The Late Sodium Current in the cardiac myocite: How viable as a new therapeutic target in angina?

SPONSORED SATELLITE SESSION

Dr Stephen Holmberg Lead Consultant for Cardiac Services Brighton & Sussex University Hospitals

Short-acting sublingual or buccal nitrate, prn

Asprin 75-150 mg od

Statin +/- titrate dose to get target cholesterol

Beta-blocker post MIBeta-blocker – no prior MI

Symptoms not controlled after dose optimisation

Add calcium antagonist or long-acting nitrate

Symptoms not controlled after dose optimisation

Consider suitability for revascularisation

Immediate short-term relief

Treatment aimed at improving prognosis

Treatment aimed at relief of symptoms

Stable angina for medical management

Contraindication (e.g. aspirin allergic)

Intolerant or contraindication

Intolerant

Interchange statins, or ezetimibewith lower dose statin, or replace with alternative lipid-lowering agent

Intolerant (e.g. fatigue) or contraindication

Calcium antagonist or long-acting nitrate or K channel opener or If inhibitor

Either substitute alternative subclass of calcium antagonist, or

long-acting nitrate

Clopidogrel 75mg od

Combination of nitrate and calcium antagonist or

K channel opener

ACE-inhibitor in proven CVD

ESC algorithmFor medical management of stable angina

Symptoms not controlled on two drugs after dose optimisation

Fox K et al. ESC guidelines, European Heart Journal 2006;27:1341-81.

Symptoms not controlled after dose optimisation

Management of Stable Angina

GTN Aspirin (Clopidogrel) Statin (Ezetimibe) ACE Inhibitor β-Blocker Second-line drug

–Calcium antagonist–Long-acting nitrate–K + agonist– If channel blocker

Management of Stable Angina

What investigations can guide therapy?

Where does revascularisation fit in?

What other drugs are available?

Are there any other options?

Management of Stable Angina

What investigations can guide therapy?–Treadmill – MIBI – Stress Echo – CMR–EBT – CT Angio – Invasive Angio

Where does revascularisation fit in?

What other drugs are available?

Are there any other options?

Prognosis in Stable Angina Generally benign

–Very difficult to demonstrate prognostic benefit of anti-anginal medication

Exercise Testing–Short treadmill tolerance (for whatever reason) is poor prognostic

feature Scale of Ischaemia

–MIBI scan accepted by DVLA/CAA Angiographic Findings

–Triple vessel disease with LV impairment–Significant Left Main Stem disease

But NOT.... Symptoms–Silent ischaemia has same prognosis as painful angina

Management of Stable Angina

What investigations can guide therapy?

Where does revascularisation fit in?–What does COURAGE tell us?

What other drugs are available?

Are there any other options?

Courage All patients had angiographic assessment

Extremely small percentage of eligible patients randomised

High level of cross-over to PCI for symptomatic patients

No assessment of ischaemia in main trial

Courage – Nuclear Sub-study

314 Patients MPS scans: Baseline, 6/12, 18/12 2 groups

–<10% ischaemia–>10% ishaemia

Endpoint–Reduction in ischaemia

PCI -2.7%. Medical -0.5%. Risk of death/MI significantly reduced for patients with

significant reduction in ischaemia especially in those with high baseline ischaemic burden

Angina symptoms persist in many patients despite revascularisationContinued angina and antianginal medication use 12 months after revascularisationfor angina (n=1205)

Adapted from Serruys PW et al. N Engl J Med 2001;344:1117-24.

Management of Stable Angina

What investigations can guide therapy?

Where does revascularisation fit in?

What other drugs are available?–Ranolazine – Perhexiline - Trimetazidine

Are there any other options?

Myocardial ischaemiaVasospasmThrombus

Atherosclerosis

AfterloadHeart rateContractilityPreload

O2SupplyO2Demand

Ischaemia

Myocardial ischaemiaOxygen Supply and Demand Are Mismatched During Ischaemia, Leading to Impaired Diastolic Relaxation

Adapted from Chaitman BR. Circulation 2006;113:2462-72.Adapted from Belardinelli L et al. Eur Heart J 2004;6(Suppl I):I3-7.

VasospasmThrombus

Atherosclerosis

AfterloadHeart rateContractilityPreload

O2SupplyO2Demand

Ischaemia

MicrovascularFlow

Sodium-InducedCalcium Overload

Diastolic WallTension

Impaired DiastolicRelaxation

Mechanisms of Drug Action

Reduce Heart Rate– β-Blockers, Verapamil/Diltiazem, Ivabradine

Reduce Blood Pressure– β-Blockers, Calcium Antagonists

Reduce Contractility– β-Blockers, Verapamil/Diltiazem

Coronary Vasodilators– Diltiazem, Amlodepine, Nicorandil, Nitrates

Ranexa®(ranolazine)

NEW CLASS“Late Cardiac Sodium Current Inhibitor”

Film-coated prolonged-release tablets containing 375 mg, 500 mg or 750 mg of ranolazine

Mechanism of action does not involve interference with haemodynamic variables

Ranolazine

Adapted from Chaitman BR. Circulation 2006:113:2462-72. Adapted from Belardinelli L et al. Eur Heart J 2004;6(Suppl I):I3-I7.

Understanding angina at the cellular level

Ischaemia

Late INa

Na+Overload

Ca2+Overload

Diastolic relaxation failure Coronary compression

Ischaemia impairs cardiomyocytesodium channel function

Impaired sodium channel function leads to:– Pathological increased late

sodium current– Sodium overload– Sodium-induced calcium overload

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

consumption– Reduces myocardial blood flow and

oxygen supply– Worsens ischaemia and angina

A pathological paradigm

Diseases/Conditions1. Acquired• Hypoxia/ROS• Ischaemia• Heart failure• CaMKII, AMPK2. Congenital (inherited)• Cardiac: SCN5A (LQT3)• SkMuscle: SCN4A

(Myotonias)• CNS: SCN1A, 2A, 3A

(seizures)• PNS: SCN9A

(neuropathic pain)

Na+ Ch inactivation failure

Enhanced late INa

Altered Na+ Ch gating leads to Ca2+- overload

The mechanism of action of Ranexa is largely unknown

Na+ - Ca2+

Exchanger

Ca2+

Overload

Na+

Na+Na+ Na+

Na+

Na+ Na+Na+

1Ca2+3Na+

3Na+1Ca2+

NCX

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

NaCh

ccccccccccccccccccccccccccccccccccccc

A pathological paradigm

Diseases/Conditions1. Acquired• Hypoxia/ROS• Ischaemia• Heart failure• CaMKII, AMPK2. Congenital (inherited)• Cardiac: SCN5A (LQT3)• SkMuscle: SCN4A

(Myotonias)• CNS: SCN1A, 2A, 3A

(seizures)• PNS: SCN9A

(neuropathic pain)

RANOLAZINEAltered Na+ Ch gating leads to Ca2+- overload

The mechanism of action of Ranexa is largely unknown

Na+ - Ca2+

ExchangerNa+

Na+Na+ Na+

Na+

Na+ Na+Na+

1Ca2+3Na+

3Na+1Ca2+

NCX

Na+

Na+

Ca2+

Overload

NaCh

cccccccccccccccccccccccccccccccccccccccccccc

MARISA efficacy

Chaitman BR et al. J Am Coll Cardiol 2004;43:1375-82.

CARISA efficacy

Chaitman BR et al. JAMA 2004;291:309-16.

ERICA efficacy:Average weekly angina attacks over 6-week study period

Stone PH et al. J Am Coll Cardiol 2006;48:566-75.

ERICA efficacy:Average weekly nitroglycerin use over 6-week study period

Stone PH et al. J Am Coll Cardiol 2006;48:566-75.

Management of Stable Angina

What investigations can guide therapy?

Where does revascularisation fit in?

What other drugs are available?

Are there any other options?–Exercise training – Spinal cord stimulation

Conclusions

Follow the ESC Guidelines

Assessment of ischaemia is important

Revascularisation where feasible/sensible

New drug therapies such as Ranolazine offer hope to refractory patients