SPONSORED SATELLITE SESSION
The Late Sodium Current in the cardiac myocite:
How viable as a new therapeutic target in angina?
Dr Stephen Holmberg
Lead Consultant for Cardiac Services
Brighton & Sussex University Hospitals

Immediate short-term relief
Treatment aimed at improving prognosis
Treatment aimed at relief of symptoms
For medical management of stable angina
Stable angina for medical management
Short-acting sublingual or buccal nitrate, prn
Asprin 75-150 mg od
Statin +/- titrate dose  to get target cholesterol
ACE-inhibitor in proven
CVD
Beta-blocker post MI
Beta-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
Contraindication (e.g. aspirin allergic)
Intolerant or contraindication
Clopidogrel 75mg od
Interchange statins, or ezetimibe with 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 I f inhibitor
Intolerant
Symptoms not controlled after dose optimisation
Either substitute alternative subclass of calcium antagonist, or long-acting nitrate
Combination of nitrate and calcium antagonist or
K channel opener
Symptoms not controlled on two drugs after dose optimisation
Fox K et al.
ESC guidelines, European Heart Journal 2006;27:1341-81.

Management of Stable Angina

GTN

Aspirin (Clopidogrel)

Statin (Ezetimibe)

ACE Inhibitor
 β-Blocker

Second-line drug
– Calcium antagonist
– Long-acting nitrate
– K + agonist
– I f 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?


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

Continued angina and antianginal medication use
12 months after revascularisation for 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?

Vasospasm
Thrombus
Atherosclerosis
O
2
Supply
O
2
Demand
Ischaemia
Afterload
Heart rate
Contractility
Preload

Oxygen Supply and Demand Are Mismatched During Ischaemia,
Leading to Impaired Diastolic Relaxation
Vasospasm
Thrombus
Atherosclerosis
O
2
Supply
O
2
Demand
Afterload
Heart rate
Contractility
Preload
Ischaemia
Microvascular
Flow
Sodium-Induced
Calcium Overload
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.
Diastolic Wall
Tension


– β-Blockers, Verapamil/Diltiazem, Ivabradine

– β-Blockers, Calcium Antagonists

– β-Blockers, Verapamil/Diltiazem

– Diltiazem, Amlodepine, Nicorandil, Nitrates

®
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

Ischaemia
Late I
Na
Na + Overload
Ca 2+ Overload
Diastolic relaxation failure
Coronary compression

Ischaemia impairs cardiomyocyte sodium 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
Adapted from Chaitman BR. Circulation 2006:113:2462-72.
Adapted from Belardinelli L et al.
Eur Heart J 2004;6(Suppl I):I3-I7.

Diseases/ Conditions
1. Acquired
• Hypoxia/ ROS
• Ischaemia
• Heart failure
• CaMKII, AMPK
2. Congenital (inherited)
•
Cardiac: SCN5A (LQT3)
•
Sk Muscle: SCN4A
(Myotonias)
• CNS: SCN1A, 2A, 3A
(seizures)
• PNS: SCN9A
(neuropathic pain)
Altered Na + Ch gating leads to Ca 2+ - overload
Na +
Na
Na +
+
Na +
Na +
Na +
Na +
Na
Na
+
+
Na +
NaCh
Na + - Ca 2+
Exchanger
1Ca 2+ 3Na +
Na +
Na +
Na +
Na +
Na +
Na +
3Na +
Na + Ch inactivation failure
NCX
1Ca 2+
Ca 2+
Overload
Enhanced late I
Na

Diseases/ Conditions
1. Acquired
• Hypoxia/ ROS
• Ischaemia
• Heart failure
• CaMKII, AMPK
2. Congenital (inherited)
•
Cardiac: SCN5A (LQT3)
•
Sk Muscle: SCN4A
(Myotonias)
• CNS: SCN1A, 2A, 3A
(seizures)
• PNS: SCN9A
(neuropathic pain)
Altered Na + Ch gating leads to Ca 2+ - overload
Na +
Na +
Na +
Na +
Na + Na +
Na +
Na +
Na +
Na +
NaCh
RANOLAZINE
Na + - Ca 2+
Exchanger
1Ca 2+ 3Na +
3Na +
NCX
1Ca 2+
Ca 2+
Overload

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

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

Average weekly angina attacks over 6-week study period
Stone PH et al.
J Am Coll Cardiol 2006;48:566-75.

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


Follow the ESC Guidelines

Assessment of ischaemia is important

Revascularisation where feasible/sensible

New drug therapies such as Ranolazine offer hope to refractory patients