Week 2 Note

Heart Sounds:

Caused by S1 Onset of ventricular systole AV (ie. mitral and tricuspid)

closure bracket systoleS2 End of ventricular systole aortic and pulmonary closureS3 Right after S2 generated by early diastolic

filling due to rapid pressures

esp. in ↑ volume situations

S4 At the end of diastole atrial contraction-mediated filling of the ventricles low frequency

systolic murmurs – turbulent flow associated w/ ventricular ejectiondiastolic murmurs – associated w/ ventricular fillingWhen heart sounds and murmurs are heard

1. Rapid acceleration (or deceleration) of blood a. Valve closing and opeining b. Ventribcular filling (Gallops)

2. Turbulant (high velocity) blood flow a. Cardiac murmurs b. Vascular bruits

Week 1W Cardiac Performance A. Two most important operating parameters that affect ventricular performance B. Preload: “LVEDP”

Distending force present in the ventricle during diastole that is available to fill it to its volume at end diastoleGoverned by Frank-Starling Law of the HeartMuscle Function Paradigm: Preload = end diastolic sarcomere length Pumping Performance Paradigm: Ventricular end diastolic volume, measured by ventricular end diastrolic pressure (VEDP); preload/VEDP = stroke volume and contractilityBUT as you turn up the VEDP more and more, less and less gain in preload because of stiffness (increasing LVEDP in upper ranges, produces smaller and smller increment of LVEDV); helps protect against overdistention

- 1 -

1. Afterload- 2 -

Force Ventricular muscle has to overcome during systole to eject

o Muscle Function Paradigm: Force acting on myocardium that opposes shortening during systole

o Pumping Performance Paradigm: Ventricular systolic pressure (ie. LVSP)

Afterload = ↓ability to shorten = ↓Stroke volume (extent that muscle can shorten is inversely related to the opposing load)

2. inotropic state

inotropy – cardiac m can alter its contractile force primarily in addition to the length-dependent alteration

inotropy 1. shift of end-systolic force-length relationship 2. systolic contractile force that is independent of

sarcomere length 3. Permits greater shortening at any given preload or

afterload BUT Inotropy in HF METABOLIC COSTS

C. 2 fundamental Performance Properties of Myocardium (muscle function paradigm)

Definition Determined by LinearityDiastolic Force-length relationship

Compliance of myocardium when inactive

Properties of non-contractile elements (TITIN)

NO

End-systolic Force-length relationship

Determined by myofilament (actin-myosin) proximity, inotropic state

Determined by contractile elements (less force @ shorter lengths)

YES

D. principle parameters to measure:a. HRb. SVc. systemic arterial pressured. LA pressure

E. output from the two sides of the heart must be equal or there would be no flow

F. Clinical Characterization of Cardiac Pumping Performance:

a. myocardial force ~ pressureb. sarcomere length ~ chamber volume

G. The Ventricular Pressure-Volume Loopa. pressure on the Y axis, volume on the Xb. ↑ diastolic volume = ↑ potential for ejectionc. ↑ systolic pressure = ↓ potential for ejection

- 3 -

H. Extrinsic effects of cardiac performance:a. preload – force available to distend the ventricles to their end diastolic volume

i. ventricular end diastolic volumeii. ventricular end diastolic pressure

b. afterload – force the ventricles must overcome to eject into the great vesselsi. arterial pressure

ii. ventricular dimension

I. LVEF = (EDV – ESV) / EDV fraction of the total EDV that is ejectedJ. or K. LVEF = (SV) / EDVL. nl is 55-65%M. requires a shortening to 30% of original lengthN. ↑ preload, ↑ EFO. ↑ afterload, ↓ EFP. ↑ inotropy, ↑ EF

Week 2A Cardiovascular Control

A. Ventricular Stroke Volume SV = EDV-ESV

1. EDV is determined by Preload a. End diastolic pressure b. Diastolic force-length relationship

2. ESV is determined by Afterload a. Systolic pressure (Early or peak)b. Inotropic state

1. Systemic Arterial Pressure a. Driving potential to deliver requisite blood flow to vascular bed

i. Contained by systemic arteries ii. Generated by LV Systolic contractions

iii. Major determinant of L ventricular afterload b. Too

i. LV afterload ii. systemic arterial system distending forces

c. Too ↓ i. Inadequate driving pressure to generate systemic blood flow

2. Pulmonary arterial pressure a. Must be higher than LA pressure (to drive blood through lungs, otherwise backflow) b. Major determinant of R ventricular AFTERLOAD

3. Left Atrial Pressure a. Distending pressure; determines LV preload

The LaPlace Relationship A) Relates force needed to the amount of unit surface area;

a. bigger ventricle needs a larger wall force to exert same pressure B) Useful relationship during systole;

- 4 -

a. as ventricle empties, ↓ sarcomere length, ↓ force needed to achieve the same pressure because the ↓Surface Area

b. ventricle “unloads” itself while it ejects C) Pathological hypertrophy is a problem because wall force needed to achieve same pressure is much higher for

greater size ventriclea. vasodilators ↓ pressure needed to eject (↓ SVR and afterload)

ComplianceA) Linear

a. Muscle paradigmb. Relates Length to the Stretching force c. Compliance = L0(ΔL/ΔF)d. More compliant structure stretches more in response to constant force

B) Chamber a. Chamber compliance b. Releates chamber volume to chamber cavity pressure c. Compliance = V0 (ΔV/ΔP)d. More compliant chamber can have a bigger volume for a constant pressure cavity e. To hold pressure constant, increasing the dimensions of chamber means greater force must be applied.

C) Pressure-Volume Loop

D) Implications of Pressure-Volume Loopa. Preload = STROKE VOLUME b. Afterload = ↓Stroke volume c. Inotropy = Ejection Fraction (shortening from same EDV given constant pressure)= Stroke Volume

1. Inotropic state can be modified by

- 5 -

E) Manipulating Ionotropic State a. by HR (rate staircase) b. by Autonomic input (be-a adrenergic )c. ↓by Myocardial metabolic state (oxidative and ionic)

ALL mEDIATED by changes in Ca –mediated contractile apparatus

REGULATION OF SYSTEMIC ARTERIAL PRESSURERole of Systemic Arterial Pressure potential energy that drives the circulation local vascular resistance determines organ perfusion narrow operating range – maintained by sensors and strategies pressure is of little value unless requisite amount of blood present Determinants of SAP:

o SVR = MAP / CO systemic vascular resistance = mean arterial pressure / cardiac output Ohm’s Law analogy

o VR (Wood Units) = ΔPressure / Flow pressure drop across the vascular bed, flow = cardiac output

Vascular Resistance (Workshop) resistance which opposes flow through the vascular bed

R = ΔP / F R = fluid resistance ΔP = pressure drop across the vascular bed F = flow through the vascular bed = cardiac output

SVR = SAP – RAP / CO nl = 12-18 Wood unitsPVR = PAP – LAP / CO nl < 1.5 Wood units

TPR = PAP / CO nl 1.5 – 3 Wood unitsmeasure of RV afterload

Integration of Vascular Control:o medulla has neural control ctro SAP sensors:

arterial baroreceptors: stretch receptors IX/X medulla carotid sinus aortic arch

ventricular baroreceptors: sense ventricular distention X medulla mechanism of syncope (fooled by low IV volume into thinking that arterial pressure is

elevated) atrial baroreceptors -- ↑ atrial volume atrial natriuretic peptide diuresis

intermediate-term regulation renal baroreceptors – sense pressure in JG apparatus renin release ATII vasoconstrict,

retain Na+ and water long term regulation

chemoreceptors: ↓P02, ↓pH, ↑PCO2 resp Δ, ↑ chemorec output vasopressor ↑ arterial pressure

- 6 -

carotid sinus aortic arch

Effector Mechanisms to regulate SAP Cardiac Adjustments:

o ANS input Systemic Arterial System – different beds respond differently to ANS input

o Vasodilator: local metabolic activity is most impt factor (mediated by adenosine release in response to

metabolic state) NO Prostacyclin

o Vasoconstrictor angiotensin endothelin thromboxane (+platelet activation)

Systemic Venous Systemo adrengergic input venoconstriction ↑ venous return to heart ↑ preload

IV Volumeo regulated by kidney

Cardiac Vasoactive Hormones:o atrial natriuretic peptide – atrial stretch o B type natriuretic peptide – ventricular stretch o C type – not well defined

o ↑ glomerular filtration, ↓ Na+ retention, diastolic relaxation, ↓ sympathetic activity, ↓ renin release

Week 2B REGULATION OF CARDIAC OUTPUT

CO is matched to body sizeo nl: 2.5-3.5 L/m/meter2

o nl adult: 5L/mino most demanding metabolic

requirement: exercise there are no defined sensors for CO –

therefore relies on input rather than feedback overriding influence is tissue metabolic activity measurement:

o indicator dilution Fick Principle Thermal Dilution

CO = HR X SV

Fick Principle, Oxygen Circulatory Transport, and RegulationOxygen binding by Hb

- 7 -

overwhelming majority of oxygen in the blood is reversibly bound to Hb (neglect the dissolved part)o oxygen binding capacity – max amount which can be bound to Hbo bound oxygen – actually covalently boundo dissolved oxygen – dissolved in physical solution in plasmao oxygen content – total quantity in the blood (bound and dissolved) – mL O2/100mL blood

physical units of measureo pO2 – partial pressure in mmHgo O2 saturation – fraction of Hb o2 binding capacity that is occupied (%)

O2 carrying capacity = Hb x 1.34

Hb-oxygen dissociation curve:

Note: mixed venous 02 saturation is an indicator of the adequacy of CO to meet metabolic requirements nl: ~75% -- only 1/3 of oxygen transport capacity is actually utilized

o HgB is 98% saturated in the blood stream, so you’re only unloading 25% of oxygen at rest

in happy circulation:o if <75% CO is not adequateo if >75% CO is excessive and might not be regulated

Examples:o anemia (<10g Hb) -- ↓ RBC, ↓Hb, ↓oxygen carrying capacity o the “shoulder” on the dissociation curve (sigmoidal) means we can tolerate a fairly large ↓ in pO2 w/o

sxs o the steep slope of the linear portion of the curve means we can unload oxygen very efficiently between

the arterial and venous circulation Calculation of CO using the Fick Principle

o Fick describes the relationship between the rate of addition of an indicator substance to a flowing stream to the difference in concentration of the indicator upstream and downstream from the point of addition

in this case the flow rate is CO and the indicator is oxygen

CO L blood/min = total body O2 consumption (mL O2/min) / 10(AVO2D) (mL O2/min)

CO = cardiac output total O2 consumption AVO2D is the difference between the arterial (measured by arterial line) and venous (measured

from the PA which which represents the lowest possible content) O2 content (usually given /100mL of blood so multiply by 10)

Examples from section: in a nl individual, about 25% of oxygen-carrying capacity is used in nl oxygen transport anemia doesn’t effect CO or CI b/c not a volume issue when CO is ↑ above the needs of the tissues its wasteful (see shock lectures) ↓CO need to extract a greater fraction of transported oxygen to the systemic tissues

Week 2C REGULATION OF SVR AND FLOW DISTRIBUTION

- 8 -

pO2 (mmHg) O2 saturation (%)150 100% (room air)100 97% (alveolar gas)40 75% (venous blood)28 50%

Role of Vascular Resistance Control:o inadequate tissue flow ischemiao excessive tissue flow hyperemia

vascular resistance is controlled almost exclusively at the level of the systemic arterioleo serve as gatekeepers to a tissue’s microcirculationo layer of VSMCs in media

VSMC are arranged in a helical layer in direct contact w/ endothelium gap jcts permit propagation of APs and maintenance of uniform resting potential maintain a tonic force mediated by cytosolic calcium concentration

many receptor-operated channels control Ca++ influx (adrenergic, histamine, 5HT, etc…) tone:

intrinsic controlo adjust vascular resistance to match flow to the tissue’s metabolic requirementso myogenic -- ↑ VR to ↑ inflow pressure (mechanism unknown)o endothelial -- ↓ VR to ↑ flow rate (shear stress NO)o metabolic -- ↑ adenosine vasodilation

extrinsic controlo adrenergic NSo get blood to places that need it (fight or flight)o can 1. alter total SVR or 2. repartition blood among the vascular beds

Examples from small group:o ↑ SVR in response to ↓ CO helps maintain BP

selective for beds suck as cutaneous, renal, and splanchnic

CIRCULATORY ADAPTATIONNS TO EXERCISE IN HEALTH ↑ metabolic rate drive primarily by ↑ in skeletal muscle activity principle substrates are oxygen and compounds that can be oxidized to generate the energy required to synthesize

ATPo exceeding the rate of ox phos anaerobic metabolism but ultimately limited by lactate

adequate oxygen delivery requires:o Hbo transfer rate to the lungso blood flow to the exercising muscle (CO)o oxygen extraction from the bloodo appropriate distribution of CO to different vascular beds

O2 transport (mLO2/min) = CO(Lblood/min) x AVO2D(mLO2/min)

Oxygen Consumptiono measured as the volume/minuteo normal range for resting oxygen consumption for an adult is ~3.5mL/kg/min = 1MET

a sedentary healthy person’s maximum oxygen consumption is 10-12 METs well conditioned athletes can reach 20 METs or more

Normal CV Response to Exerciseo Examples:

Healthy sedentary 40yo deconditioned people ↑CO by ↑HR (stroke volume doesn’t change) in “normal exercise” SV is ↑ early then HR later in a linear fashion

Healthy 40yo med student

- 9 -

↑CO by ↑SV early then HR during the last 60% 40yo marathon runner

SV and HR ↑ early on during the early stages of exercise, venous extraction of oxygen accounted for a large

portion of VO2↑ while during the latter 2/3 an ↑ in CO accounted for most of the difference

remember that CO ↓ quickly at end of exercise while vasodilation can remain for a few minutes syncope if stop too fast

CIRCULATORY ADAPTATIONS TO EXERCISE IN DISEASEo Examples:

acute loss in blood volume: to maintain CO the HR is ↑ but the SV is ↓ (volume depleted) the mixed venous saturations are low since the mm have extracted as much oxygen as is

available and total oxygen carrying capacity is low myocardial ischemia

angina limited the exercise MAP ↓ because CO couldn’t keep up with vasodilation

myocardial ischemia w/ β blocker ↓HR means ↓ myocardial oxygen consumption so ↑SV because more efficient

Week 2H CARDIAC ADAPTATION: ACUTE AND CHRONIC CHANGES IN LOADING CONDITIONS

Type of Load

Causes Adaptive Mechanism

Limitation Metabolic Cost diastolic wall stress contractility HR

Volume

↑ SV, EDV (also HR)

Exercise fill more (↑EDV) diastolic complianceCO state empty more (↓ESV) myocardial shortening requires ↑ inotropy

(symp)Regurgitation (leak)

↑HR 220-age ↑ metabolism

Pressure

↑ SBP (Eje P), ↓SV, ESV, afterload

SNS Begin contraction at ↑ EDV (

diastolic compliance ↑ diastolic wall stress↑ peak systolic wall stress

Stenosis ↑ inotropy myocardial properties ↑ peak systolic wall stress

the maximal achievable EF is 80-90% ventricular hypertrophy – remodel LV to better size/geometry to support load (nl mass = 71g/m2)

wall stress = P x r / hP = systolic BPr = chamber radiush = wall thickness

Volume Overload Pressure Overload- 10 -

requires resting LV to generate stroke volume btw 100-200mL/min2

requires LV to generate systolic pressure of 180-250mmHg

aortic regurgitation dilation = ↑ the chamber radius so need to ↑ wall

thickness to reduce wall stress eccentric hypertrophy (RWT = 0.34, nl) distortion in overall shape of heart change in myocyte length ↑ diastolic wall stress

aortic stenosis ↑ pressure means wall thickness needs to ↑ to

compensate concentric hypertrophy (RWT > 0.45) change in myocyte thickness ↑ systolic wall stress

Week 2J CONGESTIVE HEART FAILURE

I. Heart failure a. heart unable to pump blood at a rate that can meet body’s requirements or need an elevated filling

pressure to do sob. myocardial failure is the most common cause (also ischemic heart disease, valvular heart disease,

constrictive pericarditis, systemic d/os)c. NOTHING TO DO WITH EJECTION FRACTION

II. Sx a. of HF: dyspnea, fatigue, exercise intolerance, swelling; acute OR chronic (MI vs. cardiomyopathy)b. of Volume overload

i. Pulmonary congestion ii. Gisceral congecst ion

iii. Peripheral edema iv. JVD, + HJR, peripheral edema, ascites, displaced, diffuse apex, gallop rhythm

c.III. Classification by NYHA:

I asymptomaticII sxs at moderate to strenuous exertionIII sxs w/ mild exertionIV sxs at rest

IV. Physiological compensatory mechanisms a. preload b. contractile elements c. HRd. contractility

- 11 -

- 12 -

V. Ventricular Remodelling a. Eccentric

i. Due to volume overload ii. FAILURE TO CONTRACT

iii. Heart loses normal apex (geometry changes and loses apex to become more sphere like)

iv. Mitral valve regurgitation b/c L V dilated (mostly with systolic HF)

b. Concentric i. Due to pressure overload

ii. Parallel fibers; cell thickens

- 13 -

iii. Walls thicken so much it starts to encroach on the L atriumiv. Elevated Atrial Pressure causes L A distension v. Failure to relax

VI. Relation to LBBB ( QRS duration 30 160ms)a. Ischemic HD or Cardiomyopathy risk for LBBB (27 53%)

I. Pathophysiologic Mechanisms of CHFA. Mechanisms available to stabilize:

a. ↑ preload (Frank-Starling)b. hypertrophy (↑ contractile elements)c. ↑HRd. ↑ inotropye. accomplished through renin-angiotensin-aldosterone system and adrenergic system!

B. In the failing myocardium: a. RAA system activatedb. ATII

Heart +inotrope/chronotrope/LV growth.hypertrophy/remodeling

Adrenal ALD production/release Brain SNS, stimulates thirst, Na appetite, ADH release, Brain ↓release of Renin, release of NE Kidney Constricts Afferent and Efferent vasculature

Constricts mesangial cells Stimulates proximal tubular absorption of Na and HCO3

Vascular Sm Muscle Hypertrophycollagen/fibroblasts, interstitum thickening

C. ↑ circulating NE a. arrhythmias may be provoked by sympathetic overdrive

D. secondary aldosteronism a. Production by zona glomerulosa (stimulated by plasmia

ATII)b. Commensurate ↓25-50% hepatic perfusion (poor

clearance by poorly perfused liver) c. Sx: volume overload, salt craving

E. Arginine vasopressin a. Post Pituitary b. Stimulated by ATII/Baroreceptors c. Systemic Vascular Resisterd. Reduce free water clearance from kidney e. CO

F. ↑ cytokines (not amelioirated by antagonist drugs) a. endothelial abnormalitiesb. ↓ NO production vasoconstrictionc. 2 Class (Vasoconstrictive (endothelin) and Vasodepressor

proinflammatory: TNFa and IL6d. NOT causative but leads to progression of myocardial

fibrosis through SYSTEMIC effects e. Sx: fatigue anorexia, CACHEXIA, Remodelling, ANEMIA OF CHRONIC DISEASE

- 14 -

G. skeletal muscle abnormalities (changes may not be reversible)a. Inadequate mitochondrial O2 Consumptionb. ↓endurance, ↓oxidative capacity, c. ↓strength due to δsmaller cross-section area d. Irreversible

II. Compensatory Activites of the Heart1) ↓adrenergic signaling

a. downregulation of β-1 receptors,b. uncoupling of β-2 receptorsc. IN REALLY bad heart

2) Natriuretic Peptides (ANP and BNP)a. Produced in ATRIAL and VENTRICULAR CELLS b. BNP >> ANP ( is prognostic)

III. Treatment of CHF(systolic with ↓EF) MUST RULE OUT CORONARY or VALVULAR HEART DISEASE (is surgery an option?)

a. Prevention (Stage A ) vs. Reversal (B,C,D)b. 1st line therapy: ACE inhibitors c. 2nd line ARBs (if cough with ACEi)d. ↑ ACE activity ↑ bradykinin breakdowne. SOLVD Study

i. Shows that remodeling (LV mass/hypertrophy) can be stopped with Enalapril vs. Placebo @ 12months; turns back the clock

f. Rales Study (spironolactone/epleronone) to ↓ALD g. Beta blocker

i. LVEF over a few weeks with best dose h. Vasodilators ie. hydralazine best for AA who do not respond to 1st line Tx i. Cardiac Resynchronization Therapy (for pts with LBBB)

IV. Treat of CHF with preserved LVEF (diastolic) a. Treat underlying condition b. Treat HPTN, diuretics as needed (DIURETIC ONLY IMPROVE SX, DO NOT IMPROvE SURVIVAL) c. Only large study used ARB (but ARB and ACE inhibitor can be used)d. Β-blocker in some instances

- 15 -

- 16 -

SHOCK AND OTHER INADEQUATE CIRCULATORY STATES

A. BP Regulation a. Large arteries provide impedance b. Arterioles provide resistance and ctrl blood flow c. Systemic vascular resistance

- 17 -

i. Regulated by SNS (barorreceptors, chemoreceptors, catecholamines)ii. Local autoregulaton (Cerebral, coronary, renal)

iii. Humoral control (RAS) B. Monitoring shock response using PAC

a. Right heart pressures (RA and RV) b. Pulmonary artery wedge pressure (PAWP) assess LVEDP/Vc. CO via Fick or Thermodiluion d. Calculate SVR

C. Shock is acute circulatory collapse a. inadequate delivery of oxygen and other substrates to the tissuesb. result of a variety of pathophysiologic processec. high mortality!d. Shock Classification by Pulmonary Artery Catheter:

YOU MUST KNOW THIS TABLE

Causes Rx RA/RV PAWP CO SVR

hypovolemic – ex. hemorrhage:o 15% volume

loss resting tachycardia

o 20-25% volume loss orthostatic hypotension

o 30-40% volume loss hypotension and oliguria

o > 40% volume loss obtundation and circulatory collapse

blood loss or volume depletion

Inadequate preload

↓ preload compensation: SNS activation to SVR

Rx – IV fluids ↓low vol

↓low vol

↓low vol

↑reflex

distributive (SEPSIS; SUDDEN DIFFUSE INFLAMMATION) –

Sepsi (mediated by endotoxin, IL, TNF )s,

TSS, post-op, pancreatitis, trauma,

Addison’s, Myxedema, anaphylaxis

excess vasodilation

w/ maldistribution of blood flow

supportive, volume

administration,

nl nl ↑ (early)vasodil

↓leaky

cardiogenic – usually due to ACUTE event, ie. MI and loss of pump fxn (high mortality)

Acute MI, myocarditis (pump fail), acute valve

disease (ruptured papillary, etc.), acute

mechanical complicateion of MI

(ASD, VSD), dysrhythmia

↓CO ↑ filling pressures compensatory ↑ SVR

viscous cycle – the ↓bp can ↓ coronary

revascIABP “balloon pump” can inflate and obstruct the aorta and deflate before onset of systole

↑backup

↑backup

↓failure

↑maintain

bp

- 18 -

perfusion/ichemia which ↓bp, etc….

Used to diastolic pressure and ↓afterload

obstructive – mimics

hypovolemia but see elevated R heart pressures

TAMPONADEsee equalization of diastolic pressures in Atrium and ventricles

obstxn to R heart flow

acute pulm embolism,acute pulmonary HTN,

pericardial tamponade tamponade

(SPECIAL CASE OF OBSTRUCTIVE)

Acute: small volumes are critical

Chronic: V by a lot more (compensations)

see pulsus paradoxus – exagerrated ↓ in SBP w/ inspirationo

causes ↓LV preload

Pathophysiology: P in pericardial sac that causes the heart chambers to collapse (LV collapse)

thrombolytics for APE,

drain tamponade, support w/

volume

↑ ↓ ↓ ↑

D. Using ECHO to assess Hemodynamics a. IVC size and collapse – marker of SVP (RA pressure)b. LV size (underfilled, nrml, or dialted )c. LVEF (low, nrml, hyperdynamic)d. Doplar derived CO calculate estimated SV and CO based on Doppler

E. Ischemic Shock anaerobic metabolisma. inefficient eventually get cell deathb. cellular abnormalities in shock:

i. membrane damage, mt damage, lysosomal enzyme release, complement activation, eventual cell death

c. organ dysfxnF. Stages of Shock

1. preshock – early “compensated” stage reflex sympathetic activation tachycardia, ↑

inotropy, peripheral vasoconstriction bp and CO initially maintained SHOCK DOES NOT MEAN LOW BLOOD PRESSURE ONLY!

2. frank shock overwhelmed regulatory mechanisms 25% ↓ in systemic blood volume

- 19 -

large ↓ in CI urine output ↓ signs of end organ dysfxn tachypnea, tachycardia, ↓bp, oligurea

3. end organ failure ischemic acute tubular necrosis altered mental status lactic acidosis multisystem organ failure death

G. Rx TREAT THE UNDERLYING CAUSE

SHOCK WORKSHOPCommonly used drugs for shock:

Remember: nl urine output = 35cc/hr look for: cool clammy skin, Hb, renal fxn, mental status don’t give β blockers in cardiogenic shock – they’ll ↓HR and ↓CO

making him worse

Week 2L CARDIAC METABOLISM AND ISCHEMIA

I. Definitions a. Ischemia – temporary lack of blood supply in a tissue or organ (relative to the tissue requirement)b. Hypoxia – lack of oxygenc. Metabolism

d. resting – heart uses ~11% of whole body calorie consumptione. exercise -- ↑ 4x w/ 8x ↑ in total body oxygen consumptioni. pumping efficiency is 10-20% at low work and 35-45% at high work rates

ii. heart is very efficientf. enzymes of cardiac myocytes – i. mitochondria occupy about 30% of tissue volume

ii. myoglobin is highiii. creatine kinase is present and highly activeiv. respiratory enzyme content and average cardiac work rate are correlatedv. glucose uptake by inducible, insulin dependent transporters (GLUT-4)

a. glucose metabolism becomes important in ischemia

- 20 -

Drug ActionsDopamine renal vasodilator

vasodilator/inotropevasoconstrictor

Dobutamine inotropevasodilator

Milrinone vasodilatorinotrope

Nitroprusside vasodilatorIsoprotenerol inotrope

vasodilatorvasoconstrictor

Norepinepherine inotropevasoconstrictor

b. glycolysis provides ATP in circumstances of acute oxygen deficit (ischemia)c. this ATP is the primary source for membrane transporters and pumpsd. glucose oxidation is critical for the restoration of nl myocardial fxn following a period of ischemia-reperfusione. during severe ischemia glycolysis is detrimental in that it allows H+ accumulation from anaerobic glycolysis and

ATP consumptionf. upon reperfusion: Na+/H+ exchange ↑ Na+in which ↑Ca++ cell death

II. Energy Metabolism:a. Preference fatty acids > glucose b. regulated by malonyl CoA levels which are modulated by acetyl CoA carboxylase levelsc. transported in plasma bound to albumin, TGs (in VLDL) or in chylomicronsd. heart has specific binding protein that binds to CoA activated acyl groupse. glycolysis is largely inhibited in the heart – fatty acids block pyruvate dehydrogenasef. primary regulation via PFK rxng. in ischemia GAPDH is the impt regulation pointh. heart readily takes up lactate even under resting conditions

III. Overall Regulation of Cardiac MetabolismIV. glucose utilization is inhibited by FA and/or ketone oxidationV. FA ox is inh by glu catabolismVI. glu utilization is stimulated when ox phos is blocked (b/c need to use lactate!)

a. Oxygen and cardiac fxnb. facilitated diffusion of oxygen via myoglobin allows cardiac mt to be distributed throughout the volume of

the heart and not just near the membranec. Calcium

a. activates F1F0-ATPase ATP b. simultaneously ↑ consumption of ATP c. SR calcium ATPase (SERCA2a) – pumps calcium back into SR

a. activity ↓ by phospholambanb. phosphorylating phospholamban inhibits it and gets more calcium in

i. phospholamban hyperPO4 in HF c. ↑ inhibition can lead to dilated cardiomyopathy and heart failured. SERCA levels ↓ during heart failure

d. Creatine Kinase Rxna. cytoplasmic ATP levels buffered by creatine kinaseb. PCr + ADP + H+ ATP + Crc. rxn allows the heart to maintain a high ATP/ADP even if the energy demand transiently passes synthesisd. “phosphocreatine shuttle”

Ischemiaischemic preconditioning nl reversible injury phase is 15min, but we may demonstrate a prolonged

period of reversible injury – short episodes of ischemia may result in prolonged protection of the myocardium

may minimize the effects of occlusionstunning reversible decrease in contractile fxn following reperfusion in the absence of

infarction may involve both free radical damage and proteolytic modification of cardiac

- 21 -

proteins gradually reversed after reperfusion

infarcting and failure with prolonged ischemia cytoplasmic Ca++ rises and mt take up Ca++ free radical generation high on reperfusion cytochrome C release and apoptosis

ischemia-reperfusion FAox upon reperfusin may become uncoupled yielding free radicals low capacity of glutathione peroxidase upon reperfusion reperfusion injury can result

hibernation persistent contractile dysfunction in the setting of a compromised arterial blood supply

w/ 30% reduction in blood flow (chronic, sub-lethal ischemia – stenosis!) whole-cell adaptation to use ↓ energy ↓ contractility to save energy shift in cardiac isoforms, ↓ myofibrils ↑ glucose uptake and glycolysis quickly reversed after reperfusion

Week 2L REGULATION OF THE CORONARY CIRCULATION

I. Myocardial Oxygen DemandA. Determined by

a. myocardial wall tensionb. myocardial contractilityc. heart rate (ie. exercise)

Blood flow = O2 Demand II. Coronary Arteries

1. Epicardial arteriesA. Large, conductance vesselsB. arise from the ascending aorta

1.intima = thin2.media = sm muscle 3.adventitia= supportive

C. site of obstruction in coronary diseaseD. site of angioplasty/bypassE. LM LAD (diagonal/septal br) + LCX (obtuse

marginal)1.anterior, anterior IV, lateral portions of

heart2.LAD lesions

cause 40-50% of myocardial infarcts ant wall, ant 2/3 of IV septum, LV apex

F. RCA PDA and posterolateral branches1.inferior and infero-lateral portions of the heart2.supplies sinus node (60% SA artery from proximal RCA; 40% from Circumflex) and AV node (90%

distal RCA, 10% circumflex)3.RCA lesions

cause 30-40% of myocardial infarcts involve the inf/post free wall of LV, post 1/3 of IV septum, sometimes to post inf RV

- 22 -

2. Small coronary arteries A. smaller penetrating arteries

1.can form collaterals2.invisible on angiograms

B. intramyocardial coronary arterioles1.majority of coronary vascular resistance (95%)

C. capillaries1. density in sub-endocardium >> sub-epicardium 2. subendocardium more vulnerable to ischemia

3. Regulation of Flow in the Microcirculation1. 1ary control of blood flow in micro not epicardial level

a. Arterioles responsible for 95% of CVRb. Sets basal resting tone and the response to O2 demand

2. Coronary flow is determined by the driving pressure into the coronary arteries and the vascular resistance of the coronary arterial system

a. Pressure and Resistance are Regulated by i. myogenic regulation

1. constriction of vascular sm mucle in response to PP or dilation due to ↓PP2. Constriction (Via stretch induced depolarization of smooth muscle3. Vasodilation (via K ion efflex)4. Helps maintain nrml flow despite changes in PP

ii. endothelial regulation1. ENDO-dependent Vasodilation mediated by secreted NO

a. endothelial cells synthesize NO from L-arginine using NO synthase i. cGMP in vas sm muscle cells

ii. Basal levels present if NO synthase is inhibited under basal contidtions, moderate vasodilation will be observed

iii. two major isoforms: constitutive (maintain tone) and inducible (respond to shear stress)

iv. Release stimulated by v. Pulsatile stress (Shear stress by flowing blood and from contractility of

heart) stimulate NO release in resting statevi. Other mediators (ie. bradykinine, ATP< ADP, prostacylin)

2. ENDO-independent (exogenous nitroglycerin, papavarine, CaChl-Ant) iii. metabolic effects

1. ie. adenosine iv. neurohumoral effects

1. α agonists (vasoconstrict)2. β1: vadodilate via metabolic demand 3. β2 directly vasodilatory (ie. ISO)

a. cholinergic: (see ACh )i. Used to assess endothelial fxn

ii. if endothelium is damaged, iii. NO release is impaired cause paradoxical vasoconstriction due to M3

rec effectsiv. TREATING Atherosclerosis can improve this response v.

b. Relationship defined by I = E/R; Q = P/R, i. Q = flow

ii. P =pressure gradient

- 23 -

iii. R = vascular Resistance c. Driving pressure

i. perfusion pressure = central aortic pressure – LVEDP (most coronary flow during diastole)ii. Myocardial compressive forces

1. forces on subendocardial regions (due to density of arterioles)2. Creates “extravascular resistance”

a. If ↑ HR ↓ diastolic time for deliveryb. More flow in DIASTOLE c. Extravascular R on SubENDO >> subEPI

HENCE SubENDO is more vulnerable to ischemia d. Vascular resistance – generated mainly by smaller intramyocardial arteries and arterioles

i. Autoregulation1. coronary flow is held constant over a wide physiologic range of pressures2. resting and maximal flow can be maintained despite a substantial epicardial stenosis

ii. vasodilator reserve (Defined by 2 Resister model, where Q = I (R1 + R2) and R1 and R2 are the resistance of arterioles vs. epicardial vessels

1. amount by which resistance can be decreased to compensate for epicardial stenosis (up to 50% stenosis)

2. Reserve is high until a “breaking pt” at which cannot restrict any more and atherosclerosis of epicardial vessels’s will cause rapid rise in EVR

3. epicardial resistance normally LOW, artierolar resistance normally HIGH4. this reverses in case of epicardial stenosis

3. Measurement of Coronary Flowa. PET, MRI, or thermodilution b. Measure vasodilator reserve by

i. Doppler flow probe or ii. Fractional flow reserve using MP change after vasodilator dose

4.

Week 2M Ionotropic Agents A. Ionotropic Agents

a. Ca is final common pathway b. All mediated via cAMP c. Mechanism of how [Ca] is increased gives rise to differential toxicity profiles

B. Digitalis a. 1st drug and most commonly prescribed b. Extract of foxglove c. Bind Na/K/ATPase; causes UP and LEFTWARD shift of the starling curved. K+ decreased digoxin binding (protective against digoxin poisoning)

- 24 -

e. NO DESENSITIZATIONf. RENAL TOXICITY

- 25 -

Week 2U MECHANISMS OF BRADYARRHYTHMIAS

I. Dysfunction of SA nodea. Cause

i. Lack of transmission 1. Sinus exist block-intracardiac 2. Firing ok

ii. Lack of conduction at alliii. Treatment is safe but can be distinguished on EKG

b. Manifestations i. Sinus bradycardia

ii. Sinus arrest 1. Compensation: Wide-junctional beat (AV node or His, beat will be generated after a

pulse if SA fails to generate beat)iii. Chronotropic incompetence

1. Heart can’t adjust rate to meet metabolic demands 2. Criteria:

a. Failure to achieve appropriarte HR w/ exercise (70% max HR = ~220-age b. Failure to achieve >100bpm doing ADL during dayc. DELAYED SA Node recovery time (after artificial pacing of atria to see when the

node starts again) may see junctional beat after overdrive suppression iv. ’tachy-brady syndrome’

c. Physiologic (Strong vagal input) due to sudden burst of catecholamines (ie. see blood and faint) II. can’t see AV conduction on the surface ECG

III. place catheter in the region of the His bundle as it traverses the tricuspid valve

IV. His Bundle Electrogram (HBE)a. records local activity around AV node (A)b. His Bundle activity (H)

local ventricular activity (V)V. AH interval (60-125ms)

a. measures AV nodal cdxnb. disturbances usually reversible, drug induced, respond to atropine, high

escape focusVI. HV interval (35-55ms)

a. measure His-Purkinje activityb. disturbances usually ominous, not drug responsive, progress to a low escape focusc. used to determine the mechanism of arrhythmias

VII. AV Conduction Block1. 1st degree – AV DELAY

b. ↑ PR interval >200msc. Usually due to conduction slowing at AV node d. either prolonged AH or HV (block at either AV N or at HisPerk Sys)

2. 2nd degree – intermittent cdxnA. Type Mobitz I (Wenckebach)

Narrow QRS Block at AV node Pathognomic: progressively longer PR until a beat skipped

“decremental conduction” “not so bad” Grouped beating (ie. every 3 beat, 1 drop)

- 26 -

Recovery beat always has shorter PR interval right after skipped beat B. Type Mobitz II

PR constant “all or none” wide QRS At HIS-Perkinje; BELOW AV NODE sudden cdxn block usually limited to His-Purkinje Unpredictable blocked beats Less likely to have reliable escape rhythm

C. 2:1 block narrow QRS: either AVN or infra-His (usually AVN) wide QRS: escape focus in ventricle

D. 3rd degree – complete heart block no AV cdxn – P waves and QRS not related

V 2nd Degree Mobitz II vs NRML

Week 2W MECHANISMS OF TACHYARRHYTHMIASI. Definition

a. HR >100bpmb. Most frequently caused by reentryc. Severity of Sx related to HR and presence of structural defect d. SV-Tach Narrow QRSe. V-Tach wide QRS

II. Mechanisms:a. reentry (d/o of impulse conduction)b. triggered activity (d/o of impulse formation)c. automaticity (d/o of impulse formation)

Wide QRS Narrow QRS

ventricular tachycardia ventricular fibrillation torsade de pointes

regular irregular

short RP long RP atrial fibrillation (no P waves;)

wandering atrial pacemaker (P rate<100bpm)

multifocal atrial (P rate >100) tachycardia

typical AVNRT BPT tachycardia atrial tachycardia

atypical AVNRT sick sinus BPT tachycardia atrial tachycardia atrial flutter big

cycle around

- 27 -

tricuspid, atrium activated same time each circuit (typically <100bpm)

III. sinus tachycardia – upright P in I, II, IIIIV. atrial fibrillation

a. replacement of P by undulations, “bag of worms” (especially in lead V1 describes what activation sequence looks like, doesn’t beat)

b. Ventricular response abnrl, usually fast at rest and very fast in exercise c. NO PATTERN d. Etiology: HTN, post-CABGe. Sequelae: palpitations, ↓exercise tolerace, risk for stroke (LAA thrombus), and death

V. atrial flutter a. “sawtooth” pattern (Esp inferior leads) b. atrial rate is ~300bpm; circuit SOMEWHERE c. Ventricular response regular, integral relationship (2:1, 3:1, 4:1…)d. Associated with heart disease (HTN)

VI. paroxysmal supraventricular tachycardia (PSVT)a. SEE NORMAL QRS (in AV node or in atrium coming over) b. Etiology: catecholamines, exercise, caffeine, emotional upset c. sxs of palpitations/syncoped. atrial fibrillation (irregular rhythm only) e. AVNRTf. AV Reentry BPT (WPW)g. Atrial tachycardia (focal rhythm)h. Atrial flutter

VII. ventricular tachycardia a. wide QRS regular tachycardiab. etiology, advanced structural heart disease, esp healed MI

VIII. ventricular fibrillationa. QRS complexes replaced by chaotic low amplitude activity b. Associated with lack of pulsatile CO and immediate loss of consciousness c. Complications of acute MI and ischemia

Mechanisms of Arrhythmogenesis:a. Disorders of impulse Condition (reentry)b. Disorders of Impulse Generation (automaticity, triggered activity)

I. Reentry = “ circles” are developed when these conditions are fulfilled a. two distinct pathways for cdxn that haved joined and formed a loopb. the two pathways must be sufficiently different to allow for unidirectional block in 1 of them in the

presence of a premature stimulus c. slow conduction in some part of or the entire circuit but that allows recovery at the site of initial block

“failure of top to bottom”

Clinical Examples:IX. Wolff Parkinson White Syndrome and AVNRT

a. BPT (bypass tract) conducts rapidly long refractory periodb. AVN (AV node) conducts slowly short refractory periodc. BPT activation causes a delta wave in the QRS of the WPW ECG

- 28 -

d. premature impulse blocks in the BPT (long refractory) and conducts slowly in AVN (no delta wave in the early beat)

e. if it hits the BPT at just the right time, sets up reentry (below)

3. if VT – no relationship between A and H means ventricles driving the rhythm (H and V remain tied together)4. if SVT – A still driving H and V

PacemakersFour Letters Used to DescribeAVD

AVDO

InhibitoryDual

R

chamber paced chamber sensed

I won’t fire if native beat firstD inhibit AND trigger atrium

rate responsiveness

X.

XI. AV Nodal Reentrya. entire circuit contained w/in the AVNb. in this case see atrial echo on ECG ( LA is activated in a retrograde fashion after the QR

- 29 -

XII.XII.XII.XII.XII.XII.XII.XII.XII.XII.XII.XII.XII.XII.XII.XII.XII.XII.XII.XII.

Atrial Flutter and Ventricular Tachycardia (“fitting the tachycardia into the reentrant circuit”)a. atrial flutter represents reentry in the RA around the tricuspid valveb. if the arrow catches its tail (hits tissue that is refractory) the reentry stopsc. ventricular tachycardia is facilitated by slow conduction (in tissue that has survived infarct)d. antiarrhythmics may trigger reentry by slowing conduction rate and likelihood that wave will reach

repolarized cells that can less likely to catch its tail (if moving slower)XIII. atrial and ventricular fibrillation

a. Mechanism: Multiple Wavelet Reentry1. need a set amount of surface area to propagate (small animals don’t get it)2. minimum number of wavelet in humans = 6 to self-propagate

b. afib may start with flutter in pulmonary veins that self propagate (LA more prone to afib)c. Pro atrial-fibrillatory factors “bigger and slower”

1. need a set amount of surface area to propagate (small animals don’t get it)2. Differences in regional patterns of refractoriness 3. atrial size 4. Replacement of working (electrical myocytes with fibrosis) decreases conduction 5. Progression of atrial fibrillation (A-Fib is a disease among elderly)

a. Remodelling i. Electrical (↓refractory period (↓wavelength)

ii. Chemical (Ca overload)iii. Structural (atrial stuning, progressive enlargement)iv. Genetic (intermediate term changes in mRNA expression)

b. AF progresses (frequency, more likely persistent)

XIV. Automaticity: a. Nrml is SN (phase 4 epolarization) mediated by If, closing of K channels, opening of T and L type Ca

- 30 -

b. abnl automaticity occurs in cells that are less than completely repolarized – automatic tachycardias can result

XV. Triggered activity:a. regenerative response =reactivation of the local action potential without preceding electrical quiescenceb. sudden depolarization during repolarization c. afterdepolarizations may lead to a separate AP that ultimately lead to fibrillations and reentry d. early due to LONG QT intervals (reopening of Na/Ca channels during long APD) e. late due to cytosolic Ca overload (as digoxin toxicity) f. Torsade de Pointes

a. occurs in the setting of a prolonged QT interval (genetic or drug-induced)b. Triggering event is often afterdepolarizations

XVI. Treatment for tachyarhthmias a. Altering the conditions so reentry could no longer occur (ie. if 1 is slowed and 2 pathway is reentering

through 1, then block 1 completely)

- 31 -