reversal of lipids from atrosclerotic core

Key worlds:- atherosclerosis, lipid core, fibrous plaque, cholesterol , Fick’s law of diffusion , Arrhenius law

Vikram saxena
Email vikramsaxena@hotmail.com, vikram_sa2002@yahoo.com,
Add no-5 B1 abhilash apartments , veerbhadran street
Nungambakkam Chennai -34 , india

INTRODUCTION:-
The core region of atherosclerotic plaque is characterized by profuse lipid deposition and disappearance of cells and fibrous tissue elements. Enlargement of core, unless impeded or contained, leads to rupture and consequently arterial thrombosis(1)
The aggregation and fusion of lipids is the main mechanism for their extra-cellular accumulation. Diffusion of cholesterol across endothelium from arteries to sub-endothelium and subsequent fusion is the primary mechanism of plaque formation. This paper proposes a controlled raising of blood temperature to disturb equilibrium existing between cholesterol, lipoproteins and blood serum, thereby removing the depositions that may block the flow of blood.

Lipoprotein Aggregation and fusion :- A previous study of small, raised, lipid-containing lesions found in aortas from young adults suggested an early appearance of the core in human atherogenesis . In almost every lesion, the lipid appeared in two locations: superficial intimal foam cells and deep intimal core. Early atherosclerotic core in these lesions had a remarkable high content of free cholesterol, averaging 63 % of total cholesterol (2).
The extracellular lipid deposits fall into two major categories. Most areas within the core region exhibit a predominance of either cholesterol rich vesicles, associated with cholesterol crystals, or chlestereyl easter- rich oil droplets, typically without crystal (3)

The hypothesis of foam cell death, as an uncomplicated process, cannot account for extracellular lipid deposit rich in free cholesterol, because foam cell contains predominantly esterified cholesterol. It is also doubtful that foam cell death accounts for most of cholesteryl easter found in core(1). It is suggested that cholesteryl esters in the atherosclerotic cores are derived more or less directly from tissue lipoproteins, without intervening steps of uptake and processing in cells (1).

Lipoproteins , particularly LDL , aggregate and then fuse with each other in extracellular space to form microscopically visible lipid depositions (4/5/6/7/8/9/10/11/12). LDL aggregation can be induced in vitro by a wide verity of physical and biochemical agents (1).

The hyperlipidemic rabbit between the first and second weeks after the onset of cholesterol feeding provides a valuable model of extracellular arterial lipid deposition. At this time, before the migration of monocytes into the subendothelium space, deposition of extracellular lipid can be found beneath the endothelium near branch orifices in the aortic arch (13/14/15). In subsequent studies, human LDL was injected intravenously into previously normocholesterolemic rabbits to achieve high circulating levels. After only 2 hours, aggregates of LDL sized and larger particles appeared in the subendothelium space(1)
The above suggests that cholesterol enters in to subendothelium by diffusion across endothelium. Compelling evidence suggests that lipoprotein aggregation / fusion/ and diffusion across endothelium are extra cellular pathways for lipid deposition in atherosclerosis.

DIFFUSION :- cholesterol can diffuse via the aqueous phase at slow but meaningful rates (aqueous solubility , 3x10minus 8 mol/L)(1). In particular, the presence of crystals in the atherosclerotic core suggests that membranes in the vicinity may become physicochemically saturated with cholesterol at a level much higher than the physiological level for all cell membranes. One can also predict that lipoproteins in the vicinity of cholesterol crystal may become physicochemically saturated with free cholesterol or even undergo phase alteration to become vesicles (16/17). These effects could impair reverse cholesterol transport at tissue level because reverse cholesterol transport depends on physicochemical gradients to accomplish a net transfer of cholesterol from cellular plasma membranes to cholesterol acceptors including HDL (18/19)

PROGRESSION:- In the past the earliest precursors of obstructive lesions were described as thin lipid deposits in thin intima in children. It is now known that segments of thick intima (adaptive intimal thickening ) are also present in everyone from birth, particularly at bifurcations. These thicker intimal locations may also contain lipid deposits from childhood. Over time more lipid tends to accumulate in the thick locations, and an unmistakable morphological continuum of lesion types may transform adaptive thickening into obstructions that may cause symptoms. Thus, in the first three decades of life, lesions grow because more lipid accumulates and increases in specific, already thick segments of the intima. (20) ; indicating that diffusion across endothelium is a continuous process and it happens whenever there is conditions favorable for diffusion of lipid

Fick's First Law is used in steady state diffusion, i.e., when the concentration within the diffusion volume does not change with respect to time (Jin=Jout).
j = - D dφ/dx

Where
• J is the diffusion flux in dimensions of [(amount of substance) length-2 time-1], [mol m-2 s-1]
• D is the diffusion coefficient or diffusivity in dimensions of [length2 time-1], [m2 s-1]
• φ is the concentration in dimensions of [(amount of substance) length-3], [mol m-3]
• x is the position [length], [m]

Fick's Second Law

Fick's Second Law is used in non-steady or continually changing state diffusion, i.e., when the concentration within the diffusion volume changes with respect to time.
dφ/dt = Dd(square)φ/dx(square) ie dφ/dt = Dd2φ/dx2

Where
• φ is the concentration in dimensions of [(amount of substance) length-3], [mol m-3]
• t is time [s]
• D is the diffusion coefficient in dimensions of [length2 time-1], [m2 s-1]
• x is the position [length], [m]
It can be derived from the First Fick's law and the mass balance:

dφ/dt = -d/d x.J = d/dx(D.d/dxφ)

Assuming the diffusion coefficient D to be a constant we can exchange the orders of the differentiating and multiplying on the constant:

d/dx(Dd/dx.φ)= Dd/dx.d/dx.φ = Dd(square)φ/dx(square)ie Dd2φ/dx2

one obtains the form of the Fick's equations as stated above.
For the case of 3-dimensional diffusion the Second Fick's Law looks like:

dφ/dt = D(square of del operator)φ

Finally if the diffusion coefficient is not a constant, but depends upon the coordinate and/or concentration, the Second Fick's Law becomes:
dφ/dt = del operator.(D deloperator φ)



Temperature dependence of the Diffusion coefficient
The diffusion coefficient at different temperatures is often found to be well predicted by

D = Dzero exp-Ea/RT


PROPOSAL FOR REVERSAL OF CHOLESTEROL:- diffusion of cholesterol in reverse direction by changing/disturbing the equilibrium existing between lipids / lipoproteins / cholesterol / blood serum. As we have already seen that diffusion coefficient is dependent on temperature and concentration. It is proposed that blood temperature be raised and cholesterol level in blood serum be reduced. Cholesterol level in blood can be reduced by medicines and by reducing the intake of cholesterol in foods. Heating of blood can be achieved by infrared, microwave, radiofrequency or any other mechanism as is done in hyperthermia . It is proposed that further study of effects of temperature on atherosclerosis should be conducted using multi-slice computed tomography (CT scan) for determining the required increase in the temperature of the blood and its duration to dissolve atherosclerosis plaques of various sizes.

Summary In recent years the role of atherosclerotic core in promoting plaque rupture has become well recognized. Evidence suggests that lipoprotein diffusion across endothelium can be made reversible by increasing the temperature of the blood for a limited period of time.

Acknowledgments:- author acknowledge support / guidance extended by Dr A.M. Saxena and Dr Ravi Mohan Damodaran . Further to this extensive data/ facts are taken from article titled “ Development of the Lipid-Rich core in human Atherosclerosis” by Jhhn R Guyton; Keith F Klemp available on American Heart Association site.

References

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© 1996 American Heart Association, Inc.
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