Webinar: The Assessment of Cardiac Function in Nonclinical Safety Studies
Event will be recorded Listen via Broadcast Audio or Listen via Broadcast Audio, or Call in to participate
– select phone icon at bottom of attendee panel to view call information must enter Attendee IDview call information, must enter Attendee ID
– Request (raise hand icon) to be unmuted for question/comment One hour presentation; reserving 30 minutes for Q&A (submit
questions anytime using the Q&A expand to view)questions anytime using the Q&A, expand to view) SPS Annual Meeting, Boston, Sept. 20-23, 2010 Join SPS!
Assessment of Cardiac Function in Nonclinical Safety Studies
Brian D G th Ph DBrian D. Guth , Ph.D.Head of General Pharmacology
Boehringer Ingelheim Pharma GmbH & Co. KG
Michael MarkertHead of Telemetry Laboratory
Boehringer Ingelheim Pharma GmbH & Co. KG
R. Dustan Sarazan, DVM, Ph.D.Global Chief Scientific Officer, Safety Pharmacology
Covance Laboratories Inc Madison Wisconsin USACovance Laboratories, Inc. Madison, Wisconsin USA
Fundamental Properties of the Heart Inotropic Inotropic
– Effect on the “strength of contraction” of cardiac muscle– Inotropy and contractility are often used interchangeably
The focus of this webinar– The focus of this webinar Chronotropic
– Effect on Heart Rate Dromotropic Dromotropic
– Effect on conduction velocity (primarily AV node) Lusitropic
Eff t di l l ti– Effect on myocardial relaxation Bathmotropic
– Effect on excitability or irritability of heart muscle
Cardiac ContractilityCardiac Contractility Cardiac contractility is defined by
h i l i t th i t i i bilit f diphysiologists as the intrinsic ability of cardiac muscle to do work at constant end-diastolic fiber length (Katz 1977)fiber length (Katz 1977).
Thus, with increased contractility, the heart performs more work at the same diastolicperforms more work at the same diastolic fiber length (end-diastolic volume)
Contractility vs Inotropic StateContractility vs Inotropic State The terms are often used interchangeably A positive inotropic drug (positive inotrope)
causes an increase in contractility A negative inotropic drug (negative inotrope)
causes a decrease in contractility
Consequences of Changing Contractility Decreased contractility is clinically important since it results in a
reduction in the heart’s ability to perform work– Significant reduction in cardiac contractility manifests clinically as
t h i h t f ilacute or chronic heart failure – If you were developing a drug for chronic use in elderly, diabetic,
obese, hypertensive, heart failure patients, wouldn’t you want to know about this?
Increased contractility increases the work performed by the heart and is a normal physiological response to increased demand
H it d ti ll i di l– However, it dramatically increases myocardial oxygen consumption
– If you were developing a drug for patients with decreased coronary reserve due to coronary stenosis and myocardial ischemia, y y ,wouldn’t you want to know about this?
WiggersDiagramDiagram
Although the general concept of contractility is often understoodcontractility is often understood, its actual measurement is fraught
with problems!with problems!
Assumptions and limitations of a contractility index must beAssumptions and limitations of a contractility index must be understood or misinterpretations are likely
Contractility IndicesContractility Indices In addition to being affected by actual changes in
intrinsic contractility all indices commonly used inintrinsic contractility, all indices commonly used in preclinical and clinical studies are affected by changes in preload, afterload and heart rate as well.
Thus, a drug-induced change in any of these parameters can indirectly affect an index of contractility without actually changing the intrinsiccontractility without actually changing the intrinsic contractile function of the myocardium itself
How Can Contractility Be Measured? Muscle twitch velocity
– Hill experiments in frog Sartorius muscle (pioneering studies) Ejection Fraction (stroke volume ÷ end-diastolic volume)
– Extremely afterload dependent– Often measured with echocardiography or impedance catheters
dP/dtmax (an in vivo approximation of muscle twitch velocity)P l d d HR d d t– Preload and HR dependent
– Slightly less afterload dependent since it occurs prior to aortic valve opening Time varying elastance model (ESPVR, Emax)
PV Loops– PV Loops– The Gold Standard
QA interval – an approximation of the average rate of isovolumic systolic pressure developmentpressure development
Frank-Starling Mechanism“S li L Of Th H ”“Starling Law Of The Heart”
Cardiac function changes with preload
Curves are displaced with changes in contractilitywith preload changes in contractility
The End Systolic Pressure Volume Relationship (ESPVR)Relationship (ESPVR)
Emax=Slope of ESPVR
Also known as the “Time Varying Elastance Model
Suga, H., Sagawa, K., Shoukas, A.
Circ. Res. 1973
The only preload and afterload independent measure of inotropy!measure of inotropy!
dP/dt (first derivative of LVP)( )dP/dt is the instantaneousslope of the LVP curve
End-SystoleEnd-Diastole
LVPPRESSURE 150
200AC
B
dP/dtmax is the maximumvalue of that slopeduring a cardiac cycle
dP/dt
(mmHg)
20004000
0
50100
A=dP/dt40, early isovolumicsystole
B=dP/dtmax
(mmHg/sec)dP/dt
3
-4000-2000
02000
B dP/dtmaxC=dP/dt, late isovolumic
systole(X 100 mV)
ECG
-1012
TIME (Seconds)
1.8 2.0 2.2 2.4
Normal & Heart Failure
/dt (
mm
Hg/
sec)
-1000
0
1000
2000
3000
4000
ssur
e (m
mH
g)
100
150
200
250
dP/
-3000
-2000
Time (seconds)
0 1 2 3 4 5
Pres
0
50
Time (seconds)
0 1 2 3 4 5
N t D d S t li P (A P d LVP)Note: Decreased Systolic Pressure (AoP and LVP)Decreased dP/dtmaxIncreased LVEDPIncreased HR
The QA IntervalI di t f thIndirect measure of theduration of isovolumic
systole without LVPmeasurement
Also includes the time for depolarization, conduction,
excitation contraction couplingexcitation-contraction coupling and time required for propagation
of the pressure wave to the arterial pressure sensor
All are assumed tobe constant
QA Interval Assumptions Average dP/dt (P/t) varies linearly with dP/dtmax Developed pressure is constant (preload and afterload) Na+ channels are unaffected Na channels are unaffected Excitation-contraction coupling is unaffected Wave propagation velocity between the heart and the
arterial pressure sensor is unaffected– No change in compliance of the conductance vessels
“Thus, QA depends on many factors other than myocardial contractility” R.H. Hamlin
Nonetheless, QA Can Work Empirically With Pure Inotropic DrugsWith Pure Inotropic Drugs
References:C b id 1986– Cambridge, 1986
– Adeyemi, 2009– Norton, 2009
Can provide an inexpensive screen for drug effects on contractility in discovery or lead optimizationUsage as a definitive indicator of cardiovascular Usage as a definitive indicator of cardiovascular safety in IND-enabling studies is questionable
Contractility Indices - Summary All but ESPVR are sensitive to preload and
afterload changesg If preload, afterload and HR are constant in
treated and control groups, dP/dtmax provides a rob st and sensiti e inde of the inotropica robust and sensitive index of the inotropic effects of drugs in experimental animals
These three parameters must be measured These three parameters must be measured and dP/dtmax data must be interpreted with them in mind.
Part 2Part 2
O er ie on the heart and morpholog of the• Overview on the heart and morphology of the signalsForce frequency relationship• Force-frequency relationship
• Validation compoundsC t di• Case studies
LVdP/dtmaxLVdP/dtmaxLVdP/dtmin
EDP
Inotropy (LVdP/dtmax)py ( )Force-frequency relationship(positive Bowditch staircase)
Lusitropy (LVdP/dtmin)Lusitropy (LVdP/dtmin)
Effect of pos inotropic Ti f t dEffect of pos. inotropic compound on LVP
LVdP/dt40Relatively insenstive of pre-load
Tip of transducersqueezed by ventricle
Relatively insenstive of pre load
COMPOUNDdpdt max (mmHg/s)
4800
5000 Effect of positive inotropic
4000
4200
4400
4600
4800 p pcompound on Bowditch staircase
3000
3200
3400
3600
3800
2200
2400
2600
2800
3000
HR (bpm)20 50 80 110 140 170
1600
1800
2000
Effect of a compound with slightEffect of a compound with slight increase in heart rate and increase in contractilityincrease in contractility
No effect on heart rate
Pos lusitropypy
ValidationValidation
ß3 Agonist
PLEASE INSERT Presentation title
ß3 A i tß3 Agonist
VerapamilVerapamil
PLEASE INSERT Presentation title
HR LVPSAP
Ca++ antagonistsi i l tiimpair relaxation
Verapamil
Propranolol + PimobendanPropranolol + Pimobendan
PLEASE INSERT Presentation title
Propranolol + PimobendanTypical pos. inotropic effect,LVdP/dtmax LVEDPPropranolol + PimobendanLVdP/dtmax LVEDP
PLEASE INSERT Presentation title
Case studies
220 0 mg/kg3 mg/kg10 /k
Telemetry dog n = 4
180
200
10 mg/kg30 mg/kg
140
160
dp/d
t max
%
260
2800 mg/kg3 mg/kg10 mg/kg30 mg/kg
Telemetry dog n = 4100
120
100
120
140
160
180
200
220
240
hear
t rat
e %
30 mg/kg
80-1 0 1 2 3 4 5 6
time (hours)
Median of 10 min
0
20
40
60
80
100
-1 0 1 2 3 4 5 6time (hours)
Median of 10 min
150 0 mg/kg
Telemetry dog n = 4Compound X1150 0 mg/kg
Telemetry dog n = 4Compound X1Compound X2 Telemetry dog n = 4Compound X2 Telemetry dog n = 4
130
g g3 mg/kg10 mg/kg30 mg/kg
130
g g3 mg/kg10 mg/kg30 mg/kg
140 0 mg/kg1 mg/kg3 mg/kg10 mg/kg
140 0 mg/kg1 mg/kg3 mg/kg10 mg/kg
130
max
%
130
max
%
120
x %
120
x %
110
dp/d
t m 110
dp/d
t m
100
dp/d
t max
100
dp/d
t max
9090
70-1 0 1 2 3 4 5 6
time (hours)
Median of 10 min
70-1 0 1 2 3 4 5 6
time (hours)
Median of 10 min80
-1 0 1 2 3 4 5
time (hours)
Median of 10 min80
-1 0 1 2 3 4 5
time (hours)
Median of 10 min
COMPOUNDdpdt max (mmHg/s)5000
4000
4200
4400
4600
4800
3200
3400
3600
3800
4000
2200
2400
2600
2800
3000
COMPOUNDdpdt max (mmHg/s)
4400
4600
4800
5000
1400
1600
1800
2000
2200
2600
2800
3000
3200
3400
3600
3800
4000
4200
HR (bpm)20 40 60 80 100 120 140 160
1200
HR (bpm)20 50 80 110 140 170
1400
1600
1800
2000
2200
2400
2600
COMPOUNDdpdt max (mmHg/s)
4800
5000
4200
4400
4600
4800
3400
3600
3800
4000
2600
2800
3000
3200
1800
2000
2200
2400
capsulechewable tablet
HR (bpm)20 40 60 80 100 120 140 160 180
1400
1600
chewable tabletplacebo
Summaryy Contractility is an important, intrinsic
characteristic of cardiac function Controlled physiologically by autonomic input
to match cardiac output to metabolic demands Is markedly influenced by drugs, including
adrenergic agents, calcium antagonists, etc. May be modulated both positively and
negatively by drugs of all kinds (off target effects)effects)
Cardiac contractility in safety pharmacology Variety of indices allow for the assessment of y
drug-induced effects on cardiac contractility e.g. LV dP/dtmax can be integrated into g g
safety pharmacological studies A sensitive index to changes in contractility
but also influenced by HR, EDLVP Contractiliiy assessment can add to overall
safety evaluation of new pharmaceuticals
QuestionsQuestions Does introduction of an LV pressure
t d l d t h th i ?transducer lead to arrhythmias? In what species can LVP be measured? What magnitude of changes in e.g. LVdP/dt
can be of relevance? What magnitude of change can be detected with such models?change can be detected with such models?
BackupBackup
Drug-induced changes in contractility
Positive inotropic stimulation– Increased incidence of proarrhythmia (VT/VF, atrial fibrillation)
Increased mortality (catecholamines PDE III inhibitors)– Increased mortality (catecholamines, PDE-III-inhibitors)
Negative inotropic effects– Increased mortality in patients with acute/chronic heart failureIncreased mortality in patients with acute/chronic heart failure
(e. g. calcium antagonists like verapamil)
Haverkamp, 2009
PLEASE INSERT Presentation title
PLEASE INSERT Presentation title
PLEASE INSERT Presentation title
PLEASE INSERT Presentation title