Heart Failure

Question 1

Heart failure definition

Answer 1

the heart is unable to pump blood at a rate with the requirement of the body’s tissues or can do so only at elevated filling pressure

HFrEF (systolic heart failure)
HFpEF (diastolic heart failure)

Question 2

HFrEF

Answer 2

HFrEF reduced ejection fraction (systolic heart failure) - the heart pushes less blood the normal -> increased HR and contractility

Question 3

HFpEF

Answer 3

HFpEF perfused ejection fraction (diastolic heart failure) - the pushes out normally, but there is not enough filling volume in the ventricle

Question 4

Which type of “load” is affected by HFeEF?

Answer 4

Afterload, the heart can’t overcome the pressure present in the aorta -> reduced cardiac output

Question 5

Which type of “load” is affected by HFpEF?

Answer 5

Preload, not enough ventricular filling during the diastolic phase
ejection fraction is normal

Question 6

Right side of the heart fails

Answer 6

-not enough blood flow to the lungs
-blood backs up on the systemic venous side
-edema and ascites (fluid in the abdomen) and lower

Question 7

Left side of the heart fails

Answer 7

-Insufficient blood flow to the systemic circulation
-Fluid backs up in the pulmonary circulation
-Pulmonary edema (cough, dyspnea, pulmonary effusion)

Question 8

Congestion heart failure

Answer 8

-old term
-general heart failure
-left-sided HF is more common
-pulmonary edema due to “pulmonary congestion”

Question 9

Frank Starling Curve

Answer 9

Plot between Stroke volume (amount of blood pumped out from both ventricles during systolic phase
and end-diastolic volume - the volume of blood just before the blood gets pumped out

-> in HF the Frank-Starling curve for contractility falls

Question 10

Causes of HF

Answer 10

-Myocardial infarction, or heart attack: interruption of blood supply -> a portion of the heart muscle dies

-Chronic hypertension: the heart has to work hard against the pressure (afterload is harder)

-Leaky mitral valve: some blood is leaking back into the left ventricle -> more pump work for the heart

-Aortic valve stenosis: aortic valve doesn’t open fully -> more work

-heart tissue got stiff -> preventing normal filling (diastolic reduction)
-others, long-term oxidative stress or genetic cardiomyopathy

Question 11

What is aortic compliance?

Answer 11

The stretching of the aorta when blood gets pumped out

-Compliance = delta V / delta P

Question 12

What affects aortic compliance?

Answer 12

-Arteriosclerosis (artery hardening)
-Age

Question 13

Consequence of CO falling

Answer 13

-Sympathetic outflow
-> increase in ionotropy and chronotropy (HR)
-> Arterial and venous constriction

-activation of RAAS bc renal blood flow and GFR is reduced

Question 14

Law of Laplace

Answer 14

activated when the heart muscles grow too much
T = P * r
Tension, pressure, radius

as the radius increases, the tension in the wall of the heart increases -> the heart works less efficiently (Wall stress)

-> tissue damage -> tissue fibrosis builds up

Question 15

How does Angiotensin II react to reduced CO due to heart failure?

Answer 15

vasoconstriction of the arteriole -> increases Afterload

-vasoconstriction of the venous -> increases Preload

-it also stimulates remodeling of the heart (negatively, the heart gets bigger?) and activates sympathetic NS

-it tries to make the heart work harder -> but the heart can’t

Question 16

Drugs to treat HF

Answer 16

-ACEi, ARBs
-ß-blockers
-Diuretics, CC-blockers
-MRAs
-SGLT2
-Neprilysin inhibitors
-Ionotropic agents
-Nitrates

Question 17

Drug to treat pulmonary HTN

Answer 17

-Guanylate cyclase activators (riociguat, vericiguat)
-PDE5 inhibitors

Question 18

Physiology muscle relaxation

Answer 18

GTP is converted to cGMP by Guanylate cyclase (sGC or pGC)

cGMP activates PKG (protein kinase G) -> PKG deactivates MLCK and activates MLCP -> smooth muscle RELAXATION

cGMP is broken down PDE5

Question 19

Drugs causing muscle RELAXATION

Answer 19

CC-blockers: Ca activates MLCK -> low Ca2+ means less contraction

-Nitrates generate nitric oxide -> NO activates sGC -> conversion of GTP to cGMP -> cGMP activates PKG -> less contraction, more RELAXATION

-Guanylate cyclase activators (riociguat, vericiguat) increase the conversion from GTP to cGMP -> more PKG -> less contraction, more RELAXATION

-cGMP is broken down by PDE5 -> PDE5 inhibitor keep cGMP levels high -> less contraction, more RELAXATION

Question 20

MOA of MRAs

Answer 20

-prevents Aldosterone from binding to its receptors
-reduces Na+/H2O reabsorption
->reduces body fluid volume
->reduces venous return
->eases the load on the heart
->reduces pathological remodeling

Question 21

What are aldosterone-induced proteins?

Answer 21

-aldosterone binds to an intracellular receptor (in the cytosol) and forms a complex that activates transcription in the nucleus

-as a result, AIP is produced with a variety of effects, mostly to increase Na+ and water reabsorption -> increase in BP

Question 22

MRA drugs

Answer 22

-Spironolactone (not entirely specific for aldosterone, but also other steroid receptors like progesterone and androgen)

->Gynecomastia (breast growth in men)
->Dysmenorrhea (irregularities in menstruation)

-Eplerenone (more specific to mineralocorticoid receptors (MRA) -> fewer side effects

-both are K+ sparing: can cause hyperkalemia

Question 23

How to dose ß-blockers in HF

Answer 23

-HF is an ionotropic disease and ß-blockers are negatively ionotropic

-but they have been shown to work in HF, bc they reduce the work of the heart and promote healing of the tissue (from negative remodeling) and reverse fibrosis!

Question 24

How to dose ß-blockers in HF

Answer 24

-Carvedilol (non-selective), Bisoprolol, Metoprolol, Nebivolol

-start LOW and go SLOW: double the dose every 4 weeks, giving the heart the time to adjust

Question 25

Which drug promotes NO-mediated Vasodilation

Answer 25

Nebivolol (ß1-selective)

Question 26

Where is ANP produced?
What is its effect?

Answer 26

Atrium of the heart (when the atria stretches)

ANP = atrial (heart) natriuretic (Na, in the urine -> urinate Na+) peptide

Question 27

Where is BNP produced?

Answer 27

Ventricles of the heart (when the ventricles stretch)

Question 28

Effects of ANP and BNP

Answer 28

-antoganize Angiotensin II
-goes to the kidney and promotes Na+ excretion into the tubules (urine) -> diuretic, lowers BP

Question 29

How do Neprilysin inhibitors work?

Answer 29

-Neprilysin breaks down ANP and BNP
-inhibition Neprilysin results in greater levels of ANP and BNP -> more Na and water excretion in the urine (diuretic effect)

Question 30

What causes stretching in the atria and ventricles?

Answer 30

Venous return is too big -> stretching of the ventricles
Q: Why would the venous return be too big?

Ventricular output is too low -> more blood remains in the ventricular -> causing stretch

Question 31

Neprilysin inhibitor drug

Answer 31

Sacubitril in combination with Valsartan (ARB) -> Entresto
-increases levels of ANP and BNP
-has shown to work better in HFrEF (than in HFpEF)