What is the pathophysiology of heart failure?

Pathophysiology of Heart Failure

Heart failure pathophysiology is fundamentally characterized by maladaptive bidirectional organ cross-talk, where cardiac dysfunction triggers a vicious cycle of neurohormonal activation, venous congestion, and progressive multi-organ deterioration that perpetuates cardiac decompensation. 1

Core Pathophysiologic Mechanisms

Initial Cardiac Insult and Hemodynamic Derangement

• The central pathophysiologic derangement is diminished cardiac output, which occurs when myocardial dysfunction prevents the heart from pumping sufficient blood at normal cardiac pressures to meet metabolic demands, especially during exercise 1, 2
• Cardiac injury from any cause (myocardial infarction, hypertension, valvular disease, tachyarrhythmias, or cardiomyopathy) initiates the cascade by reducing stroke volume and cardiac output 2, 3
• Left ventricular dysfunction leads to decreased blood pressure with impaired tissue oxygen delivery, triggering compensatory mechanisms that ultimately become maladaptive 1
• Impaired cardiac output and progressive diastolic dysfunction raise ventricular end-diastolic pressures, which reduce coronary perfusion pressure, further impairing myocardial contractility and stroke volume 1

The Vicious Cycle of Neurohormonal Activation

• Activation of the sympathoadrenergic and renin-angiotensin-aldosterone system (RAAS) occurs in response to perceived low cardiac output, initially serving as compensatory mechanisms but becoming deleterious with disease progression 1, 4, 3
• The ANS hyperactivity, while acutely restoring cardiac function, becomes a major problem in chronic heart failure by conferring significant toxicity to the failing heart and markedly increasing morbidity and mortality 4
• Neurohormonal activation leads to systemic vasoconstriction, which significantly elevates afterload, further reduces stroke volume, and leads to deleterious cardiac remodeling 2, 5
• These pathophysiological pathways extend across hemodynamic, neurohormonal, and inflammatory axes, creating maladaptive bidirectional cross-talk where acute or chronic dysfunction of one organ drives dysfunction in other organs 1

Venous Congestion: The Pathophysiological Cornerstone

• Venous congestion is the pathophysiological cornerstone of acute heart failure, more important than low cardiac output in determining worsening kidney function in most patients 6
• Systemic venous congestion decreases venous return to right cavities (causing systemic interstitial fluid accumulation) and increases left filling pressures (causing pulmonary fluid accumulation), leading to impaired organ perfusion of kidneys, liver, lungs, and gut 1
• Increased right-sided venous filling pressure is a major determinant of worsening kidney function across the ejection fraction spectrum 6
• Venous congestion triggers RAAS and sympathetic nervous system activation, increasing sodium reabsorption and perpetuating the vicious cycle of congestion 6
• Kidney venous hypertension increases hydrostatic pressures in peritubular capillaries and interstitium, enhancing lymphatic outflow and promoting protein washout 6

Renal Dysfunction and Fluid Retention

• When contractility is reduced, alterations in the kidneys induce fluid retention to compensate for perceived low output and reduced circulating blood volume 2
• The renal response to impaired glomerular perfusion increases tubular sodium reabsorption and activates the renin-angiotensin-aldosterone axis, resulting in further volume overload and compromised diuretic effectiveness 1
• Fluid retention causes increased preload or filling pressure and symptoms of pulmonary congestion 2
• Suboptimal decongestion, diuretic resistance, and low use rates of guideline-directed medical therapy contribute to unacceptably high rates of death, hospitalizations, decline in kidney function, and poor quality of life 1

Inflammatory and Microcirculatory Dysfunction

• In response to tissue ischemia and necrosis, released inflammatory mediators further impair tissue metabolism and induce nitric oxide production, causing systemic vasodilation and exacerbating hypotension 1
• Hypoxia and pulmonary inflammation induce pulmonary vasoconstriction, increasing biventricular afterload and myocardial oxygen demand 1
• Sympathetically mediated splanchnic vasoconstriction worsens volume overload by redistributing 50% of total blood volume back to the circulation 1
• Augmented ventricular filling pressures further worsen myocardial efficiency and ischemia, especially within the right ventricle 1

Phenotypic Variations

Heart Failure with Reduced Ejection Fraction (HFrEF)

• HFrEF is centered on a reactive model where a significant initial insult leads to reduced cardiac output, triggering a cascade of maladaptive processes 5
• Predisposing factors include myocardial injury of any cause, chronically abnormal loading due to hypertension, valvular disease, or tachyarrhythmias 5
• The pathophysiologic processes behind remodeling reflect systemic neurohormonal activation, peripheral vascular effects, and localized changes affecting the cardiac substrate 5
• Although systemic neurohormonal blockade slows disease progression, localized ventricular remodeling still adversely affects contractile function 5

Cardiogenic Shock: The Most Severe Form

• Cardiogenic shock represents the most severe form of heart failure, with pathophysiology comprising overlapping components including reduced cardiac output, hemodynamic alterations, microcirculatory dysfunction, and systemic inflammatory response 1
• Compensatory mechanisms to reduce cardiac output include systemic vasoconstriction, which improves coronary and peripheral perfusion but increases cardiac afterload, leading to organ failure 1
• Systemic inflammation induced by cardiac injury leads to pathological vasodilation (high levels of nitric oxide), negative inotropic effects, and release of vasodilating inflammatory mediators 1
• Macro and micro-hemodynamic alterations lead to multi-organ dysfunction 1

Clinical Implications

• The occurrence of organ dysfunction during heart failure is associated with poor outcomes, making early identification and treatment of congestion and diuretic resistance essential 1
• Understanding that venous congestion, rather than low cardiac output, is the primary driver of kidney dysfunction in most patients fundamentally changes therapeutic approach 6
• The complex interplay of neurohormonal mechanisms that become activated to sustain cardiac output ultimately becomes maladaptive if the cardiac insult persists over time 4
• Efficient and personalized strategies to achieve decongestion while optimizing implementation of evidence-based therapies that modify the trajectory of heart failure are essential to reduce adverse outcomes and premature death 1