Micro: Septic Shock

Sepsis: syndrome (many potential causes resulting in same physiologic effect).

Cause: infection (bacteremia [most common]; fungemia; parasitemia; viremia);
septicemia (spread of microbes or toxins via bloodstream).
5 Stages:
1 Systemic inflammatory response syndrome (SIRS)
general syndrome (caused by infection, pancreatitis, trauma,

burns, ischemia, tissue injury).

2 of 4:

hyperthermia (>38C) or hypothermia (<36C)

Resp rate > 20 or PaCO2 <32torr

HR > 90, 100 (mims)

Leukocytes >12000/uL or < 4000/uL or >10% bands.

1 Sepsis: SIRS with confirmed/suspected infection.
Sx: fever/hypothermia; tachycardia; subnormal BP; subnormal urinary

output; increased CO; decreased peripheral vascular resistance.

1 Severe sepsis: sepsis with hypotension.
Sepsis-induced hypotension: SBP < 90 mmHg; decrease at least 40

mmHg from baseline BP (in absence of other causes). Can be corrected

with fluids or vasopressors.
1 Septic shock: sepsis with persistent hypotension (irreversible,
unresponsive to fluids).
hypotension organ dysfunction (disorientation; confusion;

agitation; coma)
perfusion abnormalities.

1 Multiorgan dysfunction syndrome (MODS): sepsis with altered organ

function (mild dysfx to organ failure).
Epidemiology: very young (neonates) and very old (> 60; nosocomial); > 750k
cases/year; 21.6-50.8% mortality (shock 55-65% mortality).
Causes:
Bacterial: #1 cause.
Gram + cocci: S. aureus; S. pneumoniae; S. pyogenes.
Risk factors: vascular catheterization; indwelling mechanical devices;
burns; IV drug use; toxin-mediated (non-bacteremic; TSST-1).
Gram - rods: E. coli; K. pneumonia; Proteus; Pseudomonas (Ab therapy;
burn wounds); Bacteroides (anaerobic septicemia).
risk factors: diabetes; lymphoproliferative diseases; liver cirrhosis;
burns; invasive procedures/devices; neutropenia; sickle cell
(salmonella).
Fungal: less common; Candida, Aspergillus.
Lower respiratory infections: s. pneumoniae; k. pneumoniae; s. aureus; e. coli;
legionella; haemophilus; anaerobes.

GI: e. coli; e. faecalis; bacteroides; acinetobacter; pseudomonas; enterobacter;

salmonella.
UTI: e. coli; proteus; klebsiella; pseudomonas; enterobacter; serratia.
Soft tissue infection: s. aureus; s. epidermidis; streptococci; clostridia; GNR;
anaerobes.
Infection of repoructive system: Neisseria gonorrhoeae; GNR; streptococci;
anaerobes.
Foreign bodies: s. aureus; s. epidermidis; fungi/yeasts (candida).
Other: Neisseria meningititis (most common).
Major nosocomial pathogens: aerobic gram baccili.
Neonates: highest risk of sepsis.
Early onset: group B strep (s. agalactiae); e. coli; h. influenze; l.
monocytogenes.
Late onset: s. epidermidis; s. aureus; e. coli; klebsiella; pseudomonas;
candida.
Infants: same as CNS; s. pneumoniae; n. meningitidis; h. influenza (not as
common now).
Malaria-endemic regions: p. falciparum
Dx: minimum of 2 cultures (89% sensitive in bacteremic patients); gram stain
blood/CSF/pleural fluid
(usually negative for blood stains).
Tx: stabilize patient (supportive care); remove organism (broad spectrum
antibiotics); manage
underlying disease (treat local infection; debride area; drain pus).
Virulence
Gram + bacteria:
Peptidoglycan: activate numerous host defense pathways.
Teichoic acid: intensifies response to peptidoglycan.
Superantigens: activate T cells (bind MHC to TCR outside antigen
binding site), induce cytokine response, septic shock (IL-2 production >
TNF- > shock).
S. aureus: toxic shock syndrome toxin-1 (TSST-1).
Mims: TSST-1 young women with staphylococcal infections of the genital tract

S. pyogenes: pyrogenic exotoxin (SPE).

Gram - bacteria: lipopolysaccharide (LPS); lipooligosaccharide (LOS;

Neisseria).
Endotoxin (LPS and LOS): dominant factor in gram sepsis.
Lipid A: elicit production of cytokines (TNF-); activate coagulation
cascade (DIC); activate complement cascade.

DIC: septemic infection causes TNF- release by macrophages

liver and spleen (into bloodstream); systemic edema causes
vessel collapse.

TNF-: inflam mediator secreted by activated

macrophages; activates vascular endothelium (increase
permeability); fever; mobilization of metabolites; shock
(peripheral edema).
Complement: LPS cleaves C3 (C3b cleaves C5); C5a promotes
neutrophil reactions (chemotaxis and aggregation;
degranulation; radical production).

GRAM - RODS: MacConkey agar (lactose fermentation).

Lactose fermenting:
E. coli (indole +)
K. pneumoniae (indole -).
Salmonella - Non-fermenter, H2S producing
Proteus - Urease +
GRAM + COCCI :
Staph aureus: Cata +, Coag +
Strep : Cata -hemolytic: S. pyogenes (bacitracin sensitive).
-hemolytic: S. penumoniae (optochin sensitive)
----Charcoal buffered yeast extract: legionella.
Chocolate agar: H. influenzae.
Bacteroides bile-esculin agar: bacteroides; gemtamicin kills enterococci.
this up???
Thayer martin agar: Neisseria
N. meningitides ferments glucose and maltose.
Oxidase positive: Pseudomonas.

Heart Failure
Physio
HEART FAILURE (Physiology Section Only)
(Hall, pp. 248-264, 273-282; 1021-1024, videos on portal)
Learning objectives:

Look

Upon completion of the assigned reading in Hall, the student will:

1.

Review the physiological changes that occur to the heart during and
after an acute myocardial infarction. Include a discussion of causes of death
after an acute coronary occlusion and the stages of recovery from an acute
myocardial infarction. (pgs 249-252, 256).
Acute coronary occulsion > blood ceases beyond occulsion

except for some collateral flow > muscle infarcted

Myocardial infarction
Infarction > collateral blood seeps into infarcted area + dilation

of local blood vessels > area overfilled w/ stagnant blood

Muscle fibers use up last of oxygen > Hb deoxygenated >

infarct area appears blue-brown, vessels appear engorged despite
lack of blood flow
Later stages:

Vessels become permeable, leak fluid. Muscle edematous.

Cardiac muscle cells swell d/t diminished metabolism >

w/in few hours of no blood, cells die
Subendocardial infarction - blood vessels in subendocardium

are compressed during systolic contraction, therefore any condition

that compromises blood to heard usually damages subendocardium
first then spread outward toward epicardium
Causes of death after acute coronary occulsion:
1. Decreased CO
Systolic stretch - when normal ventricular muscle

contract, the ischemic portion of muscle (dead or

nonfunctional) does not contract. Instead, it is forced
outward by the pressure inside the ventricle > dissipates
ventricular pumping force
Coronary/cardiogenic/cardiac shock (aka low cardiac

output failure)

Heart incapable of pumping enough blood into

arterial tree > peripheral ischemia > cardiac failure +
death of peripheral tissue

Results when >40% of LV is infarcted

Death in 70% of shock patients

Damming of blood in pulmonary blood vessels

Asymptomatic first few hours after MI.

Symptoms appear in a few days d/t:

Diminished CO > diminished blood to kidneys >

decreased urine excretion by kidneys adds to blood vol >
congestive sx > acute pulmonary edema > death

Ventricular fibrillation
More common after large infarct

Most likely occurs in first 10 mins after infarct or period of cardiac

irritability (starts 1hr later; lasts few hrs)
Factors that inc tendency to fibrillate:
Acute loss of blood to cardiac muscle > K+ depletion from
ischemic m. > inc [K+] in extracellular fluid around cardiac
m. fibers > inc cardiac m irritability
Ischemic m can't fully repolarize > external surface of
muscle stays negative > current flow from ischemic to
normal area causing abnormal impulses
Reduced BP after massive infarct > sympathetic reflexes
(also inc cardiac irritability)
Cardiac m weakness > excessive ventricular dilation > inc
pathway length for impulse conduction allows impulses
to re-enter muscle recovering from refractoriness > initiates
"circus movement" cycle of new excitation, process
continues on and on
Rupture of infarcted area
Few days after infarct, dead muscle degenerate > heart wall
stretched thin > systolic stretch > rupture > cardiac tamponade,
compressed heart > blood doesn't flow to RA > death d/t
decreased CO
Stages of recovery

Shortly after the occlusion, the muscle fibers in the center of the
ischemic area dies.
Then after a couple days this area of dead fibers becomes bigger
because many of the marginal fibers finally succumb to the prolonged
ischemia.
At the same time, because of enlargement of collateral arterial
channels supplying the outer rim of the infracted area, much of the
nonfunctional muscle recovers.
After a few days to three weeks, most of the nonfunctional muscle
becomes functional again or diesone or the other.
In the meantime, fibrous tissue begins developing among the dead
fibers because ischemia can stimulate growth of fibroblasts and
promote development of greater than normal quantities of fibrous
tissue.
Therefore, the dead muscle tissue is gradually replaced by fibrous
tissue.

Then, because it is a general property of fibrous tissue to undergo

progressive contraction and dissolution, the fibrous scar may grow
smaller over a period of several months to a year.
Finally, the normal areas of the heart gradually hypertrophy to
compensate at least partially for the lost dead cardiac musculature.
By these means, the heart recovers either partially or almost
completely within a few months.
degree of cardiac cellular death determined by degree of ischemia and
workload on heart muscle.
in tx of patient with MI absolute body rest during the recovery

process is a must
Describe the changes in the cardiac output curve, preload, afterload,
contractility and heart rate which occur after acute cardiac failure
(compensated heart failure) (pgs 255-257).
After damage, the immediate effect is:
Decreased CO

Damming of blood in veins > increased venous pressure

Because venous blood returning to the heart from the

body is dammed up in the RA, right atrial pressure increases

*This stage only lasts a few seconds before sympathetic nervous reflexes
occur to compensate
When CO falls low, the circulatory reflexes are activated and stimulate
sympathetic response:
Baroreceptor reflex

Chemoreceptor reflex

CNS ischemic response

Reflexes originating in damaged heart

> increase in sympathetic tone within a few seconds and inhibition of

parasympathetic nervous signals to heart
This affects the heart and peripheral vasculature.
heart becomes a stronger pump (increased contractility)

Increases venous return by increasing tone of blood vessels

(especially veins)
Raises mean systemic filling pressure

Increases flow back to heart

This further raises RAP and helps heart pump larger quantities of

blood (Increase Preload)

*This stage becomes maximally developed in about 30 seconds
After first few minutes of an acute heart attack, prolonged semichronic state begins characterized by:
Retention of fluid by the kidneys

Low CO has a large effect on renal fx -- can even cause

anuria when CO falls to half of normal.

To help increase CO (compensates for decreased pumping

ability)

also reduces venous resistance and allows for more ease

of flow of blood to the heart
Can be problematic if heart has already reached its max

pumping capability leading to

Edema (especially pulmonary)

Increased workload on heart

Overstretching of heart which weakens it

Varying degrees of recovery of the heart itself over a period of

weeks to months.
After damage > natural reparative processes help restore normal
cardiac fx
New blood supply penetrates portions of infarcted areas > much

of heart muscle to become functional again

undamaged portion hypertrophies offsetting much of cardiac

damage.
Recovery depends on the type of damage and has a wide range

After acute MI, maximal degree of recovery is achieved in

5-7 weeks
Point D on the graph is due to fluid retention which

increases RAP this will be maintained to keep CO normal (termed

compensated heart failure)

Summarize physiologic changes that occur following acute cardiac

failure including (1) instantaneous effect of cardiac damage, (2)
compensation by the sympathetic nervous system, (3) chronic
compensationsto maintain homeostasis. (Hall pgs. 260-257)
Point A: Prior to acute cardiac failure physiologic normal
Cardiac output = 5 L/min

Right atrial pressure = 0 mmHg

Point B: Instantaneous effect of cardiac damage

Pumping ability of heart is severely depressed causing

Reduced CO (2 L/min)

Damming of blood in veins inc venous pressure inc

return to RA increased RAP (4 mmHg)

Acute phase only lasts few seconds until compensatory
mechanisms kick in
Point C: Compensation by sympathetic nervous system
Sympathetics strongly stimulated (parasympathetics reciprocally
inhibited) w/in a few seconds of CO dropping
Heart becomes a stronger pump (via stimulation of non
damaged portions of ventricular muscle)
Increases venous return (via increase in tone of

vasculature increases mean systemic filling pressure)

Provides more blood returning to heart than usual & increased
pumping of blood
CO increase from immediate low level & right atrial

pressure rises
Light Green Curve: Chronic compensation to maintain homeostasis
After a few minutes of acute compensation prolonged semichronic state beings characterized by
Retention of fluid by the kidneys

Low cardiac output (below 5 L/min) dec urine

output
Moderate fluid retention is a compensatory

mechanism to increase blood volume

Increases pressure gradient increases

venous flow of blood toward heart

Distends veins > reduce venous resistance

increase blood flow toward heart

Normal urine output will not result until both CO &

RAP return to normal

Only beneficial as long as the heart is able to pump

at its maximum capacity

After a few days to weeks to months
Varying degrees of recovery of the heart (over a period of

weeks to months)
Point D: Partial recovery of heart + increased fluid retention
increases CO back to normal and maintains an elevated RAP

Describe the physiological events that occur in severe cardiac failure or

decompensated heart failure. (pgs 257-258)
severely damaged no amount of compensation (sympathetic or fluid
retention) will make heart pump normal CO
CO cannot rise high enough to make kidneys excrete normal

amount of fluid > Edema

Main cause of decompensated heart failure death = failure of heart to

pump sufficient blood to make kidneys excrete daily the necessary amount
of fluid
Figure 22-2: Graphical illustration of the physiological changes in
decompensated heart failure
Straight line CO = 5 L/min required to make kidneys

reestablish normal fluid balance

Point A: approximate state of circulation before any

compensation has occurred

Point B: state a few minutes after sympathetic stimulation

Cannot compensate enough to prevent fluid retention

As fluid starts to be retained right atrial pressure rises

Point C: state of circulation a few days after the heart failure

has begun
Diminished CO below normal means fluid continues to be

retained where?
RAP continues to rise

Point D: a few days later continued rise in RAP (d/t inc fluid

retention) & continued diminished CO (d/t lack of sufficient

compensation)
Point E: several days later CO output falls from point D d/t

overstretch of heart, edema of the heart muscle

All factors decrease hearts ability to pump

At this point fluid retention becomes detrimental rather

than beneficial (because no longer increasing CO towards normal)

Point F: Several days later CO falls to lowest value (2.5

L/min) & RAP at highest (16 mmHg)

At this point state of heart is incompatible with life =

decompensated heart failure

Overall failure of heart to have normal CO (and arterial pressure) for

normal renal function causes
Progressive retention of more and more fluid >

Progressive elevation of mean systemic filling pressure

Progressive elevation of the RAP

Until RA is so overstretched it can no longer pump

adequately

Define cardiogenic shock and explain how it contributes to heart

failure. (pg 259).

Discuss the progression of edema in the pulmonary and systemic

circulations in association with heart failure(pgs 259-261)

1.

Explain the changes in the cardiac output andvenous return curves,

which occur throughout the stages of heart failure. Describe the graphical
analysis of acute heart failure and chronic compensation, decompensated
heart failure, and high-output cardiac failure. (pgs 261-264)

1.

Describe the physiologic causes of circulatory shock and how changes

in cardiac output, venous return, TPRand mean arterial pressure can
contribute to this. (pg 273-274).

1.

Compare and contrast the physiologic changes which occur during

non-progressive, progressive, and irreversible hemorrhagic shock. (pgs 275279)

1.

Discuss the different types of positive feedback that can lead to the
progression of shock. (pgs. 259-263; 274-279; fig 24-3)

1.

Compare and contrast circulatory shock due to hemorrhage to

hypovolemic (dehydration, burns), cardiogenic, neurogenic, anaphylactic,
and septic shock. Include in the discussion the stages and progression of
the different types of shock and any hallmark signs of each type of shock.
Justify the treatment strategies for anaphylactic, burn, cardiogenic and
neurogenic shock (Guyton, pgs259-263; 273-281)

1.

Compare and contrast the overall blood flow pattern in the fetus with
that of a normal neonate, including the source of oxygenated blood.
Describe the structure, function and location for vascular shunts in the
fetus and changes which take place following birth.(pgs. 1021-1023; Video)

1.

Diagram the fetal circulatory system including the relative distribution

of blood flow to different vascular areas. Describe how this changes
following birth. (pgs 1021-1023; Figures 83-4 and 83-5; Video)

1.

Describe the relative differences in oxygen saturation and pressure for

blood in the major blood vessels and cardiac chambers of the fetus. Explain
how these values change following birth. (Video)
Oxygen content (highest to lowest): red > pink > purple > blue.

o
o

Before birth: increased pulmonary resistance (hypoxic pulmonary

vasoconstriction); increased right-heart pressure (due to high pulmonary
resistance).
After birth: reduced pulmonary resistance (air in lungs reverses
hypoxia induced vasoconstriction); drop in right-heart pressure (due to
reduced pulmonary resistance).

Describe the function in utero of the fetal ductusvenosus, foramen

ovale, and ductus arteriosus. Explain the mechanisms causing closure of
these structures at birth and how they lead to survival of the neonate.
Hypothesize the consequences if any of these fail to close (pg. 1023;
Review from pgs 269-270).

Ductus venosus: shunt to bypass liver (allow highly oxygenated blood in

umbilical vein to reach heart).
Foramen ovale: shunt RA to LA (bypass lungs).
Ductus arteriosus: shunt between pulmonary trunk and aorta (bypass lungs).
Ductus closure: smooth muscle contraction (lumen obliterated; due to
reduced prostaglandin levels).
Foramen ovale: entry of air into lungs causes dilation of pulmonary arterioles
(reduced pulmonary pressure); LA pressure now greater than RA pressure (no R
L shunt).

Clin
Monday, October 13, 2014
1:12 PM

1.

Define heart failure.

1.

State the incidence and prevalence of heart failure in the United

States.

1.

Define preload, afterload and contractility, and how changes in each

alter cardiac output.

1.

Define and calculate stroke volume.

1.

Define and calculate ejection fraction.

1.

Define and calculate cardiac output.

1.

Produce a left ventricular pressure volume loop indicating the locations

of valve openings and closings, EDV, ESV and SV.

1.

Diagram the effects of changes in preload, afterload, and contractility

on the pressure volume diagram of the cardiac cycle.

1.

List clinical relevant scenarios which can cause the changes listed
above.

1.

Discuss heart failure with reduced ejection fraction (i.e. systolic heart
failure).
1.
Discuss heart failure with preserved ejection fraction (i.e. diastolic
heart failure).
1.
Compare and contrast the treatment of heart failure with reduced
ejection fraction to that of heart failure with preserved ejection fraction, with
particular attention to treatments that provide survival benefit.
Reduced EF

Preserved EF

(i.e. systolic HF)

Cause 1.

Loss of contractility
(destruction of myocytes, abnormal
myocyte fx, fibrosis)
2.
Pressure overload (inc
resistance to flow)

1.
2.

ESPVR shifted down, inc ES.

Normal pulmonary venous return
added to inc ESV >diastolic chamber vol inc >
inc preload > compensatory rise in SV
3.
However, impaired contractility
and reduced EF cause ESV to remain elevated
Sx

Pulmonary congestion (d/t elevated LV pressure

during diastole > transmitted to LA, pul veins +
capillaries--cap hydrostatic pressure > 20
mmHg)

Tx

1.

(i.e. diastolic HF)

1.

impaired early diastolic

relaxation(an active energy
dependent process)
o
Acute myocardial
ischemia
o
Reversible:
pericardial constriction, cardiac
tamponade
2.
inc stiffness of ventricular
wall (passive process; LVH, fibrosis,
restrictive cardiomyopathy)
3.
both

Upward shift (inc vent P @ any diastolic V

> Dec EDV @ inc EDP

Vascular congestion (b/c inc diastolic P is

transmitted retrograde to pul and systemic
veins)

Correct cause, eliminate acute

precipitating cause of sx
1.
Tx pulmonary/systemic congestion
(Diuretics, dietary Na restriction)
o
Inc forward output (vasodilators, positive
iontropic drugs)
1.
Modulate neurohormonal
response*. Prolong long-term survival
Cornerstones are ACE inhibitor + beta blocker

Relive pulmonary/systemic
congestion

Diuretics
Address cause

Start w/ ACEi* (+ diuretic if

congestive sx)

ARB (or hydralazine +

isosorbide dinitrate) if pt is intolerant
to ACEi

+ B-blocker* (pts w/o recent

clinical deterioration or vol overload)

+ aldosterone antagonist
(spironolactone*) (advanced HF, class
III/IV)

Digoxin (persistent sx)

State the proportion of patients with heart failure that have

preserved ejection fraction.
1/2 of pts with HF fall into each of above categories

1.

Differentiate right-sided heart failure from left-sided heart failure.

Left Sided HF is described by the two categories already explained = HF
with reduced EF and HF with preserved EF
Right-sided HF

RV is thin walled, highly compliant

+ : accepts blood at low pressure, ejects against a low

pulmonary vascular resistance, accept a large range of blood
volumes w/o significantly altering changes in filling pressure

- : fails d/t sudden increase in afterload (acute pulmonary

embolism)

RV fails > elevated diastolic pressure transmitted retrograde to RA w/

subsequent congestion of systemic veins.

List the causes of right-sided heart failure (Table 9.2), and state the
most common cause.

MCC: presence of L-sided HF

Isolated R-HF = inc RV afterload dude to diseases of lung

parenchyma/vascul

Cor pulmonale =R-sided heart disease d/t primary pulm process

List the clinical manifestations of right-sided heart failure.

List the clinical manifestations of left-sided heart failure.
Right-sided HF

Sx

1.

RUQ/Abdomin
al discomfort (d/t
enlarged liver)
2.
weight gain
(accum of interstit fluid)
3.
Peripheral
edema (esp ankles,
feet)
4.
Anorexia,
nausea (d/t GI edema)

Physic 1.
2.
al
signs 3.

Left-sided HF

1.
2.
3.
4.
5.
6.

JVD
Hepatomegaly
Peripheral

1.

d/t enlarged

2.

edema

4.
RV:
o

Palpable
parasternal right
3.
ventricular heave
o
TR
murmur
4.
5.
Right-sided S3
or S4 gallop
5.

Dyspnea (on exertion)

Orthopnea
Paroxysmal nocturnal dyspnea
(PND)
Nocturnal cough
Hemoptysis
d/t low forward output (dec
perfusion):
o
Dulled mental status
o
Impaired urine output >
nocturia
o
Fatigue, weakness
Diaphoresis (sweating, inc
symp) + dusky (d/t dec CO)+ cool
extremities (peripheral arterial
vasoconstricy) in decompensated HF
Tachycardia, tachypnea
o
Cheyne-Stokes?
o
Pulsus alterans
Pulmonary rales ("pop
opening" of airways closed of by edema
during inspir
Coarse rhonchi, wheezing
(cardiac asthma)
Loud P2 (inc L filling pressure
> inc pulm vasc pressure)

6.
7.
8.

S3 gallop (in systol dysfx)

S4 gallop (in diastol dysfx)
MR murmur (if dilatation
separates papillary m.)
9.
LV impulse is diffuse (cardiac
myopathy), sustained (pressure overload
states: AS, HTN), lifting (vol overload: MR)
Pleural effusion in both -- dullness to percussion over posterior lung bases
Severe chronic HF sx:
Cachexia - frail wasted appearance
1.
o
d/t poor appetite + metabolic demands of increased effort in
breathing
Cheyne-Stokes respiration (not sure if this is L-sided sx)
periods of hyperventialtion and apnea
o
d/t prolonged circ time b/w lung + brain's respir center
Pulsus alterans-alternating strong and weak contractions

detected in peripheral pulse

o
Sx of advanced ventricular dysfunction

Differentiate the functional classes of the New York Heart

Association functional classification system.

Discuss the stages of heart failure, and differentiate one stage

from another, by definition as well as in clinical scenarios.
o
Stage A: no structural heart disease or HF; high risk for
developing HF (HTN; diabetes).
o
Stage B: asymptomatic + structural heart disease.
o
Stage C: past/current symptoms of HF.
o
Stage D: end-stage HF (refractory symptoms).

Discuss the diagnosis of heart failure (history and physical

findings as well as diagnostic studies).
CXR:

< 10 mmHg : Normal LA pressure

> 15 mmHg: upper-zone vascular distribution

Flow is normally greater to lung bases d/t gravity. Edema is more

prominent at bases > blood vessels in bases are compressed and
flow to upper lung less affected

> 20 mmHg: interstitial edema > indistinctness of vessels + Kerley B

lines (interlobular edema)

> 25-30 mmHg: alveolar pulmonary edema with opacification of air

spaces

Chronic HF : fewer signs due to enhanced lymph drainage

Cardiomegaly (cardiothoracic ration > 0.5 on posteroanterior film)

depending on cause

Enlarged azygous v. silhouette (d/t high RA pressure)

Pleural effusions
BNP assay - correlates well w/ degree of LV dysfx and prognosis

BNP is released when ventricular myocardium is subjected to

hemodynamic stress
Elevated BNP can distinguish HF from other dyspnea causes

Hx:

Large MI
If cause unkwn > EKG to determine systolic vent fx is normal or
depressed

Discuss the prognosis of heart failure, and identify the subset of heart
failure patients with the poorest prognosis.
Prognosis is dismal in absence of a correctable underlying cause

45%-60% 5-year mortality rate following dx

Men have worse outcomes than women

Patients with severe sx (NYA class III or IV) = 1 year survival

rate of 40%

Greatest mortality d/t refractory heart disease

But many patients die suddenly (d/t ventricular

arrhythmias)
Differentiate the clinical settings in which treatment with betablockers for heart failure is appropriate from those in which beta-blockers are
inappropriate (and potentially detrimental).
Appropriate: stable HF.
Contraindicated: acute/decompensated HF (may exacerbate
acute deterioration due to negative inotropic effect).
List the medications/classes of medications that have been
proven in clinical trials to improve long-term survival in patients with heart
failure with reduced ejection fraction.
ACEi; beta-blockers; spironolactone; isosorbide dinitrate with
hydralazine (African Americans with ACEi; patients unable to take ACEi).

Identify potential candidates for cardiac resynchronization

therapy (CRT) based on clinical information (see Lilly, p. 240).
Cardiac resynchronization therapy (CRT) - biventricular pacemaker

moderate-severe HF with dilated cardiomyopathy and infranodal

conduction delay (most commonly LBBB); improves stroke volume
(coordinated contraction of ventricle).

Candidates: LVEF < 35% AND QRS > 120 msec (esp. LBBB)
AND class III/IV despite medical therapy.

Path
Fill in Path pics
1. Differentiate pressure-overload ventricular hypertrophy from volumeoverload ventricular hypertrophy.
o
Six principle mechanisms: pump failure; obstruction to flow;
regurgitant flow; shunted flow; conduction abnormalities; rupture of
heart/major vessel.
o
Pressure-overload: concentric hypertrophy (new sarcomeres in
parallel); increased afterload (HTN; aortic stenosis).
o
Volume-overload (eccentric): ventricular dilation (new sarcomeres in
series).
o
Sx: fatigue; ascites; weakness; vascular congestion; dyspnea; JVD; GI
symptoms; rales; diminished mentation; tachycardia; peripheral edema;
hypotension.
2. Compare and contrast left-sided heart failure and right-sided heart
failure with regard to etiology, pathogenesis,
and clinical findings.
Left-sided heart failure
Cause

o
o
o
o

Findings

o
o
o
o

ischemic heart disease

HTN
aortic/mitral valvular disease
myocardial diseases
LV hypertrophied, often dilated (massive)
Dilation of left atrium (increased risk of afib).
variable degrees of fibrosis
Pulmonary congestion (hemosiderinladen
macrophages; heart failure cells).

Right-sided heart failure

o
o

left-sided h
infrequent
pulmonale [chronic p

RVH
pleural eff
passive co

o
o
o
(cirrhosis)
o
o

renal cong
anasarca.

Pharm
Congestive Heart Failure Pharmacology
Chapter 25: Integrative Cardiovascular Pharmacology:
Pages 455-463
1. Give the primary cause of heart failure.
o
LV contractile dysfx (systolic HF)
PRELOAD REDUCTION (Los 2-6)
2. Describe a major drawback in using either loop or thiazide diuretics for patients
with congestive heart failure (CHF).
o
no evidence of a mortality benefit from tx with either loop or thiazide
diuretics
3. Explain the actions of the loop diuretics furosemide or bumetanide.
o
Inhibit Na+-K + -2Cl co-transporter (NKCC2) in the thick ascending limb of
Henle > inc excretion of Na+, K+, H20
o
All diuretics dec preload
4. Explain why the vasopressin-antagonists conivaptan and tolvaptan are used to
treat CHF.
o
Pts w/ HF have elevated circulating levels of vasopressin (correlates to
severity)
o
Vasopressin antagonists (aka aquaretics) MOA:

Selective/competitive antagonism of vasopressin V2 receptor >

inc solute-free urine output and inc serum Na+ levels

Dec renal aquaporin exp and membrane trafficking > dec free
water reabsoption
o
Conivaptan (IV) - tx of hypervolemic hyponatremia
o
Tolvaptan (oral) - inc weight loss and dec edema over first week in pts with
acute decompensated HF requiring hospitalization
5. Describe the benefits of spironolactone treatment for CHF as determined by the
RALES trial.
o
Spironolactone - K+ spaing diuretic, competitive antagat aldosterone
receptor > dec Na+-K+ exchange in distal tubule and collecting duct
o
RALES trail - pts with severe, systolic HF (free of significant renal impairment
and receiving standard HF tx of AC E inhibitors, B-blockers, loop diuretics +
digoxin) were txed with low-dose spironolactone >

30 % reduction in all-cause mortality (including sudden cardiac

death and death from progressive HF) and hospital admissions for
exacerbations of HF
Therefore, spironalactone is administered in comb w/ ACEi + angiotensin
receptor blocker

6. Briefly summarize the beneficial effects of nitrates such as nitroglycerin in CHF

patients.
Nitroglycerin (NTG) - prototypical venodilator; often coadministered with
diuretics in pts w/ congestive sx
o
Inc venous capacitance > dec venous return > dec LV chamber volume >
reduced LV diastolic pressure and volume

> dec myocardial oxygen demand

Beneficial for pts w/ coexisting angina and LV dysfx

Left HF d/t acute myocardial ischemia (Patho: impaired LV

relaxation, dec LV compliance, elevated LV diastolic pressure)

Nitrates also alleviate ischemia > improve diastolic

relaxation

(therefore, nitrates reduce preload + improve LV

compliance)
AFTERLOAD REDUCTION (Los 7-9)
7. Summarize the effects of ACE inhibitors on CHF patients as shown by four
separate studies.
o
CONSENSUS trial- mortality reduction 40% at 6 mos and 31% at 1 yr
o
SOLVD Treatment trial - 16% mortality reduction
o
V-Heft II trial - 28% mortality reduction
o
SAVE trial - 19% mortality reduction in pts in the convalescent phase
following MI
8. Explain why it is reasonable to co-administer ACE inhibitors along with betablockers in patients with CHF.
o
Both have distinct MOAs and nonoverlapping toxicities
9. Give three conditions that limit the use of hydralazine in patients with CHF.
o
Hydralazine - direct-acting vasodilator > dec systemic vasc resistance >
reduce afterload

Use limited by

Induction of reflex tachycardia during IV administration

Tachyphylaxis

Drug-induced lupus syndrome during chronic administration

IONTROPIC AGENTS (Los 10-11)
10. Describe the two main paths of dobutamine action in CHF patients and under
what conditions it is used.

Dobutamine - parenteral sympathomimetic amine; tx of decompensated

systolic HF (pulmonary congestion + reduced forward CO); typically used in acute
setting (i.e. ICU)
o
MOA: synthetic congener of epinephrine that stimulates:

1-receptors > inc contractility of cardiac myocytes

2-receptors (to a lesser extent) > arterial vasodilation and

reduced afterload

1-receptors (to a lesser extent)

11. Describe the effects of phosphodiesterase inhibitors and the particular setting in
which they are used.
Phosphodiesterase inhibitors (inamrinone, milrinone)
o
inhibit cAMP degradation in cardiac myocytes > inc intracellular Ca++ >
enhance contractility (iontropy)
o
Dilation of arteriolar resistance vessels and venous capacitance vessels > dec
afterload and preload
o
Tx: short term tx of acute decompensation HF (NOTE: same use as
dobutamine)

OPP lololol
Monday, October 13, 2014
7:26 PM

Background
Neurohumoral mechanisms= key role in regulating CV system
importance of the musculoskeletal system in the establishment and
maintenance of optimal conditions for cardiovascular performance
viscerosomatic and somatovisceral reflexes form the basis for osteopathic
palpatory diagnosis and manipulative treatment of cardiovascular disease.
Learning objectives: (Brent)
Describe the vertebral segments to which osteopathic manipulative
therapy should be directed in order to alter sympathetic tone to the
heart.
o
T1 T4, as well as cervical spine
Describe the pattern of somatic dysfunction which has been
demonstrated in a significant percentage of hypertensive patients
o
A high percentage of HT pts show a consistent somatic dysfunction
pattern of C6, T2, and T6

Cardiac Transplant
Path + Clin

List the three major factors contributing to the improved outcome of

cardiac transplantation.
o
More effective immunosuppressive therapy (cyclosporin A,
glucocorticoids,etc)
o
Careful selection of candidates
o
Early histopathologic diagnosis of acute allograft rejection by
endomyocardial biopsy >
o
adjust immunosuppressive medications as needed

Describe the major complication that requires surveillance in patients

who have undergone cardiac transplantation, describe the only
current reliable means of diagnosis.
o
Allograft rejection: major complication that requires surveillance
o
Scheduled endomyocardial biopsy - only reliable dx of acute rejection
before substantial myocardial damage has occurred.

State the current major limitation to the long-term success of cardiac

transplantation.
Rejection: interstitial lymphocytic inflammation (damage to adjacent myocytes
in advanced stages; resembles myocarditis).
o
Quilty lesions: endocardial infiltrates (surface); predominantly T cells;
no tissue damage. Lymphocytes on surface

Mild acute rejection

predominantly mononuclear perivascular and/or interstitial

inflammation (not associated with myocyte necrosis). -- acute about
you see lymphocytes

Moderate/Severe acute rejection

myocyte necrosis; presence of segmented leukocytes
(eosinophils)

worsening rejection (myocyte necrosis; edema; interstitial

hemorrhage; occasional frank vasculitis).

Diffuse stenosing intimal proliferation of the coronary arteries - major current

limitation to long-term success of transplant:
o
may involve intramural vessels extensively (graft arteriopathy)

Denervation of transplanted heart: no ischemic chest pain (silent MI).

Postoperative: infection/malignancy (EBV associated B cell lymphomas).
Prognosis: 1 year (70-80%); 5 year (60%).
State the estimated 5-year and 10-year survival rates following
cardiac transplantation (Lilly, p. 250).
o
5-year: 74%
o
10-year: 55%

Congenital Heart Disease

Saturday, October 11, 2014
8:41 PM

in the embryo the lungs do not function in the normal capacity since blood is
oxygenated at the placenta.
Heart begins to develop in the 3rd week
1

How does the heart tube form?

Cardiac precursor cells

o
arise from epiblast (lateral to primitive streak) > become situated at
the cranial aspect of the embryo (rostral to the buccopharyngeal
membrane) in the splanchnic mesoderm
o
underlying endoderm induces these cells to form cardiac myoblasts
o
coelomic epithelium (myocardium + conducting system) and neural
crest (septa and media of great vessels) also contribute to formation of
the heart
o
cardiac cells surround blood islands > forming horseshoe shaped tube-cardiogenic field
2 laterally situated tubes are present by day 19

Laterally, dorsal aorta form from another set of blood islands

Cardiogenic area
o
Initally, rostral to buccopharyngeal membrane
o
Embryo folds > horseshoe tube brought together ventrally where it
fuses except at the caudal-most end = heart tube
o
Heart tube
Initially suspended by a dorsal mesentery which breaks down >

forms of transverse pericardial sinus

heart tube fuses with blood vessels (receives blood at caudal

end; expels blood from rostral end)

o
Now, heart consists of endothelium and mesoderm that develops into
two layers (myocardium and cardiac jelly)
o
cells from the splanchnic mesoderm migrate and give rise to
epicardium
1

How does the cardiac loop form and what structures are derived from it?

Describe the development of the sinus venosus.

Describe the formation of the cardiac septa.

Describe the development of the conducting system of the heart.

Describe common heart defects (i.e. the ones covered in the Study Notes).
Congenital heart disease - abnormalities of heart or great vessels present
from birth.
o
Incidence: 1% (4-50 / 1000 live births). (Lilly: 8/1000 live births)
o
Prevalence: 1M people (US)
o
Most common: VSD (42%); ASD (10%); pulmonary stenosis (8%); PDA
(7%); tetralogy of Fallot (5%); coaractation (5%); AV septal defect (4%);
aortic stenosis (4%); transposition (4%); truncus (1%); total anomalous
pulmonary venous connection (1%); tricuspid atresia (1%).
o
Cause: faulty embryogenesis (weeks 3-8).

Sporadic genetic abnormalities: main cause; single gene

mutations; small chromosomal deletions; addition/deletion whole
chromosomes (trisomy/monosomy).
Environmental : alone or combined with genetic factors.
Exposures: congenital rubella infection; gestational diabetes;
teratogens
Cyanotic congenital heart lesions
R-to-L shunt: blood from right side of circulation flows directly
to left side bypassing lungs ( 2 main shunts: foramen ovale and
ductus arteriosus)

Effect: hypoxemia and cyanosis (mixture of poorly

oxygenated with oxygenated).
Cyanosis- blue purple discoloration to skin and

mucous membranes; due to conc. of deoxygenated Hb (at

least 4g/dL)

Complication:
paradoxical embolism (embolism arising in

peripheral veins enters systemic circulation > brain

infarction, abscess)
hypertrophic osteoarthropathy (clubbing of tips

of fingers/toes)
polycythemia

Defects: all Ts-- tetralogy of Fallot; transposition of great

arteries; persistent truncus arteriosus; tricuspid atresia; total
anomalous pulmonary venous connection.
Acyanotic congenital heart lesions:
L-to-R shunt: ASD; VSD; PDA; AV septal defects.

not initially associated with cyanosis

RVH and atherosclerosis of pulmonary vasculature

(overworked)
Obstructive: coarctation of the aorta; pulmonary
stenosis/atresia; aortic stenosis/atresia.
Valvular regurgitation

Clin meeting - Bicuspid aortic valve (MC defect). Often associated with coarc of aorta
and dilation of ascending aorta
Ectopia cordis:
Sudden infant death syndrome
o
caused by abnormalities in the cardiac conducting system?
Atrial septal defects (ASD) - common atrium (i.e fixed opening in atrial
septum). Morphology: according to location.
o
can involve a persistent ostium secundum

o
o

o
o
o

o
o

90%; deficient or fenestrated oval fossa (I.e. @site of foramen

ovale); center of atrial septum; usually not associated w/ other
abnormalities.
Due to inadequate formation of the septum secundum,

excessive resorption of the septum primum, or a combo

defect in the endocardial cushions
defect involving sinus venosum
5%; located near entrance of SVC; may be associated w/

anomalous pulmonary venous return

absence of normal tissue b/w R pulmonary vein(s) and RA

(unroofing defect; not a deficiency of atrial septum)

Flow from R pulm veins and LA RA

ostium primum: 5%; adjacent to AV valves (i. e. inferior portion of the
interatrial septum)
due to failure of septum primum to fuse w/ endocardial cushions

probe patency
incomplete tissue formation (allow communication b/w LA + RA)
Sx: asymptomatic until age 30 (> pulmonary vascular disease) except
for murmur
Mumur: Widened and fixed splitting of S2

d/t inc blood flow to right side of heart > pulmonary valve
close later than aortic valve independent of
inspiration/expiration.
Tx: surgical/catheter-based closure.
Prognosis: long-term survival comparable to normal population.

Patent foramen ovale (PFO) - type of ASD; small hole created by open flap of
tissue in atrial septum (oval fossa)
o
not a true ASD (no tissue is missing)
o
Closure at birth (80% close permanently) due to increased left-heart
BP. Permanently seals by age 6 mos via atrial septa
o
Patent/pathological: 20%; unsealed flap opens with high pressures in
right-heart (> R-to-L shunt ??? Check in lilly)
sustained pulmonary HTN; bowel movement, coughing,

sneezing.
Ventricular septal defect (VSD) - Morphology: classified by size and
location.
o
defects in muscular part = common, usually spontaneously resolve
may be multiple (swiss-cheese); 50% close spontaneously

o
defects in membranous part (near outflow tracts)
serious -- clinical consequences depend defect size (large defect

> left to right shunting of blood; small defect may close

spontaneously or tolerated for years)
Associated w/ Down syndrome

o
defects in unfundibular - below the pulmonary valve.

o
o

usually associated with other congenital cardiac anomalies (70-80%;

tetralogy of fallot).
Sx: vary from asymptomatic to early symptoms of CHF (tachypnea,
poor feeding, failure to thrive, frequent lower resp tract infections)

Cor triloculare biventriculare absence of a atrial septum resulting in a

three chambered heart
Premature closure of the oval foramen leads to hypertrophy of RA and RV
and hypotrophy of left chambers; patient typically dies shortly after birth
Transposition of the great vessels/arteries - septum that normally divides
the aorta and pulmonary trunk does not form properly
o
ventriculoarterial discordance (aorta arises from RV); incompatible with
life unless shunt exists.
o
Morphology:
RVH (chamber pumping to systemic circulation)

LV thin-walled (low-resistance pulmonary circulation)

o
Severity: depends on presence of shunt (VSD; PDA).
o
Prognosis: die during first month of life unless surgically repaired
(emergent after delivery)
Dextrocardia - heart tube bends to left side > heart becomes displaced to
right; commonly seen w/ situs inversus
Pulmonary valve stenosis/Atresia:
Pulmonary stenosis may be isolated or associated with more complex anomaly [tetralogy
of Fallot; transposition of great arteries])
RVH; post-stenotic dilation of pulmonary artery
Sx: Mild to Moderate (asymptomatic); Severe (dyspnea w/ exertion,
right sided HF, abdominal/pedal edema)
Pulmonary atresia: no communication b/w RV and lungs
hypoplastic RV; ASD and PDA
Total anomalous pulmonary venous connection - pulmonary veins fail to
directly join LA; must
have PFO or ASD
Consequence: volume/pressure hypertrophy; right-heart dilation;
pulmonary trunk dilation
Morphology: hypoplastic LA; normal LV.
Sx: cyanosis may be present.
Tricuspid valve stenosis

Tricuspid valve atresia always have patency of the foramen ovale, VSD,
underdeveloped/hypoplasia RV and hypertrophy of LV
interatrial communication (ASD or PFO) and VSD
Large mitral valve
o
Sx: cyanosis from birth
o
Prognosis: high mortality (1st wks-mos)
Ebstein anomaly
o
improper formation of tricuspid valve where the valves are partially
fused to the ventricular wall
o
part of RV becomes atrialized; accompanied by tricuspid
regurgitation
o
indicated by cyanosis and heart failure
o
usually accompanied by a ASD
Hypoplastic left heart syndrome - poorly developed LV; as blood returns
from the lungs it must pass through an ASD to the right atrium, into the right
ventricle and then through a patent ductus arterious into the systemic
circulation
o
fatal w/o surgical correction
Hypertrophic Cardiomyopathy
o
affects organization / structure of cardiac muscle
o
mutation in beta-myosin heavy chain
o
results in hypertrophy of heart and affects cardiac fx and output
o
cause of sudden death in young athletes?
Tetralogy of Fallot a group of four cardiac defects [PROVe]:
1. (sub)pulmonary stenosis / Obstruction of RV outdlow (lilly)
2. right ventricular hypertrophy
3. over-riding (dextroposition of the) aorta aorta gets blood from
RV
4. ventricular septal defect
o
related to a deficiency in neural crest cells
o
conotruncal defect all 4 components result directly or indirectly
from improper formation of conotruncal septum
i.e. abnormal anterior and cephalad displacement of infundibular

(outflow tract) portion of IV septum

o
Morphology: enlarged boot-shaped heart (RVH); large VSD; narrowing
of
Infundibulum (subpulmonic stenosis); aortic valve forms superior border of
VSD.
o
Severity: depends on degree of subpulmonary stenosis (determines
amount of R-to-L shunting)

Sx:

Dyspnea on exertion
Spells- irritability, cyanosis, hyperventilation, syncope, or
seizures

can occur following exertion, feeding, or crying

Occurs when systemic vasodilatation (inc blood flow) >

inc R-to-L shunt (d/t greater demand by heart for blood flow)
Relieved by squatting (Inc systemic vascular resistance by
kinking femoral arteries decrease R-to-L shunt blood flow to
lungs)

Pentrad of Fallot all above + ASD

Persistent truncus arteriosus
o
conotruncal ridges do not fuse
o
accompanied by IV septal defect (Path: associated VSD)
o
Truncus (single great artery) gets blood from both ventricles
o
increased pulmonary blood flow (irreversible pulmonary HTN)
Aortic (Valvular) stenosis / atresia - congenital narrowing/obstruction of
aortic valve.
o
Locations:
Valvular - cusps hypoplastic, dysplastic or abnormal in #

severe (hypoplastic left heart syndrome; fatal when

ductus closes).
Subvalvular:

thickened ring (discrete type)

collar (tunnel type) of dense endocardial fibrous tissue

(below level of cusp)

prominent systolic murmur; pressure hypertrophy of LV.

Supravalvular - inherited form of aortic dysplasia

ascending aortic wall thickened (luminal constriction)

component of multiorgan developmental disorder

(deletions of chromosome 7; elastin gene).
o
Lilly - Congenital Aortic Stenosis - bicuspid leaflets instead of the
normal three-leaflet
Sx: Mostly are asymptomatic and very few (~10%) experience

HF sx
Patent ductus arteriosus: fetal structure fails to close spontaneously.
o
ductus arteriosus (vessel that connects the left pulmonary artery to the
descending aorta)
o
continuous harsh murmur (machinery-like).
o
Isolated PDA: closed as early in life as feasible.
o
Preservation of ductal patentcy: prostaglandin E; survival of infants
with congenital malformations (leave shunt open).

Sx: vary asymptomatic to development of early CHF

Atrioventricular septal defect: complete atrioventricular canal defect.

o
> incomplete closure of AV septum; malformation of tricuspid and
mitral valves.
o
Partial AVSD: primum ASD and cleft anterior mitral leaflet.
o
Complete AVSD: large combined AV septal defect; large common AV
valve.
Association: > 1/3 have Down syndrome.

Coarctation of the aorta - narrowing, constriction of aorta; males (2:1).

o
Association: Turner syndrome
o
MC associated coexisting cardiac abnormality = bicuspid aortic valve
o
Infantile ("preductal") form: tubular hypoplasia of aortic arch proximal
to PDA; symptomatic in early childhood.
PDA: manifestations early in life (symptoms may show

immediately after birth with HF sx and differential cyanosis)

cyanosis localized to lower half of body

Upper half supplied by LV and ascending aorta

well perfused w/ oxygenated blood

Lower half supplied by R-to-L flow of poorly

oxygenated blood from pulmonary artery, across PDA, into

descending aorta cyanotic
o
Adult("postductal") form: discrete ridgelike infolding of aorta opposite
closed ductus arteriosus distal to arch vessels.
Without PDA: asymptomatic into adult

HTN of upper extremities

weak pulses and hypotension in lower extremities

**CXR: notching of inferior surface of posterior

ribs ( d/t enlarged intercostal arteries supplying collateral
circulation to descending aorta),indented aorta

systolic murmur; cardiomegaly (LV pressure-overload

hypertrophy)

Pre- and postductal terms not used bc vast majority are juxtaductal
(next to the ductus), also no different etiology/cause can be found b/w
the two

Eisenmenger syndrome - severe pulmonary vascular obstruction d/t chronic

L-to-R shunting through congenital cardiac defect
o
Pulmonary vascular obstruction d/t arteriolar media hypertrophy and
intimal proliferation vessels become thrombosed inc pulmonary
vascular resistance reversal of original shunt (to R-to-L) and systemic
cyanosis
Resistance of pulmonary circulation has to exceed that of systemic
vasculature shunt flow reverses
o
Sx: exertional dyspnea and fatigue (d/t hypoxemia), cyanosis w/ digital
clubbing
1

Describe the development of the arterial system.

Describe the development of the venous system.

Describe the development of the lymphatic system.