Heart Failure: Pathophysiology and Pharmacology

What is heart failure (HF)?

A clinical syndrome where the heart cannot pump sufficient blood to meet the metabolic needs of the body

What is the most common cause of heart failure?

Low cardiac output due to cardiac dysfunction

What is high-output heart failure?

A condition where the heart is functionally normal but metabolic demands exceed cardiac output

What causes high-output heart failure?

Excessive increase in the body's metabolic demands that outpaces cardiac output

What are the three main ways heart failure is classified?

• Ejection fraction

• Left or Right ventricle

• Chronic vs acute-decompensated

What is HFrEF?

Heart failure with reduced ejection fraction characterized by EF ≤ 40% and systolic dysfunction

What type of dysfunction is seen in HFrEF?

Systolic (contraction) dysfunction

What is HFpEF?

Heart failure with preserved ejection fraction characterized by EF ≥ 50% and diastolic dysfunction

What type of dysfunction is seen in HFpEF?

Diastolic (filling) dysfunction

What is HFmrEF?

Heart failure with mid-range ejection fraction defined as EF 41-49% with HF symptoms

What is HFrecEF?

Heart failure with recovered ejection fraction where EF > 40% but was previously ≤ 40%

What is the formula for ejection fraction (EF)?

EF = SV / EDV * 100

What does stroke volume (SV) represent in EF calculation?

The amount of blood ejected from the ventricle per beat

What does end-diastolic volume (EDV) represent in EF calculation?

The volume of blood in the ventricle at the end of filling

What is left ventricular failure associated with?

Pulmonary congestion

What are common symptoms of left-sided heart failure?

Shortness of breath and fatigue

What is right ventricular failure associated with?

Systemic congestion

What are common features of right-sided heart failure?

Peripheral and abdominal fluid accumulation

What is the relationship between left-sided and right-sided heart failure?

Failure of one ventricle often leads to failure of the other

What is the most common cause of right-sided heart failure?

- Left-sided heart failure

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

- Cor pulmonale

What is cor pulmonale?

Right-sided heart failure caused by lung disease

What are the most common causes of heart failure?

Coronary artery disease and hypertension

What is the major cause of HFrEF?

Coronary artery disease ((MI) or ischemia)

What are other causes of HFrEF?

- Dilated cardiomyopathies

- Pressure overload

- Volume overload

- Rate and rhythm disorders

What is the primary pathophysiologic issue in HFpEF?

Increased ventricular stiffness and impaired relaxation

What are common causes of HFpEF?

- Ventricular hypertrophy

- Infiltrative myocardial diseases

- MI or ischemia

- Mitral or tricuspid valve stenosis

- Pericardial disease

What triggers neurohumoral activation in heart failure?

Decreased cardiac output

What are neurohumoral responses in heart failure?

Compensatory mechanisms activated to maintain perfusion

What role does angiotensin II play in HF?

Causes vasoconstriction and contributes to pathophysiology

What system releases norepinephrine and epinephrine in HF?

Sympathetic nervous system (SNS)

What is the main beneficial neurohumoral response in HF?

Natriuretic peptides

What is the overall purpose of neurohumoral responses in HF?

To compensate for decreased cardiac output and maintain perfusion

What is the most important compensatory mechanism in heart failure?

Myocardial hypertrophy

What is the initial benefit of myocardial hypertrophy in HF?

Helps maintain cardiac performance

What are key features of ventricular remodeling?

Dilation of the cardiac wall and structural changes in myocardium

Which neurohormones drive ventricular remodeling?

Angiotensin II, norepinephrine, aldosterone, and vasopressin

Where is ANP produced?

Atria (and to some extent ventricles)

What triggers the release of ANP?

Atrial stretching due to increased filling

Where is BNP primarily produced?

Ventricles

What triggers the release of BNP?

Left ventricular dysfunction or early heart failure

What is the effect of natriuretic peptides on blood vessels?

Vasodilation leading to decreased blood pressure

What is the effect of natriuretic peptides on sodium balance?

Increased natriuresis (sodium excretion)

What is the effect of natriuretic peptides on cardiac remodeling?

Antifibrotic and anti-remodeling effects

What is a key physiological trigger for natriuretic peptide release?

- Atrial wall stretch (volume overload)

- Changing from the standing to the supine position

- Exercise

What are the pathological triggers for natriuretic peptide release?

- Heart failure

- Primary aldosteronism

- Chronic renal failure

- Inappropriate ADH secretion syndrome

What enzyme degrades ANP and BNP?

Neprilysin

What is the effect of neprilysin on beneficial HF hormones?

Reduces levels of ANP and BNP

What other molecule does neprilysin break down besides natriuretic peptides?

Angiotensin II

Progression of heart failureL

• Progressive decline in cardiac performance

• Decreased cardiac output

• Increased neurohormones: norepinephrine, angiotensin II, endothelin

• Vasoconstriction → increased afterload

• Increased afterload → decreased ejection fraction

• Decreased EF → further reduced cardiac output

• Creates a vicious cycle of worsening heart failure

What are common symptoms of left-sided heart failure?

- Dyspnea on exertion

- Orthopnea

- Paroxysmal nocturnal dyspnea

- Exercise intolerance

- Tachypnea

- Cough

What are common symptoms of right-sided heart failure?

- Abdominal pain

- Anorexia

- Nausea

- Bloating

- Early satiety

- Ascites

What are signs of left-sided heart failure?

Pulmonary rales and pulmonary edema

What are signs of right-sided heart failure?

- Peripheral edema

- Jugular vein distention

- Hepatojugular reflux

- Hepatomegaly

What are common laboratory/diagnostic tests used in HF?

- ECG

- Thyroid function tests

- Serum creatinine

- Echocardiogram

- BNP/NT-proBNP

What is the role of BNP in HF diagnosis?

Released from the heart in HF and used as a biomarker

Can BNP be used alone to diagnose HF?

No, it must be used as an adjunct

What conditions other than HF can elevate BNP?

- Older age

- Renal dysfunction

- Pulmonary embolism

- Chronic pulmonary disease

How does Sacubitril/Valsartan affect BNP levels?

Increases BNP but not NT-proBNP

What does the NYHA classification focus on?

Symptom severity and functional limitation

What does the ACC/AHA staging system focus on?

Disease progression and structural heart changes

What NYHA classes are typically associated with ADHF?

Class III and Class IV

What is acute decompensated heart failure (ADHF)?

Sudden worsening of HF symptoms requiring urgent care or hospitalization

What symptom pattern is seen in ADHF?

Symptoms at minimal exertion or at rest

What are the key features of ADHF?

- Volume overload (congestion)

- Low cardiac output (hypoperfusion)

- Pulmonary edema

- Possible renal failure

- Hypotension

What is cardiac index?

Cardiac output normalized to body surface area used to assess tissue perfusion

What is pulmonary capillary wedge pressure (PCWP)?

An indirect estimate of left atrial pressure

What does PCWP assess in HF?

Left ventricular filling, mitral valve function, and volume status

What is the primary goal of heart failure treatment?

Diagnose and treat the underlying cause of heart failure

What are the short-term goals of HF treatment?

- Improve hemodynamics

- Avoid hypokalemia

- Prevent renal dysfunction

- Avoid symptomatic hypotension

- Correct neurohumoral activation

What are the long-term goals of HF treatment?

- Control hypertension

- Prevent MI and atherosclerosis

- Reduce hospitalizations

- Improve survival and quality of life

What are the three main components of HF treatment?

- Dietary and lifestyle changes

- Drugs

- Surgery

What hemodynamic effects do ACEIs and ARBs have in HF?

Reduce preload and afterload

How do ACEIs and ARBs affect ventricular remodeling?

Prevent harmful remodeling

What is the overall benefit of ARNI in HF?

Enhances beneficial natriuretic peptide effects while blocking RAAS

What happens to BNP levels with neprilysin inhibition?

BNP levels increase

Why must neprilysin inhibitors be combined with an ARB?

To counteract increased angiotensin II levels

What is a major adverse effect of Sacubitril/Valsartan?

Hypotension

What washout period is required when switching from an ACE inhibitor to ARNI?

36 hours

What is the main rationale for using beta blockers in HF?

Antagonize harmful effects of the sympathetic nervous system and slow disease progression

What are the benefits of beta blockers in HF?

• Antiarrhythmic effects

• Block/reverse ventricular remodeling

• Reduce myocyte death (↓ catecholamine-induced apoptosis/necrosis)

• Improve left ventricular systolic function

• Decrease heart rate and myocardial oxygen demand

• Inhibit plasma renin release

How long does it typically take to see benefits from beta blockers in HF?

A few months

Why might symptoms worsen initially with beta blocker therapy?

Negative inotropic effect reduces cardiac output initially

What are examples of aldosterone antagonists used in HF?

Spironolactone and eplerenone

What is the role of aldosterone in HF?

Causes fluid retention, fibrosis, and electrolyte abnormalities

How do aldosterone antagonists affect cardiac remodeling?

Reduce fibrosis and ventricular remodeling

What additional beneficial effects do aldosterone antagonists have?

Decrease inflammation, atherogenesis, and oxidative stress

What is the main rationale for using diuretics in HF?

Relieve congestion caused by sodium and water retention

What do diuretics primarily reduce in HF?

Preload

Which type of diuretics are relatively weak and used for mild fluid retention?

Thiazide diuretics

In which patients are thiazide diuretics preferred?

Mild fluid retention with elevated blood pressure

Why are thiazides less effective in renal insufficiency?

Reduced tubular secretion when CrCl < 30 mL/min

Which thiazide-like diuretic remains effective in renal insufficiency?

Metolazone

Which diuretics are typically required in HF for volume control?

Loop diuretics

When is combination diuretic therapy used?

In diuretic resistance (loop + thiazide)

What is the mechanism of action of Sodium Nitroprusside?

Nitric oxide donor that increases cGMP causing vascular smooth muscle relaxation

What type of vasodilation does Sodium Nitroprusside cause?

Both arterial and venous dilation

What is the effect of sodium nitroprusside on preload/afterload?

Decreases preload and afterload

How does Sodium Nitroprusside affect cardiac output in severe LV dysfunction?

Increases cardiac output

What are the major adverse effects of Sodium Nitroprusside?

- Hypotension

- Cyanide toxicity

- Thiocyanate toxicity

- Methemoglobinemia

What is the onset of action of Sodium Nitroprusside?

Almost immediate (~30 seconds)