Transcript The Late Sodium Current in the cardiac myocyte: how viable as a

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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
ESC algorithm
For medical management of stable angina
Stable angina for medical management
Immediate
short-term relief
Short-acting sublingual or
buccal nitrate, prn
Asprin 75-150 mg od
Clopidogrel 75mg od
Contraindication (e.g. aspirin allergic)
Statin +/- titrate dose  to
get target cholesterol
Treatment aimed at
improving prognosis
ACE-inhibitor in proven
CVD
Beta-blocker post MI
Beta-blocker – no prior MI
Intolerant (e.g. fatigue) or contraindication
Symptoms not controlled
after dose optimisation
Treatment aimed at
relief of symptoms
Interchange statins, or ezetimibe with lower dose
statin, or replace with alternative lipid-lowering agent
Intolerant or
contraindication
Calcium antagonist or long-acting nitrate
or K channel opener or If inhibitor
Symptoms not controlled
after dose optimisation
Add calcium antagonist or
long-acting nitrate
Symptoms not controlled
after dose optimisation
Intolerant
Consider suitability for
revascularisation
Fox K et al. ESC guidelines, European Heart Journal 2006;27:1341-81.
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
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 revascularisation
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?
Myocardial ischaemia
Vasospasm
Thrombus
Atherosclerosis
O2
Supply
O2
Demand
Ischaemia
Afterload
Heart rate
Contractility
Preload
Myocardial ischaemia
Oxygen Supply and Demand Are Mismatched During Ischaemia,
Leading to Impaired Diastolic Relaxation
Vasospasm
Thrombus
Atherosclerosis
O2
Supply
O2
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
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
® (ranolazine)
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
Understanding angina
at the cellular level
Ischaemia
Late INa
Na+ Overload
 Ischaemia impairs cardiomyocyte
sodium channel function
 Impaired sodium channel function
leads to:
– Pathological increased late
sodium current
– Sodium overload
– Sodium-induced calcium overload
Ca2+
Overload
Diastolic relaxation failure
Coronary compression
 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.
A pathological paradigm
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)
Na+ - Ca2+
Exchanger
Na+ Na+ Na+
Na+ Na+
+
Na+ Na
Na+
+
Na
Na+
1Ca2+
3Na+
NaCh
NCX
Na+
Na+
Na+
3Na+
Na+
Na+ Na+
Na+ Ch inactivation failure
Altered Na+ Ch gating
leads to Ca2+- overload
1Ca2+
Enhanced late I Na
The mechanism of action of Ranexa is largely unknown
ccccccccccccccccccccccccccccccccccccc
Ca2+
Overload
A pathological paradigm
Diseases/ Conditions
1. Acquired
• Hypoxia/ ROS
• Ischaemia
• Heart failure
• CaMKII, AMPK
Na+ Na+ Na+
Na+ Na+
+
Na+ Na
Na+
+
Na
Na+
1Ca2+
3Na+
NaCh
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 Ca2+- overload
Na+ - Ca2+
Exchanger
NCX
3Na+
1Ca2+
Ca2+
Overload
RANOLAZINE
The mechanism of action of Ranexa is largely unknown
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