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
1 John R. Guyton: Keith F. Klemp Development of the Lipid-Rich Core in Human Atherosclerosis : (Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:4-11.)
© 1996 American Heart Association, Inc.
2, Guyton JR, Klemp KF. Development of the atherosclerotic core region: chemical and ultrastructural analysis of microdissected atherosclerotic lesions from human aorta. Arterioscler Thromb. 1994;14:1305-1314 .
3, Guyton JR, Klemp KF. The lipid-rich core region of human atherosclerotic fibrous plaques: prevalence of small lipid droplets and vesicles by electron microscopy. Am J Pathol. 1989;134:705-717.
4, Khoo JC, Miller E, McLoughlin P, Steinberg D. Enhanced macrophage uptake of low density lipoprotein after self-aggregation. Arteriosclerosis. 1988;8:348-358.
5, Frank JS, Fogelman AM. Ultrastructure of the intima in WHHL and cholesterol-fed rabbit aortas prepared by ultra-rapid freezing and freeze-etching. J Lipid Res. 1989;30:967-978.
6, Guyton JR, Klemp KF, Mims MP. Altered ultrastructural morphology of self-aggregated low density lipoproteins: coalescence of lipid domains forming droplets and vesicles. J Lipid Res. 1991;32:953-962.
7, Kovanen PT, Kokkonen JO. Modification of low density lipoproteins by secretory granules of rat serosal mast cells. J Biol Chem. 1991;266:4430-4436.
8, Steinbrecher UP, Lougheed M. Scavenger receptor-independent stimulation of cholesterol esterification in macrophages by low density lipoprotein extracted from human aortic intima. Arterioscler Thromb. 1992;12:608-625.
9, Xu XX, Tabas I. Sphingomyelinase enhances low density lipoprotein uptake and ability to induce cholesteryl ester accumulation in macrophages. J Biol Chem. 1991;266:24849-24858.
10, Tirziu D, Dobrian A, Tasca C, Simionescu M, Simionescu N. Intimal thickenings of human aorta contain modified reassembled lipoproteins. Atherosclerosis. 1995;112:101-114.
11, Tertov VV, Orekhov AN, Sobenin IA, Gabbasov ZA, Popov EG, Yaroslavov AA, Smirnov VN. Three types of naturally occurring modified lipoproteins induce intracellular lipid accumulation due to lipoprotein aggregation. Circ Res. 1992;71:218-228.
12, Hoff HF, Whitaker TE, O'Neil J. Oxidation of low density lipoprotein leads to particle aggregation and altered macrophage recognition. J Biol Chem. 1992;267:602-609.
13, Kruth HS. Subendothelial accumulation of unesterified cholesterol: an early event in atherosclerotic lesion development. Atherosclerosis. 1985;57:337-341.
14, Simionescu N, Vasile E, Lupu F, Popescu G, Simionescu M. Prelesional events in atherogenesis: accumulation of extracellular cholesterol-rich liposomes in the arterial intima and cardiac valves of the hyperlipidemic rabbit. Am J Pathol. 1986;123:109-125.
15, Guyton JR, Klemp KF. Early extracellular and cellular lipid deposits in aorta of cholesterol-fed rabbits. Am J Pathol. 1992;141:925-936.
16, Adams CWM, Abdulla YH. The action of human high density lipoprotein on cholesterol crystals, part 1: light-microscopic observations. Atherosclerosis. 1978;31:465-471.
17, Abdulla YH, Adams CWM. The action of human high density lipoprotein on cholesterol crystals, part 2: biochemical observations. Atherosclerosis. 1978;31:473-480.
18, Johnson WJ, Mahlberg FH, Rothblat GH, Phillips MC. Cholesterol transport between cells and high-density lipoproteins. Biochim Biophys Acta. 1991;1085:273-298.
19, Warner GJ, Stoudt G, Bamberger M, Johnson WJ, Rothblat GH. Cell toxicity induced by inhibition of acyl coenzyme A:cholesterol acyltransferase and accumulation of unesterified cholesterol. J Biol Chem. 1995;270:5772-5778.
20, Herbert C. Stary, MD, CHAIR; A. Bleakley Chandler, MD; Robert E. Dinsmore, MD; Valentin Fuster, MD, PhD; Seymour Glagov, MD; William Insull, Jr, MD; Michael E. Rosenfeld, PhD; Colin J. Schwartz, MD; William D. Wagner, PhD; Robert W. Wissler, PhD, MD :- A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis
Monday, June 18, 2007
Sunday, January 21, 2007
Thursday, January 11, 2007
Reversal of lipid from atherosclerotic core
Reversal of lipid from atherosclerotic 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
ph +919444044798
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 hastening regression of atherosclerotic core. Dependence of diffusion on temperature and concentration as predicted by fick,s law of diffusion is considered while proposing raising the temperature and lowering concentration of cholesterol in blood serum. Raising of temperate can be done by various options available like infrared, microwave, radiofrequency or any other mechanism as is being done in hyperthermia.
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). Compelling evidence suggests that lipoprotein aggregation / fusion/ and diffusion across endothelium are extra cellular pathways for lipid deposition in atherosclerosis
The above suggests that cholesterol enters in to subendothelium by diffusion across endothelium and esterified cholesterol remains in liquid form in atherosclerotic core.
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).
It is well established fact that regression of atherosclerotic core is achieved by lowering the cholesterol in blood serum by medicine at a very slow rate. Fick’s law as discussed below is considered to hasten regression of atherosclerotic core.
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 = -Ddφ/dt
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 =Dd2φ/dx2 ie Dd(square φ)/dt(square)
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/dx.J = d/dx(D.d/dx.φ)
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) = D.d/dx.d/dx.φ = D.d2φ/dx2 ie Dd(square φ)/d(square x)
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)
Finally if the diffusion coefficient is not a constant, but depends upon the coordinate and/or concentration, the Second Fick's Law becomes:
Temperature dependence of the Diffusion coefficient
The diffusion coefficient at different temperatures is often found to be well predicted by
D =D0e-EA/RT
where EA is the activation energy for diffusion
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 with simultaneous lowering of cholesterol in blood serum..
Acknowledgments:-
author acknowledge support / guidance extended by Dr A.M. Saxena ,Dr Anjali 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
1 John R. Guyton: Keith F. Klemp Development of the Lipid-Rich Core in Human Atherosclerosis : (Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:4-11.)
© 1996 American Heart Association, Inc.
2, Guyton JR, Klemp KF. Development of the atherosclerotic core region: chemical and ultrastructural analysis of microdissected atherosclerotic lesions from human aorta. Arterioscler Thromb. 1994;14:1305-1314 .
3, Guyton JR, Klemp KF. The lipid-rich core region of human atherosclerotic fibrous plaques: prevalence of small lipid droplets and vesicles by electron microscopy. Am J Pathol. 1989;134:705-717.
4, Khoo JC, Miller E, McLoughlin P, Steinberg D. Enhanced macrophage uptake of low density lipoprotein after self-aggregation. Arteriosclerosis. 1988;8:348-358.
5, Frank JS, Fogelman AM. Ultrastructure of the intima in WHHL and cholesterol-fed rabbit aortas prepared by ultra-rapid freezing and freeze-etching. J Lipid Res. 1989;30:967-978.
6, Guyton JR, Klemp KF, Mims MP. Altered ultrastructural morphology of self-aggregated low density lipoproteins: coalescence of lipid domains forming droplets and vesicles. J Lipid Res. 1991;32:953-962.
7, Kovanen PT, Kokkonen JO. Modification of low density lipoproteins by secretory granules of rat serosal mast cells. J Biol Chem. 1991;266:4430-4436.
8, Steinbrecher UP, Lougheed M. Scavenger receptor-independent stimulation of cholesterol esterification in macrophages by low density lipoprotein extracted from human aortic intima. Arterioscler Thromb. 1992;12:608-625.
9, Xu XX, Tabas I. Sphingomyelinase enhances low density lipoprotein uptake and ability to induce cholesteryl ester accumulation in macrophages. J Biol Chem. 1991;266:24849-24858.
10, Tirziu D, Dobrian A, Tasca C, Simionescu M, Simionescu N. Intimal thickenings of human aorta contain modified reassembled lipoproteins. Atherosclerosis. 1995;112:101-114.
11, Tertov VV, Orekhov AN, Sobenin IA, Gabbasov ZA, Popov EG, Yaroslavov AA, Smirnov VN. Three types of naturally occurring modified lipoproteins induce intracellular lipid accumulation due to lipoprotein aggregation. Circ Res. 1992;71:218-228.
12, Hoff HF, Whitaker TE, O'Neil J. Oxidation of low density lipoprotein leads to particle aggregation and altered macrophage recognition. J Biol Chem. 1992;267:602-609.
13, Kruth HS. Subendothelial accumulation of unesterified cholesterol: an early event in atherosclerotic lesion development. Atherosclerosis. 1985;57:337-341.
14, Simionescu N, Vasile E, Lupu F, Popescu G, Simionescu M. Prelesional events in atherogenesis: accumulation of extracellular cholesterol-rich liposomes in the arterial intima and cardiac valves of the hyperlipidemic rabbit. Am J Pathol. 1986;123:109-125.
15, Guyton JR, Klemp KF. Early extracellular and cellular lipid deposits in aorta of cholesterol-fed rabbits. Am J Pathol. 1992;141:925-936.
16, Adams CWM, Abdulla YH. The action of human high density lipoprotein on cholesterol crystals, part 1: light-microscopic observations. Atherosclerosis. 1978;31:465-471.
17, Abdulla YH, Adams CWM. The action of human high density lipoprotein on cholesterol crystals, part 2: biochemical observations. Atherosclerosis. 1978;31:473-480.
18, Johnson WJ, Mahlberg FH, Rothblat GH, Phillips MC. Cholesterol transport between cells and high-density lipoproteins. Biochim Biophys Acta. 1991;1085:273-298.
19, Warner GJ, Stoudt G, Bamberger M, Johnson WJ, Rothblat GH. Cell toxicity induced by inhibition of acyl coenzyme A:cholesterol acyltransferase and accumulation of unesterified cholesterol. J Biol Chem. 1995;270:5772-5778.
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
ph +919444044798
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 hastening regression of atherosclerotic core. Dependence of diffusion on temperature and concentration as predicted by fick,s law of diffusion is considered while proposing raising the temperature and lowering concentration of cholesterol in blood serum. Raising of temperate can be done by various options available like infrared, microwave, radiofrequency or any other mechanism as is being done in hyperthermia.
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). Compelling evidence suggests that lipoprotein aggregation / fusion/ and diffusion across endothelium are extra cellular pathways for lipid deposition in atherosclerosis
The above suggests that cholesterol enters in to subendothelium by diffusion across endothelium and esterified cholesterol remains in liquid form in atherosclerotic core.
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).
It is well established fact that regression of atherosclerotic core is achieved by lowering the cholesterol in blood serum by medicine at a very slow rate. Fick’s law as discussed below is considered to hasten regression of atherosclerotic core.
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 = -Ddφ/dt
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 =Dd2φ/dx2 ie Dd(square φ)/dt(square)
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/dx.J = d/dx(D.d/dx.φ)
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) = D.d/dx.d/dx.φ = D.d2φ/dx2 ie Dd(square φ)/d(square x)
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)
Finally if the diffusion coefficient is not a constant, but depends upon the coordinate and/or concentration, the Second Fick's Law becomes:
Temperature dependence of the Diffusion coefficient
The diffusion coefficient at different temperatures is often found to be well predicted by
D =D0e-EA/RT
where EA is the activation energy for diffusion
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 with simultaneous lowering of cholesterol in blood serum..
Acknowledgments:-
author acknowledge support / guidance extended by Dr A.M. Saxena ,Dr Anjali 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
1 John R. Guyton: Keith F. Klemp Development of the Lipid-Rich Core in Human Atherosclerosis : (Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:4-11.)
© 1996 American Heart Association, Inc.
2, Guyton JR, Klemp KF. Development of the atherosclerotic core region: chemical and ultrastructural analysis of microdissected atherosclerotic lesions from human aorta. Arterioscler Thromb. 1994;14:1305-1314 .
3, Guyton JR, Klemp KF. The lipid-rich core region of human atherosclerotic fibrous plaques: prevalence of small lipid droplets and vesicles by electron microscopy. Am J Pathol. 1989;134:705-717.
4, Khoo JC, Miller E, McLoughlin P, Steinberg D. Enhanced macrophage uptake of low density lipoprotein after self-aggregation. Arteriosclerosis. 1988;8:348-358.
5, Frank JS, Fogelman AM. Ultrastructure of the intima in WHHL and cholesterol-fed rabbit aortas prepared by ultra-rapid freezing and freeze-etching. J Lipid Res. 1989;30:967-978.
6, Guyton JR, Klemp KF, Mims MP. Altered ultrastructural morphology of self-aggregated low density lipoproteins: coalescence of lipid domains forming droplets and vesicles. J Lipid Res. 1991;32:953-962.
7, Kovanen PT, Kokkonen JO. Modification of low density lipoproteins by secretory granules of rat serosal mast cells. J Biol Chem. 1991;266:4430-4436.
8, Steinbrecher UP, Lougheed M. Scavenger receptor-independent stimulation of cholesterol esterification in macrophages by low density lipoprotein extracted from human aortic intima. Arterioscler Thromb. 1992;12:608-625.
9, Xu XX, Tabas I. Sphingomyelinase enhances low density lipoprotein uptake and ability to induce cholesteryl ester accumulation in macrophages. J Biol Chem. 1991;266:24849-24858.
10, Tirziu D, Dobrian A, Tasca C, Simionescu M, Simionescu N. Intimal thickenings of human aorta contain modified reassembled lipoproteins. Atherosclerosis. 1995;112:101-114.
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