Pathophysiology course (BMED8121/6793) Sam Dudley, MD, PhD Associate Professor of Medicine and Physiology Office: VA room 2A167 Tel: 404-329-4626 Email: sdudley@emory.edu
Overview of the CV system Purposes Distribute metabolites and O 2 Collect wastes and CO 2 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 Ca 2+ Forms cisternae Approximation to T tubules (sacrolemmal invaginations) known as a dyad
Review of Cardiac Electrophysiology
Ca 2+ induced Ca 2+ release Ca 2+ K + Na + Ca 2+ ATP ATP SARCOLEMMA Ca 2+ RyR2 Ca 2+ Ca 2+ RyR2 SARCOPLASMIC RETICULUM ATP Ca 2+ SARCOMERE Ca 2+ enters from sacrolemmal Ca 2+ channels, diffuses to the SR Ca 2+ release channel (ryanodine receptor), and causes a large Ca 2+ release. SR Ca 2+ release raises intracellular Ca 2+ from 10-7 M to 10-5 M, enough to cause Ca 2+ binding to troponin, displacing tropomyosin, causing actin-myosin cross bridge cycling
The sliding filament hypothesis
Sliding filaments 2
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 O 2 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 O 2 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 Pressure (mm Hg) 120 80 40 0 ESPVR 40 80 120 Volume (ml) Inotropy Acute HF Chronic HF EDPVR
Conceptualizing Treatment for Pressure (mm Hg) 120 80 40 0 Heart Failure 40 80 120 Volume (ml) ESPVR changes by inotropy afterload EDPVR
Coupling the heart and vasculature Vascular function curve CO = Pms Pra R( 1+ cv / ca ) Where P ms, P ra, R, c v, and c a are the mean systemic pressure, right atria pressure, total peripheral resistance, arterial and venous capacitance, respectively. Cardiac function curve Normal equilibrium
The Vicious Cycle of Heart Hypertrophy Energy Starvation Failure Cell death Apoptosis Fetal gene activation Inflammation Injury Systolic dysfunction Increased Load Neurohormonal activation RAAS, SNS, ET, AVP, bradykinin
Epidemiology of HF in the US Patients in US (millions) 10 8 6 4 2 0 3.5 4.8 10.0 1991 2001 2037 Year 1. American Heart Association. Heart and Stroke Statistics- 2003 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 4.9 million patients 1 ; estimated 10 million in 2037 2 Incidence: about 550,000 new cases each year 1 Prevalence is 2% in persons aged 40 to 59 years, progressively increasing to 10% for those aged 70 years and older 3 52,000 deaths each year 1 Sudden cardiac death is 6 to 9 times higher in the heart failure population 1
Etiology of Heart Failure
Diagnosis Modalities 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 Automaticity Slow Conduction/Reentry Triggered activity Immunogenicity Mechanism of improved function contraction, remodeling How does cell therapy compare to engineered replacement tissue? Best source of cells 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 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
A Link between Contraction and Ca 2+ Sudden Death K + Na + Ca 2+ I ti I Cl ATP ATP SARCOLEMMA Ca 2+ RyR2 Ca 2+ Ca 2+ RyR2 SARCOPLASMIC RETICULUM ATP Ca 2+ SARCOMERE
Studying lethal RyR -/- using embryonic stem cells Undifferentiated mouse RyR +/+ /RyR -/- ESCs ESCs in hanging drops 2 days Embryoid bodies (EBs) Suspending EBs 5 days Plating EBs Day 7 Enzymatic isolation Electrophysiological study Spontaneously beating EBs Single cardiomyocytes Action potential morphology and triggered arrhythmias: EADs/DADs > Day 7+2-3 Day 7+12-14
Early afterdepolarizations were more common in RyR -/- ESC-derived cardiomyocytes RyR +/+ Vm (mv) 40 20 0-20 -40 Control 1 µm BayK8644 20 mm [TEA] o Vm (mv) 40 20 0-20 -40 1 µm BayK8644 20 mm [TEA] o EAD Vm (mv) 40 20 0-20 -40 Washout -60-60 -60-80 100 ms -80 100 ms -80 100 ms RyR -/- Vm (mv) 60 40 20 0-20 -40-60 -80 500 ms EADs EADs Vm (mv) 60 40 20 0-20 -40-60 -80 500 ms EADs
Delayed afterdepolarizations were more common in RyR -/- ESC-derived cardiomyocytes RyR +/+ +/+ 40 1.8 mm [Ca 2+ ] 40 3.6 mm [Ca 2+ o ] o Vm (mv) 20 0-20 -40-60 -80 500 ms Vm (mv) 20 0-20 -40-60 -80 500 ms DADs RyR -/- 60 40 Vm (mv) 20 0-20 -40-60 -80 2000 ms DADs DAD
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, 7 th Edition, Mosby, St. Louis, 1996.