Objectives for Lecture on Pharmacotherapy of Congestive Heart

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

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

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

Systolic Congestive Heart Failure

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

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

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.

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.

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.

Compensatory Responses Adrenergic Signal Transduction • Attenuation due to chronically enhanced sympathetic activity and angiotensin II production • Reduced inotropy – 50 -60% reduction in 1 receptors with lesser reduction in 2 receptors – Increased Gi – Uncoupling of receptors from Gs

Beta Receptors and Catecholamine Effects on Cardiac Remodeling • Gs-dependent signalling through β 1 receptors is a cause of cardiomyocyte hypertrophy and apoptosis. • G protein-independent β 1 signalling via the beta arrestin pathway is cardioprotective. • Abnormal coupling between β 2 receptors and Gi is also cardioprotective.

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 HCN 4 inhibitor

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

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 – Sodium-calcium exchange

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

Digoxin • Overall Effects – Greater delivery of calcium to the contractile apparatus – Increased contractility – For each 1 m. M 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

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.

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

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

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 AT 1 receptor antagonist (ARB)

AT 1 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 therapy and vice versa

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

Carvedilol • α 1β antagonist • Most studies indicate superiority when compared with metoprolol or nebivolol for systolic CHF. • High affinity binding to the β 1 receptors produces unusually prolonged block. • Arterial vasodilation due to α 1 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 β 1 receptor signalling through the beta arrestin pathway protects against myocyte apoptosis.

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

Aldosterone and Congestive Heart Failure

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.

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.

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.

Elevated Heart Rate Impairs Morbidity and Mortality in CHF

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

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 use. • What about ivabradine?

Ivabradine Improves Quality of Life in Systolic CHF

Ivabradine • HCN 4 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.

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 c. GMP in vascular smooth muscle, suppresses renin-angiotensin system, natriuresis, diuresis

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.

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.

Entresto (formerly LCZ 696) Reduced Morbidity/Mortality Better Than Enalapril

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

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.

Diastolic Congestive Heart Failure

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

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.

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.

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.

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

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