HF Pathophysiology
This occurs when the heart cannot pump enough blood to meet the metabolic demands of the body.
What is heart failure?
Core definition: inability to meet metabolic demand
This class of drugs reduces angiotensin II formation, leading to decreased afterload and preload while also reducing aldosterone secretion.
What are ACE inhibitors?
↓ Ang II → vasodilation + ↓ aldosterone → ↓ preload & afterload
These four medication classes make up the foundational “pillars” of therapy proven to reduce mortality in HFrEF.
What are ARNI (or ACEi/ARB), beta blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors?
Core GDMT = 4 pillars with mortality benefit
This is the only medication class with strong evidence to improve outcomes in HFpEF patients.
What are SGLT2 inhibitors?
Only class with consistent benefit in HFpEF (↓ CV death & HF hospitalization)
This compensatory system is activated in heart failure and increases heart rate, vasoconstriction, and renin release.
What is the sympathetic nervous system (SNS)?
SNS activation is a key early compensatory mechanism in HF
This type of heart failure is characterized by reduced ejection fraction due to impaired contractility and often presents with ventricular dilation.
What is heart failure with reduced ejection fraction (HFrEF)?
Associated with impaired systolic function and low EF
This drug class improves survival in heart failure by blocking β₁-adrenergic receptors, reducing heart rate and sympathetic nervous system activation over time.
What are beta blockers?
↓ SNS activity → improved EF and decreased mortality over time
This class is preferred over ACE inhibitors in HFrEF because it provides additional mortality benefit through neprilysin inhibition.
What is an ARNI (sacubitril/valsartan)?
Superior to ACEi alone in reducing death/hospitalization
These medications are used in HFpEF primarily for symptom relief by reducing volume overload, but they do not improve mortality.
What are diuretics?
Used for congestion control only (no mortality benefit)
This hormone, released from the adrenal cortex in response to RAAS activation, promotes sodium and water retention and contributes to cardiac remodeling.
What is aldosterone?
Leads to ↑ preload and myocardial fibrosis
In this type of heart failure, the ventricle has impaired relaxation and filling, leading to increased filling pressures but a normal ejection fraction.
What is heart failure with preserved ejection fraction (HFpEF)?
Key issue = diastolic dysfunction (filling problem)
This class inhibits the sodium-glucose cotransporter in the proximal tubule, leading to natriuresis and reduced preload, with additional unclear cardioprotective effects.
What are SGLT2 inhibitors?
↑ glucose + Na⁺ excretion → ↓ preload and improved HF outcomes
This class should be initiated only when patients are stable and euvolemic due to its potential to initially worsen symptoms by decreasing cardiac output.
What are beta blockers?
↓ HR → may transiently ↓ CO → start when stable
This underlying condition is the most common cause of HFpEF and leads to left ventricular hypertrophy due to chronic pressure overload.
What is hypertension?
Chronic pressure → LV hypertrophy → impaired relaxation
This type of heart failure leads to pulmonary edema due to increased pressure in the pulmonary circulation.
What is left-sided heart failure?
Blood backs up into lungs → pulmonary congestion
This compensatory mechanism increases cardiac output by increasing preload, based on increased stretch of myocardial fibers leading to stronger contraction.
What is the Frank-Starling mechanism?
Increased preload → increased contractile force
This drug increases intracellular calcium in cardiac myocytes by inhibiting the Na⁺/K⁺ ATPase, indirectly reducing activity of the Na⁺/Ca²⁺ exchanger.
What is digoxin?
↑ intracellular Na⁺ → ↓ Na⁺/Ca²⁺ exchange → ↑ Ca²⁺ → ↑ contractility
This class reduces mortality in HFrEF by blocking aldosterone effects, thereby decreasing sodium retention and myocardial fibrosis.
What are mineralocorticoid receptor antagonists (spironolactone, eplerenone)?
↓ aldosterone → ↓ fibrosis + ↓ preload
This class of medications may be used in HFpEF for blood pressure control and symptom management, but unlike in HFrEF, they have not consistently demonstrated a mortality benefit.
What are ACE inhibitors, ARBs, or ARNIs?
In HFpEF, these are used mainly for comorbidity management (e.g., HTN), not clear mortality benefit
In heart failure, this intracellular pump has reduced activity, leading to impaired calcium reuptake into the sarcoplasmic reticulum during diastole.
What is SERCA (sarcoplasmic reticulum Ca²⁺-ATPase)?
↓ SERCA → impaired relaxation and contractility
In heart failure, decreased SERCA activity and increased Na⁺/Ca²⁺ exchanger activity lead to impaired calcium reuptake and contribute to this abnormal force-frequency relationship.
What is a negative force-frequency relationship in heart failure?
HF causes impaired Ca²⁺ handling → reduced contractility with increased HR
This combination drug works by inhibiting neprilysin to increase natriuretic peptides while simultaneously blocking angiotensin II receptors to prevent RAAS activation.
What is sacubitril/valsartan (ARNI)?
↑ BNP/ANP (via neprilysin inhibition) + ↓ Ang II effects → ↓ remodeling & mortality
In a patient with persistent HFrEF symptoms despite maximally tolerated GDMT, this combination therapy is specifically recommended in self-identified Black patients to further reduce mortality.
What is hydralazine plus isosorbide dinitrate?
Additional mortality benefit in Black patients on GDMT
In HFpEF, this pathophysiologic change results in normal ejection fraction but reduced stroke volume due to decreased ventricular compliance.
What is increased left ventricular stiffness (decreased compliance)?
Stiff ventricle → ↓ filling → ↓ stroke volume despite normal EF
This maladaptive process in chronic heart failure involves changes in ventricular size, shape, and structure, ultimately worsening cardiac function.
What is myocardial remodeling?
Structural changes → progression of HF