Heart Failure - Pathophysiology and Pharmacology

Define heart failure (HF).

- Clinical syndrome caused by the inability of the heart to pump blood sufficiently to meet the body's metabolic needs

- Results from structural or functional cardiac disorders that impair the ability of the ventricles to fill with/eject blood properly

List signs/symptoms of HF.

Left-sided HF:

­- Dyspnea (particularly on exertion), exercise intolerance

­- Orthopnea, paroxysmal nocturnal dyspnea

­- Tachypnea

­- Cough

­- Pulmonary rales/crackles

­- Pulmonary edema

Right-sided HF:

­- Abdominal discomfort, bloating

­- Nausea, anorexia

­- Peripheral edema

­- Ascites

­- Jugular vein distention

­- Hepatojugular reflux

­- Hepatomegaly (i.e., enlarged liver)

What blood marker is commonly used in HF diagnosis?

­BNP and NT-proBNP levels

- Cannot be used in isolation to diagnose or exclude HF

- Conditions other than HF may also increase BNP (e.g., age, renal dysfunction, PE, COPD)

- Best used as an adjunctive aid for diagnosing a cardiac etiology for dyspnea

- Treatment with valsartan/sacubitril combination may increase BNP

Classify HF based on ejection fraction (EF).

HFrEF: HF with reduced EF ≤ 40%

­- Also referred to as systolic HF

HFpEF: HF with preserved EF ≥ 50%

­- Also referred to as diastolic HF

HFmrEF: HF with mid-range EF 41-49%

HFimpEF: HF with improved EF > 40% with prior documentation of lower EF

Classify HF based on side of ventricular failure.

Left-sided HF: Manifests as pulmonary congestion (e.g., SOB, fatigue)

Right-sided HF: Manifests as systemic congestion (e.g., peripheral and abdominal fluid accumulation)

Classify HF based on the NYHA functional classification system.

­Class I: No limitations

- Ordinary physical activity does not cause undue fatigue, dyspnea, palpitations, or angina

­

Class II: Slight limitation

- Comfortable at rest

- Ordinary physical activity (e.g., carrying heavy packages) may result in fatigue, dyspnea, palpitations, or angina

­

Class III: Marked limitation

- Comfortable at rest

- Less than ordinary physical activity (e.g., getting dressed) leads to symptoms

­

Class IV: Severe limitation

- Symptoms of HF or angina are present at rest and worsen with any activity

Note: Patients can move between NYHA functional classes as symptoms improve with treatment

Classify HF based on the ACC/AHA staging system.

­Stage A: At-risk for HF

- Patients who are at risk for HF but do not yet have HF symptoms, structural/functional heart disease, or abnormal biomarkers

­

Stage B: Pre-HF

- Patients without current or prior HF symptoms, but with evidence of either structural heart disease, increased filling pressures, or other risk factors

­

Stage C: Heart failure

- Patients with current or previous HF symptoms

­

Stage D: Advanced HF

- Patients with marked symptoms that interfere with daily life functions or lead to recurrent hospitalizations

Note: HF staging does not reverse, even after treatment

Neurohormonal activation: Describe the effects of vasoconstriction as a compensatory mechanism in HF.

Occurs as a result of SNS and RAS activation

Initial beneficial effects:

- Maintains BP

- Shunts blood from nonessential organs to brain and heart

­

Long-term detrimental effects:

- Increased MVO2 (i.e., O2 demand)

- Increased afterload eventually decreases stroke volume (thereby activating more compensatory responses)

Neurohormonal activation: Describe the effects of tachycardia/increased contractility as a compensatory mechanism in HF.

­Decreased CO results in the release of NE

- Stimulates β1-adrenergic receptors in the heart

- Increases chronotropy and inotropy

­

Initial beneficial effects:

- Helps maintain CO

­

Long-term detrimental effects:

- Increased MVO2

- Shortened diastolic filling time

- Downregulation of β receptors (and therefore reduced responsiveness)

- Precipitation of ventricular arrhythmias

- Increased risk of myocardial cell death

Describe the effects of increased preload as a compensatory mechanism in HF.

Occurs as a result of Na+ and H2O retention

­Initial beneficial effects:

- Optimizes stroke volume via Frank-Starling mechanism

­

Long-term detrimental effects: Chronic volume overload leads to…

- Pulmonary/systemic congestion

- Edema formation

- Increased MVO2

Describe the effects of ventricular hypertrophy/remodeling as a compensatory mechanism in HF.

­Driven by Ang II, NE, aldosterone, and vasopressin

­

Initial beneficial effects:

- Helps maintain CO

- Reduces myocardial wall stress

- Decreases MVO2

­

Long-term detrimental effects:

- Systolic and diastolic dysfunction

- Increased risk of myocardial cell death and ischemia

- Increased arrhythmia risk

- Fibrosis

Describe the effects of natriuretic peptide release as a compensatory mechanism in HF.

­Considered a beneficial physiological response, counteracting effects of SNS/RAS

- Promotes vasodilation (thereby lowering BP)

- Increases natriuresis

- Antagonizes SNS and RAS activity

- Anti-growth, anti-proliferative, anti-fibrotic effects

­

However, compensatory response becomes blunted over time

Describe the rationale for the use of ACEi/ARBs in HF.

MOA: Inhibit RAS

­- Decrease levels of Ang II (ACEi) or antagonize its effects (ARB)

­- Results in reduced Ang II-driven HF initiation and progression

Effects:

­- Decreased preload and afterload

­- Decreased ventricular remodeling and fibrosis

What is the MOA for sacubitril/valsartan (Entresto)?

ARNI (angiotensin receptor and neprilysin inhibitor)

­

Sacubitril: Inhibits neprilysin enzymes, reducing the breakdown of…

- Natriuretic peptides (thereby increasing BNP levels)

- Ang II

­

Valsartan: Blocks AT1 receptors

- Counters the unintended increase in Ang II caused by sacubitril

Describe the pharmacological effects of sacubitril/valsartan in HF.

- Decreased preload and afterload

- Decreased ventricular remodeling

- Reduced CV mortality and hospitalization for HF

What adverse effects may occur with sacubitril/valsartan? Describe its contraindications.

Adverse effects:

­- Hypotension

­- Hyperkalemia

­- Angioedema

Contraindications:

­- History of angioedema

­- Concomitant ACEi (requires 36 36-hour washout period between)

-­ Pregnancy

Describe the rationale for the use of β-blockers in HF.

MOA: Block β receptors

­- Antagonize the detrimental effects of the SNS in HF

­- Blocking of β receptors results in negative chronotropic and inotropic effects

Effects:

- Inotropic effects may cause symptoms to initially worsen (may take months to see benefits)

­- Decreased afterload

­- Decreased or reversed ventricular remodeling

­- Improvement in left ventricular systolic function

­- Reduced MVO2 (due to decreased HR and ventricular wall stress)

­- Inhibition of plasma renin release

What are examples of mineralocorticoid receptor antagonists (MRA) used in HF?

- Spironolactone (Aldactone)

- Eplerenone

Describe the rationale for the use of MRA in HF.

MOA: Block MR aldosterone receptor

­- Inhibits effects of aldosterone on cardiac ECM and collagen deposition

­- Decreases proinflammatory state, atherogenesis, and oxidative stress caused by aldosterone

Effects:

­- Decreased preload

- Reduce cardiac fibrosis and ventricular remodeling

What adverse effects may occur with MRAs?

-­ Hyperkalemia

­- Gynecomastia (with spironolactone)

Describe the rationale for the use of diuretics in HF.

MOA: Relieve congestion and fluid overload via promotion of diuresis

­- Thiazides are infrequently used as monotherapy

­- Loops are usually necessary to restore and maintain euvolemia

- Combination of thiazide and loop may be required in certain cases of diuretic resistance

Effects:

­- Decrease preload and afterload

­- No effect on mortality or remodeling

What is the MOA for sodium nitroprusside? Describe its pharmacological effects.

MOA: Releases NO, leading to increased cGMP levels and vasodilation

­- Results in NO-dependent arterial and venous dilation

Effects:

­- Decreased preload and afterload

­- Increased cardiac output in patients with severely impaired LV function

What adverse effects may occur with sodium nitroprusside?

- Excessive hypotension

- Thiocyanate and cyanide toxicity

Describe the rationale for the use of hydralazine + isosorbide dinitrate in HF.

­Hydralazine: Predominantly an arterial vasodilator

- Binds to K+ channels, resulting in K+ efflux and subsequent hyperpolarization

- Prevents Ca2+-mediated constriction of smooth muscle

- Reduces SVR and arterial BP (thereby decreasing afterload)

­

ISDN: Releases NO, leading to increased cGMP levels and smooth muscle relaxation

- Venodilation results in decreased preload

Effects:

­- Decreased preload and afterload

­- Improved symptoms and survival (especially in African American populations)

What is the MOA for vericiguat? Describe potential adverse effects.

MOA: Soluble guanylate cyclase (sGC) stimulator

­- Enhances NO-sGC-cGMP pathway independent of endogenous NO

­- Increased cGMP levels lead to vasodilation

Adverse effects:

­- Hypotension

­- Syncope

­- Anemia

What is the MOA for digoxin? Describe its pharmacological effects in HF.

MOA: Cardiac glycoside that inhibits Na+/K+-ATPase

­- Increased intracellular Na+ reduces that activity of Na+/Ca2+ exchanger

- Leads to increased intracellular Ca2+

­- Results in enhanced myocardial contractility (positive inotropic effect)

Effects:

­- Increased contractility

­- Reduced excessive SNS activation and increased PSNS activity

­- Decreased HR (negative chronotropic effect) enhances diastolic filling

What are signs/symptoms of digoxin toxicity?

­Cardiac effects:

- Ventricular arrhythmias (e.g., PVC, VTach, VFib)

- Sinus bradycardia, AV block

- Paroxysmal atrial tachycardia with AV block

­

GI effects (e.g., N/V, anorexia, abdominal pain)

­

CNS effects (e.g., fatigue, weakness, dizziness, headache, neuralgia, confusion/delirium, psychosis)

­

Visual disturbances (e.g., blurred vision, yellow-green tinted vision, haloes around lights)

What is the MOA for milrinone? Describe potential adverse effects.

MOA: Inhibits PDE3, increasing cAMP levels and leading to increased Ca2+ influx

­- Increases myocardial contractility while also promoting vasodilation (i.e., acts as an “inodilator”)

­- Venodilation reduces preload

Adverse effects:

­- Hypotension

­- Arrhythmias

- Thrombocytopenia

What is the MOA for dopamine? Describe its pharmacological effects in HF.

MOA: Stimulates adrenergic receptors, while also releasing NE from adrenergic nerve terminals

­- Low doses: Targets DA receptors,

­- Moderate doses: Targets β1 receptors, increasing inotropy and chronotropy

­- High doses: Targets α1 receptors, inducing vasoconstriction

Effects:

­- Associated with increased CO and BP (and increased MVO2)

­- Increased preload at high concentrations

What is the MOA for dobutamine? Describe its pharmacological effects in HF and potential adverse effects.

MOA: Primarily β1- and β2-adrenergic agonist

­- β1 stimulation increases cAMP levels, leading to increased Ca2+ influx and positive inotropic effects

­- β2 stimulation produces vasodilatory effects

­- Also a mild α1-adrenergic agonist (less pronounced effects compared to β2 agonism)

Effects:

­- Increased CO

­- Decreased preload

Adverse effects:

-­ Tachycardia

­- Angina, arrhythmias

­- Tachyphylaxis

What is the MOA for ivabradine? Describe potential adverse effects.

MOA: Inhibits funny (If) current in SA node

- Slow spontaneous depolarization

­- Results in dose-dependent slowing of HR (without affecting BP or contractility)

Adverse effects:

­- Bradycardia

­- Sinus arrest

­- Heart block

­- AFib

­- Visual disturbances (e.g., phosphenes)

Describe the rationale for the use of SGLT2i in HF.

Decreased cardiac preload via…

- Increased glycosuria and natriuresis

­

Decreased cardiac afterload via…

- Improved endothelial function

- Reduction in arterial wall stiffness

­

Increased LV diastolic function and decreased LV mass via…

- Improved metabolic efficiency

- Increased O2 supply

What adverse effects may occur with SGLT2i?

- Polyuria

- Dehydration

- Genitourinary infections (e.g., UTI, genital mycotic infections)

- Orthostatic hypotension

- Slight increase in LDL-C (with empagliflozin)

- Fournier's gangrene

- Risk of bladder and breast cancer (with dapagliflozin)

- DKA (rare)