---

Comprehensive Medical Review: 7 Topics

---

1. Duke Criteria (for Infective Endocarditis)

Pathologic Criteria (either alone confirms IE)

• Microorganisms identified in a vegetation, explanted prosthetic valve, aortic graft, CIED (cardiac implantable electronic device), or embolus
• Histopathological findings of active endocarditis in cardiac tissue, vegetation, prosthetic valve, or embolus

Clinical Classification

Major Criteria

• Organisms commonly causing IE in ≥2 separate blood cultures (e.g., S. aureus, S. viridans, Enterococcus)
• Organisms occasionally causing IE in ≥3 separate blood cultures
• Positive PCR/nucleic acid test from blood for Coxiella burnetii, Bartonella spp.

• Echo/CT: Vegetation, valvular perforation/aneurysm, abscess, pseudoaneurysm, intracardiac fistula, significant new valvular regurgitation, new prosthetic valve dehiscence
• [18F]-FDG PET/CT: Abnormal metabolic activity (≥3 months post-implantation) at a native/prosthetic valve, ascending aortic graft, CIED leads

• Direct inspection at cardiac surgery shows evidence of IE (in absence of other major criteria)

Minor Criteria

• Predisposition: Prior IE, prosthetic valve, prior valve repair, congenital heart disease, moderate-severe regurgitation/stenosis, endovascular CIED, HOCM, injection drug use
• Fever: Temperature ≥38.0°C (100.4°F)
• Vascular phenomena: Arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, Janeway lesions, purulent purpura
• Immunologic phenomena: Osler's nodes, Roth's spots, positive rheumatoid factor, immune complex-mediated glomerulonephritis
• Microbiologic: Positive blood cultures not meeting major criteria; single positive from sterile site (other than valve) by PCR

---

2. Diabetes Mellitus Type 1 (DM1)

Definition

Pathogenesis

• Autoimmune destruction of beta cells in pancreatic islets of Langerhans
• Mediated by autoreactive T lymphocytes; autoantibodies (anti-GAD, anti-islet cell, anti-insulin) are markers
• Results in absolute insulin deficiency - ketosis occurs even in the basal state

Genetics

• HLA association: HLA-DR3 and HLA-DR4 are most important
  • Heterozygotes (DR3/DR4): 2-3 fold increased risk
  • Homozygotes: 10-fold increased risk
• First-degree relatives have elevated risk
• Siblings: 5-10% lifetime risk
• Identical twins: ~60% concordance (proving environmental triggers also play a role)
• Rare monogenic causes: pancreatic agenesis, insulin receptor mutations, cystic fibrosis

Clinical Features

• Abrupt onset (days to weeks) in children/young adults (<14 years commonly - "juvenile diabetes")
• Classic triad: polyuria, polydipsia, polyphagia + weight loss
• Tendency to diabetic ketoacidosis (DKA) - life-threatening
• Parenteral insulin is required to sustain life

Complications (long-term)

• Diabetic neuropathy: 28-40% incidence after 20 years of DM1 onset in childhood
• Diabetic nephropathy, retinopathy, cardiovascular disease

Management

• Lifelong insulin therapy (basal-bolus regimen, insulin pump)
• Blood glucose monitoring (CGM preferred)
• Carbohydrate counting

---

3. Rheumatic Heart Disease (RHD)

Definition

Epidemiology

• Global prevalence: ~33 million cases
• ~275,000 deaths/year; >9 million DALYs lost annually
• Endemic in South America, Africa, Asia, Australasia, Pacific islands
• More than 1/3 of cardiac surgeries in adults in LMICs are for RHD

Pathogenesis

1. GAS throat infection (pharyngitis) triggers molecular mimicry
2. Antibodies cross-react with cardiac antigens (especially valvular tissue)
3. Repeated ARF episodes cause progressive valve damage
4. Mitral valve is most commonly affected (mitral stenosis is the hallmark)
5. Valvular lesion order of frequency: mitral > aortic > tricuspid > pulmonary

Valve Lesions

• Mitral stenosis (MS): Most characteristic - "fish mouth" or "button-hole" deformity on gross pathology; commissural fusion, leaflet thickening, chordal shortening
• Mitral regurgitation (MR): Often occurs earlier than MS
• Aortic regurgitation/stenosis: Second most common valve involved
• Echocardiographic screening is key to diagnosis (especially subclinical/latent RHD)

Diagnosis - Jones Criteria (for ARF, the precursor)

Prevention

• Primary: Prompt penicillin treatment of GAS pharyngitis (within 9 days prevents first ARF)
• Secondary: Long-term benzathine penicillin G prophylaxis to prevent recurrent ARF and further valve damage

---

4. Dysgerminoma (Note: the correct spelling is Dysgerminoma, not "Dyscharminoma")

Definition

Epidemiology

• Primarily affects females in the 2nd and 3rd decades of life (75% of cases)
• Can also occur in childhood
• Some cases arise in patients with gonadal dysgenesis (e.g., pseudohermaphroditism)

Pathogenesis & Molecular Features

• Expresses stem cell markers: OCT3, OCT4, NANOG (transcription factors for pluripotency)
• Strongly associated with isochromosome 12p (like seminoma)
• KIT mutations: 30-50% have activating mutations; 30% have KIT amplification - KIT is a therapeutic target
• Most have no endocrine activity; a few produce elevated hCG (due to syncytiotrophoblastic giant cells)

Morphology

• 80-90% are unilateral (though bilateral in ~10-15%)
• Range from small nodules to large masses filling the abdomen
• Cut surface: solid, yellow-white to gray-pink, soft and fleshy
• Histology: Large vesicular cells with clear cytoplasm, well-defined borders, central regular nuclei; grow in sheets/cords separated by scant fibrous stroma infiltrated by lymphocytes; non-caseating granulomas may be present (identical to seminoma pattern)

Clinical Behavior & Prognosis

• All dysgerminomas are malignant, but only ~1/3 are aggressive
• Unilateral tumor without capsular breach: >90% 10-year progression-free survival after simple salpingo-oophorectomy
• Highly radio- and chemosensitive
• Even metastatic disease is often curable (BEP chemotherapy: Bleomycin, Etoposide, Cisplatin)

Tumor Markers

• LDH (elevated in most cases - useful marker)
• hCG (mildly elevated in some)
• AFP - typically negative (important to distinguish from yolk sac tumor)

---

5. Teratoma

Definition

Classification

A. Mature (Benign) Teratoma - "Dermoid Cyst"

• Most common ovarian germ cell tumor overall
• Karyotype: 46,XX
• Arise from an ovum after the first meiotic division (genetic analysis)
• Gross: Cystic, contains hair, sebaceous material, teeth
• Histology: Stratified squamous epithelium with underlying sebaceous glands, hair shafts, other skin adnexal structures; cartilage, bone, thyroid, neural tissue may be present
• ~1% undergo malignant transformation (most commonly to squamous cell carcinoma)
• Sometimes incorporated within the wall of a mucinous cystadenoma

B. Immature (Malignant) Teratoma

• Rare; primarily in prepubertal adolescents and young females (mean age: 18 years)
• Component tissues resemble embryonal/immature fetal tissue
• Gross: Bulky, smooth external surface, solid; hair, sebaceous material, cartilage, bone, calcification; areas of necrosis and hemorrhage
• Histology: Varying amounts of immature neuroepithelium, cartilage, bone, muscle
• Grading (I-III): Based on proportion of immature neuroepithelium - critical for prognosis
• Rapidly growing, can penetrate capsule and spread locally or distantly
• Stage I, grade 1: Excellent prognosis
• Grade 2-3 confined to ovary: Adjuvant chemotherapy (BEP regimen)
• Most recurrences in first 2 years

C. Monodermal (Specialized) Teratomas

• Always unilateral
• Struma ovarii: Composed entirely of mature thyroid tissue; can cause hyperthyroidism
• Carcinoid tumor: Arises from intestinal tissue in teratoma; if large (>7 cm), can cause carcinoid syndrome even without hepatic metastases (because ovarian veins drain directly to systemic circulation)
• Strumal carcinoid: Combination of struma ovarii and carcinoid
• Only ~2% of carcinoid teratomas metastasize

D. Testicular Teratoma

• Mature teratoma in testis: Unlike the ovarian counterpart, does NOT have a benign clinical course - behaves malignantly in adults
• Immature testicular teratoma: Undifferentiated primitive tissue

---

6. Cushing Syndrome

Definition

Causes & Frequency

Clinical Features

• Truncal/central obesity
• Moon face (rounded face)
• Buffalo hump (fat over posterior neck/supraclavicular fossae)
• Hypertension
• Hirsutism
• Amenorrhea
• Depression/mood disturbance

• Thin, fragile skin
• Easy bruising
• Reddish/violaceous striae (>1 cm wide, on abdomen)
• Proximal muscle weakness (cannot rise from chair unaided)
• Osteoporosis
• Diabetes mellitus

• Hyperpigmentation (very high ACTH levels)
• Hypokalemic alkalosis

Diagnostic Testing

1. Best initial test: 24-hour urinary free cortisol (UFC) measurement
2. Alternative: Overnight low-dose dexamethasone suppression test (1 mg dex at 11 pm; cortisol at 8 am - normal if <1.8 μg/dL)
3. Alternative: Late-night salivary cortisol (11 pm - tests loss of diurnal rhythm)

• If UFC is >3-4x the upper limit of normal with compatible clinical findings = Cushing syndrome confirmed
• False positives: Severe illness, depression, phenytoin use (accelerates dexamethasone metabolism)

• Plasma ACTH level: suppressed = adrenal source; elevated = ACTH-dependent
• High-dose dexamethasone suppression test (8 mg): Suppresses cortisol in Cushing disease (pituitary) but NOT in ectopic ACTH
• MRI pituitary for Cushing disease
• CT chest/abdomen for ectopic ACTH source

---

7. Infective Endocarditis (IE)

Definition

Microbiology

Pathophysiology

1. Endothelial damage (turbulent flow, congenital lesion, prosthetic valve) → non-bacterial thrombotic endocarditis (NBTE)
2. Bacteremia seeds the NBTE vegetation
3. Bacteria multiply within the protective fibrin-platelet matrix (shielded from immune system)
4. Growing vegetation causes valve destruction, regurgitation, abscess formation
5. Fragments embolize → systemic emboli (stroke, renal/splenic infarcts, septic emboli)

Clinical Features

• Fever - most common symptom (present in >90%)
• New or changing heart murmur (valvular regurgitation)
• Peripheral stigmata (classic findings):
  • Osler's nodes: Painful raised lesions on finger/toe pads (immune complex deposition)
  • Janeway lesions: Non-tender hemorrhagic macules on palms/soles (septic emboli)
  • Roth's spots: Oval retinal hemorrhages with pale center
  • Splinter hemorrhages: Linear red-brown lines under nails
  • Petechiae: Conjunctival, oral mucosa
• Splenomegaly
• Signs of embolization: stroke, hematuria, back pain (vertebral)

Investigations

• Blood cultures x3 (from different sites, 1 hour apart) - cornerstone of diagnosis
• Echocardiography: TOE (transesophageal) is gold standard (>95% sensitivity for vegetations); TTE as initial test
• FBC: normocytic anemia, leukocytosis; elevated ESR/CRP; urinalysis (microscopic hematuria/casts - immune complex GN)

Management

• Native valve: Amoxicillin/ampicillin + gentamicin ± flucloxacillin
• Prosthetic valve: Vancomycin + gentamicin + rifampicin

• S. viridans: Penicillin G or amoxicillin (4-6 weeks); gentamicin for 2 weeks (synergy)
• S. aureus MSSA: Flucloxacillin 6 weeks; MRSA: Vancomycin
• Enterococcus: Ampicillin + gentamicin or ampicillin + ceftriaxone

• Severe valvular regurgitation with hemodynamic compromise
• Perivalvular abscess/fistula
• Persistent bacteremia despite adequate antibiotics (>7 days)
• Large vegetation (>10 mm) with embolic events
• Fungal endocarditis

---

Quick Summary Table

---

Comprehensive Medical Review: 5 Topics

---

1. Infective Endocarditis (IE) - Overview

Definition

Pathophysiology - The 3-Step Process

1. Endothelial damage from turbulent blood flow, prosthetic valves, or IV drug use creates a nidus (non-bacterial thrombotic endocarditis / NBTE)
2. Transient bacteremia seeds the NBTE vegetation (dental procedures, IV lines, GI/GU manipulation)
3. Bacteria multiply within the fibrin-platelet matrix, shielded from host defenses, growing the vegetation and destroying the valve

Microbiology

Clinical Features

• Fever - most common (>90%)
• New/changing heart murmur
• Classic peripheral stigmata:
  • Osler's nodes - painful, raised lesions on finger/toe pads (immune-complex mediated)
  • Janeway lesions - non-tender hemorrhagic macules on palms/soles (septic emboli)
  • Roth's spots - oval retinal hemorrhages with pale center
  • Splinter hemorrhages - linear red-brown streaks under nails
  • Petechiae - conjunctival, mucous membranes
• Embolic phenomena: stroke, renal infarct, splenic abscess, septic pulmonary emboli (right-sided/IVDU)
• Splenomegaly, weight loss

Diagnosis - Duke Criteria (2023)

• Definite IE: 2 major OR 1 major + 3 minor OR 5 minor criteria
• Blood cultures x3 (cornerstone) + Echocardiography (TOE gold standard)

Management

• Empirical: Amoxicillin + gentamicin ± flucloxacillin (native); vancomycin + gentamicin + rifampicin (prosthetic)
• Definitive: 4-6 weeks IV antibiotics guided by sensitivities
• Surgery indications: Hemodynamic compromise, perivalvular abscess, persistent bacteremia, large vegetations with emboli, fungal IE

---

2. ST Segment Elevation

What It Represents

Diagnostic Criteria for STEMI (2023 AHA/ACC Thresholds)

Localization of MI by ST Elevation Territory

Important Reciprocal Changes

• Reciprocal ST depression in leads opposite the infarct territory increases specificity for true MI
• Example: Inferior STEMI (ST elevation II, III, aVF) → reciprocal ST depression in I and aVL

Posterior STEMI - Important Pitfall

• Does NOT show elevation in standard leads
• Shows ST depression in V1-V3 + tall R waves in V1-V2 (mirror image of posterior elevation)
• Confirmed by posterior leads V7-V9
• Often due to LCX occlusion and frequently misdiagnosed as NSTEMI

LBBB and STEMI

• New LBBB may mask STEMI - use Sgarbossa criteria (concordant ST elevation ≥1 mm, concordant ST depression ≥1 mm in V1-V3, or discordant ST elevation ≥5 mm)
• New LBBB in acute chest pain = treat as STEMI until proven otherwise

Other Causes of ST Elevation (Non-MI)

• Pericarditis: Diffuse, concave ("saddle-shaped") ST elevation in multiple leads; PR depression; no reciprocal changes
• Prinzmetal (vasospastic) angina: Transient ST elevation during angina episode; coronaries normal at rest
• Ventricular aneurysm: Persistent ST elevation weeks after MI (V1-V4)
• Benign early repolarization: Young males; concave ST elevation; J-point notching; no symptoms
• Hyperkalemia: Peaked T waves, then ST changes, then sine wave
• Brugada syndrome: Coved-type ST elevation in V1-V2 with RBBB morphology
• LBBB/LVH: Discordant ST changes in appropriate leads

Management of STEMI

• Time is muscle - goal is rapid reperfusion
• Primary PCI (percutaneous coronary intervention): First-line if available within 120 min of first medical contact
• Fibrinolysis (thrombolytics): If primary PCI unavailable within 120 min; given within 12 hours of symptom onset
• Antiplatelet: Aspirin + P2Y12 inhibitor (ticagrelor or clopidogrel)
• Anticoagulation: Heparin/LMWH
• Beta-blockers, ACE inhibitors, statins started early

---

3. Colon Carcinoma (Colorectal Carcinoma)

Epidemiology

• 3rd most common cancer worldwide; 2nd leading cause of cancer death
• More common in high-resource nations with high-fat, low-fiber diets
• Average age of diagnosis: ~65 years (sporadic); earlier in hereditary syndromes

Risk Factors

• High animal fat, low fiber diet
• Alcohol consumption
• Obesity and sedentary lifestyle
• Cigarette smoking (especially after >35 years use)

• IBD (long-standing ulcerative colitis or Crohn's colitis) - risk proportional to duration and extent
• Primary sclerosing cholangitis (PSC) - additional risk in IBD patients
• Acromegaly (elevated IGF-1)
• Prior pelvic irradiation

• High fiber diet (vegetables)
• Calcium, selenium, vitamins A/C/E, carotenoids
• Oleic acid (olive oil, fish oil) - does NOT increase risk
• Aspirin/NSAIDs (reduce adenoma formation)

Pathogenesis - The Adenoma-Carcinoma Sequence

1. APC gene mutation (chromosome 5q) - FIRST and most important step; seen in 80% of sporadic CRC; loss of APC leads to uncontrolled Wnt/beta-catenin signaling
2. K-RAS mutation - promotes adenoma growth (activated oncogene)
3. DCC (Deleted in Colorectal Cancer) gene loss - chromosome 18q
4. p53 mutation - final step; conversion to frank carcinoma

Hereditary Syndromes

• Autosomal dominant; APC gene mutation (80% of sporadic CRC also have APC mutations)
• Hundreds to thousands of polyps; cancer inevitable if colon not removed
• Extraintestinal: CHRPE (congenital hypertrophy of retinal pigmented epithelium), desmoid tumors, epidermoid cysts, mandibular osteomas = Gardner's syndrome; CNS tumors = Turcot's syndrome
• Prophylactic colectomy required

• Fewer polyps (10-100), right-sided, later onset (avg age 55)
• CRC develops in >50%; APC mutation only 30%; MYH mutations in others (autosomal recessive)

• Most common hereditary CRC syndrome (1-3% of all CRC)
• Autosomal dominant; defects in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) → microsatellite instability (MSI)
• Average age of onset: 40-45 years
• ~70% lifetime risk of CRC; proximal colon predominance; better prognosis than sporadic
• 40% risk of synchronous/metachronous CRC
• Extracolonic cancers: endometrial carcinoma (most common in women), ovarian, gastric, urinary tract, pancreatic
• Amsterdam I criteria: 3 relatives with CRC (1 first-degree), 2 successive generations, 1 diagnosed <50 years

Clinical Presentation

• Occult blood loss → iron deficiency anemia, fatigue
• Palpable mass (large tumor, cecum/ascending colon)
• Less likely to obstruct (large lumen)

• Altered bowel habits (constipation alternating with diarrhea)
• Bright rectal bleeding / change in stool caliber ("pencil-thin stools")
• More likely to obstruct (narrow lumen, solid stool)

• Tenesmus, rectal bleeding, urgency
• Tumor palpable on DRE (digital rectal examination)

Staging (TNM / Duke's Staging)

Management

• Surgery: Primary treatment - right or left hemicolectomy, anterior resection, abdominoperineal resection (for low rectal)
• Adjuvant chemotherapy: FOLFOX (5-FU, leucovorin, oxaliplatin) for stage III (node positive)
• Targeted therapy: Bevacizumab (anti-VEGF), cetuximab/panitumumab (anti-EGFR, only for KRAS wild-type)
• Screening: Colonoscopy every 10 years from age 45; fecal occult blood testing annually

---

4. Barrett Esophagus

Definition

Epidemiology

• Occurs in up to 10% of patients with symptomatic GERD
• Present in up to 2% of the general population
• Rising incidence in parallel with rising GERD rates
• Most common in males of European descent, aged 40-60
• Familial form exists

Pathogenesis

1. Chronic acid (and bile) reflux causes repetitive mucosal injury
2. Squamous epithelium is replaced by columnar epithelium (metaplasia) as an adaptive response to acid exposure
3. Goblet cells (intestinal metaplasia) are the key histological finding - diagnostic of Barrett's
4. Accumulation of driver mutations in cancer genes leads to: Metaplasia → Low-grade dysplasia → High-grade dysplasia → Adenocarcinoma
5. Risk of developing cancer is greatest in those with goblet cells; non-goblet columnar cells alone are of debated significance

Morphology

• Tongues of red, velvety mucosa extending upward from the gastroesophageal junction (GEJ)
• Alternates with pale squamous (normal esophageal) mucosa above and light-brown columnar (gastric) mucosa below
• Long segment: ≥3 cm above GEJ (higher cancer risk)
• Short segment: <3 cm (may have no GERD symptoms; lower risk)

• Replacement of squamous epithelium with columnar epithelial cells
• Goblet cells (diagnostic): Large mucus vacuoles that stain pale blue; "wine goblet" shape
• Dysplasia classified as low-grade or high-grade
  • Both show: atypical mitoses, nuclear hyperchromasia, irregularly clumped chromatin, increased nuclear-to-cytoplasmic ratio, failure of maturation toward the surface
  • High-grade = full-thickness nuclear atypia, architecture distortion → immediate risk of progression to adenocarcinoma

Cancer Risk

• Barrett's with no dysplasia: ~0.1-0.3% per year risk of esophageal adenocarcinoma
• Low-grade dysplasia: ~0.5-1% per year
• High-grade dysplasia: ~5-10% per year (some consider this intramucosal carcinoma)
• Most esophageal adenocarcinomas are associated with Barrett's, but most Barrett's patients do NOT develop cancer

Surveillance

• No dysplasia: Endoscopy + biopsy every 3-5 years (4-quadrant biopsies every 2 cm - Seattle protocol)
• Low-grade dysplasia: Endoscopy every 6-12 months; consider ablation therapy
• High-grade dysplasia: Endoscopic mucosal resection (EMR) or ablation (radiofrequency ablation - RFA); esophagectomy if endoscopic therapy not feasible
• No RCT proof that surveillance reduces mortality, but it is recommended by major societies

Treatment

• GERD control: PPI therapy (acid suppression may reduce progression, not reverse metaplasia)
• Ablation (RFA): Preferred treatment for dysplastic Barrett's; eliminates >80% of dysplasia
• EMR (endoscopic mucosal resection): For visible nodules/raised lesions
• NSAIDs/aspirin: May reduce cancer risk (not routinely recommended for this purpose)

---

5. Atherosclerosis

Definition

Risk Factors

• Genetics / family history - most important independent risk factor; usually polygenic
• Age - MI incidence increases 5-fold between ages 40-60; death rate from IHD doubles every decade after 40
• Male sex - women protected pre-menopause by estrogens; risk equalizes post-menopause

• Hyperlipidemia - major and sufficient risk factor; LDL is the "bad" cholesterol (delivers lipid to peripheral tissues); HDL is "good" (removes cholesterol from periphery to liver for excretion)
• Hypertension - increases IHD risk by ~60% vs. normotensive; also causes LVH (surrogate marker for CV risk)
• Cigarette smoking - dose-dependent risk; accelerates atherogenesis; promotes thrombosis
• Diabetes mellitus - significantly accelerates atherosclerosis; associated with advanced glycation end-products and oxidative stress
• Inflammation - elevated CRP, hs-CRP as markers; chronic infections (e.g., C. pneumoniae) debated
• Omega-3 fatty acids (fish oils): protective; trans-fats: adverse effect on cholesterol profile

Pathogenesis - Response-to-Injury / Chronic Inflammation Model

• Risk factors (LDL, hypertension, smoking, hyperglycemia) injure the endothelium
• Loss of nitric oxide (NO) function: endothelial NO normally causes vasodilation, inhibits platelet aggregation, inhibits leukocyte adhesion, reduces smooth muscle proliferation
• Reduced NO → vasoconstriction, platelet activation, leukocyte adhesion, SMC proliferation

• LDL enters the intima and is oxidized (ox-LDL)
• Oxidized LDL is pro-inflammatory and chemotactic for monocytes

• Monocytes adhere to activated endothelium (via VCAM-1, ICAM-1) and migrate into the intima
• Monocytes differentiate into macrophages
• Macrophages engulf ox-LDL via scavenger receptors (not downregulated - unlike normal LDL receptor) → become foam cells
• Accumulation of foam cells forms the fatty streak (earliest visible lesion)

• Growth factors (PDGF, FGF) from macrophages and platelets stimulate medial SMCs to migrate into the intima
• SMCs synthesize extracellular matrix (collagen, proteoglycans) → forming the fibrous cap

• Core: Lipid-rich necrotic center (dead foam cells, cholesterol crystals) = "grumous core"
• Cap: Fibrous cap (SMCs + collagen) covering the core
• Shoulder region: Most inflammatory, macrophage-rich, and most vulnerable to rupture

• Stable angina: Gradual luminal narrowing (>70% = symptoms on exertion)
• Plaque rupture/erosion: Sudden exposure of thrombogenic core → platelet aggregation → thrombus → ACS (NSTEMI, STEMI, unstable angina)
• Aneurysm formation: Plaque increases diffusion distance to media → SMC ischemia → wall weakening
• Calcification: Dystrophic calcification of advanced plaques ("pipe-stem" arteries)
• Embolism: Plaque fragments or thrombus embolizing distally

PCSK9 and Novel Lipid Lowering

• PCSK9 (serine protease) binds LDL receptors and accelerates their degradation → elevated LDL
• Loss-of-function PCSK9 mutations → lower cholesterol
• PCSK9 inhibitors (evolocumab, alirocumab): Dramatically reduce LDL; used when statins insufficient
• Statins: Inhibit HMG-CoA reductase (rate-limiting step in hepatic cholesterol synthesis); also anti-inflammatory ("off-target" pleiotropic effects)

Consequences of Atherosclerosis

---

Quick Summary Table