Lecture #13: Heart Failure Part 2

Heart failure treatment: Goal is to reduce/slow the disease progression by tackling the
underlying causes, co-morbidities, severity of condition, and age (transplant/LVAD)
- Complex and varied etiology of heart failure often prevents direct treatment.
- Instead, treatment is designed to slow disease progression and reduce
symptoms.
Cardiac glycosides: Primary role is sodium-potassium ATPase inhibitor that is present
on the cell membrane and maintains the gradient.
- Reminder: The gradient is more sodium outside the cell and more potassium
inside the cell.
o It pumps 3 sodium out and 2 potassium in.
- Glycosides are an aglycone ring with a sugar molecule; the sugar molecule
modifies pharmacokinetics.
o Digitalis is the oldest inotropic agent discovered in 1785.
- This increases the amount of sodium ions present within the cell. NCX will switch
to reverse mode to bring calcium in while bringing sodium out.
o This causes more uptake of calcium into the SR by SERCA which means
more calcium release upon depolarization.
o This increases the contractility of a depolarization.
- NaKATPase inhibited -> NCX switch -> More intracellular calcium/in SR ->
Stronger contractility.
- It results in rising diastolic pressure because the heart cannot relax fully/has
become stiff.
o This lowers the difference in pressure between the atria and the ventricles
while relaxed, preventing blood flow from the atria to the ventricles.
- There is also a concern that it could cause an arrhythmia because it increases
intracellular calcium.
- The solution to this problem is to use the correct dose at which force is increased
by relaxation is unaffected.
o If a person has normal serum potassium, 1-2 ng/mL of drug/blood.
o If the person is hypokalemic because of diuretics, then the dose should be
0.5-1 ng/mL.
- Risks of use in combination with its lack of strong benefits has led to a major
decrease in usage.
o It is still used occasionally because it may have some value in reducing
hospitalization.
Angiotensin inhibitors:
- Angiotensinogen becomes ANG I by renin, which then gets converted into ANG II
by ACE (angiotensin converting enzyme).
 o This pathway causes vasoconstriction, sodium retention, hypertrophy,
apoptosis, fibrosis.
- Kinogen gets converted into Bradykinin by Kallikrein. Bradykinin is a vasodilator,
antioxidant, anti-atherosclerotic, and antifibrotic.
o ACE also inactivates Bradykinin by turning it into inactive peptides.
- ACE inhibitors reduce the formation of ANG II and stop the degradation of
Bradykinin.
o This will reduce the effect of hypertrophy cardiomyopathy.
o Ramipril (ACE inhibitor) reduces the proportion of death from
cardiovascular disease over time.
ARNIs: Angiotensin receptor Neprilysin Inhibitors
- ACE2 eventually converts ANG II to ANG1-7 which is cardioprotective and
vasodilatory.
o This means that ACE inhibitors block the positive effects of ANG1-7
- Neprilysin also converts Bradykinin into inactive peptides and is not stopped by
ACE inhibition.
- Angiotensin receptor blockers/inhibitors will instead block ANG II from causing its
vasoconstrictor effects.
- Sacubitril inhibits neprilysin and valsartan inhibits the angiotensin receptor.
o This combination therapy showed significantly better than Enalapril (ACE
inhibitor).
SGLT2 Inhibitors: Normally used in diabetes.
- SGLT-2 is a cotransporter located in the S1 segment proximal tubule and is
responsible for reabsorbing glucose and sodium.
o It normally was used to treat diabetes by reducing glucose levels.
- It appears to have a positive effect for heart failure with no diabetes in reducing
hospitalization/complications.
- SGLT2 inhibitors cardioprotective effects were studied in HFpEF (altered diastole
because less relaxation).
o ROS were decreased in HFpEF after receiving Empagliflozin in an animal
model.
o Inflammation was also decreased as measured with TNF-alpha and IL-6.
o Phosphorylated (N2B) titin levels as an analogue for stiffness levels
showed that Empagliflozin decreased stiffness.
 When N2B is phosphorylated, the titin/muscle is less stiff.
o Muscle mechanics were also shown to be improved upon by SGLT2i;
force production was reduced which would show that relaxation is
happening.