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Acute Coronary Syndrome (ACS)

Definition and Classification

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Epidemiology

• ~1.2 million hospitalizations annually in the United States
• ~2/3 are NSTE-ACS; 1/3 are STEMI

• 50% of NSTE-ACS patients are older than 65 years; nearly half are women

• Risk factors: atherosclerosis, peripheral vascular disease, chronic inflammatory disorders (rheumatoid arthritis, psoriasis, lupus, chronic infection)

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Pathophysiology

Type 1 MI (Most Common)

1. Platelet adhesion, activation, and aggregation at the ruptured plaque
2. Thrombus formation -> partial (NSTEMI/UA) or complete (STEMI) coronary occlusion
3. Downstream myocardial ischemia/necrosis

• Inflammatory cells (macrophages, T-lymphocytes) secrete cytokines (TNF, IL-1, IFN-γ) that inhibit collagen synthesis
• Matrix metalloproteinases and cathepsins degrade the fibrous cap
• Sites of low shear stress (vessel bifurcations) accumulate lipids and inflammatory cells, thinning the fibrous cap
• Rich plaque neovascularization (driven by VEGF, FGF, placental growth factor) contributes to intraplaque hemorrhage and rupture

Type 2 MI (Oxygen Supply-Demand Mismatch)

• Supply reduction: severe hypotension, anemia, hypoxemia, coronary vasospasm (Prinzmetal angina), cocaine, chemotherapy, triptans, spontaneous coronary artery dissection (most common in peripartum women)
• Demand increase: severe tachycardia, hypertensive crisis, thyrotoxicosis

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Clinical Features

Symptoms

• Classic: Chest pressure/tightness, radiation to left arm, jaw, or neck; diaphoresis, nausea, shortness of breath
• Atypical (more common in elderly, women, diabetics): dyspnea alone, syncope, fatigue, abdominal pain, diaphoresis, back/shoulder pain, delirium
• In patients ≥85 years, classic chest pain is present in only ~50% of STEMI cases
• One-third of women >65 years with MI present with abdominal pain alone

Physical Examination

• May be entirely normal
• Signs of heart failure: S3 gallop, pulmonary crackles, elevated JVP
• Mitral regurgitation murmur (papillary muscle dysfunction/rupture)
• Cardiogenic shock: hypotension, cool extremities, altered mental status

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Diagnosis

ECG

• STEMI: New ST elevation ≥1 mm in ≥2 contiguous limb leads, or ≥2 mm in ≥2 contiguous precordial leads; new LBBB; posterior MI (ST depression V1-V3 with tall R waves)
• NSTEMI/UA: ST depression, T-wave inversions, or normal ECG
• Serial ECGs are essential - initial ECG may be normal in up to 50% of ACS

Biomarkers

• Troponin I and T (high-sensitivity): Gold standard for myocardial necrosis. Rise within 3-4 hours, peak at 12-24 hours, remain elevated 7-10 days
• CK-MB: Less sensitive/specific; useful for re-infarction (returns to normal in 48-72 hours)
• Serial troponins (at 0 and 3 hours, or 0 and 1 hour with hs-troponin) are required to rule in or rule out MI
• Troponin elevation without ACS: myocarditis, PE, sepsis, heart failure, renal failure (type 2 MI or myocardial injury)

Imaging

• CXR: Pulmonary edema, cardiomegaly, alternative diagnoses (aortic dissection)
• Echocardiography: Regional wall motion abnormalities confirm ischemia, assess LV function, detect complications (VSD, free wall rupture, pericardial effusion)
• Coronary angiography: Definitive diagnosis and revascularization

Risk Stratification Tools

• TIMI Score (0-7): Predicts 14-day MACE in NSTE-ACS
• GRACE Score: Better calibrated for in-hospital and 6-month mortality
• HEART Score: Used in the ED to risk-stratify chest pain

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Management

Immediate General Measures (All ACS)

• MONA: Morphine (for refractory pain), Oxygen (if SpO2 <90%), Nitrates (sublingual/IV for ongoing pain), Aspirin 162-325 mg chewed immediately
• Continuous ECG monitoring, IV access, bedrest
• Avoid NSAIDs (increase cardiovascular risk)

Antiplatelet Therapy

• Aspirin: 162-325 mg loading, then 75-100 mg daily indefinitely
• P2Y12 inhibitors (dual antiplatelet therapy, DAPT):
  • Ticagrelor 180 mg load, 90 mg twice daily (preferred over clopidogrel for ACS)
  • Prasugrel 60 mg load, 10 mg daily (avoid if prior stroke/TIA, age ≥75, weight <60 kg)
  • Clopidogrel 300-600 mg load, 75 mg daily (when others contraindicated)
• DAPT duration: 12 months post-ACS; may extend or de-escalate based on bleeding/ischemic risk
• Recent meta-analyses (2024-2025) support de-escalation to ticagrelor monotherapy after 3-6 months as safe and possibly preferable to reduce bleeding (Lancet 2024, PMID 39226909)

Anticoagulation

• UFH (unfractionated heparin): IV bolus + infusion; standard for PCI
• Enoxaparin: 1 mg/kg SC twice daily; preferred for medical management
• Fondaparinux: 2.5 mg SC daily; lowest bleeding risk; not for use during PCI alone
• Bivalirudin: IV direct thrombin inhibitor; used during PCI

Anti-Ischemic Therapy

• Beta-blockers: Metoprolol or carvedilol; reduce heart rate and oxygen demand; start oral within 24 hours if no contraindications (acute HF, low-output state, AV block, reactive airway)
• Nitrates: IV nitroglycerin for ongoing ischemia, hypertension, or pulmonary edema
• Calcium channel blockers: Non-dihydropyridines (diltiazem, verapamil) when beta-blockers contraindicated; avoid if LV dysfunction
• ACE inhibitors/ARBs: Start within 24 hours; beneficial in EF <40%, anterior MI, diabetes, hypertension

Statins

• High-intensity statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) immediately; reduce recurrent events independent of LDL level

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Reperfusion Strategy

STEMI

• Primary PCI (preferred): Target door-to-balloon time <90 minutes (or <120 min if transferred). Superior to thrombolysis in reducing mortality, recurrent MI, and stroke when performed in time.
• Fibrinolytic therapy (if PCI unavailable within 120 min): tPA, tenecteplase, reteplase. Door-to-needle time <30 min. Absolute contraindications: prior intracranial hemorrhage, ischemic stroke <3 months, active bleeding, suspected aortic dissection.
• Rescue PCI: After failed thrombolysis (persistent ST elevation >50% or hemodynamic instability)

NSTE-ACS

• Early invasive strategy (coronary angiography within 24-72 hours): preferred for intermediate-high risk (elevated troponin, new ST changes, GRACE score >140, hemodynamic instability, refractory ischemia)
• Conservative (ischemia-guided) strategy: For low-risk patients or those with significant comorbidities
• Recent 2025 meta-analysis (PMID 40549394) supports early invasive approach even in older patients

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Complications

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Secondary Prevention (Post-Discharge)

• Cardiac rehabilitation (reduces mortality ~20-25%)
• Smoking cessation
• Blood pressure control (<130/80 mmHg)
• Diabetes management (HbA1c <7%)
• Physical activity (30 min moderate exercise 5 days/week after recovery)
• SGLT2 inhibitors (empagliflozin, dapagliflozin) in post-MI HFrEF for cardiorenal protection

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Special Populations

Elderly (>75 years)

• Atypical presentations predominate; ACS may mimic HF, syncope, or delirium
• Higher risk of bleeding with anticoagulants - dose-adjust enoxaparin
• Early invasive approach still beneficial (After Eighty Study: superior outcomes vs. conservative in stable octogenarians)
• Acute HF at presentation occurs in ~50% of STEMI patients ≥85 years (vs. only 1.7% in those <65 years)

Women

• More likely to present atypically; diagnosis often delayed
• Higher rates of type 2 MI; spontaneous coronary artery dissection more common
• Similar benefit from reperfusion; slightly higher bleeding risk with anticoagulants

Diabetes

• Often "silent" MI; higher risk of multivessel disease
• Aggressive glycemic and cardiovascular risk factor control; SGLT2 inhibitors reduce CV events

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Key Recent Evidence Updates (2024-2025)

• De-escalation of DAPT (PMID 39226909): Ticagrelor monotherapy after 3-6 months post-PCI reduces bleeding without increasing ischemic events vs. 12-month DAPT.
• Elderly ACS strategy (PMID 40549394): Meta-analysis confirms early invasive approach reduces major adverse cardiac events in older ACS patients.
• Monotherapy after PCI (PMID 40803759): P2Y12 inhibitor monotherapy (especially ticagrelor) may be preferred over aspirin monotherapy after short-course DAPT in ACS post-PCI.

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Asthma

Definition

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Epidemiology

• Affects ~300 million people worldwide; one of the most common chronic diseases globally
• Global burden data (Lancet Respir Med, 2025, PMID 40147466): 262 million cases in 2021, with projections to increase by 2050
• Prevalence highest in high-income English-speaking countries
• ~4% of pregnant women have asthma; one-third experience exacerbations during pregnancy
• Risk factors: atopy, family history, allergen exposure, air pollution, obesity, early childhood respiratory infections

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Pathophysiology

1. Bronchial smooth muscle contraction (bronchoconstriction) - the dominant acute component
2. Mucosal inflammation and edema - driven by eosinophils, mast cells, T lymphocytes, macrophages
3. Hypersecretion of mucus - plugging small airways

Inflammatory Cascade

• Allergen exposure -> IgE-mediated mast cell activation -> release of histamine, prostaglandins, leukotrienes
• Eosinophil recruitment driven by IL-5
• Cysteinyl leukotrienes (LTC4, LTD4, LTE4) cause smooth muscle contraction, mucosal edema, eosinophil migration
• Chronic inflammation leads to airway remodeling: subepithelial fibrosis, smooth muscle hypertrophy/hyperplasia, angiogenesis, and mucous gland enlargement

Drug targets in the leukotriene pathway:

Common Triggers

• Allergens (house dust mite, pollen, pet dander, mold)
• Respiratory infections (viral URTIs are the most common trigger)
• Exercise (especially in cold/dry air)
• Air pollutants, smoke, strong odors
• NSAIDs/aspirin (aspirin-exacerbated respiratory disease)
• Beta-blockers
• GERD, emotional stress, cold air

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Clinical Features

Symptoms (classic triad)

• Wheeze - polyphonic, expiratory (can be absent in very severe attack - "silent chest")
• Dyspnea - especially nocturnal or early morning (circadian variation in airway tone)
• Cough - may be the only symptom (cough-variant asthma); often worse at night

Signs

• Mild-moderate attack: Tachypnea, expiratory wheeze, prolonged expiratory phase, use of accessory muscles
• Severe attack: Inability to complete sentences, SpO2 <92%, pulsus paradoxus >25 mmHg, silent chest (ominous), cyanosis
• Between attacks: physical exam may be completely normal

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Diagnosis

Spirometry (cornerstone)

• Obstructive pattern: FEV1/FVC ratio <0.70 (or below lower limit of normal)
• Reversibility: ≥12% AND ≥200 mL improvement in FEV1 after bronchodilator - confirms asthma
• FEV1 may be normal in mild asthma; serial measurements are important

Bronchoprovocation Testing

• Methacholine challenge: PC20 (concentration causing ≥20% fall in FEV1) is diagnostic of airway hyperresponsiveness
• Used when spirometry is normal but asthma is suspected

Peak Expiratory Flow (PEF)

• Daily PEF monitoring: diurnal variation >20% is diagnostic
• Home monitoring guides step-up/step-down therapy

Additional Tests

• FeNO (fractional exhaled nitric oxide): Elevated (>25 ppb) indicates eosinophilic airway inflammation; predicts corticosteroid response
• Blood eosinophil count: Useful for phenotyping and biologic eligibility
• Serum IgE + skin prick testing: Identifies allergic triggers
• CXR: Usually normal; may show hyperinflation during exacerbation; rules out alternative diagnoses

ATS Impairment Rating (for disability assessment)

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Classification (GINA Framework)

By Symptom Control (treatment-based, GINA preferred)

By Symptom Frequency (NHLBI/traditional classification)

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Pharmacological Management (GINA Stepwise)

Key Drug Classes

1. Inhaled Corticosteroids (ICS) - Controller Foundation

• Mechanism: Inhibit phospholipase A2 → block arachidonic acid release → reduce leukotriene synthesis and eosinophilic inflammation; reverse mucosal edema, decrease capillary permeability
• Examples: Budesonide, fluticasone propionate/furoate, beclomethasone, mometasone, ciclesonide
• Must be used regularly to achieve benefit; several months of use reduce airway hyperresponsiveness
• Adverse effects: Oropharyngeal candidiasis, hoarseness (rinse mouth after use); high-dose systemic effects (adrenal suppression, cataracts, osteoporosis)

2. Short-Acting Beta-2 Agonists (SABA) - Reliever

• Examples: Albuterol (salbutamol), levalbuterol
• Mechanism: Activate beta-2 receptors → smooth muscle relaxation → bronchodilation
• Onset within minutes; used for acute symptom relief
• GINA update: SABA-only treatment (without ICS) is no longer first-line; as-needed low-dose ICS-formoterol preferred

3. Long-Acting Beta-2 Agonists (LABA) - Controller Add-on

• Examples: Formoterol (fast-onset), salmeterol
• Must never be used as monotherapy in asthma (FDA black box warning - increased asthma deaths)
• Always combine with ICS; ICS-LABA combinations preferred for moderate-severe asthma
• Low-dose ICS-LABA is equally effective as high-dose ICS alone for moderate-severe asthma

4. Leukotriene Receptor Antagonists (LTRA)

• Montelukast, zafirlukast - block CysLT1 receptor
• Block smooth muscle contraction, edema, eosinophil migration
• Useful adjuncts; especially beneficial in aspirin-exacerbated asthma and allergic rhinitis-asthma overlap
• Montelukast: FDA black box warning for neuropsychiatric events (mood changes, suicidality)

5. Zileuton (5-Lipoxygenase Inhibitor)

• Blocks 5-lipoxygenase → prevents leukotriene A4 synthesis → inhibits all leukotrienes
• Hepatotoxic; requires LFT monitoring

6. Anticholinergics

• Ipratropium (SAMA): Add-on to SABA in acute exacerbations in ED; not for routine maintenance
• Tiotropium (LAMA): Add-on therapy in severe asthma with frequent exacerbations; also useful in asthma-COPD overlap

7. Theophylline

• Methylxanthine bronchodilator; has anti-inflammatory properties
• Largely replaced by safer agents; narrow therapeutic index (seizures, fatal arrhythmias at toxic levels)
• Monitor serum concentrations; multiple CYP1A2 drug interactions

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GINA Stepwise Treatment (Ages ≥12 years)

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Biologic Therapies (Step 5 Add-on)

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Acute Exacerbation Management

Severity Assessment

ED Treatment

• Inhaled SABA (albuterol) - mainstay; MDI with spacer as effective as nebulizer for mild-moderate; continuous nebulization for severe
• MDI-based approach causes fewer side effects (less tachycardia, nausea, tremor) vs. nebulizer

• Oral prednisone/prednisolone 40-60 mg OR IV methylprednisolone (preferred if unable to swallow)
• Start within the first hour of ED presentation - reduces hospitalization risk and relapse
• Response begins within 1 hour; maximal at 8-12 hours
• Dexamethasone single dose (0.6 mg/kg) has shown equivalent efficacy to 5-day prednisolone course
• No taper needed for short courses (<2 weeks)

• Ipratropium bromide added to SABA in severe exacerbations; reduces hospitalizations

• IV magnesium sulfate (2 g over 20 min): Smooth muscle relaxation via calcium channel blockade; used for severe cases not responding to initial treatment (PMID 38395640 - supported in pediatric meta-analysis)
• IV beta-2 agonists: When inhaled route is insufficient due to severely diminished air entry
• Heliox (70:30 helium-oxygen): Reduces airway resistance; bridging therapy
• IV theophylline: Rarely used; risk of toxicity
• Intubation and mechanical ventilation: Last resort; use permissive hypercapnia strategy

Disposition

• Mild exacerbation with good response: Discharge with SABA + short oral steroid course
• ICS should be prescribed at discharge for all persistent asthma (not mild intermittent)
• Identify and address triggers; check inhaler technique
• Follow-up within 1-2 weeks

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Special Populations

Asthma in Pregnancy

• ~4% of pregnant women affected; 1/3 experience exacerbations
• Moderate-severe asthma increases risk of preterm birth, low birth weight, preeclampsia, perinatal death
• Pregnancy physiology: Tidal volume and minute ventilation increase (progesterone effect); FEV1, FVC, and PEFR remain unchanged; residual volume decreases
• Untreated asthma is more dangerous to the fetus than treating with medications
• Albuterol: safe for all severity levels; ICS budesonide: first-line controller (most safety data)
• Oral corticosteroids: safe for exacerbations; minimal risk of cleft palate with brief courses
• Avoid leukotriene antagonists as first-line unless well-controlled pre-pregnancy

Exercise-Induced Bronchoconstriction (EIB)

• SABA 10-15 minutes before exercise as pretreatment
• ICS reduces baseline airway inflammation and prevents EIB
• Warm-up exercise and wearing a face mask in cold weather reduces EIB

Occupational Asthma

• Work-related new-onset asthma (sensitizer-induced) or worsening of pre-existing asthma
• Common sensitizers: isocyanates, flour, animal proteins, latex
• Remove from exposure early; ICS + allergen avoidance

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Monitoring and Follow-Up

• Asthma Control Test (ACT): 5-item validated tool; score ≤19 = uncontrolled
• Asthma Control Questionnaire (ACQ): Score ≥1.5 = uncontrolled
• Assess: Symptom frequency, reliever use, nocturnal awakening, activity limitation, exacerbations, spirometry
• Step up if uncontrolled; step down if well controlled for ≥3 months
• Review inhaler technique and adherence at every visit - poor technique is a major cause of treatment failure
• Avoid known triggers (allergen avoidance, smoking cessation, treat GERD)

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Complications

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Key Recent Evidence (2024-2026)

• Global burden (PMID 40147466): 262 million cases globally in 2021; atopic dermatitis-asthma overlap is growing
• IV magnesium sulfate in children (PMID 38395640): Meta-analysis confirms benefit of IV MgSO4 in pediatric exacerbations not responding to initial therapy
• ARIA-EAACI guidelines 2024-2025 (PMID 41324154): Intranasal corticosteroids remain first-line for allergic rhinitis, which is a key driver of asthma control

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