L7 - Lipids and Cardiac Disease Flashcards

1
Q

Effects of Intermittent Fasting on Health and Aging?

A

Intermittent fasting improves multiple
indicators of cardiovascular health, including
blood pressure; resting heart rate; lipids; etc.

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2
Q

Global Burden of Cardiovascular Disease?

A

1) Aging and population growth have resulted in a global increase in
cardiovascular deaths
2) 17.3 million deaths globally from Cardiovascular disease in 2013
• 40.8% increase from 1990
• Coronary Heart Disease was the largest contributor to cardiovascular death (8.1 million)

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3
Q

Lipids’ roles?

A
  1. Hormones or hormone precursors
  2. Aids in digestion
  3. Source of metabolic fuel and energy storage
  4. Structural component of the cell membrane
  5. Insulators (aid in nerve conduction or prevent heat loss)
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4
Q

Cholesterol?

A

1) All cells and body fluids contain some cholesterol
2) Starting point of different metabolic pathways
• Vitamin D synthesis
• Steroid hormone synthesis (e.g. progesterone, aldosterone, etc.)
• Bile acid synthesis
(Bile acids – acids that are synthesized by the liver from cholesterol to aid in the absorption and digestion of fats)

3) Except for the liver and few endocrine tissues (e.g adrenal gland), most cells cannot further
catabolize/modify cholesterol

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5
Q

Lipid Fundamentals?

A

1) Major circulating lipids are cholesterol and triglyceride

2) 70% of cholesterol is esterified
• ∴ Lipids are not water soluble -> once synthesized by liver or intestine, packaged into lipoproteins for transport and circulation

3) What are Lipoproteins? Macromolecular complexes
with an outer shell and inner core
• Outer shell: molecules that solubilize the Lipoprotein
(phospholipids, cholesterol, and apolipoproteins)
• Hydroxyl group of cholesterol and phosphate groups of phospholipids are oriented toward the outside
• Amphipathic

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6
Q

Apoproteins (Apolipoproteins)?

A

• Proteins that contribute structurally to the formation
of lipoproteins
• Assist in the solubilization of lipoprotein (amphipathic)
• Ligands for cell-surface receptors and enzymes
attached to endothelial and cell surfaces

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7
Q

What are the types of Lipoproteins?

A

1) Categorized based on hydrated densities determined from ultracentrifugation:
• Chylomicrons
• VLDL
• IDL
• LDL
• HDL (HDL2, HDL3)
• Lipoprotein (a) - abbreviated as Lp (a)
2) Different physical and chemical properties due to variation in lipid and apoprotein composition

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8
Q

Chylomicron – the overnight standing test?

A

1) Normal fasting plasma does not contain chylomicrons or remnant chylomicrons
2) When plasma contains chylomicrons, the chylomicrons will float to the top and form a creamy layer overnight at 4°C
• low density (<0.95 g/mL)
• Possible causes: mutations in LPL or apo-CII

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9
Q

Lipoprotein Metabolism - Exogenous Pathway: Function?

A

Absorption of dietary
lipids and as energy carriers (i.e. delivery of
triglycerides to liver and peripheral tissues)

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10
Q

Endogenous Pathway of Lipoprotein Metabolism?

A

1) Triglycerides consumed in the diet -> bile acids
help solubilize the triglyceride -> pancreatic lipase helps to break it down to monoglycerides + free glycerol
2) Intestinal epithelial cells resynthesize triglycerides
(from monoglycerides, glycerol and free fatty acids)
and package into chylomicron along with apo B-48
3) Intestinally derived chylomicrons enter the blood stream
4) As Triglycerides are cleaved from chylomicrons they are reduced in size and is now referred to as chylomicron remnant
5) Apo C-II activates LPL -> cleaves triglyceride on chylomicrons -> taken up by muscle and adipose tissue
• LPL = Lipoprotein Lipase (degrades circulating triglycerides in blood stream)
6) Remnants reach liver for further catabolism
7) The liver produces endogenous lipoproteins for delivery of lipids to peripheral cells
8) Liver can synthesize triglycerides from carbohydrates and fatty acids especially when chylomicron remnant uptake is insufficient
9) Endogenously made triglycerides and cholesterol are packaged along with apo B-100 into VLDL
10) VLDL sheds apo C-II and triglycerides -> IDL -> additional triglyceride removed + apo E -> LDL

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11
Q

Liver connects the Exogenous and endogenous pathway?

A

1) Lipolysis = cleavage of triglycerides via lipoprotein lipase
2) LCAT- lecithin:cholesterol acyltransferase;
• Converts cholesterol in extrahepatic tissue to CE
3) CETP - cholesteryl ester transfer protein
• Transports Cholesterol Ester from HDL to LDL of the endogenous pathway

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12
Q

LDL- Cholesterol?

A
  • Liver normally removes 2/3 of LDL via interaction through hepatic LDL - Receptor
  • When LDL concentration rise, LDL deposited into sub- endothelial, subintimal space
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13
Q

What happens in Familial hypercholesterolemia?

A

Accelerated deposition of cholesterol in the walls of

arteries.

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14
Q

Familial Hypercholesterolemia (FH)

A
  • Results from mutations in the LDL-Receptor
  • Heterozygous FH is the most common monogenic disorder (in 1/250 individuals)
  • Decreased LDL-Receptor functions impair the LDL clearance
  • [LDL] is increased
  • [VLDL] may also be increased
  • Initial screening involves Lab measurement of LDL
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15
Q

Lp(a) – another atherogenic LDL?

A

1) A modified form of LDL with apoprotein(a)
covalently bound to apo B
• disulfide bond between apoB-100 of the LDL moiety
and one of the kringle domains in apo(a)
2) Kringle Domains: Repeating subunits on apo(a)
3) Variation in size as a result of varying number of kringle domains
• Variation = genetic contribution
• Genetic risk factor for MI & aortic valve stenosis
• ∴Prothrombotic – promotes the formation of thrombus
– a blood clot inside the blood vessel

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16
Q

Major role of Lipid in Atherosclerotic

Cardiovascular Disease?

A

1) Screening for hyperlipidemia aids the prevention and management of CVD
2) Atherosclerosis: chronic process involving progressive buildup of plaque
• Atheroma (Plaque): lesions composed of Cholesterol, calcium and other substances in the blood that are vessel occluding
3) Coronary Artery Disease: Atherosclerosis that narrows the heart’s arteries and can lead to ACS
• Coronary artery: artery which surround the heart

17
Q

Should you Measure Lipids in Fasting-State?

A

1) Non-fasting lipid profiles is acceptable for screening
2) Given the global burden, screening is necessary to identify those in need of treatment risk assessment
• Treatment targets can be with non-HDL-C or Apo B, which is not altered after eating
• Total HDL-C is used in 10 year risk assessment (e.g FRS), and is not altered by fasting status
3) For patients with history of TG > 4.5 mmol/L, lipids and lipoproteins should be tested in fasting state

18
Q

Clinical Risk Factors for CHD?

A
  • Age
  • Gender (males at higher risk)
  • Race (African Americans, South Asian)
  • Cigarette Smoking
  • Hypertension
  • Family history
  • Obesity
  • Diabetes Mellitus
  • Sedentary lifestyle
19
Q

Framingham Risk Score Model? Estimation of 10-year Cardiovascular Disease (Risk)

A
1) Dependent on
• Patient’s age and History
• HDL
• Total Cholesterol
• Systolic blood pressure
• Smoker/diabetes

2) Risk Levels
• Low: FRS 0 – 9 %
• Intermediate: 10 – 19%
• High: ≥ 20%

20
Q

What is Acute Coronary

Syndrome?

A

Rapid reduction in blood flow in the artery when plaque stimulates formation of a thrombus

1) Lipid deposition -> disruption of the endothelium (or the intimal cells)

2) Disruption leads to an inflammatory response
- > monocytes migration into sub- endothelium -> monocytes differentiate into macrophages

3) Macrophages digest LDL to become foam cells. -> formation of fatty streaks.
4) Plaque rupture -> amplified inflammatory response and fibrin -> thrombus formation -> ACS

21
Q

What is Atherosclerosis?

A

An inflammatory disease:

Early Atheroma -> inflammatory response

22
Q

Are laboratory markers of inflammation useful in early prediction?

A

Laboratory marker for inflammation
C-Reactive Protein (CRP)
• Synthesized in the liver in response to acute inflammatory process
• Secreted in response to IL-6 by foam cells in vascular plaques
• Elevated CRP levels relate to an increased risk of mortality

23
Q

Does ACS lead to AMI?

A

**Check image

24
Q

What is MI?

A

is defined pathologically as myocardial cell death due to prolonged ischemia

25
Q

Criteria for myocardial injury?

A
  • Detection of an elevated cardiac Troponin (cTn) value above the 99th percentile URL
  • Injury considered acute if there is a rise and/or fall of cTn values
26
Q

Criteria for AMI (types 1, 2 and 3 MI)?

A

Acute myocardial injury + one of the following:
• Symptoms of myocardial ischaemia
• New ischemic ECG changes
• Development of pathological Q waves
• Imaging evidence
• Identification of a coronary thrombus by angiography or autopsy

27
Q

Cardiac Troponin?

A

1) Contractile proteins of the myofibril expressed almost exclusively in the heart
• Binds to tropomyosin and actin of the thin filament and regulates contraction
2) The troponins are a complex of three protein subunits:
• troponin C (the calcium-binding subunit)
• troponin I (ATPase inhibiting subunit)
• troponin T (the tropomyosin-binding subunit)
3) Biochemical measurements for AMI involve troponin I and T
4) Significant increases in troponin I and T do not to occur following injury to non-cardiac tissues

28
Q

Exercise Impact on Troponin?

A

Prolonged moderate intensity walking exercise significantly elevates cTnI-levels in asymptomatic subjects

29
Q

The Marker of Choice for AMI?

A

Troponin
- If a cTn assay is not available, the best alternative is CK-MB
- As with cTn, an increased CK-MB value is defined as a
measurement above the 99th percentile URL, which is
designated as the decision level for the diagnosis of MI

30
Q

Troponin in cardiotoxicity?

A

• Chemotherapy-induced cardiotoxicity needs to
be prevented in long-term cancer survivors including breast cancer patients
• Troponin Levels can predict chemotherapy induced cardiomyopathy
• Anthracyclines and trastuzumab increase the risk of heart failure (HF) and radiation increases the risk of ischemic heart disease and HF

31
Q

Heart Failure?

A

• Reduced systemic blood flow -> activation of the RAAS
• Chronic Stimulation of RAAS causes cardiac enlargement and remodeling -> Cardiomegaly
• Stretching and cardiomegaly stimulates release of Atrial
Natriuretic Peptides (ANP) and Brain Natriuretic Peptides (BNP)

32
Q

Natriuretic Peptides?

A

1) ANP: Highest tissue content in the atrium, stored in cytoplasmic granules
• Released following acute and transient volume changes
2) BNP: gene expression takes place in both atrial and ventricular myocytes
• HF mostly associated with impaired left ventricle function and volume overload
• Ventricular BNP gene expression increases drastically in cardiac disease
• Clinical Biomarker for HF

33
Q

BNP?

A

BNP originates from inactive pre-cursor protein pre-proBNP
1) Cleaved to yield proBNP (prohormone)
2) Cleaved by enzyme corin further to produce NT-proBNP and BNP
• BNP (active hormone)
• NT-proBNP (inactive peptide)