2.2 Pathophysiology of CAD, ACS & Heart Failure Syndromes

2.2 Pathophysiology of CAD, ACS & Heart Failure Syndromes

[!NOTE] ANCC Clinical Foundation: Domain I requires mastery of coronary plaque biology, the transition from ischemia to necrosis, ECG territorial mapping, heart failure staging paradigms, neurohormonal pathways, and the hemodynamic collapse of cardiogenic shock. These mechanisms guide clinical risk stratification and rapid intervention.

Cardiovascular disease spans a continuum from intimal endothelial injury to acute coronary syndromes, progressive ventricular remodeling, and cardiogenic shock.

---

Atherogenesis & Vulnerable Plaque Biology

Atherosclerosis is an active, lipid-driven inflammatory disease of the arterial intima:

1. Endothelial Dysfunction: Hemodynamic shear stress, smoking, hypertension, and hyperlipidemia injure endothelial cells, impairing synthesis of nitric oxide (NO) and prostacyclin ($PGI_2$). Endothelial permeability increases, and adhesion molecules (VCAM-1, ICAM-1) are upregulated.
2. LDL Infiltration & Oxidation: Circulating low-density lipoproteins enter the subendothelial space, binding to intimal proteoglycans. Trapped LDL undergoes oxidation by reactive oxygen species into oxidized LDL (ox-LDL), which is cytotoxic and chemotactic.
3. Monocyte Recruitment & Foam Cells: Monocytes adhere to VCAM-1, transmigrate into the intima, and differentiate into macrophages. Macrophages ingest ox-LDL via unregulated scavenger receptors (SR-A, CD36), transforming into lipid-laden foam cells. Clusters of foam cells form the earliest visible lesion: the fatty streak.
4. Fibrous Cap Formation: Cytokines released by macrophages and $Th_1$ lymphocytes stimulate vascular smooth muscle cells (VSMCs) to migrate from the media to the intima. VSMCs proliferate and synthesize extracellular matrix (type I and III collagen), forming a protective fibrous cap over the necrotic lipid core.
5. Plaque Vulnerability: Stable plaques feature thick, collagen-rich caps and small, quiescent cores. In contrast, vulnerable plaques have a thin fibrous cap ($<65\ \mu m$), a large necrotic lipid core ($>40%$ of plaque volume), and dense macrophage infiltration at the cap shoulders. Macrophages secrete matrix metalloproteinases (MMPs) that degrade collagen, predisposing the cap to rupture.

---

Plaque Disruption, Platelet Cascades & ACS Spectrum

Acute Coronary Syndromes (ACS) result from sudden disruption of an atherosclerotic plaque:

• Primary Hemostasis:
  1. Adhesion: Plaque rupture exposes subendothelial collagen and von Willebrand factor (vWF). Platelets adhere via Glycoprotein Ib (GP Ib) binding to vWF and GP VI binding to collagen.
  2. Activation: Platelets degranulate, releasing adenosine diphosphate (ADP) from dense granules and generating thromboxane $A_2$ ($TXA_2$) via cyclooxygenase-1 (COX-1). ADP binds to platelet $P2Y_{12}$ receptors, amplifying activation.
  3. Aggregation: Inside-out signaling activates surface Glycoprotein IIb/IIIa ($GP\ IIb/IIIa$) receptors. Soluble fibrinogen bridges GP IIb/IIIa receptors on adjacent platelets, forming a platelet plug.
• Secondary Hemostasis: Plaque Tissue Factor (TF) activates the extrinsic coagulation cascade, generating thrombin (Factor IIa), which cleaves fibrinogen into insoluble fibrin strands, consolidating the thrombus.

Ischemia, Injury & Infarction

• Ischemia: Reversible cellular hypoxia causing repolarization abnormalities: symmetrical T-wave inversion or flat/downsloping ST-segment depression ($>0.5$ mm).
• Injury: Severe, prolonged cellular hypoxia causing resting membrane potential leakage, producing ST-segment elevation ($>1$ to $2$ mm).
• Infarction: Irreversible myocyte necrosis beginning within 20 to 30 minutes of complete occlusion. Necrotic tissue cannot conduct electrical currents, creating pathologic Q waves ($>0.04$ s duration, $>25%$ of R-wave amplitude).

Wavefront of Necrosis & ACS Classification

Necrosis advances as a wavefront from the vulnerable subendocardium outward toward the epicardium over 6 to 12 hours. Transmural (full-thickness) infarction causes severe wall motion abnormalities and electrical silence.

---

Heart Failure Classifications, Stages & Phenotypes

Heart failure is classified by left ventricular ejection fraction (LVEF) according to universal guidelines:

• HFrEF (Reduced EF): $\text{LVEF} \le 40%$. Primary systolic failure characterized by impaired contractility, chamber dilation, and eccentric hypertrophy.
• HFmrEF (Mildly Reduced EF): $\text{LVEF } 41% \text{ to } 49%$. Intermediate phenotype benefiting from guideline-directed medical therapy.
• HFpEF (Preserved EF): $\text{LVEF} \ge 50%$ with objective evidence of elevated LV filling pressures. Characterized by diastolic dysfunction (impaired relaxation and increased myocardial stiffness) and concentric remodeling.
• HFimpEF (Improved EF): Baseline $\text{LVEF} \le 40%$ with a follow-up measurement $>40%$ (requiring continuation of GDMT).

ACC/AHA Stages vs. NYHA Functional Classes

---

Neurohormonal Activation & Adverse Ventricular Remodeling

A reduction in cardiac output triggers neurohormonal compensatory responses that become maladaptive over time:

1. Sympathetic Nervous System (SNS): Carotid and aortic baroreceptor unloading triggers sympathetic outflow. Epinephrine and norepinephrine stimulate $\beta_1$-adrenergic receptors (increasing heart rate and contractility) and $\alpha_1$-adrenergic receptors (vasoconstriction). Chronic stimulation causes $\beta_1$-receptor downregulation, intracellular calcium overload, myocyte apoptosis, and ventricular arrhythmias.
2. Renin-Angiotensin-Aldosterone System (RAAS): Renal hypoperfusion triggers renin release from juxtaglomerular cells. Renin converts angiotensinogen to angiotensin I, and ACE converts it to Angiotensin II (Ang II). Ang II drives systemic vasoconstriction and stimulates cardiac fibroblasts, inducing myocyte hypertrophy and collagen fibrosis. Ang II stimulates adrenal secretion of aldosterone, which promotes renal sodium and water retention in exchange for potassium and magnesium excretion, driving myocardial interstitial fibrosis.
3. Arginine Vasopressin (AVP / ADH): Non-osmotic AVP release stimulates collecting duct $V_2$ receptors, promoting pure water reabsorption. This produces dilutional hyponatremia, a strong marker of disease severity.
4. Counter-Regulatory Natriuretic Peptides: Atrial stretch releases ANP, while ventricular wall stress releases BNP and NT-proBNP. Natriuretic peptides promote natriuresis, diuresis, and vasodilation, but are degraded by neprilysin and overwhelmed by chronic RAAS and SNS hyperactivity.
5. Adverse Ventricular Remodeling: Neurohormonal stimulation, wall stress, and inflammatory cytokines cause cardiomyocytes to elongate and die. Non-contractile fibrous collagen replaces myocytes, shifting ventricular geometry from an efficient ellipse to a dilated sphere. Papillary muscles displace laterally, causing secondary (functional) mitral regurgitation.

---

Pathophysiology of Cardiogenic Shock

Cardiogenic shock represents severe systemic hypoperfusion resulting from primary cardiac failure:

• Hemodynamic Diagnostic Criteria: Sustained SBP $<90$ mmHg (or vasopressor requirement to maintain MAP $\ge 65$ mmHg), $\text{Cardiac Index} \le 2.2\ \text{L/min/m}^2$ (or $\le 1.8\ \text{L/min/m}^2$ without support), and elevated filling pressures ($\text{PAOP} > 15\text{ mmHg}$, $\text{CVP} > 10\text{ mmHg}$).
• The Downward Spiral: Marked contractility loss reduces stroke volume and mean arterial pressure. Because Coronary Perfusion Pressure equals diastolic blood pressure minus PAOP ($CPP = DBP - PAOP$), hypotension combined with elevated LV filling pressures starves coronary flow, worsening myocardial ischemia. Concurrently, elevated PAOP causes severe hydrostatic pulmonary edema and hypoxemia. Compensatory sympathetic vasoconstriction elevates SVR ($>1600-2000\ \text{dynes}\cdot\text{s/cm}^5$), imposing excessive afterload on the failing ventricle. Tissue hypoperfusion releases inflammatory cytokines (IL-6, TNF-$\alpha$) and induces inducible nitric oxide synthase (iNOS), culminating in multiorgan dysfunction.