Congestive Heart Failure

Vasodilators

❖ Theory for the use of vasodilators in CHF ➢ By decreasing afterload and decreasing preload we can improve symptoms with little effects on CO, BP, or HR

Causes of CHF: Two broad classes

1. Damage to heart 2. Excess Work

Major Treatments of CHF

1. Digitalis and allied cardiac glycosides 2. ACE Inhibitors and A-II receptor antagonists 3. Other vasodilators 4. β-adrenoceptor antagonists 5. Aldosterone antagonists 6. Diuretics 7. Non-cardiac glycoside inotropic agents 8. Other drugs and developments

Digitalis and allied cardiac glycosides: Factors which will influence likelihood of toxicity

1. Renal or hepatic function 2. Serum K, Ca, and Mg levels -- (Mg is a co-factor for Na/K ATPase) 3. Cardiac ischemia, electrolyte anomalies, existing degree of myocardial damage → any arrythmogenic stimuli 4. Sensitivity to digitalis increases with age

β-Blockers - Possible MOAs: Two issues with all of the possibilities

1. Why would these reasons not be a "class" effect of all β-blockers 2. There is a poor temporal correlation with clinical improvements for all MOAs suggested ➢ All the things mentioned happen rather quickly, but it takes a person 3 months to get better when using β-blockers

The heart should cover no more than _____ of the cavity.

1/3 ➢ Note that in the picture, it is covering well over half

Angiotensin II effects

Almost everything that is mediated through AT₁ receptor is negative

In the 2-state model of receptor theory: A. An antagonist can block the effect of an inverse agonist B. Agonists have a higher affinity for the inactive state (R) C. Inverse agonists have a higher affinity for the active state (R*) D. Antagonists shift the equilibrium towards R*

Answer A: An antagonist can block the effect of an inverse agonist

Pindolol treatment: A. Produces greater bradycardia than propranolol B. Decreases heart rate in hypertension C. Produces reflex tachycardia similar to prazosin D. Is preferential for β₁-adrenoceptors

Answer B: Decreases heart rate in hypertension

Carvedilol may produce its therapeutic effect in CHF by all of the following *except*: A. Signaling via the β-arrestin pathway B. Increase signaling via the canonical Gs pathway C. Decreasing heterologous desensitization by PKA D. Having greater affinity for R than R* ➢ R* = spontaneously active conformation at Gs

Answer B: Increase signaling via the canonical Gs pathway

In the treatment of hypertension, which of the following is least likely to cause an up-regulation of the receptors involved in its own mechanism of action: A. Reserpine B. Captopril C. Clonidine D. Aliskerin

Answer C: Clonidine ➢ The only one that is an agonist (which don't produce upregulation - if anything, they desensitize receptors) so these don't produce receptor upregulation

What is normal ejection fraction?

Around 60-70

Stages: Most common classification is New York Heart Association (NYHA)

Classified into stages I (mild) - IV (severe)

TRV027 MOA

Blocks Gq, but leaves the β-arrestin pathway

Signs and Symptoms of CHF: Dyspnea

Difficulty breathing due to pulmonary congestion

Signs and Symptoms of CHF: Sinus tachycardia

Due to increased sympathetic activity

Signs and Symptoms of CHF: Wheezing

Due to pulmonary congestion

β-Blockers - Possible MOAs: Some studies show that in animal models of heart failure, chronic infusions of β-blockers elevated _____ and _____ levels to normal.

Gi, GRK

Heart Failure: Body Overview

Heart Failure is the inability of hte heart to produce enough CO to meet the oxygen demand. It is a systemic disease that involves many organs besides the heart.

The Trevena Drug Discovery Platform

Notion of "Biased signaling" → Emerging platform that we'll see in the clinic

Projected US prevalence of HF from 2012 to 2030 is shown for different races

Projects for the next 20 years, all increasing

Signs and Symptoms of CHF: Edema

Swelling of ankles and legs due to increased capillary pressure

A lot of times, in normal systems, inverse agonists look like _____ because of where the _____ is set.

antagonists, baseline

Cell Based Therapies (Very Promising)

❖ "The only treatment for heart failure is a new heart" ❖ September 6, 2016: CardioCell released data from its Phase IIa trial studying the effects of intravenous administration of ischemia-tolerant mesenchymal stem cells in patients with chronic heart failure compared to placebo. ❖ Results showed the injection was well-tolerated, with no major differences in safety endpoints. ❖ Basically you are injecting cells directly into the myocardium and having the heart regenerate (grow new cells) ❖ Only lasts about 6 weeks, but it still improves CO

"Violence in science"

❖ "Violence in science" is through letter writing ❖ This was the title of the response to the editorial (seen earlier "What doesn't kill may not make you stronger") ❖ Basically the title of the letter is about how the editorial was wrong for generalizing, by saying all β-blockers were the same

Compensatory mechanisms - Frank-Starling mechanism

❖ *Curve A*: Normal cardiac output at normal end diastolic volume (EDV) ❖ *Curve B*: Compensated heart failure. Cardiac output improved at the expense of increased ventricle size ❖ *Curve C*: Decompensated/severe heart failure. Heart muscle is stretched beyond its physiological limits. ❖ *Curve D*: Digitalis may restore some of the normal Starling properties to the heart muscle. ❖ If you don't have heart failure you heart is pumping at 5 L/min, but if you exercise you can double that (EDV) ❖ When you start to develop failure, the curve comes down. ❖ By stage four HF, you have to be bedridden and can't even go to the bathroom ❖ Goal of therapy is to get you back up to curve A and B. ➢ *Digitalis* can do this

Dose Response Curve

❖ *Full Agonist*: Very high affinity for R* relative to R ➢ In the classic model → produces AR complex with high affinity for G ❖ *Partial agonist*: Higher affinity for R* relative to R ➢ In the classic model → produces AR complex with a high affinity for G (but less than the full agonist) ❖ *Inverse Agonists*: Higher affinity for R than R* ➢ In the classic model there are only antagonists, inverse agonists are not defined in this model ❖ *Antagonist*: You block the full/partial agonists, and also the inverse agonists ➢ This is because the agonist occupies both R and R* ➢ In the classic model → produces AR complex with no affinity for G

Defining β-blockers

❖ *β-adrenoceptor inverse agonists*: A subset of β-blockers that have a higher affinity for R relative to R* ❖ *β-blockers with ISA*: These are agonists that have slightly higher affinity for R* relative to R ➢ So this affinity wouldn't be as high relative as agonists ❖ *β-adrenoceptor antagonists*: Have affinity for both R and R*

Entresto® (Novartis)

❖ A combination of valsartan (ARB) and sacubitril (pro-drug inhibitor of neprilysin) ❖ On 30 August 2014, the PARADIGM-HF trial (comparing LCZ696 with enalapril was stopped because "because the boundary for an overwhelming benefit with LCZ696 had been crossed" (~20% reduction in primary endpoint: death from cardiovascular causes or hospitalization for heart failure compared to enalapril group). ❖ July 2015 FDA approval for CHF Entresto®

Unique properties of certain β-blockers: Metoprolol

❖ A preferential β₁-blockers ❖ *Has FDA approval* ❖ At doses recommended for CHF, also likely blocks β₂ receptors

ACE Inhibitors and A-II receptor antagonists

❖ ACE inhibitors , ARBs with/without neprilysin inhibitors, β-blockers and aldosterone antagonists are the only classes that decrease mortality ➢ Fairly new drugs ❖ Not effective in decreasing mortality in heart with preserved ejection fraction ➢ True for all drugs that we will study

7TMR Signal Transduction: New Paradigm (Again)

❖ Again being reminded that as we stand now, there are at least 2 pathways for signaling ❖ "Biased Signaling" will become a big thing

Aldosterone Antagonists (Aldactone and Eplerenone)

❖ Aldactone was the first aldosterone antagonist ❖ Eplerenone is reported to have fewer steroid related side effects (gynecomastia in males, menstrual irregularities and post-menopausal bleeding in females) ❖ (In stage II heart failure patients) Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (NEJM, Nov 14, 2010).

Aldosterone Antagonists in Heart Failure

❖ Aldosterone levels are significantly elevated in heart failure ❖ Aldosterone antagonists can limit K+ loss caused by other diuretics in heart failure ❖ Aldosterone antagonists decrease mortality → not believed to be the result of the diuretic effects of these agents ❖ Aldosterone antagonists have inhibitory effects on the cardiac remodeling seen in CHF

ACE Inhibitors and A-II receptor antagonists: Hemodynamic effects

❖ As failure progresses, there is little gain from ↑EDV → (flat ventricular function curves). Increased EDV and increased venous pressure impaired energetics and dynamics ❖ Therefore, we can decrease afterload and preload (which lowers EDV), and improve symptoms with little effect on CO, BP, or HR

Types of Heart Failure: Heart Failure with Preserved Ejection Fraction EF ≥ 50 (Diastolic)

❖ Associated mainly with hypertension or anything making the heart work harder ❖ Concentric ventricular hypertrophy ❖ Left ventricle not dilated ❖ *Pharmacologic intervention does little to change mortality* ➢ Everything we've tried fails to help solve preserved EF, you can only treat what's causing it such as hypertension

Endothelin-1 (ET-1) antagonists: Tezosentan, Sitaxsentan, Bosentan

❖ Bosentan (Tracleer®) ➢ MOA: an antagonist of endothelin ET-A and ET-B receptors. Produces vasodilation with little reflex increase in HR. In humans has been shown to acutely improve PCWP, and improve dyspnea scores. ❖ *Ambisentran (Letairis®) ET-A-preferential antagonist (ambisentran + tadalafil, FDA-Approved Oct. 2015 for PH)* ❖ Lots other are under development. Some are ET-A selective (approved in Europe, Japan, Canada, Australia) ❖ *Have shown benefit in Pulmonary Hypertension* ❖ Some in trials for resistant hypertension

Digitalis and allied cardiac glycosides: Toxicity

❖ Can be lethal, very low therapeutic index (TD₅₀/ED₅₀ ~2) ❖ Arrhythmias ❖ Central nervous system ➢ Confusion (esp. in elderly), fatigue, abnormal dreams ➢ Nausea, dizziness, anorexia ➢ Altered color vision (yellow halo around objects) ❖ Not a goo drug ❖ Does cross BBB

Deaths attributable to disease of the heart (United States: 1900 - 2009)

❖ Cardiovascular deaths in thousands ❖ In the last 30 years, you can see that they are going down ❖ We have done pretty well with treating cardiovascular disease except for heart failure

β-Blockers - Possible MOAs: #2

❖ Chronic agonist exposure produces homologous and heterologous desensitization. In CHF patients, inotropic responses to histamine via H2 receptors and 5-HT via 5-HT4 receptors are impaired. Both receptors couple to Gs and are phosphorylated by PKA. β-blockers would decrease PKA and reduce heterologous desensitization. ➢ Maybe if we use β-blocker, we will lower PKA, and we would resensitize these receptors. However, these receptors are very minor players - in a normal situation, you'd never treat the histamine system, but in an HF person, the beta system is already impaired.

β-Blockers - Possible MOAs: #1

❖ Chronic exposure to high levels of NE are cytotoxic, mechanisms of cytotoxicity may involve β₁ receptor activation ➢ This is true. If you collect blood from the coronary and measure the content of catecholamine in the heart, the higher the content, the better the prediction of how fast the person will die. Direct correlation between mortality and the catecholamine content. So maybe NE is toxic and was killing some of the cardiac myocytes, so blocking it would be beneficial.

Types of Heart Failure: Heart Failure with Reduced Ejection Fraction (Systolic)

❖ Decreased ejection fraction ❖ Associated mainly with MI or other myocardium damage ❖ Eccentric ventricular hypertrophy ❖ Dilated left ventricle

ACE Inhibitors and A-II receptor antagonists: Effects on remodeling

❖ Decreases ventricular hypertrophy and remodeling of the extra-cellular matrix due to A-II ➢ Not only decreases rate of remodeling, but can produce modest reversal of existing remodeling

Effects of Cardiac Glycosides: Vascular Smooth Muscle

❖ Direct ➢ Increase in ICF Ca results in vascular contraction ❖ Indirect ➢ Hemodynamic improvements by decreasing sympathetic tone: produces vasodilation (withdrawal of α₁-adrenoceptor mediated vasoconstriction) ❖ Direct and Indirect have *opposite effects* ❖ If you take a blood vessel and put it in a organ chamber with Kreb solution and you add digoxin you will see contraction since it increases intracellular Ca, however if a person responds to digoxin, CO goes up and heart doesn't have to pump and release NE. So net effect is that you stop activating α₁ receptors sand see vasodilation. In vivo you see dilation, in vitro you will see contraction.

Effects of Cardiac Glycosides: Myocardium

❖ Direct: These make them useful as anti-arrhythmic agents ➢ Inhibits AV conduction ➢ Can produce abnormal automaticity (Ca accumulation in SR leading to spontaneous release) ➢ Can also have depression of conduction in His-Purkinje fibers and ventricular muscle ❖ Indirect ➢ If you improve CO → ↓SNS and ↓HR by improving contractility

Other drugs and developments

❖ Does it make a difference in difficulty breathing? So far, no.

Digitalis and allied cardiac glycosides

❖ First used by the Egyptians ❖ Beneficial effects first described by Withering in 1795 ❖ Study report in 1997 says only benefit of digitalis is decrease in hospitalizations from worsening of CHF - no change in mortality or quality of life. ➢ So it isn't a very good drug

Unique properties of certain β-blockers: Carvedilol

❖ First β-blocker approved for HF (~1997) ➢ There was a gap between the paper published in the 70s and the 1st approved drug ❖ β₁- and β₂- and low α₁-adrenoceptor antagonist ➢ Recall that α₁-AR antagonists like prazosin failed to protect from onset of CHF and were removed as first-line agents in hypertension ❖ Also a potent anti-oxidant. Approved for mild to severe heart failure ❖ Start dosing at 3.125 mg, titrate up to target dose of 100 mg ➢ Dose doubled every 2 weeks, have to get patient through the side effects initially

Sacubitril MOA

❖ Neprilysin is a neutral Endopeptidase (NEP) that has a role in inactivating: ➢ Natriuretic peptides ➢ Enkephalins ➢ Other peptides ❖ MOA: The inhibition of inactivating natriuretic peptides → Enhance the activity of this system leading to natriuresis, diuresis and further inhibition of the RAS ❖ Neprilysin also from family membrane metallo-endopeptidase (MME) and various other group names

β-adrenoceptor agonists vs antagonists in CHF

❖ HF is a disease of impaired cardiac contractility. The heart is not able to pump with sufficient force to meet the oxygen demands of the periphery. ❖ Our body secretes adrenaline and activates the sympathetic nervous system so we can ↑CO. This works, it makes people feel better. ❖ We used to treat people with β-agonists, and it made people feel better. Their quality of life went up, they could walk further. The problem is that *everyone died quicker* ➢ Sometimes we still use β-agonists under special circumstances ❖ β-agonists = acutely beneficial but chronically detrimental ❖ So we used to contraindicate β-blockers because of the high levels of sympathetic tone maintaining CO, primarily by activating the β receptors on the heart. If you block these receptors, the person is going to get worse. ❖ *Chronically, β blockers will ↓mortality and ↑contractility*

Remodeling

❖ Hemodynamic improvements by decreasing sympathetic tone: produces vasodilation (withdrawal of α₁) ❖ Physiologic hypertrophy: If you go to the gym and exercise regularly, you get a slightly bigger version of the normal muscle ❖ Concentric hypertrophy (HFPEF): Fatter truncated version of the normal muscle ➢ No treatment ❖ Eccentric Hypertrophy (HFREF): Skinnier longer muscle cell ➢ There is treatment

"Contraindications to beta-blockers are eroding more and more - even in COPD"

❖ If you get a case study where the patient has HF and COPD, and they say you can't give them metoprolol due to their COPD, it's wrong. → He'll argue it for you. They can use it. ❖ About 25-30% of COPD patients have HF → Don't get put on a β-blocker and they die faster from their HF ➢ Now retrospective analysis says if you put a COPD/HF patient on metoprolol or carvedilol, they gain all of the benefits that everyone else with HF does, and have no detriment to their COPD ➢ Some studies say that the incidence of COPD actually decreases with β-blockers → So now this is being studies

Two-state receptor model

❖ In the mid 90s, we said that receptors don't exist just in a single quiescent state, but actually, a percentage of the receptors that were empty but signaling. These are the R* - constitutively (spontaneously) active. ❖ In this model, the *agonist* will bind to the receptor and stabilize it, forcing the equilibrium towards making more active receptors. ❖ But then we found a subset of ligands that we call now *inverse agonists*, and these prefer the inactive receptors, and will set the equilibrium towards the inactive state → decrease the amount of active receptors. ❖ A *real antagonist* has equal affinity for both R and R*. It'll block the effect of the agonist, and it'll also block the effect of the inverse agonist. ❖ Note: One β-blocker can block the effect of other β-blockers

ACE Inhibitors and A-II receptor antagonists: MOA

❖ Inhibition of the effects of Ang-II (remodeling, etc.) ❖ Decrease both afterload and preload (easier for heart to pump)

Ivabradine Hydrochloride

❖ Inhibits I(f) → which stands for Inward 'funny' current. ❖ I(f) channel is involved in modulation cardiac pacemaker activity. ❖ Inhibition of I(f) channel produces an increase in diastolic interval ❖ August 27, 2014: FDA Granted Amgen expedited review for CHF. ❖ FDA approval April 2015 Corlanor® ❖ *Reduce cardiac rate without affecting contractility*

Causes of CHF: Damage to heart

❖ Ischemic damage > 70%. Heart Failure can have rapid onset after MI. ❖ Infections - bacterial or viral - producing damage to heart muscle ❖ Cardiotoxic drugs - doxorubicin (adriamycin) - 18% of patients at cumulative 700 mg/m2

Isosorbide dinitrate and Hydralazine (BiDil®)

❖ Isosorbide dinitrate: Preferential venodilator → *↓preload* ❖ Hydralazine: Preferential arterial dilator → *↓afterload* ❖ The combination of isosorbide dinitrate and hydralazine was originally rejected by FDA in 1997. ❖ However, it was approved by FDA in 2005 after a study demonstrated ↓mortality in African-American CHF patients ➢ The African-American Heart Failure Trial studied the effects of the drug on 1,050 black heart failure patients already on standard therapy regimens. Results were a 43% reduction in mortality and 39% decrease in hospital visits. The study was stopped early. ➢ The logic for the study was that in general, African-Americans showed less benefit (like decreases in mortality) from treatment with ACE inhibitors. ➢ However, the study results made it "the first race-based prescription drug", and drew lots of criticism.

Classical Paradigm of 7TMR

❖ Let's say this is a β₂ receptor. When an agonist binds, it will stimulate Gs → ↑cAMP → activate PKA → PKA and other mechanism will feedback to desensitize the receptor and shut down signaling by recruiting GRK and β-aresstin ❖ If PKA levels are too high, it will also phosphorylate and desensitize other Gs receptors → heterologous desensitization ❖ GRK: Primarily responsible for homologous desensitization

Non-cardiac glycoside inotropic agnets: Dobutamine

❖ MOA ➢ Activates β₁ receptors ➢ Less α-agonist properties than dopamine ❖ Only used *acutely* for short-term support ➢ Chronic use will ↑mortality ➢ Will only keep you alive for like 2-3 weeks like if you are waiting on a transplant ➢ Can also be used if needed for surgery ➢ *Last resort*

Amrinone and Milrinone

❖ MOA ➢ competitive inhibitors of type III phosphodiesterase (PDE) ➢ PDE-III is the predominant isoform in cardiac and vascular tissue ➢ Increasing cAMP increase contractility in heart and increases relaxation in vasculature. ➢ *Milrinone preferred* over amrinone due to possible dangerous arrythmias with amrinone. ➢ Milrinone used if acute problem while on chronic "β-blocker" treatment ❖ Again, just like β-agonists, they increase mortality with chronic use

Nadolol in Mild Asthmatics (NIMA)

❖ NIH funded multicenter, double-blind, placebo controlled, clinical trial. ❖ Nick Hanania, MD (BCM), lead investigatorAlkis Togias, MD, NIH Program Officer ❖ Results not published ❖ Nadolol → Shuts down both pathways

Digitalis and allied cardiac glycosides: Cellular MOA

❖ Na/Ca exchanger aids in Ca removal by influx of Na and extrusion of Ca ❖ Na/K ATPase helps maintain low levels of ICF Na ❖ ICF Na concentration influences ICF Ca ❖ By increasing ICF Na, Ca extrusion is reduced, and ICF Ca rises ➢ *This is accomplished when Digoxin binds to and inhibits the NA/K-ATPase → ↑ICF NA → CA extrusion reduced → ↑ICF CA* ❖ Rice in ICF Ca may also increase sequestration in SR making the release pool larger and increasing sequestration in SR ❖ Increasing ICF Ca results in positive inotropic action

Ventricular Function Curves

❖ Normal Person: Move EDV from 200 → 100, we reduce CO by 3 L/min ❖ Person with HF: Move EDV from 350 → 250 and no change of CO, but symptoms get better (less swelling and difficulty breathing)

Signs and Symptoms of CHF: Cardiomegaly

❖ On CXR over half the thorax, increase thickness of the myocardium, more spherical geometry ➢ Increased A-II produces changes in extracellular matrix, fibrous deposition, and cardiac myocyte orientation resulting in a more spherical geometry ➢ The anatomical changes further impair cardiac contractility

Chronic activation of the RAS and SNS

❖ One of the few positive feedback loops in biology ➢ β₁-adrenoreceptors activate *renin* release ➢ AT₁-angiotensin receptors facilitate *NE* release ❖ Before 2005, the activating of the RAAS and SNS were called compensatory mechanisms ➢ Then we learned that if we interrupted these people lived longer so we decided to call them mal-adaptive ➢ *Obviously it's neither ❖ This positive feedback loop worsens CHF

Heart failure

❖ One of very few cardiovascular diseases with increasing prevalence. ➢ Primarily due to higher survival of MI's, but there is also an increase in survival of HF patients due to better therapies. ❖ In the US ~6 million cases with ~500,00 - 700,000 new cases per year. ❖ 50% Mortality within 5 years of diagnosis (higher mortality than the combined average for all types of cancer). ➢ 10% 1 year mortality. ❖ Very debilitating, no quality of life at the end, essentially bedridden

µ-opioid receptor agonist

❖ Pain med that is an analgesic that has zero respiratory depression, yet is as potent as morphine ➢ This means that respiratory depression is mediated through the β-arresting signaling ❖ With this drug people can use very high doses and still not die ❖ Biased because it only signals through Gi, but blocks β-arrestin

Endothelin-1 (ET-1)

❖ Pathophysiologic actions of ET-1: ➢ Family of endothelins consists of closely related peptides: ET-1, (its precursor big ET-1), ET-2, ET-3, and ET-4. ET-1 is the most potent at mediating biological actions. ➢ There are at least two distinct ET receptors, ET-A and ET-B. ➢ *ET-A receptors* mediate vasoconstriction and cell proliferation. ➢ *ET-B receptors* mediate vasodilation via release of NO and prostacyclin, the clearance of ET-1, inhibition of cell apoptosis, and inhibition of endothelin converting enzyme (ECE-1) expression. ➢ Levels of ET-1 and big ET-1 are positively correlated with mortality after myocardial infarction and in patients with CHF.

Unique properties of certain β-blockers: Bucindolol

❖ Pharmacology similar to carvedilol ❖ No benefit (almost reached significance for ↑mortality) ❖ *Not FDA approved* ❖ There is no "class" approval for β blockers (others failed like celiprolol) ➢ Only 2 approved are metoprolol and carvedilol ➢ Bisoprolol is approved in Europe

Carvedilol Study

❖ Placebo: half of patients are dead or in the hospital ❖ Carvedilol: Only about 25% dead so this is a huge improvement

Propranolol in Asthma Study

❖ Propranolol didn't work ➢ Not the same as nadolol (which shuts down both pathways)

Comparing propranolol to carvedilol

❖ Propranolol is like carvedilol ➢ β-arresting signaling is bad for asthma

Diuretics (Usually loop diuretics)

❖ Rationale for use in CHF ➢ They decrease circulating blood volume and can decrease preload leading to improved symptoms ❖ Patient response ➢ Patient feels better due to decreased edema and pulmonary Congestion ➢ Don't change mortality ➢ Won't decrease CO ❖ *Furosemide* used most often

Serelaxin (Novartis) recombinant human relaxin-2

❖ Relaxin-like peptide family belongs in the *insulin superfamily* and consists of 7 peptides ❖ 4 known relaxin receptors RXFP1 - 4 (GPCRs) ❖ Relaxin-2 is a vasoactive peptide hormone with many biological and hemodynamic effects ❖ In *acute heart failure* patients *48-hour intravenous infusions* of serelaxin produced significant reductions of dyspnea and fewer deaths after 180 days (37%) ❖ The same amount of people died in the hospital between those that received this and those who didn't, it only decreased things that occurred after 180 days ➢ We don't know why

Devices

❖ Several devices that can be used to prevent sudden death ❖ Cardiac Resynchronization Therapy (CRT) (biventricular pacing devices) ❖ Implantable Cardioverter Defibrillators (ICD) ↓sudden death ❖ *Transplant is still the only cure*

Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): Randomized controlled trial

❖ Showed that carvedilol was significantly better for CHF than metoprolol ❖ This creates shaky ground because metoprolol is a better inverse agonist than carvedilol ➢ This shows that it isn't exactly the fact of being an inverse agonist that makes it the best for treating CHF

University of Alabama at Birmingham study

❖ Study being done to see if β-blockers actually improve COPD ❖ It's possible that it's not *just* the benefits seen for their HF ❖ Remember, for HF, and to prevent 2nd MI, there are no substitutes for β-blockers in therms of efficacy, so they want to see if β-blockers are for COPD patients as well

Causes of CHF: Excess Work

❖ Systemic or pulmonary hypertension ❖ Valvular insufficiency - inefficient pumping produces hypertrophy and eventual failure ❖ Thyrotoxicosis - excess thyroid hormone produces increased peripheral O2 demand and a chronic increase in CO ❖ Anemia - similar mechanisms to thyrotoxicosis ➢ Not delivering enough blood so you have an increase in CO ❖ Arterio-venous fistula - similar to anemia ➢ Mixing of deoxygenated blood with oxygenated blood

β-Blockers - Possible MOAs: #3

❖ The "whipping a dead horse hypothesis" ➢ The body has already activated everything, so maybe you can just rest the heart

How do β-blockers improve cardiac function in CHF?

❖ The paradox, "why does shutting down a system whose primary function is to increase contractility result in an increase in contractility (↑LVEF) ❖ In normal patients, just like with CO, you can double the force of contraction with increase in HR. But in patients with HF, if you ↑HR, you can't increase force of contraction, if anything it impairs it ❖ Maybe: β-blockers will reduce HR, so if take a patient from 180 and put him on a β-blocker, the contractility will go up a bit. *This is a stretch* → Marginal increase

Contractility of cardiac myocytes from CHF patients

❖ These are cardiac myocytes from patients that got a new heart after having a heart with severe heart failure → They measured the force of contractions ❖ Metoprolol: Upper left graph ➢ If we added adrenaline, we would see an increase of contraction, but when we add metoprolol we the opposite, so this is an *inverse agonist* ❖ Carvedilol: Upper right graph ➢ Also an inverse agonist ➢ There was one patient in which this was an exception ❖ Bucindolol: Bottom graph ➢ It was a weak inverse agonist in half the patients and a weak agonist in the other half → net curve = antagonist ❖ Carvedilol and metoprolol were approved but bucindolol wasn't → So they agreed that for a β-blockers to work for CHF, it needed to have inverse agonist activities ❖ These people's hearts already have trouble pumping, then you give them an inverse agonist and make this even worse → This is why they feel so terrible in the beginning → Eventually they get better

"Biased" agonism at β₂AR signaling pathways

❖ This experiment has β₁ blockade so we only see β₂ ❖ For the first 3 curves, the ligands bind to both Gi and Gs ➢ When Gi is taken out, the response through Gs improves. This means that Gi was actually part of the response before. ❖ *Fenoterol* is biased to Gs compared to these other drugs because when we removed Gi, the response was the same ❖ Concept of "Ligand-directed trafficking of receptors stimulus" ➢ The ligand that sits on the receptor may be able to tell the receptor which pathway to take ➢ So for the first 3 drugs, we see it mostly telling it to take Gs, but also some Gi ➢ For the fenoterol curve, it is telling the receptor to only take the Gs curve ➢ Name may be reduced to "biased agonism" or "biased signaling"

Chronic treatment with metoprolol in patients with dilated cardiomyopathy

❖ This graph represents level of left ventricular ejection fractions → index of cardiac contractility ❖ They were using 1/16th of the dose of metoprolol that they hoped to get at the end. In one day things already got worse, so everyone told them to stop the experiment ❖ However, a Swedish resident decided to keep a person on it, and after 3 months the contractility improves and the chances of survival increases dramatically. ➢ Before the 3 months, there were some serious adverse effects (paradox)

Inverse Antagonism: Carvedilol vs. Metoprolol

❖ This graph shows that carvedilol is not as good of an inverse agonist as metoprolol ➢ So the inverse agonist properties probably aren't a good indication for carvedilol being better than metoprolol at the trials ❖ Measured cAMP accumulation ➢ Quite a few β-blockers have ISA: weak agonists compared to isoproterenol (full agonist)

β-arrestin pathway: Carvedilol vs. Metoprolol

❖ This is measuring the β-arrestin pathway that activates ERK using the same ligands (not cAMP) ❖ Here carvedilol is a good agonist of ERK and metoprolol isn't ❖ So we now know that carvedilol is a biased ligand for the β-arrestin pathway, but metoprolol shuts down both pathways (cAMP and ERK) ❖ Of all the inverse agonists the only ones that stimulate β-arrestin are carvedilol and propranolol

5 groups of ligands

❖ This machine separates out all the drugs based of how they behave ❖ *Group I*: Full agonists ➢ Isoproterenol and EPI ❖ *Group II*: Partial agonists ➢ Salbutamol and salmeterol ❖ *Group III*: β-bockers with ISA ❖ *Group IV*: Inverse agonists that activate ERK ➢ Propranolol and carvedilol ❖ *Group V*: Inverse agonists

Classic receptor model

❖ This model works in 90% of situations ❖ Here, we have a receptor in a single quiescent state, and if a ligand (A=agonist) binds to it, they produce this binary complex (A+R). If this binary complex has an affinity for the G protein, it'll eventually generate a response. ❖ So in this model we have one state of the receptor, and 2 properties: affinity (KA) and efficacy (KAR). High efficacy drug would have high affinity for G. ❖ An antagonist in this model has affinity to produce the binary complex, but it has no affinity for G - zero efficacy. ❖ The agonist is the only one that generates a response, and the magnitude of the response depends on how much agonist is binding. The antagonist will stop at the binary complex; it'll not bind to the G protein and will not generate a response, it just sits on the receptor preventing an agonist to from binding. ❖ Bucindolol: Failed this model ➢ In this model you have a single receptor state, and the antagonist have an affinity for the receptor bot don't produce a response ➢ All β-blockers should follow this model, but some failed, so the model had to be thrown out for the β-blocker class

Ventricular Remodeling after Infarction (Panel A) and in Diastolic and Systolic Heart Failure (Panel B)

❖ Top: Someone is having an infarction and you get thin and large cardiomyopathy ❖ HF*P*EF: Thicker Walls ❖ HF*R*EF: Thinner walls and cover more area

Receptor theory: Isolated 3 state model

❖ We have 2 "two-state" models here ❖ Carvedilol ➢ Binds to the R of the left pathway (Gs pathway) so here it is an inverse agonist ➢ Binds to R** of the right pathway (β-arrestin pathway) so here it is an agonist ❖ Metoprolol binds to R for either pathway so it is an inverse agonist in both places ❖ Activating ERK is not "good" or "bad" but is likely favorable for heart failure ❖ So the ideal ligand for heart failure has highest affinity for R**, and next highest affinity for R ❖ This represents why sometimes carvedilol looks like and inverse agonist and other times it looks like an agonist

Events Accompanying Heart Failure: A Positive Feedback Cycle

❖ We want the end result to be an *increase* in calcium ❖ The drugs we use bind and inhibit the Na/K ATPase → ↑Na inside the cell → Na/Ca exchanger is impaired → Keep more Ca inside the cell

β-adrenoceptor antagonists

❖ Went from contraindicated to the drug of choice ❖ This will be the greatest story in the history of pharmacology. ❖ Heart failure is basically when your heart fails as a pump. ❖ β-blockers decrease HR and contractility so why would you give a person with HF a beta blocker? ➢ You would thing that people would get sicker but some swedish resident put a woman with HF on a β-blocker and then she got better. ❖ In 1997 first β-blocker got approved.

Non-cardiac glycoside inotropic agnets: Dopamine

❖ β-agonist ❖ MOA ➢ Activates β₁ receptors to increase CO and BP ➢ At low doses, activates dopamine receptors leading to an increase in renal blood flow, which helps maintain GFR ❖ Only used *acutely* for short-term support ➢ Chronic use will ↑mortality ➢ Will only keep you alive for like 2-3 weeks like if you are waiting on a transplant ➢ Can also be used if needed for surgery ➢ *Last resort*

7TMR Signal Transduction: New Paradigm

❖ β-arresting was named arrestin because it arrested/terminated signaling ➢ It actually acts more like a policeman that says, "stop here, but signal through this way" ➢ So carvedilol can shut down Gs but signal through MAP to improve cardiac function

Current working hypothesis for the beneficial effects of certain β-adrenoceptor antagonists (ligands) in CHF

❖ β₂-adrenoceptors can signal via at least 2 or 3 pathways. ❖ In CHF at least 2 pathways (Gs and β-arrestin) are involved ❖ Ligands that are biased towards activating β-arrestin, and are inverse agonists at Gs, like carvedilol, are most beneficial in CHF ❖ Hypothesis from ~2003 to ~2010 was only inverse agonists would work in CHF ❖ Prior to ~1997 β-blockers were contraindicated in CHF