Arterial Hypertension/pathophysiology

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1. Definitions

• Hypertension: A chronic, sustained elevation of systemic arterial blood pressure, defined by current ACC/AHA guidelines as systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg on multiple occasions.
• Primary (Essential) Hypertension: Elevated blood pressure without an identifiable secondary cause. It accounts for approximately 90-95% of cases. It is a diagnosis of exclusion, characterized by complex, multifactorial pathophysiological interactions.
• Secondary Hypertension: Elevated blood pressure attributable to a specific, identifiable underlying structural or functional disorder (e.g., renal parenchymal disease, renovascular disease, endocrine disorders). It accounts for 5-10% of cases and is often potentially curable upon treatment of the primary condition.
• Note: Usual classification of hypertension into "primary" (essential) and "secondary" (identifiable cause) is increasingly considered ‘wrong’, due to advancements in diagnostics and the identification of underlying causes previously labeled as "primary” and how we treat primary HT in general - [Is It Essential to Change the Term “Essential Hypertension”? – by Yoram Yagil and Chana Yagil (27/11/04)]

2. Etiologies

• Primary Hypertension: Etiology is multifactorial and polygenic. Major contributing factors include:
  • Genetic Predisposition: Heritability is estimated at 30-50%. Multiple gene polymorphisms affect renal sodium handling, vascular tone, and RAAS activity.
  • Environmental/Dietary Factors: High sodium intake, low potassium intake, caloric excess/obesity, excessive alcohol consumption, and chronic psychosocial stress.
  • Physiological Dysregulation: Includes increased sympathetic nervous system (SNS) tone, activation of the renin-angiotensin-aldosterone system (RAAS), endothelial dysfunction, and chronic low-grade inflammation.
• Secondary Hypertension: Etiologies are categorized by organ system:
  • Renal (Most Common Category): Chronic kidney disease (glomerulonephritis, diabetic nephropathy), renal artery stenosis (atherosclerotic or fibromuscular dysplasia).
  • Endocrine: Primary aldosteronism (Conn's syndrome), Cushing's syndrome, pheochromocytoma, hyperthyroidism.
  • Vascular: Coarctation of the aorta.
  • Neurogenic: Sleep apnea, increased intracranial pressure.
  • Drug-Induced: NSAIDs, corticosteroids, decongestants, oral contraceptives, calcineurin inhibitors.

3. Pathophysiological Mechanisms of Primary Hypertension

The dominant model is failed renal-pressure natriuresis. In a normotensive individual, increased blood pressure prompts the kidneys to excrete more sodium and water (pressure natriuresis), restoring normal volume and pressure. In primary hypertension, this mechanism is reset to a higher set point.

Key interconnected mechanisms perpetuate this reset:

• Vascular Mechanisms: Endothelial dysfunction reduces nitric oxide (vasodilator) and increases endothelin-1 (vasoconstrictor). This, coupled with vascular smooth muscle hypertrophy and increased peripheral vascular resistance, is a final common pathway.
• Renal Mechanisms: Genetic or acquired defects in renal sodium excretion (e.g., altered activity of Na+/K+ ATPase, Na+/Li+ counter transport, or epithelial sodium channels [ENaC]) necessitate a higher perfusion pressure to maintain sodium balance.
• Neurohormonal Activation:
  • Sympathetic Nervous System (SNS): Chronic overactivity increases cardiac output, triggers renin release, and causes direct renal vasoconstriction.
  • Renin-Angiotensin-Aldosterone System (RAAS): Angiotensin II is a potent vasoconstrictor and stimulates aldosterone secretion, promoting sodium and water retention. It also promotes vascular remodeling and inflammation.
    

    The pathophysiology of primary hypertension
• Inflammation and Immune Activation: Infiltration of monocytes/macrophages and T lymphocytes into the vessel wall and kidney promotes oxidative stress and fibrosis, furthering endothelial and renal injury.

4. Diagnostic Approach

• Confirmation: Based on multiple, properly measured office readings or validated ambulatory/home blood pressure monitoring.
• Evaluation Goals: Assess for organ damage (e.g., LVH on ECG/echo, retinopathy, elevated creatinine) and identify secondary causes.
• History & Physical Exam: Focus on medication review, symptoms suggestive of secondary causes (e.g., paroxysms, muscle weakness), and signs (e.g., abdominal bruit, delayed femoral pulses).
• Laboratory/Imaging (To Exclude Secondary Causes & Establish Baseline):
  • Basic: Serum electrolytes (low K+ may suggest aldosteronism), creatinine, eGFR, fasting glucose, lipid profile, urinalysis.
  • Further Testing if Indicated: Plasma aldosterone/renin ratio (primary aldosteronism), 24-hr urinary metanephrines (pheochromocytoma), renal duplex ultrasound (renal artery stenosis), sleep study.

5. Therapeutic Strategies and Mechanisms of Action

Therapy is guided by stage, comorbidities, and, if found, the specific secondary cause.

A. Non-Pharmacologic Therapy:

Weight reduction, Dietary Approaches to Stop Hypertension (DASH) diet, sodium restriction, potassium supplementation, regular physical activity, moderation of alcohol.

B. Pharmacologic Therapy (Major Classes):

1. Angiotensin-Converting Enzyme Inhibitors (ACEi) / Angiotensin II Receptor Blockers (ARBs):
   • Mechanism: ACEi block conversion of Ang I to Ang II. ARBs selectively block the AT1 receptor. Both reduce vasoconstriction, aldosterone secretion, and vascular remodeling. They also potentiate bradykinin (ACEi only), promoting vasodilation.
2. Calcium Channel Blockers (Dihydropyridines, e.g., amlodipine):
   • Mechanism: Block L-type calcium channels in vascular smooth muscle, inhibiting calcium influx and causing vasodilation, thus reducing peripheral resistance.
3. Thiazide/Thiazide-like Diuretics (e.g., chlorthalidone, hydrochlorothiazide):
   • Mechanism: Initially reduce plasma volume via inhibition of the Na+/Cl- cotransporter in the distal convoluted tubule. Long-term action involves direct arteriolar vasodilation through unknown mechanisms.
4. Mineralocorticoid Receptor Antagonists (e.g., spironolactone, eplerenone):
   • Mechanism: Competitive inhibition of aldosterone binding in the distal nephron, promoting sodium excretion and potassium retention. Particularly effective in states of aldosterone excess or resistant hypertension.
5. Beta-Adrenergic Blockers (not first-line unless comorbid condition):
   • Mechanism: Reduce heart rate, cardiac contractility, and cardiac output. Some inhibit central sympathetic outflow and renin release.

Therapeutic Note: For secondary hypertension, definitive treatment targets the underlying cause (e.g., adrenalectomy for aldosteronism, stenting for renal artery stenosis, CPAP for sleep apnea).