What is the pathophysiology of hypertension?

Pathophysiology of Hypertension

Hypertension results from complex dysregulation of multiple interconnected physiological systems—including renal, cardiovascular, neurohormonal, vascular, and immune mechanisms—that normally maintain blood pressure homeostasis, with approximately 90% of cases being primary (essential) hypertension of unknown exact cause and 10% being secondary hypertension with identifiable underlying disorders. 1

Primary (Essential) Hypertension Mechanisms

Genetic and Environmental Interactions

• Primary hypertension arises from complex interactions between genetic predisposition, environmental factors, and behavioral influences, though genetic variants collectively account for only about 3.5% of blood pressure variability 2, 3
• The exact cause remains unknown, but multiple genes influence blood pressure in this polygenic disorder 2
• Environmental and psychosocial elements interact with genetic factors to produce the hypertensive phenotype 1

Key Pathophysiological Systems

Neurohormonal Dysregulation:

• Overactivation of the renin-angiotensin-aldosterone system (RAAS) is central to hypertension development and maintenance 1, 3
• Sympathetic nervous system overactivity directly or indirectly drives multiple hypertensive mechanisms, representing the maximum association with hypertension 4
• Disturbed basal sympathetic tone arising from hypothalamic dysfunction, possibly affected by cortical influences, suggests hypertension involves alterations in autonomic nervous system and cortical-hypothalamic connections 4
• Inhibition of the cardiac natriuretic peptide system contributes to blood pressure elevation 1

Renal Mechanisms:

• Dysregulation of renal sodium handling and pressure natriuresis plays a fundamental role 1, 3
• Sodium disrupts normal autoregulation of glomerular filtration rate, exposing the glomerulus to inappropriately high systemic blood pressure and causing hemodynamic injury 3
• Dietary sodium acts as a direct vascular toxin by augmenting production of injury mediators such as TGF-beta and is necessary for aldosterone to inflict target-organ fibrosis 3

Vascular Mechanisms:

• Endothelial dysfunction impairs normal vascular regulation 1, 3
• Increased peripheral vascular resistance from arteriolar changes elevates diastolic and secondarily systolic blood pressure 3, 5
• Vascular remodeling with structural changes in vessel walls perpetuates hypertension 1, 3
• Fibrosis and inflammation in the microcirculation contribute to sustained blood pressure elevation 1, 3
• Decreased vascular compliance from arterial changes increases systolic and decreases diastolic blood pressure 5

Immune System Involvement:

• Vascular and immune mechanisms are involved in hypertension pathophysiology 1
• An imbalance of neuro-immune systems results from enhancement of the "proinflammatory sympathetic" arm with dampening of the "anti-inflammatory parasympathetic" arm 6
• Key inflammatory responses relay back to the central nervous system and alter neuronal communication to the periphery 6

Major Contributing Factors

Obesity:

• Obesity is responsible for 40% of hypertension cases overall and up to 78% in men and 65% in women 2, 3
• The relationship between body mass index and blood pressure is continuous and almost linear, with no threshold 2

Dietary Sodium:

• Sodium intake is positively associated with blood pressure and accounts for much of the age-related increase in blood pressure 2
• Excessive sodium consumption is independently associated with increased risk of stroke, cardiovascular disease, and other adverse outcomes beyond its blood pressure effects 2

Other Dietary Factors:

• Insufficient intake of potassium, calcium, magnesium, protein, fiber, and fish fats are associated with high blood pressure 2

Lifestyle Factors:

• Poor diet, physical inactivity, and excess alcohol consumption, alone or in combination, are the underlying cause of a large proportion of hypertension 2
• Excessive alcohol intake (≥3 standard drinks per day) shows a strong, direct relationship with blood pressure elevation 2, 3

Hemodynamic Mechanisms

• Hypertension is caused by increased cardiac output and/or increased peripheral resistance 4
• The mean blood pressure (weighted average of systolic and diastolic pressures) is the product of cardiac output and peripheral resistance 5
• During early phases, transient exacerbated alterations in pressure-flow relation occur in subjects with hyperresponsive cardiovascular systems due to altered vascular properties 5
• If stimulation is too frequent, changes in vascular properties provide hemodynamic mechanisms for additional vascular alterations, further amplifying pressure increases 5

Secondary Hypertension Mechanisms

Identifiable Causes:

• Secondary hypertension accounts for approximately 10% of cases and has identifiable, potentially reversible causes with specific pathophysiologic mechanisms 1, 2, 3
• In patients presenting with malignant hypertension, secondary causes can be found in 20-40%, most often consisting of renal parenchymal disease and renal artery stenosis 1

Specific Secondary Causes:

• Chronic kidney disease and renal parenchymal disease are common secondary causes 2
• Primary aldosteronism presents with hypokalemia, muscle cramps, and weakness 2
• Pheochromocytoma causes blood pressure lability, episodic pallor, and dizziness 2
• Cushing's syndrome presents with central obesity, facial rounding, and easy bruisability 2
• Hyperthyroidism causes weight loss, palpitations, and heat intolerance 2
• Obstructive sleep apnea presents with snoring and hypersomnolence 2
• Drug-induced hypertension from NSAIDs, cocaine, amphetamines, corticosteroids, and calcineurin inhibitors 2

Progression to Organ Damage

Self-Perpetuating Mechanisms:

• Once hypertension develops, it tends to be self-perpetuating via amplifying mechanisms mediated by secondary structural changes in blood vessels, heart, and kidney 7
• These adaptive structural changes amplify and perpetuate hypertension by increasing systemic vascular resistance, enhancing cardiac output, and impairing renal sodium and water excretion 7

Target Organ Damage:

• Persistently elevated blood pressure leads to hypertension-mediated organ damage (HMOD) affecting the heart, brain, kidneys, eyes, and vessels (macrocirculation and microcirculation) 1, 3
• Organs undergo structural and functional changes when exposed to uncontrolled hypertension 1
• Cardiac complications include left ventricular hypertrophy, heart failure, atrial fibrillation, coronary artery disease, and myocardial infarction 3
• Cerebrovascular complications include stroke, transient ischemic attacks, dementia, and cognitive decline 3

Clinical Implications

Distinguishing Primary from Secondary:

• Historical features suggesting primary hypertension include gradual blood pressure increase with slow rate of rise, lifestyle factors favoring higher blood pressure, and strong family history of hypertension 2
• Historical features suggesting secondary hypertension include absence of family history, sudden onset or rapid progression, and specific symptoms pointing to underlying causes 2, 3