5.2 Cardiovascular and Respiratory Pathophysiology

5.2 Cardiovascular and Respiratory Pathophysiology

Exam Focus: Evaluating cardiovascular and respiratory pathophysiology requires understanding vascular remodeling, neurohormonal feedback loops, electrophysiological aberrancies, and pulmonary airflow mechanics. Candidates must master the pathophysiological differences between systolic and diastolic heart failure, ischemic coronary syndromes, cardiac arrhythmias (such as atrial fibrillation and QT prolongation), and obstructive airway diseases (asthma versus COPD) according to Canadian clinical practice standards.

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Cardiovascular Pathophysiology

1. Hypertension: Vascular Remodeling and Pathogenesis

Systemic arterial blood pressure is the mathematical product of Cardiac Output (CO) and Total Peripheral Resistance (TPR):

$\text{Mean Arterial Pressure (MAP)} = \text{Cardiac Output (CO)} \times \text{Systemic Vascular Resistance (SVR)}$

• Primary (Essential) Hypertension ($> 90%$ of cases): Multi-factorial etiology driven by:
  • Sympathetic Nervous System (SNS) Overactivity: Increased circulating catecholamines elevate heart rate, inotropic contractility, and peripheral arteriolar vasoconstriction.
  • Renin-Angiotensin-Aldosterone System (RAAS) Activation: Excessive angiotensin II production promotes potent direct vasoconstriction, vascular smooth muscle hypertrophy, oxidative stress, and aldosterone-mediated renal sodium and water retention.
  • Vascular Endothelial Dysfunction: Reduced bioavailability of the vasodilator nitric oxide (NO) coupled with increased endothelin-1 yields basal vasoconstriction and progressive arterial wall stiffening.
  • Renal Sodium Excretion Defect: A rightward shift in the pressure-natriuresis curve impairs renal sodium excretion at normal arterial pressures.
• Secondary Hypertension ($< 10%$ of cases): Identified by identifiable underlying causes: Renal Artery Stenosis (atherosclerotic or fibromuscular dysplasia), Chronic Kidney Disease, Primary Aldosteronism (Conn's syndrome; unprovoked hypokalemia with suppressed plasma renin), Pheochromocytoma (catecholamine-secreting chromaffin tumor), Cushing's syndrome, Obstructive Sleep Apnea (OSA), and drug-induced etiologies (NSAIDs, systemic decongestants [pseudoephedrine], oral contraceptives, systemic corticosteroids, calcineurin inhibitors [tacrolimus, cyclosporine], and VEGF inhibitors [bevacizumab]).
• Hypertensive Crises ($\text{BP} > 180/120\text{ mmHg}$):
  • Hypertensive Urgency: Severe blood pressure elevation without acute target-organ damage. Managed with oral antihypertensive agents over 24 to 48 hours.
  • Hypertensive Emergency: Severe blood pressure elevation with acute, life-threatening target-organ injury (hypertensive encephalopathy, acute aortic dissection, acute myocardial infarction, acute pulmonary edema, or acute renal failure). Mandates immediate admission to an intensive care setting for titrated intravenous antihypertensive therapy (e.g., labetalol, nicardipine, sodium nitroprusside), aiming for a controlled blood pressure reduction of no more than $20%\text{ to }25%$ within the first hour to prevent cerebral and coronary hypoperfusion.

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|                   PATHOGENESIS OF ATHEROSCLEROSIS                       |
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|                                                                         |
|  1. Endothelial Injury (Hypertension, Smoking, Hyperlipidemia, Toxins)  |
|                                |                                        |
|                                v                                        |
|  2. Subendothelial Infiltration & Oxidation of LDL Particles            |
|                                |                                        |
|                                v                                        |
|  3. Monocyte Adhesion, Transmigration, & Differentiation to Macrophages |
|                                |                                        |
|                                v                                        |
|  4. Scavenger Receptor Uptake of Ox-LDL -> Foam Cell Formation          |
|                                |                                        |
|                                v                                        |
|  5. Fatty Streak Formation & VSMC Proliferation (Fibrous Cap Deposition)|
|                                |                                        |
|                                v                                        |
|  6. Plaque Rupture / Erosion -> Platelet Thrombus -> Occlusive ACS      |
|                                                                         |
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2. Atherosclerosis and Ischemic Heart Disease (CAD)

Atherogenesis represents a chronic, lipid-driven inflammatory process affecting large and medium-sized muscular arteries:

1. Endothelial Dysfunction: Hemodynamic shear stress, cigarette toxins, elevated LDL, and hyperglycemia disrupt endothelial integrity, upregulating vascular cell adhesion molecules (VCAM-1).
2. Lipid Accumulation and Oxidation: Circulating LDL particles penetrate the subendothelial space of the intima, where they undergo enzymatic and non-enzymatic oxidation (ox-LDL).
3. Foam Cell and Fatty Streak Generation: Circulating monocytes adhere to VCAM-1, migrate into the intima, differentiate into tissue macrophages, and internalize ox-LDL via scavenger receptors (SR-A, CD36). The resulting lipid-laden foam cells aggregate to form macroscopic fatty streaks.
4. Fibrous Cap Formation: Secretion of PDGF and TGF-$\beta$ stimulates vascular smooth muscle cells (VSMCs) to migrate from the media into the intima, synthesizing extracellular collagen matrix to form a protective fibrous cap over the necrotic lipid core.
5. Plaque Vulnerability and Rupture: Macrophages within unstable plaques secrete matrix metalloproteinases (MMPs) that degrade collagen in the fibrous cap. Cap thinning and hemodynamic stress precipitate rupture, exposing the thrombogenic lipid core and tissue factor to flowing blood, triggering immediate platelet adhesion, activation, and occlusive thrombus formation.

The Clinical Spectrum of Ischemic Heart Disease

3. Heart Failure: Systolic vs Diastolic Dysfunction and Remodeling

Heart failure is a complex clinical syndrome resulting from structural or functional cardiac impairment that reduces the ability of the ventricles to fill or eject blood.

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|               HEART FAILURE: PHENOTYPIC DIFFERENTIATION                 |
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|                                                                         |
|  [HFrEF] (LVEF <= 40%)                  [HFpEF] (LVEF >= 50%)           |
|  - Systolic Contractile Failure         - Diastolic Filling Impairment  |
|  - Eccentric Hypertrophy                - Concentric Hypertrophy        |
|  - Dilated, Thin-Walled LV              - Stiff, Thickened LV Wall      |
|  - Increased End-Diastolic Volume       - Elevated Filling Pressures    |
|  - Common: Ischemia, Dilated CM         - Common: Aging, HTN, Obesity   |
|                                                                         |
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• Heart Failure with Reduced Ejection Fraction (HFrEF; $\text{LVEF} \le 40%$):
  • Primary defect: Impaired myocardial contractility (systolic failure) and progressive ventricular dilatation (eccentric hypertrophy).
  • Etiologies: Myocardial infarction, coronary artery disease, chronic volume overload, dilated cardiomyopathy.
  • Ventricular wall stress leads to progressive cardiomyocyte apoptosis, interstitial fibrosis, and spherical geometric remodeling.
• Heart Failure with Preserved Ejection Fraction (HFpEF; $\text{LVEF} \ge 50%$):
  • Primary defect: Impaired ventricular relaxation and increased myocardial stiffness during diastole (diastolic failure), resulting in elevated left ventricular end-diastolic filling pressures despite a preserved ejection fraction.
  • Pathogenesis: Systemic microvascular endothelial inflammation driven by comorbidities (hypertension, diabetes, obesity, advanced age, CKD), causing cardiomyocyte concentric hypertrophy and myocardial collagen deposition.
• Neurohormonal Maladaptation in Heart Failure:
  • Sympathetic Activation: Low cardiac output stimulates baroreceptors, triggering sustained norepinephrine release. This causes peripheral vasoconstriction, elevated afterload, tachycardia, and down-regulation of $\beta_1$-adrenergic receptors, directly promoting myocardial fibrosis and arrhythmogenesis.
  • RAAS Activation: Renal hypoperfusion triggers renin secretion. Angiotensin II induces systemic vasoconstriction, oxidative damage, and ventricular remodeling, while aldosterone stimulates myocardial interstitial collagen deposition and renal sodium/water retention.
  • Natriuretic Peptide System: Ventricular stretch stimulates release of ANP and BNP/NT-proBNP, promoting natriuresis, diuresis, and vasodilation. Endogenous neutral endopeptidase (neprilysin) degrades these beneficial natriuretic peptides. Inhibiting neprilysin (via sacubitril) augments endogenous peptide signaling.

4. Cardiac Electrophysiology, Arrhythmias, and Conduction Abnormalities

• Atrial Fibrillation (AF): Rapid, chaotic atrial depolarization ($350\text{ to }600\text{ bpm}$) originating predominantly within sleeves of atrial myocardium extending into the pulmonary veins. Loss of organized atrial contraction ("atrial kick") reduces cardiac output by $20%\text{ to }30%$. Sluggish, turbulent blood flow within the left atrial appendage (LAA) causes local stasis, promoting intra-atrial thrombus formation and systemic thromboembolic stroke. Diagnosed on ECG by absent discrete P waves, fibrillatory baseline waves, and an irregularly irregular ventricular rhythm.
• Ventricular Tachyarrhythmias:
  • Ventricular Tachycardia (VT): Three or more consecutive broad QRS complexes ($> 120\text{ ms}$) originating below the bundle of His at a rate $> 100\text{ bpm}$. Driven by myocardial scar reentry post-infarction or automaticity.
  • Ventricular Fibrillation (VF): Disorganized, chaotic ventricular depolarization without mechanical cardiac output, causing sudden cardiac death.
• Acquired Long QT Syndrome and Torsades de Pointes (TdP):
  • Delayed myocardial repolarization caused by block of the rapid delayed rectifier potassium current ($I_{Kr}$, encoded by hERG gene). Prolongation of the corrected QT interval ($\text{QTc} > 450\text{ ms}$ in men, $> 460\text{ ms}$ in women; $\text{QTc} > 500\text{ ms}$ represents a critical risk threshold) allows early afterdepolarizations (EADs) during phase 2 or 3 of the action potential to trigger Torsades de Pointes, a polymorphic ventricular tachycardia exhibiting a characteristic "twisting of the points" around the isoelectric line.
  • High-risk drug classes include antiarrhythmics (Class IA: procainamide, quinidine; Class III: amiodarone, sotalol), macrolide and fluoroquinolone antibiotics, azole antifungals, typical/atypical antipsychotics (haloperidol, ziprasidone), tricyclic antidepressants, methadone, and citalopram/escitalopram.

5. Venous Thromboembolism (VTE)

Venous thromboembolism encompasses Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), governed by Virchow's Triad:

1. Endothelial Injury: Vessel wall trauma, surgery (total hip/knee arthroplasty), central venous catheterization.
2. Venous Stasis: Immobilization, prolonged hospitalization, travel, obesity, heart failure.
3. Hypercoagulability: Active malignancy, pregnancy, exogenous estrogens (OCPs/HRT), antiphospholipid syndrome, genetic thrombophilias (Factor V Leiden mutation, Prothrombin G20210A, Antithrombin III deficiency, Protein C/S deficiency).

• Pulmonary Embolism Pathophysiology: Detachment of an embolus from proximal lower-extremity deep veins travels through the inferior vena cava and right heart chambers to lodge in pulmonary arterial branches. This causes immediate ventilation-perfusion ($V/Q$) mismatch, acute increase in pulmonary vascular resistance, right ventricular strain/dilation, acute tricuspid regurgitation, systemic hypotension, and cardiogenic shock.

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Respiratory Pathophysiology

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|                   ASTHMA VS COPD PATHOPHYSIOLOGY                        |
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|                                                                         |
|  [ASTHMA]                               [COPD]                          |
|  - Etiology: Allergens, Genetics        - Etiology: Tobacco, Toxins     |
|  - Inflammation: Eosinophils, CD4+ T    - Inflammation: Neutrophils, CD8|
|  - Cytokines: IL-4, IL-5, IL-13, IgE    - Cytokines: LTB4, TNF-a, IL-8  |
|  - Pathology: Airway hyperreactive,     - Pathology: Emphysema, mucus   |
|    smooth muscle hypertrophy              gland hypertrophy, air trap   |
|  - Airflow Obstruction: REVERSIBLE      - Airflow Obstruction: FIXED    |
|                                                                         |
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1. Asthma: Immunopathogenesis and Airway Remodeling

Asthma is a heterogeneous chronic inflammatory disease of the conducting airways characterized by recurring episodes of wheezing, breathlessness, chest tightness, and cough with variable expiratory airflow limitation.

• Type 2 (T2-High) Eosinophilic Allergic Pathway:
  • Inhaled allergens are captured by dendritic cells and presented to naive T helper cells, driving differentiation into $T_H2$ cells.
  • $T_H2$ cells secrete specific interleukins:
    • IL-4 & IL-13: Stimulate B-cell immunoglobulin class switching to IgE. IgE binds to high-affinity $Fc\epsilon RI$ receptors on mast cells.
    • IL-5: Mediates eosinophil differentiation, maturation, bone marrow release, and survival.
    • IL-13: Promotes goblet cell hyperplasia, mucus hypersecretion, and direct bronchial hyperresponsiveness.
  • Early-Phase Reaction (minutes): Allergen cross-links IgE on mast cells, triggering degranulation and release of preformed histamine, leukotrienes ($LTC_4, LTD_4, LTE_4$), and prostaglandin $PGD_2$, causing acute bronchospasm and microvascular leakage.
  • Late-Phase Reaction (4 to 8 hours): Infiltration of recruited eosinophils, basophils, and neutrophils releasing major basic protein, eosinophil cationic protein, and reactive oxygen species, sustaining chronic mucosal inflammation.
• Airway Remodeling: Repeated cycles of inflammation and repair lead to permanent structural modifications: subepithelial basement membrane thickening (collagen deposition), bronchial smooth muscle hypertrophy and hyperplasia, goblet cell metaplasia, and subepithelial neovascularization, causing progressive non-reversible airflow decline over time.

2. Chronic Obstructive Pulmonary Disease (COPD)

COPD is characterized by persistent, usually progressive airflow limitation associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases (predominantly cigarette smoke and biomass fuels).

• Non-Type 2 Neutrophilic and Macrophagic Inflammation: Inhaled oxidants activate alveolar macrophages and epithelial cells to release chemotactic factors (IL-8, Leukotriene $B_4$ [$LTB_4$]), recruiting neutrophils and $CD8^+$ cytotoxic T lymphocytes. Neutrophils release proteolytic enzymes, including neutrophil elastase, matrix metalloproteinases (MMPs), and cathepsins.
• Pathological Components:
  • Chronic Bronchitis: Small airway disease (obstructive bronchiolitis). Chronic irritants cause goblet cell hyperplasia and hypertrophy of submucosal mucus glands (elevated Reid Index $> 0.50$), excessive mucus secretion, ciliary dysfunction, and luminal mucus plugging. Clinically defined as a productive cough on most days for at least 3 consecutive months in 2 successive years.
  • Emphysema: Protease-antiprotease imbalance. Excessive neutrophil elastase overwhelms endogenous antiproteases (such as $\alpha_1$-antitrypsin). This causes enzymatic destruction of alveolar elastin and alveolar septal walls, producing irreversible enlargement of air spaces distal to terminal bronchioles.
• Dynamic Hyperinflation and Air Trapping: Destruction of alveolar attachments reduces elastic tethering of small airways, causing premature expiratory airway collapse. Air becomes trapped in the lungs during expiration, progressively elevating end-expiratory lung volume (dynamic hyperinflation), flattening the diaphragm, impairing mechanical inspiratory efficiency, and generating the clinical "barrel chest" deformity.

3. Spirometric Diagnostics: Obstructive vs Restrictive Defects

4. Lower Respiratory Infections and Gas Exchange Failure

• Pneumonia: Inhalation or aspiration of pathogens (e.g., Streptococcus pneumoniae) overwhelms alveolar macrophage defenses. Infection triggers an acute inflammatory cascade characterized by intra-alveolar exudation of protein-rich fluid, neutrophils, and erythrocytes (consolidation).
• Pathophysiology of Hypoxemia: Consolidated, non-ventilated alveoli continue to receive pulmonary capillary blood flow, creating severe intrapulmonary right-to-left shunting (areas where ventilation $V = 0$ with perfusion $Q > 0$). This extreme form of ventilation-perfusion ($V/Q$) mismatch impairs alveolar-capillary oxygen diffusion, leading to hypoxemic respiratory failure.