HF Pathophysiology

Lecture Objectives

  • Define Heart Failure and the classification of different kinds of heart failure

  • Distinguish between left-sided heart failure vs. right-sided heart failure, systolic vs diastolic heart failure, chronic heart failure vs. acute decompensated heart failure

  • Explain the normal processes of cardiac contraction and its regulation

  • Describe the role of compensatory mechanisms including pathophysiological and beneficial physiological responses activated in heart failure

  • Describe the pathophysiological progression of heart failure

  • Describe the role of neurohumoral responses (sympathetic nervous system, renin-angiotensin system, natriuretic peptides) play in heart failure

  • List the signs and symptoms of heart failure

  • Identify the blood markers used in the diagnosis of heart failure

  • Classify heart failure based on ACC/AHA and NYHA staging and classification systems

  • Describe the pharmacology of drugs used in heart failure – rationale for their use, mechanism of action, pharmacological effects, effects on preload, afterload, ventricular modeling, nonhumoral modulation, contractility, heart rate, and cardiac energy metabolism, adverse effects, and contraindications.

Definitions

  • Heart Failure (HF): clinical syndrome caused by inability of the heart to pump sufficient blood to meet the metabolic needs of the body

    • Most commonly because of low CO due to cardiac dysfunction → Low-output failure

    • High Output HF: heart is functionally normal but there is an excessive increase in the body’s metabolic demands that outpaces the increase in CO

    • May occur in presence or absence of fluid overload

Classification of HF

  • Ejection fraction (EF)

    • Heart Failure with Reduced LV Ejection Fraction (HFrEF): EF < 40%, systolic (contraction) dysfunction

    • Heart Failure with Preserved LVEF (HFpEF): EF > 50%, diastolic (filling) dysfunction)

    • HF with mid-range EF → Symptoms of HF and LVEF between 41-49%

    • HF with recovered EF → LVEF greater than 40% but at one time had LVEF less than 40%

  • Left or right ventricle

    • Left Ventricle Failure: Pulmonary congestion → SOB and fatigue

    • Right Ventricle Failure: Systemic congestion → Peripheral and abdominal fluid accumulation

      • Left-sided failure

      • Left-to-right cardiac shunt due to atrial or ventricular septal defect

      • Cor pulmonale

    • Failure of one ventricle leads to failure of other ventricle

  • Chronic vs. Acute-Decompensated HF

Etiology of HF

  • Most Common

    • CAD

    • HTN

  • Less Common

    • Valvular disease

    • Excessive alcohol intake

    • Illicit drugs

    • Cardiotoxic drugs

    • Chest radiation

    • Viral infections

    • Diabetes

HFrEF Etiology

  • CAD (i.e. MI, ischemia) - Major cause (70%)

  • Dilated cardiomyopathies

  • Pressure overload

    • HTN, aortic or pulmonic valve stenosis

  • Volume overload

    • Valvular regurgitation, shunts, high-output states

  • Rate and rhythm disorders

    • Chronic bradyarrhythmias, chronic tachyarrhythmias

HFpEF Etiology

  • Increased ventricular stiffness → Impaired ventricular relaxation

  • Ventricular hypertrophy

    • Hypertrophic cardiomyopathy, HTN

  • Infiltrative myocardial disease

    • Amyloidosis, sarcoidosis, endomyocardial fibrosis

  • Myocardial infarction or ischemia

  • Mitral or tricuspid valve stenosis

  • Pericardial disease

Neurohumoral Activation in HF

  • In response to decrease in cardiac output → Body activated compensatory neurohumoral responses

  • Pathophysiological Compensatory Responses

    • RAAS

      • Angiotensin II

      • Aldosterone

      • Vasopressin

    • SNS

      • Norepinephrine

      • Epinephrine

    • Helpful short-term, harmful long-term

  • Beneficial Compensatory Responses

    • Natriuretic peptides


Pathophysiological Compensatory Responses - RAAS + SNS


Pathophysiological Responses: Short-Term Benefit vs. Long-Term Harm


Ventricular Remodeling and Hypertrophy

  • Most important compensatory mechanism is myocardial hypertrophy → Increase in muscle mass helps maintain cardiac performance

  • Hypertrophy can lead to ischemic changes → Impairment of diastolic filling and alterations in ventricular geometry

  • Remodeling refers to:

    • Dilation of cardiac wall

    • Slow structural changes that occur in stressed myocardium

    • Proliferation of connective tissue cells as well as myocardial cells with abnormal biochemical characteristics

  • Neurohormones + factors that drive ventricular remodeling → Angiotensin II, norepinephrine, aldosterone, vasopressin

Pathophysiological Cardiac Remodeling


Beneficial Compensatory Response - Natriuretic Peptides

  • ANP is synthesized and stored in atria and to some extent in ventricles → Released into circulation during atrial stretching (filling)

  • BNP is synthesized by ventricles and released in LV dysfunction or early HF

  • Act via guanylate cyclase receptors to stimulate

    • Vasodilation: results in lowering BP

    • Natriuresis: results in Na+ loss

  • Antagonize

    • Sympathetic nervous system

    • RAAS activity (angiotensin II, aldosterone)

    • Growth or hypertrophy of cells → Antifibrotic/anti-remodeling effects

Natriuretic Peptides: Triggers for Release

  • Physiological triggers

    • Atrial wall stretch (volume overload)

    • Changing from standing to supine position

    • Exercise

  • Pathological triggers

    • HF

    • Primary aldosteronism

    • Chronic renal failure

    • Inappropriate ADH secretion syndrome

Natriuretic Peptides: Degradation

  • ANP/BNP are degraded by an enzyme called neprilysin → Inactive metabolites

    • Neprilysin also breaks down angiotensin II

Progression of HF

  • Progressive decline in cardiac performance with HF progression

  • Reduced cardiac output → Increase in vasoconstriction (norepinephrine, angiotensin II, endothelin)

  • Increased afterload and further decreases EF and cardiac output

  • Cycle continues and performance keeps decreasing

HF Signs + Symptoms

  • LV Failure (Pulmonary Congestion)

    • Dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, exercise intolerance, tachypnea, cough

    • Pulmonary rales, pulmonary edema

  • RV Failure (Systemic Congestion)

    • Abdominal pain, anorexia, nausea, bloating, poor appetite with early satiety, ascites

    • Peripheral edema, jugular vein distention, hepatojugular reflux, hepatomegaly

Diagnosis of HF

  • Laboratory tests

    • ECG, thyroid function tests, serum creatinine, echocardiogram

    • BNP and NT-proBNP levles in blood

      • Cannot be used in isolation to diagnose or exclude

      • Conditions that increase BNP: older age, renal dysfunction, pulmonary embolism, chronic pulmonary disease

      • Treatment with valsartan/sacubitril increases BNP

NYHA HF Functional Classification and ACC/AHA HF Staging


Acute Decompensated HF (ADHF)

  • NYHA class III or IV

    • III: comfortable at rest, less than ordinary physical activity causes fatigue, dyspnea, palpitation, angina

    • IV: symptoms at rest, any physical activity increases discomfort

  • Sudden worsening of HF symptoms → Requiring urgent medical attention

    • Symptoms upon minimal exertion or at rest

  • Causes of decompensation

    • 40-50% have no cause

    • Noncompliance with medications or dietary restrictions, uncontrolled HTN, ischemia, arrhythmias, exacerbation of COPD, renal dysfunction, infections, DM, anemia, side effects of medications (NSAIDs, CCBs, thiazolidinediones)

  • Features: systemic volume overload (congestion), low cardiac output (hypoperfusion), pulmonary edema, renal failure, hypotension

  • Management:

    • Cardiac Index: normalized value of cardiac output to body surface area → Determines tissue perfusion

    • Pulmonary Capillary Wedge Pressure (PCWP): indirect estimate of left atrial pressure, used to assess left ventricular filling and mitral valve function. Marker for congestion and volume status

      • High PCWP → High congestion or edema


Treatment of HF

  • Short-Term Goals

    • Improving symptoms of hemodynamics, avoid hypokalemia, renal dysfunction, symptomatic hypotension, correcting neurohumoral activation

  • Long-Term Goals

    • Correcting HTN, preventing MI and atherosclerosis, reducing hospitalizations, improving survival and quality of life

  • Treatment involves: dietary/lifestyle changes, drugs, surgery


Neurohumoral Blocking Agents

  • Improve symptoms, slow disease progression, improve survival in chronic HF

  • ACEi, ARBs, ARNI, beta-blockers, aldosterone receptor antagonists

ACEi/ARBs


  • Decrease levels (ACEi) or antagonize effects (ARB) of angiotensin II attenuating effects that drive initiation and progression

  • ACEi prevents breakdown of bradykinin → Enhances release of vasodilatory prostaglandins and histamines → Arterial and venous dilation

  • Reduce preload and afterload → Reducing myocardial work → Preventing ventricular remodeling

  • Concerns: Renal dysfunction and hyperkalemia

    • Cough and angioedema with ACEi

ARNI

  • Angiotensin Receptor Neprilysin Inhibitor - Entresto

  • Valsartan: inhibits harmful effects of angiotensin II

  • Sacubitril: inhibits neprilysin mediated breakdown of BNP → Increase in BNP and beneficial effects

    • Neprilysin breaks down ANP, BNP, substance P, bradykinin, angiotensin II

    • Inhibition will increase BNP + angiotensin II levels → Need for an ARB

  • Reduces CV death and hospitalization

  • ADR: hypotension

  • Contraindications

    • ACEi use → 36 hour washout period

    • Pregnancy


Beta-Blockers (BB)

  • Antagonizes harmful effects of sympathetic nervous system in HF and slows disease progression

    • Antiarrhythmic effects

    • Blockade or reversal of ventricular remodeling

    • Reduction of myocyte death from catecholamine-induced necrosis or apoptosis

    • Improvement in LV systolic function

    • Reductions in HR and ventricular wall stress → Reduces myocardial oxygen demand

    • Inhibition of plasma renin release

  • Improves symptoms over time → May require a few months

  • Negative inotropic effects (reduction of CO) → Some symptomatic worsening may occur initially

Aldosterone Antagonists

  • Spironolactone, Eplerenone

  • Aldosterone causes fluid retention, cardiac fibrosis, electrolyte abnormalities

  • Aldosterone antagonists inhibit aldosterone effects on cardiac extracellular matrix and collagen deposition → Reduces cardiac fibrosis and ventricular remodeling

    • Decreases proinflammatory state, atherogenesis, oxidative stress

  • ADR: hyperkalemia

    • Eplerenone is selective for MR and does not cause endocrine ADR (gynecomastia, breast tenderness, menstrual irregularities)

Diuretics

  • Compensatory mechanisms in HF stimulate excessive sodium and water retention → Systemic and pulmonary congestion

  • Diuretics used for relief of acute symptoms of congestion and maintenance of euvolemia → Reduce preload and fluid retention

  • Thiazides

    • Weak, infrequently used alone

    • Preferred in those with mild fluid retention and elevated BP

    • Limited efficacy in renal insufficiency

  • Loops

    • Necessary to restore and maintain euvolemia

    • Retain efficacy in impaired renal function

Sodium Nitroprusside

  • MOA

    • Nitric oxide donor that causes venous and arterial vasodilation by activating guanylate cyclase which increase cGMP production in vascular smooth muscle cells

  • Effects

    • Reduces preload and afterload

    • Causes venous pooling and reduced arterial resistance

    • In patients with severely impaired LV function → Increase CO

    • Modest increase in HR and overall reduction in O2 demand

  • ADR

    • Hypotension, thiocyanate, cyanide toxicity, methemoglobinemia

  • PK

    • Onset is immediate

    • Duration: 1-10 min, continuous infusion required

  • Extremely potent, rebound HTN can occur upon discontinuation

  • Monitor: BP, HR, cyanide toxicity

Hydralazine + Isosorbide Dinitrate (ISDN)

  • Hydralazine

    • Activates voltage-gated K+ channels → Efflux of K+ and hyperpolarization of cell

    • Prevents calcium-mediated constriction of smooth muscle → Vasodilation

    • Acts mainly on arterial smooth muscle to reduce SVR (afterload) and BP

    • Increase stroke volume and cardiac output

  • Isosorbide Dinitrate

    • Releases NO and activated guanylyl cyclase resulting in an increase cGMP and venodilation

    • Venous pooling and reduction in preload

  • Beneficial effects

    • Increase in NO bioavailability secondary to NO donation and hydralazine-mediated reduction in oxidative stress

    • Reduces development of nitrate tolerance upon long-term use

    • Survival benefit in african-american

  • ADR

    • ISDN requires frequent dosing

    • Hypotension, headache, dizziness, GI distress, tachycardia

    • Hydralazine associated with lupus risk

Nitroglycerin

  • MOA

    • Releases NO → Increase cGMP → Vascular smooth muscle relaxation

    • Venodilation → Decrease preload

    • Mild arterial dilation at higher doses → Decrease afterload

  • Effects

    • Decrease LV end-diastolic pressure, pulmonary congestion, MVO2, rapid symptom relief

    • Useful when elevated preload is the issue

    • Tolerance develops with continuous exposure → Nitrate-free period

  • ADR

    • Hypotension, reflex tachycardia, headache, avoid with PDE-5 inhibitors

Guanylyl Cyclase

  • Family of enzymes that catalyze formation of cGMP

  • Membrane-bound (mGC)

    • Single extracellular domain, transmembrane, intracellular domain

    • Receptor for atrial natriuretic peptide

  • Soluble guanylate cyclase (sGC)

    • Heme and not bound to membrane

    • Receptor for NO → Activated by NO

Vericiguat

  • MOA: directly stimulates sGC independent of NO → Increases cGMP → Vasodilation

  • ADR: hypotension, syncope, anemia, fetal toxicity

  • Endothelial dysfunction and ROS → Reduced NO bioavailability→ Decrease in cGMP levels

Digoxin

  • Cardiac glycoside that acts as inotropic agent

    • Binds and inhibits Na+, K+, ATPase on cardiac myocytes → Decreases Na+ removal and increasing cytosolic Na+

    • Decreases Na+-Ca2+ exchange → Less Ca2+ removed and more Ca2+ accumulated in SR

    • Increase in Ca2+ → Enhanced myocardial contractility or positive inotropy

  • Benefits

    • Increased stroke volume

    • Increased EF

    • Decrease HR

  • Electrical Effects


  • Effects in HF

    • Reduces excessive sympathetic nervous system activation

    • Increases parasympathetic activity

    • Decreases HR and enhances diastolic filling

    • Positive inotropic and negative chronotropic

  • Toxicity

    • Non-cardiac ADR:

      • Anorexia, N/V, abdominal pain

      • Blurred vision, visual disturbances

      • Halos, photophobia, problems with color perception, scotomata

      • Fatigue, weakness, dizziness, headache, confusion, delirium

    • Cardiac ADR:

      • Ventricular arrhythmias

      • Premature ventricular depolarizations, bigeminy, trigeminy, ventricular tachycardia, ventricular fibrillation

      • AV block

      • Arrhythmias

      • Paroxysmal atrial tachycardia with AV block

      • Sinus bradycardia

  • Antidote

    • Narrow TI, long-half life

    • Digibind

    • K+ supplementation

Milrinone

  • Increases myocardial contractility and is also a vasodilator (inodilator)

  • MOA: inhibits PDE-3 → Increase in cAMP → Increase in intracellular Ca2+ → Increase force of contraction

  • Increase in SV, CO, HR

  • Lowers preload

  • ADR: hypotension, arrhythmias, headache, angina pectoris, thrombocytopenia

Dopamine

  • Low systolic BP and approaching cardiogenic shock

  • MOA: stimulates adrenergic receptors and releases NE from adrenergic nerve terminals

  • Higher doses → Chronotropy (increase HR) and vasoconstriction

  • Increase CO, BP, MVO2, cardiac work, and preload at high concentrations

  • ADR: arrhythmias

Dobutamine

  • Inotropic agent

  • MOA

    • B1/B2 receptor agonist with some A1 agonist effects

    • Does not result in release of NE

    • Positive inotropic effects due to B1

    • Vasodilation due to B2 effect

    • Increase in CO and decrease in preload

  • ADR

    • Tachycardia and increase in MVO2

    • Potential for producing angina or arrhythmias in patients with CAD

    • Tachyphylaxis


Ivabradine

  • MOA: inhibits funny current in SA node → Slows spontaneous depolarization of SA node → Dose-dependent slowing of HR

    • Does not affect BP or contractility

  • Reduced hospitalization and death

  • ADR: bradycardia, sinus arrest, heart block, a-fib, visual disturbances

  • Metabolized by CYP3A4

SGLT2 Inhibitors

  • Dapagliflozin reduces risk of hospitalization for HF, CV deaths, and urgent HF visits

  • Emapgliflozin reduces hospitalizations for HF and CV deaths

  • HF benefit


  • Cardiac energy metabolism


  • Overall HF benefits

    • Glycosuria, natriuresis

    • Decrease in preload, afterload, BP

    • Reduction in arterial stiffness

    • Renal protection → Reduction in renal blood flow and GFR

    • Improved cardiac energy metabolism

  • ADR

    • Diuresis, hypotension, dehydration

    • Slight increase in LDL cholesterol

    • UTI

    • Fournier’s gangrene

    • Risk of bladder and breast cancer

    • Increased fracture risk

    • Diabetic ketoacidosis

  • Sotagliflozin

    • Dual inhibitor of SGLT1/2

      • SGLT1-i: reduces intestinal absorption of glucose and sodium → Diarrhea

    • ADR: UTI, volume depletion, hypoglycemia, dizziness, genital mycotic infection

Summary