Hypertension: Pathophysiology, Secondary Causes & Emergencies

Primary hypertension

Definitions. By ACC/AHA criteria, normal BP is under 120/80 mmHg. Elevated BP is 120–129 systolic with diastolic under 80. Stage 1 hypertension is 130–139 systolic or 80–89 diastolic, and stage 2 is at least 140 systolic or at least 90 diastolic. About 90% of hypertension is primary (essential). Hypertension is the leading modifiable risk factor for stroke, MI, heart failure and CKD.

Risk factors. Risk rises with age, obesity, family history, high sodium and low potassium intake, excess alcohol, physical inactivity, diabetes and obstructive sleep apnea. In Black individuals hypertension is more common, starts earlier and causes more end-organ damage, often with a low-renin, salt-sensitive pattern.

Mechanisms. Everything converges on BP = CO × TPR. The kidney is central: if it needs a higher pressure to excrete a given salt load (pressure-natriuresis reset upward), Na+ and water are retained. The extra volume raises CO, tissues autoregulate against the excess flow by constricting arterioles, and TPR rises. Over time arteriolar smooth muscle hypertrophies and remodels, locking TPR high while CO returns to normal. RAAS activation and sympathetic overactivity add vasoconstriction and further Na+ retention. With aging, the large arteries stiffen and can no longer buffer each stroke, producing isolated systolic hypertension with a wide pulse pressure.

Secondary hypertension

When to look. Secondary causes account for about 5–10% of cases. Clues are onset before age 30, resistant hypertension (uncontrolled on three drugs including a diuretic), abrupt onset or sudden worsening of previously controlled BP, unprovoked hypokalemia, and end-organ damage out of proportion to the duration.

Renovascular hypertension. Atherosclerotic renal artery stenosis affects older smokers with vascular disease and involves the ostium or proximal segment. Fibromuscular dysplasia affects young to middle-aged women. It is nonatherosclerotic and noninflammatory, beads the mid-to-distal renal artery ("string of beads"), and can also involve the carotids. When both kidneys are underperfused, glomerular filtration depends on angiotensin II constricting the efferent arteriole, so an ACE inhibitor or ARB makes creatinine rise sharply.

Primary aldosteronism. The cause is either an adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia. Aldosterone drives Na+ reabsorption and K+ and H+ secretion, producing hypertension, hypokalemia and metabolic alkalosis, and the expanded volume suppresses renin. Pressure natriuresis and ANP limit Na+ retention ("aldosterone escape"), so edema is absent. Many patients have a normal K+, so resistant hypertension is screened with the aldosterone:renin ratio. An adenoma is removed laparoscopically; hyperplasia is treated with spironolactone or eplerenone.

Pheochromocytoma. This catecholamine-secreting tumor of adrenal medullary chromaffin cells causes paroxysmal or sustained hypertension with headache, sweating and tachycardia. Plasma free or 24-hour urine metanephrines make the diagnosis. Associations include MEN2A and MEN2B (RET), von Hippel–Lindau and NF1. Preparation for surgery starts with α-blockade (phenoxybenzamine), followed by a β-blocker for tachycardia, before resection.

Cortisol and thyroid. In Cushing syndrome, cortisol at high levels overwhelms renal 11β-HSD2 and activates mineralocorticoid receptors. It also increases hepatic angiotensinogen and vascular sensitivity to catecholamines. Hyperthyroidism raises CO and lowers TPR, giving systolic hypertension with a wide pulse pressure. Hypothyroidism raises TPR, giving diastolic hypertension.

Coarctation of the aorta. In older children and adults the narrowing lies near the ligamentum arteriosum. The arms are hypertensive while femoral pulses are weak and delayed (radiofemoral delay), and arm BP exceeds leg BP. Dilated intercostal collaterals erode the undersurfaces of the posterior ribs (rib notching), and the indented aorta forms a "3" sign on chest x-ray. Coarctation is associated with Turner syndrome and bicuspid aortic valve.

OSA and CKD. In sleep apnea, repeated hypoxemia and arousals cause sympathetic surges and loss of the normal nocturnal fall in BP. OSA is among the most common causes of resistant hypertension, and CPAP lowers BP modestly. CKD raises BP through Na+ and water retention and RAAS activation, and the hypertension accelerates the loss of nephrons.

Drugs and substances that raise BP

• Estrogen-containing oral contraceptives: increase hepatic angiotensinogen.
• NSAIDs: block renal vasodilatory prostaglandins, causing Na+ retention and blunting antihypertensives.
• Decongestants (pseudoephedrine, phenylephrine): α1 agonism.
• Cocaine and amphetamines: sympathomimetic surge.
• Calcineurin inhibitors (cyclosporine, tacrolimus): renal vasoconstriction.
• Others: glucocorticoids, erythropoietin, VEGF inhibitors, MAO inhibitors with tyramine, and rebound after abrupt clonidine withdrawal.
• Licorice: glycyrrhetinic acid inhibits 11β-HSD2, so cortisol activates mineralocorticoid receptors, causing hypertension and hypokalemia with low renin and low aldosterone.

End-organ damage

Heart. Pressure overload adds sarcomeres in parallel, producing concentric LVH: a thick wall around a normal or small cavity. The stiff ventricle causes diastolic dysfunction, an S4 and HFpEF, and later systolic failure. Hypertension also accelerates coronary disease, and the hypertrophied muscle needs more O2. It predisposes to AF.

Aorta and arteries. Hypertension is the most important risk factor for aortic dissection. Shear stress on a degenerating media opens an intimal tear, causing tearing chest pain radiating to the back and unequal arm pressures. It also accelerates atherosclerosis in the aorta and the coronary, carotid and peripheral arteries.

Brain. Chronic pressure weakens small penetrating arteries (classically the lenticulostriates), producing Charcot–Bouchard microaneurysms. Their rupture causes deep intraparenchymal hemorrhage in the putamen and basal ganglia, thalamus, pons and cerebellum. Lipohyalinosis of the same vessels causes lacunar infarcts. Severe acute elevations cause hypertensive encephalopathy. A lobar hemorrhage in an older normotensive patient suggests cerebral amyloid angiopathy instead.

Retina. Early changes are arteriolar narrowing, copper or silver wiring and AV nicking. Advanced retinopathy adds flame hemorrhages, cotton-wool spots (microinfarcts of the nerve fiber layer) and hard exudates. Papilledema signals malignant hypertension.

Kidney. Long-standing benign hypertension, like diabetes, causes hyaline arteriolosclerosis, in which leaked plasma proteins thicken the arteriolar wall into a pink, glassy band. The result is nephrosclerosis with small, finely granular kidneys and CKD; hypertension is the second leading cause of end-stage renal disease after diabetes. Malignant hypertension causes hyperplastic ("onion-skin") arteriolosclerosis with fibrinoid necrosis, petechial hemorrhages that give a "flea-bitten" kidney surface, and acute kidney injury.

Hypertensive emergency and IV agents

Emergency vs urgency. A hypertensive emergency is severe hypertension, often ≥180/120 mmHg, with acute end-organ injury. Examples are encephalopathy, stroke or intracerebral hemorrhage, ACS, acute pulmonary edema, aortic dissection, AKI, eclampsia, papilledema and microangiopathic hemolysis. It is treated with IV titratable drugs in an ICU. Severe hypertension without acute organ injury is hypertensive urgency, treated with oral agents and gradual lowering.

Aortic dissection is the main exception: SBP goes below 120 mmHg within minutes, with an IV β-blocker given before any vasodilator to blunt reflex tachycardia and shear. In acute ischemic stroke, BP is allowed to run high unless thrombolysis is planned, which requires a BP below 185/110 mmHg.

Cyanide toxicity. Each nitroprusside molecule carries cyanide groups. When detoxification is overwhelmed, cyanide blocks cytochrome c oxidase (complex IV). The result is confusion, seizures and lactic acidosis, and because tissues cannot use O2, venous blood looks bright red. Hydroxocobalamin binds cyanide to form cyanocobalamin, which is excreted in urine. Sodium thiosulfate supplies sulfur so that rhodanese can convert cyanide to thiocyanate.

Never give a β-blocker first in pheochromocytoma. Unopposed α1 vasoconstriction can precipitate a hypertensive crisis, so phenoxybenzamine (or phentolamine in a crisis) comes first.