Insulin Resistance Vs “Bad Cholesterol” · PDF filewith thanks to Gabor Erdosi MSc...

…with thanks to

Gabor Erdosi MSc Molecular Biology / Molecular Genetics

Primary Causes of Heart DiseaseInsulin Resistance Vs “Bad Cholesterol”

Ivor Cummins, BE(Chem) CEng MIEI

Disclosure

1. My work is supported by David Bobbett and the Irish

Heart Disease Awareness (http://www.ihda.ie/)

2. David Bobbett and the IHDA are funding myself and Dr.

Gerber’s new book which includes the content in this

presentation

3. No financial ties to the heart imaging industry (!)

http://www.ihda.ie/

BE Chemical Engineering (Biochemical)

6 years Medical Device Engineering

20 years High-Volume Engineering

Structured Problem Solving Focus

Myself:

Myself:

Abnormal blood test readings

Apparently a medical mystery

Apply engineering problem-solving skill

Mystery resolved – and then some…

2013, Personal health issue arises:

BE Chemical Engineering (Biochemical)

6 years Medical Device Engineering

20 years High-Volume Engineering

Structured Problem Solving Focus

Atherosclerosis Risk in Communities Surveillance: 2005–2011 and Cardiovascular Health Study.

Mozaffarian D et al. Circulation. 2015;131:e29-e322

Why you should be interested in this chat…

A. In this room, over a third of you

From the graph “Annual number of adults per 1000 having diagnosed heart attack or fatal coronary heart disease (CHD) by age and sex”

…will have a heart attack by your early 70’s.

Atherosclerosis Risk in Communities Surveillance: 2005–2011 and Cardiovascular Health Study.

Mozaffarian D et al. Circulation. 2015;131:e29-e322

Why you should be interested in this chat…

…will have a heart attack by your early 70’s.

From the graph “Annual number of adults per 1000 having diagnosed heart attack or fatal coronary heart disease (CHD) by age and sex”

B. You could do some pretty simple measurements

- and mostly know who’ll be going down…

A. In this room, over a third of you

Content

1. The Cholesterol Conundrum High Level

2. Beyond Cholesterol - to CVD Primary Causes

3. The Ultimate Test for CVD Presence - CAC

4. A Critique of “Cholesterol as Cause”

The ‘Cholesterol Conundrum’

(the quick version!)

PART 1

From VLDL to LDL….. to Damaged LDL

YER

LIVER !


YER

LIVER !

Cholesterol!

Triglyceride!


YER

LIVER !

BodyFat

Tg

Tg

Tg


BodyFat

YER

LIVER !

Tg

Tg

Tg


YER

LIVER !

BodyFat

Tg

Tg

Tg


YER

LIVER !

BodyFat

Tg

Tg

Tg

ATHEROSCLEROSIS(and MORE…)

TgChChCh

LDLOX

LDL Particle

Count / ApoB

Blood Sugar HDL

Blood Triglyceride

Middle

Obesity

Blood

Insulin

Blood Pressure

Blood Clotting AGE’s

LDL Particle

Count / ApoB


YER

LIVER !

BodyFat

Tg

Tg

Tg

ATHEROSCLEROSIS(and MORE…)

TgChChCh

LDLOXBlood Sugar HDL

Blood Triglyceride

Middle

Obesity

Blood

Insulin

Blood Pressure

Blood Clotting AGE’s

PART 2Beyond ‘Cholesterol’

To The Primary Drivers of Heart Disease

‘Cholesterol and Disease’ Experts are called ‘Lipidologists’

What do Leading-Edge Experts Say?

One of the USA’s foremost is Thomas Dayspring, MD, FACP, FNLA, NCMP

Clinical Assistant Professor of Medicine, Director of Cardiovascular Education





My translation:

1) In reality, the majority of Heart Attacks are due to INSULIN RESISTANCE





My translation:

1) In reality, the majority of Heart Attacks are due to INSULIN RESISTANCE

2) LDL is a near-worthless predictor for cardiovascular issues*

*(people with LDLc above 200mg/dL, or 5.3mmol/L are rare…)

So what’s this ‘Insulin Resistance’ thing then?


LDLWell, if this is ‘LDL’ as a causal

driver of Coronary Vascular

Disease…


INSULIN RESISTANCE

LDL

…then this is

INSULIN

RESISTANCE !

Well, if this is ‘LDL’ as a causal

driver of Coronary Vascular

Disease…

INSULIN RESISTANCE - PHASE 1

”The Adipose Tissue falls first…”

I

SA

T

MHNW (Metabolically Healthy Normal Weight)

Bad Food

Excessive Food

INSULIN SENSITIVE. Risk Level

AdipoShield© - Bodyfat as universal Energy Buffer System

SA

T


Bad Food

Excessive Food

SA

T

MONW (Metabolically Obese Normal Weight)

Bad Food

Excessive Food

INSULIN RESISTANT. Risk LevelINSULIN SENSITIVE. Risk Level


VA

T

SA

T


Bad Food

Excessive Food

SA

T


Bad Food

Excessive Food SA

T

MUO (Metabolically Unhealthy Obese)

Bad Food

Excessive Food



VA

T

VA

T

INSULIN RESISTANT. Risk Level

SA

T


Bad Food

Excessive Food SA

T

MHO (Metabolically Healthy Obese)

Bad Food

Excessive Food

SA

T


Bad Food

Excessive Food SA

T

MUO (Metabolically Unhealthy Obese)

Bad Food

Excessive Food

VA

T


INSULIN SENSITIVE. Risk Level


VA

T

VA

T

INSULIN RESISTANT. Risk Level

And what can IS vs IR Obesity Phenotypes Tell Us?

Insulin-sensitive obesity Am J Physiol Endocrinol Metab 299: E506–E515, 2010.

~45 y.o.

BMI:45

IS

Obese

IR

Obese

GIR 42.4 14.2

Fast Ins 4.4 15.4

HbA1c 5.3 5.7

Trig/HDL 1.8 4.1

LDL 3 3.1

IS IR

2.X



2.X

~45 y.o.

BMI:45

IS

Obese

IR

Obese

GIR 42.4 14.2

Fast Ins 4.4 15.4

HbA1c 5.3 5.7

Trig/HDL 1.8 4.1

LDL 3 3.1

IS IR



IS

IR

2.X

~45 y.o.

BMI:45

IS

Obese

IR

Obese

GIR 42.4 14.2

Fast Ins 4.4 15.4

HbA1c 5.3 5.7

Trig/HDL 1.8 4.1

LDL 3 3.1

IS IR


“Low macrophage infiltration into omental fat and higher circulating adiponectin

almost entirely predict the IS obese Phenotype r 2=0.98, P < 0.0001”


IS

IRIS

IR

2.X

Adipose TissueINS

INS

INS

Pancreas

The Insulin Resistance Journey

Insulin…

Insu

lin

Insulin

Adipose TissueINS

INS

INS

Insu

lin

Pancreas

GlucagonINS

INS

INS

INS

INS


Insulin…

Insu

lin

Insulin

Adipose TissueINS

INS

INS

Insu

lin

Pancreas

Glucagon

GLUT4

DNLINS

INS

INS

INS

INS


CARBOHYDRATES

(i.e. Glucose)

Insulin…

Insu

lin

Insulin

Adipose TissueINS

INS

Insu

lin

Pancreas

GlucagonINS

INS

INS

INS

INS


INS

GLUT4

DNL

CARBOHYDRATES

(i.e. Glucose)

Insulin…

Insu

lin

Insulin

Adipose TissueINS

INS

INS

Insu

lin

GLUT4

DNL

Pancreas

“Too Much”

INS

INS

INS

INS

INS


CARBOHYDRATES

(i.e. Glucose)

Adipose Tissue

GLUT4

DNL

Insulin…

Insu

lin

Insulin

INS

INS

INS

Insu

lin

Pancreas

“Too Much” #1INS

INS

INS

INS

INS

INS

INS

INS

INSINS


CARBOHYDRATES

(i.e. Glucose)Insulin…

Insu

lin

Insulin

Adipose TissueINS

INS

INS

Insu

lin

GLUT4

DNL

Pancreas

“Too Much” #1INS

INS

INS

INS

INS

INS

INS

INS

INSINS


CARBOHYDRATES

(i.e. Glucose)Insulin…

Insu

lin

Insulin

Adipose TissueINS

INS

INS

Insu

lin

GLUT4

DNL

Pancreas

“Too Much”

#2

#1INS INS

INS

INS

INS

INS

INS

INS

INSINS

INS

INS

INSINSINS

INS


CARBOHYDRATES

(i.e. Glucose)

Adipose Tissue

Insulin…

Insu

lin

Insulin

INS

INS

INS

Insu

lin

Pancreas

“Too Much”

#2

#1INS INS

INS

INS

INS

INS

INS

INS

INSINS

INS

INS

INSINSINS

INS


Smoking Genetic

TendencyLow Sleep

/ Exercise

Sedentary

Behaviour

Omega 6

Seed OilsLow Sun /

Vitamin DLow Omega 3

Stress

CARBOHYDRATES

(i.e. Glucose)

Adipose Tissue

“Too Much”

Insulin…

Insu

lin

Insulin

INS

INS

INS

#2

Pancreas

#1INS INS

INS

INS

INS

INS

INS

INS

INSINS

INS

INS

INSINSINS

INS


Insu

lin

Smoking Genetic

TendencyLow Sleep

/ Exercise

Sedentary

Behaviour

Omega 6

Seed OilsLow Sun /


Stress#3

CARBOHYDRATES

(i.e. Glucose)

Adipose Tissue

“Too Much”

Insulin…

Insu

lin

Insulin

INS

INS

INS

Insu

lin

#2

Pancreas

#1INS INS

INS

INS

INS

INS

INS

INS

INSINS

INS

INS

INSINSINS

INS


Smoking Genetic

TendencyLow Sleep

/ Exercise

Sedentary

Behaviour

Omega 6

Seed OilsLow Sun /


Stress#3

CARBOHYDRATES

(i.e. Glucose)Insulin

… Insu

lin

Insulin

Adipose TissueINS

INS

INS

Insu

lin

#2

“Too Much” INS INS

INS

INS

INS

INS

INS

INS

INSINS

INS

INS

INSINSINS

INS INS

INS

INS

INS

INS

INS

INS

INS

INS INS INS

INS

INSINS

INS

INS

INS

INS

INS

INS

INS

PancreasINS

INS INS INS

#1


CARBOHYDRATES


… Insu

lin

Insulin

Adipose TissueINS

INS

INS

Insu

lin

#2


INS

INS

INS

INS

INS

INS

INSINS

INS

INS

INSINSINS

INS INS

INS

INS

INS

INS

INS

INS

INS

INS INS INS

INS

INSINS

INS

INS

INS

INS

INS

INS

INS

PancreasINS

INS INS INS

#1


Adipose

Macrophage

(Inflammation)

CARBOHYDRATES


… Insu

lin

Insulin

Adipose TissueINS

INS

INS

Insu

lin

#2


INS

INS

INS

INS

INS

INS

INSINS

INS

INS

INSINSINS

INS INS

INS

INS

INS

INS

INS

INS

INS

INS INS INS

INS

INSINS

INS

INS

INS

INS

INS

INS

INS

PancreasINS

INS INS INS

#1


Adipose

Macrophage

(Inflammation)But Blood Glucose is still under control…

…so how do you get into Endgame?

CARBOHYDRATES

(i.e. Glucose)

Adipose TissueINS

INS

INS

#2

“Too Much”

Pancreas

#1

Insulin…

Insu

lin

INS

INS

INS

INS

INS

INS

Insulin


Adipose

Macrophage

(Inflammation)


CARBOHYDRATES

(i.e. Glucose)

Adipose TissueINS

INS

INS

#2

“Too Much”

Pancreas

#1

Insulin…

Insu

lin

INS

INS

INS

INS

INS

INS

Insulin

Brake Failure


CARBOHYDRATES

(i.e. Glucose)

Adipose TissueINS

INS

INS

#2

“Too Much”

Pancreas

#1

Insulin…

Insu

lin

INS

INS

INS

INS

INS

INS

Insulin

Free

Fatty

Acids

Glycerol

Brake Failure

Brake Failure


CARBOHYDRATES

(i.e. Glucose)

Adipose TissueINS

INS

INS

#2

“Too Much”

Pancreas

#1

Insulin…

Insu

lin

INS

INS

INS

INS

INS

INS

Insulin

Free

Fatty

Acids

Glycerol

Brake Failure

Brake Failure

LIVER

GLUCOSE

OUTPUT

INS


CARBOHYDRATES

(i.e. Glucose)

Adipose Tissue

INS

INS

#2

“Too Much”

Pancreas

#1

Insulin…

Insu

lin

INS

INS

INS

INS

INS

INS

Insulin

Free

Fatty

Acids

Glycerol

INSERT INSULIN

TO CONTINUE

Brake Failure

Measuring it - part 1

Metabolic Mayhem

THE

METABOLIC

SYNDROME

Defined in 1988 by Gerald M Reaven, MDProfessor emeritus in medicine at the Stanford University School of Medicine

Diabetes December 1988 vol. 37 no. 12 1595-1607 doi:10.2337/diab.37.12.1595.

Measuring Metabolic Mayhem…

1. Low HDL “Good Cholesterol”

2. High Blood Triglycerides

3. Large Waist Measurement

4. Elevated Blood Pressure

5. High Blood Sugar

THE

METABOLIC

SYNDROME


THE

METABOLIC

SYNDROME1. Low HDL “Good Cholesterol”




5. High Blood Sugar

Atherosclerosis

Coronary Heart

Disease


THE

METABOLIC





5. High Blood Sugar

Atherosclerosis

(*Obesity)

Fatty Liver Disease

Gout

Arthritis

Type 2 Diabetes

Stroke

Alzheimer's

Asthma

Etc. etc. …

Cancer

Coronary Heart

Disease


THE

METABOLIC





5. High Blood Sugar

Atherosclerosis

(*Obesity)

Fatty Liver Disease

Gout

Arthritis

Type 2 Diabetes

Stroke

Alzheimer's

Asthma

Etc. etc. …

Cancer

Coronary Heart

Disease

But…didn’t I say earlier that

Insulin Resistance

was the big player…?


Atherosclerosis

Coronary Heart

Disease

(*Obesity)

Fatty Liver Disease

Gout

Arthritis

Type 2 Diabetes

Stroke

Alzheimer's

Asthma

Etc. etc. …

Cancer1. Low HDL “Good Cholesterol”




5. High Blood Sugar

INSULIN

RESISTANCE

SYNDROME






5. High Blood Sugar

INSULIN

RESISTANCE

SYNDROME

Atherosclerosis

Coronary Heart

Disease

(*Obesity)

Fatty Liver Disease

Gout

Arthritis

Type 2 Diabetes

Stroke

Alzheimer's

Asthma

Etc. etc. …

Cancer

Master Measure…





5. High Blood Sugar

INSULIN

RESISTANCE

SYNDROME

Atherosclerosis

Coronary Heart

Disease

(*Obesity)

Fatty Liver Disease

Gout

Arthritis

Type 2 Diabetes

Stroke

Alzheimer's

Asthma

Etc. etc. …

Cancer

“IF YOU DOn’t MEASURE It,It DOn’t GEt FIXED.”

Master Measure…

Master Measures

Measuring it - part 2

Dr. Joseph R. Kraft, MD, MS, FCAPChairman, Department of Clinical Pathology and Nuclear Medicine,

St. Joseph’s Hospital 1962-1990 (appointed Chairman Emeritus on retirement)

The Kraft “Diabetes In Situ” Test


1. Drink 75g Glucose…


1. Drink 75g Glucose…

2. Measure the Insulin Response over time…

Kraft Pattern 1- Euinsulinemia (Non-Diabetic)

1

Kraft Pattern 2, 3, 4 - Hyperinsulinemia (Diabetes in Situ)

2

3

4

1

Kraft Pattern 2, 3, 4 - Hyperinsulinemia (Diabetes in Situ)

2

3

4

1

“The Earliest Laboratory Diagnosis for

Diabetes” - Dr. Joseph R. Kraft

Patterns of Insulin Concentration During the OGTT Predict the Risk of Type 2 Diabetes in Japanese AmericansDIABETES CARE, VOLUME 36, MAY 2013

Kraft predicts Full-blown T2D…2013 Study

DIABETES

INCIDENCE

11 Years Later

OR

IGIN

AL

And did you know…

And did you know…

Menke A, et al. JAMA. 2015;314(10):1021-1029. doi:10.1001/jama.2015.10029.

That 49%-52% in the US are now…

pre-Diabetic or Diabetic.Pre-Diabetic ≈ Diabetic ≈ Insulin Resistant ≈ Hyperinsulinemic

And did you know…


Using Kraft’s test, probably >65% would have

Hyperinsulinemia / Diabetes In Situ

And did you know…


“Those with cardiovascular disease not

identified with diabetes… are simply

undiagnosed” - Dr. Joseph R. Kraft

Latest Data…2015 Study

I’d be surprised if many of the remaining 34% would pass a Kraft Test…

Latest Data…2015 Study

So now let’s see the

Root Cause Diagram for CVD...and how you avoid the mess.

Draft Root Cause Diagram for Cardiovascular Disease

IR FATTY LIVER…

INSULIN RESISTANCE

HYPERINSULINEMIA


↑ BLOOD

INSULIN

↑ BLOOD

PRESSURE

IR FATTY LIVER…

INSULIN RESISTANCE

HYPERINSULINEMIA

↑ BLOOD

GLUCOSE


ATHEROGENIC DYSLIPIDEMIA

↑VLDL

↑LDL

COUNT

↑ BLOOD

INSULIN↓HDL

↑TRIGLCERIDES↑ BLOOD

PRESSURE↑OXIDISED

LDL

IR FATTY LIVER…

↑Tot/HDL

Ratio

INSULIN RESISTANCE

HYPERINSULINEMIA

↑ BLOOD

GLUCOSE



↑VLDL ↑ BLOOD

INSULIN↓HDL


PRESSURE↑OXIDISED

LDL

IR FATTY LIVER…

HEART DISEASE

↑Tot/HDL

Ratio

INSULIN RESISTANCE

HYPERINSULINEMIA

↑ BLOOD

GLUCOSE

↑LDL

COUNT



↑VLDL ↑ BLOOD

INSULIN↓HDL


PRESSURE↑OXIDISED

LDL

IR FATTY LIVER…

HEART DISEASE

↑Tot/HDL

Ratio

INSULIN RESISTANCE

HYPERINSULINEMIA

↑ BLOOD

GLUCOSE

And what about the ACTIONABLE Root Causes of this Mess?

↑LDL

COUNT



↑VLDL

Excess

Fructose

Excess

Carb

↑ BLOOD

INSULIN↓HDL


PRESSURE↑OXIDISED

LDL

AND

IR FATTY LIVER…

HEART DISEASE

↑Tot/HDL

Ratio

INSULIN RESISTANCE

HYPERINSULINEMIA

↑ BLOOD

GLUCOSE

↑LDL

COUNT



↑VLDL

Excess

Fructose

Excess

Carb

Sub-Opt

Omega 3

↑ BLOOD

INSULIN↓HDL


PRESSURE

Excess

Omega 6

AND

↑OXIDISED

LDL

AND

IR FATTY LIVER…

HEART DISEASE

↑Tot/HDL

Ratio

INSULIN RESISTANCE

HYPERINSULINEMIA

↑ BLOOD

GLUCOSE

↑LDL

COUNT



↑VLDL

Excess

Fructose

Excess

Carb

Sub-Opt

Omega 3

↑ BLOOD

INSULIN↓HDL


PRESSURE

Sub-Opt

K2, C, Mg

Excess

Omega 6

AND

Sub-Opt

Sun / Vit D

↑OXIDISED

LDL

AND

Genetic

Tendency

IR FATTY LIVER…

HEART DISEASE

↑Tot/HDL

Ratio

INSULIN RESISTANCE

HYPERINSULINEMIA

↑ BLOOD

GLUCOSE

↑LDL

COUNT



↑VLDL

Excess

Fructose

Excess

Carb

Sub-Opt

Omega 3

↑ BLOOD

INSULIN↓HDL


PRESSURE

Sub-Opt

K2, C, Mg

Excess

Omega 6

AND

Sub-Opt

Sun / Vit D

↑OXIDISED

LDL

Lack of

Sleep /

Exercise

AND

Genetic

Tendency

IR FATTY LIVER…

Smoking

HEART DISEASE

Pollutants

↑Tot/HDL

Ratio

INSULIN RESISTANCE

HYPERINSULINEMIA

↑ BLOOD

GLUCOSE

↑LDL

COUNT



↑VLDL

Excess

Fructose

Excess

Carb

Sub-Opt

Omega 3

↑ BLOOD

INSULIN↓HDL


PRESSURE

Sub-Opt

K2, C, Mg

Excess

Omega 6

AND

Sub-Opt

Sun / Vit D

↑OXIDISED

LDL

Lack of

Sleep /

Exercise

AND

Genetic

Tendency

IR FATTY LIVER…

Smoking

HEART DISEASE

OTHER

Pollutants

↑Tot/HDL

Ratio

INSULIN RESISTANCE

HYPERINSULINEMIA

↑ BLOOD

GLUCOSE

↑LDL

COUNT



↑VLDL

Excess

Fructose

Excess

Carb

Sub-Opt

Omega 3

↑ BLOOD

INSULIN↓HDL


PRESSURE

Sub-Opt

K2, C, Mg

Excess

Omega 6

AND

Sub-Opt

Sun / Vit D

↑OXIDISED

LDL

Lack of

Sleep /

Exercise

AND

Genetic

Tendency

IR FATTY LIVER…

Smoking

HEART DISEASE

OTHER

Pollutants

↑Tot/HDL

Ratio

INSULIN RESISTANCE

HYPERINSULINEMIA

↑ BLOOD

GLUCOSE

↑LDL

COUNT

Multiple

Non-IR

Mechs



↑VLDL

↑LDL

COUNT

Excess

Fructose

Excess

Carb

Sub-Opt

Omega 3

↑ BLOOD

INSULIN↓HDL


PRESSURE

Sub-Opt

K2, C, Mg

Excess

Omega 6

AND

Sub-Opt

Sun / Vit D

↑OXIDISED

LDL

Lack of

Sleep /

Exercise

AND

Genetic

Tendency

IR FATTY LIVER…

Smoking

HEART DISEASE

OTHER

Pollutants

↑Tot/HDL

Ratio

INSULIN RESISTANCE

HYPERINSULINEMIA

↑ BLOOD

GLUCOSE

Multiple

Non-IR

Mechs

PART 3The Power of the CAC Score

The Ultimate Test for CVD Presence

“We Stand on the Shoulder’s of Giants…”

Bruce Brundage

CardiologistFormer Professor David Geffan

School of Medicine UCLA

Doug Boyd

Physicist, Inventor of CAC TechnologyFormer Professor of Radiology (Physics)

UCSF

Harvey S. Hecht

CardiologistProfessor Mount Sinai Medical

Centre New York

John A. Rumberger

CardiologistPrinceton Longevity Centre

Matthew J. Budoff

CardiologistProfessor of Medicine UCLA

Arthur Agatston

CardiologistAssociate Professor of Medicine

University of Miami

The CT Scan – and the CAC Score

What about Studies on CAC?

?

10%10%

Muddy Waters:

Framingham

Risk Score

AND WITHYOUR CAC SCORE ?

0 1-80 81-400 401-600 >600

Framingham Versus Calcium Scoring & CAC

? ? ? ? ?

?

10%10% 2.4% 5.4% 16% 25% 36%

Muddy Waters:

Framingham

Risk Score


0 1-80 81-400 401-600 >600


? ? ?

?

10%10% 2.4% 5.4% 16% 25% 36%

Muddy Waters:

Framingham

Risk Score


0 1-80 81-400 401-600 >600


? ?

?

10%10% 2.4% 5.4% 16% 25% 36%

Muddy Waters:

Framingham

Risk Score


0 1-80 81-400 401-600 >600


?

MUDDY FRAMInGhAM tAkES A GUESS…

10%10% 2.4% 5.4% 16% 25% 36%

Muddy Waters:

Framingham

Risk Score


0 1-80 81-400 401-600 >600


?

The calcium scan sees the disease.MUDDY FRAMInGhAM tAkES A GUESS…

10%10% 2.4% 5.4% 16% 25% 36%

Muddy Waters:

Framingham

Risk Score


0 1-80 81-400 401-600 >600


Always the best test, across all the studies….

Screening for Ischemic Heart Disease with Cardiac CT: Current Recommendations Volume 2012, Article ID 812046, http://dx.doi.org/10.6064/2012/812046

Study Screening Power of CAC Scoring

2005 St Francis Heart Predicted ~10x Risk with CAC > 100 Vs CAC < 100 (after RF adjustment, and CRP failed)

2008 MESA Predicted ~8x Risk with CAC > 100 Vs CAC < 100 (after RF adjustment)

2003 Kondos et Al Predicted ~7x Risk with CAC > 170 Vs CAC < 170 (after RF adjustment)

2005 Taylor et al Predicted ~12x Risk with CAC > 0 Vs CAC < 0 (after RF adjustment, and CRP failed)

2005 Yeboah et al CAC beat all predictors as always (CIMT, brachial flow dilation etc. failed again).

2008/2010/2012

Pencina/Polonsky et al

CAC re-classified ~60% of Middle-Risk people…20% became High-Risk, 39% became Low-Risk

(CAC blew away CIMT and other predictors by a full order of magnitude)

Budoff et al 2009 CAC = 1 to 10 showed 20x more first-year events vs. CAC = 0 (note factor changes over time…!)

Raggi/Greenland et al

2000/2010

CAC > 400 had 4.8% cardiac events per year, versus 0.1% for CAC = 0.

Greenland et al verified CAC = 0 had 0.1% events over 3-5 years, independent of Risk Factors…

Always the best test, across all the studies….

Screening for Ischemic Heart Disease with Cardiac CT: Current Recommendations Volume 2012, Article ID 812046, http://dx.doi.org/10.6064/2012/812046

100’s of thousands of people tracked in these and other CAC studies.

Study Screening Power of CAC Scoring

2005 St Francis Heart Predicted ~10x Risk with CAC > 100 Vs CAC < 100 (after RF adjustment, and CRP failed)

2008 MESA Predicted ~8x Risk with CAC > 100 Vs CAC < 100 (after RF adjustment)

2003 Kondos et Al Predicted ~7x Risk with CAC > 170 Vs CAC < 170 (after RF adjustment)

2005 Taylor et al Predicted ~12x Risk with CAC > 0 Vs CAC < 0 (after RF adjustment, and CRP failed)

2005 Yeboah et al CAC beat all predictors as always (CIMT, brachial flow dilation etc. failed again).

2008/2010/2012

Pencina/Polonsky et al

CAC re-classified ~60% of Middle-Risk people…20% became High-Risk, 39% became Low-Risk

(CAC blew away CIMT and other predictors by a full order of magnitude)

Budoff et al 2009 CAC = 1 to 10 showed 20x more first-year events vs. CAC = 0 (note factor changes over time…!)

Raggi/Greenland et al

2000/2010

CAC > 400 had 4.8% cardiac events per year, versus 0.1% for CAC = 0.

Greenland et al verified CAC = 0 had 0.1% events over 3-5 years, independent of Risk Factors…

CAC Score

Calcium Score Risk Equivalent 10-Year Event Rate, %

0 Very low 1.1-1.7

1-100 Low 2.3-5.9

101-400 Intermediate 12.8-16.4

>400 High 22.5-28.6

>1000 Very high 37

J Am Coll Cardiol Img. 2015;8(5):579-596

CAC Score Obliterates the “Risk Factors”…!

And what about CAC Score progression ??

“Progression of Coronary Artery Calcium and Risk of First Myocardial Infarction in Patients Receiving Cholesterol-Lowering Therapy”

Paolo Raggi, Tracy Q. Callister, Leslee J. Shaw. Arterioscler Thromb Vasc Biol, 2004. DOI: 10.1161/01.ATV.0000127024.40516.ef


3.5 Years Pass by…Starting Score

100-1000

“Progression of Coronary Artery Calcium and Risk of First Myocardial Infarction in Patients Receiving Cholesterol-Lowering Therapy”

Paolo Raggi, Tracy Q. Callister, Leslee J. Shaw. Arterioscler Thromb Vasc Biol, 2004. DOI: 10.1161/01.ATV.0000127024.40516.ef

6 Years Pass by…Starting Score

100-1000


3.5 Years Pass by…Starting Score

100-1000

PART 4“Cholesterol Capers”

Hyperinsulinemia as Prime Driver

….versus Cholesterol as Cause.

2.Y

LDLc

“The Bad Cholesterol”

Insulin Versus ‘Bad Cholesterol’

Hyperinsulinemia Predicts Coronary Heart Disease Risk in Healthy Middle-

aged Men. Circulation. 1998;98:398-404

Helsinki: One of the

few studies to properly

use a Kraft-type test…

INSULIN






INSULIN




Hyperinsulinemia /

Insulin Resistance

“Bad

Cholesterol”




INSULIN




“Bad

Cholesterol”

Hyperinsulinemia /

Insulin Resistance




INSULIN


Insulin Vs ‘Bad Cholesterol’ in head-to-head Studies

Circ J 2004; 68: 47 –52

StudyInsulin

/Glucose

‘Bad

Cholesterol’

'Abnormal glucose tolerance – a common risk factor in patients with acute…’ (2004) Highly Significant Not Significant

"Insulin Resistance and Fasting Hyperinsulinemia Are Risk Factors for New…” (2004) Highly Significant Not Significant

“Lipid levels in patients hospitalized with coronary artery disease:…” (2009) Not available Inverse !

“Interrelation between angiographic severity of coronary artery disease and…” (1993) Highly Significant Not Significant

"Progression of Coronary Artery Calcium and Risk of First Myocardial…” (2004) Highly Significant Not Significant

“The joint effects of apolipoprotein B, apolipoprotein A1, LDL cholesterol…” (2008) Highly Significant Inverse !

“Low admission LDL-cholesterol…increased 3-year all-cause mortality” (2009) Not available Inverse !

Association of Plasma Tryglyceride and C-Peptide with CHD…” (1990) Highly Significant Not Significant

Doi:10.1111/j.1365-2796.2004.01371.x

http://dx.doi.org/10.1016/j.ahj.2008.08.010

Am J Cardiol. 1993 Aug 15;72(5):397-401

Doi:10.1161/01.ATV.0000127024.40516.ef

doi:10.1093/eurheartj/ehp221

Cardiol J. 2009;16(3):227-33.

Diabetologia. 1990 Aug;33(8):489-96.

Prospective Predictions Based on IR Level

Insulin Resistance as a Predictor of Age-Related Diseases The Journal of Clinical Endocrinology & Metabolism 86(8):3574–3578

Apparently healthy, non-obese (body mass index < 30 kg/m2) individuals

Split into tertiles of Insulin Resistance by SSPG via Insulin Suppression Test

What happened ~6.5 years later?




Well, here’s what transpired:





What happened ~6.5 years later?


AND…If CAC Score Obliterates the “Risk Factors”…

…which it does

The mainstream hypothesis that LDL cholesterol drives atherosclerosis may have been falsified by non-invasive imaging of coronary artery plaque burden and progression.

Medical Hypotheses 73 (2009) 596–600

Then WHY doesn’t LDLc correlate with it?

/CAC

LDLp (ApoB)

“The New Bad Cholesterol”(ApoB)

LDLp

What about LDLp/ApoB Independence… ?


↑VLDL

↑LDL

COUNT

Excess

Fructose

INSULIN RESISTANCE

HYPERINSULINEMIA

Excess

Carb

Sub-Opt

Omega 3

↑ BLOOD

INSULIN

(+ GLUCOSE)↓HDL

↓Tot/HDL

↑TRIG

↑ BLOOD

PRESSURE

↑ MIDDLE

OBESITY

Heart Disease

Excess

Fructose

Excess

Carb

Sub-Opt

K2, C, Mg

Excess

Omega 6

AND

Sub-Opt

Sun / Vit D

OXIDISED

LDL

Lack of

Sleep /

ExerciseAND

Genetic

Tendency

FATTY

LIVER

IR LIVER…

Excess

Natural

Fats…?

Sub-Opt

Sun / Vit D

Sub-Opt

K2, C, Mg

Genetic

Tendency

Sub-Opt

Omega 3

Smoking

Smoking

↑ BLOOD

GLUCOSE

Multiple

Non-IR

Mechs

Lack of

Sleep /

Exercise

Excess

Omega 6

AOTHER(Stress etc.)


↑VLDL

↑LDL

COUNT

Excess

Fructose

INSULIN RESISTANCE

HYPERINSULINEMIA

Excess

Carb

Sub-Opt

Omega 3

↑ BLOOD

INSULIN

(+ GLUCOSE)↓HDL

↓Tot/HDL

↑TRIG

↑ BLOOD

PRESSURE

↑ MIDDLE

OBESITY

Heart Disease

Excess

Fructose

Excess

Carb

Sub-Opt

K2, C, Mg

Excess

Omega 6

AND

Sub-Opt

Sun / Vit D

OXIDISED

LDL

Lack of

Sleep /

ExerciseAND

Genetic

Tendency

FATTY

LIVER

IR LIVER…

Excess

Natural

Fats…?

Sub-Opt

Sun / Vit D

Sub-Opt

K2, C, Mg

Genetic

Tendency

Sub-Opt

Omega 3

Smoking

Smoking

↑ BLOOD

GLUCOSE

Multiple

Non-IR

Mechs

Lack of

Sleep /

Exercise

Excess

Omega 6

A

“ApoB/ApoA1 ratio in regression model had

an OR of 17.95 for Insulin Resistance” ”Association of the Apolipoprotein B/Apolipoprotein A-I Ratio, Metabolic

Syndrome Components, Total Cholesterol, and Low-Density Lipoprotein

Cholesterol with Insulin Resistance in the Population of Georgia” International

Journal of Endocrinology Volume 2014 (2014), Article ID 925650


OTHER(Stress etc.)


↑VLDL

↑LDL

COUNT

Excess

Fructose

INSULIN RESISTANCE

HYPERINSULINEMIA

Excess

Carb

Sub-Opt

Omega 3

↑ BLOOD

INSULIN

(+ GLUCOSE)↓HDL

↓Tot/HDL

↑TRIG

↑ BLOOD

PRESSURE

↑ MIDDLE

OBESITY

Heart Disease

Excess

Fructose

Excess

Carb

Sub-Opt

K2, C, Mg

Excess

Omega 6

AND

Sub-Opt

Sun / Vit D

OXIDISED

LDL

Lack of

Sleep /

ExerciseAND

Genetic

Tendency

FATTY

LIVER

IR LIVER…

Excess

Natural

Fats…?

↑LDL PARTICLE

COUNT ALONE

AS CAUSAL ?

Sub-Opt

Sun / Vit D

Sub-Opt

K2, C, Mg

Genetic

Tendency

Sub-Opt

Omega 3

OTHER(Stress etc.)

Smoking

Smoking

↑ BLOOD

GLUCOSE

Multiple

Non-IR

Mechs

?

Lack of

Sleep /

Exercise

Excess

Omega 6

AB







↑LDL PARTICLE

COUNT ALONE

AS CAUSAL ???


↑VLDL

↑LDL

COUNT

Excess

Fructose

INSULIN RESISTANCE

HYPERINSULINEMIA

Excess

Carb

Sub-Opt

Omega 3

↑ BLOOD

INSULIN

(+ GLUCOSE)↓HDL

↓Tot/HDL

↑TRIG

↑ BLOOD

PRESSURE

↑ MIDDLE

OBESITY

Heart Disease

Excess

Fructose

Excess

Carb

Sub-Opt

K2, C, Mg

Excess

Omega 6

AND

Sub-Opt

Sun / Vit D

OXIDISED

LDL

Lack of

Sleep /

ExerciseAND

Genetic

Tendency

FATTY

LIVER

IR LIVER…

Excess

Natural

Fats…?

Sub-Opt

Sun / Vit D

Sub-Opt

K2, C, Mg

Genetic

Tendency

Sub-Opt

Omega 3

Smoking

Smoking

↑ BLOOD

GLUCOSE

Multiple

Non-IR

Mechs

?

Lack of

Sleep /

Exercise

Excess

Omega 6

B






A


OTHER(Stress etc.)

Lp(a)

“The Sexy Bad Cholesterol”

Ask WHY ?

Lipoprotein(a) Concentration and the Risk of Coronary Heart Disease,

Stroke, and Nonvascular Mortality JAMA. 2009 July 22; 302(4): 412–423.

Ask WHY ?

Why is high Lp(a) only significant for people with existing inflammatory issues?Lipoprotein(a) Concentration and the Risk of Coronary Heart Disease,

Stroke, and Nonvascular Mortality JAMA. 2009 July 22; 302(4): 412–423.

WRAPUP“Striking at the Root”

What would I personally prioritise?

2.Y

Cancers

Obesity/

HypertensionDiabetes &

Alzheimers

“There are a thousand hacking at the branches of evil, - to one who is

striking at the root (causes).”

General Chronic

Disease / early

death

Cardiovascular

Disease

Cancers

Obesity/


Alzheimers



General Chronic

Disease / early

death

Cardiovascular

Disease

INSU

LIN

Etc

.

SIG

NA

LLIN

G

Cancers

Obesity/


Alzheimers

↓Sleep/

↓Exercise



General Chronic

Disease / early

death

Cardiovascular

Disease

INSU

LIN

Etc

.

SIG

NA

LLIN

G

Cancers

Obesity/


Alzheimers

↓Sleep/

↓Exercise

“There are a thousand hacking at the branches of evil - to one who is


General Chronic

Disease / early

death

Cardiovascular

Disease

INSU

LIN

Etc

.

SIG

NA

LLIN

G

A Recent Irish Example…


44 y.o. Engineer.

3 children.

Concerned.

* Brother quadruple bypass at 52

* Cousin died of Heart Attack at 50

* Other nasty family history…


44 y.o. Engineer.

3 children.

Concerned.




* Cholesterol Good

* Other Bloods Good

* All Good – no worries!


44 y.o. Engineer.

3 children.

Concerned.




* Cholesterol Good

* Other Bloods Good


* Stress Test Good

* Echocardiogram Good



44 y.o. Engineer.

3 children.

Concerned.




* Cholesterol Good

* Other Bloods Good


* Stress Test Good



Our engineer

demands a…

Calcium Scan


44 y.o. Engineer.

3 children.

Concerned.




* Cholesterol Good

* Other Bloods Good


* Stress Test Good



* CAC=25. Diffuse Calcification

throughout coronary vessels

* It’s NOT All Good.

Our engineer

demands a…

Calcium Scan

* It’s NOT “No Worries”.


44 y.o. Engineer.

3 children.

Concerned.




* Cholesterol Good

* Other Bloods Good


* Stress Test Good






Our engineer

demands a…

Calcium Scan

* His Framingham Risk was 5%

* CAC = 25 means arteries of

* His real (MESA) risk is >30%

a 64 year old. (+/- 2 years)



44 y.o. Engineer.

3 children.

Concerned.




* Cholesterol Good

* Other Bloods Good


* Stress Test Good






Our engineer

demands a…

Calcium Scan






“I’m all over it Ivor…

I’m all over it”

Insulin Resistance Vs “Bad Cholesterol” · PDF filewith thanks to Gabor Erdosi MSc...

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Transcript of Insulin Resistance Vs “Bad Cholesterol” · PDF filewith thanks to Gabor Erdosi MSc...