What is the pathophysiology of heart failure?

Pathophysiology of Heart Failure

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

Central Pathophysiologic Derangement

The core problem in heart failure is diminished cardiac output occurring when myocardial dysfunction prevents the heart from pumping sufficient blood at normal cardiac pressures to meet metabolic demands. 1

• Left ventricular dysfunction decreases blood pressure and impairs 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—creating a self-perpetuating cycle. 1

The Neurohormonal Activation Cascade

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

• 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
• The hyperactive sympathetic nervous system pushes the heart to work at a level much higher than the cardiac muscle can handle, conferring significant toxicity to the failing heart and markedly increasing morbidity and mortality. 2

Venous Congestion: The Critical Pathophysiologic Driver

Venous congestion is the pathophysiological cornerstone of acute heart failure, more important than low cardiac output in determining worsening kidney function in most patients. 1

• Systemic venous congestion decreases venous return to right cavities and increases left filling pressures, leading to impaired organ perfusion of kidneys, liver, lungs, and gut. 1
• Venous congestion decreases the arteriovenous pressure gradient, reducing renal perfusion pressure and compromising kidney function. 3
• Increased right-sided venous filling pressure is a major determinant of worsening kidney function in heart failure across the ejection fraction spectrum. 3
• Kidney venous hypertension increases hydrostatic pressures in both peritubular capillaries and the interstitium, enhancing lymphatic outflow and promoting washout of proteins. 3

Renal Dysfunction and the Cardiorenal Axis

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

• Venous congestion causes elevated urinary angiotensinogen primarily through increased kidney interstitial pressure, enhanced RAAS activation, and altered intrarenal hemodynamics. 3
• Right atrial pressure is independently associated with glomerular filtration rate, even after adjusting for renal blood flow, highlighting the importance of venous congestion in renal function. 3
• Venous congestion triggers activation of the RAAS and sympathetic nervous system, increasing sodium reabsorption and perpetuating the vicious cycle of congestion. 3

Cardiac Remodeling and Structural Changes

• Depressed contractility results in reduction of blood pressure, leading to compensatory neurohormonal activation and vasoconstriction, which significantly elevate afterload, further reduce stroke volume, and lead to deleterious cardiac remodeling. 4
• Localized ventricular remodeling adversely affects contractile function through structural changes in cardiac muscle cells and in the shape of the ventricular chamber. 5

Clinical Consequences and Pitfalls

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

• 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
• Common pitfall: Focusing solely on low cardiac output rather than recognizing venous congestion as the primary driver of organ dysfunction and clinical decompensation. 1
• Common pitfall: Failing to recognize that although systemic neurohormonal blockade slows disease progression, localized ventricular remodeling still adversely affects contractile function. 6