L17: part 2

Question 1

What are NAD+ precursors?

Answer 1

 Co-enzyme, exists in all living cells
 Important for energy production
 Two forms: NAD+ (oxidized, accepts electrons) and NADH (Reduced, donates electrons).

Question 2

Role of NAD in cardiac energy metabolism: essential coenzyme?

Answer 2

Glycolysis, beta-ox and TCA cycle all need NAD+.
NADH is especially needed in oxidative phosphorylation.

Question 3

ATP, calcium, NAD+, mito’s…. all is declined during ageing. shocking

Answer 3

ok

Question 4

Is there a way to supplement NAD+? With what?

Answer 4

Yes, with

1. NAM (Nicotinamide)
2. NA (Nicotic acid) Ken dit Plaatje uit je hoofd!!
3. NR (Nicotinamide riboside)

These are all vit B3!

Question 5

How does supplementing nicotinamide work for improving heart?

Answer 5

 Nicotinamide (NAM) supplementation improves diastolic dysfunction and HFpEF by
1. increasing energy metabolism
2. decreasing acetylation

Question 6

What is atrial fibrillation (AF)? Is it bad? Is it common?

Answer 6

• rapid + irregular activation of the atria (400-600bpm)
• progressive disease without curative therapy
• most common arrythmea

Question 7

In AF (atrial fibrillation), does the heart actually beat 400-600 times?

Answer 7

Not all waves can reach the ventricles. Therefore, they don’t beat as fast as 400-600 bpm. More like 2x higher (120-200).

Question 8

Risk factors of AF?

Answer 8

• Ageing
• Obesity
• Diabetes
• Hypertension
• Vulvar heart disease
• ….

Question 9

Consequences of AF?

Answer 9

• Stroke
• Heart failure
• Death

Question 10

AF classification?

Answer 10

Paroxysmal: <1 week
Persistent: >1 week
Long standing persistent: > 12 months
Permanent

Question 11

What do all AF treatments have in common?

Answer 11

target the symptoms.

Question 12

What is the underlying cause for AF?

Answer 12

atrial remodeling.
This is the pathological changes of the atria

Reason for progressiveness.

Question 13

What three types of atrial remodeling are there?

Answer 13

Electrical: e.g. reduced calcium amplitude
Metabolic: e.g. mito dysf, NAD metabolism.
Structural: e.g. degration contractile proteins

First, within couple of days: electrical remodelling. Change in action potential.
Metabolic remodeling in the middle, structural remodeling happening later

Question 14

Metabolic remodeling: how come?

Answer 14

AF: energy demand is higher, bc of high contraction rate, than the supply. Energy deficit.
Over time, this causes mitochondrial damage. = metabolic remodeling

Question 15

Major roles of NAD(H) in cellular physiology:

Answer 15

1. As co-enzyme (energy production)
2. As co-substrate (cellular signalling).

Question 16

NAD+ declines with ageing. Shocker. But why?

Answer 16

due to increased consumption. Production of NAD+ does NOT change.

Question 17

Enzyme often involved in AF = PARP1 enzyme. explain.

Answer 17

More PAR = more activation of PARP1 enzyme = more NAD+ depletion

PARP1 is activated during DNA damage, over-activation =DNA depletion + cell death

Question 18

 In AF: significantly high PAR (indicating PARP activity), leading to much NAD+ depletion.

Answer 18

ok

Question 19

How to prevent loss of NAD+ in the cells? Two ways. Which one better?

Answer 19

 PARP inhibitor: prevents loss of NAD+ in the cells. Or, supply with NAD+

• NAD+: vit B3 precursor is a natural product, safer.
• Too much inhibition of PARP1 might not be good for other cells, other than the heart.

Question 20

Pipeline for developing new treatment for AF?

Answer 20

invitro cellular
in vitro drosophila
in vitro mammalian
human clinical trials