7: Pathophysiology of Heart Failure

Pathophysiology of Heart Failure

• Heart failure is the inability of the heart to deliver adequate blood flow and oxygen to organs, or to do this only at elevated filling pressures.

Learning Objectives

• Define heart failure and list major causes
• Differentiate between systolic (HFrEF) and diastolic dysfunction (HFpEF)
• Explain how systolic dysfunction affects Frank-Starling curves, pressure-volume loops (EDV, ESV, EF), and ventricular compliance
• Explain how diastolic dysfunction affects ventricular compliance and pressure-volume loops (EDV, ESV, EF)
• Describe the beneficial and deleterious effects of neurohumoral compensatory responses to heart failure
• Describe how heart failure impairs the cardiovascular responses to exercise

Definition of Heart Failure

• Inability of the heart to deliver adequate blood flow and oxygen to organs or perform this task only at elevated filling pressures.

Two Major Categories of Heart Failure

• Heart Failure with Reduced Ejection Fraction (HFrEF):
  • Systolic dysfunction: Loss of the heart's ability to contract, resulting in decreased forward flow and clinical symptoms. Ejection Fraction (EF) ≤40%.
• Heart Failure with Preserved Ejection Fraction (HFpEF):
  • Diastolic dysfunction: Impaired ventricular filling with elevated filling pressures leading to decreased forward flow and clinical symptoms. Ejection Fraction (EF) ≥50%.

Causes of Heart Failure

• HFrEF:
  • Ischemic heart disease and infarction
  • Dilated cardiomyopathies
  • Myocarditis
  • Persistent tachycardia
  • Chronic volume and pressure overload
  • Valve disease
  • Chronic hypertension
  • Congenital cardiac defects
  • Pregnancy
• HFpEF:
  • Ventricular concentric hypertrophy caused by:
    • Chronic hypertension
    • Aortic valve stenosis
    • Genetic defect (hypertrophic cardiomyopathy, HCM)
  • Restrictive cardiomyopathy
  • Cardiac tamponade
  • Impaired relaxation (e.g., ischemia)

Neurohumoral Compensation in Heart Failure

• Sympathetic nerves and catecholamine release are activated by:
  • Baroreceptor reflex (acute failure)
  • Cardiac stretch receptors
  • Chronic, central sympathetic activation
  • Increased circulating angiotensin II (peripheral and central effects)
• RAAS activated by:
  • Reduced renal perfusion
  • Increased sympathetic activity
  • Enhanced release of vasopressin (stimulated by sympathetic activation and angiotensin II) and ANP (stimulated by atrial distension)

Summary of Neurohumoral Responses to Heart Failure

• Increased systemic vascular resistance, arterial pressure and blood volume, and venous pressures
• Increased blood volume leads to pulmonary and systemic edema.
• This response of the body’s systems causes the heart to work harder.

Sympathetic Activation and Catecholamine Release

• Acute heart failure:
  • Hypotension causes decreased firing of arterial baroreceptors, leading to reflex sympathetic activation.
  • Sympathetic stimulation releases adrenal catecholamines.
• Chronic heart failure:
  • Central activation of the sympathetic system is stimulated by angiotensin and cardiopulmonary receptors.

Renin-Angiotensin-Aldosterone System (RAAS) Activation

• Activated by:
  • Reduced renal perfusion
  • Sympathetic stimulation
• Causes:
  • Renal retention of sodium and water
  • Increased blood volume and venous pressures
  • Vascular constriction
  • Stimulates vasopressin (ADH) release
  • Enhance sympathetic activity
  • Cardiac remodeling

Natriuretic Peptides (ANP)

• Release:
  • Synthesized and released by atria
  • Release stimulated by atrial stretch
  • Sympathetic stimulation
  • Angiotensin II (AII)
• Actions:
  • Inhibits RAAS system, promoting natriuresis and diuresis.
  • Causes arterial and venous vasodilation
  • Lowers arterial and venous pressures

Vasopressin (ADH) Release

• Activated by:
  • Sympathetic stimulation
  • Increased angiotensin II
  • Hyperosmolarity
  • Decreased atrial receptor firing
• Causes:
  • Renal reabsorption of water (H2O)
  • Increased blood volume and venous pressures
  • Arterial constriction

Benefits of Neurohumoral Activation

• Increased blood volume helps maintain stroke volume via the Frank-Starling mechanism.
• Cardiac stimulation and systemic vasoconstriction help maintain arterial pressure to support vital organ perfusion.
• Cardiac remodeling

Deleterious Effects of Neurohumoral Activation

• Increased blood volume causes increased venous pressures, leading to pulmonary and systemic edema.
• Systemic vasoconstriction increases afterload and impairs ventricular ejection.
• Stimulates molecular and biochemical changes that promote cardiac dysfunction over time.
• Promotes arrhythmias.

Heart Failure Signs and Symptoms

• Cause(s):
  • Exertional dyspnea: Pulmonary edema, affecting gas exchange; chemoreceptor responses
  • Exercise intolerance: Impaired oxygen delivery to muscles.
  • Cognition deficits, Fatigue: Impaired brain and peripheral blood flow
  • Cough or wheezing: Pulmonary edema caused left heart failure, increased blood volume
  • Swelling of legs, abdomen: Systemic edema, caused by right heart failure, increased blood volume.
  • Arrhythmias: Remodeling of cardiac chambers (stretching, hypertrophy); myocardial ischemia.
  • Cardiac murmurs : Chamber dilation, causing valve regurgitation

Systolic Dysfunction

• Acute loss of inotropy reduces Stroke Volume (SV) and Ejection Fraction (EF) at a given ventricular preload.
• Cardiac compensation includes ventricular dilation (may not involve remodeling), increased end-diastolic volume and pressure, and increased heart rate.
• Acute systolic dysfunction results in reduced SV, resulting in a decreased stroke work.

Effects of Acute Systolic Dysfunction on Pressure-Volume Loops

• Loss of intrinsic inotropy (↓ESPVR) causes a reduction in stroke volume.
• This is followed by a decrease in systolic and diastolic aortic pressures
• Cardiac compensation includes ventricular passive dilation (not remodeling), increased end-diastolic volume and pressure, and increased heart rate.

Acute vs. Chronic Systolic Dysfunction and Ventricular Compliance

• Ventricular compliance is inversely related to cardiac stiffness.
• Acute dysfunction moves up the normal ventricular compliance curve, resulting in an elevated end-diastolic pressure.
• Chronic dysfunction leads to increased compliance and end-diastolic volume, but reduces the increase in end-diastolic pressure

Effects of Chronic Systolic Dysfunction on Ventricular Pressure-Volume Relationship

• Loss of inotropy leads to decreased systolic pressure reserve (ESPVR).
• Chronic dilation (remodeling) increases compliance but results in a decreased end-diastolic volume/pressure reserve.

HFrEF: Cardiopulmonary & Systemic Changes

• Reduced stroke volume (SV) and Ejection Fraction (EF).
• Increased filling pressures (elevated LVEDV, LVEDP, LAP, RVEDP, and RAP, pulmonary pressures).
• Pulmonary congestion and edema
• Increased blood volume
• Systemic edema

Diastolic Dysfunction

• Reduced ventricular compliance leads to increased end-diastolic pressure (EDP).
• A given EDV leads to increased pressure.
• Diastolic dysfunction often increases end-diastolic pressure (EDP).

Effects of Diastolic Dysfunction on Ventricular Pressure-Volume Relationship

• Reduced ventricular compliance leads to lower preload volume (EDV) and higher preload pressure (EDP).
• Reduced stroke volume (SV) may result from reduced afterload.
• Ratio of stroke volume to EDV may not change significantly

HFpEF: Cardiopulmonary & Systemic Changes

• Reduced Stroke Volume (SV), but normal Ejection Fraction (EF).
• Increased filling pressures (elevated LVEDV, LVEDP, LAP, RVEDP, and RAP, pulmonary pressures).
• Pulmonary congestion and edema.
• Increased blood volume.
• Systemic edema.

Combined Systolic and Diastolic Dysfunction

• Decreased ejection (systolic dysfunction) leads to increased End-systolic Volume (ESV) and reduced peak systolic pressure.
• Decreased filling (diastolic dysfunction) leads to decreased End-diastolic volume (EDV) and reduced preload pressure.
• Results in reduced stroke volume (SV) and ejection fraction (EF), increased end-diastolic pressure (EDP), and reduced stroke work.

Impaired Exercise Responses in Heart Failure

• Maximal cardiac output is reduced, limited by dyspnea and fatigue.
• Normal increases in stroke volume are reduced.
• Impaired inotropic responses in heart failure patients.
• Dyspnea and muscle fatigue limit exercise.
• Impaired gas exchange, caused by pulmonary congestion/edema and impaired pulmonary perfusion, coupled to respiratory fatigue.
• Skeletal muscle fatigue caused by insufficient oxygen delivery.

CV responses in CHF patients

• Maximal cardiac output is reduced.
• Maximal heart rate is limited by dyspnea and fatigue.
• Normal increases in stroke volume are reduced.
• Impaired inotropic responses (particularly in HFrEF patients).
• Dyspnea and muscle fatigue limit exercise response and causes impaired gas exchange, caused by pulmonary congestion and edema and impaired pulmonary perfusion/coupled to respiratory fatigue.
• Skeleteal muscle fatigue resulting from insufficient oxygen delivery to contracting muscles.

Answers to Questions

• Q1: Decreased ventricular compliance (D) causes ESV to increase and SV to decrease during systolic dysfunction.
• Q2: Reducing afterload with arterial vasodilation helps improve left ventricular ejection during systolic dysfunction because it increases myocyte shortening velocity and ejection velocity, which then decreases ESV and ultimately increases stroke volume (SV). (D)
• Q3: Left ventricular diastolic dysfunction causes pulmonary edema because it leads to increases in LVEDP and LVEDV, thus increasing pulmonary capillary hydrostatic pressure. (C)