Current anti-anginal therapy. Current antianginal strategies Current anti-anginal strategies Non...

Current anti-anginal therapyCurrent anti-anginal therapy

Current antianginal strategiesCurrent antianginal strategies

Current anti-anginal strategiesCurrent anti-anginal strategies

Non pharmacologic

Pharmacologic

TrimetazidineTrimetazidine

FasudilFasudil NicorandilNicorandil

IvabradineIvabradine

RanolazineRanolazine

Exercise Exercise trainingtraining

EECPEECP ChelationChelationtherapytherapy

SCSSCS

TMRTMR

Exercise TrainingExercise Training Enhanced external Enhanced external

counterpulsation counterpulsation (EECP)(EECP) Endothelial functionEndothelial function Promotes coronary Promotes coronary

collateral formationcollateral formation Peripheral vascular Peripheral vascular

resistanceresistance Ventricular functionVentricular function Placebo effectPlacebo effect

Chelation therapyChelation therapy

Current nonpharmacologic Current nonpharmacologic antianginal strategiesantianginal strategies

Transmyocardial Transmyocardial revascularization (TMR)revascularization (TMR) Sympathetic denervationSympathetic denervation AngiogenesisAngiogenesis

Spinal cord stimulation Spinal cord stimulation (SCS)(SCS) Neurotransmission Neurotransmission

of painful stimuliof painful stimuli Release of Release of

endogenous opiatesendogenous opiates Redistributes myocardial Redistributes myocardial

blood flow to ischemic areasblood flow to ischemic areas

Allen KB et al. N Engl J Med. 1999;341:1029-36.Bonetti PO et al. J Am Coll Cardiol. 2003;41:1918-25.

Murray S et al. Heart. 2000;83:217-20.

Potential cardioprotective Potential cardioprotective benefits of exercisebenefits of exercise

Domenech R. Circulation. 2006;113:e1-3. Kojda G et al. Cardiovasc Res. 2005;67:187-97. Shephard RJ et al. Circulation. 1999;99:963-72.

NO NO productionproduction

ROS ROS generationgeneration

ROS ROS scavengingscavenging

Other Other mechanismsmechanisms

VasculatureVasculature ThrombosisThrombosisMyocardiumMyocardium

EECP - Enhanced External EECP - Enhanced External CounterPulsationCounterPulsation

External, pneumatic compression of lower External, pneumatic compression of lower extremities in diastole.extremities in diastole.


Sequential Sequential inflation of inflation of

cuffscuffs Retrograde aortic Retrograde aortic

pressure wave pressure wave Increased Coronary Increased Coronary

perfusion pressureperfusion pressure Increased Venous Increased Venous

ReturnReturn Increased PreloadIncreased Preload Increased Cardiac Increased Cardiac

OutputOutput

Simultaneous Simultaneous deflation of deflation of cuffs in late cuffs in late

DiastoleDiastole Lowers Systemic Lowers Systemic

Vascular Resistance Vascular Resistance Reduced Preload Reduced Preload Decreased Cardiac Decreased Cardiac

workload workload Decreased Oxygen Decreased Oxygen

ConsumptionConsumption


35 total treatments35 total treatments 5 days per week x 7 weeks5 days per week x 7 weeks 1 hour per day1 hour per day

Appears to reduce severity of Angina Appears to reduce severity of Angina Not shown to improve survival or reduce Not shown to improve survival or reduce

myocardial infarctionsmyocardial infarctions Indicated for CAD not amenable to Indicated for CAD not amenable to

revascularization revascularization Anatomy not amenable to proceduresAnatomy not amenable to procedures High risk co-morbidities with excessive riskHigh risk co-morbidities with excessive risk

May be beneficial in treatment of refractory CHF May be beneficial in treatment of refractory CHF too, but generally this is not an approved too, but generally this is not an approved indication.indication.

EECP – Contraindications & EECP – Contraindications & PrecautionsPrecautions

Arrhythmias that interfere with machine Arrhythmias that interfere with machine triggeringtriggering

Bleeding diathesisBleeding diathesis Active thrombophlebitis & severe lower Active thrombophlebitis & severe lower

extremity vaso-occlusive diseaseextremity vaso-occlusive disease Presence of significant AAAPresence of significant AAA PregnancyPregnancy

TMLR - Transmyocardial Laser TMLR - Transmyocardial Laser RevascularizationRevascularization

High power CO2 YAG High power CO2 YAG and excimer laser and excimer laser conduits in myocardial to conduits in myocardial to create new channels for create new channels for blood flowblood flow

Possible explanations for Possible explanations for effecteffect Myocardial angiogenesisMyocardial angiogenesis Myocardial denervationMyocardial denervation Myocardial fibrosis with Myocardial fibrosis with

secondary favorable secondary favorable remodelingremodeling

TMLR – Direct TrialTMLR – Direct Trial

Only major blinded studyOnly major blinded study 298 pts with low dose, 298 pts with low dose,

high dose, or no laser high dose, or no laser channelschannels

No benefit to TMLR vs No benefit to TMLR vs Med therapy to Med therapy to Patient survivalPatient survival Angina classAngina class Quality of life assessmentQuality of life assessment Exercise durationExercise duration Nuclear perfusion imagingNuclear perfusion imaging Leon MB, et al. JACC 2005; 46:1812Leon MB, et al. JACC 2005; 46:1812

High Surgical Risk High Surgical Risk (Mortality 5%)(Mortality 5%)

Mainly used as adjunct Mainly used as adjunct therapy during CABG to therapy during CABG to treat myocardial that treat myocardial that cannot be bypassed.cannot be bypassed.

Chelation TherapyChelation Therapy

IV EDTA infusionsIV EDTA infusions 30 treatments over 30 treatments over

about 3 monthsabout 3 months Cost – about $3,000Cost – about $3,000 Aggressive marketing Aggressive marketing

by 500 to 1000 by 500 to 1000 physicians offering this physicians offering this treatmenttreatment

PLACEBO effect onlyPLACEBO effect only

Claimed Claimed pathophysiologic effectspathophysiologic effects Liberation of Calcium Liberation of Calcium

in plaquein plaque Lower LDL, VLDL, and Lower LDL, VLDL, and

Iron storesIron stores Inhibit platelet Inhibit platelet

aggregationaggregation Relax vasomotor toneRelax vasomotor tone Scavenge “free Scavenge “free

radicals”radicals”

Spinal Cord StimulationSpinal Cord Stimulation

power source conducting wires electrodes atstimulation site

Stimulation typicallyadministered for 1-2 hrs tid

Therapeutic mechanism appears to be alteration of anginal pain perception

Long-term Outcomes Following Long-term Outcomes Following SCSSCS

02468

101214161820

TotalAngina

Angina atRest

ExertAngina

NTGUse/wk

CCSClass

# HospAdms

Days inHosp

BaselineSCS

Prospective Italian Registry: 104 Patients, Follow-up 13.2 Mo

Episodes/wk

* p<0.0001

* * ** * *

*

(DiPede, et al. AJC 2003;91:951)

Randomized Trial of SCS vs. CABG Randomized Trial of SCS vs. CABG For Patients with Refractory AnginaFor Patients with Refractory Angina

14.6 15.216.2

13.7

4.4 4.15.2

3.1

02468

1012141618

Anginal attacks NTGconsumption

Anginal attacks NTGconsumption

Mean number

perweek

Baseline

6 months

Spinal cord stimulation (n=53) CABG (n=51)

*P < 0.0001

****

(Mannheimer, et al. Circulation 1998;97:1157)

104 Patients with refractory angina, not suitable for PCI and high risk for re-op (3.2% of patients accepted for CABG)

No difference in symptom relief between SCS and CABG

Current pharmacologic Current pharmacologic antianginal strategiesantianginal strategies

New mechanistic approaches to anginaNew mechanistic approaches to angina Rho kinase inhibition (Rho kinase inhibition (fasudilfasudil)) Metabolic modulation (Metabolic modulation (trimetazidinetrimetazidine)) Preconditioning (Preconditioning (nicorandilnicorandil)) Sinus node inhibition (Sinus node inhibition (ivabradineivabradine)) Late Na+ current inhibition (Late Na+ current inhibition (ranolazineranolazine))

Rho kinase inhibition: FasudilRho kinase inhibition: Fasudil Rho kinase triggers vasoconstriction through Rho kinase triggers vasoconstriction through

accumulation of phosphorylated myosinaccumulation of phosphorylated myosin

Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8.

Ca2+ Ca2+

PLC

SR Ca2+

Receptor

Agonist

Myosin

Myosin-P

Myosin phosphatase

PIP2

IP3

MLCK

VOC ROC

Ca2+

Calmodulin

Rho

Rho kinase

Fasudil

Metabolic modulation (pFOX): Metabolic modulation (pFOX): TrimetazidineTrimetazidine

O2 requirement of O2 requirement of glucose pathway is glucose pathway is lower than FFA lower than FFA pathwaypathway

During ischemia, During ischemia, oxidized FFA levels oxidized FFA levels rise, blunting the rise, blunting the glucose pathwayglucose pathway

FFA Glucose

Acyl-CoA

Acetyl-CoA

Pyruvate

Energy for contraction

Myocytes

β-oxidation

Trimetazidine

MacInnes A et al. Circ Res. 2003;93:e26-32.Lopaschuk GD et al. Circ Res. 2003;93:e33-7.

Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45.

pFOX = partial fatty acid oxidationFFA = free fatty acid

Preconditioning: NicorandilPreconditioning: Nicorandil

Nitrate-associated effects• Vasodilation of coronary epicardial arteries

Activation of ATP-sensitive K+ channels• Ischemic preconditioning• Dilation of coronary resistance arterioles

IONA Study Group. Lancet. 2002;359:1269-75.Rahman N et al. AAPS J. 2004;6:e34.

N O

O NO2

HN

Sinus node inhibition: IvabradineSinus node inhibition: Ivabradine

DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.

SA = sinoatrial



SA = sinoatrial

SA node

AV node Common bundle

Bundle branches

Purkinje fibers


IIf f current is an inward current is an inward Na+/K+ current that Na+/K+ current that activates pacemaker activates pacemaker cells of the SA nodecells of the SA node

IvabradineIvabradine Selectively blocks ISelectively blocks Iff in in

a current-dependent a current-dependent fashionfashion

Reduces slope of Reduces slope of diastolic depolarization, diastolic depolarization, slowing HRslowing HR


40

20

0

–20

–40

–60

0.5

Potential (mV)

Control Ivabradine 0.3 µM

Time (seconds)

SA = sinoatrial

SodiumCurrent

0

Late

Peak

0

Late

Peak

SodiumCurrent

Na+

ImpairedImpairedInactivationInactivation

ImpairedImpairedInactivationInactivation

Na+

Ischemia

Myocardial ischemia causes Myocardial ischemia causes enhanced late INaenhanced late INa

Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;(8 suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.

Late Na+ current inhibition: Late Na+ current inhibition: RanolazineRanolazine

Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;(6 suppl I):I3-7.

Myocardial ischemia

Late INa

Na+ Overload

Ca2+ Overload

Mechanical dysfunction LV diastolic tension

Contractility

Electrical dysfunctionArrhythmias

Ranolazine

Understanding Angina at the Understanding Angina at the Cellular LevelCellular Level

Ischemia impairs cardiomyocyte Ischemia impairs cardiomyocyte sodium channel functionsodium channel function

Impaired sodium channel function Impaired sodium channel function leads to:leads to: Pathologic increased late sodium Pathologic increased late sodium

currentcurrent Sodium overloadSodium overload Sodium-induced calcium overloadSodium-induced calcium overload

Calcium overload causes diastolic Calcium overload causes diastolic relaxation failure, which:relaxation failure, which: Increases myocardial oxygen Increases myocardial oxygen

consumptionconsumption Reduces myocardial blood flow Reduces myocardial blood flow

and oxygen supplyand oxygen supply Worsens ischemia and anginaWorsens ischemia and angina

Ranolazine

Ischemia

↑ Late INa

Na+ Overload

Diastolic relaxation failureExtravascular compression

Ca++ Overload

Chaitman BR. Circulation. 2006;113:2462-2472

Na+/Ca2+ overload and Na+/Ca2+ overload and ischemiaischemia

Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.

Late Na+ current

Diastolic wall tension (stiffness)

Intramural small vessel compression( O2 supply)

O2 demand

Na+ overload

Ca2+ overload

Myocardial ischemia

Ischaemia( oxygen supply/ Demand)

late Na+ current

Na+/Ca++ exchange pump activation

[Ca2+] overload

Diastolic wall tension (stiffness)

Vascular compression

[Na+]i

RanolazineRanolazine

Ranolazine – hemodynamic Ranolazine – hemodynamic affects affects

No affect of Blood Pressure or Heart No affect of Blood Pressure or Heart RateRate

Can be added to Conventional Medical Can be added to Conventional Medical therapy, especially when BP and HR do therapy, especially when BP and HR do not allow further increase in dose of not allow further increase in dose of BetaBlockers, Ca Channel blockers, and BetaBlockers, Ca Channel blockers, and Long Acting Nitrates.Long Acting Nitrates.

Ranolazine has twin pronged action.Ranolazine has twin pronged action.1.1. pFOXpFOX

2.2. Late Na inward entry blockadeLate Na inward entry blockade

Metabolic modulation (pFOX) Metabolic modulation (pFOX) and ranolazineand ranolazine

Clinical trials showed ranolazine SR 500–Clinical trials showed ranolazine SR 500–1000 mg bid (~2–6 µmol/L) reduced angina1000 mg bid (~2–6 µmol/L) reduced angina

Experimental studies demonstrated that Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% ranolazine 100 µmol/L achieved only 12% pFOX inhibitionpFOX inhibition Ranolazine does not inhibit pFOX substantially at Ranolazine does not inhibit pFOX substantially at

clinically relevant doses clinically relevant doses Fatty acid oxidation Inhibition is not a major Fatty acid oxidation Inhibition is not a major

antianginal mechanism for ranolazineantianginal mechanism for ranolazineMacInnes A et al. Circ Res. 2003;93:e26-32.

Antzelevitch C et al. J Cardiovasc Pharmacol Therapeut. 2004;9(suppl 1):S65-83.

Antzelevitch C et al. Circulation. 2004;110:904-10.

pFOX = partial fatty acid oxidation

Ranolazine: Key conceptsRanolazine: Key concepts

Ischemia is associated with ↑ Na+ entry into Ischemia is associated with ↑ Na+ entry into cardiac cells cardiac cells Na+ efflux by Na+/Ca2+ exchange results in ↑ Na+ efflux by Na+/Ca2+ exchange results in ↑

cellular [Ca2+]i and eventual Ca2+ overload cellular [Ca2+]i and eventual Ca2+ overload Ca2+ overload may cause electrical and Ca2+ overload may cause electrical and

mechanical mechanical dysfunctiondysfunction ↑ ↑ Late INa is an important contributor to the Late INa is an important contributor to the

[Na+]i - dependent Ca2+ overload[Na+]i - dependent Ca2+ overload Ranolazine reduces late INa Ranolazine reduces late INa

Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;(6 suppl I):I3-7.

Na+ and Ca2+ during Na+ and Ca2+ during ischemia and reperfusionischemia and reperfusion

Tani M and Neely JR. Circ Res. 1989;65:1045-56.

Na+

(μmol/g dry)

Ca2+

(μmol/g dry)

Time (minutes)

Rat heart model

Ischemia Reperfusion90

60

30

0

12

8

4

00 10 20 30 40 50 60

Intracellular levels

Medication Medication ClassClass

Impact Impact on HRon HR

Impact Impact on BPon BP

Physiologic Physiologic MechanismMechanism

Beta Beta BlockersBlockers

Decrease pump Decrease pump functionfunction

Calc Calc Channel Channel BlockersBlockers

Decrease Pump Decrease Pump function + Vaso-function + Vaso-dilitationdilitation

NitratesNitrates Vaso-dilitationVaso-dilitation

RanolazineRanolazine OO OO Reduced Cardiac Reduced Cardiac StiffnessStiffness

Pharmacologic Classes for Treatment of Angina

Late Na+ accumulation Late Na+ accumulation causes LV dysfunctioncauses LV dysfunction

Fraser H et al. Eur Heart J. 2006.

Isolated rat hearts treated with ATX-II, an enhancer of late INa

LV dP/dt(mm Hg/sec, in thousands)

LV-dP/dt

LV+dP/dt

(-)

(+)

Time (minutes)

ATX-II 12 nM(n = 13)A

TX

-II

Ranolazine 8.6 µM(n = 6)

Ran

ola

zin

e

10 20 30 40 50

-4

-3

-2

-1

0

1

2

3

4

5

6

LV end diastolic pressure

Baseline 15 30 45 600

10

20

30

40

50

60

70

Vehicle (n = 10)Ranolazine 10 µM (n = 7)

*

*

Reperfusion time (minutes)

mm

Hg

LV -dP/dt (Relaxation)

Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.Gralinski MR et al. Cardiovasc Res. 1994;28:1231-7.

*P < 0.05

Vehicle Ranolazine

Baseline 30 60 75 90

-1000

-800

-600

-400

-200

0

***

*

mm

Hg

/sec

Reperfusion time (minutes)

Vehicle (n = 12)Ranolazine 5.4 µM (n = 9)

Isolated rabbit hearts

Late INa blockade - Late INa blockade - blunts blunts experimental ischemic LV damageexperimental ischemic LV damage

Myocardial ischemia: Myocardial ischemia: Sites of Sites of action of anti-ischemic medicationaction of anti-ischemic medication

Consequences of ischemia

Ca2+ overloadElectrical instabilityMyocardial dysfunction(↓systolic function/ ↑diastolic stiffness)

Ischemia

↑ O2 DemandHeart rateBlood pressurePreloadContractility↓ O2 Supply

Development of ischemia

Traditionalanti-ischemicmedications:β-blockersNitratesCa2+ blockers

Courtesy of PH Stone, MD and BR Chaitman, MD. 2006.

Ranolazine

SummarySummary

Ischemic heart disease is a prevalent clinical Ischemic heart disease is a prevalent clinical conditioncondition

Improved understanding of ischemia has Improved understanding of ischemia has prompted new therapeutic approachesprompted new therapeutic approaches Rho kinase inhibitionRho kinase inhibition Metabolic modulationMetabolic modulation PreconditioningPreconditioning Inhibition of IInhibition of Iff and late INa currents and late INa currents

SummarySummary

Late INa inhibition and metabolic modulation Late INa inhibition and metabolic modulation reduce angina with minimal or no reduce angina with minimal or no pathophysiologic effectspathophysiologic effects Mechanisms of action is complementary to Mechanisms of action is complementary to

traditional agentstraditional agents

Stable CAD: Multiple Stable CAD: Multiple treatment optionstreatment options

Reduce symptoms

Treat underlying

disease

PCI & CABG

Lifestyle intervention

Alternative TX

Medical

therapy

ECGECG

R

Q

T

UP

S

mV

+

-

PWave

SpaceQRS

ST

T

PQ

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