Cardio Flashcards

Question

``` [Cardiovascular Physiology] 1. Describe the cardiac output curves 2. Describe the effects on curves + examples of: A. inotropy B. venous return C. total peripheral resistance ```

Answer 1

1. Cardiac output (y axis) increases with right atrial pressure (x axis) until a maximum - Venous return decreases with increased RAP until it hits 0 --> mean systemic pressure (mean pressure in circulatory system when blood can redistribute equally) - CO = venous return at operating point (equilibrium) 2. In general, v hard to isolate these factors bc autonomic nervous system affects them all A. inotropy - shifts cardiac output curve only More inotropy --> shifts upwards e.g. digoxin Less inotropy --> shifts downwards e.g. uncompnesated heart failure, narcotic OD B. venous return - shifts venous return curve only More volume, venous tone --> shift upwards e.g. blood infusion Less volume, venous tone --> shift downwards e.g. hemorrhage, venodilators C. total peripheral resistance - redistribution of blood to venous side when decreased, vice versa Increased TPR --> decreased slope of venous return and CO curves e.g. isolated arteriolar venoconstriction Decreased TPR --> increased slope of venous return and CO curves e.g. exercise, AV shunt

Answer 2

1. LV pressure on Y axis, LV volume on X axis cardiac cycle needs to lie between end systolic PV relationship ESPVR (contractility) and end diastolic PV relationship EDPVR (compliance) [SEE PICTURE OF CARDIAC CYCLE CURVE] 2A. increased preload - EDV increases, but ESV stays the same --> SV increases B. increased afterload - ESV increases --> SV decreases C. increased contractility - ESV decreases --> SV increases

Answer 3

1. systolic heart failure - due to decreased inotropy/contractility or pressure overload --> reduced ejection fraction - decreased slope (SV is y axis and EDVP/preload is x axis) --> decrease in SV for same level of preload 2. 3 main types of systolic heart failure: A. myocardial infarction - loss of myocardium (irreversible membrane disruption) B. alcoholism - ventricular dilatation due to cardiomyopathy C. pressure overload 3. Diastolic heart failure - stiff ventricle inhibits ventricular filling --> EF normal or elevated

Answer 4

1. Heart sounds S1 - mitral and tricuspid valve closure; heard loudest at mitral area S2 - aortic and pulmonary valve closure; heard loudest at left sternal border S3 gallop "Kentucky"- (abnormal) occurs after S2 early diastole during rapid ventricular filling; associated with increased filling pressures and volume overload (eg heart failure) but can be normal in children and pregnant women S4 gallop "Tennessee"- (abnormal) "atrial kick" in late diastole right before S1 due to high atrial pressure; associated with ventricular hypertrophy when LA pushes against stiff LV 2. Splitting A. Physiologic - (expiration) A2 closes before P2 - but close enough that its 1 sound (inspiration) chest expands --> intrathoracic pressure becomes more negative --> ↑ venous return --> ↑ RV filling + increased capacitance --> takes longer to empty --> delayed pulmonic valve closure = delayed P2 B. Wide - A2/P2 splitting during expiration and inspiration (worse on inspiration) due to delayed pulmonic valve closure due to pulmonic stenosis, right BBB C. Fixed - A2/P2 splitting that is constantly wide during expiration and inspiration due to ASD D. Paradoxical - (expiration) P2 occurs before delayed A2 (Inspiration) single sound due to delayed aortic valve closure due to aortic stenosis, left BBB

Answer 5

Cushing reflex - terminal stages of acute head injury: triad of HTN, bradycardia, and respiratory depression cerebral injury --> increased intracranial pressure --> constricts arterioles in brain --> cerebral ischemia --> Activates SNS --> increased HR and contractility --> increases BP (to ensure blood and 02 delivery to the brain) --> but increased BP activates baroreceptors --> Activates PSNS --> bradycardia * only get part of baroreceptor reflex bc SNS is dominant in vasculature, while PSNS is dominant in heart and overrides SNS tachycardia drive

Answer 6

1. Most common vessels - large and medium-sized muscular arteries Most common sites - bifurcations, branch points, regions of high curvature 2. Endothelial cells (ECs) line up in direction of blood flow; modulate immune response, have anticoagulant functions, release vasodilators (e.g. NO, prostacyclin), anti-hypertrophic properties 3. First step - endothelial dysfunction / injury A. mechanical endothelial injury: at branch points, laminar flow disturbed --> flow becomes turbulent, with low flow areas --> disturbed shear leads to high EC turnover, poor alignment, inflammatory genes/altered gene expression, high permeability, oxidative stress *problem is exacerbated by high pressure (eg HTN) B. Chemical injury e.g. dyslipidemia (direct correlation bw plasma cholesterol and heart disease), cigarette smoking, diabetes 4. Both mechanical + chemical injury --> alter endothelial behavior so they are no longer anti-inflammatory, but become pro - alter substances to be vasoconstrictive - recruit leukocytes - release inflammatory cytokines - produce ROS, become prothombotic

Answer 7

1. Endothelial dysfunction allows lipoprotein entry and modification in subendothelial space; principal culprits are LDLs bc of their overflow pathway (high proportion of cholesterol, contain ApoB100) 2. Exogenous (small intestine) - lipids (cholesterol, fat, monoglycerides, etc) in food packaged into bile salt micelles --> taken up by intestinal epithelial cell --> broken down into cholesterol esters, phospholipids, and triglycerides --> packaged into chylomicrons which are TG-rich and have ApoB-48 --> released into lymph --> acquire ApoA, ApoE, ApoC from HDLs in the bloodstream --> binds to lipoprotein lipase and offloads TGs to muscle and fat in the form of FFAs --> chylomicron remnants go back to liver and taken up 3. Endogenous pathway (liver) - VLDLs composed of TGs and cholesterol, packaged with ApoB-100 --> circulate in blood and interact with HDLs --> acquire ApoE, ApoC, and cholesterol esters --> binds to lipoprotein lipase and offload TGs to muscle and fat in the form of FFAs --> VLDL remnants return to liver --> 50% cleared via ApoE receptor and 50% processed by hepatic triglyceride lipase and LPL to form LDL * HDL involved in reverse cholesterol transport - transfer of cholesterol from VLDL, IDL, LDL in periphery to liver

Answer 8

1A. Familial hypercholesterolemia - autosomal dominant (incompletely dominant) B. Defects: most commonly LDL receptor mutation (300+ mutations IDed) - also Apo-B100, PCSK9 mutations C. Homozygous FH - severely elevated cholesterol levels >600 mg/dL - Heterozygous FH - elevated cholesterol > 250mg/dL - normal total cholesterol level (incl LDL and HDL): <200 mg/dL Other genetic dyslipidemias (FOR STEP REVIEW): familial combined hyperlipidemia, Type III hyperlipidemia, ApoC-II deficiency --> atherosclerosis leads to high CRP levels (marker of inflammation) longer and lower the reduction in circulating LDL-cholesterol --> lower incidence of coronary heart disease e.g. MI

Answer 9

Endothelial dysfunction --> Lipoprotein entry --> Inflammation --> leukocyte recruitment --> SCM and ECM proliferation After lipoproteins (LDL particles) enter cell, they become oxidized or glycated by the inflammatory processes going on in EC --> recognized by scavenger receptors on macrophages also drawn to the area by the injury --> inflammasome activation of inflammatory process --> forms foam cells (fat-laden macrophages) Smooth muscle cells SMC in the media become activated as a result of the inflammation --> migrate into the intima - injury response -- body is recognizing atherogenesis as damage/injury and tries to contain it via a fibrous cover --> process makes vessel more and more narrow ("Fatty streak") but does stabilize atherogenesis and prevents thrombus --> becomes calcified (do not know etiology) Fatty streak --> plaque progression --> plaque obstructive plaque (Stable angina) --> disruption (unstable angina)--> thrombus (MI/heart attack)

Answer 10

Risk factors for atherosclerosis are multiplicative 1. List non-modifiable risk factors - advanced age - M>>F - heredity 2. List modifiable risk factors - dyslipidemia (elevated LDL) - smoking - HTN - diabetes, metabolic syndrome - lack of physical activity 3. Primary - delaying/preventing onset of the disease Secondary - patient already has the problem - goal is to prevent progression of disease 4. Biomarkers A. C-reactive protein (CRP) - marker of inflammation associated with CAD --> released from liver in response to inflammatory cytokines B. Lipoprotein a - linked to ApoB-100, structurally related to prothrombotic plasminogen; size and concentration is genetically determined C. homocysteine - independent risk factor for cardiovascular disease

Answer 11

1. Microscopic anatomy: A. Intima - endothelial cells overlying internal elastic lamina B. Media - smooth muscle cells and extracellular matrix of collagen (Strength) and elastic fibers (distension) - lamellar unit - can withstand high pressure and distend in response --> allows pressure to evenly flow to extremities C. Adventitia - vaso vasorum (blood vessels) 2. Fibrillin-1 - glycoprotein that helps maintain structural integrity of aortic wall and valve leaflets by tethering smooth muscle cells to elastin/collagen matrix - deficiency --> VSMC detachment from matrix --> loss of ECM structural integrity --> Marfan syndrome 3. Properties - how distensible aorta is (based on shape and mechanical properties) determines: - how hard LV has to work diastolic pressure in aorta determines: - coronary blood flow - efficiency/dist of blood flow *elastic component degenerates with age --> aorta stiffens --> systolic bp rises

Answer 12

1. Coarctation - constriction of aorta, esp isthmus - occurs right as the ductus arteriosus joins the aorta (juxtaductal) - congenital do not know etiology - associated with other congenital heart defects --> bicuspid aortic valve, Turner syndrome (XO) 2. Does not cause problems in utero bc blood shunts from ductus arteriosus and down descending aorta, bypassing the constriction - problem when baby is born and ductus closes 3. Pathophysiology - increased load caused by obstruction of the aorta leads to: - increases afterload (increased pressure the heart has to work against) --> increased LV wall stress --> compensatory LV hypertrophy - HTN (due to obstruction itself and also bc renal arteries are underperfused --> make renin to boost pressure) - aortic collaterals --> rib notching *classic finding* seen later, in kids (not babies)

Answer 13

1. Classic finding - notching on inferior surface of posterior ribs (chest X-ray) A. Infants - differential cyanosis (bottom half of body), congestive heart failure (tachycardia, poor feeding) B. Older children/adults --> systolic HTN in upper extremities, reduced lower extremity systolic BP (>20 mmHg) - radial to femoral pulse delay 2. Symptoms and signs: - majority of adults detected via incidental HTN - one of the few murmurs that is heard on the back --> under left scapula - bicuspid aortic valve in 30% adults (systolic murmur following ejection click)

Answer 14

1. Bicuspid aortic valve - 2 leaflets fuse during development --> bicuspid aortic stenosis - M>>F - unknown developmental etiology: common, can be sporadic or familial (AD) - 1/2 have dilated aortic root (need to be screened for this)--> can lead to aortic dissection, rupture - structural alteration similar to that in CT disorders (Marfan, Ehlers-Danlos) *could be tied into etiology - BAV associated with Turner syndrome, aortic coarctation 2. Clinical presentation: congenital - aortic stenosis is most common, presentation at young age - systolic ejection murmur/click that decreases with valsalva (↑ in intraabdominal pressure --> ↓ venous return to the heart --> ↓ blood flow through stenotic aorta)

Answer 15

Valsalva --> ↑ in intraabdominal pressure --> ↓ venous return of the heart --> ↓ volume of heart - Rapid standing --> also ↓ venous return (orthostatic hypotension) - can reduce murmur by increasing preload (squatting) or afterload (handgrip) 1. Mitral valve prolapse --> billowing of mitral leaflets happens sooner after S1 with lower blood flow --> mid-systolic click happens sooner 2. Hypertrophic cardiomyopathy HCM --> exacerbates LV outflow tract obstruction bc ventricles come closer together with lower blood flow

Answer 16

1. Aortic dissection: - damage to aortic wall - combo of mechanical (HTN) and atherosclerosis --> degeneration of the media (necrosis and fibrosis) - intimal layer tears (close to Aortic valve) --> high pressure allows blood to gain access to the underlying damaged media --> - creates "false lumen" in which blood travels within media --> - blood can propagate proximally (Towards heart) or distally (along aorta) and even encircle the aorta 2. Classification (Stanford) - A - involves arch - treated surgically - B - does NOT involve arch - treated medically 3. Etiology - chronic arterial HTN *most important risk factor* - smoking, cocaine use, eclampsia pregnancy, trauma - genetic (Turner, CT disorders e.g Marfan) - M>>F - 2x more common to begin in ascending (Vs descending) aorta

Answer 17

1. Clinical presentation - sudden, severe "tearing/ripping" chest pain - starts at maximal intensity (10/10) --> pain radiates to back/scapula --> Death - HTN on presentation - 1/2 have aortic regurgitation (blowing, decrescendo murmur heard best at 3rd L intercostal space) - 1/3 have pulse deficits (can occlude branches of aorta) 2. MI - pain starts at lower level and gradually increases as myocardium becomes ischemic --> pain radiates to arm, shoulder, neck bilaterally 3. Catastrophic dissection A. False lumen ruptures --> patient dies (nothing you can do) B. Occlusion of coronary ostia/opening --> MI C. Proximal rupture into pericardium --> pericardial tamponade --> death

Answer 18

1. High risk conditions - Marfan's, family h/x of aortic disease, known aortic valve disease, recent aortic manipulation 2. High risk pain features *most important* - chest, back, abdominal pain described as abrupt onset, severe (10/10) intensity, and "ripping or tearing" 3. High risk physical findings - perfusion deficit (pulse deficit, systolic BP difference, focal neurological) - new aortic regurgitation murmur (early diastolic decrescendo murmur, wide pulse pressure) - hypotension

Answer 19

1. Aortic aneurysm - localized/diffuse dilation of artery with diameter greater than 50% normal size (>3cm in abdominal aorta) - most aortic aneurysms occur below renal arteries (infrarenal aorta), but can occur anywhere 2. Pathophys - ischemic injury of media (due to atherosclerosis), degradation of aortic medial connective tissue --> media broken down by proteases, poor quality vascular connective tissue --> expansion of aorta and thinning of wall A. Pseudo-aneurysm - iatrogenic (post-surgical) resulting in hematoma (collection of blood in surrounding tissue) that remains in continuity with arterial lumen 3. Etiology - most abdominal aortic aneurysms AAA are acquired due to degenerative disease (HTN, smoking, atherosclerosis), acquired infection (Syphilis), inflammatory condition; M 65+ should be screened A. Thoracic aortic aneurysm associated with family history / underlying genetic disorders e.g. Turner, CT disorders (Marfan, Ehlers-Danlos), Bicuspid aortic valve 4. Clinical presentation: usually asymptomatic before rupture - typical finding is pulsatile abdominal mass A. Symptoms of rupture - sudden onset abdominal OR back pain + hypotension = ruptured AAA

Answer 20

1. HMG CoA reductase inhibitors e.g. lovastatin (Mevacor), simvastatin (Zocor), atorvastatin (Lipitor) *first-line --> treatment and prevention of cardiovascular disease, decreased incidence of coronary events/death A. MOA: Statins are competitive inhibitors of HMG CoA reductase (RLS in de novo cholesterol synthase from HMG CoA --> mevalonate) - when cholesterol is down in the cell, SREBP (sterol regulatory element binding protein) is activated --> increases de novo biosynthesis (moot point bc of competitive inhibitor) AND upregulates LDL receptors --> clears atherogenic lipoproteins from circulation via receptor mediated endocytosis B. Serum lipid concentration - decreases levels of TG, LDL - little effect on HDL C. Adverse effects - side effects: myopathy (muscle aches, rhabdomyolysis), increased liver enzymes - contraindicated for active/chronic liver disease, for pregnant women - interactions: drugs that inhibit organic anion transporter e.g. cyclosporin --> higher plasma levels of statins - red yeast rice is form of statin - natural but unregulated

Answer 21

2. PCSK9 Inhibitors e.g. evolocumab, alirocumab A. MOA: inhibit PCSK9 - protein that binds to LDL receptors and delivers to lysosome for disposal --> higher levels of LDL receptors B. Serum lipid concentration - decreases levels of LDL - little effect on TG (decrease), HDL (increase) C. Adverse effects - side effects - hypersensitivity rxns - effective in reducing cardiovascular events, well tolerated but v expensive

Answer 22

3. Cholesterol absorption inhibitors e.g. ezetimibe (Zetia) A. MOA: inhibits enterocyte brush border protein NPC1L1 - which inhibits uptake of dietary sterols --> leads to cholesterol uptake in small intestine --> decreased intestinal delivery of cholesterol to liver, increased LDL-R expression B. Effects on serum lipid concentration - decreased LDL - no change in TGs - slight increase in HDL C. Adverse effects - impaired hepatic function - used with statins

Answer 23

4. Bile acid sequestrants (resins) e.g. cholestyramine, colestipol, colesevelam A. MOA: positively charged plastics that bind negatively charged bile acids --> prevent their reabsorption --> bile acids secreted in stool --> increased hepatic bile acid synthesis from cholesterol --> liver [cholesterol] decreases - LDL receptors increased - but de novo cholesterol production also increased --> this homeostasis offsets LDL reduction B. Effects on serum lipid concentration - decrease in LDL - slight increase in TGs - slight increase in HDL C. Adverse effects - increase in hepatic TG synthesis --> contraindicated in patients with high TGs (>400 mg/dL) - side effects from the plastics --> GI distress - prevent interactions with other drugs by taking them at different times

Answer 24

5. Niacin A. MOA: water soluble B3 vitamin that is incorporated into NAD B. Effects: not been shown to have significant effects even in combo with statins but can decrease LDL, TG, and increase HDL C. Adverse effects: causes niacin flush; hyperuricemia (gout), hyperglycemia, hepatotoxicity 6. Fibrates A. MOA: Activate transcription factor PPARalpha - controls lipid metabolism B. Effects: Reduces plasma TGs, little effect on LDL (may even increase) C. Adverse effects: increase risk of myopathy in patients on statins

Answer 25

1. Sympathetic neuron cell bodies in T1-L2 intermediolateral horns of spinal cord, leave through ventral horn --> why pain from viscera is so vague compared to pain from somatic nervous system 2. Presynaptic - ACh Postsynaptic - adrenergic (NE/E but mostly norepi) except ACh in sweat glands and D1 in renal vessels/ smooth muscle 3A. Cytoplasm: Tyrosine + (tyrosine hydroxylase *RLS*) --> Dopa --> Dopamine B. Synaptic vesicles: Dopamine --> Norepinephrine C. Adrenal medulla: Norepinephrine (acts as neurotransmitter) --> epinephrine (acts as hormone) - NE/E are stored in chromaffin granules of adrenal *When NE is released into synaptic space --> ATP is released as well 4A. reuptake into synaptic terminal (blocked by cocaine, TCAs) B. Metabolism of NE to inactive metabolite (MAO in mitochondria, COMT in post-synaptic nerve) C. diffusion away from nerve terminal

Answer 26

1. Alpha1 adrenergic receptors A. MOA: receptor coupled to Gq protein--> activates phospholipase C ---> activates inositol triphosphate IP3-DAG cascade --> increased intracellular Ca2+ B. Located on postsynaptic membrane --> post junctional C. Effects: i. alpha1B (in vasculature) --> peripheral vasoconstriction and venoconstriction--> increases systolic and diastolic blood pressure - increased SVR, MAP, and BP --> decreased HR / reflex bradycardia due to baroreceptor reflex * minimal effects on heart ii. alpha1A (in bladder sphincter) --> urethral sphincter and prostatic SMC contraction --> urinary retention iii. mydriasis --> increased intraocular pressure when iris pulls back and obstructs canal of schlemm --> glaucoma

Answer 27

2. Alpha2 adrenergic receptors A. MOA: receptor coupled to Gi --> IP3-DAG cascade --> decrease cAMP levels --> inhibits release of neurotransmitters (NE and ACh) B. Located on presynaptic membrane - nerve terminals of adrenergic and cholinergic neurons C. Effects: - autonomic modulation - inhibit NE and ACh release - inhibit insulin release - inhibit lipolysis - decrease aqueous humor production --> decrease intraocular pressure

Answer 28

3. Beta adrenergic receptors - three types (1,2,3) A. MOA: increase cAMP levels --> activates protein kinase A --> increase Ca2+ levels - can be turned off by phophorylation B. Location: i. Beta1 - postsynaptic; heart, juxtaglomerular apparatus cells in nephron ii. Beta2 - pre and postsynaptic; smooth muscle in periphery iii. Beta3 - adipocytes C. Effects: i. Beta1 - increased Ca2+ --> increased inotropy (contractility) - increased rate of conduction - increased chronotropy (heart rate) by affecting funny current If; RMP more positive (cells more depolarized), fire more quickly bc close to threshold and reach threshold faster (slope to depolarization steeper) - increased renin release in kidney nephrons ii. Beta2 - increased bronchodilation, vasodilation, uterine relaxation - increased insulin --> moves glucose and K+ into liver and skeletal muscle, respectively --> gluconeogenesis and hypokalemia - decreased peripheral vascular resistance (opposite of alpha1) - increased neurotransmitter release (if presynaptic) - increased aqueous humor production iii. Beta3 - lipolysis

Answer 29

Epinephrine 1. Key features: lower doses acts on beta, higher doses has alpha effects; B1=B2, alpha1=2 affinity 2. Cardiovascular effects - Beta1 - increased contractility, HR --> increased CO and systolic BP *increased myocardial 02 demand - initially, B2 vasodilation in splanchnic beds --> decreased diastolic BP - then, alpha1 contraction -->increased systolic and decreased diastolic BP --> mean arterial pressure MAP remains the same but pulse pressure increases 3. Clinical uses: #1 drug of choice for anaphylaxis (IV) - cardiac arrest - asthma (bronchospasm) - local anesthetic - open angle glaucoma 4. Toxicities - palpitations, HTN, tremor, anxiety - contraindicated in hyperthyroidism and those on non-selective beta blockers

Answer 30

Norepinephrine 1. Key features: alpha1=2; Beta1>>2 - at lower concentrations has high affinity for alpha - at high concentrations, acts on Beta1 (heart) 2. Cardiovascular effects - increased SVR (systemic vascular resistance) - increased systolic and diastolic BP --> increased mean arterial pressure - reflex drop in heart rate through baroreceptor response 3. Clinical uses: #1 drug of choice for hypotension in sepsis (IV) --> septic shock (type of distributive shock) 4. Toxicities:

Answer 31

Dopamine 1. Key features: effects are dose dependent 2. Cardiovascular effects: - (low dose) DA1 receptors in kidney --> increased renal perfusion --> diuresis - (medium dose) Beta1 receptor in heart --> increase in contractility - (high dose) Beta + alpha1 receptor --> increase in peripheral resistance --> increase contractility, HR, BP 3. Clinical uses: hypotension, low CO 4. Toxicities: arrhythmia (Ventricular and supraventricular, widened QRS, angina)

Answer 32

Phenylephrine 1. Key features: most specific for alpha1 agonist 2. Cardiovascular effects: increased arterial vasoconstriction (skin, splanchnic vessels, skeletal muscles) --> increase BP - decreased HR due to baroreceptor reflex (reflex bradycardia) 3. Clinical uses: #2 drug for hypotension (IV) if you cannot use NE - rhinitis (vasoconstricts to treat nasal congestion) - mydriasis 4. Toxicities: black box warning bc it is has active metabolite in liver/tissues --> can cause HTN when supine

Answer 33

Clonidine 1. Key features: alpha2 agonist at presynaptic receptors in medullary brainstem; imadazoline compound; oral and transdermal 2. Cardiovascular effects: decrease central SNS outflow --> decrease HR, decrease SVR, increase capacitance 3. Clinical uses: - resistant and urgent forms of HTN - mgmt of Tourette's, ADHD - also used for hot flashes, addiction withdrawal 4. Toxicities: dry mouth, sedation, depression, rebound HTN * other drugs in same class: guanabenz, guanfacine (not used)

Answer 34

Isoproterenol 1. Key features: IV only; acts non-selectively at beta receptors; beta1=2 agonist 2. Cardiovascular effects: - Beta1 - increase HR (chronotropy), contractility (intotropy), conduction velocity - Beta2 - decrease peripheral vascular resistance (decreased afterload on the heart) --> decreased diastolic BP 3. Clinical uses: stokes-adams attack (syncope due to absent pulse), cardiac arrest, heart block 4. Toxicities: tachycardia, HTN, dysrhythmia * not really used clinically

Answer 35

Dobutamine 1. Key features: beta1 selective but (-) isomer has some alpha1 effects 2. Cardiovascular effects: increased contractility >> chronotropic effect - alpha1 action maintains peripheral resistance (makes it a better drug than isoproterenol) 3. Clinical uses: #1 drug for cardiogenic shock with maintained BP - add to NE in septic shock with low CO - stress test 4. Toxicities: tachyarrhythmia, PVCs, HTN

Answer 36

Phenoxybenzamine 1. Key features: non-selective alpha antagonist --> blocks both alpha1 and 2 but 1>>2; irreversible (blockade lasts 2 days), oral administration only 2. Cardiovascular effects: blocks reuptake at presynaptic terminals --> blocks catecholamine-mediated vasoconstriction --> decrease TPR - metabolically neutral - no effects on glucose, lipids, GFR, ions, etc 3. Clinical uses: oral - pheochromocytoma (adrenal medulla tumor with excessive production of catecholamines NE/E) --> causes paroxysmal hypertension * only used to premedicate patients with this condition before surgery; start with alpha blocker, then beta - or they could suffer a stroke in the OR 4. Toxicities: orthostatic hypotension, reflex tachycardia, nasal stuffiness, fatigue, nausea

Answer 37

Phentolamine 1. Key features: non-selective alpha antagonist; alpha1=2; reversible (lasts 4 hours); IV or IM only 2. Cardiovascular effects: blocks peripheral resistance, causes cardiac stimulation 3. Clinical uses: NE extravasation (when IV with NE leaks into the tissue and causes vasoconstriction and necrosis); pheochromocytoma, treating patients on MAO inhibitors who eat tyramine-containing foods (wine, cheese) 4. Toxicities: severe tachycardia, arrhythmias, myocardial ischemia

Answer 38

Prazosin 1. Key features: highly alpha1 selective (1000x >> than alpha2) antagonist - other drugs are terazosin, doxazosin, tamulosin 2. Cardiovascular effects: post-junctional antagonist - relaxes arterial and venous smooth muscle --> increases venous capacitance --> vasoilation, decreased TPR - relaxes smooth muscle in prostate - metabolically neutral - no effect on glucose, GFR, etc 3. Clinical uses: benign prostatic hyperplasia BPH - also HTN, but not first line therapy (which is diuretics) - used in older men with HTN and BPH 4. Toxicities: postural hypotension, dizziness, headache, drowsiness, ejaculation problems

Answer 39

Beta blockers 1. Key features: metabolized extensively --> limited bioavailability with oral administration - Beta1 - in SA node (increase HR), cardiac muscle (contractility, SV), and renal juxtaglomerular cells (renin release) - Beta2 - on VSM cells (vasodilitation) 2. Effects: immediate CO ↓ and TPR ↑ - only has BP lowering effect when BP is high - negative chronotrope (slows HR) - negative inotrope (decreases contractility)--> lowers CO, workload, V02 - can increase PVR initially, but normalizes long-term - bronchoconstriction, even if B1 selective - metabolic/endocrine: block lipolysis --> increased VLDL, decreased HDL; blocks glucose mobilization - eye: decreases aqueous humor production --> reduce intraocular pressure in the eye 3. Clinical uses - propranolol - acute STEMI (decreases myocardial 02 consumption) - metoprolol in symptomatic heart failure - hyperthyroidism, glaucoma, migraine - no longer first line for HTN - 4. Toxicities - drug rebound - can precipitate acute MI on sudden withdrawal - CHF exacerbation - in patients with acute decompensated heart failure - bradyarrhythmia - in patients with AV conduction defect - bronchoconstriction - contraindicated with severe obstructive disease - weight gain, lipid metabolism, worsened glycemic control in DM II

Answer 40

1. List non-selective antagonists: - propranolol - prototypical - pindolol - partial agonist - nadolol - LONG duration of action - timolol - ophthalmic, topical tx for glaucoma 2. Beta1 selective antagonists - used in patients with asthma, COPD, DM ABEAM Acebutolol - partial agonist Betaxolol Esmolol - parenteral, SHORT duration (10 min 1/2 life) Atenelol - prototypicals Metoprolol - prototypicals - nebivolol - most highly selective beta1; vasodilation via NO release; does not affect lipid/glycemic control 3. Non-selective beta blockers + alpha blocking activity - carvedilol - used in CHF and HTN; best choice with nebivolol in diabetic patients - labetolol - treats HTN in pregnancy

Answer 41

1. Ischemia - myocardial 02 demand >> supply; most common cause is atherosclerosis; causes chest pain, decreased contractility, congestive heart failure, necrosis 2. Supply = 02 content (coronary blood flow, determined by perfusion pressure and resistance) - resistance determined by A. external compression (more blood flow during diastole when less resistance) B. arterial tone C. metabolic factors (adenosine vasodilator released with lack of ATP) D. endothelial factors (endothelial cells release NO --> activates cGMP --> relaxes smooth muscle cells and prevents platelet aggregation ) E. neural factors (SNS - alpha and beta2) 3. Demand = 02 consumption A. Ventricular wall stress S = P * r/2h [Laplace Law] - wall stress is difficult to calculate so we use blood pressure instead B. Heart rate C. Ventricular contractility

Answer 42

1. Stable angina - chest pain that occurs with activity/emotions/stress; constant pattern that can be predicted; due to atherosclerotic narrowing of coronary artery 2. Unstable angina - chest pain with changes in pattern , gets worse over time; due to platelet aggregation secondary to plaque rupture 3. Variant angina i.e. atypical, Prinzmetal's - occurs with decrease in coronary flow due to transient coronary vasospasms 4. Silent ischemia - patients who do not have any warning systems of pain 5. Syndrome X - EKG shows ischemia and patient complains of chest pain, but you cannot find any obstruction (believed to be at capillary level) A. Unstable angina - partially occlusive thrombus; serum biomarkers / enzymes negative, ST depression and/or T wave inversion B. NSTEMI - enzymes positive, ST depression and/or T wave inversion C. STEMI - enzymes positive, ST elevation bc transmural infarction (all walls of heart), Q waves later

Answer 43

1. Descriptors: elephant sitting on chest, burning sensation, choking feeling in throat, toothache, bra too tight 2. EKG: ST segment no longer isoelectric - goes up (transmural ischemia) or down (subendocardial ischemia) from baseline - T wave become inverted - gold standard diagnosis in first 6 hours post MI 3. Lab: creatinine kinase isoenzymes; MB fraction is in cardiac muscle (and a little in skeletal muscle); peaks 24 hrs and normalizes after 2 days - troponin - I and T; peaks 18 hrs post MI and stay elevated longer, for 7-10 days - LDH - comes from all muscle, but from the myocardium it stays for a long time - myoglobin - specific for myocardium but v expensive 4. Gold standard for diagnosis - coronary angiography --> injecting dye in coronary arteries - radioisotope scan - fibrous tissue forms after MI and does not take up radioisotopes

Answer 44

1. Treatment A. treating acute angina - nitroglycerine and other organic nitrates B. treating variant angina - organic nitrates, Ca2+ channel blockers, but NOT beta blockers C. prevention of recurrent angina - beta blockers (most effective for reducing cardiac ischemia), organic nitrates, Ca2+ channel blockers D. prevention of acute events - ASA (aspirin), clopidogrel or prasugrel (antiplatelet agent - prevents adhesion step), ACE inhibitors, statin (to lower cholesterol) *Ca2+ channel blockers used when nitrates or Beta blockers are poorly tolerated (eg bronchospastic disorders, peripheral vascular disease, DMII, dyslipidemia) 2. Myocardial revascularization - need to open up artery w/in 90 min A. percutaneous coronary intervention B. coronary artery bypass graft (CABG)

Answer 45

Organic nitrates - nitroglycerin, amyl nitrite, isosorbide dinitrate 1. MOA: release NO into smooth muscle cells --> NO activates guanylate cyclase --> increased cGMP --> Activates phosphorylation cascade --> dephosphorylation of myosin light chain --> muscle relaxation 2. Cardiovascular effects - no increase in coronary blood flow A. Low doses (usually dose administered) - affects capacitance vessels (veins) --> venous pooling, venodilation, ↓ diastolic filling pressure --> ↓ venous return (ie preload) B. High doses - affects resistance vessels (arteries) --> ↓ systemic peripheral resistance, reflex cardiac stimulation of rate and contractility C. Overall - ↓ heart size and wall tension during systole --> ↓ work of heart; ↓ myocardial 02 demand 3. Pharmacokinetics: first pass inactivation by nitrate reductase in liver; resistant to denitration in tissues --> release N02 slowly and can be used in larger doses - tolerance, physical dependence - oral forms are longer-acting than sublingual forms - amyl nitrate is only inhalant, shortest half-life 4. Adverse effects: flushing, headache, orthostatic hypotension, GI distress

Answer 46

1. NO mediates erectile function by promoting cGMP and relaxing smooth muscle in the corpora cavernosa - PDE5 - phosphodiesterase mediating cGMP breakdown - Sildenafil (Viagra) - PDE inhibitor --> ↑ cGMP --> ↑ blood flow --> ↑ erections in males with intact innervation/NO synthesis - potentiates actions of nitrates used for angina --> could lead to severe hypotension and MI - other drugs like viagra include vardenafil HCl (Levitra), and tadalafil (Cialis) 2. Pentoxifylline, cilostazol - inhibit phosphodiesterase which breaks down cAMP --> ↑ cAMP --> promotes relaxation 3. Ranolazine (Ranexa) - inhibits inward Na+ current --> reduces intracellular Ca2+ concentration --> reduces tension in heart wall - for chronic angina, also lowers incidence of atrial flutter

Answer 47

1. Sources of Ca2+ in smooth muscle cells: A. release from sarcoplasmic reticulum when stimulated by IP3 following alpha receptor stimulation B. entry through Ca2+ selective channels C. exit through Ca2+/Na+ exchanger NCX (Na+ enters cell through concentration gradient and Ca2+ leaves) *intracellular free Ca2+ maintains arterial smooth muscle tone 2. Types of Calcium channels T (fast) - pacemaker N and P - neurotransmitters L (slow) - important in resistance vessel SMCs, myocardial cells --> contraction - ↑ in membrane potential, activation of alpha1A receptors --> ↑ probability of L channel opening

Answer 48

Nifedipine, Amlodipine and dihydropyridines DHPs 1. MOA: inhibit Ca2+ selective L channels carrying slow inward current during depolarization - nifedipine and DHPs bind to closed L channels --> decrease frequency of opening - decreased total peripheral resistance TPR 2. Effects: - increase coronary blood flow due to vasodilation with modest cardiac stimulation * stronger vasodilation with nifedipine than verapamil due to action on smooth muscle - nifedipine used to treat pregnancy-induced HTN - dihydropyridines treat HTN - also Raynaud's, prevent vasospasms in subarachnoid hemorrhages 3. Pharmacokinetics - nifedipine: prototype DHP Ca2+ entry blocker; orally effective but large first-pass transformation - no tolerance and metabolically neutral (Does not aggravate diabetes, glucose, etc) 4. Adverse effects - flushing, headaches, hypotension, peripheral edema - reflex tachycardia (can exacerbate ischemia - avoid in pts with MI)

Answer 49

Verapamil and diltiazem - nondihydropyridines, greatest effect on cardiac muscle 1. MOA: inhibit Ca2+ selective L channels carrying slow inward current during depolarization - verapamil and diltiazem bind to open L channels 2. Cardiovascular effects: - increase coronary blood flow due to vasodilation with moderate cardiac suppression * stronger vasodilation with nifedipine; of resistance but not capacitance vessels - anti-arrhythmic properties- - decrease cardiac contractility and output - bradycardia (act on SA node_ 3. Pharmacokinetics - orally effective, but large first-pass transformation - no tolerance (unlike organic nitrates), and no aggravation of diabetes, peripheral vascular disease, bronchospasm, glucose, potassium 4. Adverse effects - flushing, GI distress, left ventricular dysfunction - constipation (verapimil) - excess AV block when in combo with BBs - skin rash (Steven Johnson syndrome) - inhibit CYP450

Answer 50

Indirect thrombin inhibitors - heparin, enoxaparin (Lovenox, LMWH), fondaparinux (synthetic pentasaccharide) 1. MOA: contains pentasaccharide that binds and activates antithrombin --> Acts as suicide substrate that traps protease (thrombin IIa or Xa) - highly sulfated mucopolysaccharide --> (-) charge A. unfractionated heparin (UFH) - inactivates II and X B. low molecular weight (LMWH) - inactivates X C. fondaparinaux - inactivates X 2. Pharmacokinetics: not absorbed from GI tract - give parenterally; does not cross placenta or breast milk - continuous IV for: DVT treatment/prophylaxis, PE prophylaxis, acute MI treatment - reverse action by discontinuing (1/2 life ~1 hr) OR giving (+) protamine sulfate antidote for heparin A. heparin - monitor apTT B. enoxaparin LMWH has longer 1/2 life and less thrombin inhibition --> used to prevent DVT post-op, treat acute thromboembolic disease C. fondaparinaux - longest 1/2 life, does not cause HIT but contraindicated in patients with renal failure 3. Adverse effects: major bleeding (2% with UFH, 1% with LMWH); contraindicated for any bleeding risk/condition - osteoporosis - hypoaldosteronism --> hypokalemia - heparin induced thrombocytopenia HIT (immune response with Ab against heparin --> activate platelets --> paradoxical thrombosis)

Answer 51

Direct thrombin inhibitors - desirudin, bivalirudin, argatroban 1. MOA: derived from hirudin protein found in leech - desirudin (recombinant hirudin) and bivalirudin ( bind to catalytic site and exosite 1 of thrombin (II) - argatroban binds to catalytic site of thrombin 2. Pharmacokinetics: can reach and inactivate fibrin-bound thrombin A. Desirudin: most potent thrombin inhibitor, approved for prevention of DVT post-op; t1/2 of ~2 hrs post subcutaneous admin; renal clearance B. Bivalirudin: used in coronary angioplasty, HIT; t1/2 of ~30 min C. Argatroban: IV, t1/2 of ~1 hr, monitored by aPTT, used for patients with HIT 3. Adverse effects: hemorrhage, allergic reactions

Answer 52

Oral anticoagulants - warfarin, dabigatran, rivaroxaban, apixaban, edoxaban 1. MOA A. warfarin: competitive inhibitor of VKORC1 enzyme required to recycle vitamin K to reduced form --> inhibits carboxylation of Vit K dependent clotting factors into functional forms --> inhibits biosynthesis of factors X, IX, VII, II as well as Proteins C and S B. Novel oral anticoagulants NOACs: i. dabigatran - direct thrombin inhibitor ii. rivaroxaban, apixaban, edoxaban - direct factor Xa inhibitors 2. Pharmacokinetics A. Warfarin: delayed onset of action bc acts at synthesis of factors (not on the factors directly), narrow TI - ↓ stroke, complications/recurrence of DVT/PE, risk of valve thrombosis/embolism with mechanical heart valves - coadminister with heparin to prevent skin necrosis during early hypercoagulable state (Factor VII, Protein C down but factors II, IX, X still up) B. NOACs - are non-inferior to warfarin; have similar overall bleeding but no ability to monitor 3. Adverse effects A. Warfarin: bleeding (4%) --> give fresh frozen plasma to reverse, teratogenic - birth defects/abortion, skin necrosis during early hyper-coagulable state - conditions that alter response to warfarin: Vit K in diet, pregnancy, liver disease, other drugs (lots of interactions)

Answer 53

Fibrinolysis - breaking down fibrin when clot has already formed a thrombus or become an emboli alteplase (Activase) - recombinant tissue plasminogen administered as a bolus 1. MOA: activates plasminogen that is bound to fibrin of thrombus --> activated plasmin dissolves the clot - non-specific plasmin activation 2. Pharmacokinetics: t1/2 ~5 min -- IV bolus then infusion - used in acute ischemic stroke, acute MI, PE, DVT, central venous catheter occlusion 3. Adverse effects: bleeding - contraindicated in hemorrhage (eg prior, internal, hemorrhagic stroke), head trauma, or surgery - cerebral vascular lesion, pregnancy, peptic ulcer, severe HTN

Answer 54

Antiplatelet drugs - aspirin 1. MOA: irreversible acetylates and inhibits cycloxygenase COX1 and COX2 (activated in inflammation) --> platelets can no longer produce thromboxane TXA2 --> inhibits ability to activate other platelets - also inhibits production of antiplatelet prostacyclin PGI2 in endothelial cells * low dose aspirin inhibits TXA2 and spares PGI2 2. Pharmacokinetics: oral; primary prophylaxis of MI 3. Adverse effects: bleeding (hemorrhagic stroke, GI bleeding), ↑ risk of peptic ulcer disease - pseudo-allergy due to excess leukotriene synthesis

Answer 55

Antiplatelet agents - clopidogrel (Plavix), prasugrel (Eficient), ticarelor (Brilinta) 1. MOA: more effective than aspirin bc ADP is stronger stimulus of platelet aggregation - clopidogrel and prasugrel irreversibly inhibit ADP receptor binding - ticarelor reversible inhibits binding 2. Pharmacokinetics: oral - dual antiplatelet therapy - ADP inhibitor + aspirin --> prevent coronary stent thrombosis - triple therapy - add oral anticoagulant on top - indications: reduce long-term risk of cardiovascular events in patients with CAD, peripheral artery disease 3. Adverse effects: bleeding - ticlodipine ADP receptor inhibitors causes granulocytopenia

Answer 56

Antiplatelet agents - Abciximab, tirofiban, epitifibatide 1. MOA: block GP IIb/IIIa - platelet membrane receptor that binds to fibrinogen/vWF --> inhibits formation of platelet plug * most effective antiplatelets - block aggregation and adherence regardless of activating stimulus (TXA2 or ADP) 2. Pharmacokinetics: IV, used during PCI (percutaenous coronary intervention) procedures A. abciximab - monoclonal antibody against GPIIb/IIIa complex; coronary angioplasty, acute coronary syndrome B. tirofiban - occupies receptor and inhibits binding C. eptifibatide - occupies receptor and inhibits binding 3. Adverse effects: bleeding, thrombocytopenia

Answer 57

1. Sinus node and AV node pacemaker cells have slower upstrokes --> slow L-type CA2+ depolarizing current --> takes longer to go from one cell to the other * beta blockers have most effect * affected by ANS All else (Atrial muscle, ventricular muscle, Purkinje fibers) have fast upstroke --> due to fast Na+ depolarizing current (these channels are inactivated in pacemakers) aforementioned Na+ and Ca2+ are depolarizing currents - inwards flow K+ channels are repolarizing currents - outwards flow 2. Bazett's formula - normalizes QT for rate bc when rate is fast, QT will be short and vice versa QTc = QT / sqrt(RR) - when you need faster conduction in ventricles, action potential shortens to accommodate

Answer 58

1. Sinus node automaticity due to spontaneous phase 4 depolarization - maximum diastolic potential (MDP) is -60mV, as opposed to RMP = -90mV in atrial and ventricular myocardium - Phase 4 depolarization - due to inward "If" funny current that goes through HCN (hyperpolarization-activated cyclic nucleotide-gated) channels - If current causes depolarization from -60mV to threshold, which is -40mV --> Ca2+ influx depolarization --> action potential --> K+ efflux repolarizes cell --> determines sinus rate 2. HCN channels mediated by ANS, through M2 and beta1 receptors (either decrease or increase cAMP) A. PSNS muscarinic stimulation via ACh decreases HCN channel activity --> fewer HCN channels open --> longer to reach threshold --> increase cycle length --> decrease sinus rate - also more rectifier channels open --> K+ efflux --> MDP is more negative - fewer open Ca2+ channels --> shifts action potential threshold to be less negative --> takes longer to reach B. SNS adrenergic stimulation via epi --> more channels available to conduct If current --> faster phase 4 depolarization --> decrease cycle length --> increase sinus rate / automaticity - increases open Ca2+ channels --> shifts action potential threshold to be more negative --> reach threshold faster

Answer 59

1. Latent pacemaker activity A. Overdrive suppression - dominant SA node removes the pacemaker activity of other latent centers --> rapid depolarization of SA node causes buildup of intracellular Na+ --> activates Na+/K+ ATPase which pumps out 3 Na+ for every 2K+ in the cell --> hyperpolarizes cell so it takes longer to reach threshold potential AND antagonizes the depolarizing If current--> suppresses If automaticity - can try to induce this (make heart work faster) to make arrhythmias go away B. Electrotonic interactions - if there are gap junctions that connect myocardial and pacemaker cells --> intercellular current will cause relative myocardial depolarization and pacemaker cell hyperpolarization --> slow rate of the pacemaker - myocardial resting potential RP = -90 mV - pacemaker max diastolic potential MDP = -60mV - SA node cells less tightly coupled to myocytes compared to AV node and Purkinje fibers 2. Pacemaker hierarchy Sinus (60-100 depol/min) >> AV (40-60 depol/min) >> Purkinje (30-40) >> ventricular (20-40)

Answer 60

1. alterations in normal SA automaticity - sinus tachycardia, bradycardia - escape rhythms - junctional (AV) or ventricular control --> escape beat - SA >> AV node >> atrial tissue - sensitive to PSNS vagal stimulation 2. enhanced automaticity of latent pacemakers - normally latent pacemakers take control if SA node slows below their intrinsic rate; decreased coupling bw latent pacemakers and adjacent myocardial cells --> latent pacemakers fire faster than sinus node --> ectopic beat - junctional premature complexes - junctional tachycardia (due to catecholamines, MI, digitalis, aortic/mitral valve surgery) 3. abnormal automaticity - cells that normally do not have activity develop pacemaking potential under disease states (eg MI, ischemia) --> spontaneous phase IV depolarization even without If current - ventricular premature complexes (VPCs) or tachycardia - atrial premature complexes (PACs) or tachycardia

Answer 61

Triggered activity - not de novo depolarizations, occur after cell has been activated and triggered by that action potential Early afterdepolarization - another depolarization occurs before/during repolarization (phases II or III) - occurs when action potential duration is long (long QT), caused by influx of Ca2+ in the slow phase - series of early afterdepolarizations leads to tachyarrhythmia --> torsades de pointes ventricular tachycardia (iatrogenic - caused by drugs that prolong action potentials) Delayed afterdepolarization - another depolarization occurs after the cell has repolarized, due to Ca2+ overload of cells - when they get faster and larger can cause arrhythmia - due to digitalis, catecholaminergic polymorphic ventricular tachycardia (congenital), right ventricular outflow tachycardia, repetitive monomorphic VT

Answer 62

Decremental conduction and block - impaired conduction that can lead to bradycardia or reentry; occurs in nerve fibers with reduced membrane potential 1. Causes: due to fibrosis (Lev-Lenegre syndrome which affects SA and AV nodes), MI (abnormal scar tissue), or hyperkalemia 2. Electrophysiologic mechanisms: - Na+ channel inactivation --> widened QRS - gap junction abnormalities - prolonged refraction due to disease processes 3. Nernst equation: K+ eq potential is dependent on K+ outside the cell and inside the cell -- usually around -89 mV - main determinant of RMP is K+ eq potential - there are other ions that also have permeability (Na+ and Cl-); but at rest, main permeability is K+ --> so in reality actual RMP is a little more positive than K+ eq potential (around -82 mV) Hyperkalemia: depolarized resting potential BUT decreased excitability - ↑ extracellular K+ --> ↓ driving force for K+ to leave cell via rectifier channels --> RMP depolarized compared to normal --> more Na+ channels open but are then inactivated --> fewer Na+ channels available for Phase 0 depolarization --> ↓ conduction velocity --> ↑ QRS

Answer 63

3 mechanisms of causing tachyarrhythmias: enhanced automaticity, triggered activity, reentry 1. Reentry - impulse does not die out after normal activation and re-excites heart after normal refractory period has ended (once pathway is repolarized) 2. Caused by unidirectional block and slow conduction velocity (due to fibrotic/scarred myocardium, sequelae to MI) 3. Arrhythmias due to reentry: A. Anatomical reentry (fixed pathway) --> atrial flutter, AVNRT, AVRT (Eg WPW syndrome), ventricular tachycardia due to scar tissue B. Functional reentry (multiple locations): atrial fibrillation, ventricular fibrillation, polymorphic VT 4. Wavelength = conduction velocity + refractory period --> path length or circumference needs to be greater than wavelength to support reentry

Answer 64

1. Ventricular pre-excitation --> atrial electrical impulses reach ventricles earlier than expected due to conduction down abnormal accessory pathway (Bundle of Kent) --> bypasses the AV node and connects SA node to ventricular myocardium used interchangeably with Wolff-Parkinson-White (wpw) syndrome --> ventricular pre-excitation leading to atrioventricular reentrant tachycardias (AVRTs), type of supraventricular tachyarrhythmias (SVTs) *afib in pt with wpw v dangerous --> can have sudden cardiac death --> need to ablate; treat with procainamide but NOT CCBs or BBs 2. EKG signs (anterograde down both AV node and accessory pathway): - short PR interval --> shortened AV nodal delay - delta wave (blurred upstroke of QRS) --> impulse making it to ventricles prematurely - widened QRS --> fusion bw normal conduction and bypass track

Answer 65

1. High BP determined by Cardiac Output (CO) and Peripheral Resistance (TPR) A. for younger people, high CO influences HTN --> isolated diastolic HTN - for older people, high TPR influences HTN --> isolated systolic HTN due to lower arterial compliance (stiffer due to atherosclerosis) B. BP goes down at night and if it doesn't --> increased CVD risk 2A. Essential (Primary) HTN - 90%+ - unknown etiology but related to changes in SNS and renin/angiotension/aldosterone system RAAS, renal dysfunction, genetics, environment B. Secondary HTN - 5-10% - acute/ chronic kidney disease - renal artery stenosis --> renal HTN - endocrine: aldosteronism, hyperthyroid, Cushing - aortic coarctation (upper extremity HTN) - obstructive sleep apnea - drug-induced

Answer 66

HTN causes ↑ afterload, arterial damage; pressure overload causes concentric hypertrophy (increased risk of ischemic injury bc farther away from bv) 1. Ischemic heart disease / MI A. ↑ myocardial 02 demand bc of ↑ afterload B. ↓ myocardial 02 supply bc of atherosclerosis due to arterial damage 2. Heart failure A. systolic dysfunction bc of ↑ afterload B. diastolic dysfunction bc of LVH due to ↑ afterload 3. Stroke A. Thrombosis / emboli (cerebral/carotid) due to accelerated atherosclerosis bc of arterial damage B. Cerebral hemorrhage due to weakened vessel wall bc of arterial damage 4. Aortic aneurysm/dissection due to atherosclerosis and weakened vessel walls bc of arterial damage - hyaline arteriosclerosis with benign HT - hyperplastic arteriosclerosis with malignant HT 5. Nephrosclerosis and renal failure due to weakened vessels walls in kidney 6. Retinopathy due to weakened vessel walls in the eye

Answer 67

``` 1. BP limits for: A. Normal: <120 and <80 B. PreHTN: 120-39 or 80-89 C. Stage 1 HTN: 140-159 or 90-99 D. Stage 2 HTN: >160 or >100 ``` 2. JNC-7 Treatment guidelines A. lifestyle modifications (rarely work) B. drugs for pts 140/90+ (or diabetes/renal pts 130/80+) - Stage 1: thiazide diuretics HCTZ - Stage 2: two drug combo (HCTZ + ACEI/ARB) *not much difference between the different HTN drugs

Answer 68

Acetazolamide (Diamox) 1. MOA: Acts in proximal tubule - inhibits carbonic anhydrase--> blocks interconversion of H20 + C02 into H2C03 --> blocks reabsorption of HC03- and also Na+ --> ions + water excreted 2. Clinical uses: - mainly to alkalinize urine or counteract metabolic alkalosis - glaucoma (topical) - acute mountain sickness - raises C02 content of tissue --> stabilizes deoxyHb - anticonvulsant 3. Adverse effects - alkalinization of urine (pH in urine increases) - blood pH decreases --> hyperchloremic metabolic acidosis --> compensatory Kussmaul breathing (hyperventilation with deep respiration) - efficacy in sustaining diuresis is not great / reduces bc Na+ can be reabsorbed at other points in the tubule - side effects: somnolence, renal K+ wasting - contraindications: pts with hepatic cirrhosis, allergies to sulfonamides

Answer 69

Osmotic diuretics - mannitol, glycerin *parenteral administration* 1. MOA: act in proximal tubule and descending limb of Henle - increase osmolarity inside the tubule itself --> oncotically traps water inside the tubular fluid --> expand extracellular fluid volume, decrease blood viscosity, inhibit renin release --> diuresis 2. Clinical uses: - increase water excretion preferentially over Na+ excretion - eliminate toxic substances from GI tract (along with activated charcoal), or renal toxins - reduce intracranial and intraocular pressure (before optho procedures) 3. Adverse effects - side effects: headache, nausea, vomiting - before diuresis: extracellular volume expansion --> hyponatremia, exacerbation of HF - after diuresis: dehydration and hypernatremia (from excessive use w/out monitoring)

Answer 70

Loop diuretics - furosemide (Lasix), ethacrynic acid *most effective diuretics available* 1. MOA: act at thick ascending limb TAL of loop of Henle - normally NKCC2 creates positive electrical potential --> drives reabsorption of Mg2+ and Ca2+ ; Loop diuretics inhibit NKCC2 --> increase in Mg2+ and Ca2+ excretion, NaCl and K+ excretion - block tubuloglomerular feedback by inhibiting salt transport into macula densa - increase expression of COX2 --> induce PGE2 synthesis --> increase renal blood flow + inhibit salt transport *NSAIDs interfere with loop diuretics* 2. Clinical uses: - first-line for HF - esp tx of acute decompensated HF with fluid overload - symptomatic tx of pulmonary edema in exacerbation of acute HF (crackles, pitting edema, JVD) - treats ascites in liver failure - HTN in patients with comorbid conditions (HF) - acute hypercalcemia, hyperkalemia 3. Adverse effects: - hypokalemic metabolic alkalosis - hypomagnesiumia, hypocalcemia (rarer) - ototoxicity (reversible) - hyperuricemia --> precipitates gout - contraindications: allergies to sulfonamides (except ethacrynic acid, which does not have sulfonamide)

Answer 71

Thiazides - HCTZ *most common drug prescribed for HTN*, chlorthiazide (IV), chlorthalidone (longer half life) 1. MOA: act at distal convoluted tubule - inhibits Na+/Cl- NCC symporter on the apical membrane--> less Na+ inside the cell --> increases basolateral Na+/Ca2+ exchanger to concentrate (brings Na+ inside cell and excretes Ca2+ into the interstitium/blood) --> increased Ca2+ reabsorption from lumen/urine (PTH-regulated), increased Na+ and Cl- excretion 2. Clinical uses: - first-line for mild-moderate hypertension - adjunctive with loop diuretics for heart failure - nephroliathiasis i.e. kidney stones (excess Ca2+ in tubular fluid) - nephrogenic diabetes insipidus (ADH insensitivity) 3. Adverse effects - hypokalemic metabolic alkalosis - hyperuricemia --> precipitate gout - hyponatremia, hypocalcemia - hyperglycemia, hyperlipidemia - inhibited by NSAIDs - contraindications: allergies to sulfonamides

Answer 72

K+ sparing diuretics - spironolactone, eplerenone (more selective, fewer side-effects) 1. MOA: acts on collecting tubule - competitive antagonists of aldosterone receptor --> decrease in Na+ reabsorption, K+ and H+ secretion 2. Clinical uses: mainly used as aldosterone antagonists - cirrhosis v responsive to spironolactone - heart failure (decreased mortality in HF) - renalvascular HTN - adrenal tumors - cardiac or nephrotic edema - prevents cardiac remodeling 3. Adverse effects: - spironolactone may be inhibited by NSAIDs, can cause gynecomastia, impotence, decreased libido - hyperkalemia - hyperchloremic metabolic acidosis - contraindication: chronic renal insufficiency

Answer 73

K+ sparing diuretics - triamterine, amiloride 1. MOA: acts on collecting tubule - inhibit ENaC Na2+ reabsorption channels in apical cells of collecting tubule --> decrease in Na+ reabsorption, K+ and H+ secretion 2. Clinical uses: - hypokalemia from other diuretics mineralocorticoid excess due to - primary hypersecretion (Conn'a syndrome, ecoptic ACTH production) - secondary aldosteronism (heart failure, cirrhosis, nephrotic syndrome) - Liddle's syndrome (gain of function ENaC mutation) 3. Adverse effects: - triamterene may be inhibited by NSAIDs - hyperkalemic metabolic acidosis

Answer 74

ADH antagonist (vaptans/aquaretics) - conivaptan (V1 and V2), lixivaptan (V2), tolvaptan (V2) 1. MOA: act at the principal cells of the collecting tubule - Non-selective antagonists of V1 and/or V2 ADH receptors --> decrease number of AQP2 channels on apical surface --> decreased water reabsorption - Lithium and demeclocyline - reduce cAMP in principal cell via unknown etiology 2. Clinical uses: - SIADH - other causes of elevated ADH 3. Adverse effects: - nephrogenic diabetes insipidus (treat Li-induced NDI with amiloride) - renal failure (Lithium and demeclocyline) - lot of side effects for lithium (thyroid, cardiotoxicity)

Answer 75

Direct vasodilators - [oral] hydralazine and minoxidil (Rogaine), [parenteral] nitroprusside and diazoxide 1. MOA: ↑ cGMP --> smooth relaxation --> lowers total peripheral resistance --> ↓ afterload - vasodilates arterioles >> veins (unlike nitrates) - minoxidil - opens K+ channels, most potent 2. Clinical uses: - severe or refractory HTN - nitroprusside used for HTN emergencies - use with nitrates to treat HF - pseudotolerance - effect wears off quickly unless you use diuretic + beta blocker (to slow HR) 3. Adverse effects: - reduced perfusion pressure to kidney --> increased renin and volume retention --> edema - reflex SNS stimulation --> tachycardia - hydralazine - lupus syndrome w/ pericarditis - minoxidil - hypertrichosis (hair growth)

Answer 76

1A. ACEI - inhibits conversion of Angiotensin I --> II - ↓ Ang II and aldosterone levels - ↑ vasodilatory peptides eg bradykinin - ↑ plasma renin level, plasma renin activity PRA B. ARBs - block AT1 (Ang II) receptors - ↑ plasma renin level, PRA - ↑ Ang II levels - ↓ aldosterone levels C. DRI - inhibition of renin on its substrate - ↓ PRA, Ang I, Ang II, aldosterone levels 2. Adverse effects - hyperkalemia (aldosterone inhibition) - hypotension - worsen renal insufficiency - fetal injury (teratogenic) *do not give in pregnancy* * ACEI - cough 3. Overall: Start thiazide, CCB, ACEI, or ARB - blacks: start thiazide or CCB (blacks have lower renin output) - chronic kidney disease: include renin antagonist - diabetes: RAAS drug (ACEI or ARB), NO diuretics

Answer 77

Sinus bradycardia 1. Mechanism - decreased automaticity of SA node 2. EKG: lower than 60 bpm 3. Etiology - ↑ PSNS tone, medication (beta blockers, Ca2+ channel blockers) - age, atrial fibrosis, SCN5A mutations - sick sinus syndrome (syndrome incl brady-tachy) 4. Clinical presentation: fatigue, dizziness, asymptomatic 5. Treatment: None, underlying cause if symptomatic, pacemaker (esp with brady-tachy syndrome which can cause afib)

Answer 78

First Degree AV block 1. Mechanism - slowed conduction in AV node (not really a block) 2. EKG - prolonged PR interval due to ↑ AV delay (0.20+ sec i.e. 5+ small boxes) 3. Etiology A. Reversible: ↑ PSNS tone, medications, Lyme disease B. Structural: MI, degenerative disease 4. 4. Clinical presentation - older patients, on beta blockers/Ca2+ channel blockers, digitalis; usually asymptomatic 5. Treatment - adjust meds or nothing

Answer 79

2st Degree AV block 1. Mechanism - intermittent failure of AV conduction (no QRS after P wave) A. Mobitz Type I - impaired conduction in AV node B. Mobitz Type II - conduction block distal to AV node (Bundle of His or Purkinje) --> no possibility for escape rhythm 2. EKG A. Mobitz Type I - degree of AV delay increases (PR interval gets longer) until complete block (no QRS after P wave) - Wenckebach - PR interval ↑ and RR interval ↓ B. Mobitz Type II - sudden block in AV conduction without gradual lengthening of PR 3. Etiology A. Mobitz Type I: ↑ PSNS tone, medications (BB, CCB, digitalis), inferior MI, congenital AV block, myocarditis B. Mobitz Type II: structural damage/degeneration in His-Purkinje, anterior MI 4. Clinical presentation A. Mobitz Type I: asymptomatic, benign, transient - seen in children, athletes, people with high vagal tone B. Mobitz Type II: dizziness, Stokes-Adam syncope (treat with isoproterenol) 5. Treatment A. Mobitz Type I: reversible with removing meds B. Mobitz Type II: pacemaker even if asymptomatic

Answer 80

3rd degree heart block - complete heart block 1. Mechanism - complete failure of conduction between atria and ventricles --> AV dissociation 2. EKG - P waves and QRS complexes have separate rates - P waves --> still depolarize to SA node - QRS normal width, 40-60 bpm --> AV escape rhythm - QRS widened, slower rate --> His-Purkinje escape 3. Etiology - block below level of AV node (His-Purkinje), anterior MI, degeneration of His-Purkinje 4. Clinical presentation - syncope, light-headedness - many patients also have BBB 5. Treatment - pacemaker

Answer 81

Sinus tachycardia 1. Mechanism - increased automaticity of SA node 2. EKG - rate greater than 100 bpm - normal P waves and QRS complexes 3. Etiology - increased SNS (or decreased PSNS) 4. Clinical presentation - exercise or excitement - pathological: fever, pain, low CO, CHF, anemia, hyperthyroidism 5. Treatment: underlying cause, not the rhythm

Answer 82

Atrial premature complexes (PAC) = atrial premature beats (APB) 1. Mechanism - abnormal automaticity, reentry in atria, delayed afterdepolarizations (triggered activity) 2. EKG - earlier than expected P wave with abnormal shape (bc impulse does not originate from SA node), followed by normal QRS (ventricular conduction not impaired) 3. Etiology - ↑ SNS tone, stretch, fibrosis - healthy or diseased hearts - can lead to atrial tachycardia (ectopic pacemaker is atrial myocyte and not SA node) --> p waves inverted in inferior leads; starts and ends suddenly 4. Clinical presentation - caffeine, alcohol - palpitations or asymptomatic 5. Treatment - remove precipitating factors, or beta blockers - treat focal atrial tachycardia with cardiac ablation

Answer 83

Atrial flutter - prototypic reentry arrhythmia 1. Mechanism - reentrant circuit in RA along tricuspid valve annulus 2. EKG - saw-tooth, rapid, regular P waves - most commonly 300 bpm with 2:1 block --> ventricular rate SVT = 150 bpm 3. Etiology - areas of scarring, prior surgery, but most often with no heart disease - related to afib 4. Clinical presentation - palpitations, dyspnea, chest discomfort 5. Treatment - diagnose via adenosine/vagal maneuver (Carotid sinus massage)--> increases ACh --> AV node conduction block increases --> slow ventricular rate but flutter continues unabated A. Acute - BBs, CCBs to slow conduction and decrease ventricular rate; cardioversion to restore sinus rhythm B. Chronic - Ablation

Answer 84

Atrial fibrillation 1. Mechanism - multiple wandering reentrant circuits within the atria --> continual AV node stimulation - paroxysmal afib (less than 7 days, stop on their own) --> pulmonary vein triggers 2. EKG - no distinct P waves - irregularly irregular ventricular rate 3. Etiology - left atrial enlargement or scarring 4. Clinical presentation - palpitations, dyspnea, chest pain --> can lead to heart failure, CVA (stroke) *afib one of leading causes of stroke* - mostly pts with enlarged LA (due to HTN, mitral stenosis, CHF, etc) 5. Treatment - A. Acute - BBs, CCBs to reduce ventricular rate; cardioversion (shock on QRS) to restore sinus rhythm B. Chronic - heparin for stroke i. Rate control - BBs, CCBs ii. Rhythm control - Class 1C (flecainide), Class 3 (amiodarone, sotalol, ibultilide) to maintain sinus

Answer 85

1. PSVT: A. Sudden onset and termination B. atrial rates 140-250 bpm C. narrow/normal QRS complexes (due to AV conduction) - due to reentry, initiated by premature atrial beat (PAC) - treat with IV adenosine, vagal maneuver, ablation 2. AVNRT - most common form of PSVT - 2 pathways in/near the AV node (antereograde through slow and retrograde through fast pathways) - EKG: hidden p waves, normal QRS complexes - usually teenagers with palpitations, dizziness - rates usually 190/min 3. AVRT - one limb of reentry loop is myocardial bypass tract (e.g. Wolff-Parkinson-White syndrome) - orthodromic AVRT: anterograde through AV node and retrograde through accessory pathway (inverted P wave after QRS) - rates usually 220 bpm 4. Atrial tachycardia - ectopic pacemaker is atrial myocyte --> p wave morphology different bc depolarization is from abnormal location (not SA node) - focal or reentrant - AV node block (BB, CCBs) until ablation

Answer 86

Premature ventricular complexes (PVCs) = ventricular premature beats (VPB) 1. Mechanism - ectopic ventricular focus fires action potential due to abnormal automaticity, delayed afterdepolarization, reentry 2. EKG - widened QRS complex (ectopic beat travels slowly through cell to cells and not fast His-Purkinje) 3. Etiology - can occur in healthy and diseased hearts - ↑ SNS, cardiomyopathy, structural disease - caffeine, hypoxia 4. Clinical presentation - often asymptomatic and benign - palpitations 5. Treatment - beta blockers if symptomatic

Answer 87

Ventricular Tachycardia incl monomorphic, polymorphic, and torsades 1. Mechanism - delayed afterpolarizations (pts w/out structural heart disease), reentry (pts post MI) 2. EKG - 3+ consecutive premature ventricular complexes (wide QRS) at 100+ bpm - monomorphic - due to reentry --> QRS same and regular rate - polymorphic - multiple ectopic focuses or changing reentry circuits--> QRS complexes and rate change - torsades de pointes - type of polymorphic VT --> due to early afterdepolarizations in patients with prolonged QT (longer action potential) 3. Etiology - scar from MI, cardiomyopathy, electrolyte abnormality (hyperkalemia), idiopathic 4. Clinical presentation - palpitations, dizziness, syncope - sustained (30+ sec) 5. Treatment: A. Pts post MI - lidocaine, procainamide, cardioversion --> then ICD, amiodarone, K+ channel block B. Pts w/out structural disease - defibrillation --> then verapamil, BBs, ablation

Answer 88

Ventricular Fibrillation 1. Mechanism - multiple reentry circuits --> no coordinated contractions --> no cardiac output 2. EKG - chaotic irregular appearance, no QRS complexes 3. Etiology - initiated by Vtach; due to Long QT, Brugada, prior MI, idiopathic 4. Clinical presentation - cardiac arrest 5. Treatment - defibrillation --> then ICD (defibrillator) if pt survives and amiodarone to block recurrence

Answer 89

1. Long QT syndrome - *most common* ion channel mutation (K+ or Na+) --> long action potential duration - precipitated by hypokalemia, swimming, auditory --> syncope, sudden cardiac death - due to LQT1, 2, 3 genes 2. Brugada - loss of function of Na+ channel --> peculiar ECG pattern --> predisposes to vfib and sudden cardiac death; M>>F 3. Familial catecholaminergic polymorphic VT - Ca2+ handling mutation eg Ryanidine receptor RyR2 --> delayed afterdepolarizations --> stress-induced SCD in patients with normal ECGs, no structural heart disease 4. Arrhythmogenic Right Ventricular Cardiomyopathy - mutations in desmosomes --> gap junctions affected -- > replacement of RV with fibrous tissue

Answer 90

Class 1A Drugs e.g. procainamide, quinidine, disopyramide 1. MOA - moderate blockade of Na+ channel --> intermediate use dependence and slowing of Phase 0 upstroke - also block K+ channels --> prolong action potential duration --> prolong refractory period (QT prolongation) 2. Clinical uses - both atrial fibrillation and ventricular arrhythmias, esp post MI - procainamide treats wolff-parkinson-white syndrome 3. Adverse effects - - QT prolongation --> can precipitate early afterdepolarizations --> ↑ risk of torsades, syncope - quinidine- cinchonism (tinnitus, headache, dizziness), thrombocytopenia - procainamide - lupus-like syndrome - disopyramide - exacerbates HF; contraindicated in urinary retention

Answer 91

Class 1B Drugs e.g. lidocaine, tocainide, mexiletine 1. MOA: low binding affinity for open or inactivated Na+ channels with fast kinetics--> low use-dependence - shorten phases 2 and 3 --> shorten action potential duration and refractory period 2. Clinical uses - treat ischemia-induced ventricular arrhythmias - termination of vtach, prevention of vfib - digitalis-induced arrhythmias - 1b best post-MI (also amiodarone) 3. Adverse effects - one of least cardiotoxic --> neurologic incl paresthesia, tremor, convulsions - extensive first pass metabolism (IV admin)

Answer 92

Class 1C Drugs e.g. flecainide, morizine, propafenone 1. MOA - strong inhibition of Na+ channels in Phase 0 bc of slow kinetics --> strong use-dependene and marked decrease in upstroke of Phase 0 - minimal effect on action potential duration 2. Clinical uses - treat both atrial and ventricular arrhthmias - SVTs including afib + aflutter - can restore/maintain sinus rhythms 3. Adverse effects - exacerbation of arrhythmias eg atrial flutter, vtach; can cause heart failure - 1C contraindicated in structural or ischemic heart disease

Answer 93

Class 2 Drugs are Beta blockers e.g. propranolol, esmolol 1. MOA - affects SA and AV nodes (pacemaker potential) - block SNS --> lower cAMP --> reduction of Na+ and Ca2+ currents --> suppresses abnormal pacemakers - AV node particularly sensitive --> ↓ phase 4 slope --> ↓ rate of firing --> ↓ automaticity and increased PR interval - prolonged repolarization --> ↓ reentry 2. Clinical uses - suppress PVCs, terminate paroxysmal SVTs (eg AVNRT, AVRT) - esmolol - Beta1 selective with short t1/2 (9 min), used after cardiac surgery for rate control --> controls ventricular response in afib or atrial flutter - propranolol - post MI as death prophylaxis, vfib 3. Adverse effects - contraindicated in Wolff-Parkinson-White (wpw) - SNS suppression --> hypotension, bradycardia, AV block - exacerbation of COPD and asthma due to bronchoconstriction * ivabradine also decreases pacemaker activity --> blocks If in SA node --> reduces HR

Answer 94

Class 3 Drugs e.g. sotalol, ibutilide, finde, amiodarone 1. MOA - affects myocytes --> block K+ potassium channels --> prolong action potential duration --> ↑ effective refractory period --> ↑ QT interval - little effect on phase 0 or conduction velocity - in addition amiodarone decreases phase 4 slope of pacemaker potential --> decreased automaticity of pacemakers 2. Clinical uses: A. Sotalol - beta blocker and K+ channel blocker --> treats ventricular arrhythmias incl vtach B. Ibutilide - conversion of acute atrial flutter and fib to normal sinus rhythm C. Amiodarone *most effective of all* can block Na, Ca, K, and beta receptors (Class 1-4 activity) --> treats afib, atach, vtach, vflutter 3. Adverse effects - QT prolongation - reverse use dependent (all except amiodarone)- action potential prolonged least at fast HRs and most at slow rates (precipitation of EADs --> torsades risk) - amiodarone: neurologic effects, gray corneal microdeposits, pulmonary fibrosis and restrictive lung disease, hyper/hypothyroidism, gray-blue skin discoloration and photodermatitis, heart failure, hypersensitivity hepatitis (check LFTs)

Answer 95

Class 4 Drugs - Calcium Channel blockers e.g. verapamil, diltiazem 1. MOA - affects SA and AV nodes, esp AV node - block activated and inactivated (but not resting) L-type Ca2+ channels --> prolonged phase 4 --> ↓ automaticity --> ↓ sinus rate - decrease slope of phase 0 --> ↓ conduction velocity and ↑ refractory periods --> ↓ reentry and ↑ PR interval 2. Clinical uses: - prevent paroxysmal supraventricular arrhythmias - (AVNRT, AVRT) - rate control of rapid ventricular response in afib and atrial flutter 3. Adverse effects - peripheral vasodilation; AV block, hypotension, constipation - contraindicated in Wolff-Parkinson-White (wpw) bc conduction in accessory pathway is NOT slowed --> worsens reentry, beta blockers

Answer 96

1. Adenosine- purine nucleoside that binds to A1 receptor --> activates rectifier K+ current and inhibits L-type CA2+ current --> K+ leaves and Ca2+ cannot enter --> cell is hyperpolarized - inhibits AV nodal conduction --> ↑ AV nodal refractory period --> conversion of SVTs to sinus rhythm - t1/2 = 15 sec - adenosine receptor antagonists - theophylline and caffeine - side effects: headache, hypotension, flushing, sense of impending doom 2. Potassium - both hypo and hyperkalemia can cause arrhythmias - hypo - U wave after T wave - hyper - peaked T wave with shortened QT interval 2. Magnesium - ER pts given IV Mg, even if serum levels normal; used to treat torsades 3. Digoxin (Digitalis)- positive inotrope with direct vagus PSNS stimulation --> rate control in afib or atrial flutter in patients having heart failure A. Digoxin Immune Fab - adjunctive to temporary cardiac pacemaker; treatment of digoxin toxicity

Answer 97

1. Congenital heart disease - anatomic (not genetic) abnormality in cardiocirculatory structure/function present at birth - most common type of congenital effect 2. Congenital aortic stenosis - tight aortic valve --> LV concentric hypertrophy (muscle becomes thicker) + dilated ascending aorta - M>>F, symptoms incl poor feeding, tachycardia, tachypnea - harsh crescendo-decrescendo murmur loudest at base 3. Pulmonic stenosis - causes increased RV pressure and hypertrophy - symptoms incl dyspnea, exercise intolerance, right sided heart failure (Edema) - harsh crescendo-decrescendo murmur at L upper sternal border - can hear a pulmonic valve click - ONLY R sided sound that decreases with inspiration (more blood coming in on inspiration stretches the valve and makes click less pronounced)

Answer 98

1. Anomalous coronaries - coronary artery comes from somewhere else (should be Left main from Left cusp and Right from Right cusp) - Left main coronary artery from right cusp AND courses between great vessels (pulmonary artery and aorta) --> can cause sudden death (vessels get bigger during exercise and can constrict LCA) --> need bypass surgery - everything else does not require treatment 2. Atrioventricular septal defect - inadequate fusion of the superior and inferior endocardial cushions --> large hole between the atria and ventricles - presentation is before age 1 w frequent respiratory infections, poor weight gain, heart failure

Answer 99

Mitral stenosis - diastolic murmur 1. Most common cause is chronic rheumatic fever (fishmouth mitral stenosis) --> occurs after untreated Group A strep infection 2. Pathophys: inflammation --> leaflet thickening and calcification --> chordal fusion - LA>>LV pressure gradient --> backs up into pulmonary venous system --> pulmonary edema --> backs up into pulmonary arterial system --> pulmonary HTN - LA enlargement --> LA dilatation --> stretches atrial conduction fibers --> afib --> thrombus --> stroke 3. Presentation: dyspnea with exercise at first, at rest when MS is more severe - increasing HR (Exercise, stress, pregnancy, infection) --> reduces filling time --> worsens MS --> reduces CO 4. Examination: low-pitched middiastolic rumble (decrescendo) murmur - opening snap post S2 (tensing of stenotic leaflets) - shorter interval bw S2 and OS --> more severe - EKG: LA enlargement (p wave abnormality on V1) + RVH

Answer 100

Mitral regurgitation - systolic murmur 1. Etiology: A. Acute - damage - e.g. papillary rupture post-MI, chordae rupture with infective endocarditis Bi. Primary chronic - mitral valve prolapse Bii. Secondary chronic / Functional - LV dilatation 2. Pathophys: portion of LV stroke volume ejected back into LA --> ↑ LA volume and pressure + ↓ CO + ↑ LV volume A. Acute: ↓ SV (no time to compensate) B. Chronic: compensation through ↑ LA dilatation, LV eccentric hypertrophy, ↑ LV stroke volume --> EF maintained - decompensated phase: volume overload --> ↓ SV --> ↓ CO --> heart failure 3. Presentation A. Acute: pulmonary edema and congestion B. Chronic: dyspnea, orthopnea, fatigue, right HF 4. Examination A. Acute: decrescendo, not holosystolic bc LV and LA equilibriate B. Chronic: holosystolic "blowing" murmur, heard best at apex and radiates to axilla; can develop S3 (LV volume overload) - intensifies with ↑SVR (eg clenching fists) - EKG: LA enlargement (p wave abnormality on V1) + LVH

Answer 101

Mitral valve prolapse - systolic murmur 1. Etiology: familial (AD) or non (connective tissue disease) 2. Pathophysiology: billowing of mitral leaflets into LA during ventricular systole - leaflets enlarged and myxomatous CT (instead of elastin/collagen) - can be w/out mitral regurg (but common cause of MR) 3. Presentation: asymptomatic or chest pain 4. Examination: mid-systolic click (tensing of chordae) and then late crescendo systolic murmur heard best at apex - ↑ Venous return (Eg squatting from standing position) --> decreases murmur --> click and murmur occur later after S1 - vice versa (murmur increases upon valsalva/standing)

Answer 102

Aortic stenosis 1. Etiology - calcification of aortic valve (adults - normal aging; young adults - bicuspid valve) 2. Pathophysiology - blood flow impeded --> ↑ LV pressure needed --> LV concentric hypertrophy --> ↓ LV compliance --> LA hypertrophy to facilitate filling 3. Presentation: triad = SAD (syncope, angina, dyspnea) - Angina - 02 demand (↑ muscle mass and wall stress) >> 02 supply - Syncope during exertion - vasodilation + ventricle cannot ↑ CO due to fixed stenotic valve --> decreased cerebral perfusion pressure - Congestive heart failure - high afterload --> LV dysfunction --> ↑ pressure of LV, then LA, then pulmonary venous system --> HF, pulmonary congestion 4. Examination - crescendo-decrescendo systolic ejection murmur with ejection click that radiates to carotids - weakened and delayed carotid pulse "pulsus parvus et tardus" - can develop S4 (stiff LV), or paradoxical splitting (late A2 component of S2 in expiration)

Answer 103

Aortic regurgitation = Aortic insufficiency - diastolic murmur 1. Etiology - aortic root dilatation - 1/2 of all cases - bicuspid aortic valve - postinflammatory (endocarditis, RF) 2. Pathophysiology - blood regurgitates from aorta into LV --> compensate with ↑ SV --> ↑ systemic systolic pressure Acute AR: ↑ pressure of LV, then LA, then pulmonary venous system --> dyspnea and pulmonary edema Chronic AR: volume overload --> LV compensates with eccentric hypertrophy --> reduces aortic (therefore systemic) diastolic pressure --> widened pulse pressure 3. Presentation - strong bounding pulses, head bobbing - chronic AR: water-hammer pulses, capillary pulsations on nail beds 4. Examination - blowing decrescendo murmur at left sternal border - (severe AR) Austin Flint murmur - mid-diastolic rumbling heard at cardiac apex (due to mitral flow)

Answer 104

R side heart murmurs increase with inspiration and decrease with expiration (except for pulmonic valve click seen in pulmonic stenosis) 1. Tricuspid stenosis - v rare, sequelae of rheumatic fever - opening snap and diastolic rumbling murmur; intensifies on inspiration - increased a wave on JVP 2. Tricuspid regurgitation - functional (due to RV enlargement); sequelae of rheumatic valvulitis (due to RF) - holosystolic murmur that increases with inspiration, heard best at lower left sternal border - pulsatile liver - increased v wave on JVP 3. Pulmonic stenosis - congenital, systolic crescendo-decrescendo murmur heard best at 2nd L intercostal space with pulmonic valve click 4. Pulmonic regurgitation - due to severe pulmonary HTN, high-pitched decrescendo murmur - sounds the same as aortic regurgitation

Answer 105

1. Shock - physiological state with insufficient 02 delivery to the tissues (hypoperfusion) --> cellular energy deficit (low ATP) - people can be hypoperfused but maintain normal BP through compensatory mechanisms BP = CO x SVR 2. CO = SV * HR Low CO shock due to problems with SV --> determined by myocardial contractility, preload, and afterload A. Myocardial contractility --> cardiogenic shock B. Preload i. decrease in volume --> hypovolemic shock ii. obstruction in filling --> Obstructive shock C. Afterload --> PE *Compensatory mechanism for low CO shock = tachycardia 3. Distributive shock due to problems with systemic vascular resistance A. septic shock B. neurogenic shock C. anaphylactic shock

Answer 106

Shock --> hypotension --> compensation 1. Compensatory responses *irreversible shock if they fail* A. Baroreceptor response - ↓ arterial pressure --> ↓ baroreceptor firing (aortic arch via CN X; carotid sinus via CN IX) --> synapse on nucleus solitarius (medulla) --> removes tonic inhibition of SNS --> activates SNS, inhibits PSNS --> ↑ vasoconstriction + ↑ HR and BP B. RAAS (Renin-Angiotensin System) - renin release --> angiotensin II activation --> vasoconstriction and Na+ reabsorption (aldosterone)--> net water retention --> ↑ volume 2. Compensatory response: Low CO --> divert blood flow from nonessential vascular beds e.g. skin, muscle, GI tract to heart and brain --> patient appears pale/gray, skin is cool/clammy; mental status changes (agitation, confusion) - long capillary refill time + cold skin temperature + Livedo reticularis (mottled skin pattern) --> strong likelihood ratio of low CO/shock - metabolic acidosis --> Tachypnea (compensatory respiratory alkalosis)

Answer 107

1. Cardiogenic shock A. Etiology - most common cause of pump failure is MI, but also myocarditis, arrhythmia, and valvular heart disease - leading cause of death for patients with MI, esp STEMI B. Pathophys: ischemia --> ↓ myocardial contractility --> ↓ CO --> ↓ BP --> ↓ coronary perfusion --> exacerbates ischemia --> worsens myocardial dysfunction --> death C. Clinical findings i. High filling pressures --> congestion --> elevation of JVP, pulmonary rales, wheezing, S3 ii. High PVR --> hypoperfusion --> mental status changes, cool/clammy skin, pale/gray, oliguria (low urine output) iii. Low CO --> low mean arterial pressure (BP) --> tachycardia, faint pulses, PMI displaced laterally

Answer 108

2. Hypovolemic shock A. Etiology - i. blood cell loss - hemorrhage due to trauma, post-op ii. plasma volume loss - GI (cholera), burn B. Pathophys: intravascular volume depletion --> ↓ preload --> ↓ CO --> ↓ BP C. Clinical finding - first sign is narrow pulse pressure due to ↑ peripheral vasoconstriction --> ↑ diastolic BP - once 2+ L (40% circulating vol) is lost --> ↑ HR and ↓ systolic and diastolic BPs *however, cold + clammy skin is seen at 1L volume lost when HR and BP are still normal i. Low filling pressure (bc of volume loss) --> clear lungs, normal heart sounds ii. High PVR --> hypoperfusion --> mental status changes, cool/clammy skin, pale/gray, iii. Low CO --> low mean arterial pressure (BP) --> tachycardia, faint pulses, PMI displaced laterally

Answer 109

3. Obstructive shock A. Etiology i. Pericardial tamponade - fluid accumulates within pericardium (which normally has a little fluid to accommodate heart beating) ii. Tension pneumothorax - injury to lung --> air enters chest bw visceral and parietal pleura --> mediastinum shifts and lung collapses B. Pathophys: impaired venous return (volume is normal but cannot get into heart) --> ↓ preload --> ↓ CO --> ↓ BP C. Clinical findings i. Pericardial tamponade: Beck's triad of hypotension, muffled heart sounds, and JV distension - also pulsus paradoxus --> big inspiratory drop in BP; normally small drop in bp but with ↑ pressure --> ↓ compliance in wall of heart --> interventricular septum shifts L --> impedes filling of the LV --> ↓ CO --> big BP drop - also electrical alternans - morphology of QRS changes beat to beat on same lead --> heart is moving in the chest - high filling pressure (like cardiogenic shock) but lungs clear ii. Tension pneumothorax - absent breath sounds, JVD, tracheal/mediastinum deviation to contralateral side

Answer 110

Distributive shock - due to decreased systemic vascular resistance SVR; compensatory response is ↑ CO 1. Septic shock - ↓ in peripheral vascular resistance A. Etiology: caused by Gram (+) organisms --> endotoxins trigger release of inflammatory mediators --> problems B. Pathophys: endothelial cell injury --> ↑ permeability of cell wall --> fluid can escape into the vasculature - peripheral vasodilatation (NO) --> ↑ CO --> but impaired oxygen utilization C. Clinical findings: fever, tachypnea i. low filling pressure --> flat neck veins, tachycardia ii. low PVR --> warm, dry skin; pink iii. high CO --> but decreased mean arterial pressure bc of relative volume depletion 2. Neurogenic shock - loss of SNS tone due to spinal cord injury 3. Anaphylactic shock - due to release of vasodilators incl histamine, leukotriene C4, prostaglandin D2 - treat with epinephrine

Answer 111

1. Stage A: high risk for HF without structural disease or symptoms - HTN, diabetes, obesity, metabolic syndrome, family history Stage B: structural heart disease w/out devlpt of HF - prior MI - depressed LV EF, or LVH - valvular heart disease Stage C: structural heart disease with current or prior heart failure symptoms - diuretics, then ACEI or ARB or BB - digoxin if systolic dysfunction with afib or S3 Stage D: End-stage HF with refractory symptoms - treatments are beyond BBs, CCBs --> transplant, hospice - positive inotropes for palliation

Answer 112

1. Frank-Starling mechanism - ↓ contractility --> ↓ SV --> ↑ LV EDV --> ↑ contractility 2. Neuro-hormonal activation - body activates systems to maintain perfusion to vital organs (brain, heart, lungs); acutely beneficial but chronic bad (congestion, cardiac fibrosis) - SNS - ↑ HR, contractility, peripheral vasoconstriction - RAAS - ↓ CO --> ↓ renal perfusion --> ↑ renin --> Ang I (via angiotensinogen) --> Ang II (via ACE) --> ↑ SVR, ↑ intravascular volume - ADH (posterior pituitary) - mediated by arterial baroreceptor and Ang II --> ↑ water retention in nephron 3. Natriuretic peptides - ANP and BNP - produced in response to stretch --> ↑ Na+ and H20 excretion, promotes vasodilation, and inhibits renin - counteracts RAAS - ↑ BNP levels indicate HF 4. Ventricular hypertrophy and remodeling - ↑ wall thickness --> ↓ wall stress as per Laplace's law where stress = P x R / 2h(thickness)

Answer 113

1. Symptoms A. LHF: from ischemic HD, HTN, myocardial diseases i. Pulmonary congestion (due to ↑ LV EDV) --> SOB, orthopnea, leg edema, ↑ JVD, nocturnal cough ii. Low CO --> fatigue, confusion, low urine output --> activates RAAS to increase volume B. RHF: most commonly due to LHF; abdominal discomfort/distension, early satiety, weight gain - can get isolated RHF from primary pulmonary HTN --> R sided hypertrophy and dilation (cor pulmonale) 2. Physical findings - can present the same way! A. LHF: rales, wheezing, tachypnea, tachycardia - S3/S4, MR murmur - weak pulse, diffuse apical impulse - cachexia (wasting) - pulmonary edema R. RHF: RV heave - R sided S3/S4 - ascites - hepatic enlargement, portal hypertension, splenomegaly - peripheral pitting edema

Answer 114

Diuretics 1. Loop diuretics (furosemide) - block NKCC2 in thick ascending limb; reduce ECF fluid volume and LV filling pressure (preload) --> reduce congestive symptoms - hypokalemia - monitor K+ levels! - hypomagnesia 2. Thiazides - block NCC in distal convoluted tubule; reduce BP --> reduce afterload and increase Na+ urinary excretion --> Reduce extracellular fluid volume - hypokalemia, hypomagnesia, and hyponatremia 3. K+ sparing diuretics - ENaC blockers (amiloride) and aldosterone antagonists (spironolactone) - spironolactone and eplerenone prevents cardiac fibrosis/remodeling induced by aldosterone + reduces mortality in heart failure

Answer 115

Vasodilators 1. ACE inhibitors (enalopril, lisonopril)- block conversion of Ang I to Ang II --> ↓ vasoconstriction/ peripheral resistance --> ↓ afterload - ↓ aldosterone secretion --> ↓ ECF --> ↓ preload - action enhanced by diuretics / Na+ restriction - adverse effects: cough, angioneurotic edema (due to decrease in degradation of bradykinin) 2. ARBs (sartans) - block Angiotensin II receptors - same effects as ACEIs but do not cause cough or angioedema AND do not affect bradykinin - not as effective in reducing mortality, so not first line 3. BiDil (hydralazine + isosorbide dinitrate) - for black patients 4. Aliskeren - renin inhibitor; same side effects as ACEIs 5. Enestro - inhibits neprilysin (breaks down natruiretics) and contains valsartan; in clinical trials, could replace ACEIs 6. Nitroprusside - given IV for acte HF (dilates to ↑ CO)

Answer 116

Beta blockers - v low dose BB to blunt the high levels of compensatory SNS effects (decrease arrhythmias, reduce remodeling) - one of the earliest drugs you begin to introduce, sometimes before ACEI - all drugs have similar efficacies - bisoprolol, carvedilol, metoprolol succinate - adverse effects: bradycardia, hypotension, fatigue, can exacerbate acute decompensated heart failure

Answer 117

Inotropes 1. Cardiac glycosides (digoxin, ouabain) - block Na/K pump --> ↑ [Ca+] in heart --> ↑ CO - digitalis works well --> ↑ renal function (↓ preload), ↑ CO, ↓ heart size, ↓ EDV, ↓ venous pressure, ↓ SNS (↓ HR) - digoxin used, ouabin is not (low lipid solubility) - adverse effects: digitalis antagonized by K+ (has low TI) --> Arrhythmias; AV block, visual disturbances - enhances vagal tone --> slows conduction velocity and increases refraction period 2. Beta1 agonists (dobutamine)- stimulates Beta1, beta2, and alpha receptors --> ↑ contractility but does not increase peripheral resistance (beta2 balances alpha) --> BP not affected - norepi for warm septic shock - epi for cardiac arrest 3. Ca2+ sensitizers - enhance ability of myosin to contract 4. Bypyridines (milrinone, inamrinone) - PDE3 inhibitors --> prevent breakdown of cAMP to AMP --> increase contractility, HR, and also peripheral venous dilator - safe for short-term, but can cause arrhythmias long-term

Answer 118

2x2: Congestion at rest (orthopnea i.e. SOB on lying down, JVD, edema, ascites) x Low perfusion at rest (sleepy, hypotension with ACEI, narrow pulse pressure, low Na+) 1. Warm and dry - No congestion x Normal perfusion - stable chronic HF - what we want patients to be - symptoms are from something else 2. Warm and wet - Congestion x Normal perfusion *majority of patients* - diurese (furosemide, then thiazide) - then add vasodilators to ↓ afterload and ↑ perfusion (esp with pulmonary edema or severe HTN) 3. Cold and wet - Congestion x Low perfusion - warm up first (↑ perfusion) with inotropes (dobutomine, milrinone) - then diuretics 4. Cold and dry - No congestion x Low perfusion (End stage) - vasodilators if BP is okay; inotropes if BP is low

Answer 119

I. Dilated cardiomyopathy - dilated heart 1. Etiology - many cases idiopathic or familial (AD), others include: A. viral myocarditis eg coxsackie group B, parvovirus B19, adenovirus - young, previously healthy - immune-mediated myocyte loss and fibrosis - self-limited, supportive tx but 1/3 progress to HF B. Toxins - chronic alcohol use (5+ years) *reversible* - oxidative stress and apoptosis - chemo agents - due to free radicals and apoptosis C. Peripartum - multifactorial incl prolactin and oxidative stress, 50% recovery rate 2. Pathophysiology - ventricular dilatation with decreased contractile function and minimal hypertrophy - myocyte degeneration and volume overload override compensation (↑ SV and SNS) --> ↓ contractility --> ↓ CO and ↑ ventricular filling pressures 3. Clinical findings - CHF symptoms eg systemic congestion (JVD, edema) and pulmonary congestion (dyspnea, rales) - S3 (poor systolic function) - leftward apical impulse displacement - mitral regurgitation

Answer 120

II. Hypertrophic cardiomyopathy 1. Etiology - familial - AD with variable penetration; mutations in sarcomere genes 2. Pathophysiology - LVH not caused by chronic pressure overload (eg HTN, aortic stenosis) - most common is asymmetric septal hypertrophy - normal LV systolic function but muscle is stiff (myocyte disarray and fibrosis)--> impaired ventricular compliance + high diastolic pressures --> impaired filling 3. Clinical findings - usually asymptomatic; most common etiology behind sudden death of young athletes --> prone to arrhythmias (Vfib/VT) due to myocyte disarray - SOB from increased diastolic LV pressure - S4 gallop due to contraction into stiff LV

Answer 121

II. Hypertrophic cardiomyopathy 4. 1/4 patients have LV outflow tract obstruction by mitral leaflet --> ↑ LV pressure --> ↑ wall stress + ↑ 02 consumption --> angina - worsened with ↓ preload (ventricles come together), ↓ afterload and ↑ contractility (heart contracts more vigorously with less resistance --> closer the walls come together) - myocytes in disarray 5. Distinguishing HCM (systolic diamond-shape) murmur from aortic stenosis: - does not radiate to carotids - accompanied by mitral regurgitation MR (blowing holosystolic murmur) - valsalva - ↑ HCM (↓ LV size) but ↓ aortic stenosis (↓ blood flow across aorta) - squatting - ↓ HCM (↑ preload ↑ LV size) but ↑ aortic stenosis (↑ stroke volume) - can differentiate by administering amyl nitrate (↓ preload and afterload --> makes HCM louder but AS softer) 6. Treatment: - beta blockers "-olols" (negative inotrope) --> need to decrease HR so heart can fill - avoid diuretics (causes dehydration --> ↓ preload), vasodilators (↓ afterload, also with alcohol and hot tub)

Answer 122

III. Restrictive cardiomyopathy - abnormally rigid (but not thickened) ventricles --> diastolic dysfunction 1. Etiology - fibrosis/scarring of endomyocardium - infiltration of myocardium eg amyloidosis (deposition of misfolded insoluble protein) - primary (multiple myeloma), secondary (inflammatory condition eg RA), familial, or senile; stain with congo red 2. Pathophysiology - fibrosis/infiltration --> ↓ ventricle compliance --> ↑ diastolic pressure --> A. ↑ atrial filling pressure --> ↑ systemic and pulmonary venous pressure B. ↓ ventricle cavity size --> ↓ filling --> ↓ SV --> ↓ CO - diastolic HF with preserved EF 3. Clinical findings - biatrial enlargement - R HF >> L HF --> JVD (↑ with inspiration = Kussmaul sign), ascites, peripheral edema, hepatic congestion - ↓ CO --> weakness, fatigue - low voltage EKG

Answer 123

IV. Arrhythmogenic cardiomyopathy - affects RV as opposed to I-III (LV) 1. Etiology - genetic - mutations in desmosomes; progressive 2. Pathophysiology - replacement of RV myocardium with fatty and fibrotic tissue --> contractile dysfunction + ventricular arrhythmias 3. Clinical findings - another cause of SCD among young athletes - use cardiac MRI V. Unclassified cardiomyopathy A. LV non-compaction - genetic; arrested devlpt of myocardial compaction during fetal growth --> thick myocardium with trabeculae and recesses --> contractile dysfunction + HF + thromboemboli + Ventricular arrhythmias B. Stress-induced cardiomyopathy - "broken heart syndrome" precipitated by emotional/physical stress - transient apical ballooning --> chest pain, T wave inversion, troponin - aka takotsubo (pot japanese catch octupus in)

Answer 124

1. Vasculitis - immune-mediated, inflammatory destruction of blood vessels; v rare - etiology unknown; classified by the pathological findings and types of arteries affected - can present with: A. T cell response with granuloma formation B. Immune complex deposition C. Anti-Neutrophil Cytoplasmic Antibodies (ANCAs) esp diseases that affect capillaries *marker, not part of pathology* 2A. Constitutional symptoms - fever, rash, myalgia, arthralgia, malaise, weight loss B. Vascular injury symptoms - depend on vascular bed involved - ischemia/infarction of affected organs --> thrombosis, fibrosis

Answer 125

Giant cell arteritis - large vessel disorder; most common vasculitis in pts 50+, esp Europeans 1. Pathology - affects L and M size extracranial branches of external carotid carotid artery e.g. vertebral, ophthalmic, temporal - all layers of artery - etiology unknown (infectious?) --> initiates CD4+ T-cell immune response --> monocytes coalesce into giant cells --> cytokine response 2. Histology - granuloma formation in the media (collection of multinucleated giant cells ie macrophages) --> internal elastic lamina fragmentation --> intimal thickening/fibrosis - mononuclear cell infiltrates (T cells, that then draw in monocytes) - skip lesions (not continuous) - need to take large piece when biopsying 3. Clinical - age 50+ with headache, jaw claudication (pain bc of decreased blood flow), visual symptoms - scalp tenderness, temporal artery tenderness - Lab: elevated erythrocyte sedimentation rate (indicates inflammatory process) - optic nerve ischemia --> BLINDNESS (but v responsive to steroids ie prednisone)

Answer 126

Takayasu's Arteritis - large vessel disorder; affects young women 25-35 yo, esp Asian 1. Pathology - granulomatous vasculitis of aortic arch; pathologically indistinguishable from Giant cell arteritis --> differs in arteries and people affected - transmural (across entire wall) fibrous thickening of aortic arch --> narrowing of the major branches ESP subclavian 2. Histology *same as giant cell arteritis* - granuloma formation in the media (collection of multinucleated giant cells ie macrophages) --> internal elastic lamina fragmentation --> intimal thickening/fibrosis - -> thickening of vessel wall --> occlusion 3. Clinical - systemic - fatigue, malaise, weight loss - pulseless disease - asymmetric BP (upper vs lower extremities, R vs L, carotid vs brachial), bruits over and diminished pulses below subclavian - pain with use of upper extremities - renal HTN common

Answer 127

Polyarteritis Nodosa - medium artery disorder; affects adults 45-65 - does NOT affect arterioles, capillaries, veins --> NO pulmonary involvement, NO glomerulonephritis (RBC or casts) 1. Pathology - necrotizing arteritis of medium/muscular arteries esp at branch points of vessels - disruption of internal and external elastic lamina --> weakened arterial wall - large arteries feeding into kidney most commonly affected * linked to Hepatitis B Virus 2. Histology - lesions at different stages - acute - transmural inflammation of arterial wall with fibrinoid necrosis - healing stage - fibrosis/thickening --> nodule forms --> narrowing of vasculature --> impaired perfusion and ischemic atrophy - neutrophils are big component (not T cells) 3. Clinical - systemic inflammation - fever, myalgias, weight loss - mononeuritis multiplex - asymmetric neurologic deficit (vasa nervosum - small nerve motor root ischemia) - renal - HTN due to renal artery stenosis - skin lesions - palpable purpura (damage to small arteries in dermis --> neutrophilic infiltration of small vessels --> extravasation of RBCs) - treat with corticosteroid + cyclophosphamide

Answer 128

Kwasaki disease - medium artery disorder; patients under the age of 4 --> #1 cause of acquired heart disease in children 1. Pathology - unknown - neutrophil influx --> inflammatory response --> transmural intimal destruction --> aneurysms in coronary arteries - or can remodel --> thrombotic occlusion --> myocardial ischemia 2. Histology - affects all arterial layers 3. Clinical - CRASH and burn Conjunctival erythema (red, irritated eyes) Rash on trunk and genitals Adenopathy - swollen neck lymph nodes Strawberry tongue + cracked lips Hand-food changes - Desequamation (peeling) of palms/soles of feet + burn - unremitting fever 5+ days in ALL patients, unresponsive to tylenol or NSAIDs treat with immune globulin (IVIG) + aspirin

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Buerger disease - aka thromboanginitis obliterans; heavy smokers, males under 40 yo 1. Pathology - intermittent claudication associated with smoking 2. Histology - segmental necrotizing vasculitis 3. Clinical - gangrene --> autoamputation of digits

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1. Peripheral arterial occlusive disease (PAD) - flow-limiting stenotic lesion in artery that provides blood supply to limbs A. commonly caused by atherosclerosis - during exercise, blood flow increases 10x due to CO increase and compensatory vasodilation --> distal pressure even more reduced --> reduced perfusion to muscle groups distal to atherosclerotic lesion B. pathology identical to coronary artery disease (risk factors: hyperlipidemia, HTN, smoking, DMII, FH) - 1/2 patients with PAD have CAD 2. Clinical presentation - most common manifestation is intermittent claudication (esp in lower extremities - angina in legs) --> pain with exertion due to reduced blood flow, ceases with standing in place and reproducible within same muscle groups (calf, thigh, etc) - quantify in terms of street blocks walked - location of pain determined by anatomical location of lesion e.g. in superficial femoral artery --> calf pain; aortoiliac area --> thigh and buttock pain, male ED A. similar to neurogenic claudication caused by spinal stenosis --> except latter has discomfort on standing and pain is relieved by sitting down and flexing back 3. Clinical findings - absent/diminished pulses eg no dorsalis pedis - bilateral calf atrophy, shiny skin, hair loss below knees, thickened toe nails - dependent rubor (peripheral arteries don't constrict as they should bc ischemic --> hyperemia) - ankle brachial index ABI- measure systolic bp in arms vs ankles --> normally, ankle pressure should be higher (bc of gravity) --> normally ABI 1+, decreases with arterial disease - intervene on rest pain or non-healing wounds

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Acute limb ischemia - limb-threatening event 1. Pathogenesis: most commonly due to emboli of cardiac origin --> lodge at artery bifurcations eg femoral artery, iliac, aorta, popliteal ``` 2. 5 P's Pain - severe, acute onset Pulseless Paresthesias - nerves most quickly affected by ischemia Poikylothermia - cold extremities Paralysis - irrecoverable injury ``` Surgical emergency!

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Infective endocarditis 1. Pathology - microbial infection of heart endocardium (innermost surface + underlying structures) incl heart valves, mural endocardium (walls of the heart chambers) - damaged endothelium --> platelet adhesion --> formation of vegetation (cluster of platelets, fibrin, cellular debris) --> bacteremia (infection eg dental procedure, contaminated needle) --> allows bacterial attachment and proliferation 2. Risk factors: - age 60+, M - poor dentition or dental infections --> organism is Strep viridans - IV drug use (tricuspid) --> organism is Staph aureus - structural heart disease (valvular, congenital) - prosthetic valve or intravascular devices (catheters, pacemakers) --> organisms are Staph or HACEK - colon cancer --> S. bovis - used to be associated with rheumatic fever (post strep pharyngitis infection) in developing countries

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3. Clinical presentation A. acute - systemic toxicity due to virulent (Staph aureus, strep pyogenes) attacking normal heart --> destruction of native valve + fatal - acute onset fever, chills, CHF; hx eg prosthetic, IV drug use B. subacute - indolent due to common (Strep viridans, enterococci) affecting abnormal heart e.g. structural or congenital heart disease - fatigue, weight loss, low-grade fever 4. Clinical diagnosis - new regurgitant murmur + recurrent/unremitting fever = endocarditis ``` 5. Physical findings - FROM JANE Fever Roth spots Osler nodes (painful, on fingertips) Murmur Janeway lesions (painless, on palm/sole) Anemia Nailbed "splinter" hemorrhage Emboli (common with IV drug use) - can also have neurologic complications --> ischemic and hemorrhage stroke ```

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Myocarditis 1. Pathology - viral infection of myocardial cells --> inflammatory infiltrate (of lymphocytes) --> cytokine release --> necrosis and degeneration to adjacent myocytes --> dilated cardiomyopathy 2. Clinical presentation - varied presentation but seen in otherwise healthy, young patients --> heart failure and ventricular arrhythmias --> cardiogenic shock - need to exclude CAD, non-inflammatory diseases 3. Etiology A. Noninfectious - cardiotoxic chemo agents B. Infectious - most common = cardiotropic viruses (parvovirus, HHV6, Coxsackie A and B virus) - also Borrelia, Trypanosoma cruzi (chagas)

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Lyme carditis 1. Pathology - caused by Borrelia burgdorferi --> lyme spirochetes directly invade tissues of the heart 2. Clinical presentation - erythema migrans, rheumotologic (large joints), neurologic (facial nerve palsy) + palpitations, syncope, chest pain - AV block (2nd or 3rd/complete) Chagas disease 1. Pathology - Trypanasoma cruzi (protozoan) infection --> go into quiescent phase and cause chronic-immune mediated myocarditis --> cardiac insufficiency (cardiomyopathy) develops over time

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Acute rheumatic fever - 1. Pathology - autoimmune disease that is sequelae of Group A beta-hemolytic strep infection (eg strep pharyngitis "strep throat") - immune-mediated molecular mimicry (M protein is structurally similar to collagen --> Ab against collagen) --> NOT direct infection as with lyme carditis or chagas 2. Clinical presentation - most commonly children (5-15yo); JONES Criteria: J-Joints --> polyarthritis (affects large joints) - presents first and disappears within 2-4 wks w no sequelae O-heart problems --> carditis (SOB, DOE, chest pain), murmur N-subcutaneous Nodules E-Erythema marginatum (serpiginous, nonpruritic) S-Sydenham chorea In order of how common: carditis >> migratory polyarthritis --> chorea >> erythema and nodules 3A. Acute RF - Pan-carditis = inflammation of the entire heart (affects all the layers) --> can cause long-term disability (Systolic dysfunction) + death i. endocarditis - causes mitral regurg ii. myocarditis - pathognomonic is Aschoff bodies (due to lymphocytes) iii. pericarditis - friction rub B. Chronic RF - valvular changes 20+ years post ARF - immune-mediated inflammatory process continues --> mitral "fishmouth" stenosis

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1. Pericardium - membrane enclosing the heart, composed of visceral layer on top of epicardial muscle and parietal layer fused to fibrous pericardium (composed of collagen and elastin) 2. Functions: - limits motion of heart via attachments to diaphragm and mediastinum - barrier - limits spread of infection from lungs - fluid provides lubrication between visceral and parietal layers 3. Pericarditis - inflammatory disease of pericardium - acute or chronic etiology - majority are idiopathic (probs viral) - also infectious (viral, bacterial, fungal), non-infectious (post MI, uremia, lupus, trauma) 4. Clinical features: - fever - chest pain - pleuritic (aggravated by inspiration and coughing), and positional (relieved by sitting forward, worsened by lying down); radiates to trapezius ridge - pericardial friction rub - extra heart sound with 3 components - ventricular systole, early diastolic filling, and atrial contraction - EKG - diffuse ST segment elevation in ALL leads EXCEPT aVR and V1; PR segment depression

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1. Pericardial effusion - accumulation of fluid within the pericardial sac; increase in volume --> marked increase in pressure --> can compress heart chambers (pericardial tamponade) --> compromises CO Clinical features: - soft heart sounds - reduced intensity of pericardial friction rub - Ewart sign (dullness over posterior left lung bc of large heart) 2. Constrictive pericarditis - post acute pericarditis --> fusion of pericardial layers --> fibrosis and calcification --> impaired diastolic filling - commonly post radiation or surgery, or idiopathic Clinical features: i. reduced CO --> hypotension, fatigue, tachycardia ii. elevated systemic venous pressures (backward RHF) --> JVD, hepatomegaly, ascites, peripheral edema - pericardial knock - high - frequency S3 gallop --> increased y descent of pressure tracing (atrial pressure drop during diastole) - kussmaul sign - JVD increases/worsens with inspiration - R and L end diastolic pressures are the same (normally R is lower) 3. Pulsus paradoxus in cardiac tamponade - kussmaul sign on constrictive pericarditis - equal L and R filling pressures in both - JVP recording: absent y descent in tamponade (ventricular filling impaired), prominent y descent in constriction (y = Atrial pressure decrease during diastole)