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Hypertension: Basics to Clinical Medicine

1. Definition

"Like height and weight, blood pressure is a continuously distributed variable; moreover, detrimental consequences increase progressively as the pressure rises, with no rigidly defined threshold dependably predicting total safety." - Robbins & Kumar Basic Pathology, p. 547

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2. Classification (ACC/AHA 2017 Guidelines)

Special Forms

• Isolated systolic hypertension: SBP ≥ 140 with DBP < 90. Common in the elderly due to arterial stiffening.
• White coat hypertension: Elevated only in clinical settings; normal on ambulatory monitoring.
• Masked hypertension: Normal in office; elevated on ambulatory monitoring.
• Resistant hypertension: BP ≥ 130/80 on ≥ 3 antihypertensive agents (including a diuretic) at maximal doses, or controlled BP on ≥ 4 agents.
• Hypertensive urgency: Severely elevated BP (often > 180/120) without acute end-organ damage.
• Hypertensive emergency: Severely elevated BP WITH evidence of acute end-organ damage (brain, heart, kidneys, retina, large vessels).
• Malignant hypertension: BP > 200/120 with bilateral advanced retinopathy (flame hemorrhages, papilledema).

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3. Epidemiology

• Over 40% of U.S. adults are hypertensive by ACC/AHA 2017 criteria (approx. 116 million adults).
• 73.9% of hypertensives in the U.S. have uncontrolled BP.
• For non-hypertensive individuals aged 55-65 years, lifetime risk of developing hypertension is 90%.
• African Americans have the highest prevalence in the U.S. due to combined genetic and environmental factors.
• Without treatment, ~50% of hypertensives die from ischemic heart disease or heart failure; ~33% from stroke.
• Nearly one-third of the world's adults have hypertension.

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4. Etiology and Types

Primary (Essential) Hypertension

• Accounts for 90-95% of all cases.
• No single identifiable cause; multifactorial (genetic + environmental).
• Key contributing factors: obesity/visceral adiposity, sedentary lifestyle, high sodium intake, insulin resistance, excessive alcohol, stress.

Secondary Hypertension (5-10%)

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5. Pathophysiology

The Core Formula

Renal-Pressure Natriuresis (The Long-Term Regulator)

• Black patients
• The elderly
• Patients with CKD
• Those with low plasma renin activity

Renin-Angiotensin-Aldosterone System (RAAS)

1. Reduced renal perfusion or sympathetic activation → renin released from juxtaglomerular cells
2. Renin cleaves angiotensinogen → Angiotensin I
3. ACE (in lungs) converts Ang I → Angiotensin II (Ang II)
4. Ang II effects:
   • Vasoconstriction (AT1 receptor) → ↑ TPR
   • Adrenal cortex → aldosterone → Na+ and water retention → ↑ blood volume → ↑ CO
   • Proximal tubule → Na+/H+ exchange → ↑ Na+ reabsorption
   • CNS → vasopressin release, sympathetic activation, thirst

Sympathetic Nervous System

• Catecholamines cause vasoconstriction (α1) and increase heart rate/contractility (β1)
• Chronic sympathetic overactivation is a feature of essential hypertension
• Renal sympathetics enhance tubular Na+ reabsorption and stimulate renin release

Endothelial Dysfunction

• Nitric oxide (NO) normally causes vasodilation and inhibits vascular smooth muscle growth
• NO deficiency impairs pressure natriuresis and promotes vasoconstriction
• Endothelin-1 (ET-1) is a potent vasoconstrictor - elevated in salt-sensitive hypertension
• Atrial natriuretic peptide (ANP) enhances pressure natriuresis and lowers BP; its blockade produces salt-sensitive hypertension

Vascular Remodeling

• Chronic elevated BP leads to structural changes: vessel wall thickening, capillary rarefaction
• Long-term mechanisms maintain tissue blood flow via angiogenesis adaptations
• This vascular remodeling becomes self-perpetuating

Immune/Inflammatory Component

• Innate and adaptive immunity contribute to hypertension
• T-cell infiltration in kidneys and vessels promotes sodium retention and oxidative stress

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6. Cardiovascular Risk Factors in Hypertension

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7. Target Organ Damage

• Left ventricular hypertrophy (LVH) - from pressure overload
• Coronary artery disease and myocardial infarction
• Heart failure (HFpEF and HFrEF)
• Atrial fibrillation

• Ischemic stroke (most common)
• Intracerebral hemorrhage (hypertension is the leading cause)
• Lacunar infarcts, white matter changes
• Hypertensive encephalopathy (in emergency: lethargy, seizures, cortical blindness, coma)
• Vascular dementia

• Hypertensive nephrosclerosis (thickening of afferent arterioles, glomerular ischemia)
• CKD progression - BP control is the #1 intervention to slow CKD progression
• Proteinuria (a marker of glomerular damage and cardiovascular risk)

• Arteriolar narrowing (Grade I)
• AV nicking (Grade II)
• Flame hemorrhages and cotton wool spots (Grade III)
• Papilledema (Grade IV - malignant hypertension)

• Aortic aneurysm and dissection
• Peripheral arterial disease
• Accelerated atherosclerosis

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8. Diagnosis and Evaluation

Blood Pressure Measurement

• Must be performed on multiple occasions under unstressful conditions (seated, legs uncrossed, empty bladder, after 5 minutes of rest)
• Do not diagnose hypertension on a single reading unless BP > 180/120 or end-organ damage is present
• Two or more abnormal readings over several weeks before initiating therapy
• Ambulatory BP monitoring (ABPM) is the gold standard for ruling out white coat hypertension and masked hypertension
• Osler sign (Osler maneuver): Palpable artery after cuff inflation suggests pseudohypertension (common in elderly with stiff vessels)

Diagnostic Workup

• Urinalysis (proteinuria, casts)
• Hematocrit
• Fasting glucose, HbA1c
• Serum potassium (hypokalemia → consider primary aldosteronism)
• Serum creatinine/eGFR
• Calcium, uric acid
• Fasting lipid panel

• ECG (LVH, ischemia, arrhythmias)
• Chest X-ray
• Echocardiography (for LVH, structural abnormalities, valvular disease)

• Plasma aldosterone:renin ratio (primary aldosteronism)
• 24-hour urine metanephrines/catecholamines (pheochromocytoma)
• Renal Doppler/CTA (renal artery stenosis)
• TSH (thyroid disease)
• Overnight dexamethasone suppression test (Cushing's)
• Sleep study (OSA)

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9. Treatment

Treatment Goals

• Target BP: < 130/80 mmHg for most patients (ACC/AHA 2017)
• Based on SPRINT trial data, lower targets reduce CVD events
• Older adults (≥ 65): SBP < 130 mmHg as tolerated

Lifestyle Modifications (First Line for All)

When to Start Pharmacotherapy

• Elevated BP (120-129/< 80): Lifestyle only; reassess in 3-6 months
• Stage 1 (130-139/80-89):
  • Low risk (no ASCVD, 10-year CVD risk < 10%): Lifestyle first; reassess 3-6 months
  • High risk (ASCVD or 10-year risk ≥ 10%): Lifestyle + pharmacotherapy; target < 130/80
• Stage 2 (≥ 140/≥ 90): Always start pharmacotherapy + lifestyle; reassess in 1 month

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10. Antihypertensive Drug Classes

Four First-Line Drug Classes

1. Thiazide/Thiazide-Like Diuretics

• Mechanism: Block Na/Cl cotransporter in distal convoluted tubule → ↓ plasma volume
• Agents: Hydrochlorothiazide (HCTZ), Chlorthalidone (preferred - longer acting), Indapamide
• Preferred in: Black patients (often used as initial monotherapy or in combination), elderly, isolated systolic HTN, osteoporosis, calcium nephrolithiasis
• Side effects: Hypokalemia, hypomagnesemia, hyperuricemia, hyperglycemia, hyperlipidemia, hyponatremia, hypercalcemia
• Note: Chlorthalidone has greater risk of hypokalemia and glucose intolerance than HCTZ but is more effective

2. Calcium Channel Blockers (CCBs)

• Mechanism: Block L-type voltage-gated calcium channels → vasodilation (dihydropyridines) or reduce heart rate/contractility (non-dihydropyridines)
• Classes:
  • Dihydropyridines (amlodipine, nifedipine, felodipine) - primarily vascular
  • Non-dihydropyridines: Verapamil (phenylalkylamine) - more cardiac; Diltiazem (benzothiazepine) - intermediate
• Use long-acting agents only - short-acting dihydropyridines increase ischemic cardiac events
• Preferred in: Black patients, angina, isolated systolic HTN, elderly
• Side effects: Peripheral edema (dihydropyridines), bradycardia/AV block (non-dihydropyridines), constipation (verapamil), flushing, gingival hyperplasia

3. ACE Inhibitors (ACEi)

• Mechanism: Block ACE → ↓ Ang II → vasodilation + ↓ aldosterone + efferent arteriolar dilation → ↓ intraglomerular pressure
• Agents: Enalapril, lisinopril, ramipril, perindopril, benazepril
• Compelling indications: Diabetes with proteinuria, CKD with proteinuria, post-MI LV dysfunction, heart failure with reduced EF (HFrEF), high cardiovascular risk
• Special property: Reduce proteinuria independently of BP effect - key for renoprotection
• Side effects: Dry cough (bradykinin accumulation, 10-15%), angioedema (rare but serious), hyperkalemia, acute kidney injury (bilateral renal artery stenosis - contraindicated)
• Contraindicated in: Pregnancy, bilateral renal artery stenosis, prior angioedema with ACEi

4. Angiotensin Receptor Blockers (ARBs)

• Mechanism: Block AT1 receptor directly → similar effects to ACEi without bradykinin accumulation
• Agents: Losartan, valsartan, irbesartan, olmesartan, telmisartan, candesartan
• Same compelling indications as ACEi; preferred when ACEi causes cough
• Side effects: Hyperkalemia, AKI; no cough, angioedema very rare
• Key rule: Never combine ACEi + ARB - dual RAAS blockade increases hyperkalemia and AKI risk without additional cardiovascular benefit

Other Drug Classes

• Mechanism: Block β1 (heart) → ↓ HR, ↓ contractility → ↓ CO; also ↓ renin release
• Selective agents: Atenolol, bisoprolol, metoprolol, nebivolol (also vasodilatory via NO)
• Non-selective: Propranolol, nadolol
• Compelling indications: Post-MI, HFrEF, angina, tachyarrhythmias
• Avoid in: Decompensated HF, severe bradycardia, high-degree AV block, asthma (non-selective)
• Do not stop abruptly (rebound hypertension and angina)

• Spironolactone, eplerenone - competitive aldosterone inhibitors
• Especially useful in resistant hypertension (add-on therapy)
• Finerenone is nonsteroidal MRA approved for HF/CKD but NOT for HTN
• Triamterene/Amiloride - ENaC blockers; often combined with HCTZ
• Side effects: Hyperkalemia; spironolactone causes gynecomastia/breast tenderness (eplerenone does not)

• Furosemide, bumetanide, torsemide, ethacrynic acid
• Block Na/K/2Cl cotransporter in thick ascending limb of loop of Henle
• Preferred when eGFR < 35 mL/min (thiazides lose efficacy in advanced CKD)
• Side effects: Hypokalemia, hypomagnesemia, hypocalcemia, ototoxicity (dose-related, especially IV)

• Prazosin, doxazosin, terazosin - block α1 receptors → peripheral vasodilation
• Useful in resistant hypertension; also treat benign prostatic hypertrophy (BPH)
• Risk of first-dose orthostatic hypotension

• Clonidine, methyldopa
• Reduce central sympathetic outflow → ↓ HR, ↓ TPR
• Methyldopa is drug of choice in pregnancy
• Abrupt discontinuation causes rebound hypertension (especially clonidine)

• Hydralazine (arterial), minoxidil (arterial) - used in refractory hypertension
• Hydralazine: Used IV in hypertensive emergencies of pregnancy
• Minoxidil: Very potent; causes reflex tachycardia, hirsutism, fluid retention

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11. Drug Selection by Clinical Scenario

Combination Therapy

• Most stage 2 hypertensives need ≥ 2 drugs
• Black patients and those with SBP ≥ 150 or DBP ≥ 90 often need 2 drugs initially
• Effective combinations:
  • Thiazide + ACEi/ARB
  • CCB + ACEi/ARB
  • Thiazide + CCB
• Avoid: ACEi + ARB together
• Triple therapy: Thiazide + CCB + ACEi or ARB

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12. Hypertensive Emergency - Management

• Admit to ICU for parenteral therapy
• Reduce MAP by 10-20% in first hour, then a further 5-15% over the next 23 hours
• Avoid overly rapid reduction - causes ischemia (cerebral, coronary, renal)

• Acute ischemic stroke: Permissive hypertension (do not aggressively lower unless > 220/120, or thrombolysis planned)
• Acute aortic dissection: Target SBP < 120 mmHg within minutes (IV beta-blocker + nitroprusside)
• Intracerebral hemorrhage: Controlled BP lowering (target SBP < 140 in first 24 hours)

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13. Secondary Hypertension - Key Clues

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14. Hypertension in Special Populations

• Gestational hypertension: New-onset HTN ≥ 20 weeks without proteinuria
• Pre-eclampsia: HTN ≥ 20 weeks + proteinuria (> 300 mg/24h) or other organ dysfunction
• Eclampsia: Pre-eclampsia + seizures
• Safe agents: Methyldopa, labetalol, nifedipine
• Contraindicated: ACEi, ARBs (teratogenic - fetal renal agenesis, oligohydramnios)

• ACEi or ARB is first-line (reduces proteinuria beyond BP effect)
• Add thiazide-like diuretic as second line; switch to loop diuretic when eGFR < 35
• Target BP < 130/80

• Isolated systolic HTN is common (stiff arteries)
• CCB or thiazide-like diuretic preferred
• Caution with overly aggressive lowering → orthostatic hypotension, falls

• ACEi or ARB is first line (renoprotection)
• Target BP < 130/80 mmHg

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Recent Evidence (PubMed, 2024)

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Quick Reference Summary

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The Process of a Heart Attack (Myocardial Infarction)

What Is a Heart Attack?

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Step-by-Step: How a Heart Attack Happens

Stage 1 - The Silent Build-Up: Atherosclerosis

1. Repeated endothelial injury (from hypertension, smoking, high LDL, diabetes) allows lipoproteins to accumulate beneath the arterial intima
2. Oxidized LDL triggers macrophage recruitment; macrophages engulf lipid and become foam cells
3. Foam cells accumulate → form the fatty streak (earliest visible lesion)
4. Smooth muscle cells migrate in, secrete collagen → fibrous cap forms over a lipid-rich necrotic core
5. Over time, the plaque grows, narrows the lumen, and may calcify
6. A plaque narrowing 70% or more causes symptoms only during exertion (stable angina)

Stage 2 - The Trigger: Plaque Rupture or Erosion

1. Plaque disruption - An atheromatous plaque is eroded or suddenly disrupted by endothelial injury, intraplaque hemorrhage, or mechanical shear forces. This exposes the subendothelial collagen and the highly thrombogenic necrotic plaque contents to circulating blood.
2. Platelet activation and aggregation - Platelets adhere to the exposed collagen, activate, and release:
   • Thromboxane A₂ (potent vasoconstrictor + platelet aggregator)
   • ADP (recruits more platelets)
   • Serotonin (vasoconstriction) This triggers a cascade of further platelet aggregation and vasospasm.
3. Coagulation cascade activation - Exposed tissue factor activates the extrinsic coagulation pathway → thrombin generated → fibrin mesh formed around the platelet plug → the thrombus rapidly grows.
4. Complete occlusion - Within minutes, the enlarging thrombus may completely occlude the coronary artery lumen, cutting off all blood flow to the downstream myocardium.

Angiography performed within 4 hours of MI onset demonstrates coronary thrombosis in nearly 90% of cases. - Robbins & Kumar Basic Pathology

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Stage 3 - Ischemia: The Clock Starts

• It is the last area to receive blood delivered by epicardial vessels (greatest distance from supply)
• It is exposed to the highest intramural pressures during systole, which further impedes blood inflow
• It has the highest oxygen consumption in the heart wall

Stage 4 - The Wavefront of Necrosis

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Cellular and Biochemical Consequences

1. ATP depletion → Na+/K+ ATPase fails → intracellular Na+ and Ca²+ rise
2. Massive Ca²+ influx activates proteases, phospholipases → membrane damage
3. Lactic acidosis → enzyme denaturation
4. Free radical formation (especially on reperfusion) → oxidative membrane damage
5. Sarcolemmal rupture → intracellular proteins (troponin, CK-MB, myoglobin) leak into blood → the basis of cardiac biomarkers

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ECG Changes: The Electrical Signature

• Minutes to hours: Hyperacute tall T waves → ST elevation (in STEMI)
• Hours to days: ST elevation persists; T wave inversion develops
• Days to weeks: ST normalizes; Q waves appear (electrically silent scar)
• Weeks: Q waves may persist permanently (evidence of old MI)

• V1-V4: Anterior (LAD territory)
• I, aVL, V5-V6: Lateral (LCx territory)
• II, III, aVF: Inferior (RCA territory)
• Posterior MI: Tall R in V1-V2 + ST depression (reciprocal)

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STEMI vs. NSTEMI

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Cardiac Biomarkers: Timing and Significance

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Clinical Presentation

• Severe, crushing substernal chest pain - often described as "pressure," "tightening," or "elephant on my chest"
• Pain radiates to the left arm, jaw, neck, epigastrium, or back
• Pain lasts minutes to hours (unlike angina, it does NOT resolve with rest or nitrates)
• Diaphoresis (profuse sweating)
• Nausea and vomiting (especially inferior MI - vagal activation)
• Dyspnea (from impaired LV function → pulmonary congestion)
• Rapid, weak pulse

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Complications of MI

Electrical (Most Dangerous in First Hour)

• Ventricular fibrillation (VF) - leading cause of pre-hospital MI death; risk is highest in first 10 minutes, then again at 1-2 hours
• Ventricular tachycardia (VT)
• Heart block (especially with inferior MI affecting AV node via RCA)
• Bradycardia, asystole

1. Potassium leaks from ischemic cells → elevated extracellular K+ → increased myocardial irritability
2. Injury current flows between ischemic and normal zones → triggers ectopic beats
3. Sympathetic reflex activation (from reduced BP) → further irritability
4. Dilated ventricle → longer conduction pathways → re-entry circuits

Mechanical

Rupture occurs most often 3-7 days after MI - when lysis of necrotic myocardium is maximal and much of the infarct has been converted to soft, friable granulation tissue. - Robbins & Kumar Basic Pathology

Late Complications

• Pericarditis - Day 2-3; friction rub, pleuritic chest pain; from transmural infarct triggering surface inflammation
• Dressler syndrome - Weeks later; autoimmune pericarditis (antibodies against injured myocardium)
• Mural thrombus - Stasis in akinetic LV + endocardial damage → thrombus formation → risk of systemic embolism/stroke
• Ventricular aneurysm - Late; thinned scar bulges during systole; risk of thrombus, arrhythmia, HF (does NOT rupture)
• Chronic ischemic cardiomyopathy / HFrEF - Progressive heart failure from cumulative myocardial loss

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Reperfusion: Salvage and Its Paradox

"Time is muscle" - every minute of ischemia = more irreversible muscle death

• Calcium overload (intracellular Ca²+ floods in when ATP-dependent pumps restart unevenly)
• Oxygen free radical burst on reoxygenation
• Neutrophil infiltration
• Contraction band necrosis - irreversibly damaged cells exposed to calcium influx develop hypercontracted sarcomeres fixed in a permanent agonal state - this is the microscopic hallmark of reperfused infarction

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Treatment: The Clinical Response

Immediate Goals

1. Relieve ischemia and pain
2. Restore blood flow (reperfusion)
3. Prevent thrombus extension
4. Treat life-threatening arrhythmias

STEMI - Time-Sensitive Reperfusion

• Balloon angioplasty + stent placement
• Door-to-balloon (first medical contact to device) time: ≤ 90 minutes at PCI-capable center; ≤ 120 minutes if transfer required
• Success rate > 90% for restoring flow

• Within 30 minutes of ED arrival
• Agents: Alteplase (tPA), tenecteplase, streptokinase
• Contraindicated in prior hemorrhagic stroke, recent surgery, uncontrolled hypertension

Drug Treatment (STEMI and NSTEMI)

Post-MI (Long-term secondary prevention)

• DAPT for 12 months post-stent (aspirin + P2Y12 inhibitor)
• Lifelong aspirin
• High-intensity statin (e.g., atorvastatin 40-80 mg)
• Beta-blocker (especially if EF reduced)
• ACE inhibitor/ARB (especially if EF reduced, diabetic, or hypertensive)
• Aldosterone antagonist (eplerenone/spironolactone) if EF ≤ 40% with HF or diabetes
• Cardiac rehabilitation - exercise-based program; reduces mortality and rehospitalization
• Lifestyle: Smoking cessation, DASH diet, weight management, physical activity

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Mortality and Prognosis

• 1/3 of STEMI patients die before reaching hospital - usually from VF within 1 hour of onset
• In-hospital mortality: ~10% (STEMI), ~6% (NSTEMI)
• Cardiogenic shock (>40% LV infarcted): 40-50% short-term mortality
• Long-term prognosis depends primarily on residual LV function (ejection fraction) and extent of remaining coronary disease

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Summary: The Heart Attack Process in a Nutshell

Atherosclerosis (years) 
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Plaque rupture / erosion (minutes)
        ↓
Platelet activation + thrombus formation (minutes)
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Complete coronary occlusion
        ↓
Ischemia begins → ATP depletion, loss of contractility (seconds)
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Irreversible cell death starts at subendocardium (20-40 min)
        ↓
Wavefront of necrosis spreads outward (hours)
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Inflammatory response → granulation tissue (days)
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Dense fibrous scar replaces dead muscle (6-8 weeks)
        ↓
Permanent loss of contractile tissue → risk of HF, arrhythmia, death

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