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AHS11 Chris Masterjohn - Heart Disease and Macular Degeneration
Heart Disease and Molecular Degeneration The New Paradigm Presented by Chris Masterjohn, Doctoral Candidate (UConn) Cholesterol-And-Health.Com
Cholesterol… <ul><li>What does it mean to you? </li></ul>
The Cholesterol Warriors Joseph Goldstein and Michael Brown Nobel Prize, 1985 LDL Receptor Pathway, 1976 “ Although the Cholesterol Wars are not over, major battles have been won by the anti-cholesterol forces, i.e. those who condemn cholesterol as the culprit. Like modern armies, the anti-cholesterol forces have been aided by powerful new weapons.” – Brown and Goldstein “ In war, the first casualty is truth.” – Aeschylus, Greek tragic dramatist, (525 BC – 456 BC)
The Cholesterol Skeptics “ Cholesterol and lipoproteins were indicted, tried, and ultimately found guilty as major contributors to the atherosclerotic lesion.” – Daniel Steinberg, MD, PhD “ There exists a massive volume of scientific evidence that completely absolves dietary cholesterol, saturated fat, and elevated blood cholesterol of any harmful role in heart disease.” – Anthony Colpo
Heart Disease and Molecular Degeneration <ul><li>The cholesterol-fed rabbit is relevant. </li></ul><ul><li>Familial hypercholesterolemia is important. </li></ul><ul><li>Blood lipids do play a role in heart disease. </li></ul><ul><li>High cholesterol levels do not cause heart disease. </li></ul><ul><li>Atherosclerosis is an adaptive, homeostatic response to a pathological process. </li></ul><ul><li>A disease of molecular degeneration and cellular miscommunication . </li></ul>
The Lipid Hypothesis <ul><li>Elevated levels of cholesterol in the blood, or specifically LDL-associated cholesterol, infiltrate the blood vessel, which causes heart disease. </li></ul>
The Diet-Heart Hypothesis <ul><li>Saturated fat and cholesterol in the diet increase cholesterol levels in the blood, which causes heart disease. </li></ul>
Rabbits Developed Advanced Human-Like Atherosclerotic Lesions Baboons Cats Chickens Chimpanzees Dogs Goats Monkeys Mice Parrots Pigs Pigeons Rats Guinea Pigs Hamsters “ In human atherosclerosis the conditions are different . It is quite certain that such large quantities of cholesterin are not ingested with the ordinary food. In human patients we have probably to deal with a primary disturbance of the cholesterin metabolism , which may lead to atherosclerosis even if the hypercholesterinemia is less pronounced, provided only that it is of long duration and associated with other injurious factors.
A Clue in the Needle – Injection of Free Cholesterol Doesn’t Cut It Feeding rabbits cholesterol produced atherosclerosis . Injecting rabbits with cholesterol did not produce atherosclerosis. Isolate lipoproteins Injecting rabbits with lipoproteins did produce atherosclerosis.
Hypercholesterolemia, Xanthomas, and Heart Disease <ul><li>1889 -- Xanthomas tied to heart problems. </li></ul><ul><li>Some researchers noted hypercholesterolemia associated with xanthomas. </li></ul><ul><li>1908 – Xanthomas composed of cholesterol esters. </li></ul>
Familial Hypercholesterolemia is a Defect in the LDL Receptor Joseph Goldstein and Michael Brown Nobel Prize, 1985 LDL Receptor Pathway, 1976
Familial Hypercholesterolemia (FH) Causes CHD in Childhood J Pediatr. 1982;100(5):757-9 “ We are aware of one death from myocardial infarction in a white South African homozygous child 18 months of age . The oldest homozygote in our series was L.Fl., whose death at age 27 following his third myocardial infarction was described above.” – Frederickson and Levy. Familial Hyperlipoproteinemia. In: Stanbury, et al., eds. The Metabolic Basis of Inherited Disease. 1972.
CHD Risk After Age 30 Increases Dramatically in Heterozygote FH Umans-Eckenhausen, et al. Low-Denisty Lipoprotein Receptor Gene Mutations and Cardiovascular Risk in a Large Genetic Cascade Screening Population. Circulation. 2002;106:3031-6.
FH Produces the Largest Survival Gap Ages 30-60, But the Gap Remains Through the 70s Umans-Eckenhausen, et al. Low-Denisty Lipoprotein Receptor Gene Mutations and Cardiovascular Risk in a Large Genetic Cascade Screening Population. Circulation. 2002;106:3031-6.
Increased LDL Receptor Activity Virtually Abolishes Risk of CHD CohenJC, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-72.
Does LDL Receptor Activity Matter for Everyone Else? ?
Cholestyramine Reduces the Risk of Heart Disease
Testing the Lipid Hypothesis: Cholestyramine and the Coronary Primary Prevention Trial Cholestyramine binds bile acids. Excretion Liver converts cholesterol to bile acids. LDL-R Liver takes cholesterol from the blood by increasing its expression of the LDL receptor.
Statins – Greater Cholesterol Reduction, Greater CHD Reduction <ul><li>Individual squares represent individual trials. </li></ul><ul><li>Size of square represents number of participants. </li></ul><ul><li>Horizontal axis represents reduction in LDL-C </li></ul><ul><li>Vertical axis represents relative risk reduction in CHD. </li></ul>Baigent et al. Lancet. 2005;366(9493):1267-78.
Statins Lower Cholesterol by Increasing LDL Receptor Activity cholesterol synthesis in liver free cholesterol concentration LDL-R LDL receptor takes cholesterol in from the blood
Thyroid Hormone Activates LDL Receptor Expression SRE – Sterol Regulatory Element communicates that the cell needs cholesterol TRE – Thyroid Response Element communicates that the body is in a state of abundance Lopez D. Biochimica et Biophysica Acta. 2007;1771:1216-25.
Thyroid Extract Decreases CVD Incidence 4- to 7-Fold Kountz, WB. Thyroid Function and its Possible Role in Vascular Degeneration. American Lecture Series. 1951.
LDL Oxidation – It’s About Time! Young and McEneny. Lipoprotein oxidation and atherosclerosis. Biochem Soc Trans. 2001;29:358-62.
LDL Oxidation, Not Concentration, Determines Macrophage Uptake Human LDL incubated with human endothelial cells. Human LDL incubated in cell-free dishes. Henrisksen T, Mahoney EM, Steinberg D. Enhanced macrophage degradation of biologically modified low density lipoprotein. Arterioscelrosis. 1983;3(2):149-59
Oxidized LDL is Toxic to Endothelial Cells Sata M, Walsh K. Endothelial Cell Apoptosis Induced by Oxidized LDL is Associated with the Down-regulation of the Cellular Caspase Inhibitor FLIP. J Biol Cehm. 1998;273(50):3303-6
The Atherosclerotic Plaque is a Toxic Waste Superfund Site Foam Cell Oxidized LDL
Strategies for Preventing Atherosclerosis <ul><li>Optimize thyroid status </li></ul><ul><li>Support the antioxidant defense system </li></ul><ul><li>Support proper regulation of inflammation </li></ul>
Heart Disease And the Violence of Molecular Degeneration poverty (nutritional deficiency) war (toxic and inflammatory factors) miscommunication (missing signals of abundance and inflammation resolution)