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86 Cards in this Set
- Front
- Back
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FAST-RESPONSE ACTION POTENTIALS
- five phases & ions - part of AP & ECG - types of drugs blocking which stage? - type of cardiac cell |
Non-pacemaker Myocardiocytes
Phase 0: Fast Upstroke - Fast Na+ INflux - Class I anti-arrhythmics Phase 1: Brief Repolarization - Stop Na+, Activate brief K+ efflux QRS = Phase 0 & 1 Phase 2: Plateau - Slow L-type Ca2+ influx (v-gate) - Slow Na+ influx - K+ efflux holds Vm constant - Ca2+ channel blockers shorten this - ST SEGMENT Phase 3: Rapid Repolarization - Big K+ efflux (delayed rectifier current); v-gate - Inactivate Slow Na+ & Ca2+ - Quinidine = Decrease K+ efflux, increase AP duration - Lidocaine = Increase K+ efflux, shorten AP duration = T WAVE Phase 4: Restoration - Na/K ATPase restores [ion] - NCE & SERCA remove Ca2+ - Vm is held constant |
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SLOW-RESPONSE AP
- what type of cell - unique - phases & ions |
CARDIAC PACEMAKER CELLS
- LESS negative membrane potential (-60 mV vs. -80 mV) - Slower phase 0 upstroke, NO phase 1 spike, No phase 2/plateau, SHORTER Phase 0: Upstroke - Slow Ca2+ influx - Slow Na+ influx (minor) - Fast Na+ doesn't help bc resting Vm is not negative enough to activate it Phase 3: Repolarize - Delayed Rectifier K+ efflux Phase 4: Spontaneou depolarization - Slow Na+ (If) influx (at -60 mV) - Slow Ca2+ influx (at -40 mV) - Inactivate K+ efflux *Reach threshold --> AP! |
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ANS & PACEMAKER CELLS
- receptors - para vs sym - ion currents affected |
Controls the rate of Spontaneous Depolarization in SA node
OPPOSITES! SYM: B1-R - Increases If & slow Ca2+ currents - Increases SA node firing & increases conduction speed thru AV node PARA: Musc-R - Increases K+ efflux - Decreases If influx - Vm is driven toward Ek = Decreased SA node firing rate & slowed conduction thru AV node |
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REFRACTORINESS IN FAST-RESPONSE APs
*PHASES OF THE AP* - absolute (ARP) - Effective (ERP - rELATIVE (rrp) - Supranormal (SNP |
Vm level determines recovery rate of inactivated Fast Na+ channels****
ARP: Phase 2 - not really absolute *triggered activity* ERP: Phase 3 - need larger than normal stimulus = ADDITIONAL depolarization - NOT a NEW AP RRP: Phase 3 (latter) - larger than normal stimulus = new AP SNP: supranormal period - Phase 3-4 - SMALLER than normal stimulus = new AP |
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REFRACTORINESS IN SLOW RESPONSE, CA2+ dep AP
- diff from fast-response |
Fast-response: Vm determines recovery rate of inactivated fast Na+ channels
Slow response: TIME determines recovery rate of inactivated slow Ca2+ channels **TIME DEPT** - Longer ERP & RRP --> Prevent 1:1 conduction thru the AV node during atrial flutter & fibrillation |
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CHAMBER DILATATION & ARRHYTHMIAS
- what kind of channels are open? |
RECEPTOR-GATED ion channels
- chamber dilatation stretches the heart & opens them - Receptors open/close in response to changes in physical environment -> Supraventricular & ventricular arrhythmias |
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Equation for Ion equilibrium state
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NERNST:
VeqION = -61.5 log [ion]in/ [ion]out (K+ = -90 mV; Na+ = -70 mV) |
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EQUATION FOR RESTING MEMBRANE POTENTIAL
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GOLDMAN-HODGKINS-KATZ
- combined effects of ions on resting Vm Vm = -61.5 log Pk [K+]i + Pna [Na+]i + Pcl [Cl]OUT + Pca[Ca]i DIVIDED BY THE OPPOSITE ([ion]outside; except for Cl-) |
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DIFFERENCE BW FAST-RESPONSE & SLOW-RESPONSE CARDIAC TISSUE
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FAST:
- atrial muscle, ventricular m, His-Purkinje fibers - complex, good connections - 1-4 METERS/SEC SLOW: - SA & AV nodes - can be pacemaker OR non-packemaker - Sparse, crappy connections - 0.01 - 0.1 METERS/SEC *pacemaker cells do NOT have a stable resting Vm* |
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MECHANISMS OF CARDIAC ARRHYTHMIAS
- def of automaticity - where? |
- automaticity: spontaneous depolarization reaches threshold --> New AP
1. Enhanced Automaticity - SA node and AV nodes 2. Abnormal Automaticity - non-packemaker cells 3. Triggered Activity: Afterdepolarizations - rare a. EADs: only in fast-response tissues - long QT syn b. DADs 4. REENTRY - MCC!! a. Anatomical: rare; only AV node b. Functional: MCC = MIschemia 5. Bradyarrhythmias a. decreased automaticity b. impaired conduction (AV block) |
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MECHANISMS OF ENHANCED AUTOMATICITY
- WHAT KIND OF CELLS? - WHY? - EXAMPLES |
PACEMAKER CELLS (SA & AV)
1. iNCREASED RATE OF PHASE 4 DEPOLARIZATION - Increased intrinsic rate = SNS act or Atrial dilatation 2. More negative THRESHOLD potential - HYPOCALCEMIA 3. Less negative MEMBRANE potential - HYPERKALEMIA; ISCHEMIA ex// sinus tachy and AV nodal tachy |
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what does α2 couple with in smooth muscle? what does their coupling result in?
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Gi; decreased cAMP activity which results in smooth muscle relaxation
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TRIGGERED ACTIVITY IN TACHYARRHYTHMIAS
- afterdepolarizations? - EADs - when? - Mech **RARE cause of tachyarrhythmias |
AD: small depolarizing oscillations in Vm following AP
- if big enough, can TRIGGER new AP WHEN? - Phase 2: late plateau (^ inward Ca2+ or Dec outward K+) - Phase 3: early-repolarization (^ inward slow Na+) - Whenever AP is abnormally LONG - Long QT interval **esp SLOW INWARD CA2+ ^^** *only in fast-response tissues* |
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LONG QT SYNDROME
**Torsades de Pointes** - twisting of the points |
Auto dom AND acquired
- many meds that prolong QT more can exacerbate it - usually asymptomatic Predisposed to EADs & tachyarrhythmias. - may also be due to re-entry --> tachyarrythmias |
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TRIGGERED ACTIVITY IN TACHYARRHYTHMIAS
- DADs - when? - mechanism? - causes **triggered activity is DEPENDENT on previous AP** - NOT a form of automaticity |
LATE phase 3 and phase 4
- after repolarization if complete/nearly complete - ^^ [Ca2+]in MECHANISMS: 1. SR gets too full --> 2' spontaneous release of Ca2+ 2. 3Na+/1Ca+ out exchanger 3. Fast Na+ current - if membrane is repolarized enough to activate fast Na+ CAUSES: long AP - Digitalis tox - Excess SNS: Increase slow inward Ca2+ - MIschemia / heart failure --> increased cAMP & weird ryanodine channel |
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TACHYARRHYTHMIAS DUE TO REENTRY
**MCC of clinical tachyarrhythmias - paroxysmal atrial tachy - atrial flutter/fib - v-fib - THREE REQUIREMENTS? |
1. Unidirectional block of an electrical impulse
- normally fast path (longer refractory period) 2. Slow conduction of AP in one part of the circuit - slow path, shorter refractory period 3. Differences in refractoriness among regions of the circuit |
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ANTIARRHYTHMICS THAT PROLONG AP
- indication? - caution? |
Prolong AP duration in Purkinje Fibers
ex// Quinidine and Procainamide INDICATION: EADs & triggered activity PARADOXICALLY - cause ventricular arrhythmias (torasdes de pointes) in pts undergoing anti-arrhythmic tx |
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RE-ENTRY
HOW DOES IT WORK? reentrant pathways can be present & asymptomatic *triggers: electrolyte imbalance,decreased vagal tone, increased SNS |
REMEMBER THREE REQUIREMENTS?
1. Premature impulse 2. Unidirectional block - rapid path is still refractory 3. Travels down Slow path 4. Depolarizes ventricles 5. RETROGRADE travel to fast path = SELF-PERPETUATING CIRCUIT - NOT reliant on SA node **espcially in paroxysmal SVT** |
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DRUGS TO FIGHT RE-ENTRY
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*Trying to get fast pathway to be dominant pathway
- NOT shitty slow pathway 1. slow atrial impulse formation - stop premature impulse 2. Decrease conduction through the slow AV pathway ex// Ca2+ channel blockers (verapamil) & Adenosine - NOT prophylactic - restores sinus rhythm |
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TYPES OF REENTRANT PATHWAYS IN <3
*Fibrillations are multiple reentering circuits - MCC death post-mI = V-FIB |
1. Anatomic
A. Acc paths in AV node only (SVT) B. Bypass tracks around AV node (WPW syn) C. Scarred myocardium (MI) - V.tach 2. FUNCTIONAL: MCC v. tach - MYOCARDIAL ISCHEMIA - Closed electrical gap channels = BLOCK - Cellular electrical uncoupling (decreased conduction velocity) - can occur ANYwhere in heart |
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BRADYARRHYTHMIAS
- MECHANISMS |
1. ABNL IMPULSE FORMATION
- Decreased automaticity - Decreased phase 4 slope = sinus bradycardia = AV nodal rhythm ("escape rhythm") 2. Decreased impulse conduction - 1/2/3 AV block! - ant. MI *only symptom is usually increased fatigue w/ exercise |
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3RD DEGREE (COMPLETE) AV BLOCK
- ECG FINDINGS |
= DECREASED CO (MAJOR)
1. NORMAL P WAVE - unrelated to QRS 2. NO PR INTERVAL 3. NO QRS (N/A) 4. NO RELATIONSHIP BW P & RS |
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CLINICAL FINDINGS OF ARRHYTHMIAS
- risk factors of sudden death |
1. Palpitations/skipped beats/irreg rhythm
2. Syncopes resolving w/in 5 min - neuro syncope: prolonged confusion & premonitions - cardiac syncope: alert upon awakening; onset w/ dec SV 3. Sudden Cardiac Death - w/in 1 hr symptoms - MCC: V-tach/fib - majority 2' long QT inherited syn. - RISK: Previous MI, CHF, >60 yo 4. Asymptomatic: most (until sudden death) |
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LONG QT SYN & ANK B GENE MTT
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All long QTs deal with EAD and abnormal current flow
Ankyrin is a membrane protein that anchors NCE, NKA, & IP3-R - Coordinates Na/K ATPase & NCE - Def: ^ intracell Ca2+ and long QT |
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PRIMARY HTN
- THINGS TO ASK IN HX - AGE OF ONSET |
#1 FAMILY HX? = 75% ESSENTIAL HTN
ONSET: 35-55 yo TARGET ORGAN DAMAGE: - Heart: cardiac ROS - Brain: TIA & stroke - Chronic Kidney - Retinopathy: vision loss - Peripheral arterial disease: Claudication |
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HYPERACTIVE SNS & 1' HTN
- Populations at risk - mech |
1. Hypertensive YOUNG adults
- higher resting HR & CO 2. Repeat emotional stress - High plasma [epi] - Adrenal epi is released & taken up by sympathetic nn --> re-released as a co-NT 3. Middle-aged (abd.) obese pts with insulin resistance - adipocytes release cytokines for TG metab = Sytemic vasoconstriction & Na/H2O reabs *Catecholamines = Pressor-growth promoter** |
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PRESSOR-GROWTH HORMONES
- HOW DO THEY WORK? - EXAMPLES? |
MECHANISM OF VSMH
1. Activate PLC 2. ^ IP3 & DAG 3. IP3 --> ^ Ca2+ --> Contraction (Calmodulin & MLCK) 4. DAG --> PKC --> NHE (Na+ in/H+ out) = Intracell Alkalosis 5. DNA synthesis 6. VSM Hypertrophy!! examples: Catecholamines, ATN II, PDGF-1, Endothelin-1 |
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PRORENIN
- from where? - what it do? **ACEIs & ARBs don't prevent remodeling caused by PRORENIN ** |
JG releases it
normally only 4:1 of renin: prorenin - also made in eyes of diabetic & ovaries of preggers - diabetic w/ microalbuminuria 1:4 (renin:prorenin) ACTIVE WHEN BOUND TO PRORENIN-R = CLEAVES Angiotensionogen --> ATN I RESULTS 1. Increase ATN I 2. Heart: hypertrophy & fibrosis (remodeling) 3. Vessels: " " |
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AT1-R AXNS
- LIGAND - AXN |
VASOCONSTRICTOR
- makes IP3 & DAG in VSM Ligand = ATN II (Pressor growth hormone) --> increased intracell Ca2+ & VSM Hypertrophy |
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ATN II EFFECTS ON BP
**Renin, Angiotensinogen & ATN II are made LOCALLY by systemic arterioles** - NOT only JG cells |
1. Increased catecholamines & sensitivity of VSM to them
2. VSMH (p-g hormone) 3. Increased renal Na+ reabs via NHE in PROXIMAL convoluted tubule 4. ^ Aldosterone = increased na+ reabs in distal nephron 5. Increased plasminogen activator inhibitor-1 = accelerates atherosclerosis |
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ATN III effects
- from where? **CNS-mediated HTN** |
BRAIN: aminopeptidase-A cleaves ATN ii --> ATN III
- binds AT1-R & AT2-R 1. Stimulates Vasopressin release - hypothalamic paraventricular nuclei 2. IncreaseS salt appetitE 3. sTIMULATES sns |
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JG CELL FUNCTION
(baroreceptor) - MD is a chemo-R - WHAT INCREASES RENIN RELEASE? - WHAT DECREASES?? |
INCREASED RENIN RELEASE
1. ^ JG cell cAMP a. Beta1-agonist: + a. cyclase b. PGE2 & NO from macula densa (stim = dec. NaCl) 2. Decreased JG cell Ca2+ a. Dec. cell stretch - JG cell baroreceptor (dec. BP) b. Cell hyperpolarization - Serum HYPOkalemia DECREASED RENIN RELEASE 1. Dec. JG cell cAPM a. Beta1-ANTAGonist b. Adenosine** from MD 2. Increased JG cell Ca2+ a. Increased cell stretch b. Cell depolarization - serum HYPERkalemia 3. ATN II - binds AT1-R on JG cell to inhibit renin release |
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MACULA DENSA
- WHAT? - FXN? |
Chemoreceptor in TAL
- measures changes in tubular NaCl 1. NaCl def - Releases PGE2 & NO to JG - INCREASE RENIN && DILATES aff. arteriole = ^ GFR 2. NaCl excess - ADENOSINE --> JG && CONSTRICTS aff arterioles 2 decrease GFR **anywhere else, adenosine vasodilates** |
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HYPORENINEMIC HYPOALDOSTERNOISM
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*PGE2 & PGI2 = renal prostaglandins*
- made in Macula Densa - decreased in chronic diabetes --> hyporeninemic hypoaldosternoism = metabolic acidosis & mild serum hyperkalemia |
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define shock
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ACUTE circulatory FAILURE
- generalized reduction in tissue perfusion - doesn't meet metabolic demands - usually accompanied by hypotension (MAP <60mmHg) **BUT HYPOTENSION AND SHOCK ARE NOT SYNONMYOUS** - esp in hypertensive pts who drop to normal in shock - early shock = normal BP shock can cause cellular injury --> inflamm mediators released --> accelerate cellular injury --> MODS |
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COMPONENTS OF CIRCULATORY SYSTEM
- CHANGES IN SHOCK - initiating event in hypovolemic shock? |
Heart: Pump fxn
Muscular arterioles - resistance vessel = AF Intravascular volume = Preload Capillaries = fluid exchange - abnormal fluid exchange in all types of shock Venous resistance vessels - post-cap venules control capillary fluid exchange METARTERIOLES: - Shunt; Vasodilatory shock ex// glomus LARGE VV - capacitance vessels = 80% intravasc vol - PRELOAD - diilated in spinal & anaphylactic shock & obstructive shock |
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initiators of each type of shock
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1. Hypovolemic:
- Blood loss = decreased intravascular volume (main determinant of PRELOAD) 2. CARDIOGENIC: - CARDIAC PUMP FAILURE 3. DISTRIBUTIVE/VASODILATORY - Severely decreased SVR 4. OBSTRUCTIVE - Obstruction in venous capacitance vessels |
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STAGES OF SHOCK (BRIEFLY)
- SEEN IN ALL TYPES OF SHOCK |
1. COMPENSATED
- normal BP & tissue perfusion - resting tachy & cutaneous pallor; mildly anxious - easily missed at this stage 2. DECOMPENSATED - Normal BP supine + Orthostatic hypotention - looks worse: ^ tachy, diaphoretic, pale/mottled - Organ hypoperfusion; decreased urine; obtunded 3. IRREVERSIBLE - supine hypotension - organ ischemia & lactic aidosis - Heart failure - intestinal ischemia --> sepsis - ARDS & decreased urine (organ hypoperfusion) |
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STAGE 3 IRREVERSIBLE SHOCK
- FEATURES |
SUPINE HYPOTENSION
1. Anaerobic metabolism - blood lactate > 1.5 mmol/L 2. Metabolic anion gap acidosis --> VASODILATION 3. GI Tract Ischemia - sepsis - cytokine mediated systemic VASODILATION 4. HEART FAILURE - myocardial depressants - sys & dias heart fail 5. Renal & Pulmonary Hypoperfusion - acute tubular necrosis (esp. proximal tubule & TAL) = NO URINE - ARDS |
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relative vs absolute hypotension
(shock = relative hypotension) |
- absolute hypotension (eg, systolic blood pressure <90 mmHg)
- relative hypotension (eg, a drop in systolic blood pressure >40 mmHg). |
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cardinal features of shock
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Cardinal features of shock include hypotension, oliguria, abnormal mental status, metabolic acidosis, and, in some patients, cool and clammy skin
(sepsis = warm skin) |
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HYPOVOLEMIC SHOCK CAUSES
**MOST COMMON TYPE OF CARDIOVASCULAR SHOCK |
1. Sudden decrease in RBCs AND PLASMA
(hemorrhage --> 4 classes of shock) 2. Acute loss of plasma volume only (No RBCs) - GI / renal / cutaneous loss DECREASE IN VENOUS RETURN --> DECREASE IN PRELOAD (Same frank-starling curve) |
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CA2+ channel blockers & effects on RAAS (in essential htn)
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only block L-TYPE Ca2+ channels
1.) Decreased L-type Ca2+ current in jG cells = INCREASE RENIN RELEASE 2.) Dilate afferent art (relax VSM) = Stretched JG cells = ^ Receptor-gated Ca2+ influx = DECREASED RENIN RELEASE NET EFFECT - no change in renin, ATN I, or ATN II |
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EFFECTS OF CERTAIN MEDS/DRUG CLASS ON RENIN/ATN I / ATN II
- Diuretics - Renin inhibitors - ACEIs - ARBs - a1-adrenergic antagonists - Hydralazine **BP meds: Decrease BP, increase renin |
ALL INCREASE RENIN
- decrease BP --> ^ Renin (want to increase perfusion) 1.) Diuretics: Increase all 2.) Renin Inhibitors: Aliskiren - increase Renin, decreased ATN I/II 3.) ACEIs: Captopril - Increase Renin/ ATN II only 4.) ARBs: Losartan - Increase ALL 5.) a1 antags: Increase all - vasoconstrict 6.) Hydralazine: ^ cGMP + reflex SNS activation --> increase ALL (assc'd with drug-induced SLE) |
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DRUG EFFECTS ON RAAS
- beta1-antags - alpha2-agonists - NSAIDS |
1.) beta1 Antagonists
- DECREASE ALL - decreases Renin @ JG cell 2.) Alpha2 Agonist: Clonidine - Decrease ALL - vasodilate: increased Ca2+ influx in JG cells 3.) NSAIDs: block PGs - Macula densa unable to signal decreased sodium; PGs unable to increase cAMP in JG cell |
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PLASMA RENIN PROFILES IN ESSENTIAL HTN Pts
- who has high vs normal vs low? - %age in each category |
1.) HIGH plasma renin activity - 15%
- young white males - Strong support that ^ renin = ^ BP - low ECF volume (right) - only HALF of these pts respond to ACEIs 2.) NORMAL - 65% - Widespread in population - still, renin activity is inappropriately HIGH for ^ BP (Renin should dec when bp ^ ) *Eating LESS sodium doesn't help these people *Most of them DO response to ACEIs*** 3.) LOW - 20% - African americans - Increased ECF volume - DON'T give ACEIs - give DIURETICS |
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9 Potential causes of Primary/Essential HTN
- proposed theories |
1.) Increased SNS activity
- stress 2.) Overactive RAAS - esp young white males 3.) Endothelial dysfxn - Endothelin1 vs NO 4.) Hyperinsulinemia: Metabolic X syndrome 5.) Kinin deficiency - bradykinins - blacks 6.) Decreased NaCl excretion 7.) Hyperuricemia - give Losartan 8.) Environment: - Increased NaCl intake - Decreased K+ - Decreased Ca2+ - obesity - ethanol: Pressor - ^ Ca2+ - Smoking: nicotine = ^ NE 9.) Hereditary: Blacks; Adducin, etc |
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COMPLICATIONS OF ESSENTIAL HTN
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1.) Premature atherosclerosis
2.) LVH 3.) Heart arrhythmias 4.) Large vessel dz - abdominal aortic aneurysm 5.) Stroke - Charcot-bouchard aneur. 6.) End stage renal disease |
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ENDOTHELIAL DYSFXN IN 1' HTN
- POPULATION - imbalance of what 2 factors? |
Important in 1' HTN & Systolic HTN of elderly
IMBALANCE OF 1.) Endothelin-1: Released 2' physical forces & ATN II - 2 receptor types A.) BAD: ET-A higher in blacks w/ HTN --> vasoconstrict & VSM-H B.) Kidneys have ET-B receptors --> Increased Na+ & Water excretion *Decreased RENAL endothelin-1 synthesis = Decreased renal Na+ excretion 2.) NO: vasodilator & ^ renal Na+ excretion - decreased = HTN in elderly, metabolic syn, chronic renal failure |
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NITRIC OXIDE
- ROLE IN HTN - who do you give nitrates (NO donors) to? |
DECREASED NO PRODUCTION IN HTN
- part of endothelial dysfn - there's an iNOS & eNOS 1.) Systolic HTN of elderly - increased wall stiffness & collagen in LARGE elastic aa - Decreased NO synthesis tx: Nitrates: veno/vaso-dilate, thiazide diuretics, ACEIs, & dietary Na+ restriction - ACEIs & diruetics = increase compliance of aa 2.) Metabolic Syn - decreased NO in hyperinsulinemia - vessel diameter is imbalanced 3.) Chronic renal failure - increased ADMA reduces eNOS activity = ^ BP |
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COMPLICATIONS OF ESSENTIAL HTN
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1.) Premature atherosclerosis
2.) LVH 3.) Heart arrhythmias 4.) Large vessel dz - abdominal aortic aneurysm 5.) Stroke - Charcot-bouchard aneur. 6.) End stage renal disease |
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ENDOTHELIAL DYSFXN IN 1' HTN
- POPULATION - imbalance of what 2 factors? |
Important in 1' HTN & Systolic HTN of elderly
IMBALANCE OF 1.) Endothelin-1: Released 2' physical forces & ATN II - 2 receptor types A.) BAD: ET-A higher in blacks w/ HTN --> vasoconstrict & VSM-H B.) Kidneys have ET-B receptors --> Increased Na+ & Water excretion *Decreased RENAL endothelin-1 synthesis = Decreased renal Na+ excretion 2.) NO: vasodilator & ^ renal Na+ excretion - decreased = HTN in elderly, metabolic syn, chronic renal failure |
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NITRIC OXIDE
- ROLE IN HTN - who do you give nitrates (NO donors) to? |
DECREASED NO PRODUCTION IN HTN
- part of endothelial dysfn - there's an iNOS & eNOS 1.) Systolic HTN of elderly - increased wall stiffness & collagen in LARGE elastic aa - Decreased NO synthesis tx: Nitrates: veno/vaso-dilate, thiazide diuretics, ACEIs, & dietary Na+ restriction - ACEIs & diruetics = increase compliance of aa 2.) Metabolic Syn - decreased NO in hyperinsulinemia - vessel diameter is imbalanced 3.) Chronic renal failure - increased ADMA reduces eNOS activity = ^ BP |
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EFFECTS OF INSULIN ON BLOOD VESSELS
- IN NORMAL PEOPLE |
NET: SMALL reduction in BP
OPPOSING ACTIONS in normals: 1.) ^ SNS = Vasoconstrict 2.) Relaxes VSM = vasodilate - increase NO |
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HYPERINSULINEMIA & HTN
- WHAT'S THE LINK? *more common in caucasians |
Common finding in OBESE pts w/ HTN
- also some non-obese caucasian pts. MECHANISMS: Insulin causes 1.) ^ SNS activity + Decreased NO production - normal: insulin causes ^ NO 2.) ^ ECF volume & ^ SV - Increased aldo sens to ATN ii - Decreased renal Na+ excretion: + NHE & Na-Glucose co-transport 3.) ^ NHE exchange in VSM - PG hormone; VSH & remodeling 4.) Decreased CA2+ extrusion - increased Ca2+ intracell - 2' NHE (increased na+ intracell) |
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VSM CELL
- NHE & NCX - effects of hyperinsulinemia |
1.) Insulin increases NHE activity
- Increased Na+ influx - Increased H+ efflux 2.) Alkalosis --> protein synthesis --> hypertrophy 3.) Increased Na+ intracell inhibits NCX - increased Ca2+ intracell 4.) VASOCONSTRICTION |
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METABOLIC SYNDROME & HTN
tx in these pts |
Best evidence that ^ insulin = ^ BP
Glucose intolerance --> hyperinsulinemia tx: Thiazolidinediones (pioglitazone) - improves periph tissue insulin sensitivyt - lower BP when used by Obese, diabetic pts w/ metabolic syndrome |
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KININ DEFICIENCY & HTN
- normal axn - deficient in which population? |
Kinins - potent vasodilator, diuretic, natriuretic
--> activate eNOS LOCAL axn (inactivated by lung) - cause natriuresis in kidneys AF-AMs with 1' HTN have SUUUUper low kinin - give ACEIs (even tho they already have low renin) - ACE inactivates bradykinin --> ACEIs retard kinin metabolism *bradykinin causes COUGH* |
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DECREASED RENAL NA+ EXCRETION & 1' HTN
- typical of industrial societies w/ high sodium intake |
Repetitive subclinical injuries = decreased ability to excrete Na+
--> Retain fluid --> HTN 3 Mechanisms: 1.) Hyperactive SNS and/or RAAS ^ ATN II --> Renal ischemia - tubulointerstitial injury - insufficient PGE2 & NO to vasodilator & maintain GFR --> afferent arteriolopathy = decreased GFR & Na+ excretion **HTN restores GFR & Na+ excretion 2.) Digitalis-Like Inhibition of Na/K ATPase - released in response ^ ECF **[ ] directly correlates w/ HTN severity** - VSM: increase dias BP - Kidneys: Increase Na+ excretion: brings ECF back down - Heart: Increased Ca2+ = ^ SV & contractility = ^ SYS BP 3.) Increased NHE activity kidneys: ^ H exc & ^ Na+ reabs = ^ ECF VSM: acts like insulin - hypertrophy & vasoconstrict |
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DECREASED RENAL NA+ EXCRETION & PRESSURE-NATRIURESIS CURVES
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1.) Decreased sodium intake
2.) MAP climbs as RAAS increases 3.) HTN!! **ultimately move on a different, right shifted curve to obtain normal Na+ excretion |
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HYPERURICEMIA AND HTN
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**Predicas subsequent development of HTN
1.) Stimulates RAAS - causes renal injury - decreased Na+ excretion - increased ECF volume 2.) ENDOTHELIAL DYSFXN - increased free radicals - decreased NO synthesis - Accelerates NO degradation 3.) VSH - ^ PDGF & other mitogens - renal afferent arteriolopathy = decreased Na+ exc tx:LOSARATAN (ATN II-R Blocker) uricosuric properties (increases exc of uric acid) |
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EXCESS DIETARY NACL & HTN
- which population especially? |
ESP in elderly & middle aged blacks
Decreases eNOS - dietary restriction has opposite effect Dietary sodium excess correlates w/ HTN heart disease & cardiac fibrosis - increase LV mass & extracell collagen **Subset of Na+ sensitive pts have HTN ONLY if dietary K+ and/or Ca2+ i is low too |
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LOW DIETARY K+ AND HTN
- normal response to ^ k+ diet vs acute decrease vs chronic decrease in K+ |
Subset of Na+ sensitive patients have HTN ONLY if dietary K+ is low
^ K+ Diet = ^ Aldo - Increase K+ exc & Na+ reabs Acute Low K+ Intake = Low Aldo - Decreased K+ exc & Na+ reabs Chronic Low K+ Intake - Increased K+ exc & Increased Na+ reabs --> depolarizes VSM (weird - looks like acute HYPERK+) |
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HYPOKALEMIA & HTN
- effects of thiazide diuretics - chronic hypokalemia - K+ supplementation |
Hypokalemia augments high dietary Na+
Chronic Hypokalemia - closes K+ channels in VSM --> vasoconstriction - ^ luminal NHE activity - Simulates Na/K+ ATPase = Increased sodium reabs Thiazide Diuretics: Block NKCC symport - Increase renal Na+ exc - hyperpolarize VSM --> close V-gated Ca2+channels -= systemic vasodilation K+ supplementation: Reduces BP in pts who like eating salt - avoid in pts w/ impaired kidneys or taking K+ sparing diuretics |
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HYPOCALCEMIA & HTN
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Esp true in high sodium diet pts
Increased dietary Na+ = Increased Ca2+ excretion 1.) ^ Na+ reabs depolarizes Distal tubule cell 2.) Less Ca2+ is reabsorbed (2' positive charges repelling) 3.) Hypocalcemia - ^ PTH & 1,25 dihydroxy Vit D3 4.) INHIBIT - Na/K ATPase & NCX = Increased VSM intracell Ca2+ (2' Vit D3 - Increases VSM ca2+ intake) VASOCONSTRICT |
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Calcium supplementation in HTN
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1. Increased calcium intake = decreased sodium reabs
(Concentration trumps charge) 2. Stabilizes VSM membrane - lowers PTH & vit D3 - less permeable to extracell Ca - 3 Na+ In to be excreted : 1 Ca2+ reabs Hypocalcemia is rare only in lactose intolerant - blacks & asian |
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OBESITY & HTN
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Abdominal obesity
- peripheral insulin resistance - hyperinsulinemia --> bad stuff - Increased FFA release --> decreases hepatic insulin extraction - Increased leptin (+ SNS) - fat cells make TONS of ATN ii, TNF-a, Aldo --> PG hormones |
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ETHANOL & HTN
- most treatable & reversible form of HTN in the US |
> 2 ozs a day
- dose related - 10% of adult HTN PRESSOR effect - Increases Ca2+ influx into VSM - ^ SNS - hyperinsulinemia - increases cortisol secretion |
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CIGARETTE SMOKING & HTN
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nicotine stimulates SNS
- ^ NE - increases local endothelin *transient effects: ~ 30 min |
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GENETICS & HTN
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Family hx = 4x ^ risk of HTN
ADDUCIN: - variant of alpha-adducin gene assc'd with salt-sensitive 1' HTN - membrane skeleton protein - increases Na/K pump activity in renal tubules Polymorphic Angiotensinogen & ACE genes EX// 1.) African americans - increased renal Na+ reabs - higher intravascular volume - reduced plasma renin activity - increased ET-A-R - kinin deficient tx: diuretics 2.) Caucasians - respond better to beta antagonist tx (act on JG cells) |
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PREMATURE ATHEROSCLEROSIS & HTN
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- Endothelial dysfxn (increased endothelial adehsion molecules)
- Vascular Inflamm (increased oxidative stress from hyperuricemia) 1.) Prothrombotic state - increased platelet reactivity - decreased fibrinolysis 2.) Increased CAD risk |
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LVH & HTN
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present in 30% of HTN adults
90% of severe HTN pts 1.) Concentric LVH - increased LVH - reduces myocardial wall stress & AF - maintains CO - but impairs ventricular filling --> Diastolic myocardial dysfunction 2.) Eccentric LVH - systolic dysfxn causes ventricular dilatation --> eccentric growth **HTN is the MC identifiable risk factor for the development of CHF |
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CARDIAC ARRHYTHMIAS & HTN
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A-FIB ESPECIALLY
- Ventricular arrhythmias & sudden <3 death can complicate sustained HTN w/ LVH |
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LARGE VESSEL DISEASE & STROKE IN HTN
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Abdominal aortic aneurysm & dissecting aortic aneurysm is significantly more common
Stroke: More common if > 130/85 >75% 2' arterial thrombosis or embolism - MC is MORNING: highest BP - Wide pulse pressure during sleep & sudden BP drop during sleep - Cognitive impairment in elderly : wide pulse pressure & sys HTN (TIA) |
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htn & renal disease
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second only to Diabetes as leading cause of end stage renal disease in US
1.) Glomerular injury - proteinuria - glomerulosclerosis - ATN II damages podocytes 2.) Interstitial fibrosis & tubular atrophy 3.) Proteinuria worsens, GFR falls more, renal failure ensues |
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how does chamber dilatation precipitate Supraventricular & ventricular arrhythmias?
(sys dysfxn) |
chamber dilatation stretches BOTH pacemaker & non-pacemaker cells to open receptor-gated ion channels
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OXYGEN TRANSPORT
- NORMAL O2 VALUES - PaO2 = oxygen tension - %Sa02 - dissolved o2 - Cao2 - equation for total o2 content - P50 |
PaO2 = 100 mmHg
- dissolved O2 = 0.3 mL %SaO2 = 97% - 19.4 mL of O2 bound CaO2 = (0.003xPaO2) + (Hbx1.36x%SaO2) - total O2 content = 20 mL/100 mL blood **can ONLY use dissolved O2 to give cells** P50 = 27 mmHg P25 = 40 mmHg **Total amt of O2 to be delivered to tissues = CaO2 x CO |
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Tissue oxygen use
- normal amt consumed - normal AV O2 difference |
5 mL/1dL of blood
--> 250 mL of O2 / min vs. 1000mL/min DELIVERED (based on CO = 5L/min) A-V O2 difference = 4-5 mL (90 mmHg vs 40 mmHg) |
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Physiologic adjustments in CHRONIC ANEMIA
- heart - RBCs |
HEART: ^ CO (4-5x) & ^ SV
1. ^ HR: carotid body hypoxia activates SNS 2. ^ Preload: - RAAS & Vasopression secretion (2' SNS) - Constrict splanchnics & skin BF (redistribution) 3. Decreased AF - decreased viscosity w/o Hb - Systemic vasodilation (build up metabolites, adenosine) = NL sys BP; Dec dias BP (wide pulse pressure) **HIGH OUTPUT CARDIAC FAILURE POSSIBLE** - MVO2 eventually outstrips O2 supply --> systolic dysfxn |
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CHRONIC ANEMIA S/S
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Palpations
Angina (decreased myocardial O2 delivery) Systolic Murmurs: - midsys: ^ SV - holosys: sys dysfxn (MR) Hyperventilation --> respiratory alkalosis CUTANEOUS PALLOR - vasoconstriction - mucous membranes, conjunctiva, lips, nail beds = heat intolerance & low grade fever NEUROMUSC: - Cerebral hypoxia: vertigo, headaches, ADD, drowsy - Generalized muscle wkness - Papilledema & retinal hemorrhages |
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HYPOXEMIA VS HYPOXI
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HYPOXEMIA = LUNG DZ
- LOW PaO2 hYPOXIA: O2 deficiency at tissue level - hypoxic: low PaO2 - Anemic: low CaO2 only - Ischemic: heart failure (dec CvO2) & distributive shock (^CvO2) - Histotoxic: Cyanide poisoning (CvO2 ^ only) |
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Pattern Recognition Molecules
(Innate Immunity) TLR-4 TLR-2 CD14 LBP BPI |
TLR4: LPS (lipid A); gram negative
TLR2: Peptidoglycan; teichoic acids, lipotheichoic acids; gram + CD14: soluble or cell bound - binds LBP/LPS, LPS, peptidoglycan - interacts w/ MD2/TLR2 & TLR2 on vascular endothelium LBP: likes hexacetylated LIPID A - soluble - delivers it to CD14 BPI: bactericidal permeability increasing protein - binds circulating LPS - soluble - prevents LPS binding to LBP or CD14 **keeps inflammation in check** |
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TNF-ALPHA
- FROM WHERE? - AXNS> |
FROM: mononuclear leukocytes & CD4 Th1 cells
1. Pyrogenic: FEVER - PGE2 in hypothalamus & cAMP + sleep, lethargy 2. Toxic to endothelium - effs up tight jcts 3. ^ Endothelial adhesion molecules: E-selectin & P-selectin - anchor activated neutrophils - ^ neutrophil migration --> damage vascular entohelium w/ its free radicals 4. Procoagulation - releases tissue factors 5. Systemic vasodilation******* - even wITHOUT endotoxin, it can cause this |
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IL-1B
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FROM TH1 HELPER CELLS & MONONUCLEAR LEUKOCYTES
Pyrogenic enhances tissue sensitivity to TNFa promotes release of neutrophils from bone marrow |
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IL-10
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ANTI-INFLAMMATORY CYTOKINE
- from CD4 TH2 helper cells IMMUNE SUPPRESSION (delayed hypoactive response) --> leads to 2' superinfxns |
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HMGB1
HIGH MOBILITY GROUP BOX what it do? - when? |
From activated macros stimulated by inflamm cytokines
DELAYED RESPONSE by like 1-2d post-infxn - MAINTAINS INFLAMM (severe sepsis) |
