The Late Sodium Current in the cardiac myocite: How viable as a new therapeutic target in angina?
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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
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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. Management of Stable Angina. GTN Aspirin (Clopidogrel) - PowerPoint PPT Presentation
Transcript of The Late Sodium Current in the cardiac myocite: How viable as a new therapeutic target in angina?
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
