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First_Aid_Step1. The fundamental principles of pathology are key to understanding diseases in all organ systems. Major topics such as inflammation and neoplasia appear frequently in questions across different organ systems, and such topics are definitely high yield. For example, the concepts of cell injury and inflammation are key to understanding the inflammatory response that follows myocardial infarction, a very common subject of board questions. Similarly, a familiarity with the early cellular changes that culminate in the development of neoplasias—for example, esophageal or colon cancer—is critical. Finally, make sure you recognize the major tumor-associated genes and are comfortable with key cancer concepts such as tumor staging and metastasis.


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First_Aid_Step1. Apoptosis ATP-dependent programmed cell death. Intrinsic and extrinsic pathways; both pathways activate caspases (cytosolic proteases)  cellular breakdown including cell shrinkage, chromatin condensation, membrane blebbing, and formation of apoptotic bodies, which are then phagocytosed. Characterized by deeply eosinophilic cytoplasm and basophilic nucleus, pyknosis, and karyorrhexis. Cell membrane typically remains intact without significant inflammation (unlike necrosis). DNA laddering (fragments in multiples of 180 bp) is a sensitive indicator of apoptosis. Executioner caspases Cytoplasmic bleb Apoptotic body Ligands for macrophage cell receptors Macrophage Cytotoxic T cell Perforin Granzyme B FasL TNF-αTNFRFas Misfolded proteins Hypoxia p53 activation BAX/BAK Cytochrome C Bcl-2 Initiator caspases Initiator caspases Nuclear fragmentation (mitochondrial) pathway (death receptor) pathway DNA damage Radiation, ROS, toxins Cytoskeletal dispersion


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First_Aid_Step1. Necrosis Exogenous injury  plasma membrane damage  cell undergoes enzymatic degradation and protein denaturation, intracellular components leak  local inflammatory reaction (unlike apoptosis). Ischemia Inadequate blood supply to meet demand. Mechanisms include  arterial perfusion (eg, atherosclerosis),  venous drainage (eg, testicular torsion, Budd-Chiari syndrome), shock. Regions most vulnerable to hypoxia/ischemia and subsequent infarction: Brain ACA/MCA/PCA boundary areasa,b Colon Splenic flexure (Griffith point),a rectosigmoid junction (Sudeck point)a aWatershed areas (border zones) receive blood supply from most distal branches of 2 arteries with limited collateral vascularity. These areas are susceptible to ischemia from hypoperfusion. bNeurons most vulnerable to hypoxic-ischemic insults include Purkinje cells of the cerebellum and pyramidal cells of the hippocampus and neocortex (zones 3, 5, 6). Types of infarcts


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First_Aid_Step1. Types of infarcts Red infarct Occurs in venous occlusion and tissues with multiple blood supplies (eg, liver, lung A , intestine, testes), and with reperfusion (eg, after angioplasty). Reperfusion injury is due to damage by free radicals. Pale infarct Occurs in solid organs with a single (endarterial) blood supply (eg, heart, kidney B ). Free radical injury Free radicals damage cells via membrane lipid peroxidation, protein modification, DNA breakage. Initiated via radiation exposure (eg, cancer therapy), metabolism of drugs (phase I), redox reactions, nitric oxide (eg, inflammation), transition metals, WBC (eg, neutrophils, macrophages) oxidative burst. Free radicals can be eliminated by scavenging enzymes (eg, catalase, superoxide dismutase, glutathione peroxidase), spontaneous decay, antioxidants (eg, vitamins A, C, E), and certain metal carrier proteins (eg, transferrin, ceruloplasmin). Examples:


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First_Aid_Step1. Oxygen toxicity: retinopathy of prematurity (abnormal vascularization), bronchopulmonary dysplasia, reperfusion injury after thrombolytic therapy Drug/chemical toxicity: acetaminophen overdose (hepatotoxicity), carbon tetrachloride (converted by cytochrome P-450 into CCl3 free radical  fatty liver [cell injury • apolipoprotein synthesis  fatty change], centrilobular necrosis) Metal storage diseases: hemochromatosis (iron) and Wilson disease (copper) Types of calcification Calcium deposits appear deeply basophilic (arrow in A ) on H&E stain. Lipofuscin A yellow-brown “wear and tear” pigment A associated with normal aging. Composed of polymers of lipids and phospholipids complexed with protein. May be derived through lipid peroxidation of polyunsaturated lipids of subcellular membranes. Autopsy of elderly person will reveal deposits in heart, colon, liver, kidney, eye, and other organs.


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First_Aid_Step1. Primary amyloidosis AL (from Ig Light chains) Seen in Plasma cell disorders Manifestations include: (eg, multiple myeloma) • Cardiac (eg, restrictive GI (eg, macroglossia, hepatomegaly) Renal (eg, nephrotic syndrome) Hematologic (eg, easy bruising, splenomegaly) Neurologic (eg, neuropathy) Musculoskeletal (eg, carpal tunnel syndrome) Inflammation Response to eliminate initial cause of cell injury, to remove necrotic cells resulting from the original insult, and to initiate tissue repair. Divided into acute and chronic. The inflammatory response itself can be harmful to the host if the reaction is excessive (eg, septic shock), prolonged (eg, persistent infections such as TB), or inappropriate (eg, autoimmune diseases such as SLE).


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First_Aid_Step1. Fever Pyrogens (eg, LPS) induce macrophages to release IL-1 and TNF  COX activity in perivascular cells of hypothalamus • PGE2  temperature set point Acute inflammation Transient and early response to injury or infection. Characterized by neutrophils in tissue A , often with associated edema. Rapid onset (seconds to minutes) and short duration (minutes to days). Represents a reaction of the innate immune system (ie, less specific response than chronic inflammation). STIMuLI Infections, trauma, necrosis, foreign bodies. Leukocyte Extravasation predominantly occurs at postcapillary venules. extravasation GlyCAM-1, CD34 L-selectin CD11/18 integrins (LFA-1, Mac-1) VLA-4 integrin Chronic inflammation Prolonged inflammation characterized by mononuclear infiltration (macrophages, lymphocytes, plasma cells), which leads to simultaneous tissue destruction and repair (including angiogenesis and fibrosis). May be preceded by acute inflammation.


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First_Aid_Step1. STIMuLI Persistent infections (eg, TB, T pallidum, certain fungi and viruses)  type IV hypersensitivity, autoimmune diseases, prolonged exposure to toxic agents (eg, silica) and foreign material. MeDIATOrS Macrophages are the dominant cells. Interaction of macrophages and T lymphocytes  chronic inflammation. OuTCOMeS Scarring, amyloidosis, and neoplastic transformation (eg, chronic HCV infection  chronic inflammation  hepatocellular carcinoma; Helicobacter pylori infection  chronic gastritis • gastric adenocarcinoma). FGF Stimulates angiogenesis TGF-β Angiogenesis, fibrosis EGF Stimulates cell growth via tyrosine kinases (eg, EGFR/ErbB1)


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First_Aid_Step1. FGF Stimulates angiogenesis TGF-β Angiogenesis, fibrosis EGF Stimulates cell growth via tyrosine kinases (eg, EGFR/ErbB1) HISTOLOGY Focus of epithelioid cells (activated macrophages with abundant pink cytoplasm) surrounded by lymphocytes and multinucleated giant cells (formed by fusion of several activated macrophages). Two types: Caseating: associated with Central necrosis. Seen with infectious etiologies (eg, TB, fungal). Noncaseating A : no central necrosis. Seen with autoimmune diseases (eg, sarcoidosis, Crohn disease). APCs present antigens to CD4+ Th cells and secrete IL-12 • CD4+ Th cells differentiate into Th1 cells Th1 secretes IFN-γ • macrophage activation Macrophages  cytokine secretion (eg, TNF)  formation of epithelioid macrophages and giant cells. Anti-TNF therapy can cause sequestering granulomas to break down • disseminated disease. Always test for latent TB before starting anti-TNF therapy.


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First_Aid_Step1. Associated with hypercalcemia due to  1α-hydroxylase activity in activated macrophages, resulting in  vitamin D activity. Bacterial: Mycobacteria (tuberculosis, leprosy), Bartonella henselae (cat scratch disease; stellate necrotizing granulomas), Listeria monocytogenes (granulomatosis infantiseptica), Treponema pallidum (3° syphilis) Fungal: endemic mycoses (eg, histoplasmosis) Parasitic: schistosomiasis Immune-mediated: sarcoidosis, Crohn disease, 1° biliary cholangitis, subacute (de Quervain/ granulomatous) thyroiditis Vasculitis: granulomatosis with polyangiitis (Wegener), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), giant cell (temporal) arteritis, Takayasu arteritis Foreign bodies: berylliosis, talcosis, hypersensitivity pneumonitis


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First_Aid_Step1. Foreign bodies: berylliosis, talcosis, hypersensitivity pneumonitis Scar formation Occurs when repair cannot be accomplished by cell regeneration alone. Nonregenerated cells (2° to severe acute or chronic injury) are replaced by connective tissue. 70–80% of tensile strength regained at 3 months; little tensile strength regained thereafter. Associated with excess TGF-β. Normal cells Normal cells with basal  apical polarity. See cervical example A , which shows normal cells and spectrum of dysplasia, as discussed below. Loss of uniformity in cell size and shape (pleomorphism); loss of tissue orientation; nuclear changes (eg,  nuclear:cytoplasmic ratio) A . Carcinoma in situ/ Irreversible severe dysplasia that involves the entire thickness of epithelium but does not preinvasive penetrate the intact basement membrane A . Cells have invaded basement membrane using collagenases and hydrolases (metalloproteinases). Cell-cell contacts lost by inactivation of E-cadherin.


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First_Aid_Step1. Cells have invaded basement membrane using collagenases and hydrolases (metalloproteinases). Cell-cell contacts lost by inactivation of E-cadherin. Metastasis Spread to distant organ(s) via lymphatics or blood. Tumor nomenclature Carcinoma implies epithelial origin, whereas sarcoma denotes mesenchymal origin. Both terms generally imply malignancy. Benign tumors are usually well-differentiated and well-demarcated, with low mitotic activity, no metastases, and no necrosis. Malignant tumors (cancers) may show poor differentiation, erratic growth, local invasion, metastasis, and • apoptosis. Terms for non-neoplastic malformations include hamartoma (disorganized overgrowth of tissues in their native location, eg, Peutz-Jeghers polyps) and choristoma (normal tissue in a foreign location, eg, gastric tissue located in distal ileum in Meckel diverticulum). Epithelium Adenoma, papilloma Adenocarcinoma, papillary carcinoma Blood cells Leukemia, lymphoma


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First_Aid_Step1. Epithelium Adenoma, papilloma Adenocarcinoma, papillary carcinoma Blood cells Leukemia, lymphoma Tumor grade vs stage Differentiation—degree to which a tumor resembles its tissue of origin. Well-differentiated tumors (often less aggressive) closely resemble their tissue of origin, whereas poorly differentiated tumors (often more aggressive) do not. Anaplasia—complete lack of differentiation of cells in a malignant neoplasm. Grade Degree of cellular differentiation and mitotic activity on histology. Ranges from low grade (well-differentiated) to high grade (poorly differentiated, undifferentiated, or anaplastic). Low grade High grade Stage Degree of localization/spread based on site and size of 1° lesion, spread to regional lymph nodes, presence of metastases. Based on clinical (c) or pathologic (p) findings. Stage T generally has more prognostic value than Lymphgrade (eg, a high-stage yet low-grade tumor is node N tumor). Stage determines Survival. Blood or lymphatic vessel


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First_Aid_Step1. Lymphgrade (eg, a high-stage yet low-grade tumor is node N tumor). Stage determines Survival. Blood or lymphatic vessel TNM staging system (Stage = Spread): Spread to otherT = Tumor size/invasiveness, N = Node organs and tissues involvement, M = Metastases, eg, cT3N1M0. Each TNM factor has independent prognostic value; N and M are often most important. Cancer epidemiology Skin cancer (basal > squamous >> melanoma) is the most common cancer (not included below). Common metastases Most sarcomas spread hematogenously; most carcinomas spread via lymphatics. However, Four Carcinomas Route Hematogenously: Follicular thyroid carcinoma, Choriocarcinoma, Renal cell carcinoma, and Hepatocellular carcinoma. Brain Lung > breast > melanoma, colon, kidney 50% of brain tumors are from metastases A Commonly seen as multiple well-circumscribed tumors at gray/white matter junction CD and lung are the most common sites Sometimes Penetrates liver) of metastasis after the regional lymph nodes


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First_Aid_Step1. CD and lung are the most common sites Sometimes Penetrates liver) of metastasis after the regional lymph nodes Bone Prostate, Breast > Kidney, Thyroid, Lung (Painful Bones Kill The Lungs) Bone metastasis E F >> 1° bone tumors (eg, G Bone metastasis can be: Lytic (eg, thyroid, kidney, non-small cell lung cancer) Blastic (eg, prostate, small cell lung cancer) Mixed (eg, breast cancer) Tumor suppressor Loss of function  cancer risk; both (two) alleles of a tumor suppressor gene must be lost for genes expression of disease. EBV Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, 1° CNS lymphoma (in immunocompromised patients) HBV, HCV Hepatocellular carcinoma Serum tumor markers Tumor markers should not be used as the 1° tool for cancer diagnosis or screening. They may be used to monitor tumor recurrence and response to therapy, but definitive diagnosis is made via biopsy. Some can be associated with non-neoplastic conditions.


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First_Aid_Step1. P-glycoprotein Also known as multidrug resistance protein 1 (MDR1). Classically seen in adrenocortical carcinoma but also expressed by other cancer cells (eg, colon, liver). Used to pump out toxins, including chemotherapeutic agents (one mechanism of  responsiveness or resistance to chemotherapy over time). Psammoma bodies Laminated, concentric spherules with dystrophic calcification A , PSaMMOMa bodies are seen in: Papillary carcinoma of thyroid Cachexia Weight loss, muscle atrophy, and fatigue that occur in chronic disease (eg, cancer, AIDS, heart failure, COPD). Mediated by TNF-α, IFN-γ, IL-1, and IL-6. effusions, periostosis of tubular bones Endocrine “One pill makes you larger, and one pill makes you small.” “I was under medication when I made the decision not to burn the tapes.” “I wondher why ye can always read a doctor’s bill an’ ye niver can read his purscription.” “One of the first duties of the physician is to educate the masses not to take medicine.”


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First_Aid_Step1. Preparation for pharmacology questions is straightforward. Know all the mechanisms, clinical use, and important adverse effects of key drugs and their major variants. Obscure derivatives are low-yield. Learn their classic and distinguishing toxicities as well as major drug-drug interactions. Reviewing associated biochemistry, physiology, and microbiology concepts can be useful while studying pharmacology. The exam has a strong emphasis on ANS, CNS, antimicrobial, and cardiovascular agents as well as on NSAIDs, which are covered throughout the text. Specific drug dosages or trade names are generally not testable. The exam may use graphs to test various pharmacology content, so make sure you are comfortable interpreting them. Michaelis-Menten Km is inversely related to the affinity of the [S] = concentration of substrate; V = velocity. kinetics enzyme for its substrate. Vmax is directly proportional to the enzyme concentration.


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First_Aid_Step1. Vmax is directly proportional to the enzyme concentration. curve (ie, Michaelis-Menten kinetics); however, enzymatic reactions that exhibit a Effects of enzyme inhibition kinetics (eg, hemoglobin). Lineweaver-Burk plot The closer to 0 on the Y-axis, the higher the 1 Vmax. V The closer to 0 on the X-axis, the higher the Km. −K The higher the Km, the lower the affinity. 1 Competitive inhibitors cross each other, [S] whereas noncompetitive inhibitors do not. Effects of enzyme inhibition Kompetitive inhibitors increase Km. Bioavailability (F) Fraction of administered drug reaching systemic circulation unchanged. For an IV dose, F = 100%. Orally: F typically < 100% due to incomplete absorption and first-pass metabolism. Can be calculated from the area under the curve in a plot of plasma concentration over time.


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First_Aid_Step1. Volume of distribution Theoretical volume occupied by the total amount of drug in the body relative to its plasma (Vd) concentration. Apparent Vd of plasma protein–bound drugs can be altered by liver and kidney disease ( protein binding,  Vd). Drugs may distribute in more than one compartment. amount of drug in the body Low Intravascular Large/charged molecules; plasma protein bound Medium ECF Small hydrophilic molecules High All tissues including Small lipophilic molecules, especially if bound fat to tissue protein Clearance (CL) The volume of plasma cleared of drug per unit time. Clearance may be impaired with defects in cardiac, hepatic, or renal function. rate of elimination of drug Half-life (t1/2) The time required to change the amount of drug in the body by 1⁄2 during elimination. In first-order kinetics, a drug infused at a constant rate takes 4–5 half-lives to reach steady state. It takes 3.3 half-lives to reach 90% of the steady-state level.


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First_Aid_Step1. t1/2 = 0.7 × Vd in first-order elimination CL Drug metabolism Geriatric patients lose phase I first. Patients who are slow acetylators have  side effects from certain drugs because of  rate of metabolism (eg, isoniazid). Elimination of drugs Weak bases Examples: TCAs, amphetamines. Trapped in acidic environments. Treat overdose with ammonium chloride to acidify urine. TCA toxicity is generally treated with sodium bicarbonate to overcome the sodium channel-blocking activity of TCAs, but not for accelerating drug elimination. pKa pH at which drugs (weak acid or base) are 50% ionized and 50% nonionized. The pKa represents the strength of the weak acid or base. Efficacy Maximal effect a drug can produce. Represented by the y-value (Vmax).  y-value =  Vmax =  efficacy. Unrelated to potency (ie, efficacious drugs can have high or low potency). Partial agonists have less efficacy than full agonists.


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First_Aid_Step1. Potency Amount of drug needed for a given effect. Represented by the x-value (EC50). Left shifting = • EC50 =  potency =  drug needed. Unrelated to efficacy (ie, potent drugs can have high or low efficacy). 0.1 1.0 10 100 1000 0.1 1.0 10 100 1000 0.1 1.0 10 100 1000 Agonist dose Agonist dose Agonist dose Therapeutic index Measurement of drug safety. TD50 median toxic dose Therapeutic window—dosage range that can safely and effectively treat disease. % of patients responding TITE: Therapeutic Index = TD50 / ED50. Safer drugs have higher TI values. Drugs with lower TI values frequently require monitoring (eg, Warfarin, Theophylline, Digoxin, Antiepileptic drugs, Lithium; Warning! These Drugs Are Lethal!). LD50 (lethal median dose) often replaces TD50 in animal studies. Types of drug interactions Autonomic receptors


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First_Aid_Step1. LD50 (lethal median dose) often replaces TD50 in animal studies. Types of drug interactions Autonomic receptors SOMATICSmooth muscle, gland cells, nerve terminals, cardiac muscle Sweat glands Smooth muscle, gland cells, nerve terminals, cardiac muscle Renal vasculature smooth muscle Cardiac muscle, vessels Skeletal muscle ParasympatheticBrainstem Spinal cord Post (long) SympatheticPost (short) ACh NN Pre (long) ACh NN AChM ACh D NE M D1 ACh NM ACh NN ACh NN ACh NN Adrenal medulla Voluntary motor nerve Neuromuscular junction Catecholamine transmission Blood ˜1˜2°1 Epi ˜1˜2°1°2 NE ˜1˜2°1 Pre (short) Pelvic splanchnic nerves and CNs III, VII, IX and X are part of the parasympathetic nervous system. Adrenal medulla is directly innervated by preganglionic sympathetic fibers. Sweat glands are part of the sympathetic pathway but are innervated by cholinergic fibers (sympathetic nervous system results in a “chold” sweat).


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First_Aid_Step1. M˜-receptor bladder function via coordination of sympathetic and parasympathetic nervous Pelvic nerve β˜-receptor (parasympatheticsystems. • ⊕ parasympathetic  urine voiding. Some (sympathetic input) sphincter autonomic drugs act on smooth muscle External urethral receptors to treat bladder dysfunction. q • vascular smooth muscle contraction,  pupillary dilator muscle contraction (mydriasis),  intestinal and bladder sphincter muscle contraction i • sympathetic (adrenergic) outflow,  insulin release,  lipolysis,  platelet aggregation,  aqueous humor production s • heart rate,  contractility (one heart),  renin release,  lipolysis s Vasodilation, bronchodilation (two lungs),  lipolysis,  insulin release, glycogenolysis,  uterine tone (tocolysis),  aqueous humor production, β3 s lipolysis,  thermogenesis in skeletal muscle,  bladder relaxation Cholinergic (accommodation),  insulin release, endothelium-mediated vasodilation Dopamine


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First_Aid_Step1. D1 s Relaxes renal vascular smooth muscle, activates direct pathway of striatum D2 i Modulates transmitter release, especially in brain, inhibits indirect “After qisses (kisses), you get a qiq (kick) out of siq (sick) sqs (super qinky sex).” H1, ˜1, V1, Protein HAVe 1M&M. M1, M3 kinase C Lipids ° 1, ° 2, ° 3, D1, Receptor Gs ATP H2, V2 M2, ˜2, D2 inhibit themselves. Autonomic drugs Release of norepinephrine from a sympathetic nerve ending is modulated by NE itself, acting on presynaptic α2-autoreceptors • negative feedback. Amphetamines use the NE transporter (NET) to enter the presynaptic terminal, where they utilize the vesicular monoamine transporter (VMAT) to enter neurosecretory vesicles. This displaces NE from the vesicles. Once NE reaches a concentration threshold within the presynaptic terminal, the action of NET is reversed, and NE is expelled into the synaptic cleft, contributing to the characteristics and effects of  NE observed in patients taking amphetamines.


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First_Aid_Step1. ACh NE Choline Choline+ Acetyl-CoA Ca2+ Choline + acetate AChE ACh receptor DOPA Dopamine Reuptake Di˜usion, metabolism NET VMAT Adrenoreceptors ˜ or °Cocaine, TCAs, amphetamine Botulinum toxin -Ca2+ NE + --AChE inhibitors AXON Tyrosine ACh Tyrosine ˜2 AT II Reserpine -Release-modulating receptors Negativefeedback AXON ChAT -+ Amphetamine, ephedrine + + represents transporters. Atropine Muscarinic antagonist. Used to treat bradycardia and for ophthalmic applications. Eye  pupil dilation, cycloplegia Blocks muscarinic effects (DUMBBELSS) of anticholinesterases, but not the nicotinic Airway Bronchodilation,  secretions effects. AdVERSE EFFECTS  body temperature (due to  sweating); • HR; dry mouth; dry, flushed skin; cycloplegia; constipation; disorientation Can cause acute angle-closure glaucoma in elderly (due to mydriasis), urinary retention in men with prostatic hyperplasia, and hyperthermia in infants.


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First_Aid_Step1. Side effects: Hot as a hare Fast as a fiddle Dry as a bone Red as a beet Blind as a bat Mad as a hatter Full as a flask Jimson weed (Datura)  gardener’s pupil (mydriasis due to plant alkaloids) priapism. Indirect sympathomimetics Ephedrine Indirect general agonist, releases stored catecholamines Narcolepsy, obesity, ADHD. Causes vasoconstriction and local anesthesia. Caution when giving β-blockers if cocaine intoxication is suspected (can lead to unopposed α1 activation • extreme hypertension, coronary vasospasm). Nasal decongestion (pseudoephedrine), urinary incontinence, hypotension. β1, refex tachycardia Epinephrine response exhibits reversal of mean arterial Phenylephrine response is suppressed but not reversed pressure from a net increase (the α response) to a net because it is a “pure” α-agonist (lacks β-agonist decrease (the β2 response). properties). In platelets:  cAMP  inhibition of platelet aggregation


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First_Aid_Step1. In platelets:  cAMP  inhibition of platelet aggregation Cardiac stress testing (dipyridamole only, due to coronary vasodilation) Prevention of coronary stent restenosis Nausea, headache, facial flushing, hypotension, abdominal pain aCilostazol is a PDE-3 inhibitor, but due to its indications is categorized as a platelet inhibitor together with dipyridamole. bDipyridamole is a nonspecific PDE inhibitor, leading to inhibition of platelet aggregation. It also prevents adenosine reuptake by platelets • extracellular adenosine • vasodilation. Beers criteria Widely used criteria developed to reduce potentially inappropriate prescribing and harmful polypharmacy in the geriatric population. Includes > 50 medications that should be avoided in elderly patients due to  efficacy and/or  risk of adverse events. Examples: α-blockers ( risk of hypotension) Anticholinergics, antidepressants, antihistamines, opioids ( risk of delirium, sedation, falls, constipation, urinary retention)


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First_Aid_Step1. Anticholinergics, antidepressants, antihistamines, opioids ( risk of delirium, sedation, falls, constipation, urinary retention) Benzodiazepines ( risk of delirium, sedation, falls) NSAIDs ( risk of GI bleeding, especially with concomitant anticoagulation) PPIs ( risk of C difficile infection) AChE inhibitors, organophosphates Atropine > pralidoxime Antimuscarinic, anticholinergic agents Physostigmine (crosses BBB), control hyperthermia Arsenic Dimercaprol, succimer β-blockers Atropine, glucagon, saline Iron (Fe) Deferoxamine, deferasirox, deferiprone Salicylates NaHCO3 (alkalinize urine), dialysis Warfarin Vitamin K (delayed effect), PCC (prothrombin complex concentrate)/FFP (immediate effect) Anticholinergics (eg, atropine, TCAs, Sympatholytics (eg, α2-agonists) tropicamide, scopolamine, antihistamines) Drugs of abuse (eg, amphetamines, cocaine, Drugs of abuse (eg, heroin/opioids) LSD), meperidine


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First_Aid_Step1. Drugs of abuse (eg, amphetamines, cocaine, Drugs of abuse (eg, heroin/opioids) LSD), meperidine Sympathomimetics Parasympathomimetics (eg, pilocarpine), organophosphates Sulfa drugs Sulfonamide antibiotics, Sulfasalazine, Scary Sulfa Pharm FACTS Probenecid, Furosemide, Acetazolamide, Celecoxib, Thiazides, Sulfonylureas. Patients with sulfa allergies may develop fever, urinary tract infection, Stevens-Johnson syndrome, hemolytic anemia, thrombocytopenia, agranulocytosis, acute interstitial nephritis, and urticaria (hives). “Medicine is a science of uncertainty and an art of probability.” “There are two kinds of statistics: the kind you look up and the kind you make up.” “On a long enough timeline, the survival rate for everyone drops to zero.” “There are three kinds of lies: lies, damned lies, and statistics.”


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First_Aid_Step1. A heterogenous mix of epidemiology, biostatistics, ethics, law, healthcare delivery, patient safety, quality improvement, and more falls under the heading of public health sciences. Biostatistics and epidemiology are the foundations of evidence-based medicine and are very high yield. Make sure you can quickly apply biostatistical equations such as sensitivity, specificity, and predictive values in a problem-solving format. Also, know how to set up your own 2 × 2 tables. Quality improvement and patient safety topics were introduced a few years ago on the exam and represent trends in health system science. Medical ethics questions often require application of principles. Typically, you are presented with a patient scenario and then asked how you would respond.


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First_Aid_Step1. Clinical trial Experimental study involving humans. Compares therapeutic benefits of ≥2 treatments, or of treatment and placebo. Study quality improves when study is randomized, controlled, and double-blinded (ie, neither patient nor doctor knows whether the patient is in the treatment or control group). Triple-blind refers to the additional blinding of the researchers analyzing the data. Four phases (“Does the drug SWIM?”). Evaluation of Sensitivity and specificity are fixed properties Disease diagnostic tests of a test. PPV and NPV vary depending on disease prevalence in population being tested. SN-N-OUT = highly SeNsitive test, when Negative, rules OUT disease SP-P-IN = highly SPecific test, when Positive, rules IN disease PPV varies directly with pretest probability (baseline risk, such as prevalence of disease): NPV varies inversely with prevalence or pretest Quantifying risk Definitions and formulas are based on the classic 2 × 2 or contingency table.


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First_Aid_Step1. NPV varies inversely with prevalence or pretest Quantifying risk Definitions and formulas are based on the classic 2 × 2 or contingency table. Odds ratio Typically used in case-control If in a case-control study, 20/30 lung a/c ad studies. Represents the odds of cancer patients and 5/25 healthy b/d bc exposure among cases (a/c) vs individuals report smoking, the OR odds of exposure among controls is 8; so the lung cancer patients are 8 (b/d). times more likely to have a history of smoking. Relative risk Typically used in cohort studies. Risk of developing disease in the exposed group divided by risk in the unexposed group. RR = 1  no association between exposure and disease. RR > 1  exposure associated with occurrence. RR < 1  exposure associated with disease occurrence.


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First_Aid_Step1. If 5/10 people exposed to radiation are a/(a + b) diagnosed with cancer, and 1/10 people c/(c + d) not exposed to radiation are diagnosed with cancer, the RR is 5; so people exposed to radiation have a 5 times greater risk of developing cancer. For rare diseases (low prevalence), OR approximates RR. Relative risk The proportion of risk reduction If 2% of patients who receive a flu RRR = 1 − RR reduction attributable to the intervention as shot develop the flu, while 8% of compared to a control. unvaccinated patients develop the flu, then RR = 2/8 = 0.25, and RRR = 0.75. Attributable The difference in risk between If risk of lung cancer in smokers is 21% a c risk exposed and unexposed groups. and risk in nonsmokers is 1%, then the a + b c + d attributable risk is 20%. RR − 1


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First_Aid_Step1. Absolute The difference in risk (not the If 8% of people who receive a placebo c a risk proportion) attributable to the vaccine develop the flu vs 2% of people c + d a + b reduction intervention as compared to a who receive a flu vaccine, then ARR = control. 8%–2% = 6% = 0.06. Number Number of patients who need to NNT = 1/ARR needed to be treated for 1 patient to benefit. treat Lower number = better treatment. Number Number of patients who need to NNH = 1/AR needed to be exposed to a risk factor for 1 harm patient to be harmed. Higher number = safer exposure. Case fatality Percentage of deaths occurring If 4 patients die among 10 cases of deaths rate among those with disease. meningitis, case fatality rate is 40%. cases Incidence vs # of new cases Incidence looks at new cases(incidents). Incidence = (per unit of time) prevalence # of people at risk Prevalence =# of existing cases (at a point in Prevalence looks at all current cases.


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First_Aid_Step1. Incidence = (per unit of time) prevalence # of people at risk Prevalence =# of existing cases (at a point in Prevalence looks at all current cases. Total # of people time) 1 – prevalence of disease Prevalence ≈ incidence for short duration disease Prevalence ∼ pretest probability. (eg, common cold).  prevalence  PPV and  NPV. Prevalence > incidence for chronic diseases, due to large # of existing cases (eg, diabetes). Precision (reliability) The consistency and reproducibility of a test. Random error  precision in a test. The absence of random variation in a test.  precision  standard deviation.  precision  statistical power (1 −β). Accuracy (validity) The closeness of test results to the true values. Systematic error  accuracy in a test. The absence of systematic error or bias in a test.


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First_Aid_Step1. Accuracy (validity) The closeness of test results to the true values. Systematic error  accuracy in a test. The absence of systematic error or bias in a test. ROC curve demonstrates how well a diagnostic 1 test can distinguish between 2 groups (eg, disease vs healthy). Plots the true-positive rate (sensitivity) against the false-positive rate (1 – specificity). The better performing test will have a higher area under the curve (AUC), with the curve closer to the upper left corner. No predictive value (AUC = 0.5)TP rate (sensitivity) FP rate (1 – specifcity) 1 A ctual test (0.5 < AU C < 1 ) Selection bias Nonrandom sampling or treatment allocation of subjects such that study population is not representative of target population. Most commonly a sampling bias. Berkson bias—cases and/ or controls selected from hospitals are less healthy and have different exposures than general population


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First_Aid_Step1. Berkson bias—cases and/ or controls selected from hospitals are less healthy and have different exposures than general population Attrition bias—participants lost to follow up have a different prognosis than those who complete the study Randomization Ensure the choice of the right comparison/reference group Recall bias Awareness of disorder alters Patients with disease recall Decrease time from exposure recall by subjects; common in exposure after learning of to follow-up retrospective studies similar cases Measurement bias Information is gathered in a Using a faulty automatic Use objective, standardized, systemically distorted manner sphygmomanometer to and previously tested methods measure BP of data collection that are Hawthorne effect—participants planned ahead of time change behavior upon Use placebo group awareness of being observed


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First_Aid_Step1. Procedure bias Subjects in different groups are Patients in treatment group not treated the same spend more time in highly specialized hospital units Blinding (masking) and use of placebo reduce influence of participants and researchers on procedures and interpretation of outcomes as neither are aware of group assignments Confounding bias Factor related to both exposure and outcome (but not on causal path) distorts effect of exposure on outcome (vs effect modification, in which the exposure leads to different outcomes in subgroups stratified by the factor) An uncontrolled study shows an association between drinking coffee and lung cancer. However, coffee drinkers also smoke more, which can account for the association Multiple/repeated studies Crossover studies (subjects act as their own controls) Matching (patients with similar characteristics in both treatment and control groups)


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First_Aid_Step1. Crossover studies (subjects act as their own controls) Matching (patients with similar characteristics in both treatment and control groups) Lead-time bias Early detection is confused Early detection makes it seem Measure “back-end” survival with  survival like survival has increased, (adjust survival according to but the disease’s natural the severity of disease at the history has not changed time of diagnosis) Length-time bias Screening test detects diseases A slowly progressive cancer A randomized controlled trial with long latency period, is more likely detected by a assigning subjects to the while those with shorter screening test than a rapidly screening program or to no latency period become progressive cancer screening symptomatic earlier Mode = most common value. Least affected by outliers. Measures of Standard deviation = how much variability σ = SD; n = sample size. dispersion exists in a set of values, around the mean of Variance = (SD)2. these values. SE = σ/√n.


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First_Aid_Step1. Measures of Standard deviation = how much variability σ = SD; n = sample size. dispersion exists in a set of values, around the mean of Variance = (SD)2. these values. SE = σ/√n. Standard error = an estimate of how much SE  as n . variability exists in a (theoretical) set of sample means around the true population mean. Normal distribution Gaussian, also called bell-shaped. Mean = median = mode. 68% 95% 99.7% Bimodal Suggests two different populations (eg, metabolic polymorphism such as fast vs slow acetylators; age at onset of Hodgkin lymphoma; suicide rate by age). Positive skew Typically, mean > median > mode. Asymmetry with longer tail on right. Negative skew Typically, mean < median < mode. Mode Asymmetry with longer tail on left. Statistical hypotheses Outcomes of statistical hypothesis testing


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First_Aid_Step1. Asymmetry with longer tail on right. Negative skew Typically, mean < median < mode. Mode Asymmetry with longer tail on left. Statistical hypotheses Outcomes of statistical hypothesis testing Correct result Stating that there is an effect or difference when Reality one exists (null hypothesis rejected in favor of HH alternative hypothesis). Stating that there is no effect or difference when none exists (null hypothesis not rejected). Blue shading = correct result. Confidence interval Range of values within which the true mean of the population is expected to fall, with a specified probability. CI for sample mean = x¯ ± Z(SE) The 95% CI (corresponding to α = .05) is often used. As sample size increases, CI narrows. For the 95% CI, Z = 1.96. For the 99% CI, Z = 2.58. If the 95% CI for a mean difference between 2 variables includes 0, then there is no significant difference and H0 is not rejected. If the 95% CI for odds ratio or relative risk includes 1, H0 is not rejected.


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First_Aid_Step1. If the 95% CI for odds ratio or relative risk includes 1, H0 is not rejected. If the CIs between 2 groups do not overlap  statistically significant difference exists. If the CIs between 2 groups overlap  usually no significant difference exists. Meta-analysis A method of statistical analysis that pools summary data (eg, means, RRs) from multiple studies for a more precise estimate of the size of an effect. Also estimates heterogeneity of effect sizes between studies. Improves power, strength of evidence, and generalizability of study findings. Limited by quality of individual studies and bias in study selection. Autonomy Obligation to respect patients as individuals (truth-telling, confidentiality), to create conditions necessary for autonomous choice (informed consent), and to honor their preference in accepting or not accepting medical care.


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First_Aid_Step1. Beneficence Physicians have a special ethical (fiduciary) duty to act in the patient’s best interest. May conflict with autonomy (an informed patient has the right to decide) or what is best for society (eg, mandatory TB treatment). Traditionally, patient interest supersedes. Nonmaleficence “Do no harm.” Must be balanced against beneficence; if the benefits outweigh the risks, a patient may make an informed decision to proceed (most surgeries and medications fall into this category). Justice To treat persons fairly and equitably. This does not always imply equally (eg, triage). Informed consent A process (not just a document/signature) that requires: Disclosure: discussion of pertinent information (using medical interpreter, if needed) Understanding: ability to comprehend Capacity: ability to reason and make one’s own decisions (distinct from competence, a legal determination) Voluntariness: freedom from coercion and manipulation


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First_Aid_Step1. Capacity: ability to reason and make one’s own decisions (distinct from competence, a legal determination) Voluntariness: freedom from coercion and manipulation Patients must have an intelligent understanding of their diagnosis and the risks/benefits of proposed treatment and alternative options, including no treatment. Patient must be informed that he or she can revoke written consent at any time, even orally. Exceptions to informed consent (WIPE it away): Waiver—patient explicitly waives the right of informed consent Therapeutic Privilege—withholding information when disclosure would severely harm the patient or undermine informed decision-making capacity


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First_Aid_Step1. Therapeutic Privilege—withholding information when disclosure would severely harm the patient or undermine informed decision-making capacity Consent for minors A minor is generally any person < 18 years old. Parental consent laws in relation to healthcare vary by state. In general, parental consent should be obtained, but exceptions exist for emergency treatment (eg, blood transfusions) or if minor is legally emancipated (eg, married, self-supporting, or in the military). Situations in which parental consent is usually not required: Sex (contraception, STIs, pregnancy) Rock and roll (emergency/trauma) Physicians should always encourage healthy minor-guardian communication. Physician should seek a minor’s assent even if their consent is not required.


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First_Aid_Step1. Rock and roll (emergency/trauma) Physicians should always encourage healthy minor-guardian communication. Physician should seek a minor’s assent even if their consent is not required. Physician must determine whether the patient is psychologically and legally capable of making a particular healthcare decision. Note that decisions made with capacity cannot be revoked simply if the patient later loses capacity. Intellectual disability alone (eg, Down syndrome, autism) is not an exclusion criterion for informed decision-making. Capacity is determined by a physician for a specific healthcare-related decision (eg, to refuse medical care). Competency is determined by a judge and usually refers to more global categories of decision making (eg, legally unable to make any healthcare-related decision). Components (think GIEMSA): Decision is consistent with patient’s values and Goals Patient is Informed (knows and understands)


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First_Aid_Step1. Components (think GIEMSA): Decision is consistent with patient’s values and Goals Patient is Informed (knows and understands) Decision is not a result of altered Mental status (eg, delirium, psychosis, intoxication), Mood disorder Patient is ≥ 18 years of Age or otherwise legally emancipated Advance directives Instructions given by a patient in anticipation of the need for a medical decision. Details vary per state law. Oral advance directive Incapacitated patient’s prior oral statements commonly used as guide. Problems arise from variance in interpretation. If patient was informed, directive was specific, patient made a choice, and decision was repeated over time to multiple people, then the oral directive is more valid. Do not resuscitate DNR order prohibits cardiopulmonary resuscitation (CPR). Other resuscitative measures that may order follow (eg, feeding tube) are also typically avoided.


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First_Aid_Step1. Do not resuscitate DNR order prohibits cardiopulmonary resuscitation (CPR). Other resuscitative measures that may order follow (eg, feeding tube) are also typically avoided. Confidentiality Confidentiality respects patient privacy and autonomy. If the patient is incapacitated or the situation is emergent, disclosing information to family and friends should be guided by professional judgment of patient’s best interest. The patient may voluntarily waive the right to confidentiality (eg, insurance company request). General principles for exceptions to confidentiality: Potential physical harm to others is serious and imminent Alternative means to warn or protect those at risk is not possible Self-harm is likely Steps can be taken to prevent harm Examples of exceptions to patient confidentiality (many are state specific) include the following (“The physician’s good judgment SAVED the day”): Suicidal/homicidal patients. Abuse (children, elderly, and/or prisoners).


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First_Aid_Step1. Suicidal/homicidal patients. Abuse (children, elderly, and/or prisoners). Duty to protect—state-specific laws that sometimes allow physician to inform or somehow protect potential Victim from harm. Epileptic patients and other impaired automobile drivers. Reportable Diseases (eg, STIs, hepatitis, food poisoning); physicians may have a duty to warn public officials, who will then notify people at risk. Dangerous communicable diseases, such as TB or Ebola, may require involuntary treatment. Patient is not adherent. Attempt to identify the reason for nonadherence and determine his/her willingness to change; do not coerce the patient into adhering and do not refer him/her to another physician. A patient’s family member asks you not to disclose the results of a test if the prognosis is poor because the patient will be “unable to handle it.”


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First_Aid_Step1. A patient’s family member asks you not to disclose the results of a test if the prognosis is poor because the patient will be “unable to handle it.” Attempt to identify why the family member believes such information would be detrimental to the patient’s condition. Explain that as long as the patient has decision-making capacity and does not indicate otherwise, communication of information concerning his/her care will not be withheld. However, if you believe the patient might seriously harm himself/herself or others if informed, then you may invoke therapeutic privilege and withhold the information. Patient is suicidal. Assess the seriousness of the threat. If it is serious, suggest that the patient remain in the hospital voluntarily; patient can be hospitalized involuntarily if he/she refuses. Discounted fee-for-Patient pays for each individual service at a discounted rate predetermined by providers and payers service (eg, PPOs).


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First_Aid_Step1. Discounted fee-for-Patient pays for each individual service at a discounted rate predetermined by providers and payers service (eg, PPOs). Medicare and Medicaid—federal social healthcare programs that originated from amendments to the Social Security Act. Medicare is available to patients ≥ 65 years old, < 65 with certain disabilities, and those with end-stage renal disease. Medicaid is joint federal and state health assistance for people with limited income and/ or resources. MedicarE is for Elderly. MedicaiD is for Destitute. The 4 parts of Medicare: Part A: HospitAl insurance, home hospice care Part B: Basic medical bills (eg, doctor’s fees, diagnostic testing) Part C: (parts A + B = Combo) delivered by approved private companies Part D: Prescription Drugs


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First_Aid_Step1. Part B: Basic medical bills (eg, doctor’s fees, diagnostic testing) Part C: (parts A + B = Combo) delivered by approved private companies Part D: Prescription Drugs Hospice care Medical care focused on providing comfort and palliation instead of definitive cure. Available to patients on Medicare or Medicaid and in most private insurance plans whose life expectancy is < 6 months. During end-of-life care, priority is given to improving the patient’s comfort and relieving pain (often includes opioid, sedative, or anxiolytic medications). Facilitating comfort is prioritized over potential side effects (eg, respiratory depression). This prioritization of positive effects over negative effects is called the principle of double effect. Common causes of death (US) by age


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First_Aid_Step1. Common causes of death (US) by age Safety culture Organizational environment in which everyone Event reporting systems collect data on errors for can freely bring up safety concerns without internal and external monitoring. fear of censure. Facilitates error identification. Human factors design Forcing functions (those that prevent undesirable actions [eg, connecting feeding syringe to IV tubing]) are the most effective. Standardization improves process reliability (eg, clinical pathways, guidelines, checklists). Simplification reduces wasteful activities (eg, consolidating electronic medical records). Deficient designs hinder workflow and lead to staff workarounds that bypass safety features (eg, patient ID barcodes affixed to computers due to unreadable wristbands). PDSA cycle Process improvement model to test changes in real clinical setting. Impact on patients:


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First_Aid_Step1. PDSA cycle Process improvement model to test changes in real clinical setting. Impact on patients: Swiss cheese model Focuses on systems and conditions rather than an individual’s error. The risk of a threat becoming a reality is mitigated by differing layers and types of defenses. Patient harm can occur despite multiple safeguards when “the holes in the cheese line up.” Types of medical May involve patient identification, diagnosis, monitoring, nosocomial infection, medications, errors procedures, devices, documentation, handoffs. Medical errors should be disclosed to patients, independent of immediate outcome (harmful or not). “Symptoms, then, are in reality nothing but the cry from suffering organs.” “Man is an intelligence in servitude to his organs.” “When every part of the machine is correctly adjusted and in perfect harmony, health will hold dominion over the human organism by laws as natural and immutable as the laws of gravity.” —Andrew T. Still


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First_Aid_Step1. Skin, and Connective Tissue 445 In this section, we have divided the High-Yield Facts into the major Organ Systems. Within each Organ System are several subsections, including Embryology, Anatomy, Physiology, Pathology, and Pharmacology. As you progress through each Organ System, refer back to information in the previous subsections to organize these basic science subsections into a “vertically integrated” framework for learning. Below is some general advice for studying the organ systems by these subsections. Relevant embryology is included in each organ system subsection. Embryology tends to correspond well with the relevant anatomy, especially with regard to congenital malformations.


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First_Aid_Step1. Relevant embryology is included in each organ system subsection. Embryology tends to correspond well with the relevant anatomy, especially with regard to congenital malformations. Several topics fall under this heading, including gross anatomy, histology, and neuroanatomy. Do not memorize all the small details; however, do not ignore anatomy altogether. Review what you have already learned and what you wish you had learned. Many questions require two or more steps. The first step is to identify a structure on anatomic cross section, electron micrograph, or photomicrograph. The second step may require an understanding of the clinical significance of the structure.


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First_Aid_Step1. When studying, stress clinically important material. For example, be familiar with gross anatomy and radiologic anatomy related to specific diseases (eg, Pancoast tumor, Horner syndrome), traumatic injuries (eg, fractures, sensory and motor nerve deficits), procedures (eg, lumbar puncture), and common surgeries (eg, cholecystectomy). There are also many questions on the exam involving x-rays, CT scans, and neuro MRI scans. Many students suggest browsing through a general radiology atlas, pathology atlas, and histology atlas. Focus on learning basic anatomy at key levels in the body (eg, sagittal brain MRI; axial CT of the midthorax, abdomen, and pelvis). Basic neuroanatomy (especially pathways, blood supply, and functional anatomy), associated neuropathology, and neurophysiology have good yield. Please note that many of the photographic images in this book are for illustrative purposes and are not necessarily reflective of Step 1 emphasis.


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First_Aid_Step1. The portion of the examination dealing with physiology is broad and concept oriented and thus does not lend itself as well to fact-based review. Diagrams are often the best study aids, especially given the increasing number of questions requiring the interpretation of diagrams. Learn to apply basic physiologic relationships in a variety of ways (eg, the Fick equation, clearance equations). You are seldom asked to perform complex calculations. Hormones are the focus of many questions, so learn their sites of production and action as well as their regulatory mechanisms. A large portion of the physiology tested on the USMLE Step 1 is clinically relevant and involves understanding physiologic changes associated with pathologic processes (eg, changes in pulmonary function with COPD). Thus, it is worthwhile to review the physiologic changes that are found with common pathologies of the major organ systems (eg, heart, lungs, kidneys, GI tract) and endocrine glands.


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First_Aid_Step1. Questions dealing with this discipline are difficult to prepare for because of the sheer volume of material involved. Review the basic principles and hallmark characteristics of the key diseases. Given the clinical orientation of Step 1, it is no longer sufficient to know only the “buzzword” associations of certain diseases (eg, café-au-lait macules and neurofibromatosis); you must also know the clinical descriptions of these findings. Given the clinical slant of the USMLE Step 1, it is also important to review the classic presenting signs and symptoms of diseases as well as their associated laboratory findings. Delve into the signs, symptoms, and pathophysiology of major diseases that have a high prevalence in the United States (eg, alcoholism, diabetes, hypertension, heart failure, ischemic heart disease, infectious disease). Be prepared to think one step beyond the simple diagnosis to treatment or complications.


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First_Aid_Step1. The examination includes a number of color photomicrographs and photographs of gross specimens that are presented in the setting of a brief clinical history. However, read the question and the choices carefully before looking at the illustration, because the history will help you identify the pathologic process. Flip through an illustrated pathology textbook, color atlases, and appropriate Web sites in order to look at the pictures in the days before the exam. Pay attention to potential clues such as age, sex, ethnicity, occupation, recent activities and exposures, and specialized lab tests.


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First_Aid_Step1. Preparation for questions on pharmacology is straightforward. Learning all the key drugs and their characteristics (eg, mechanisms, clinical use, and important side effects) is high yield. Focus on understanding the prototype drugs in each class. Avoid memorizing obscure derivatives. Learn the “classic” and distinguishing toxicities of the major drugs. Do not bother with drug dosages or trade names. Reviewing associated biochemistry, physiology, and microbiology can be useful while studying pharmacology. There is a strong emphasis on ANS, CNS, antimicrobial, and cardiovascular agents as well as NSAIDs. Much of the material is clinically relevant. Newer drugs on the market are also fair game.


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First_Aid_Step1. “As for me, except for an occasional heart attack, I feel as young as I ever did.” “Hearts will never be practical until they are made unbreakable.” —The Wizard of Oz “As the arteries grow hard, the heart grows soft.” —H. L. Mencken “Nobody has ever measured, not even poets, how much the heart can hold.” “Only from the heart can you touch the sky.” “It is not the size of the man but the size of his heart that matters.”


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First_Aid_Step1. The cardiovascular system is one of the highest yield areas for the boards and, for some students, may be the most challenging. Focusing on understanding the mechanisms instead of memorizing the details can make a big difference, especially for this topic. Pathophysiology of atherosclerosis and heart failure, MOA of drugs (particular physiology interactions) and their adverse effects, ECGs of heart blocks, the cardiac cycle, and the Starling curve are some of the more high-yield topics. Differentiating between systolic and diastolic dysfunction is also very important. Heart murmurs and maneuvers that affect these murmurs have also been high yield and may be asked in a multimedia format. Septation of the chambers


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First_Aid_Step1. Septation of the chambers Septum primum grows toward endocardial cushions, narrowing foramen primum. Foramen secundum forms in septum primum (foramen primum regresses). Septum secundum develops on the right side of septum primum, as foramen secundum maintains right-to-left shunt. Septum secundum expands and covers most of foramen secundum. The residual foramen is the foramen ovale. Remaining portion of septum primum forms the one-way valve of the foramen ovale. 6. Septum primum closes against septum secundum, sealing the foramen ovale soon after birth because of  LA pressure and  RA pressure. 7. Septum secundum and septum primum fuse during infancy/early childhood, forming the atrial septum. Patent foramen ovale—caused by failure of septum primum and septum secundum to fuse after birth; most are left untreated. Can lead to paradoxical emboli (venous thromboemboli entering the systemic arterial circulation) as can occur in ASD.


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First_Aid_Step1. Muscular interventricular septum forms. Opening is called interventricular foramen. Aorticopulmonary septum rotates and fuses with muscular ventricular septum to form membranous interventricular septum, closing interventricular foramen. Growth of endocardial cushions separates atria from ventricles and contributes to both atrial septation and membranous portion of the interventricular septum. Ventricular septal defect—most common congenital cardiac anomaly, usually occurs in membranous septum. Primitive ventricle Trabeculated part of left and right ventricles Primitive atrium Trabeculated part of left and right atria Left horn of sinus venosus Coronary sinus Right horn of sinus venosus Smooth part of right atrium (sinus venarum) Endocardial cushion Atrial septum, membranous interventricular septum; AV and semilunar valves Posterior, subcardinal, and supracardinal veins Inferior vena cava (IVC) Primitive pulmonary vein Smooth part of left atrium


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First_Aid_Step1. Posterior, subcardinal, and supracardinal veins Inferior vena cava (IVC) Primitive pulmonary vein Smooth part of left atrium Prostaglandins E1 and E2 kEEp PDA open. Ductus arteriosus Ligamentum arteriosum Near the left recurrent laryngeal nerve Allantois  urachus Median umbilical ligament Urachus is part of allantoic duct between bladder and umbilicus Blood in umbilical vein has a Po2 of ≈ 30 mm Hg and is ≈ 80% saturated with O2. Umbilical arteries have low O2 saturation. 3 important shunts: Blood entering fetus through the umbilical vein is conducted via the ductus venosus into the IVC, bypassing hepatic circulation. of the highly Oxygenated blood reaching the heart via the IVC is directed through the foramen Ovale into the left atrium. blood from the SVC passes through the RA  RV  main pulmonary artery • Ductus arteriosus • Descending aorta; shunt is due to high fetal pulmonary artery resistance (due partly to low O2 tension).


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First_Aid_Step1. blood from the SVC passes through the RA  RV  main pulmonary artery • Ductus arteriosus • Descending aorta; shunt is due to high fetal pulmonary artery resistance (due partly to low O2 tension). At birth, infant takes a breath • resistance in pulmonary vasculature  left atrial pressure vs right atrial pressure foramen ovale closes (now called fossa ovalis);  in O2 (from respiration) and  in prostaglandins (from placental separation)  closure of ductus arteriosus. Indomethacin helps close the patent Ductus arteriosus  ligamentum arteriosum (remnant of ductus arteriosus). Come In and close the Door. Anatomy of the heart LA is the most posterior part of the heart A ; enlargement of the LA (eg, in mitral stenosis) can lead to compression of the esophagus (dysphagia) and/or the left recurrent laryngeal nerve, a branch of the vagus nerve, causing hoarseness (Ortner syndrome). RV is the most anterior part of the heart and most commonly injured in trauma. Key:


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First_Aid_Step1. RV is the most anterior part of the heart and most commonly injured in trauma. Key: LAD and its branches supply anterior 2/3 of interventricular septum, anterolateral papillary muscle, and anterior surface of LV. Most commonly occluded. PDA supplies AV node (dependent on dominance), posterior 1/3 of interventricular septum, posterior 2/3 walls of ventricles, and posteromedial papillary muscle. RCA supplies SA node (blood supply independent of dominance). Infarct may cause nodal dysfunction (bradycardia or heart block). Right (acute) marginal artery supplies RV. Dominance: Right-dominant circulation (85%) = PDA arises from RCA. Left-dominant circulation (8%) = PDA arises from LCX. from both LCX and RCA. Coronary blood flow peaks in early diastole. Force of contraction is proportional to end-diastolic length of cardiac muscle fiber (preload). contractility with catecholamines, positive inotropes (eg, digoxin).


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First_Aid_Step1. Force of contraction is proportional to end-diastolic length of cardiac muscle fiber (preload). contractility with catecholamines, positive inotropes (eg, digoxin). contractility with loss of functional myocardium (eg, MI), β-blockers (acutely), non-dihydropyridine Ca2+ channel blockers, dilated cardiomyopathy. Resistance, pressure, flow ΔP = Q × R Similar to Ohm’s law: ΔV = I × R Volumetric flow rate (Q) = flow velocity (v) × Q πr4 Total resistance of vessels in series: RT = R1 + R2 + R3 . . . Total resistance of vessels in parallel: 1 111 Capillaries have highest total cross-sectional area and lowest flow velocity. Pressure gradient drives flow from high pressure to low pressure. Arterioles account for most of TPR. Veins provide most of blood storage capacity. Viscosity depends mostly on hematocrit. Viscosity  in hyperproteinemic states (eg, multiple myeloma), polycythemia. Viscosity  in anemia.


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First_Aid_Step1. volume, venous tone TPR TPRCardiac output/venous return Cardiac output/venous return Vascularfunction curve Cardiac function curve ↓↓↓↓↓↓volume, venous tone inotropy inotropy Mean systemic pressure Normal Intersection of curves = operating point of heart (ie, venous return and CO are equal, as circulatory system is a closed system). Changes often occur in tandem, and may be reinforcing (eg, exercise  inotropy and  TPR to maximize CO) or compensatory (eg, HF  inotropy  fluid retention to  preload to maintain CO). Pressure-volume loops and cardiac cycle The black loop represents normal cardiac physiology. Phases—left ventricle: valve opening; period of highest O2 consumption Heart sounds: S1—mitral and tricuspid valve closure. Loudest at mitral area. S2—aortic and pulmonary valve closure. Loudest at left upper sternal border. Considered abnormal if palpable. Jugular venous pulse (JVP): a wave—atrial contraction. Absent in atrial fibrillation (AF).


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First_Aid_Step1. Considered abnormal if palpable. Jugular venous pulse (JVP): a wave—atrial contraction. Absent in atrial fibrillation (AF). filling phase. Best heard at apex with patient in left lateral decubitus position. Associated with  filling pressures (eg, MR, AR, HF, ventricles (but can be normal in children, young adults, athletes, and pregnancy). S4—in late diastole (“atrial kick”). Best heard at apex with patient in left lateral decubitus position. High atrial pressure. Associated with ventricular noncompliance (eg, hypertrophy). Left atrium must push against stiff LV wall. bulging into atrium). x descent—downward displacement of closed (aka J.V.P) ejection phase. Reduced or absent in tricuspid regurgitation and right HF because pressure gradients are reduced. v wave— right atrial pressure due to filling 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 (“villing”) against closed tricuspid valve.


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First_Aid_Step1. Time (sec) y descent—RA emptying into RV. Prominent in constrictive pericarditis, absent in cardiac tamponade. 120  ESV due to  resistance and due to  LA volume/pressure from because of impaired ventricular filling Splitting of S2 Wide splitting Seen in conditions that delay RV emptying (eg, E pulmonic stenosis, right bundle branch block). S1 A2P2 Causes delayed pulmonic sound (especially on inspiration). An exaggeration of normal Abnormal delay splitting. Fixed splitting Heard in ASD. ASD  left-to-right shunt  RA and RV volumes  flow through pulmonic valve  delayed pulmonic valve S1 A2P2 closure (independent of respiration). I closure (eg, aortic stenosis, left bundle branch S1 P2A2 block). Normal order of semilunar valve closure is reversed so that P2 sound occurs before delayed A2 sound. On inspiration, P2 closes later and moves closer to A2, “paradoxically” eliminating the split. On expiration, the split can be heard (opposite to physiologic splitting).


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First_Aid_Step1. Auscultation of the heart (eg, physiologic murmur) Aortic valve sclerosis Where to listen: APT M 111234567777777 Left sternal border: Aortic regurgitation Pulmonic regurgitation cardiomyopathy PA M T Aortic area: Systolic murmur Pulmonic area: Tricuspid area: Mitral area (apex): Crescendo-decrescendo systolic ejection murmur and soft S2 (ejection click may be present). LV >> aortic pressure during systole. Loudest at heart base; radiates to carotids. “Pulsus parvus et tardus”—pulses are weak with a delayed peak. Can lead to Syncope, Angina, and Dyspnea on exertion (SAD). Most commonly due to age-related calcification in older patients (> 60 years old) or in younger patients with early-onset calcification of bicuspid aortic valve.


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First_Aid_Step1. Holosystolic, high-pitched “blowing murmur.” Mitral—loudest at apex and radiates toward axilla. MR is often due to ischemic heart disease (post-MI), MVP, LV dilatation. Tricuspid—loudest at tricuspid area. TR commonly caused by RV dilatation. Rheumatic fever and infective endocarditis can cause either MR or TR. Late systolic crescendo murmur with midsystolic click (MC) due to sudden tensing of chordae tendineae as mitral leaflets prolapse into the LA (Chordae cause Crescendo with Click). Most frequent valvular lesion. Best heard over apex. Loudest just before S2. Usually benign. Can predispose to infective endocarditis. Can be caused by myxomatous degeneration (1° or 2° to connective tissue disease such as Marfan or Ehlers-Danlos syndrome), rheumatic fever (particularly in developing countries), chordae rupture.


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First_Aid_Step1. High-pitched “blowing” early diastolic decrescendo murmur. Best heard at base (aortic root dilation) or left sternal border (valvular disease). Long diastolic murmur, hyperdynamic pulse, and head bobbing when severe and chronic. Wide pulse pressure. Causes include Bicuspid aortic valve, Endocarditis, Aortic root dilation, Rheumatic fever (BEAR). Progresses to left HF. Follows opening snap (OS; due to abrupt halt in leaflet motion in diastole, after rapid opening due to fusion at leaflet tips). Delayed rumbling mid-to-late diastolic murmur ( interval between S2 and OS correlates with  severity). LA >> LV pressure during diastole. Often a late (and highly specific) sequela of rheumatic fever. Chronic MS can result in pulmonary congestion/hypertension and LA dilation  atrial fibrillation and Ortner syndrome. Patent ductus arteriosus Continuous machine-like murmur. Best heard at left infraclavicular area. Loudest at S2. Often due to congenital rubella or prematurity.


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First_Aid_Step1. Patent ductus arteriosus Continuous machine-like murmur. Best heard at left infraclavicular area. Loudest at S2. Often due to congenital rubella or prematurity. “PDAs (Public Displays of Affection) are continuously annoying.” Phase 0 = rapid upstroke and depolarization— voltage-gated Na+ channels open. Phase 1 = initial repolarization—inactivation of voltage-gated Na+ channels. Voltage-gated K+ channels begin to open. Phase 2 = plateau—Ca2+ influx through voltage-gated Ca2+ channels balances K+ efflux. Ca2+ influx triggers Ca2+ release from sarcoplasmic reticulum and myocyte contraction. Phase 3 = rapid repolarization—massive K+ efflux due to opening of voltage-gated slow delayed-rectifier K+ channels and closure of voltage-gated Ca2+ channels. Phase 4 = resting potential—high K+ permeability through K+ channels. In contrast to skeletal muscle: Cardiac muscle action potential has a plateau due to Ca2+ influx and K+ efflux.


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First_Aid_Step1. Phase 4 = resting potential—high K+ permeability through K+ channels. In contrast to skeletal muscle: Cardiac muscle action potential has a plateau due to Ca2+ influx and K+ efflux. Cardiac muscle contraction requires Ca2+ influx from ECF to induce Ca2+ release from sarcoplasmic reticulum (Ca2+-induced Ca2+ release). Cardiac myocytes are electrically coupled to each other by gap junctions. Occurs in all cardiac myocytes except for those in the SA and AV nodes. Occurs in the SA and AV nodes. Key differences from the ventricular action potential include: Phase 0 = upstroke—opening of voltage-gated Ca2+ channels. Fast voltage-gated Na+ channels are permanently inactivated because of the less negative resting potential of these cells. Results in a slow conduction velocity that is used by the AV node to prolong transmission from the atria to ventricles. Phases 1 and 2 are absent.


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First_Aid_Step1. Phases 1 and 2 are absent. Phase 3 = repolarization—inactivation of the Ca2+ channels and  activation of K+ channels  K+ efflux. Phase 4 = slow spontaneous diastolic depolarization due to If (“funny current”). If channels responsible for a slow, mixed Na+/K+ inward current; different from INa in phase 0 of ventricular action potential. Accounts for automaticity of SA and AV nodes. The slope of phase 4 in the SA node determines HR. ACh/adenosine  the rate of diastolic depolarization and  HR, while catecholamines • depolarization and  HR. Sympathetic stimulation  the chance that If channels are open and thus  HR. Electrocardiogram Conduction pathway: SA node  atria  bundle of His  right and left bundle branches  Purkinje fibers left bundle branch divides into left anterior and posterior fascicles. SA node—located at junction of RA and SVC; “pacemaker” inherent dominance with slow phase of upstroke.


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First_Aid_Step1. SA node—located at junction of RA and SVC; “pacemaker” inherent dominance with slow phase of upstroke. AV node—located in posteroinferior part of interatrial septum. Blood supply usually from RCA. 100-msec delay allows time for ventricular filling. Pacemaker rates: SA > AV > bundle of His/ Purkinje/ventricles. Speed of conduction: His-Purkinje > Atria > Ventricles > AV node. He Parks At Ventura Avenue. P wave—atrial depolarization. PR interval—time from start of atrial depolarization to start of ventricular depolarization (normally 120-200 msec). QRS complex—ventricular depolarization (normally < 100 msec). QT interval—ventricular depolarization, mechanical contraction of the ventricles, ventricular repolarization.


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First_Aid_Step1. QRS complex—ventricular depolarization (normally < 100 msec). QT interval—ventricular depolarization, mechanical contraction of the ventricles, ventricular repolarization. T wave—ventricular repolarization. T-wave inversion may indicate ischemia or recent MI. J point—junction between end of QRS complex and start of ST segment. ST segment—isoelectric, ventricles depolarized. U wave—prominent in hypokalemia (think hyp“U”kalemia), bradycardia. SA node AV node Bundle of His Torsades de pointes Polymorphic ventricular tachycardia, characterized by shifting sinusoidal waveforms on ECG; can progress to ventricular fibrillation (VF). Long QT interval predisposes to torsades de pointes. Caused by drugs,  K+,  Mg2+, • Ca2+, congenital abnormalities. Treatment includes magnesium sulfate. Drug-induced long QT (ABCDE): AntiArrhythmics (class IA, III) AntiBiotics (eg, macrolides) Anti“C”ychotics (eg, haloperidol) AntiDepressants (eg, TCAs) AntiEmetics (eg, ondansetron)


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First_Aid_Step1. Drug-induced long QT (ABCDE): AntiArrhythmics (class IA, III) AntiBiotics (eg, macrolides) Anti“C”ychotics (eg, haloperidol) AntiDepressants (eg, TCAs) AntiEmetics (eg, ondansetron) Torsades de pointes = twisting of the points Brugada syndrome Autosomal dominant disorder most common in Asian males. ECG pattern of pseudo-right bundle branch block and ST elevations in V1-V3.  risk of ventricular tachyarrhythmias and SCD. Prevent SCD with implantable cardioverter-defibrillator (ICD). Atrial fibrillation Chaotic and erratic baseline with no discrete P waves in between RR˜ RR ˜RR˜RR irregularly spaced QRS complexes. Irregularly irregular heartbeat. Most common risk factors include hypertension and coronary artery disease (CAD). Occasionally seen after binge drinking (“holiday heart syndrome”). Can lead to thromboembolic events, particularly stroke. Treatment: anticoagulation, rate and rhythm control and/or cardioversion.


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First_Aid_Step1. Treatment: anticoagulation, rate and rhythm control and/or cardioversion. First-degree The PR interval is prolonged (> 200 msec). Benign and AV block asymptomatic. No treatment required. <<PR1PR2PR3P wave, absent QRS =PR1PR2P wave, absent QRS Baroreceptors and chemoreceptors Receptors: • Aortic arch transmits via vagus nerve to solitary nucleus of medulla (responds to changes in BP). • Carotid sinus (dilated region at carotid bifurcation) transmits via glossopharyngeal nerve to solitary nucleus of medulla (responds to changes in BP). Baroreceptors: parasympathetic stimulation  vasoconstriction,  HR,  contractility,  BP. Important in the response to severe hemorrhage. Carotid massage— pressure on carotid sinus  stretch  afferent baroreceptor firing  AV node refractory period  HR.


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First_Aid_Step1. Carotid massage— pressure on carotid sinus  stretch  afferent baroreceptor firing  AV node refractory period  HR. Component of Cushing reflex (triad of hypertension, bradycardia, and respiratory depression)— intracranial pressure constricts arterioles  cerebral ischemia • pCO2 and  pH  central reflex sympathetic  in perfusion pressure (hypertension)  stretch  peripheral reflex baroreceptor– induced bradycardia. Chemoreceptors: Peripheral—carotid and aortic bodies are stimulated by  Pco2,  pH of blood, and  Po2 (< 60 mm Hg). Central—are stimulated by changes in pH and Pco2 of brain interstitial fluid, which in turn are influenced by arterial CO2 as H+ cannot cross the blood-brain barrier. Do not directly respond to Po2. Central chemoreceptors become less responsive with chronically  Pco2 (eg, COPD) • dependence on peripheral chemoreceptors to detect  O2 to drive respiration.


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First_Aid_Step1. pressures in mm Hg) is a good approximation of left atrial pressure. In mitral stenosis, PCWP > LV end diastolic pressure. PCWP is measured with pulmonary artery catheter (Swan-Ganz catheter). Autoregulation How blood flow to an organ remains constant over a wide range of perfusion pressures.


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First_Aid_Step1. Autoregulation How blood flow to an organ remains constant over a wide range of perfusion pressures. Capillary fluid Starling forces determine fluid movement through capillary membranes: exchange • Pc = capillary hydrostatic pressure—pushes fluid out of capillary πi = interstitial fluid colloid osmotic pressure—pulls fluid out of capillary Jv = net fluid flow = Kf [(Pc − Pi) −σ(πc −πi)] Kf = capillary permeability to fluid σ= reflection coefficient (measure of capillary permeability to protein) Edema—excess fluid outflow into interstitium commonly caused by: •  capillary pressure ( Pc; eg, HF) •  capillary permeability ( Kf; eg, toxins, infections, burns) •  interstitial fluid colloid osmotic pressure (• πi; eg, lymphatic blockage) •  plasma proteins (• πc; eg, nephrotic syndrome, liver failure, protein malnutrition) D-transposition of great vessels leaves LV (posterior)  separation of systemic


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First_Aid_Step1. D-transposition of great vessels leaves LV (posterior)  separation of systemic Pulmonary and pulmonary circulations. Not compatible artery with life unless a shunt is present to allow mixing of blood (eg, VSD, PDA, or patent foramen ovale). Left Due to failure of the aorticopulmonary septum to ventricle spiral (“egg on a string” appearance on CXR). Without surgical intervention, most infants die Right ventricle within the first few months of life. Tricuspid atresia Absence of tricuspid valve and hypoplastic RV; requires both ASD and VSD for viability. Tetralogy of Fallot Caused by anterosuperior displacement of the infundibular septum. Most common cause of early childhood cyanosis. Pulmonary infundibular stenosis (most important determinant for prognosis) Right ventricular hypertrophy (RVH)— boot-shaped heart on CXR


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First_Aid_Step1. Pulmonary stenosis forces right-to-left flow across VSD  RVH, “tet spells” (often caused by crying, fever, and exercise due to exacerbation of RV outflow obstruction). PROVe. Squatting:  SVR,  right-to-left shunt, improves cyanosis. Associated with 22q11 syndromes. lEFT-TO-RIGHT SHuNTS Acyanotic at presentation; cyanosis may occur Right-to-Left shunts: eaRLy cyanosis. years later. Frequency: VSD > ASD > PDA. Left-to-Right shunts: “LateR” cyanosis. Ventricular septal Asymptomatic at birth, may manifest weeks O2 saturation  in RV and pulmonary artery. defect later or remain asymptomatic throughout life. Most self resolve; larger lesions B may lead to LV overload and HF.


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First_Aid_Step1. Defect in interatrial septum C ; wide, fixed split S2. Ostium secundum defects most common and usually an isolated finding; ostium primum defects rarer and usually occur with other cardiac anomalies. Symptoms range from none to HF. Distinct from patent foramen ovale in that septa are missing tissue rather than unfused. O2 saturation  in RA, RV, and pulmonary artery. May lead to paradoxical emboli (systemic venous emboli use ASD to bypass lungs and become systemic arterial emboli). Associated with Down syndrome. In fetal period, shunt is right to left (normal). In neonatal period,  pulmonary vascular resistance  shunt becomes left to right  progressive RVH and/or LVH and HF. Associated with a continuous, “machine-like” murmur. Patency is maintained by PGE synthesis and low O2 tension. Uncorrected PDA D can eventually result in late cyanosis in the lower extremities (differential cyanosis). PDA is normal in utero and normally closes only after birth.


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First_Aid_Step1. PDA is normal in utero and normally closes only after birth. Uncorrected left-to-right shunt (VSD, ASD, PDA)  pulmonary blood flow • pathologic remodeling of vasculature  pulmonary arterial hypertension. RVH occurs to compensate  shunt becomes right to left. Causes late cyanosis, clubbing E , and polycythemia. Age of onset varies. Coarctation of the aorta Aortic narrowing F near insertion of ductus arteriosus (“juxtaductal”). Associated with bicuspid aortic valve, other heart defects, and Turner syndrome. Hypertension in upper extremities and weak, delayed pulse in lower extremities (brachial-femoral delay). With age, intercostal arteries enlarge due to collateral circulation; arteries erode ribs  notched appearance on CXR. Complications include HF,  risk of cerebral hemorrhage (berry aneurysms), aortic rupture, and possible endocarditis. defect associations Alcohol exposure in utero (fetal alcohol VSD, PDA, ASD, tetralogy of Fallot syndrome)


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First_Aid_Step1. defect associations Alcohol exposure in utero (fetal alcohol VSD, PDA, ASD, tetralogy of Fallot syndrome) Infant of diabetic mother Transposition of great vessels, VSD Marfan syndrome MVP, thoracic aortic aneurysm and dissection, aortic regurgitation Turner syndrome Bicuspid aortic valve, coarctation of aorta 22q11 syndromes Truncus arteriosus, tetralogy of Fallot Hypertension Persistent systolic BP ≥ 130 mm Hg and/or diastolic BP ≥ 80 mm Hg. RISK FACTORS  age, obesity, diabetes, physical inactivity, excess salt intake, excess alcohol intake, cigarette smoking, family history; African American > Caucasian > Asian.


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First_Aid_Step1. RISK FACTORS  age, obesity, diabetes, physical inactivity, excess salt intake, excess alcohol intake, cigarette smoking, family history; African American > Caucasian > Asian. FEATuRES 90% of hypertension is 1° (essential) and related to  CO or  TPR. Remaining 10% mostly 2° to renal/renovascular diseases such as fibromuscular dysplasia (characteristic “string of beads” appearance of renal artery A , usually seen in women of child-bearing age) and atherosclerotic renal artery stenosis or to 1° hyperaldosteronism. Hypertensive urgency—severe (≥ 180/≥ 120 mm Hg) hypertension without acute end-organ damage. Hypertensive emergency—severe hypertension with evidence of acute end-organ damage (eg, encephalopathy, stroke, retinal hemorrhages and exudates, papilledema, MI, HF, aortic dissection, kidney injury, microangiopathic hemolytic anemia, eclampsia).


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First_Aid_Step1. PREdISPOSES TO CAD, LVH, HF, atrial fibrillation; aortic dissection, aortic aneurysm; stroke; CKD (hypertensive nephropathy); retinopathy. Xanthomas Plaques or nodules composed of lipid-laden histiocytes in skin A , especially the eyelids (xanthelasma B ). Tendinous xanthoma Lipid deposit in tendon C , especially Achilles. Corneal arcus Lipid deposit in cornea. Common in elderly (arcus senilis D ), but appears earlier in life with hypercholesterolemia. Arteriosclerosis Hardening of arteries, with arterial wall thickening and loss of elasticity. Arteriolosclerosis Common. Affects small arteries and arterioles. Two types: hyaline (thickening of vessel walls 2° to plasma protein leak into endothelium in essential hypertension or diabetes mellitus A ) and hyperplastic (“onion skinning” in severe hypertension B with proliferation of smooth muscle cells).


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First_Aid_Step1. Atherosclerosis Very common. Disease of elastic arteries and largeand medium-sized muscular arteries; a form of arteriosclerosis caused by buildup of cholesterol plaques in intima. lOCATION Abdominal aorta > Coronary artery > Popliteal artery > Carotid artery > circle of Willis. A CoPy Cat named Willis. RISK FACTORS Modifiable: smoking, hypertension, dyslipidemia ( LDL,  HDL), diabetes. Non-modifiable: age, sex ( in men and postmenopausal women), family history. SYMPTOMS Angina, claudication, but can be asymptomatic. PROGRESSION Inflammation important in pathogenesis: endothelial cell dysfunction  macrophage and LDL accumulation  foam cell formation  fatty streaks  smooth muscle cell migration (involves PDGF and FGF), proliferation, and extracellular matrix deposition  fibrous plaque  complex atheromas A  calcification (calcium content correlates with risk of complications). COMPlICATIONS Aneurysms, ischemia, infarcts, peripheral vascular disease, thrombus, emboli.


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First_Aid_Step1. COMPlICATIONS Aneurysms, ischemia, infarcts, peripheral vascular disease, thrombus, emboli. Aortic aneurysm Localized pathologic dilation of the aorta. May cause abdominal and/or back pain, which is a sign of leaking, dissection, or imminent rupture. Abdominal aortic Usually associated with atherosclerosis. Risk factors include history of tobacco use,  age, male aneurysm sex, family history. May present as palpable pulsatile abdominal mass (arrows in A point to outer dilated calcified aortic wall, with partial crescent-shaped non-opacification of aorta due to flap/ clot). Most often infrarenal (distal to origin of renal arteries). Traumatic aortic Due to trauma and/or deceleration injury, most commonly at aortic isthmus (proximal descending rupture aorta just distal to origin of left subclavian artery). X-ray may reveal widened mediastinum.


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First_Aid_Step1. Longitudinal intimal tear forming a false lumen. Associated with hypertension, bicuspid aortic valve, inherited connective tissue disorders (eg, Marfan syndrome). Can present with tearing, sudden-onset chest pain radiating to the back +/− markedly unequal BP in arms. CXR can show mediastinal widening. Can result in organ ischemia, aortic rupture, death. Two types: Stanford type A (proximal): involves Ascending aorta (red arrow in A ). May extend to aortic arch or descending aorta (blue arrow in A ). May result in acute aortic regurgitation or cardiac tamponade. Treatment: surgery. Stanford type B (distal): involves only descending aorta (Below left subclavian artery). Treatment: β-blockers, then vasodilators. Angina Chest pain due to ischemic myocardium 2° to coronary artery narrowing or spasm; no myocyte necrosis.


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First_Aid_Step1. Angina Chest pain due to ischemic myocardium 2° to coronary artery narrowing or spasm; no myocyte necrosis. Stable—usually 2° to atherosclerosis (≥ 70% occlusion); exertional chest pain in classic distribution (usually with ST depression on ECG), resolving with rest or nitroglycerin. Vasospastic (also called Prinzmetal or Variant)—occurs at rest 2° to coronary artery spasm; transient ST elevation on ECG. Smoking is a risk factor; hypertension and hypercholesterolemia are not. Triggers include cocaine, alcohol, and triptans. Treat with Ca2+ channel blockers, nitrates, and smoking cessation (if applicable). Unstable—thrombosis with incomplete coronary artery occlusion; +/− ST depression and/or T-wave inversion on ECG but no cardiac biomarker elevation (unlike NSTEMI);  in frequency or intensity of chest pain or any chest pain at rest.


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First_Aid_Step1. Sudden cardiac death Death from cardiac causes within 1 hour of onset of symptoms, most commonly due to a lethal arrhythmia (eg, VF). Associated with CAD (up to 70% of cases), cardiomyopathy (hypertrophic, dilated), and hereditary ion channelopathies (eg, long QT syndrome, Brugada syndrome). Prevent with ICD. Evolution of Commonly occluded coronary arteries: LAD > RCA > circumflex. myocardial infarction Symptoms: diaphoresis, nausea, vomiting, severe retrosternal pain, pain in left arm and/or jaw, shortness of breath, fatigue. 0–24 hr Dark mottling Early coagulative necrosis Ventricular arrhythmia, HF,  cell content released into cardiogenic shock blood; edema, hemorrhage, wavy fibers  hypercontraction of Dark mottling; stripes) pale with tetrazolium stain Tissue surrounding infarct pericarditis shows acute inflammation with neutrophils 3–14 days Macrophages, then granulation Free wall rupture  tamponade; tissue at margins papillary muscle rupture due to macrophage-mediated


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First_Aid_Step1. LV pseudoaneurysm (risk of rupture) 2 weeks to several Contracted scar complete Dressler syndrome, HF, months arrhythmias, true ventricular aneurysm (risk of mural thrombus) Multiples of upper limit of normal return to normal after 48 hours. Large MIs lead to greater elevations in troponin I and CK-MB. Exact curves vary with testing procedure. ECG changes can include ST elevation (STEMI, transmural infarct), ST depression (NSTEMI, subendocardial infarct), hyperacute (peaked) T waves, T-wave inversion, new left bundle branch block, and pathologic Q waves or poor R wave progression (evolving or old transmural infarct). Ventricular 3–14 days: free wall rupture contained by adherent pericardium or scar tissue B ;  CO, risk of pseudoaneurysm arrhythmia, embolus from mural thrombus. formation Ventricular free wall 5–14 days: free wall rupture C  cardiac tamponade. LV hypertrophy and previous MI protect rupture against free wall rupture. Acute form usually leads to sudden death.


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First_Aid_Step1. Ventricular free wall 5–14 days: free wall rupture C  cardiac tamponade. LV hypertrophy and previous MI protect rupture against free wall rupture. Acute form usually leads to sudden death. 60–70% of cases are familial, autosomal dominant (most commonly due to mutations in genes encoding sarcomeric proteins, such as myosin binding protein C and β-myosin heavy chain). Causes syncope during exercise and may lead to sudden death (eg, in young athletes) due to ventricular arrhythmia. Findings: S4, systolic murmur. May see mitral regurgitation due to impaired mitral valve closure. Treatment: cessation of high-intensity athletics, use of β-blocker or non-dihydropyridine Ca2+ channel blockers (eg, verapamil). ICD if syncope occurs. Diastolic dysfunction ensues. Marked ventricular concentric hypertrophy (sarcomeres added in parallel) B , often septal predominance. Myofibrillar disarray and fibrosis.


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First_Aid_Step1. Diastolic dysfunction ensues. Marked ventricular concentric hypertrophy (sarcomeres added in parallel) B , often septal predominance. Myofibrillar disarray and fibrosis. Physiology of HOCM—asymmetric septal hypertrophy and systolic anterior motion of mitral valve  outflow obstruction  dyspnea, possible syncope. Other causes of concentric LV hypertrophy: chronic HTN, Friedreich ataxia. Postradiation fibrosis, Löffler endocarditis, Endocardial fibroelastosis (thick fibroelastic tissue in endocardium of young children), Amyloidosis, Sarcoidosis, Hemochromatosis (although dilated cardiomyopathy is more common) (Puppy LEASH). Diastolic dysfunction ensues. Can have low-voltage ECG despite thick myocardium (especially in amyloidosis). Löffler endocarditis—associated with hypereosinophilic syndrome; histology shows eosinophilic infiltrates in myocardium.


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First_Aid_Step1. Löffler endocarditis—associated with hypereosinophilic syndrome; histology shows eosinophilic infiltrates in myocardium. Heart failure Clinical syndrome of cardiac pump dysfunction  congestion and low perfusion. Symptoms include dyspnea, orthopnea, fatigue; signs include S3 heart sound, rales, jugular venous distention (JVD), pitting edema A . Systolic dysfunction—reduced EF,  EDV;  contractility often 2° to ischemia/MI or dilated cardiomyopathy. Diastolic dysfunction—preserved EF, normal EDV; • compliance ( EDP) often 2° to myocardial hypertrophy. Right HF most often results from left HF. Cor pulmonale refers to isolated right HF due to pulmonary cause. ACE inhibitors or angiotensin II receptor blockers, β-blockers (except in acute decompensated HF), and spironolactone  mortality. Loop and thiazide diuretics are used mainly for symptomatic relief. Hydralazine with nitrate therapy improves both symptoms and mortality in select patients.


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First_Aid_Step1. of hemosiderin-laden macrophages (“HF” cells) in lungs. Right heart failure Shock Inadequate organ perfusion and delivery of nutrients necessary for normal tissue and cellular function. Initially may be reversible but life threatening if not treated promptly. Compression of the heart by fluid (eg, blood, effusions [arrows in A ] in pericardial space)  CO. Equilibration of diastolic pressures in all 4 chambers. Findings: Beck triad (hypotension, distended neck veins, distant heart sounds),  HR, pulsus paradoxus. ECG shows low-voltage QRS and electrical alternans B (due to “swinging” movement of heart in large effusion). Pulsus paradoxus— in amplitude of systolic BP by > 10 mm Hg during inspiration. Seen in constrictive Pericarditis, obstructive pulmonary disease (eg, Croup, OSA, Asthma, COPD), cardiac Tamponade (Pea COAT).


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First_Aid_Step1. Bacterial endocarditis Acute—S aureus (high virulence). Large vegetations on previously normal valves A . Rapid onset. Subacute—viridans streptococci (low virulence). Smaller vegetations on congenitally abnormal or diseased valves. Sequela of dental procedures. Gradual onset. Symptoms: fever (most common), new murmur, Roth spots (round white spots on retina surrounded by hemorrhage B ), Osler nodes (Ouchy raised lesions on finger or toe pads C due to immune complex deposition), Janeway lesions (small, painless, erythematous lesions on palm or sole) D , splinter hemorrhages E on nail bed. Associated with glomerulonephritis, septic arterial or pulmonary emboli. May be nonbacterial (marantic/thrombotic) 2° to malignancy, hypercoagulable state, or lupus. FROM JANE with ♥: Fever Roth spots Osler nodes Murmur Janeway lesions Anemia Nail-bed hemorrhage Emboli Requires multiple blood cultures for diagnosis. If culture ⊝, most likely Coxiella burnetii,


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First_Aid_Step1. FROM JANE with ♥: Fever Roth spots Osler nodes Murmur Janeway lesions Anemia Nail-bed hemorrhage Emboli Requires multiple blood cultures for diagnosis. If culture ⊝, most likely Coxiella burnetii, Bartonella spp. Mitral valve is most frequently involved. Tricuspid valve endocarditis is associated with IV drug abuse (don’t “tri” drugs). Associated with S aureus, Pseudomonas, and Candida. S bovis (gallolyticus) is present in colon cancer, S epidermidis on prosthetic valves. Native valve endocarditis may be due to HACEK organisms (Haemophilus, Aggregatibacter [formerly Actinobacillus], Cardiobacterium, Eikenella, Kingella). Inflammation of the pericardium [ A , red arrows]. Commonly presents with sharp pain, aggravated by inspiration, and relieved by sitting up and leaning forward. Often complicated by pericardial effusion [between yellow arrows in A ]. Presents with friction rub. ECG changes include widespread ST-segment elevation and/or PR depression.


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First_Aid_Step1. Causes include idiopathic (most common; presumed viral), confirmed infection (eg, coxsackievirus B), neoplasia, autoimmune (eg, SLE, rheumatoid arthritis), uremia, cardiovascular (acute STEMI or Dressler syndrome), radiation therapy. Treatment: NSAIDs, colchicine, glucocorticoids, dialysis (uremia). Myocarditis Inflammation of myocardium  global enlargement of heart and dilation of all chambers. Major cause of SCD in adults < 40 years old. Presentation highly variable, can include dyspnea, chest pain, fever, arrhythmias (persistent tachycardia out of proportion to fever is characteristic). Multiple causes: Viral (eg, adenovirus, coxsackie B, parvovirus B19, HIV, HHV-6); lymphocytic infiltrate with focal necrosis highly indicative of viral myocarditis. Parasitic (eg, Trypanosoma cruzi, Toxoplasma gondii) Bacterial (eg, Borrelia burgdorferi, Mycoplasma pneumoniae, Corynebacterium diphtheriae) Toxins (eg, carbon monoxide, black widow venom) Drugs (eg, doxorubicin, cocaine)


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First_Aid_Step1. Bacterial (eg, Borrelia burgdorferi, Mycoplasma pneumoniae, Corynebacterium diphtheriae) Toxins (eg, carbon monoxide, black widow venom) Drugs (eg, doxorubicin, cocaine) Autoimmune (eg, Kawasaki disease, sarcoidosis, SLE, polymyositis/dermatomyositis) Complications include sudden death, arrhythmias, heart block, dilated cardiomyopathy, HF, mural thrombus with systemic emboli. Buerger disease Heavy smokers, males < 40 years old. Segmental thrombosing vasculitis with vein and (thromboangiitis Intermittent claudication. May lead to nerve involvement. obliterans) gangrene C , autoamputation of digits, Treatment: smoking cessation. superficial nodular phlebitis. Raynaud phenomenon is often present.


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First_Aid_Step1. C , autoamputation of digits, Treatment: smoking cessation. superficial nodular phlebitis. Raynaud phenomenon is often present. Kawasaki disease Asian children < 4 years old. CRASH and burn on a Kawasaki. (mucocutaneous Conjunctival injection, Rash (polymorphous May develop coronary artery aneurysms E ; lymph node  desquamating), Adenopathy (cervical), thrombosis or rupture can cause death. syndrome) Strawberry tongue (oral mucositis) D , Hand-Treatment: IV immunoglobulin and aspirin. foot changes (edema, erythema), fever. Polyarteritis nodosa Usually middle-aged men. Hepatitis B seropositivity in 30% of patients. Fever, weight loss, malaise, headache. GI: abdominal pain, melena. Hypertension, neurologic dysfunction, cutaneous eruptions, renal damage. Typically involves renal and visceral vessels, not pulmonary arteries. Different stages of transmural inflammation with fibrinoid necrosis.


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First_Aid_Step1. Typically involves renal and visceral vessels, not pulmonary arteries. Different stages of transmural inflammation with fibrinoid necrosis. Innumerable renal microaneurysms F and spasms on arteriogram (string of pearls appearance). Treatment: corticosteroids, cyclophosphamide. Granulomatosis with polyangiitis (Wegener) Upper respiratory tract: perforation of nasal septum, chronic sinusitis, otitis media, mastoiditis. Lower respiratory tract: hemoptysis, cough, dyspnea. Renal: hematuria, red cell casts. Triad: Necrotizing glomerulonephritis PR3-ANCA/c-ANCA H (anti-proteinase 3). CXR: large nodular densities. Treatment: cyclophosphamide, corticosteroids. Cardiac tumors Most common heart tumor is a metastasis (eg, melanoma).


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First_Aid_Step1. Cardiac tumors Most common heart tumor is a metastasis (eg, melanoma). Myxomas Most common 1° cardiac tumor in adults (arrows in A ). 90% occur in the atria (mostly left atrium). Myxomas are usually described as a “ball valve” obstruction in the left atrium (associated with multiple syncopal episodes). IL-6 production by tumor  constitutional symptoms (eg, fever, weight loss). May auscultate early diastolic “tumor plop” sound. Histology: gelatinous material, myxoma cells immersed in glycosaminoglycans. Adults make myxed drinks. Calcium channel Amlodipine, clevidipine, nicardipine, nifedipine, nimodipine (dihydropyridines, act on vascular blockers smooth muscle); diltiazem, verapamil (non-dihydropyridines, act on heart). MECHANISM Block voltage-dependent L-type calcium channels of cardiac and smooth muscle  muscle contractility. Vascular smooth muscle—amlodipine = nifedipine > diltiazem > verapamil. Heart—verapamil > diltiazem > amlodipine = nifedipine (verapamil = ventricle).


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First_Aid_Step1. ClINICAl uSE Dihydropyridines (except nimodipine): hypertension, angina (including vasospastic type), Raynaud phenomenon. Nimodipine: subarachnoid hemorrhage (prevents cerebral vasospasm). Nicardipine, clevidipine: hypertensive urgency or emergency. Non-dihydropyridines: hypertension, angina, atrial fibrillation/flutter. AdvERSE EFFECTS Gingival hyperplasia. Dihydropyridine: peripheral edema, flushing, dizziness. Non-dihydropyridine: cardiac depression, AV block, hyperprolactinemia (verapamil), constipation. MECHANISM  cGMP  smooth muscle relaxation. Vasodilates arterioles > veins; afterload reduction. ClINICAl uSE Severe hypertension (particularly acute), HF (with organic nitrate). Safe to use during pregnancy. Frequently coadministered with a β-blocker to prevent reflex tachycardia. AdvERSE EFFECTS Compensatory tachycardia (contraindicated in angina/CAD), fluid retention, headache, angina, drug-induced lupus.