opposed to the decrease or increase of the other two, a counter- ∆VWd values due to +∆INTd, -∆MEDd, and +∆ADVd.

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Comparisons of semi-range ratios ∆INT, ∆MEDd, or ∆ADVd to ∆VWd and ∆Rlu showed 248 variability in the single semi-range values (Table 7). Naturally, the summed semi-range 249 values ∆INTd, ∆MEDd, and ∆ADVd in proportion to semi-range ∆VWd equaled 1, but in  Their summed values in proportion to ∆VWd and ∆Rlu. Triplets are arranged in descending order based on ∆Rlu-VWd trendline a-values. Bold marks the 255 transition from stage 2 to stage 3.

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Atherosclerotic and non-atherosclerotic sections cannot be differentiated by triplet behavior.

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For example, ∆INTd growth with atherosclerosis is marked only by a shift from stage 1 to 291 stage 3. This illustrates that even atherosclerotic sections exhibit an increase in ∆Rlu in 292 relation to ∆VWd growth, which implies independence from vessel wall constitution. Support 293 for this view is given by the summed semi-range values ∆INTd, ∆MEDd, and ∆ADVd in 294 proportion to semi-range ∆Rlu, which is similar to the ∆VWd/∆Rlu ratio in absolute terms.

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Therefore, the atherosclerotic coronary vessel wall cannot be considered inert, but still proves 296 to be a well-adapting 'organ'.

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The ∆Rlu course is entirely dependent on the ∆VWd course, but their relationship is only 298 consistent within each triplet and, as such, variable between different triplets. Consequently, 299 the ∆VWd has a dissimilar course within each singular triplet, indicating that the quest for a specific coronary vessel wall dimension as parameter of 'physiological' or 'pathological' is 301 futile. The same is valid for the intima, media, and adventitia dimensions. Both course-302 determining factors prove the existence of a strict control mechanism active within all 303 sections and un-altered by the atherosclerotic process.

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Successive events describe a system's course, which is artificial in regards to non-consecutive

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Atherosclerosis is an umbrella term for a process in which plaques are ultimately formed. The 319 aorta appears more ulcerative (craters) than the coronary arteries and the processes leading to 320 these differences uncertain. Therefore, findings on coronary atherosclerotic processes cannot 321 be considered normative for the aortic processes. Differences could exist between muscular 322 and elastic arteries, or even between different muscular or elastic arteries. This is illustrated by the coronary arteries initially lacking the sub-endothelial (intimal) layer, in contrast to 324 cerebral arteries initially lacking the adventitial layer, making them translucent in vivo. 325 Therefore, our study is only the first step in understanding the process from arterial