1. Objectives for Lecture on Pharmacotherapy of Congestive Heart Failure (CHF)
By the end of this class students will be able to:
Distinguish between systolic and diastolic CHF based on their pathology, pathophysiology, and epidemiology
Use this diagnosis to develop a treatment plan
Describe the compensatory changes in the heart that lead to CHF over the long term
Name the major drugs and drug classes used to treat systolic and diastolic CHF
Describe the actions in the body of each drug, explain the mechanism by which it produces those actions, and explain why the drug is useful in treating that specific form of CHF

2. Congestive Heart Failure
Def: The pathophysiologic state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with tissue requirements or to be able to do so only from an elevated filling pressure.
Symptoms: Breathlessness and fatigue, increased resting heart rate, pulmonary edema, generalized edema, reduced organ perfusion

3. Congestive Heart Failure and Stroke Volume
SV = Volume of Blood in the Ventricle X LVEF
Systolic CHF -  Ventricular Volume,  LVEF
Diastolic CHF -  Ventricular Filling (low LVEDV, especially during exercise), normal LVEF
These forms of congestive heart failure may, at least in some instances, represent two stages of the same disorder, with diastolic CHF as the early stage and systolic CHF as the late stage

4. Systolic Congestive Heart Failure

5. Systolic Congestive Heart Failure
Associated with ischemic heart disease, more rapid progression to this stage in persons with sodium-dependent hypertension even in the absence of overt ischemic heart disease
Dilated, weak ventricles
Reduced left ventricular ejection fraction (<55%)
Poor prognosis

6. Approaches to Pharmacotherapy of Systolic Congestive Heart Failure
Must address both components of the condition: congestion (pulmonary edema) and heart failure
Traditional: Normalize the physiological variables
Inotropy: Digoxin
Preload: Diuretic
Afterload: Vasodilator
Contemporary: Base pharmacotherapy on an understanding of the underlying molecular and cellular pathophysiology

7. Compensatory Responses Baroreceptor Reflex
Reduced sensory input to the vasomotor center
Increased sympathetic outflow, reduced parasympathetic outflow
Short term: Improved tissue perfusion due to increased heart rate, myocardial contractility, blood pressure
Long term: Cardiac damage due to increased afterload, reduced ejection fraction, reduced cardiac output, reduced renal perfusion. Excessive exposure to catecholamines contributes to the pathologic remodeling of the heart and vasculature, especially hypertrophy and apoptosis of cardiomyocytes. Increased heart rate in itself is a known risk factor for development of cardiovascular disease and worse outcomes from cardiovascular disease.

8. Compensatory Responses Angiotensin II/Aldosterone
Increased production of angiotensin II and aldosterone
Short term: Improved tissue perfusion due to maintenance of blood volume and increased blood pressure
Long term: Edema, increased preload, increased afterload. Angiotensin II, aldosterone, and excess Na+ largely drive the endothelial damage and fibrosis in the heart and arteries. Angiotensin II contributes to the myocyte hypertrophy and apoptosis.

9. Compensatory Responses Myocardial Anatomy
Slow structural changes (“remodeling”)
Proliferation of connective tissue, hypertrophy followed by apoptosis of cardiomyocytes
Short term: Maintenance of cardiac performance in the face of pressure or volume overload
Long term: Loss of functional tissue due to apoptosis and replacement by connective tissue reduces contractility. Weakened ventricle with death of myocytes and ischemia. Increased myocardial volume and mass, along with a net loss of myocytes, are the hallmark of myocardial remodeling in systolic congestive heart failure.

10. Compensatory Responses Adrenergic Signal Transduction
Attenuation due to chronically enhanced sympathetic activity and angiotensin II production
Reduced inotropy
50-60% reduction in b1 receptors with lesser reduction in b2 receptors
Increased Gi
Uncoupling of b receptors from Gs

11. Beta Receptors and Catecholamine Effects on Cardiac Remodeling
Gs-dependent signalling through β1 receptors is a cause of cardiomyocyte hypertrophy and apoptosis.
G protein-independent β1 signalling via the beta arrestin pathway is cardioprotective.
Abnormal coupling between β2 receptors and Gi is also cardioprotective.

12. Outline of Pharmacotherapy Systolic CHF
Symptomatic
Diuretic
Digoxin
Vasodilator (included in other groups)
Anti-Remodeling
ACE inhibitor/ARB
β blocker
Aldosterone antagonist
Isosorbide dinitrate/hydralazine
HCN4 inhibitor

13. Digoxin
A positive inotrope - increases the force of contraction of the heart for any values of preload and afterload
One of the cardiac glycosides
Convenient pharmacokinetics
High oral bioavailability, can be given iv
Easily monitored
Improves morbidity, but not mortality, in persons with systolic CHF
Not useful in diastolic CHF

15. Calcium Dynamics in Cardiac Myocytes
Contraction - Calcium Entry
Voltage-dependent L-type calcium channels
Calcium-induced calcium release from sarcoplasmic reticulum
Sodium-calcium exchange
Relaxation
Sarcoplasmic reticulum calcium ATPase
Plasma membrane calcium ATPase

17. Digoxin
Inhibition of sodium-potassium ATPase, reducing the sodium gradient across the plasma membrane
Increased calcium influx through sodium-calcium exchange
Reduced calcium extrusion through sodium-calcium exchange
Enhanced calcium-induced calcium release
Greater calcium accumulation by sarcoplasmic reticulum for subsequent calcium-induced calcium release

18. Digoxin Overall Effects
Greater delivery of calcium to the contractile apparatus
Increased contractility
For each 1 mM rise in intracellular sodium, contractility increases by as much as 20-30%!
Increased left ventricular ejection fraction
Reduces oxygen consumption for a given amount of cardiac work

21. Digoxin-Induced Arrhythmias
Tachyarrhythmias
Triggered activity from calcium overload – DAD. Potentiated by hypokalemia.
Bradyarrhythmias
Caused by stimulation of activity in the vagus (parasympathetic) nerve
Due to digoxin’s low therapeutic index, current practice is to reserve its use for patients in systolic failure who have a very low LVEF (<30%) and who do not improve sufficiently with anti-remodeling therapy + diuretic.

22. Diuretics
Used to relieve congestion (pulmonary and generalized edema), reduce preload and, to some extent, afterload
Mild congestive heart failure - Thiazide
Moderate-to-severe congestive heart failure - Furosemide
Severe congestive heart failure - Thiazide + Furosemide
Combination with ACE Inhibitor/ARB
Little concern with K+ loss
Potentially large reduction in blood pressure

23. ACE Inhibitors
Improve morbidity and mortality when combined with diuretic or digoxin and a diuretic. More effective than other vasodilators, presumably due to their anti-remodeling action.
Important mechanisms
Increased excretion of Na+ and water
*Reduced synthesis of angiotensin II
Improved renal blood flow
Reduced sympathetic activity
*Reversal of ventricular remodeling

24. Toxicity of ACE Inhibitors
Intractable dry cough
Angioedema (<1%, seen twice as often in black patients)
Teratogenesis
Hyperkalemia (unlikely with diuretic, but requires monitoring)
Hypotension, especially when combined with a diuretic
Alternative in case of troublesome cough or angioedema is AT1 receptor antagonist (ARB)

25. AT1 Receptor Antagonists (ARBs)
Can be used in place of ACE inhibitor or as alternative to ACE inhibitor when ACE inhibitor produces unacceptable side effects of dry cough or angioedema
Appear to be therapeutically equivalent to ACE inhibitors
Not beneficial if ACE inhibitor is already part of the therapy and vice versa

26. Beta Blockers
Low doses of β blocker upregulate cardiac 1 receptors, thus restoring normal sympathetically-mediated inotropy in systolic congestive heart failure
Original rationale for their use, now believed much less important
Contribute importantly to reversal of cardiac remodeling
Important reason for their use; oppose cardiomyocyte hypertrophy and subsequent apoptosis
Reduce heart rate
Considered their most beneficial action
Most persons with systolic CHF cannot tolerate doses required to reduce heart rate optimally due to β blocker-induced reduction in LVEF
Improve morbidity and mortality
Much less risky in systolic congestive heart failure than once believed

27. Carvedilol α1β antagonist
Most studies indicate superiority when compared with metoprolol or nebivolol for systolic CHF.
High affinity binding to the β1 receptors produces unusually prolonged block.
Arterial vasodilation due to α1 antagonism triggers reflex sympathetic discharge to the heart, minimizing cardiodepression. This allows a higher dose to be used, increasing the anti-remodeling action.
Intrinsic anti-oxidant activity reduces inflammation, endothelial damage, fibrosis, and cardiomyocyte apoptosis.
Stimulation of β1 receptor signalling through the beta arrestin pathway protects against myocyte apoptosis.

28. Aldosterone Antagonists
Used for their ability to antagonize aldosterone, not for their diuretic action
High cardiac aldosterone levels in persons with congestive heart failure, because:
ACE inhibitors do not completely block adrenal secretion
Inactivation by liver is reduced to 25-50% of normal
Heart itself produces aldosterone
Aldosterone plays a key role in ventricular (and arterial) remodeling, particularly in the development of fibrosis and endothelial damage

29. Aldosterone and Congestive Heart Failure

30. Aldosterone Antagonists
Aldosterone antagonists improve morbidity and mortality at all stages of CHF
Hyperkalemia usually not clinically significant when combined with ACE inhibitor/ARB and diuretic, but serum K+ must be monitored
Standard antagonist is spironolactone
Also weak antagonist of androgen receptor (gynecomastia, sexual dysfunction), weak agonist of progesterone receptor (menstrual irregularities)
Superior aldosterone receptor antagonist: eplerenone. More receptor specific; much lower incidence of side effects. Improves outcome after MI with low LVEF.

31. Isosorbide Dinitrate + Hydralazine
Increase NO levels in tissue. Isosorbide dinitrate serves as a source of NO in vascular smooth muscle. Hydralazine inhibits the production of ROS that inactivate NO. This is the primary mechanism.
NO is not only a vasodilator, it also inhibits cardiovascular remodeling.

32. Isosorbide Dinitrate + Hydralazine
Confirmed to reduce morbidity and mortality only in the African-American population. Appears to be more efficacious in African-Americans than ACE inhibitor/ARB.
The first drug (Bidil®, the combination) approved by the FDA for use in patients from one ethnic group. Cheaper to use the two drugs individually.
May indicate ethnic differences in the etiology of CVD.

33. Elevated Heart Rate Impairs Morbidity and Mortality in CHF

34. Adverse Effects of Elevated Heart Rate
Increased oxidative stress
Endothelial dysfunction
Acceleration of atherogenesis
Exposure to higher catecholamine concentrations
Every increment of 10/min above baseline is associated with a sequential increase in cardiovascular death

35. Reducing Heart Rate in Systolic CHF
Much of the benefit from a beta blocker is attributable to reduced heart rate. However, most patients cannot tolerate enough beta blocker to reduce heart rate by 10/min.
Verapamil and diltiazem reduce heart rate, but are contraindicated in systolic CHF. Any benefit is outweighed by reduced LVEF.
Digoxin reduces heart rate, but toxicity limits its use.
What about ivabradine?

36. Ivabradine Improves Quality of Life in Systolic CHF

37. Ivabradine
HCN4 is the pacemaker channel in the SA node. Ivabradine changes the voltage-dependence of opening, such that greater hyperpolarization is required. The result is slower heart rate.
Ivabradine reduces heart rate without changing cardiac contractility, LVEF, conduction through the AV node, or blood pressure
Ivabradine improves morbidity and mortality. Adding ivabradine to standard therapy to achieve a heart rate reduction of 10/min reduced the risk of hospital admission or death by 18% in the SHIFT trial.

38. BNP
B-type (Brain) natriuretic peptide (BNP); produced by cardiac ventricular tissue and secreted into the circulation
Plasma concentrations are elevated in congestive heart failure due to ventricular stress, and the concentration found by laboratory assay can be used to assess the severity of tissue underperfusion.
Vasodilates by increasing cGMP in vascular smooth muscle, suppresses renin-angiotensin system, natriuresis, diuresis

39. Neprilysin
A neutral endopeptidase that degrades several bioactive peptides including BNP, ANP, bradykinin, and beta amyloid.
Sacubitril is a prodrug converted to the active sacubitrilat by esterases. Sacubitrilat inhibits neprilysin, thus raising the plasma concentration of all its substrate peptides.
The resulting vasodilation, diuresis, and natriuresis is attributable, in large part, to the increase in circulating BNP.

40. Entresto®
A 1:1 combination of sacubitril and valsartan, a commonly-used ARB
In the PARADIGM-HF trial Entresto reduced cardiovascular mortality and hospitalizations for acute decompensated heart failure by ~20% and reduced all-cause mortality by 16%. It was significantly more beneficial than the ACE inhibitor enalapril.
Gained FDA approval in 2015 as an alternative to ACE inhibitor/ARB.
It is not clear how much of the benefit was attributable to sacubitril compared with valsartan.
Cough and/or angioedema developed in a few patients, possibly due to the increase in bradykinin. Increased levels of other peptides normally degraded by neprilysin might also produce adverse effects.

41. Entresto (formerly LCZ696) Reduced Morbidity/Mortality Better Than Enalapril

42. Treatment of Choice for Acute Therapy of Systolic and Diastolic CHF
Loop Diuretic + Nitroglycerin + Oxygen

43. Treatment of Choice for Chronic Therapy of Systolic CHF
Diuretic: thiazide diuretic, loop diuretic, or both, depending on severity of congestion
Anti-Remodeling Therapy: ACE inhibitor (or ARB or Entresto) + β blocker + aldosterone antagonist if serum K+ can be monitored regularly. Consider adding ivabradine, if β blocker ± digoxin does not reduce heart rate to 70-75/min.
Digoxin: add if LVEF remains low (<30%) or declines despite optimal use of diuretic + anti-remodeling therapy.
Hydralazine + Isosorbide Dinitrate: consider for African-Americans in addition to or as a substitute for ACE inhibitor/ARB.

44. Diastolic Congestive Heart Failure

45. Diastolic Congestive Heart Failure
Associated with long-standing hypertension
Thick-walled, poorly-compliant ventricles
Impaired ventricular filling, but normal or elevated LVEF; failure of LVEDV to increase appropriately with exercise
Increasing proportion of persons with congestive heart failure as the population ages
Prognosis similar to that of patients with systolic CHF

46. Diastolic Congestive Heart Failure
The same pathophysiologic processes that lead to reduced cardiac output in systolic congestive heart failure also occur in diastolic congestive heart failure. Cardiac myocytes hypertrophy and connective tissue proliferates, reducing ventricular compliance.
This takes place in response to a different set of hemodynamic and circulatory factors. Cardiac myocytes hypertrophy, but do not undergo apoptosis. The strength of contraction is maintained or enhanced.
In diastolic dysfunction, the major problem is reduction in ventricular filling. The result is low cardiac output in the face of a normal ejection fraction.
Unlike systolic CHF, role of chemical mediators is unclear. Blocking their action does not extend the lifespan.

47. Beta Blockers
In diastolic CHF, β blocker prolongs diastole, facilitates diastolic relaxation, and lowers diastolic filling pressure. These actions allow more time for the ventricle to fill with blood and reduces wall stiffness. The effect is to increase LVEDV.
Unlike systolic CHF, β blocker does not increase the lifespan.
No evidence that any β blocker is superior to any other.

48. Calcium Channel Blockers
Verapamil and Diltiazem only
Action similar to beta blocker. Facilitate diastolic relaxation, lower diastolic filling pressure, prolong diastole. The effect is to increase LVEDV. Also reduce afterload.
Alternative for patients who cannot tolerate a beta blocker.

49. ACE Inhibitors/ARBs
Used in diastolic CHF to reduce afterload through arterial vasodilation.
Unlike systolic CHF, these drugs do not increase the lifespan.

50. Treatment of Choice for Chronic Therapy of Diastolic CHF
Diastolic congestive heart failure is treated symptomatically.
Diuretic: thiazide diuretic, loop diuretic, or both, depending on severity of congestion
ACE inhibitor (or ARB) + β blocker, verapamil, or diltiazem