Hypertension Pathogenesis

Core Hemodynamic Framework

BP = Cardiac Output (CO) × Peripheral Vascular Resistance (PVR)

• CO is determined by stroke volume (myocardial contractility + vascular compartment size) and heart rate.
• PVR is governed by functional and structural changes in small arteries (lumen 100–400 μm) and arterioles.

Major Pathophysiological Mechanisms

1. Renin-Angiotensin-Aldosterone System (RAAS)

• Renin (released by juxtaglomerular cells in response to low renal perfusion, low Na⁺, or SNS activation) cleaves angiotensinogen → Angiotensin I
• ACE (in lung endothelium) converts Ang I → Angiotensin II (Ang II)
• Ang II acts on AT₁ receptors to cause:
  • Potent vasoconstriction (↑ PVR)
  • Aldosterone release → Na⁺ and water retention (↑ CO)
  • Direct renal tubular Na⁺ reabsorption
  • Vascular smooth muscle hypertrophy (structural remodeling)
  • Central sympathetic activation
  • Oxidative stress and endothelial dysfunction

2. Sympathetic Nervous System (SNS) Overactivity

• Increased efferent SNS tone elevates BP via:
  • Increased heart rate and contractility (↑ CO)
  • Vasoconstriction (↑ PVR)
  • Renal vasoconstriction → renin release (activating RAAS)
  • Na⁺ retention
• Triggers include stress, obesity (leptin-mediated), sleep apnea, and baroreceptor dysfunction
• Chronic SNS activation resets the baroreflex to a higher set point

3. Renal Mechanisms — Pressure-Natriuresis Dysfunction

• The pressure-natriuresis curve is shifted rightward — higher BP is required to achieve the same natriuresis
• Causes include reduced nephron number (Brenner hypothesis), intrarenal RAAS activation, and tubular Na⁺ transporter upregulation (NHE3, ENaC)
• Volume expansion → sustained ↑ CO → ↑ BP

4. Vascular Remodeling and Endothelial Dysfunction

5. Genetic and Polygenic Contributions

• Hypertension is highly heritable (~30–50%)
• Monogenic forms (rare): Liddle syndrome (ENaC gain-of-function), glucocorticoid-remediable aldosteronism, Gordon syndrome (WNK kinase mutations)
• Common/polygenic: hundreds of SNPs each with small effect, involving Na⁺ transport, RAAS components, adrenergic receptors, and endothelial function
• As noted in the management guidelines (GLGCA, p. 17), "the contribution of these factors may differ among males and females"

6. Salt Sensitivity and Volume Dysregulation

• ~50% of hypertensives are salt-sensitive (BP rises with Na⁺ load)
• More prevalent in Black populations, elderly, CKD, and diabetics
• Mechanisms: blunted renal dopamine response, RAAS over-activation, aldosterone excess, reduced renal medullary prostaglandins

7. Neuroinflammation and Immune Activation

• T lymphocytes (particularly Th17 cells) infiltrate the kidney and vasculature in hypertension
• Ang II drives T-cell activation → release of IL-17, TNF-α
• These cytokines promote renal Na⁺ retention and vascular inflammation
• An emerging mechanism explaining why anti-inflammatory pathways can lower BP experimentally

8. Obesity and Metabolic Factors

• Adipose tissue is a source of angiotensinogen (direct RAAS input)
• Leptin hypersecretion activates the SNS (renal and adrenal)
• Insulin resistance → hyperinsulinemia → Na⁺ retention, SNS activation
• Obstructive sleep apnea causes intermittent hypoxia → chemoreceptor activation → chronic SNS elevation

Integrated Model

Genetic predisposition + Environmental factors (Na⁺, obesity, stress)
                        ↓
        ↑ RAAS + ↑ SNS + Renal Na⁺ retention
                        ↓
           ↑ CO and/or ↑ PVR → Elevated BP
                        ↓
        Vascular remodeling + Endothelial dysfunction
                        ↓
        BP elevation becomes structural and self-sustaining

Secondary Hypertension — Distinct Pathogenic Pathways