An Engineering Analysis of the Human Cholesterol Control System, covering the core Biochemistry, control mechanisms, correlative analysis, mechanistic physics, and importantly - the experimental inferences that illustrate root causes of dysfunction.
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The Cholesterol Conundrum: Final Cut
1. The Cholesterol Conundrum
What does the Latest Science Say?
Ivor Cummins BE (Chem)
May 19th 2014
2013 Ivor Cummins BE(Chem) MIEI
2. What happened since Oct 2013 Seminar…?
At last, The unbiased experts
are stepping up to the plate:
• Six teaspoons max in 24 hours?
• That’s less than a single can of
your favorite sugary beverage, and
assumes NO other added sugar for
the rest of the day? Mmmmn….
• Looks like the Emperor’s suit is
getting frayed…..but is anyone
listening?
2013 Ivor Cummins BE(Chem) MIEI
3. 2013 Ivor Cummins BE(Chem) MIEI
1. The Key Molecules
2. The Key Particles
3. The Common Enemy
4. How the Cholesterol Processing
System Works – High Level
5. The Risk Factors
6. The $1M Question – What Drives up
the Risk Factors?
The Conundrum Content:
5. Cholesterol and Triglyceride
• Cholesterol is a Sterol Molecule that is used to build
cells, hormones and other core physiological elements
Cholesterol – for Life Itself
2013 Ivor Cummins BE(Chem) MIEI
6. Cholesterol and Triglyceride
• Cholesterol is a Sterol Molecule that is used to build
cells, hormones and other core physiological elements
• Is critical, and fundamental for life to exist
Cholesterol – for Life Itself
2013 Ivor Cummins BE(Chem) MIEI
7. Cholesterol and Triglyceride
• Cholesterol is a Sterol Molecule that is used to build
cells, hormones and other core physiological elements
• Is critical, and fundamental for life to exist
• Is a key element of your bodies damage repair system
Cholesterol – for Life Itself
2013 Ivor Cummins BE(Chem) MIEI
8. Cholesterol and Triglyceride
• Cholesterol is a Sterol Molecule that is used to build
cells, hormones and other core physiological elements
• Is critical, and fundamental for life to exist
• Is a key element of your bodies damage repair system
• Is a precursor to the synthesis of Vitamin D, which in
turn is one of the most important agents for mortality
deferral – we’ll look at this later….
Cholesterol – for Life Itself
2013 Ivor Cummins BE(Chem) MIEI
9. Cholesterol and Triglyceride
• Cholesterol is a Sterol Molecule that is used to build
cells, hormones and other core physiological elements
• Is critical, and fundamental for life to exist
• Is a key element of your bodies damage repair system
• Is a precursor to the synthesis of Vitamin D, which in
turn is one of the most important agents for mortality
deferral – we’ll look at this later….
• Finally, cholesterol generally gets blamed for disease
pretty much as a paramedic on the scene might be
blamed for the car crash
Cholesterol – for Life Itself
2013 Ivor Cummins BE(Chem) MIEI
10. Cholesterol and Triglyceride
• Cholesterol is a Sterol Molecule that is used to build
cells, hormones and other core physiological elements
• Is critical, and fundamental for life to exist
• Is a key element of your bodies damage repair system
• Is a precursor to the synthesis of Vitamin D, which in
turn is one of the most important agents for mortality
deferral – we’ll look at this later….
• Finally, cholesterol generally gets blamed for disease
pretty much as a paramedic on the scene might be
blamed for the car crash
Cholesterol – for Life Itself
• Triglyceride (aka Triacylglycerol) is a form of fat
Trigylceride – for Energy
2013 Ivor Cummins BE(Chem) MIEI
11. Cholesterol and Triglyceride
• Cholesterol is a Sterol Molecule that is used to build
cells, hormones and other core physiological elements
• Is critical, and fundamental for life to exist
• Is a key element of your bodies damage repair system
• Is a precursor to the synthesis of Vitamin D, which in
turn is one of the most important agents for mortality
deferral – we’ll look at this later….
• Finally, cholesterol generally gets blamed for disease
pretty much as a paramedic on the scene might be
blamed for the car crash
Cholesterol – for Life Itself
• Triglyceride (aka Triacylglycerol) is a form of fat
• Is three Fatty Acids on a glycerol (sugar-like) backbone
Trigylceride – for Energy
2013 Ivor Cummins BE(Chem) MIEI
12. Cholesterol and Triglyceride
• Cholesterol is a Sterol Molecule that is used to build
cells, hormones and other core physiological elements
• Is critical, and fundamental for life to exist
• Is a key element of your bodies damage repair system
• Is a precursor to the synthesis of Vitamin D, which in
turn is one of the most important agents for mortality
deferral – we’ll look at this later….
• Finally, cholesterol generally gets blamed for disease
pretty much as a paramedic on the scene might be
blamed for the car crash
Cholesterol – for Life Itself
• Triglyceride (aka Triacylglycerol) is a form of fat
• Is three Fatty Acids on a glycerol (sugar-like) backbone
• Enters the body via fat-containing food
Trigylceride – for Energy
2013 Ivor Cummins BE(Chem) MIEI
13. Cholesterol and Triglyceride
• Cholesterol is a Sterol Molecule that is used to build
cells, hormones and other core physiological elements
• Is critical, and fundamental for life to exist
• Is a key element of your bodies damage repair system
• Is a precursor to the synthesis of Vitamin D, which in
turn is one of the most important agents for mortality
deferral – we’ll look at this later….
• Finally, cholesterol generally gets blamed for disease
pretty much as a paramedic on the scene might be
blamed for the car crash
Cholesterol – for Life Itself
• Triglyceride (aka Triacylglycerol) is a form of fat
• Is three Fatty Acids on a glycerol (sugar-like) backbone
• Enters the body via fat-containing food
• Is also synthesized by the body (neolipogenisis) for
various reasons
Trigylceride – for Energy
2013 Ivor Cummins BE(Chem) MIEI
14. Cholesterol and Triglyceride
• Cholesterol is a Sterol Molecule that is used to build
cells, hormones and other core physiological elements
• Is critical, and fundamental for life to exist
• Is a key element of your bodies damage repair system
• Is a precursor to the synthesis of Vitamin D, which in
turn is one of the most important agents for mortality
deferral – we’ll look at this later….
• Finally, cholesterol generally gets blamed for disease
pretty much as a paramedic on the scene might be
blamed for the car crash
Cholesterol – for Life Itself
• Triglyceride (aka Triacylglycerol) is a form of fat
• Is three Fatty Acids on a glycerol (sugar-like) backbone
• Enters the body via fat-containing food
• Is also synthesized by the body (neolipogenisis) for
various reasons
• Can be good or bad: depends on source, location and
quantity….
Trigylceride – for Energy
2013 Ivor Cummins BE(Chem) MIEI
16. The Lipoprotein Particles – Boats for Cargo
Trigylceride/
Cholesterol
An Apo-
Lipoprotein
Phospholipids The LIPOPROTEIN PARTICLES are transport vessels
(“boats”) created in the body to deliver
Triglyceride and Cholesterol (“cargo”), for energy
transfer, critical synthesis, and healing purposes….
2013 Ivor Cummins BE(Chem) MIEI
17. The Lipoprotein Particles – Boats for Cargo
Trigylceride/
Cholesterol
An Apo-
Lipoprotein
Phospholipids The LIPOPROTEIN PARTICLES are transport vessels
(“boats”) created in the body to deliver
Triglyceride and Cholesterol (“cargo”), for energy
transfer, critical synthesis, and healing purposes….
The Chylomicron is the big one, created to ferry
dietary fat and cholesterol, for energy and healing
Chylomicron
2013 Ivor Cummins BE(Chem) MIEI
18. The Lipoprotein Particles – Boats for Cargo
Trigylceride/
Cholesterol
An Apo-
Lipoprotein
Phospholipids The LIPOPROTEIN PARTICLES are transport vessels
(“boats”) created in the body to deliver
Triglyceride and Cholesterol (“cargo”), for energy
transfer, critical synthesis, and healing purposes….
The Chylomicron is the big one, created to ferry
dietary fat and cholesterol, for energy and healing
Chylomicron
VLDL is made in the liver to ferry Trigs and Chol…
VLDL
2013 Ivor Cummins BE(Chem) MIEI
19. The Lipoprotein Particles – Boats for Cargo
Trigylceride/
Cholesterol
An Apo-
Lipoprotein
Phospholipids The LIPOPROTEIN PARTICLES are transport vessels
(“boats”) created in the body to deliver
Triglyceride and Cholesterol (“cargo”), for energy
transfer, critical synthesis, and healing purposes….
The Chylomicron is the big one, created to ferry
dietary fat and cholesterol, for energy and healing
Chylomicron
VLDL is made in the liver to ferry Trigs and Chol…
LDLVLDL
2013 Ivor Cummins BE(Chem) MIEI
LDL (from VLDL) is the so-called “BAD Cholesterol”
20. The Lipoprotein Particles – Boats for Cargo
Trigylceride/
Cholesterol
An Apo-
Lipoprotein
Phospholipids The LIPOPROTEIN PARTICLES are transport vessels
(“boats”) created in the body to deliver
Triglyceride and Cholesterol (“cargo”), for energy
transfer, critical synthesis, and healing purposes….
The Chylomicron is the big one, created to ferry
dietary fat and cholesterol, for energy and healing
Chylomicron sdLDL
VLDL is made in the liver to ferry Trigs and Chol…
LDLVLDL
2013 Ivor Cummins BE(Chem) MIEI
LDL (from VLDL) is the so-called “BAD Cholesterol”
Oxidized LDL is the real “BAD Cholesterol”
21. The Lipoprotein Particles – Boats for Cargo
Trigylceride/
Cholesterol
An Apo-
Lipoprotein
Phospholipids The LIPOPROTEIN PARTICLES are transport vessels
(“boats”) created in the body to deliver
Triglyceride and Cholesterol (“cargo”), for energy
transfer, critical synthesis, and healing purposes….
The Chylomicron is the big one, created to ferry
dietary fat and cholesterol, for energy and healing
Chylomicron sdLDL
VLDL is made in the liver to ferry Trigs and Chol…
HDLLDLVLDL
2013 Ivor Cummins BE(Chem) MIEI
HDL is the so-called “GOOD Cholesterol”
LDL (from VLDL) is the so-called “BAD Cholesterol”
Oxidized LDL is the real “BAD Cholesterol”
22. 2013 Ivor Cummins BE(Chem) MIEI
And now, a word from
our “Sponsor”…..
23. 2013 Ivor Cummins BE(Chem) MIEI
And now, a word from
our “Sponsor”…..
3. The Common Enemy
25. Atherosclerosis and CVD Mechanism
Ingress of Lipoprotein Particles through Endothelium (inner wall)
The Disease Sequence:
TgCh
ChCh
B100
2013 Ivor Cummins BE(Chem) MIEI
26. Atherosclerosis and CVD Mechanism
Ingress of Lipoprotein Particles through Endothelium (inner wall)
Uptake of these by immune system Macrophage
The Disease Sequence:
+
Macrophage
TgCh
ChCh
B100
2013 Ivor Cummins BE(Chem) MIEI
27. Atherosclerosis and CVD Mechanism
Ingress of Lipoprotein Particles through Endothelium (inner wall)
Uptake of these by immune system Macrophage
Subsequent transformation into “Foam Cells” and buildup of Plaque
The Disease Sequence:
+ Ch
Ch Ch
Macrophage
=
FOAM CELL
TgCh
ChCh
B100
2013 Ivor Cummins BE(Chem) MIEI
28. Atherosclerosis and CVD Mechanism
Ingress of Lipoprotein Particles through Endothelium (inner wall)
Uptake of these by immune system Macrophage
Subsequent transformation into “Foam Cells” and buildup of Plaque
Ultimately a decline in vascular health, then breakouts, blockages…..
The Disease Sequence:
+ Ch
Ch Ch
Macrophage
=
FOAM CELL
TgCh
ChCh
B100
2013 Ivor Cummins BE(Chem) MIEI
29. Atherosclerosis and CVD Mechanism
Ingress of Lipoprotein Particles through Endothelium (inner wall)
Uptake of these by immune system Macrophage
Subsequent transformation into “Foam Cells” and buildup of Plaque
Ultimately a decline in vascular health, then breakouts, blockages…..
The Disease Sequence:
+ Ch
Ch Ch
Macrophage
=
FOAM CELL
The Million Dollar Question: What mediates this inflammatory process?
TgCh
ChCh
B100
2013 Ivor Cummins BE(Chem) MIEI End
30. 2013 Ivor Cummins BE(Chem) MIEI
4. How the Cholesterol
Processing System
Works - High Level
31. The Lipoprotein Particles – Boats for Cargo
Trigylceride/
Cholesterol
An Apo-
Lipoprotein
Phospholipids The LIPOPROTEIN PARTICLES are transport vessels
(“boats”) created in the body to deliver
Triglyceride and Cholesterol (“cargo”), for energy
transfer, critical synthesis, and healing purposes….
The Chylomicron is the big one, created to ferry
dietary fat and cholesterol, for energy and healing
Chylomicron sdLDL
VLDL is made in the liver to ferry Trigs and Chol…
HDLLDLVLDL
2013 Ivor Cummins BE(Chem) MIEI
HDL is the so-called “GOOD Cholesterol”
LDL (from VLDL) is the so-called “BAD Cholesterol”
Oxidized LDL is the real “BAD Cholesterol”
1 2 3
32. 2013 Ivor Cummins BE(Chem) MIEI
4. Lipoprotein Type 1 of 3 :
The CHYLOMICRON
(for Dietary Fat and Cholesterol
Transport…)
44. VLDL, IDL,LDL…..and Small Dense LDL
LDLR
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
SR-B1
Ch
Ch
Ch
2013 Ivor Cummins BE(Chem) MIEI
45. VLDL, IDL,LDL…..and Small Dense LDL
C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
SR-B1
Ch
Ch
Ch
2013 Ivor Cummins BE(Chem) MIEI
46. VLDL, IDL,LDL…..and Small Dense LDL
C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
SR-B1
Ch
Ch
Ch
2013 Ivor Cummins BE(Chem) MIEI
47. VLDL, IDL,LDL…..and Small Dense LDL
C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
SR-B1
HL
Ch
Ch
Ch
Tg
2013 Ivor Cummins BE(Chem) MIEI
48. VLDL, IDL,LDL…..and Small Dense LDL
C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
TgCh
ChCh
B100
LDL
SR-B1
HL
Ch
Ch
Ch
2013 Ivor Cummins BE(Chem) MIEI
Tg
49. VLDL, IDL,LDL…..and Small Dense LDL
C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
TgCh
ChCh
B100
LDL
SR-B1
HL
Ch
Ch
Ch
Ch
Ch
To tissues
and cells
2013 Ivor Cummins BE(Chem) MIEI
Tg
50. VLDL, IDL,LDL…..and Small Dense LDL
C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
TgCh
ChCh
B100
LDL
SR-B1
HL
Ch
Ch
Ch
2013 Ivor Cummins BE(Chem) MIEI
Ch
Tg
Ch
To tissues
and cells
51. VLDL, IDL,LDL…..and Small Dense LDL
C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
TgCh
ChCh
B100
LDL
SR-B1
TgCh
ChCh
B100
LDL
SD
HL
HL
Ch
Ch
Ch
TgCh
ChCh
B100
LDL
OX
2013 Ivor Cummins BE(Chem) MIEI
Tg
Ch
Ch
To tissues
and cells
Gluc
52. VLDL, IDL,LDL…..and Small Dense LDL
C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
TgCh
ChCh
B100
LDL
SR-B1
TgCh
ChCh
B100
LDL
SD
HL
Ch
Ch
Ch
TgCh
ChCh
B100
LDL
OX
2013 Ivor Cummins BE(Chem) MIEI
Tg
Ch
Ch
To tissues
and cells
HL
Gluc
53. VLDL, IDL,LDL…..and Small Dense LDL
C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
TgCh
ChCh
B100
LDL
SR-B1
TgCh
ChCh
B100
LDL
SD
HL
Ch
Ch
Ch
Ch
Ch Ch
IMMUNE SYSTEM
MACROPHAGE / FOAM CELL
TgCh
ChCh
B100
LDL
OX
2013 Ivor Cummins BE(Chem) MIEI
Tg
Ch
To tissues
and cellsCh
HL
Gluc
End
54. 2013 Ivor Cummins BE(Chem) MIEI
4. Lipoprotein Type 3 of 3 :
The HDL Species
(For Cholesterol Management, and a few
other important things…)
63. Key Predictors of Mortality
–Dysfunctional Lipoprotein Status
• LDL/HDL Ratio (or better still, ApoB/ApoA Ratio)
• High Serum Triglyceride Levels, larger VLDL particles…
• Small Dense LDL and associated LDL Particle COUNT (ApoB)
2013 Ivor Cummins BE(Chem) MIEI
64. Key Predictors of Mortality
–Dysfunctional Lipoprotein Status
• LDL/HDL Ratio (or better still, ApoB/ApoA Ratio)
• High Serum Triglyceride Levels, larger VLDL particles…
• Small Dense LDL and associated LDL Particle COUNT (ApoB)
–Insulin Levels and Insulin Resistance Status
2013 Ivor Cummins BE(Chem) MIEI
65. Key Predictors of Mortality
–Dysfunctional Lipoprotein Status
• LDL/HDL Ratio (or better still, ApoB/ApoA Ratio)
• High Serum Triglyceride Levels, larger VLDL particles…
• Small Dense LDL and associated LDL Particle COUNT (ApoB)
–Insulin Levels and Insulin Resistance Status
–Blood Glucose Level and HbA1C
2013 Ivor Cummins BE(Chem) MIEI
66. Key Predictors of Mortality
–Dysfunctional Lipoprotein Status
• LDL/HDL Ratio (or better still, ApoB/ApoA Ratio)
• High Serum Triglyceride Levels, larger VLDL particles…
• Small Dense LDL and associated LDL Particle COUNT (ApoB)
–Insulin Levels and Insulin Resistance Status
–Blood Glucose Level and HbA1C
–High Blood Pressure
• generally driven by the same root causes that drive the above
2013 Ivor Cummins BE(Chem) MIEI
67. Key Predictors of Mortality
–Dysfunctional Lipoprotein Status
• LDL/HDL Ratio (or better still, ApoB/ApoA Ratio)
• High Serum Triglyceride Levels, larger VLDL particles…
• Small Dense LDL and associated LDL Particle COUNT (ApoB)
–Insulin Levels and Insulin Resistance Status
–Blood Glucose Level and HbA1C
–High Blood Pressure
• generally driven by the same root causes that drive the above
–Other markers of Systemic Inflammation
• GGT, CRP, Serum Ferritin, etc
2013 Ivor Cummins BE(Chem) MIEI
68. Total Cholesterol as a predictive factor?
Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the
Norwegian HUNT 2 study (>58,000 Participants)
Halfdan Petursson MD,1 Johann A. Sigurdsson MD Dr med,2 Calle Bengtsson MD Dr med,3
Tom I. L. Nilsen Dr Philos4 and Linn Getz MD PhD5
ALL CAUSE
DEATH….
2013 Ivor Cummins BE(Chem) MIEI
Increasing Cholesterol
IncreasedRisk
69. Total Cholesterol as a predictive factor?
Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the
Norwegian HUNT 2 study (>58,000 Participants)
Halfdan Petursson MD,1 Johann A. Sigurdsson MD Dr med,2 Calle Bengtsson MD Dr med,3
Tom I. L. Nilsen Dr Philos4 and Linn Getz MD PhD5
ALL CAUSE
DEATH….
IncreasedRisk
2013 Ivor Cummins BE(Chem) MIEI
Increasing Cholesterol = lower risk
Key Takeaways:
Increasing Cholesterol
70. Total Cholesterol as a predictive factor?
Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the
Norwegian HUNT 2 study (>58,000 Participants)
Halfdan Petursson MD,1 Johann A. Sigurdsson MD Dr med,2 Calle Bengtsson MD Dr med,3
Tom I. L. Nilsen Dr Philos4 and Linn Getz MD PhD5
ALL CAUSE
DEATH….
IncreasedRisk
2013 Ivor Cummins BE(Chem) MIEI
Increasing Cholesterol = lower risk
Key Takeaways:
Increasing Cholesterol
Engineering Explanations for the mistake:
71. Total Cholesterol as a predictive factor?
Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the
Norwegian HUNT 2 study (>58,000 Participants)
Halfdan Petursson MD,1 Johann A. Sigurdsson MD Dr med,2 Calle Bengtsson MD Dr med,3
Tom I. L. Nilsen Dr Philos4 and Linn Getz MD PhD5
ALL CAUSE
DEATH….
IncreasedRisk
2013 Ivor Cummins BE(Chem) MIEI
Increasing Cholesterol = lower risk
Age Confounding was a serious issue
Key Takeaways:
Increasing Cholesterol
Engineering Explanations for the mistake:
72. Total Cholesterol as a predictive factor?
Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the
Norwegian HUNT 2 study (>58,000 Participants)
Halfdan Petursson MD,1 Johann A. Sigurdsson MD Dr med,2 Calle Bengtsson MD Dr med,3
Tom I. L. Nilsen Dr Philos4 and Linn Getz MD PhD5
ALL CAUSE
DEATH….
IncreasedRisk
2013 Ivor Cummins BE(Chem) MIEI
Increasing Cholesterol = lower risk
Age Confounding was a serious issue
Key Takeaways:
Non-Representative populations,
inclusion of Hypercholesteremia cases
Increasing Cholesterol
Engineering Explanations for the mistake:
73. Total Cholesterol as a predictive factor?
Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the
Norwegian HUNT 2 study (>58,000 Participants)
Halfdan Petursson MD,1 Johann A. Sigurdsson MD Dr med,2 Calle Bengtsson MD Dr med,3
Tom I. L. Nilsen Dr Philos4 and Linn Getz MD PhD5
ALL CAUSE
DEATH….
IncreasedRisk
2013 Ivor Cummins BE(Chem) MIEI
Increasing Cholesterol = lower risk
Age Confounding was a serious issue
Endemic Research Bias
Key Takeaways:
Non-Representative populations,
inclusion of Hypercholesteremia cases
Increasing Cholesterol
Engineering Explanations for the mistake:
74. Total Cholesterol as a predictive factor?
Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the
Norwegian HUNT 2 study (>58,000 Participants)
Halfdan Petursson MD,1 Johann A. Sigurdsson MD Dr med,2 Calle Bengtsson MD Dr med,3
Tom I. L. Nilsen Dr Philos4 and Linn Getz MD PhD5
Increasing Cholesterol = lower risk
Age Confounding was a serious issue
Endemic Research Bias
ALL CAUSE
DEATH….
IncreasedRisk
Key Takeaways:
In short, Total Cholesterol effectively not
considered any more by the leading edge
researchers in the field
Non-Representative populations,
inclusion of Hypercholesteremia cases
2013 Ivor Cummins BE(Chem) MIEI
Engineering Explanations for the mistake:
Increasing Cholesterol
75. LDL & HDL as predictive factors?
Diagram adapted from article in Journal of Cardiovascular Medicine 2011, Vol 00, No 00
2.58 4.13 5.68
HDL=0.65
HDL = 1.16
HDL = 1.68
HDL = 2.20
RiskofHeartDiseaseafter4Years
Increasing LDL (the “Bad Cholesterol”)
Heart Disease Risk Vs LDL & HDL
Data from the Framingham Heart Study showing incidence of CAD over 4 years in men 50-70 years old
2013 Ivor Cummins BE(Chem) MIEI
Decreasing HDL
(the “Good
Cholesterol”)
76. LDL & HDL as predictive factors?
Diagram adapted from article in Journal of Cardiovascular Medicine 2011, Vol 00, No 00
2.58 4.13 5.68
HDL=0.65
HDL = 1.16
HDL = 1.68
HDL = 2.20
RiskofHeartDiseaseafter4Years
HDL being adequate/higher is VERY important
Heart Disease Risk Vs LDL & HDL
Data from the Framingham Heart Study showing incidence of CAD over 4 years in men 50-70 years old
2013 Ivor Cummins BE(Chem) MIEI
Increasing LDL (the “Bad Cholesterol”)
Decreasing HDL
(the “Good
Cholesterol”)
77. LDL & HDL as predictive factors?
Diagram adapted from article in Journal of Cardiovascular Medicine 2011, Vol 00, No 00
2.58 4.13 5.68
HDL=0.65
HDL = 1.16
HDL = 1.68
HDL = 2.20
RiskofHeartDiseaseafter4Years
HDL being adequate/higher is VERY important
The benefit of LDL being low………totally depends on the HDL status
Heart Disease Risk Vs LDL & HDL
Data from the Framingham Heart Study showing incidence of CAD over 4 years in men 50-70 years old
2013 Ivor Cummins BE(Chem) MIEI
Increasing LDL (the “Bad Cholesterol”)
Decreasing HDL
(the “Good
Cholesterol”)
78. LDL & HDL as predictive factors?
Diagram adapted from article in Journal of Cardiovascular Medicine 2011, Vol 00, No 00
2.58 4.13 5.68
HDL=0.65
HDL = 1.16
HDL = 1.68
HDL = 2.20
RiskofHeartDiseaseafter4Years
HDL being adequate/higher is VERY important
The benefit of LDL being low………totally depends on the HDL status
Risk is determined primarily by the RATIO of these parameters
Heart Disease Risk Vs LDL & HDL
Data from the Framingham Heart Study showing incidence of CAD over 4 years in men 50-70 years old
2013 Ivor Cummins BE(Chem) MIEI
Increasing LDL (the “Bad Cholesterol”)
Decreasing HDL
(the “Good
Cholesterol”)
79. LDL & HDL as predictive factors?
Diagram adapted from article in Journal of Cardiovascular Medicine 2011, Vol 00, No 00
2.58 4.13 5.68
HDL=0.65
HDL = 1.16
HDL = 1.68
HDL = 2.20
RiskofHeartDiseaseafter4Years
HDL being adequate/higher is VERY important
Risk is determined primarily by the RATIO of these parameters
Diagnosing via LDL is minimally useful in the face of the current science
Heart Disease Risk Vs LDL & HDL
Data from the Framingham Heart Study showing incidence of CAD over 4 years in men 50-70 years old
2013 Ivor Cummins BE(Chem) MIEI
Increasing LDL (the “Bad Cholesterol”)
Decreasing HDL
(the “Good
Cholesterol”)
The benefit of LDL being low………totally depends on the HDL status
80. Decreasing HDL
(the “Good
Cholesterol”)
LDL & HDL as predictive factors?
Diagram adapted from article in Journal of Cardiovascular Medicine 2011, Vol 00, No 00
2.58 4.13 5.68
HDL=0.65
HDL = 1.16
HDL = 1.68
HDL = 2.20
RiskofHeartDiseaseafter4Years
HDL being adequate/higher is VERY important
Risk is determined primarily by the RATIO of these parameters
Diagnosing via LDL is minimally useful in the face of the current science
Heart Disease Risk Vs LDL & HDL
Data from the Framingham Heart Study showing incidence of CAD over 4 years in men 50-70 years old
XXX
2013 Ivor Cummins BE(Chem) MIEI
Guess Who?
The benefit of LDL being low………totally depends on the HDL status
Increasing LDL (the “Bad Cholesterol”)
81. LDL & HDL as predictive factors?
Diagram adapted from article in Journal of Cardiovascular Medicine 2011, Vol 00, No 00
2.58 4.13 5.68
HDL=0.65
HDL = 1.16
HDL = 1.68
HDL = 2.20
RiskofHeartDiseaseafter4Years
HDL being adequate/higher is VERY important
Risk is determined primarily by the RATIO of these parameters
Diagnosing via LDL is minimally useful in the face of the current science
Heart Disease Risk Vs LDL & HDL
Data from the Framingham Heart Study showing incidence of CAD over 4 years in men 50-70 years old
XXX
2013 Ivor Cummins BE(Chem) MIEI
And this Guy?
The benefit of LDL being low………totally depends on the HDL status
Increasing LDL (the “Bad Cholesterol”)
Decreasing HDL
(the “Good
Cholesterol”)
82. Key Predictors of Mortality
Ready for more of
the REAL
Engineering?
2013 Ivor Cummins BE(Chem) MIEI
83. SERUM TRIGLYCERIDE as a Predictive Factor
Assmann G, Schulte H. Am J Cardiol. 1992;70:733–737.
Data from the PROCAM Munster Study
Blood Triglyceride Levels are an important Risk Factor for Coronary Disease
However, they should not be judged alone – vital to balance with other factors
Again we see the importance of LDL/HDL Ratios and interactions with Trigs
Key Takeaways:
2013 Ivor Cummins BE(Chem) MIEI
84. SERUM INSULIN as a Predictive Factor
Assmann G, Schulte H. Am J Cardiol. 1992;70:733–737.
Data from the PROCAM Munster Study (from "Interesting slideset around…):
Insulin is fundamental to Coronary Disease and Mortality Risk
Insulin has been grossly underemphasized as a risk factor for decades
Triglyceride risk totally outgunned by Insulin Status here
Key Takeaways:
2013 Ivor Cummins BE(Chem) MIEI
Data from the Quebec Study Cardiovascular Study:
Despres JP, et al. N Engl J Med. 1996;334:952-957.
85. SERUM INSULIN and LDL Particle Count
Data from the Quebec Study Cardiovascular Study:
Assmann G, Schulte H. Am J Cardiol. 1992;70:733–737.
Again Insulin is key, but significant interaction with LDL Particle Count (ApoB)
LDL Particle Count tracks with Small Dense LDL – I’ll explain this shortly!
Interaction is the operative word – synergy closely follows
Key Takeaways:
2013 Ivor Cummins BE(Chem) MIEI
Lamarche B, et al. Circulation. 1997;95:69-75.
86. Small Dense LDL as a Predictive Factor
Assmann G, Schulte H. Am J Cardiol. 1992;70:733–737.
Small Dense LDL and associated LDL Particle Count are Key
These, along with Insulin / Insulin Resistance Status, are Master Markers
Key Takeaways:
2013 Ivor Cummins BE(Chem) MIEI
Reprinted from St-Pierre AC, et al. Circulation. 2001;104:
2295–2299, with permission from Wolters Kluwer Health.
87. Data taken from Table 2: Association of Hemoglobin A1c with Cardiovascular Disease and Mortality in
Adults: The European Prospective Investigation into Cancer in Norfolk
Kay-Tee Khaw, MBBChir, FRCP; Nicholas Wareham, MBBS, FRCP; Sheila Bingham, PhD; Robert Luben, BSc; Ailsa Welch, BSc;
and Nicholas Day, PhD
Glucose Levels Anyone? - HbA1c as a Risk Factor
Assmann G, Schulte H. Am J Cardiol. 1992;70:733–737.
HbA1c is the alteration of Red Blood Cells driven by blood glucose levels
This again is closely related to Insulin & Insulin Resistance Status
HbA1c from this particular study is also an independent risk factor
Key Takeaways:
2013 Ivor Cummins BE(Chem) MIEI
88. 2013 Ivor Cummins BE(Chem) MIEI
6. The $1M Question –
What Primarily
Drives up the Risk
Factors???
89. Improving the Total Chol / HDL RatioTotCholesterol/HDL
2013 Ivor Cummins BE(Chem) MIEI
Tot Chol / HDL is a good
metric
Increasingly Lower Carb
delivers dose-response
increased improvement
Low Carb exceeds benefits of
low fat regime – even with
NO dieting
Even during the starvation
period, Low Fat regime
struggles
Separate effects of reduced carbohydrate intake and weight loss on
atherogenic dyslipidemia1–3
Ronald M Krauss, Patricia J Blanche, Robin S Rawlings, Harriett S Fernstrom, and Paul T Williams
Data adapted from from Jeff Volek Summary of:
90. Improving the LDL / HDL Particle Ratio
Separate effects of reduced carbohydrate intake and weight loss on
atherogenic dyslipidemia1–3
Ronald M Krauss, Patricia J Blanche, Robin S Rawlings, Harriett S Fernstrom, and Paul T Williams
Data adapted from from Jeff Volek Summary of:
ApoB/ApoA
LDL / HDL key (here we have
even better metric – the
particle COUNT ratio)
Increasingly Lower Carb
delivers dose-response
increased improvement
2013 Ivor Cummins BE(Chem) MIEI
Low Carb far exceeds
benefits of low fat regime –
even with NO dieting
Even during the starvation
period, Low Fat regime fails
91. Improving the Serum Triglyceride Level
TrigReduction
2013 Ivor Cummins BE(Chem) MIEI
Serum Triglyceride –
important to keep this down
Increasingly Lower Carb
delivers dose-response
increased improvement
Even during the starvation
period, Low Fat regime fails
Separate effects of reduced carbohydrate intake and weight loss on
atherogenic dyslipidemia1–3
Ronald M Krauss, Patricia J Blanche, Robin S Rawlings, Harriett S Fernstrom, and Paul T Williams
Data adapted from from Jeff Volek Summary of:
Low Carb far exceeds
benefits of low fat regime –
even with NO dieting
92. Improving LDL Particle DiameterLDLParticleDiameter
2013 Ivor Cummins BE(Chem) MIEI
LDL Particle Diameter is a
serious metric
Increasingly Lower Carb
delivers dose-response
increased improvement
Low Carb far exceeds
benefits of low fat regime,
especially if you don’t diet
Even during the starvation
period, Low Fat regime
struggles
Separate effects of reduced carbohydrate intake and weight loss on
atherogenic dyslipidemia1–3
Ronald M Krauss, Patricia J Blanche, Robin S Rawlings, Harriett S Fernstrom, and Paul T Williams
Data adapted from from Jeff Volek Summary of:
93. Improving HDL LevelsHDL“good”Chol
2013 Ivor Cummins BE(Chem) MIEI
HDL – the higher the better
Increasingly Lower Carb
delivers dose-response
increased improvement
Low Carb far exceeds
benefits of low fat regime,
again even with no dieting
Even during the starvation
period, Low Fat regime fails
Separate effects of reduced carbohydrate intake and weight loss on
atherogenic dyslipidemia1–3
Ronald M Krauss, Patricia J Blanche, Robin S Rawlings, Harriett S Fernstrom, and Paul T Williams
Data adapted from from Jeff Volek Summary of:
94. Another Recent Trial
xxxxx.
ALL markers better with Low Carb regime – including all Inflammatory ones!
Only Low Carb enhances HDL, improves small LDL, and ApoB/ApoA ratio
Scientifically this appears to be a fundamental rule, but rigorously challenged?
2013 Ivor Cummins BE(Chem) MIEI
HIGH CARB, LOW FATHIGH FAT, VERY LOW CARB
95. 2013 Ivor Cummins BE(Chem) MIEI
(Richard David Feinman summary of referenced Studies)
Another of Many….
ALL markers better with Low Carb / High Fat regime
Only Low Carb enhances HDL, though low GI has a go (!)
Scientifically this appears to be a fundamental rule, but rigorously challenged?
HIGH CEREAL
JENKINS LOW GLYCEMIC INDEX
WESTMAN LOW GLYCEMIC INDEX
WESTMAN LOW CARB HIGH FAT
Jenkins DJ, Kendall CW, McKeown-Eyssen G, Josse RG,
Silverberg J, Booth GL, Vidgen E, Josse AR, Nguyen TH,
Corrigan S et al: Effect of a low-glycemic index or a high-
cereal fiber diet on type 2 diabetes: a randomized trial.
JAMA 2008, 300(23):2742-2753
Westman EC, Yancy WS, Mavropoulos JC, Marquart M,
McDuffie JR: The Effect of a Low-Carbohydrate,
Ketogenic Diet Versus a Low-Glycemic Index Diet on
Glycemic Control in Type 2 Diabetes Mellitus. Nutr
Metab (Lond) 2008, 5(36).
96. Let’s Cut to The Bottom Line….
Selection of people with Coronary
issues and Pattern B tendencies –
the perfect cohort to explore
Examined the effect of dietary
carbohydrate on their true “Bad
Cholesterol” proportion
Surprising Result? No…
Rather the Expected Result.
“Pattern B” is the Small Dense
Cholesterol profile I described
earlier (The BAD)
2013 Ivor Cummins BE(Chem) MIEI
Higher % Carb in Diet
Krauss RM: Atherogenic lipoprotein phenotype and diet-gene
interactions. J Nutr 2001, 131(2):340S-3S.
97. Let’s Cut to The Bottom Line….
So Type B (dysfunctional LDL pattern), lowers directly with lowered Carb in Diet
R = 0.95, i.e. direct dose-response improvement with low carb
Incredible evidence – but still rigorously ignored………how can this be?
Selection of people with Coronary
issues and Pattern B tendencies –
the perfect cohort to explore
Examined the effect of dietary
carbohydrate on their true “Bad
Cholesterol” proportion
Surprising Result? No…
Rather the Expected Result.
“Pattern B” is the Small Dense
Cholesterol profile I described
earlier (The BAD)
2013 Ivor Cummins BE(Chem) MIEI
R = 0.95 - any engineers in the audience today??
Higher % Carb in Diet
Krauss RM: Atherogenic lipoprotein phenotype and diet-gene
interactions. J Nutr 2001, 131(2):340S-3S.
98. So, Driving Risk Factors: Where are you?
Disease Risk
Marker
High Carb
Low Fat
Low Carb /
High Fat*
Is Lean / Fit
Kcal Control / active
Carb Tolerant
(~30% of people?)
Is Not Lean / Is Not Fit
High Kcal / Sedentary
Carb Intolerant
(~70% of people?)
Enables:
Lean / Fit
Kcal Control / Active
Health and Wellbeing
Visceral Fat: Waist+
HDL
Tot Chol / HDL
Serum Glucose
Serum Insulin
Blood Pressure
Serum Triglyceride
Inflammation
markers various
LDL **
* Following Metabolic Adaptation period of 3 weeks to 2 months
** Not a primary marker, particularly requires analysis of other factors to interpret
2013 Ivor Cummins BE(Chem) MIEI
100. Evidence-Based Science Comeback
2013 Ivor Cummins BE(Chem) MIEI
Driven by a GP who did
the work and figured out
Root Cause: Dietary Carb
Reported to the Swedish
Health Board to get her
License Revoked
Real Science Wins Out….
in Sweden anyway
Exonerated by a 2 year
investigation by a
Government Panel of
Doctors & PHD’s
101. N = 1 (But the Important One!)
HDL
1.47
1.73
GGT
112
42
Trig
0.78
0.92
Trig/HDL
1.03
1.44
Tot Chol
/HDL
3.5
4.5
C
Expt
35
530
230
Ferritin
>1.00
mmol
/L
< 200
approx
<4.0
<35
approx
< 1.5
mmol
/L
< 2.0
Note: converted from mmol/L to
mg/dL to get ratio guidelines
2013 Ivor Cummins BE(Chem) MIEI
Old Ivor, watching the fat…..duh! New Ivor, keeping the carb down…
102. N=1 Continued….
Weight
81kg
95
5k run
time
<24min
28
Waist
<32”
35
Sys BP
125
145
Dia BP
75
95
C
Expt
Ideal
~82Kg
Ideal
32”
<80
mmHg
<130
mmHg
Avg of 20+ readings from same Equipment
2013 Ivor Cummins BE(Chem) MIEI
Old Ivor, watching the fat…..duh! New Ivor, keeping the carb down…
104. 2013 Ivor Cummins BE(Chem) MIEI
Human Evolution, low Insulin Regime for ~1 Million Years to 1970….
105. 2013 Ivor Cummins BE(Chem) MIEI
Human Evolution, low Insulin Regime for ~1 Million Years to 1970…. High Carb “Science”
106. 2013 Ivor Cummins BE(Chem) MIEI
Human Evolution, low Insulin Regime for ~1 Million Years to 1970…. High Carb “Science”
107. 2013 Ivor Cummins BE(Chem) MIEI
Discussion / Questions
Human Evolution, low Insulin Regime for ~1 Million Years to 1970…. High Carb “Science”
108. Future “Biochemistry for Life” Topics:
• 25 Hydroxy Vitamin D
The history, latest science, and significant mortality implications of this
critical agent
• Insulin – a Billion Years in Service
The evolutionary importance and critical functionality of Insulin,
increasingly dysfunctional and pathogenic in our modern environment
• Keto-Adaptation
Living in an advantaged metabolic state – it’s much more than simply
having an edge
• Omega 6 Vegetable Oils
The interesting story of how a machine lubricant became a health food
– but should have stayed in the machine….
2013 Ivor Cummins BE(Chem) MIEI
110. Fundamental Truth
• To successfully gain excellent health and years of
extra life, I believe that you must actually
understand this science to a reasonable degree,
not just “follow the diet”
• To achieve this understanding will likely be the
best thing you ever do for yourself.
• Also, everyone has a different genetic makeup,
and this must be understood also – it’s not one
size fits all – know your phenotype!
(but the key drivers do have much commonality)
2013 Ivor Cummins BE(Chem) MIEI
111. Total Cholesterol as a predictive factor?
Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the
Norwegian HUNT 2 study (>58,000 Participants)
Halfdan Petursson MD,1 Johann A. Sigurdsson MD Dr med,2 Calle Bengtsson MD Dr med,3
Tom I. L. Nilsen Dr Philos4 and Linn Getz MD PhD5
Cardiovascular
Death
IncreasedRisk
IncreasedRisk
Ischemic Heart
Disease Death
2013 Ivor Cummins BE(Chem) MIEI
112. Chylomicron Summary
Dietary Fat and Cholesterol is packaged into the
Large Chylomicrons (100-1000nm)
The latter deliver Triglyceride Molecules For
Energy Use in the Heart / Skeletal Muscles
Following this energy transfer, the Chylomicron
remnants have a short half-life of ~20min in the
bloodstream, and are readily taken up by the liver,
thus completing the cycle
However, the latter description assumes moderate
carbohydrate ingestion and insulin secretion….high
carb will spike insulin, suppress Triglyceride utilization,
and increase remnant residence time….
2013 Ivor Cummins BE(Chem) MIEI
113. VLDL to LDL Summary
VLDL is produced by the liver to transport Triglyceride
cargo for energy uses, and Cholesterol for building tasks
As Triglyceride is depleted, Apo CII is shed and the
VLDL becomes an IDL; further depletion and shedding
of Apo E results in an LDL particle with Apo B100 only
LDL should deliver cholesterol and ideally be taken up
by the liver receptors before it becomes sdLDL or is
oxidized (bad boats, increasing numbers, more risk!)
Oxidized LDL reduces take-up by liver – and enhances
take-up by macrophage – inflammation and the disease
process is augmented
2013 Ivor Cummins BE(Chem) MIEI
114. HDL Summary
HDL has many functions, one of which is to
remove Cholesterol excess from problematic areas
Low / dysfunctional HDL relative ratios generally track
with high blood triglyceride, higher sdLDL and higher
inflammatory status
Thus the various risk factors are connected and
synergistic – and have common drivers
We’ll see how to influence HDL health shortly – and it’s
not as hard as you might think!
2013 Ivor Cummins BE(Chem) MIEI
HDL’s other key role is in moderating oxidation in
general, and of LDL specifically
115. Why are we in this room today
- How does this come about?
Academic /
Educational History
Problem Solving
Experience / Aptitude
2013 Ivor Cummins BE(Chem) MIEI