Download Systems Physiology II

Systems Physiology II
Sam Dudley, MD, PhD
Associate Professor of Medicine and Physiology
Office: VA room 2A167
Tel: 404-329-4626
Email: [email protected]
Overview of the CV system
• Purposes
–
–
–
–
Distribute metabolites and O2
Collect wastes and CO2
Thermoregulation
Hormone distribution
• Components
–
–
–
–
Heart – the driving force
Arteries – distribution channels
Veins - collection channels
Capillaries – exchange points
Parallel and series design
RA LA
RV LV
Organ 1
Organ 2
Organ 3
• A given volume of blood
passes through a single
organ
• Blood entering an organ
has uniform composition
• Perfusion pressure is the
same for each organ
• Blood flow to each organ
can be controlled
independently
Cardiac anatomy
•
•
The myocardial syncytium
– All atrial cells are coupled, all ventricular cells are coupled, the AV node
links the two
– Connections between cells are known as intercalated disks
Electrical activation leads to contraction (EC coupling)
Cardiac cellular anatomy
• Basic unit is a sarcomere
(Z line to Z line)
– Think filaments of myosin
in the A band
– Thin filaments of actin in
the I band
• Sarcoplasmic reticulum
– Holds Ca2+
– Forms cisternae
– Approximation to T tubules
(sacrolemmal
invaginations) known as a
dyad
Review of Cardiac Electrophysiology
2+
Ca
induced
2+
Ca
release
Ca2+
K+ Na+
Ca2+
SARCOLEMMA
ATP
Ca2+
ATP
RyR2
Ca2+
Ca2+
RyR2
SARCOPLASMIC
RETICULUM
ATP
Ca2+
SARCOMERE
•
•
Ca2+ enters from sacrolemmal Ca2+ channels, diffuses to the SR Ca2+ release
channel (ryanodine receptor), and causes a large Ca2+ release.
SR Ca2+ release raises intracellular Ca2+ from 10-7 M to 10-5 M, enough to
cause Ca2+ binding to troponin, displacing tropomyosin, causing actin-myosin
cross bridge cycling
Sliding filaments
Length-tension (Frank-Starling Effect)
•
•
•
•
Length of a fiber
determines force
generation
The major determinate
of length in the heart is
chamber volume
The ascending limb
results from lengthdependent changes in
EC coupling
The descending limb
derives mostly from the
number of thick and
thin filament cross
bridge interactions
Pressure-volume loops
• Determinants of cardiac
output (stroke volume x
heart rate)
– Preload or ventricular end
diastolic volume
– Afterload or Aortic pressure
– Contractility or modulation
of active force generation
(ESPVR, inotropy)
– Ventricular compliance
(EDPVR, lusitropy)
– Heart rate
ESV= end systolic volume;
EDV = end-diastolic volume;
SV = stroke volume
Myocardial work
• Most myocardial work is potential work
W = ∫ PdV
• Myocardial O2 consumption is a function of myocardial
wall tension, contractility, and heart rate
• The law of Laplace:
T = Pr/ 2
where T is tension, P is pressure, and r is the radius.
– Larger ventricles have higher wall tension and O2 utilization to
produce the same pressure as smaller ones
The Idea of Heart Failure
RH
LH
• Vasoconstriction
• Fluid retention
Right heart failure
Left heart failure
The Effect of Heart Failure
ESPVR
Pressure (mm Hg)
120
↓Inotropy
Acute HF
80
Chronic HF
40
EDPVR
0
40
80
120
Volume (mL)
Conceptualizing Treatment for
Heart Failure ESPVR changes by
• ↑ inotropy
• ↓ afterload
Pressure (mm Hg)
120
80
40
EDPVR
0
40
80
120
Volume (mL)
Coupling the heart and vasculature
Cardiac function curve
Vascular function curve
CO =
Pms − Pra
R(1 + cv / ca )
Where Pms, Pra, R, cv,
and ca are the mean
systemic pressure,
right atria pressure,
total peripheral
resistance, arterial
and venous
capacitance,
respectively.
Normal
equilibrium
The Vicious Cycle of Heart
Failure
Injury
• Cell death
• Apoptosis
• Fetal gene activation
• Inflammation
Systolic dysfunction
Hypertrophy
Energy Starvation
Increased Load
Neurohormonal activation
• RAAS, SNS, ET, AVP, bradykinin
Epidemiology of HF in the US
Patients in US (millions)
10.0
10
• Incidence: about 550,000
new cases each year1
8
6
4
• 4.9 million patients1;
estimated 10 million in 20372
4.8
• Prevalence is 2% in persons
aged 40 to 59 years,
progressively increasing to
10% for those aged 70 years
and older3
3.5
2
0
1991
2001
2037
Year
1. American Heart Association. Heart and Stroke Statistics2003 Update.
2. Croft JB et al. J Am Geriatr Soc 1997;45:270–75.
3. National Heart, Lung, and Blood Institute. Congestive Heart
Failure Data Fact Sheet. Available at:
http://www.nhlbi.nih.gov/health/public/heart/other/CHF.htm
• 52,000 deaths each year1
• Sudden cardiac death is 6 to
9 times higher in the heart
failure population1
Etiology of Heart Failure
Diagnosis Modalities
•
•
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•
•
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•
•
Physical examination
Chest X ray
Echocardiography
Bioimpedance
MRI
CT (Electron beam and Multidetector-row)
Nuclear scintigraphy
Cardiac catheterization
Chest X ray
•
•
•
•
•
No temporal information
No quantification
Requires radiation
No valvular/coronary information
Two dimensional
Echocardiography
Limitations to Echocardiography
• Two dimensional
• Views limited by anatomy
• Image quality frequently poor
– Improved signal to noise ratios
– Improved contrast
•
•
•
•
Limited quantitative information
Need better contrast agents for flow
Need higher resolution images
Acoustic shadowing
Magnetic Resonance
•
•
•
•
•
•
Need for more rapid acquisition
Breathing artifacts
Better contrast agents
Higher spatial resolution
Thinner slices
3D Reconstruction
Complications of Heart Failure
• Progressive pump dysfunction
– End organ underperfusion
– Pulmonary and systemic congestion
• Sudden death
Options for Pump Dysfunction
When Medications Fail
• Left ventricular reconstruction/left ventricular
resection
• Biventricular pacing (BiV)
• Left ventricular assist devices (LVAD)
• Cell/tissue replacement therapy
• Cardiac transplant
Biventricular pacing
Problems with BiV Pacing
•
•
•
•
Not all people benefit
Technical insertion failures
Not all people have wide QRS
Optimum intervals and pacing sites
unknown
• Diaphragmatic pacing
• Frequent premature beats alter timing
LVADs
•
•
•
•
•
Pulsatile vs. nonpulsatile
Centrifugal, axial flow,
pneumatic pumps
Extracorporeal (short term) vs.
implantable (longer term)
Bleeding, hemolysis, DIC,
embolism (air or thrombotic),
battery life, bulk, mechanical
failure, cost, infection, surgery
Valvular/coronary
disease/arrhythmias/con-genital
defects limit use
Cardiac Cell
Transplantation
Cell replacement therapy
Unresolved issues
• Arrhythmogenicity
–
–
–
• Best source of cells
Automaticity
Slow Conduction/Reentry
Triggered activity
• Immunogenicity
• Mechanism of improved
function
– contraction, remodeling
• How does cell therapy
compare to engineered
replacement tissue?
– adult, fetal, embryonic, tissue,
species, differentiated,
undifferentiated
• Best route of application
– injection, mobilization, IC, IV
•
•
•
Timing of application
How does homing occur?
Which types of cells are
necessary?
Cardiac transplantation
•
•
•
•
•
•
Limited donors
Infection
Rejection
Renal failure
Tumors
Accelerated Vascular
Disease
Sudden Death in HF
Risk Predictors for Sudden Death
•
•
•
•
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•
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Left ventricular dysfunction
Frequent premature ventricular contractions
Nonsustained ventricular tachycardia
Inducible ventricular tachycardia on programmed electrical
stimulation
Abnormal signal averaged ECG (presence of late
potentials)
Reduced heart rate variability
Presence of T wave alternans
Increased QT segment dispersion
Finding (Mapping) Arrhythmias
• Contact vs. noncontact
• Baskets vs. single
electrodes
• No integration of mapping
and imaging
• Difficulty interpreting
activation patterns and
electrograms
• Cannot measure full
thickness of myocardium
• Map resolution/accurate
anatomical display
Implanted Cardiac Defibrillators
(ICDs)
•
•
•
•
•
•
•
•
Battery life
Inappropriate shocks
Limited event recording
Infection/bleeding/perforation/unstable
leads/pneumothorax/erosion
Lead failure/dislodgement
Pain
Incessant VT/VF
EM interference
ICD in action
Future Challenges for the
Bioengineer
• Develop cellular/nanotechnology solutions
– Will require more knowledge of pathogenesis
• Implement tissue engineering solutions
• Improve biomedical imaging
– More noninvasive solutions
– Integrate with therapy
– Molecular imaging
• Need better bioinformatics risk predictive models
References
1. Katz A.M., Physiology of the Heart,
Lippincott Williams & Wilkins, New
York, 2001.
2. Berne and Levy, Cardiovascular
Physiology, 7th Edition, Mosby, St. Louis,
1996.