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Webinar: The Assessment of Cardiac Function in Nonclinical Safety Studies

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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


HR LVPSAP

Ca++ antagonistsi i l tiimpair relaxation

Verapamil

Propranolol + PimobendanPropranolol + Pimobendan


Propranolol + PimobendanTypical pos. inotropic effect,LVdP/dtmax LVEDPPropranolol + PimobendanLVdP/dtmax LVEDP


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


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


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

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