What is the pathophysiology of heart failure, including the role of decreased cardiac output, Renin-Angiotensin-Aldosterone System (RAAS) and Sympathetic Nervous System (SNS) activation?

Pathophysiology of Heart Failure

The Central Pathophysiologic Derangement

Heart failure fundamentally begins with diminished cardiac output when myocardial dysfunction prevents the heart from pumping sufficient blood at normal pressures to meet metabolic demands, triggering a cascade of compensatory mechanisms that ultimately become maladaptive and perpetuate cardiac deterioration. 1

The Initiating Cardiac Injury and Hemodynamic Consequences

• Myocardial injury (from ischemia, infarction, hypertension, or cardiomyopathy) impairs ventricular contractility, reducing stroke volume and cardiac output 2, 3
• Decreased cardiac output leads to reduced blood pressure and impaired tissue oxygen delivery, creating the perceived threat of arterial underfilling 2, 1
• Elevated ventricular filling pressures develop as diastolic dysfunction progresses, transmitting backward through the pulmonary circulation to cause pulmonary capillary wedge pressure elevation 2
• Reduced coronary perfusion pressure results from elevated end-diastolic pressures, further impairing myocardial contractility in a self-perpetuating cycle 1

Neurohormonal Activation: The Compensatory Response That Becomes Pathologic

Renin-Angiotensin-Aldosterone System (RAAS) Activation

• RAAS activates in response to perceived arterial underfilling and renal hypoperfusion, representing a primitive survival response to maintain blood pressure and intravascular volume 2, 3
• Renin release from juxtaglomerular cells increases angiotensin II production, which causes systemic vasoconstriction, increased afterload, and direct myocardial toxicity 4, 3
• Aldosterone secretion promotes sodium and water retention by the kidneys, increasing preload and contributing to volume overload 2, 4
• Chronic angiotensin II exposure produces eccentric ventricular hypertrophy, progressive ventricular remodeling, myocyte apoptosis, and interstitial fibrosis 2, 4
• Aldosterone independently drives myocardial fibrosis, vascular stiffness, and endothelial dysfunction even when angiotensin II is blocked 4

Sympathetic Nervous System (SNS) Activation

• SNS activation occurs early in heart failure, even in patients with asymptomatic left ventricular dysfunction, before RAAS activation becomes prominent 2, 3
• Increased catecholamine release (norepinephrine and epinephrine) initially augments cardiac contractility and heart rate to maintain cardiac output 2, 3
• Chronic sympathetic overstimulation causes β1-adrenergic receptor downregulation and desensitization, resulting in blunted chronotropic reserve and reduced contractile response to exercise 2
• Peripheral vasoconstriction mediated by α-adrenergic receptors increases systemic vascular resistance and afterload, further stressing the failing heart 2, 3
• Direct myocardial toxicity from sustained catecholamine exposure promotes myocyte hypertrophy, apoptosis, and arrhythmogenesis 4, 3

Additional Neurohormonal Mediators

• Vasopressin (ADH) is released non-osmotically, causing water retention and hyponatremia 2
• Endothelin levels increase, promoting vasoconstriction and adverse remodeling 2
• Natriuretic peptides (ANP, BNP) are released from stretched atria and ventricles as counterregulatory hormones, but peripheral resistance develops 2

The Vicious Cycle: From Compensation to Decompensation

• Neurohormonal activation creates maladaptive bidirectional organ cross-talk where cardiac dysfunction triggers systemic responses that perpetuate cardiac deterioration 1
• Sodium and water retention from RAAS and SNS activation increases preload, elevating ventricular filling pressures and worsening pulmonary and systemic congestion 2, 1
• Increased afterload from systemic vasoconstriction further reduces cardiac output and stroke volume, intensifying the neurohormonal response 3
• Progressive ventricular remodeling occurs with myocyte hypertrophy, chamber dilatation, wall thinning, and spherical shape change, reducing mechanical efficiency 2
• Myocardial fibrosis and extracellular matrix remodeling stiffen the ventricle, impairing both systolic and diastolic function 2

Clinical Manifestations: The Syndrome of Heart Failure

Manifestations of Low Cardiac Output

• Fatigue and exercise intolerance result from inadequate oxygen delivery to skeletal muscles during exertion 2
• Skeletal muscle hypoperfusion occurs as only 50-60% of cardiac output reaches exercising muscles (versus 90% in normal subjects), due to excessive vasoconstriction 2
• Cold extremities and confusion reflect peripheral hypoperfusion and reduced cerebral blood flow 2
• Renal hypoperfusion causes oliguria, azotemia, and progressive kidney dysfunction 1

Manifestations of Venous Congestion

• Pulmonary congestion from elevated left atrial and pulmonary venous pressures causes dyspnea, orthopnea, and paroxysmal nocturnal dyspnea 2
• Pulmonary edema develops when pulmonary capillary wedge pressure exceeds oncotic pressure 2
• Systemic venous congestion from right heart failure causes jugular venous distension, hepatomegaly, ascites, and peripheral edema 2, 1
• Hepatic congestion elevates liver enzymes (typically 2-3 times normal) and can progress to cardiac cirrhosis with chronic severe congestion 5

Arrhythmogenic Manifestations

• Atrial fibrillation develops from atrial stretch, fibrosis, and altered calcium handling, creating a bidirectional relationship where AF begets HF and HF begets AF 2
• Ventricular arrhythmias result from myocardial fibrosis, electrolyte abnormalities, and catecholamine toxicity 3

Critical Pathophysiologic Pitfalls

• Diuretics activate RAAS through two mechanisms: volume depletion triggers compensatory neurohormonal responses, and direct blockade of sodium transporters at the macula densa stimulates renin secretion 2
• Rate control alone in atrial fibrillation may not improve symptoms because rhythm irregularity itself decreases cardiac output independent of ventricular rate 2
• Venous congestion, not low cardiac output, is the dominant mechanism causing organ dysfunction (kidney, liver) in most heart failure patients 5, 1
• Inotropic agents that increase contractility through β-adrenergic stimulation or phosphodiesterase inhibition worsen long-term outcomes despite short-term hemodynamic improvement 2