- Email: [email protected]
The Lipid Regulatory Hypothesis II
Abstracts
Methods: Iodometric approaches were used to measure the effects of EPA on lipid hydroperoxide (LOOH) formation in membrane vesicles reconstituted as binary mixtures of cholesterol and dilinoleoylphosphatidylcholine. Vesicles were prepared at a cholesterol-to-phospholipid mole ratio of 0.6:1, in the absence or presence of EPA at a drug-tophospholipid mole ratio of 1:30, and subjected to autoxidation at 37 C for 72 hr. Small angle x-ray diffraction was used to measure the effect of EPA on cholesterol domain formation in membrane lipid vesicles before and after exposure to oxidative stress. Results: Membrane cholesterol domain formation was evident in vehicle-treated controls as a function of exposure to oxidative stress. Cholesterol domain peak intensity, calculated from multiple x-ray diffraction measurements and directly proportional to domain levels, was 77.6 6 58.5 after exposure to oxidative conditions. This large change in membrane structural organization corresponded to an increase in LOOH formation from 89 6 1 mM to 6616 6 250 mM (P , 0.001). Treatment with EPA completely blocked membrane cholesterol domain formation and reduced LOOH levels by . 90% (728 6 30 mM) as compared to untreated controls (P , 0.001). Conclusions: EPA inhibited cholesterol crystalline domain formation in a manner related to its potent antioxidant effects in PUFA-enriched model membranes. These data suggest that EPA blocks membrane lipid oxidation and structural reorganization through free radical chainbreaking mechanism.
Pathophysiology of Atherosclerosis
273 150-174 mg/dL, 125-149 mg/dL, 100-124 mg/dL, and , 99 mg/dL. Associated HDL levels were then determined. Results: In each LDL sextile, a lower HDL was associated with an earlier average of ATD onset and a higher HDL was associated with a later average age of ATD onset. Conclusions: The atherogenicity of any given LDL is dependent upon its associated HDL.
163 The Lipid Regulatory Hypothesis II W. E. Feeman Jr., MD, (Bowling Green, Ohio)
Lead Author’s Disclosures: None Study Funding: None Synopsis: The Lipid Regulatory Hypothesis was advanced by Esko Nikkila, MD, in the 1970’s and states that atherothrombotic disease (ATD) can be prevented, or if extant then regressed, by therapy to simultaneously lower LDL and raise HDL. Since the pathophysiological basis of ATD resides in the ATD plaque, then therapy that fulfills The Lipid Regulatory Hypothesis criteria should stabilize/ regress ATD plaque. Purpose: Purpose/Problem: The purpose is to show that, in fact raising HDL and simultaneously lowering LDL will stabilize/regress plaque and it makes a difference, how HDL is raised and how LDL is lowered–i.e., some lipid modification therapies are more successful than others at stabilizing/regressing plaque. Methods: In 2000 CE, the author published a metaanalysis of eight published angiographic regression trials. These trials will be reviewed to determine whether the
162 The Lipid Regulatory Hypothesis I W. E. Feeman Jr., MD, (Bowling Green, Ohio)
Lead Author’s Disclosures: None Study Funding: None Synopsis: The Lipid Regulatory Hypothesis; was advanced by Esko Nikkila, MD, in the 1970’s and states that atherothrombotic disease (ATD) can be prevented, or if extant then regressed, by simultaneously lowering LDL and raising HDL. This concept was initially ignored by the NCEP, though NCEP III has begun to approach it by suggesting treating low HDL. Purpose: The purpose is to show that the atherogenicity of LDL is dependent on its associated HDL level. This linkage is necessary to lay the basis for Abstract II and III. Methods: The author has done a chart review to examine LDL and HDL levels in 710 patients in his practice who developed some form of clinical ATD during the 4 November 1974-4 November 2003 time frame. LDL levels were divided into sextiles: . 200 mg/dL, 175-199 mg/dL,
Change in LDL vs. Change in HDL in Angiographic Outcomes in POSCH Change in HDL (mg/dL)
274
Journal of Clinical Lipidology, Vol 7, No 3, June 2013
Change in LDL vs. Change in HDL in Angiographic Outcomes in POSCH Change in HDL (mg/dL)
Change in LDL (mg/dL) Decrease . 30 mg/dL Decrease 10-29 mg/dL Decrease 9 to Increase 9 mg/dL Increase 10-29 mg/dL Increase . 30 mg/dL
Increase .10 mg/dL
Increase 5-9 mg/dL
Increase 4 to decrease 4 Mg/dL
Decrease 5-9 mg/dL
Decrease .10 mg/dL
72 11 11
82 14 20
195 453 2426
542 216 12
249 8 12
3 2
53 2
333 12
11 2
6 5
POSCH means Program on the Surgical Control of Hyperlipidemia LDL means low-density lipoprotein cholesterol HDL means high-density lipoprotein cholesterol
criteria of The Lipid Regulatory Hypothesis are associated with plaque stabilization/regression. Results: The results of this analysis are shown in the two attachments. In the attachment with the numbers, the number in the left upper corner represents the cases of plaque non-progression and the number in the right lower corner represents the cases of plaque progression. If no number appears, there are no cases. POSCH perfectly demonstrates that simultaneously raising HDL and lowering LDL results in plaque stabilization/regression and that these lipid changes are reciprocal. The other seven trials follow these results, but imperfectly, with some cases of progression occurring when LDL is lowered and HDL is raised and other cases of stabilization/regression occurring when LDL is raised and HDL is lowered. Conclusions: The Lipid Regulatory Hypothesis is validated by POSCH, and to a lesser extent by the other seven angiographic regression studies. This finding also supports the idea that it makes a difference how lipids are modified as regards changes in plaque. It may be that the partial ileal bypass engenders some other factor that independently affects plaque, though this is conjecturorial. 164 The Lipid Regulatory Hypothesis III W. E. Feeman Jr., MD, (Bowling Green, Ohio)
Lead Author’s Disclosures: None Study Funding: None Synopsis: The Lipid Regulatory Hypothesis was advanced by Esko Nikkila, MD, in the 1970’s and states atherothrombotic disease (ATD) can be prevented, or if extant then regressed, by simultaneously lowering LDL and raising HDL. This concept was initially ignored by the NCEP, though NCEP III has begun to approach it by suggesting treatment of low HDL. Purpose: The purpose is to show that the Cholesterol Retention Fraction (CRF, or [LDL-HDL]/LDL) fulfills The Lipid Regulatory Hypothesis criteria and changes in the CRF are associated directly with changes in plaque volume.
Methods: In 2000 CE the author published an metaanalysis of eight angiographic regression trials,examining the ability of a risk factor graph utilizing the CRF in predicting plaque stabilization/regression. For this presentation, the author examined changes in CRF by itself and in combination with LDL in predicting plaque progression vs non-progression in these trials. Results: In POSCH (Program On Surgical Control of Hyperlipidemia), no one whose CRF declined progressed their plaque and no one whose CRF rose had plaque stabilization/regression. (See Table I) The other trials had more mixed results, but in general followed the POSCH findings. Additionally, plotting CRF vs LDL revealed combinations– see upload–that strongly favor plaque progression (red squares), favored plaque non-progression (yellow squares), and strongly favored plaque non-progression (green squares). (See Figure and Table II) Again, these findings were more clearly seen in POSCH than in the other trials. Conclusions: The CRF is a useful tool in evaluating the effect of therapy for dyslipidemia on plaque progression vs non-progression
Table I Change in CRF In Angiographic Outcome Trials Progression vs. Non -Progression P Change in CRF NP P % NP Decreased . 0.15 0.10-0.14 0.05-0.09 0.01-0.04 No Change 0.00 Increased 0.01-0.04 0.05-0.09 0.10-0.14 . 0.15
270 75 92 112
0 0 0 0
270 75 92 112
100% 100% 100% 100%
10
23
23
43%
0 0 0 0
92 42 8 7
92 42 8 7
0% 0% 0% 0%
‘‘P’’ Means Progression ‘‘NP’’ Means Non-Progression
Methods: Iodometric approaches were used to measure the effects of EPA on lipid hydroperoxide (LOOH) formation in membrane vesicles reconstituted as binary mixtures of cholesterol and dilinoleoylphosphatidylcholine. Vesicles were prepared at a cholesterol-to-phospholipid mole ratio of 0.6:1, in the absence or presence of EPA at a drug-tophospholipid mole ratio of 1:30, and subjected to autoxidation at 37 C for 72 hr. Small angle x-ray diffraction was used to measure the effect of EPA on cholesterol domain formation in membrane lipid vesicles before and after exposure to oxidative stress. Results: Membrane cholesterol domain formation was evident in vehicle-treated controls as a function of exposure to oxidative stress. Cholesterol domain peak intensity, calculated from multiple x-ray diffraction measurements and directly proportional to domain levels, was 77.6 6 58.5 after exposure to oxidative conditions. This large change in membrane structural organization corresponded to an increase in LOOH formation from 89 6 1 mM to 6616 6 250 mM (P , 0.001). Treatment with EPA completely blocked membrane cholesterol domain formation and reduced LOOH levels by . 90% (728 6 30 mM) as compared to untreated controls (P , 0.001). Conclusions: EPA inhibited cholesterol crystalline domain formation in a manner related to its potent antioxidant effects in PUFA-enriched model membranes. These data suggest that EPA blocks membrane lipid oxidation and structural reorganization through free radical chainbreaking mechanism.
Pathophysiology of Atherosclerosis
273 150-174 mg/dL, 125-149 mg/dL, 100-124 mg/dL, and , 99 mg/dL. Associated HDL levels were then determined. Results: In each LDL sextile, a lower HDL was associated with an earlier average of ATD onset and a higher HDL was associated with a later average age of ATD onset. Conclusions: The atherogenicity of any given LDL is dependent upon its associated HDL.
163 The Lipid Regulatory Hypothesis II W. E. Feeman Jr., MD, (Bowling Green, Ohio)
Lead Author’s Disclosures: None Study Funding: None Synopsis: The Lipid Regulatory Hypothesis was advanced by Esko Nikkila, MD, in the 1970’s and states that atherothrombotic disease (ATD) can be prevented, or if extant then regressed, by therapy to simultaneously lower LDL and raise HDL. Since the pathophysiological basis of ATD resides in the ATD plaque, then therapy that fulfills The Lipid Regulatory Hypothesis criteria should stabilize/ regress ATD plaque. Purpose: Purpose/Problem: The purpose is to show that, in fact raising HDL and simultaneously lowering LDL will stabilize/regress plaque and it makes a difference, how HDL is raised and how LDL is lowered–i.e., some lipid modification therapies are more successful than others at stabilizing/regressing plaque. Methods: In 2000 CE, the author published a metaanalysis of eight published angiographic regression trials. These trials will be reviewed to determine whether the
162 The Lipid Regulatory Hypothesis I W. E. Feeman Jr., MD, (Bowling Green, Ohio)
Lead Author’s Disclosures: None Study Funding: None Synopsis: The Lipid Regulatory Hypothesis; was advanced by Esko Nikkila, MD, in the 1970’s and states that atherothrombotic disease (ATD) can be prevented, or if extant then regressed, by simultaneously lowering LDL and raising HDL. This concept was initially ignored by the NCEP, though NCEP III has begun to approach it by suggesting treating low HDL. Purpose: The purpose is to show that the atherogenicity of LDL is dependent on its associated HDL level. This linkage is necessary to lay the basis for Abstract II and III. Methods: The author has done a chart review to examine LDL and HDL levels in 710 patients in his practice who developed some form of clinical ATD during the 4 November 1974-4 November 2003 time frame. LDL levels were divided into sextiles: . 200 mg/dL, 175-199 mg/dL,
Change in LDL vs. Change in HDL in Angiographic Outcomes in POSCH Change in HDL (mg/dL)
274
Journal of Clinical Lipidology, Vol 7, No 3, June 2013
Change in LDL vs. Change in HDL in Angiographic Outcomes in POSCH Change in HDL (mg/dL)
Change in LDL (mg/dL) Decrease . 30 mg/dL Decrease 10-29 mg/dL Decrease 9 to Increase 9 mg/dL Increase 10-29 mg/dL Increase . 30 mg/dL
Increase .10 mg/dL
Increase 5-9 mg/dL
Increase 4 to decrease 4 Mg/dL
Decrease 5-9 mg/dL
Decrease .10 mg/dL
72 11 11
82 14 20
195 453 2426
542 216 12
249 8 12
3 2
53 2
333 12
11 2
6 5
POSCH means Program on the Surgical Control of Hyperlipidemia LDL means low-density lipoprotein cholesterol HDL means high-density lipoprotein cholesterol
criteria of The Lipid Regulatory Hypothesis are associated with plaque stabilization/regression. Results: The results of this analysis are shown in the two attachments. In the attachment with the numbers, the number in the left upper corner represents the cases of plaque non-progression and the number in the right lower corner represents the cases of plaque progression. If no number appears, there are no cases. POSCH perfectly demonstrates that simultaneously raising HDL and lowering LDL results in plaque stabilization/regression and that these lipid changes are reciprocal. The other seven trials follow these results, but imperfectly, with some cases of progression occurring when LDL is lowered and HDL is raised and other cases of stabilization/regression occurring when LDL is raised and HDL is lowered. Conclusions: The Lipid Regulatory Hypothesis is validated by POSCH, and to a lesser extent by the other seven angiographic regression studies. This finding also supports the idea that it makes a difference how lipids are modified as regards changes in plaque. It may be that the partial ileal bypass engenders some other factor that independently affects plaque, though this is conjecturorial. 164 The Lipid Regulatory Hypothesis III W. E. Feeman Jr., MD, (Bowling Green, Ohio)
Lead Author’s Disclosures: None Study Funding: None Synopsis: The Lipid Regulatory Hypothesis was advanced by Esko Nikkila, MD, in the 1970’s and states atherothrombotic disease (ATD) can be prevented, or if extant then regressed, by simultaneously lowering LDL and raising HDL. This concept was initially ignored by the NCEP, though NCEP III has begun to approach it by suggesting treatment of low HDL. Purpose: The purpose is to show that the Cholesterol Retention Fraction (CRF, or [LDL-HDL]/LDL) fulfills The Lipid Regulatory Hypothesis criteria and changes in the CRF are associated directly with changes in plaque volume.
Methods: In 2000 CE the author published an metaanalysis of eight angiographic regression trials,examining the ability of a risk factor graph utilizing the CRF in predicting plaque stabilization/regression. For this presentation, the author examined changes in CRF by itself and in combination with LDL in predicting plaque progression vs non-progression in these trials. Results: In POSCH (Program On Surgical Control of Hyperlipidemia), no one whose CRF declined progressed their plaque and no one whose CRF rose had plaque stabilization/regression. (See Table I) The other trials had more mixed results, but in general followed the POSCH findings. Additionally, plotting CRF vs LDL revealed combinations– see upload–that strongly favor plaque progression (red squares), favored plaque non-progression (yellow squares), and strongly favored plaque non-progression (green squares). (See Figure and Table II) Again, these findings were more clearly seen in POSCH than in the other trials. Conclusions: The CRF is a useful tool in evaluating the effect of therapy for dyslipidemia on plaque progression vs non-progression
Table I Change in CRF In Angiographic Outcome Trials Progression vs. Non -Progression P Change in CRF NP P % NP Decreased . 0.15 0.10-0.14 0.05-0.09 0.01-0.04 No Change 0.00 Increased 0.01-0.04 0.05-0.09 0.10-0.14 . 0.15
270 75 92 112
0 0 0 0
270 75 92 112
100% 100% 100% 100%
10
23
23
43%
0 0 0 0
92 42 8 7
92 42 8 7
0% 0% 0% 0%
‘‘P’’ Means Progression ‘‘NP’’ Means Non-Progression