Transcript Anginal Pectoris Refractory to Standard Medical Therapy

Current anti-anginal therapy
Current antianginal strategies
TMR
EECP
Exercise
training
Chelation
therapy
Non pharmacologic
SCS
Current anti-anginal strategies
Fasudil
Pharmacologic
Trimetazidine
Nicorandil
Ivabradine
Ranolazine
Current nonpharmacologic
antianginal strategies
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Exercise Training
Enhanced external
counterpulsation
(EECP)
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 Endothelial function
Promotes coronary
collateral formation
 Peripheral vascular
resistance
 Ventricular function
Placebo effect
Chelation therapy

Transmyocardial
revascularization (TMR)
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Sympathetic denervation
Angiogenesis
Spinal cord stimulation
(SCS)
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 Neurotransmission
of painful stimuli
 Release of
endogenous opiates
Redistributes myocardial
blood 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.
Potential cardioprotective
benefits of exercise
NO
production
ROS
generation
Vasculature
ROS
scavenging
Myocardium
Other
mechanisms
Thrombosis
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.
EECP - Enhanced External
CounterPulsation

External, pneumatic compression of lower
extremities in diastole.
EECP - Enhanced External
CounterPulsation
EECP - Enhanced External
CounterPulsation
Sequential
inflation of
cuffs
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Retrograde aortic
pressure wave
Increased Coronary
perfusion pressure
Increased Venous
Return
Increased Preload
Increased Cardiac
Output
Simultaneous
deflation of
cuffs in late
Diastole
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
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Lowers Systemic
Vascular Resistance
Reduced Preload
Decreased Cardiac
workload
Decreased Oxygen
Consumption
EECP - Enhanced External
CounterPulsation

35 total treatments
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Appears to reduce severity of Angina
Not shown to improve survival or reduce
myocardial infarctions
Indicated for CAD not amenable to
revascularization
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5 days per week x 7 weeks
1 hour per day
Anatomy not amenable to procedures
High risk co-morbidities with excessive risk
May be beneficial in treatment of refractory CHF
too, but generally this is not an approved
indication.
EECP – Contraindications &
Precautions
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Arrhythmias that interfere with machine
triggering
Bleeding diathesis
Active thrombophlebitis & severe lower
extremity vaso-occlusive disease
Presence of significant AAA
Pregnancy
TMLR - Transmyocardial Laser
Revascularization
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High power CO2 YAG
and excimer laser
conduits in myocardial to
create new channels for
blood flow
Possible explanations for
effect
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Myocardial angiogenesis
Myocardial denervation
Myocardial fibrosis with
secondary favorable
remodeling
TMLR – Direct Trial
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Only major blinded study
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298 pts with low dose,
high dose, or no laser
channels
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No benefit to TMLR vs
Med therapy to
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Patient survival
Angina class
Quality of life assessment
Exercise duration
Nuclear perfusion imaging
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Leon MB, et al. JACC 2005; 46:1812
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High Surgical Risk
(Mortality 5%)
Mainly used as adjunct
therapy during CABG to
treat myocardial that
cannot be bypassed.
Chelation Therapy

IV EDTA infusions
30 treatments over
about 3 months
 Cost – about $3,000
 Aggressive marketing
by 500 to 1000
physicians offering this
treatment
 PLACEBO effect only
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Claimed
pathophysiologic effects
Liberation of Calcium
in plaque
 Lower LDL, VLDL, and
Iron stores
 Inhibit platelet
aggregation
 Relax vasomotor tone
 Scavenge “free
radicals”

Spinal Cord Stimulation
power source
conducting wires
electrodes at
stimulation site
Stimulation typically
administered for 1-2 hrs tid
Therapeutic mechanism appears to be alteration of anginal pain perception
Long-term Outcomes Following
SCS
Prospective Italian Registry: 104 Patients, Follow-up 13.2 Mo
20
18
16
14
12
10
8
6
4
2
0
Baseline
SCS
* p<0.0001
*
Total Angina at
Angina
Rest
*
Exert
Angina
*
NTG
Use/wk
*
*
CCS
Class
# Hosp
Adms
*
*
Days in
Hosp
Episodes/wk
(DiPede, et al. AJC 2003;91:951)
Randomized Trial of SCS vs. CABG
For Patients with Refractory Angina
104 Patients with refractory angina, not suitable for PCI and
high risk for re-op (3.2% of patients accepted for CABG)
18
16
14
Mean 12
number 10
8
per
6
week
4
2
0
16.2
15.2
14.6
*
4.4
13.7
*
*
5.2
4.1
*
Baseline
6 months
3.1
*P < 0.0001
Anginal attacks
NTG
consumption
Anginal attacks
Spinal cord stimulation (n=53)
NTG
consumption
CABG (n=51)
No difference in symptom relief between SCS and CABG
(Mannheimer, et al. Circulation 1998;97:1157)
Current pharmacologic
antianginal strategies

New mechanistic approaches to angina
Rho kinase inhibition (fasudil)
 Metabolic modulation (trimetazidine)
 Preconditioning (nicorandil)
 Sinus node inhibition (ivabradine)
 Late Na+ current inhibition (ranolazine)
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Rho kinase inhibition: Fasudil
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Rho kinase triggers vasoconstriction through
accumulation of phosphorylated myosin
Ca2+
Ca2+
Agonist
PLC
VOC
ROC
Receptor
PIP2
Fasudil
IP3
Rho
Rho kinase
SR Ca2+
Myosin
Myosin phosphatase
MLCK
Ca2+
Calmodulin
Myosin-P
Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8.
Metabolic modulation (pFOX):
Trimetazidine
Myocytes
FFA
Glucose
Acyl-CoA
Pyruvate

β-oxidation
Trimetazidine
Acetyl-CoA
Energy for contraction
pFOX = partial fatty acid oxidation
FFA = free fatty acid

O2 requirement of
glucose pathway is
lower than FFA
pathway
During ischemia,
oxidized FFA levels
rise, blunting the
glucose pathway
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.
Preconditioning: Nicorandil
Activation of ATP-sensitive K+ channels
• Ischemic preconditioning
• Dilation of coronary resistance arterioles
N
O
HN
O NO2
Nitrate-associated effects
• Vasodilation of coronary epicardial arteries
IONA Study Group. Lancet. 2002;359:1269-75.
Rahman N et al. AAPS J. 2004;6:e34.
Sinus node inhibition: Ivabradine
SA = sinoatrial
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.
Sinus node inhibition: Ivabradine
SA node
AV node
Common bundle
Bundle branches
Purkinje fibers
SA = sinoatrial
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.
Sinus node inhibition: Ivabradine

Control
Ivabradine 0.3 µM
40
20
0
–20
–40
0.5
Time
(seconds)

If current is an inward
Na+/K+ current that
activates pacemaker
cells of the SA node
Ivabradine

–60
Potential (mV)

Selectively blocks If in
a current-dependent
fashion
Reduces slope of
diastolic depolarization,
slowing HR
SA = sinoatrial
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.
Myocardial ischemia causes
enhanced late INa
0
0
Sodium
Current
Ischemia
Late
Sodium
Current
Late
Na+
Peak
Peak
Impaired
Inactivation
Na+
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:
Ranolazine
Myocardial ischemia
 Late INa
Ranolazine
Na+ Overload
Ca2+ Overload
Mechanical dysfunction
 LV diastolic tension
 Contractility
Electrical dysfunction
Arrhythmias
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.
Understanding Angina at the
Cellular Level

Ischemia
Ranolazine

↑ Late INa
Na+ Overload

Ca++ Overload
Diastolic relaxation failure
Extravascular compression
Chaitman BR. Circulation. 2006;113:2462-2472
Ischemia impairs cardiomyocyte
sodium channel function
Impaired sodium channel function
leads to:
 Pathologic 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 ischemia and angina
Na+/Ca2+ overload and
ischemia
Myocardial
ischemia
Intramural small vessel compression
( O2 supply)
 Late Na+ current
 O2 demand
Na+ overload
 Diastolic wall tension (stiffness)
Ca2+ overload
Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.
Ranolazine
Ischaemia
( oxygen supply/ Demand)
 Vascular
compression
•  late Na+ current
 Diastolic wall
tension (stiffness)
•  Na+/Ca++ exchange
pump activation
[Ca2+] overload
 [Na+]i
Ranolazine – hemodynamic
affects

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No affect of Blood Pressure or Heart
Rate
Can be added to Conventional Medical
therapy, especially when BP and HR do
not allow further increase in dose of
BetaBlockers, Ca Channel blockers, and
Long Acting Nitrates.
Ranolazine has twin pronged action.
1.
2.
pFOX
Late Na inward entry blockade
Metabolic modulation (pFOX)
and ranolazine
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
Clinical trials showed ranolazine SR 500–
1000 mg bid (~2–6 µmol/L) reduced angina
Experimental studies demonstrated that
ranolazine 100 µmol/L achieved only 12%
pFOX inhibition

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Ranolazine does not inhibit pFOX substantially
at clinically relevant doses
Fatty acid oxidation Inhibition is not a major
antianginal mechanism for ranolazine
pFOX = partial fatty acid oxidation
MacInnes 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.
Ranolazine: Key concepts

Ischemia is associated with ↑ Na+ entry into
cardiac cells
Na+ efflux by Na+/Ca2+ exchange results in ↑
cellular [Ca2+]i and eventual Ca2+ overload
 Ca2+ overload may cause electrical and
mechanical dysfunction
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↑ Late INa is an important contributor to the
[Na+]i - dependent Ca2+ overload
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
ischemia and reperfusion
Rat heart model
Intracellular levels
Ischemia
Reperfusion
90
Na+
(μmol/g dry)
60
30
0
12
Ca2+
(μmol/g dry)
8
4
0
0
10
20
30
40
50
60
Time (minutes)
Tani M and Neely JR. Circ Res. 1989;65:1045-56.
Pharmacologic Classes for
Treatment of Angina
Medication
Class
Beta
Blockers
Calc
Channel
Blockers
Nitrates
Ranolazine
Impact Impact Physiologic
on HR on BP Mechanism
Decrease pump
function
Decrease Pump
function + Vasodilitation
Vaso-dilitation
O
O
Reduced Cardiac
Stiffness
Late Na+ accumulation
causes LV dysfunction
Isolated rat hearts treated with ATX-II, an enhancer of late INa
6
5
(+)
ATX-II
3
LV dP/dt
(mm Hg/sec, 2
in thousands) 1
Ranolazine 8.6 µM
(n = 6)
Ranolazine
4
LV+dP/dt
ATX-II 12 nM
(n = 13)
0
10
-1
-2
-3
-4
20
30
40
50
LV-dP/dt
(-)
Time (minutes)
Fraser H et al. Eur Heart J. 2006.
Late INa blockade - blunts
experimental ischemic LV damage
Isolated rabbit hearts
LV -dP/dt (Relaxation)
60
75
90
*
Baseline 30
70
*
LV end diastolic pressure
0
60
*
20
mm Hg/sec
30
-400
-600
-800
10
*
40
*
mm Hg
-200
*
50
-1000
0
Baseline 15
30
45
60
Reperfusion time (minutes)
Vehicle
*P < 0.05
Reperfusion time (minutes)
Vehicle (n = 10)
Ranolazine 10 µM (n = 7)
Ranolazine
Vehicle (n = 12)
Ranolazine 5.4 µM (n = 9)
Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.
Gralinski MR et al. Cardiovasc Res. 1994;28:1231-7.
Myocardial ischemia: Sites of
action of anti-ischemic medication
Development of ischemia
↑ O2 Demand
Heart rate
Blood pressure
Preload
Contractility
↓ O2 Supply
Traditional
anti-ischemic
medications:
β-blockers
Nitrates
Ca2+ blockers
Consequences of ischemia
Ischemia
Ca2+ overload
Electrical instability
Myocardial dysfunction
(↓systolic function/
↑diastolic stiffness)
Ranolazine
Courtesy of PH Stone, MD and BR Chaitman, MD. 2006.
Summary


Ischemic heart disease is a prevalent clinical
condition
Improved understanding of ischemia has
prompted new therapeutic approaches
Rho kinase inhibition
 Metabolic modulation
 Preconditioning
 Inhibition of If and late INa currents

Summary

Late INa inhibition and metabolic modulation
reduce angina with minimal or no
pathophysiologic effects

Mechanisms of action is complementary to
traditional agents
Stable CAD: Multiple
treatment options
Lifestyle
intervention
Medical
Reduce
symptoms
Treat
underlying
disease
PCI & CABG
therapy
Alternative
TX
ECG
R
mV
+
T
P
U
Q
Wave
Space
P
PQ
S
T
QRS
ST