Heart Failure 1

myths and misinformation about alcohol and heart health

• J-shaped curve - low levels of consumption healthy

• likely the product of higher income, more activity & healthier lifestyle

what is the safe level of alcohol consumption

• cardiomyopathy risk rises at >80g/day over 5 years

• risk for women appears to rise at 50% of the level for males

• many confounding variables like diet, exercise, etc

• other risks (cancer, accidents, cirrhosis, etc)

ethanol is metabolized by CYP2E1 to acetaldehyde

acetaldehyde increases circulating acetaldehyde

ALDH2 metabolizes acetaldehyde to acetate

excess acetate is transferred to lipogenesis and becomes adipose tissue (increases CVD risk)

what becomes the rate limiting step when you consume too much

acetaldehyde → enters blood → is a toxin → causes hangover → acute acetaldehyde poisoning

what step backs up when you have too much to drink

acetate → this step backs up because too much NADH

effects of chronic high acetaldehyde

DNA damage → increased apoptosis

• w/ loss of cardiac myocytes, you lose contractility

impaired mitochondrial function

• disrupts energy proteins

• increased oxidative stress

• release of proapoptotic factors (e.g. cytochrome C)

• mtDNA damage (decreased mt biogenesis)

cardiomyocyte cell death, fibrosis

• loss cardiac myocytes and replace with fibrosis… stiffer, acts as a load, harder to contract

endothelial dysfunction

• ROS-driven apoptosis

• decreased NO production

• vasodiltion

• increased shear stress

DNA damage causes what

• increased apoptosis

• ventricular dilation

with loss of cardiac myocytes, you lose contractility

impaired mitochondrial function causes what

• apoptosis

• decreased contractility

• decreased ATP production

disrupts energy proteins

higher oxidative stress

release of proapoptotic factors

mtDNA damage

cardiomyocyte death causes what

• decreased contractility

lose cardiac myocytes and replace with fibrosis

stiffer, acts as a load, harder to contract

endothelial dysfunction leads to what

• increased apoptosis

ROS-driven apoptosis

decreased NO production

decreased vasodilation

increased shear stress

oxidized myofilaments effect

decreased contractility

oxidized RyR effect

Arrhythmias (AFib)

• SR Ca2+ leak

quebec beer drinkers

almost 50 pts with acute sudden onset DCM

all alcoholics

stopped drinking and DCM regressed

did not appear to be alcoholic cardiomyopathy

what caused the cardiomyopathy in the Quebec alcoholics

quebec pts drank Dow beer

cobalt was in the beers to increase foam stability

cobalt created an acute and transient poison that caused DCM

how did cobalt cause cardiomyopathy

cobalt competes with magnesium and calcium (binds to binding sites)

disrupts enzymes for metabolism

effects not often seen with cobalt alone → require other issues like thiamine deficiency and alcoholism

• alcoholics often thiamine deficient (poor diet and stomach damage limits uptake)

can you use alcohol to an advantage

yes, for hypertrophic cardiomyopathy

• catheter inserted in femoral → guided to coronary artery… balloon inflated to block and alcohol is released… kills part of your heart you dont want (i.e. enlarged part) + it decreases, yes, damaged, but now blood can flow through aorta

Takotsubo Cardiomyopathy

a stress induced, acute cardiac syndrome

stress is often emotional in origin

much more prevalent in women

apical akinesis is typical (apical region doesn’t move)

is takotsubo cardiomyopathy always associated with negative emotions

no, sometimes it can be triggered by a strong positive emotion

why does takotsubo cardiomyopathy occur

• catecholamine surge targets heart (high local catecholamines)

• B1 adrenergic receptors stimulated to increase contractility

• B2 adrenergic receptors stimulated to decrease contractility

• high concentration on B2 adrenergic receptors in apex

• may allow for conditional depression of myocardium

there is a high concentration of which type of receptor in the apex

high concentration of B2 receptors in the apex

more even distribution of B1 and B2 in the basal region

what leads to apical region akinesis

the higher concentration of B2 receptors in the apex, leads to more of an inhibitory drive in the apex of the heart\

eventually, apical region will be depressed, leading to regional akinesis

what are B1 adrenergic receptors preferentially activated by

NE>E

40% more SNS fibers in basal area

neuro-NE preferentially stimulates basal contractilty

*Acute

B2-adrenergic receptors preferentially activated by what

E>NE

• circulating E preferentially affects apical LV

• chronic stimulation induces ‘stimulus trafficking’

• as SNS fades, sustained drive comes from epinepherine

*Chronic

when active B1 and B2 usually both increase contractility, but in this case,

the B2s undergo this switching wheret he Gs is switched to Gi and now there is an active inhibition ny targeting myofilaments to reduce their contraction, targeting Ca2+ so it doesnt enter as much

Gs activation does what

increases PKA activity

PKA phosphorylates B2-adrenergic receptor and couples to Gi

are B blockers the solution if B-adrenergic receptor overactivation is the problem

no, because if you block B1 + B2, you are removing inhibition (B1), but also removing stimulus (B2)

inconsistency in studies due to the type of B-blocker used

are they specific to B2 or not?

why else may B-blockers might not work

because there is an additional pathway,

SNS terminals release NE

high stimulation also release NPY (neuropeptide - Y)

high circulating levels of NPY (adrenals)

NPY activates PNS terminals to release Ach

Ach depresses contraction (binds to muscarinic receptors)

YR2 expression in apex (apical inhibition)

adrenal glands are still stimulated hours later - still releasing NPY - suppress contractility through muscariniwhatc receptors

what happens with takotsubo when you exercise

decreased phosphoreactive levels

thus, small decrease in energy supply (ATP)

when you exercise + place demand, pushes over edge + develop MI or HF

what is the rate of mortality 5 years after like

similar to that of MI

is takotsubo benign

mostly considered benign because few die and many fully recover

what is the magic number it takotsubo

10 days → if at 10 days HF is normal you will likely recover

if at 10 days not normal, may not fully recover