EECP therapy provides an alternative treatment for refractory angina by increasing coronary perfusion pressure and reducing cardiac workload through the sequential inflation and deflation of compressive cuffs on the lower limbs. It has been shown to significantly reduce angina symptoms and improve quality of life. EECP therapy involves 35 hours of treatment over 7 weeks, with daily 1-2 hour sessions separated by rest periods. It appears to be a safe and effective option for refractory angina patients who are not candidates for revascularization.

1. Alternative therapyAlternative therapy
for medicallyfor medically
refractory anginarefractory angina
BY- DR SARITA CHOUDHARYBY- DR SARITA CHOUDHARY

2. Refractory anginaRefractory angina
Angina pectoris is a condition characterized by chest discomfort due to
myocardial ischaemia associated with coronary artery disease.
It is defined by presence of severe angina with objective evidence of
ischemia as demonstrated by exercise treadmill testing, stress imaging
studies or coronary physiologic studies and failure to relieve symptoms
with conventional medical therapy and even with revascularization
techniques.
Patients with refractory angina have either marked limitation of ordinary
physical activity or are unable to perform any ordinary physical activity
without discomfort (Canadian Cardiovascular Society [CCS] functional
class III or IV).

3.  Refractory angina pectoris is a chronic conditionRefractory angina pectoris is a chronic condition
characterized by the presence of angina caused by coronarycharacterized by the presence of angina caused by coronary
insufficiency in the presence of coronary artery diseaseinsufficiency in the presence of coronary artery disease
which cannot be controlled by a combination of medicalwhich cannot be controlled by a combination of medical
therapy, angioplasty and coronary bypass surgery.therapy, angioplasty and coronary bypass surgery.
 The presence of reversible myocardial ischemia should beThe presence of reversible myocardial ischemia should be
clinically established to be the cause of the symptoms.clinically established to be the cause of the symptoms.
 Chronic is defined as a duration of more than 3 monthsChronic is defined as a duration of more than 3 months
 So it is the disabling chest pain that persistsSo it is the disabling chest pain that persists
 Despite lifestyle adjustment andDespite lifestyle adjustment and
 Despite optimal medical therapy andDespite optimal medical therapy and
 Despite invasive coronary interventionsDespite invasive coronary interventions

4. ss
Algorithm to assess and treat refractory anginaAlgorithm to assess and treat refractory angina

5. Medical Therapy Commonly Prescribed forMedical Therapy Commonly Prescribed for
Angina PectorisAngina Pectoris
 Beta-blockers—decrease heart rate and contractilityBeta-blockers—decrease heart rate and contractility
 Calcium channel blockers—act as arterial vasodilator and decrease heartCalcium channel blockers—act as arterial vasodilator and decrease heart
rate and contractility.rate and contractility.
 Nitrates—act as venous and arterial vasodilatorNitrates—act as venous and arterial vasodilator
 Ranolazine- fRanolazine- fatty acid oxidation inhibitionatty acid oxidation inhibition ,inhibition of the late Na+ flux.,inhibition of the late Na+ flux.
 Trimetazidine- metabolic modulationTrimetazidine- metabolic modulation
 Nicorandil- preconditioningNicorandil- preconditioning
 Fasudil- rhokinase inhibitionFasudil- rhokinase inhibition
Antiplatelet agents—for anti-inflammatory activityAntiplatelet agents—for anti-inflammatory activity
Angiotensin-converting enzyme inhibitors—improve endothelial function, andAngiotensin-converting enzyme inhibitors—improve endothelial function, and
for anti-inflammatory activityfor anti-inflammatory activity
Statins—improve endothelial function, and for anti-inflammatory activityStatins—improve endothelial function, and for anti-inflammatory activity

6. Chronic ischemic heart disease: Treatment gapsChronic ischemic heart disease: Treatment gaps
 Many patients have relative intolerances to maximum
doses of traditional antianginal agents (β-blockers, CCBs,
and nitrates)
1 year after PCI or CABG 25% of patients still have angina
Many patients are deemed “inoperable”
Condition not suitable for PCI or CABG
Co-morbidities make procedure too high risk
 Patients continue to experience myocardial ischemia
 β-blockers and many CCBs have similar depressive
hemodynamic and electrophysiologic effects

7. The most common reasons why further revascularizationThe most common reasons why further revascularization
procedure is not possibleprocedure is not possible
 Unsuitable anatomy, such as diffuse coronary sclerosisUnsuitable anatomy, such as diffuse coronary sclerosis
 One or several previous CABGs and/or PTCAs which excludeOne or several previous CABGs and/or PTCAs which exclude
further benefit or possibility of further revascularization.further benefit or possibility of further revascularization.
 Lack of graft material.Lack of graft material.
 Impaired left ventricular function in patients with previousImpaired left ventricular function in patients with previous
CABG and/or PTCA.CABG and/or PTCA.
 Extracardiac diseases which increase perioperative/Extracardiac diseases which increase perioperative/
postoperative morbidity or mortality, such as generalpostoperative morbidity or mortality, such as general
arteriosclerotic disease, renal insufficiency, carotid stenosis andarteriosclerotic disease, renal insufficiency, carotid stenosis and
pulmonary disease.pulmonary disease.
 Age—often in combination with the above mentioned factors.Age—often in combination with the above mentioned factors.

8. Correlation - anxiety and ischaemic burdenCorrelation - anxiety and ischaemic burden
‘Angina is damaging my heart’
Restricted lifestyle
Increasing anxiety, depression
Reduced activity
Deconditioning
Worsening
symptoms at
lower thresholds

9. Cardicare
Angina Pectoris -Angina Pectoris -
Understanding the optionsUnderstanding the options
when Standard Therapywhen Standard Therapy
FailsFails

10. CAD: Multiple treatment optionsCAD: Multiple treatment options
Reduce
symptoms
Treat
underlying
disease
PCI & CABG
Lifestyle
intervention
Alternative
TX
Medical
therapy

11. Current antianginal strategiesCurrent antianginal strategies
Current anti-anginal strategiesCurrent anti-anginal strategies
Non pharmacologic
Pharmacologic
TrimetazidineTrimetazidine
FasudilFasudil NicorandilNicorandil
IvabradineIvabradine
RanolazineRanolazine
EECPEECP
ChelationChelation
therapytherapy
SCSSCS
TMRTMR

12.  Enhanced externalEnhanced external
counterpulsation (EECP)counterpulsation (EECP)
 TransmyocardialTransmyocardial
revascularizationrevascularization
(surgical and(surgical and
percutaneous)percutaneous)
 Chelation therapyChelation therapy
 Spinal cord stimulationSpinal cord stimulation
(SCS)(SCS)
Therapeutic Options for RefractoryTherapeutic Options for Refractory
Angina PectorisAngina Pectoris
 Coronary sinus reducerCoronary sinus reducer
 Gene therapyGene therapy
 Percutaneous in situPercutaneous in situ
coronary venouscoronary venous
arterializationarterialization
 Heart transplantationHeart transplantation
Allen KB et al. N Engl J Med. 1999;341:1029-36. Bonetti PO et al. J Am Coll Cardiol. 2003;41:1918-
25. Murray S et al. Heart. 2000;83:217-20.

13. EECP - Enhanced ExternalEECP - Enhanced External
CounterPulsationCounterPulsation
 It is a non invasive outpatient therapy consisting of ECG-gatedIt is a non invasive outpatient therapy consisting of ECG-gated
sequential leg compression.sequential leg compression.
 External, pneumatic compression of lower extremities in diastole.External, pneumatic compression of lower extremities in diastole.

14. EECP therapy, consisting of a patient bedEECP therapy, consisting of a patient bed
attached to an air compressor unit, computerized controlattached to an air compressor unit, computerized control
console, and 3 sets of cuffs wrapped around theconsole, and 3 sets of cuffs wrapped around the
lower legs and the buttocks of the patient.lower legs and the buttocks of the patient.

15. Early externalEarly external
counterpulsation devicescounterpulsation devices

16. The history...The history...
 Research in external counterpulsation goes back nearly 50 years, to 1953Research in external counterpulsation goes back nearly 50 years, to 1953
when thewhen the Kantrowitz brothersKantrowitz brothers described the concept of increased coronarydescribed the concept of increased coronary
artery blood flow and perfusion at higher pressure when blood pressure isartery blood flow and perfusion at higher pressure when blood pressure is
raised during diastole – this israised during diastole – this is diastolic augmentationdiastolic augmentation..
 Sarnoff and colleaguesSarnoff and colleagues showed that left ventricular work and myocardialshowed that left ventricular work and myocardial
oxygen consumption are more related to the pressure at which the leftoxygen consumption are more related to the pressure at which the left
ventricle must work, than the volume of blood it pumps. Mechanical leftventricle must work, than the volume of blood it pumps. Mechanical left
ventricular unloadingventricular unloading, therefore, reduces the heart’s energy requirements., therefore, reduces the heart’s energy requirements.
 BirtwellBirtwell combined thecombined the two principlestwo principles in a system that increased coronaryin a system that increased coronary
perfusion pressure in diastole and decreased left ventricular tension duringperfusion pressure in diastole and decreased left ventricular tension during
systole.systole.
 GorlinGorlin named this process “named this process “counterpulsation”.counterpulsation”.
 By the early 1960’sBy the early 1960’s Birtwell and Soroff, Dennis, and OsbornBirtwell and Soroff, Dennis, and Osborn allall
independently developed hydraulic external counterpulsation systems. Toindependently developed hydraulic external counterpulsation systems. To
create counterpulsation, all these devices pumped water in and out of acreate counterpulsation, all these devices pumped water in and out of a
single chamber enclosing the legs. They were used in all early U.S. clinicalsingle chamber enclosing the legs. They were used in all early U.S. clinical
studies of external counterpulsation.studies of external counterpulsation.

17. The EECP ProcedureThe EECP Procedure
:• Series of 3 cuffs resembling oversized blood pressure cuffs
wrapped around calves, lower thighs, upper thighs and buttocks
• The cuffs receive sequential distal-to-proximal pneumatic
inflation upon onset of diastole.The compression of the lower
extremity vascular bed increases diastolic pressure and flow and
increases venous return.

18. • The pressure is thenThe pressure is then released at the onset of systole.released at the onset of systole.
• Inflation and deflation are timed according to the R wave onInflation and deflation are timed according to the R wave on
the patient’s cardiac monitor.the patient’s cardiac monitor.
• The pressures applied and the inflation–deflation timing canThe pressures applied and the inflation–deflation timing can
be altered by using the pressure waveforms and ECG on thebe altered by using the pressure waveforms and ECG on the
EECP therapy monitor.EECP therapy monitor.
• A finger plethysmogram is used throughout treatment toA finger plethysmogram is used throughout treatment to
monitor diastolic and systolic pressure waveforms.monitor diastolic and systolic pressure waveforms.
• The current EECP device can generate external cuffThe current EECP device can generate external cuff
pressures as high as 220 to 300 mm Hg.pressures as high as 220 to 300 mm Hg.

20. Hemodynamic effects of EECP-:Hemodynamic effects of EECP-:
 IncreasedIncreased retrograde aortic blood flow;retrograde aortic blood flow; diastolic augmentationdiastolic augmentation
toto increase coronary perfusion pressureincrease coronary perfusion pressure and consequently,and consequently,
coronary blood flow to ischemic regions.coronary blood flow to ischemic regions.
 IncreasedIncreased systolic unloadingsystolic unloading to decrease cardiac workloadto decrease cardiac workload
and myocardial oxygen demand.and myocardial oxygen demand.
 Increased venous returnIncreased venous return toto raise cardiac outputraise cardiac output
 Improved left ventricular diastolic filling, peripheral flow-Improved left ventricular diastolic filling, peripheral flow-
mediated dilation, and endothelial function.mediated dilation, and endothelial function.
 Other putative mechanisms include recruitment of collaterals,Other putative mechanisms include recruitment of collaterals,
attenuation of oxidative stress and proinflammatory cytokinesattenuation of oxidative stress and proinflammatory cytokines
promotion of angiogenesis and vasculogenesis, and apromotion of angiogenesis and vasculogenesis, and a
peripheral training effectperipheral training effect

21. Hemodynamic effects of EECP therapy. Right upper corner: showing the ECG tracing and fingerHemodynamic effects of EECP therapy. Right upper corner: showing the ECG tracing and finger
pletysmogram. As soon as the device turned on (yellow line) diastolic augmentation starts. Rightpletysmogram. As soon as the device turned on (yellow line) diastolic augmentation starts. Right
lower corner: showing the diastolic augmentation by echocardiography. a, aortic notch.lower corner: showing the diastolic augmentation by echocardiography. a, aortic notch.

22. SequentialSequential
inflation ofinflation of
cuffscuffs
 Retrograde aorticRetrograde aortic
pressure wavepressure wave
 Increased CoronaryIncreased Coronary
perfusion pressureperfusion pressure
 Increased VenousIncreased Venous
ReturnReturn
 Increased PreloadIncreased Preload
 Increased CardiacIncreased Cardiac
OutputOutput
SimultaneousSimultaneous
deflation ofdeflation of
cuffs in latecuffs in late
DiastoleDiastole
 Lowers SystemicLowers Systemic
Vascular ResistanceVascular Resistance
 Reduced PreloadReduced Preload
 Decreased CardiacDecreased Cardiac
workloadworkload
 Decreased OxygenDecreased Oxygen
ConsumptionConsumption

23. The mechanism....The mechanism....
 The specific mechanisms of action of EECP® therapy are not as yetThe specific mechanisms of action of EECP® therapy are not as yet
defined.defined.
 However, clinical studies continue to identify components of theHowever, clinical studies continue to identify components of the
physiological, neurohumoral, and hemodynamic effects.physiological, neurohumoral, and hemodynamic effects.
 Studies have shown that the hemodynamics ofStudies have shown that the hemodynamics of EECP® therapy closelyEECP® therapy closely
resemble those of the intra-aortic balloon pump (IABP).resemble those of the intra-aortic balloon pump (IABP).

25. BENEFITS....BENEFITS....
Significant benefits associated with EECP therapy include-Significant benefits associated with EECP therapy include-
 Angina reductionAngina reduction
 Improvement in quality of lifeImprovement in quality of life
 Prolongation of the time to exercise-induced ST-segmentProlongation of the time to exercise-induced ST-segment
depressiondepression
 Resolution of myocardial perfusion defectsResolution of myocardial perfusion defects
 Reduction of nitrate useReduction of nitrate use
 Reduction in hospitalizationReduction in hospitalization
 Low MACE rates at long-term follow-upLow MACE rates at long-term follow-up

26.  35 hours total treatments35 hours total treatments
 5 days per week x 7 weeks5 days per week x 7 weeks
 1-2 hour per day1-2 hour per day
 2 hours daily2 hours daily treatment sessions are separated by atreatment sessions are separated by a
30 minutes rest interval30 minutes rest interval
 Appears to reduce severity of AnginaAppears to reduce severity of Angina
 Not shown to improve survivalNot shown to improve survival
 Indicated for CAD not amenable toIndicated for CAD not amenable to
revascularizationrevascularization
 Anatomy not amenable to proceduresAnatomy not amenable to procedures
 High risk co-morbidities with excessive riskHigh risk co-morbidities with excessive risk

27. Contraindications & PrecautionsContraindications & Precautions
 Arrhythmias that interfere with machine triggeringArrhythmias that interfere with machine triggering
 Bleeding diathesisBleeding diathesis
 Active thrombophlebitis & severe lower extremity vaso-Active thrombophlebitis & severe lower extremity vaso-
occlusive diseaseocclusive disease
 Presence of significant AAAPresence of significant AAA(5 mm) or dissection(5 mm) or dissection
 PregnancyPregnancy
 Decompensated heart failureDecompensated heart failure
 Severe aortic regurgitationSevere aortic regurgitation
 Severe hypertension: greater than 180/ 110 mm HgSevere hypertension: greater than 180/ 110 mm Hg
 Severe chronic obstructive pulmonary diseaseSevere chronic obstructive pulmonary disease

28. Side effectsSide effects
 ParesthesiasParesthesias
 Skin abrasion or ecchymosesSkin abrasion or ecchymoses
 BruisesBruises
 Worsening of heart failure in patients withWorsening of heart failure in patients with
arrhythmiasarrhythmias
 Leg or waist pain,Leg or waist pain,
 OedemaOedema

29. SUNY Stony Brook: The first publication -SUNY Stony Brook: The first publication -
19921992
Background:Background: Of 18 patients with chronic angina refractory to medical therapy:Of 18 patients with chronic angina refractory to medical therapy:
- 8 had 19 prior revascularization attempts- 8 had 19 prior revascularization attempts
- 7 had 14 prior mycardial infarcts- 7 had 14 prior mycardial infarcts
Methods:Methods: 36 one-hour treatment sessions36 one-hour treatment sessions
Pre- and post-treatment thallium treadmill stress tests toPre- and post-treatment thallium treadmill stress tests to
identical exercise timesidentical exercise times
Separate post-treatment maximal routine treadmill stress testSeparate post-treatment maximal routine treadmill stress test
Results:Results: All patients reported improvement in anginal symptoms:All patients reported improvement in anginal symptoms:
- 16 patients (- 16 patients (89%89%) reported no angina during usual activities:) reported no angina during usual activities:
- 12 patients (- 12 patients (67%67%) with resolution of reversible perfusion defects) with resolution of reversible perfusion defects
- 2 patients (- 2 patients (11%11%) with improvement of reversible perfusion defects) with improvement of reversible perfusion defects
- 4 patients (- 4 patients (22%22%) with no change) with no change
Lawson WE, Hui JCK, Soroff HS, et al. Efficacy of enhanced external counterpulsation in the treatmentLawson WE, Hui JCK, Soroff HS, et al. Efficacy of enhanced external counterpulsation in the treatment
of angina pectoris.of angina pectoris. Am J Cardiol.Am J Cardiol. 1992;70:859-862.1992;70:859-862.

30. SUNY Stony Brook: 5-year Follow-upSUNY Stony Brook: 5-year Follow-up
Background:Background: A five-year follow-up was conducted on 33 anginaA five-year follow-up was conducted on 33 angina
patients treated between 1989 and 1992 with EECP,patients treated between 1989 and 1992 with EECP,
to assess morbidity and mortality.to assess morbidity and mortality.
Methods:Methods: Review of patient records at 5 years post-EECPReview of patient records at 5 years post-EECP
(range 4-7 years).(range 4-7 years).
Results:Results: 29 of 33 patients remained alive. Of these, 9 patients29 of 33 patients remained alive. Of these, 9 patients
were hospitalized (4 acute MI, 6 CABG/PTCA,were hospitalized (4 acute MI, 6 CABG/PTCA,
1 unstable angina and 1 other cardiac surgery).1 unstable angina and 1 other cardiac surgery).
Conclusions:Conclusions: Five-year survival without an interim event of 60% of patients treated with EECPFive-year survival without an interim event of 60% of patients treated with EECP
appears similar to that seen with comparable populations treated withappears similar to that seen with comparable populations treated with
CABG/PTCA.CABG/PTCA.
Lawson WE, Hui JCK, Burger L, et al. Five-year follow-up of morbidity and mortality in 33 angina patientLawson WE, Hui JCK, Burger L, et al. Five-year follow-up of morbidity and mortality in 33 angina patient
treated with enhanced external counterpulsation.treated with enhanced external counterpulsation. J Invest Med.J Invest Med. 1997;45:212A.1997;45:212A.

31. The Multicenter Study of Enhanced ExternalThe Multicenter Study of Enhanced External
Counterpulsation (MUST-EECP)Counterpulsation (MUST-EECP)
Design:Design: Multicenter, randomized, sham-controlled, double-blinded trialMulticenter, randomized, sham-controlled, double-blinded trial
Randomization:Randomization: Even assignment to EECP group or sham group in blocks of 10Even assignment to EECP group or sham group in blocks of 10
allocated to each centerallocated to each center
Subjects:Subjects: 139 patients with chronic stable angina pectoris139 patients with chronic stable angina pectoris
Duration:Duration: May 1995 - July 1997May 1995 - July 1997
Evaluate effectEvaluate effect
of EECP on...of EECP on... Measured by…Measured by…
Exercise abilityExercise ability Exercise durationExercise duration
Time to ST-segment depressionTime to ST-segment depression
Clinical statusClinical status Frequency of anginal episodesFrequency of anginal episodes
Intake of nitroglycerinIntake of nitroglycerin

32. MUST-EECP:ExerciseMUST-EECP:Exercise
ResultsResults
37
-4
42
26
-10 0 10 20 30 40 50
Time to ST
Depression
Exercise
Duration
Active Sham
Seconds
Adjusted mean of change from baseline
p = ns
p = 0.01
}
}

33. Summary of Clinical ResultsSummary of Clinical Results
Compared to sham, EECP:Compared to sham, EECP:
• Increased time to exercise-induced ST segment depression (Increased time to exercise-induced ST segment depression (pp= 0.01)= 0.01)
• Decreased the frequency of angina episodes (Decreased the frequency of angina episodes (pp< 0.04)< 0.04)
Compared to baseline:Compared to baseline:
• Exercise duration increased significantly in both groupsExercise duration increased significantly in both groups
(Sham- p<0.03, Active- p< 0.001)(Sham- p<0.03, Active- p< 0.001)
• Time to ST segment depression increased significantly in Active GroupTime to ST segment depression increased significantly in Active Group
only (p< 0.002)only (p< 0.002)
 EECP is a safe and effective treatment for angina pectoris refractory to medical therapyEECP is a safe and effective treatment for angina pectoris refractory to medical therapy
 Benefits of EECP include an improvement of functional status in more than 70% ofBenefits of EECP include an improvement of functional status in more than 70% of
patientspatients
 Benefits accrue both short-term and long-termBenefits accrue both short-term and long-term

34.  In a meta-analysis of 13 observational studies that tracked 949 patients, CCSIn a meta-analysis of 13 observational studies that tracked 949 patients, CCS
anginal class was improved by ≥1 class in 86% of EECP-treated patients.anginal class was improved by ≥1 class in 86% of EECP-treated patients.**
 The EECPThe EECP Consortium reported results from 2289 consecutive patientsConsortium reported results from 2289 consecutive patients
undergoing EECP therapy treatment was associated with improved perfusionundergoing EECP therapy treatment was associated with improved perfusion
images and increased exercise duration. **images and increased exercise duration. **
 Similarly, the International EECP Registry reported improvement of ≥1 CCSSimilarly, the International EECP Registry reported improvement of ≥1 CCS
angina class in 81% of patients after EECP.***angina class in 81% of patients after EECP.***
 Moreover, follow-up data indicate that the clinical benefit may be maintainedMoreover, follow-up data indicate that the clinical benefit may be maintained
for up to 5 years in patients with a favorable initial clinical responsefor up to 5 years in patients with a favorable initial clinical response
**Daemen J, Boersma E, Flather M, et al. Long-term safety and efficacy of percutaneous coronary intervention with stenting and coronary arteryDaemen J, Boersma E, Flather M, et al. Long-term safety and efficacy of percutaneous coronary intervention with stenting and coronary artery
bypass surgery for multivessel coronary artery disease: a meta-analysis with 5-year patient-level data from the ARTS, ERACI-II, MASS-II,bypass surgery for multivessel coronary artery disease: a meta-analysis with 5-year patient-level data from the ARTS, ERACI-II, MASS-II,
and SoS trials. Circulation. 2008;118:1146-54.and SoS trials. Circulation. 2008;118:1146-54.
** Rodriguez A, Rodriguez AM, Baldi J, et al. Coronary stenting versus coronary bypass surgery in patients with multiple vessel disease and** Rodriguez A, Rodriguez AM, Baldi J, et al. Coronary stenting versus coronary bypass surgery in patients with multiple vessel disease and
significant proximal LAD stenosis: results from the ERACI II study. Heart. 2003;89:184-8.significant proximal LAD stenosis: results from the ERACI II study. Heart. 2003;89:184-8.
*** Mercado N, Maier W, Boersma E, et al. Clinical and angiographic outcome of patients with mild coronary lesions treated with balloon angioplasty*** Mercado N, Maier W, Boersma E, et al. Clinical and angiographic outcome of patients with mild coronary lesions treated with balloon angioplasty
or coronary stenting. Implications for mechanical plaque sealing. Eur Heart J. 2003;24:541-51or coronary stenting. Implications for mechanical plaque sealing. Eur Heart J. 2003;24:541-51

35. The Food & Drug Administration (FDA) has approved EECP® forThe Food & Drug Administration (FDA) has approved EECP® for
treatment oftreatment of cardiovascular disease:cardiovascular disease:
 In theIn the 1970s, EECP® was first approved for cardiogenic shock1970s, EECP® was first approved for cardiogenic shock andand
acute myocardial infarction .acute myocardial infarction .
 EECP was approved by the US Food and Drug Administration in 1995 forEECP was approved by the US Food and Drug Administration in 1995 for
the treatment of patients with CAD and refractory angina pectoris who fail tothe treatment of patients with CAD and refractory angina pectoris who fail to
respond to standard revascularization procedures and aggressiverespond to standard revascularization procedures and aggressive
pharmacotherapy.pharmacotherapy.
 In JuneIn June 2002, EECP® was approved for congestive heart2002, EECP® was approved for congestive heart failurefailure

36. TMLR - Transmyocardial LaserTMLR - Transmyocardial Laser
RevascularizationRevascularization
 High power CO2 YAG and excimer laserHigh power CO2 YAG and excimer laser
conduits in myocardial to create new channelsconduits in myocardial to create new channels
for blood flowfor blood flow

37. Transmyocardial laser revascularization (TMLR) was first used
in 1983 in association with CABG as a complementary technique
(Smith 1995).
In this surgical procedure , after left lateral
thoracotoy 1-mm full-thickness holes through the left
ventricle are made with a laser on the
epicardial surfac of the left ventricle,
creating 10 to 50 small channels from the
epicardium to the endocardium1 cm apart
in a line from the base to the apex,
and then in other lines 1 cm from each other,
creating a total of 20 to 40 channels.
These channels and the capillaries that
grow out from them provide a way for
oxygenated blood in the left ventricle
to nourish myocardium.

38.  The epicardial channel opening usually closes spontaneouslyThe epicardial channel opening usually closes spontaneously
and mimic the sinusoids in a reptile’s heart, which has noand mimic the sinusoids in a reptile’s heart, which has no
coronary arteries.coronary arteries.
 20 percent of these remain patent; and new capillaries20 percent of these remain patent; and new capillaries
0.1 to .3 mm in diameter, lined with endothelium, extend out0.1 to .3 mm in diameter, lined with endothelium, extend out
into the myocardium from the channels.into the myocardium from the channels.
 The laser is triggered to fire on the R wave of theThe laser is triggered to fire on the R wave of the
electrocardiogram when the ventricle is in diastole, maximallyelectrocardiogram when the ventricle is in diastole, maximally
distended and electrically quiescent. Synchronization of thedistended and electrically quiescent. Synchronization of the
very brief laser pulse to the R wave of the electrocardiogramvery brief laser pulse to the R wave of the electrocardiogram
reduces the risk of arrhythmia.reduces the risk of arrhythmia.

39. Biologic Plausibility of TMRBiologic Plausibility of TMR
• MyocardialMyocardial DenervationDenervation
– Mylenated fiberMylenated fiber
– Sympathetic fibersSympathetic fibers
• Endocardial channelsEndocardial channels
– 20 % stay remain patent20 % stay remain patent
• Neoangiogenesis from channelsNeoangiogenesis from channels
– New capillaries 0.1-0.3 diameterNew capillaries 0.1-0.3 diameter
with endotheliumwith endothelium
formation of new capillaries from pre-existingformation of new capillaries from pre-existing
ones (angiogenesis) or by the enlargement andones (angiogenesis) or by the enlargement and
functional recruitment of pre-existing collateralfunctional recruitment of pre-existing collateral
vessels (arteriogenesis)vessels (arteriogenesis)
COCO22 LaserLaser
Full-thickness 1 mm channelFull-thickness 1 mm channel
created with a 20 joules singlecreated with a 20 joules single
pulse.pulse.

40.  Relief of angina does not simply result from denervation because theRelief of angina does not simply result from denervation because the
benefits of TMR extend out to 5 years, beyond the time when the nervesbenefits of TMR extend out to 5 years, beyond the time when the nerves
would have grown back.would have grown back.
 Its beneficial effect is a consequence of neoangiogenesis, resulting inIts beneficial effect is a consequence of neoangiogenesis, resulting in
improved myocardial blood flow.improved myocardial blood flow.
 Patients with poor left ventricular ejection fraction are not goodPatients with poor left ventricular ejection fraction are not good
candidates for laser therapy.candidates for laser therapy.

41. Possible perioperative and postoperative complicationsPossible perioperative and postoperative complications
encompass –encompass –
 mortality rates range from 5–20% and the perioperativemortality rates range from 5–20% and the perioperative
morbidity has been between 32 and 68% in different studiesmorbidity has been between 32 and 68% in different studies
 myocardial infarctionmyocardial infarction
 low output syndromelow output syndrome
 ventricular arrhythmias, atrial fibrillationventricular arrhythmias, atrial fibrillation
 sudden development of mitral regurgitation as a result ofsudden development of mitral regurgitation as a result of
laser injury to the chordae tendineaelaser injury to the chordae tendineae
 bleedingbleeding
 postoperative complications, such as wound infection orpostoperative complications, such as wound infection or
pneumonia.pneumonia.

42.  A single randomized multicenter comparison of TMRA single randomized multicenter comparison of TMR
(with a holmium:YAG laser) plus CABG versus CABG(with a holmium:YAG laser) plus CABG versus CABG
alone in patients in whom some myocardial segmentsalone in patients in whom some myocardial segments
were perfused by arteries considered not amenable towere perfused by arteries considered not amenable to
grafting showed a significant reduction in perioperativegrafting showed a significant reduction in perioperative
mortality (1.5% vs 7.6%, respectively), with the survivalmortality (1.5% vs 7.6%, respectively), with the survival
benefit of the TMR–CABG combination present after 1benefit of the TMR–CABG combination present after 1
year of follow-up.*year of follow-up.*
* Allen KB, Dowling RD, DelRossi AJ, et al. Transmyocardial laser revascularization combined with coronary artery bypass grafting: a* Allen KB, Dowling RD, DelRossi AJ, et al. Transmyocardial laser revascularization combined with coronary artery bypass grafting: a
multicenter, blinded, prospective, randomized, controlled trial. J Thorac Cardiovasc Surg 2000;119:540–9multicenter, blinded, prospective, randomized, controlled trial. J Thorac Cardiovasc Surg 2000;119:540–9..

43. PERCUTANEOUSPERCUTANEOUS TRANSMYOCARDIAL LASERTRANSMYOCARDIAL LASER
REVASCULARIZATIONREVASCULARIZATION
 TMR has also been performed percutaneously, using aTMR has also been performed percutaneously, using a
less-invasive catheter-based approach that is referred to asless-invasive catheter-based approach that is referred to as
PTMLR.PTMLR.
 A catheter laser fiberoptic system is introduced through theA catheter laser fiberoptic system is introduced through the
femoral artery and through the aortic valve into the leftfemoral artery and through the aortic valve into the left
ventricle. The laser-made channels in the myocardium areventricle. The laser-made channels in the myocardium are
created from the endocardium towards the epicardiumcreated from the endocardium towards the epicardium
guided by fluoroscopy and simultaneous transoesophagealguided by fluoroscopy and simultaneous transoesophageal
echocardiographic monitoring.echocardiographic monitoring.
 Injury to the epicardial coronary artery, chordae tendineae,Injury to the epicardial coronary artery, chordae tendineae,
bleeding into the pericardial sac and neurologicalbleeding into the pericardial sac and neurological
complications are possible.complications are possible.

44.  The mortality rate is estimated to 1%.The mortality rate is estimated to 1%.
 Further scientific data are needed before the role ofFurther scientific data are needed before the role of
percutaneous laser revascularization in the therapeuticpercutaneous laser revascularization in the therapeutic
arsenal can be determined.arsenal can be determined.
 The Potential Angina Class Improvement FromThe Potential Angina Class Improvement From
Intramyocardial Channels (PACIFIC) trial was a multicenter,Intramyocardial Channels (PACIFIC) trial was a multicenter,
randomized study comparing PTMLR in addition to medicalrandomized study comparing PTMLR in addition to medical
therapy with medical therapy alone in patients with CCStherapy with medical therapy alone in patients with CCS
class III or IV RAP. At 12 months, exercise toleranceclass III or IV RAP. At 12 months, exercise tolerance
significantly increased in the PTMLR group, as did anginalsignificantly increased in the PTMLR group, as did anginal
class scores and quality-of-life measurements. There wasclass scores and quality-of-life measurements. There was
no significant difference, however, in overall mortalityno significant difference, however, in overall mortality
Oesterle SN, Sanborn TA, Ali N, et al. Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial.Oesterle SN, Sanborn TA, Ali N, et al. Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial.
Potential class improvement from Intramyocardial channels. Lancet 2000;356:1705–10.Potential class improvement from Intramyocardial channels. Lancet 2000;356:1705–10.

45. DIRET TRIALDIRET TRIAL
Stone GW, Teirstein PS, Rubenstein R, et al. A prospective, multicenter, randomized trial ofStone GW, Teirstein PS, Rubenstein R, et al. A prospective, multicenter, randomized trial of
percutaneous transmyocardial laser revascularization in patients with nonrecanalizable chronic total occlusions. J Am Coll Cardiolpercutaneous transmyocardial laser revascularization in patients with nonrecanalizable chronic total occlusions. J Am Coll Cardiol
2002;39:1581–72002;39:1581–7 .. Leon M. DIRECT trial: Late breaking trials. Presentedat: Transcatheter Therapeutics. Washington,DC, OctoberLeon M. DIRECT trial: Late breaking trials. Presentedat: Transcatheter Therapeutics. Washington,DC, October
20, 2000.20, 2000.
 The results of the direct myocardial revascularization in theThe results of the direct myocardial revascularization in the
Regeneration of Endomyocardial Channels Trial (DIRECT)Regeneration of Endomyocardial Channels Trial (DIRECT)
tempered the initial enthusiasm surrounding PTMLR.tempered the initial enthusiasm surrounding PTMLR.
 This randomized, placebo-controlled, prospective trialThis randomized, placebo-controlled, prospective trial
enrolled 298 patients into 3 treatment arms: placebo PTMLRenrolled 298 patients into 3 treatment arms: placebo PTMLR
procedure, low-dose PTMLR (10–15 channels created), orprocedure, low-dose PTMLR (10–15 channels created), or
high-dose PTMLR (20–25 channels created).high-dose PTMLR (20–25 channels created).
 The results were similar for treatment arms, representing aThe results were similar for treatment arms, representing a
large placebo effect.large placebo effect.
 It demonstrated no therapeutic benefitIt demonstrated no therapeutic benefit on patient survivalon patient survival
angina class, Quality of life ,exercise durationangina class, Quality of life ,exercise duration and thisand this
therapy was thus promptly abandoned.therapy was thus promptly abandoned.

46.  TMR and PTMLR have been recently evaluated byTMR and PTMLR have been recently evaluated by
Schofield and McNab.Although there was anSchofield and McNab.Although there was an
improvement in the more subjective outcome measuresimprovement in the more subjective outcome measures
(including exercise tolerance testing, angina score, and(including exercise tolerance testing, angina score, and
quality of life), this was counterbalanced by a higher riskquality of life), this was counterbalanced by a higher risk
of postoperative mortality(5%) and morbidity (includingof postoperative mortality(5%) and morbidity (including
MI, heart failure, thromboembolic events, pericarditis,MI, heart failure, thromboembolic events, pericarditis,
acute mitral insufficiency, and neurologic events).*acute mitral insufficiency, and neurologic events).*
 Mainly used as adjunct therapy during CABG to treatMainly used as adjunct therapy during CABG to treat
myocardial that cannot be bypassed.myocardial that cannot be bypassed.
 Class llb indication in ACC/AHA 2012 CAD guidelinesClass llb indication in ACC/AHA 2012 CAD guidelines
* Schofield PM, McNab D. NICE evaluation of transmyocardial laser revascularization and percutaneous laser revascularisation for refractory* Schofield PM, McNab D. NICE evaluation of transmyocardial laser revascularization and percutaneous laser revascularisation for refractory
angina. Heart 2010;96:312–3.angina. Heart 2010;96:312–3.

47. CHELATION THERAPYCHELATION THERAPY
 It was first proposed as a potential treatment forIt was first proposed as a potential treatment for
atherosclerosis in the 1950s, after it was noted thatatherosclerosis in the 1950s, after it was noted that
patients treated for lead poisoning felt relief of theirpatients treated for lead poisoning felt relief of their
anginal symptoms after undergoing ethylenediamine-anginal symptoms after undergoing ethylenediamine-
tetraacetic acid (EDTA) therapy.tetraacetic acid (EDTA) therapy.
 Since then, various small, uncontrolled studies have beenSince then, various small, uncontrolled studies have been
published, with conflicting results.published, with conflicting results.
 It consists of a series of intravenous infusions of EDTA inIt consists of a series of intravenous infusions of EDTA in
combination with other substances, has been touted as acombination with other substances, has been touted as a
putative noninvasive means of improving blood flow inputative noninvasive means of improving blood flow in
atherosclerotic vessels, treating angina, and preventingatherosclerotic vessels, treating angina, and preventing
cardiac events.cardiac events.

48.  The hypothesis for atherosclerosis regression involves theThe hypothesis for atherosclerosis regression involves the
ability of EDTA to extract calcium from the atheroscleroticability of EDTA to extract calcium from the atherosclerotic
plaque. This hypothesis has never been scientificallyplaque. This hypothesis has never been scientifically
validated and, in fact, is no longer applicable.validated and, in fact, is no longer applicable.
 Probable mechanism include EDTA reduces oxidative stressProbable mechanism include EDTA reduces oxidative stress
in the vascular wall,in the vascular wall, lowers LDL, VLDL, and Iron stores,lowers LDL, VLDL, and Iron stores,
inhibits platelet aggregation and relaxes vasomotor tone.inhibits platelet aggregation and relaxes vasomotor tone.
 Consist of 30 treatments over about 3 monthsConsist of 30 treatments over about 3 months
 Program to assess Alternative Treatment strategies to achieve CardiacProgram to assess Alternative Treatment strategies to achieve Cardiac
Health (PATCH) trial showed the ineffectiveness of chelation therapy .Health (PATCH) trial showed the ineffectiveness of chelation therapy .
Knudson ML, Wyse DG, Gailbraith PD, et al. Chelation therapy for ischemic heart disease: a randomized controlled trial. JAMA 2002; 287:481–6Knudson ML, Wyse DG, Gailbraith PD, et al. Chelation therapy for ischemic heart disease: a randomized controlled trial. JAMA 2002; 287:481–6

49. TACT (Trial to Assess Chelation Therapy)TACT (Trial to Assess Chelation Therapy)
Lamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelationLamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelation
regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309:1241–regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309:1241–
5050 ..
 RCT comparing chelation with placebo in patients who hadRCT comparing chelation with placebo in patients who had
experienced MI.experienced MI.
 The primary composite endpoint of total mortality, recurrentThe primary composite endpoint of total mortality, recurrent
MI, stroke, coronary revascularization, or hospitalization forMI, stroke, coronary revascularization, or hospitalization for
angina occurred in 222 (26%) patients in the chelation groupangina occurred in 222 (26%) patients in the chelation group
and 261 (30%) patients in the placebo group (hazard ratio:and 261 (30%) patients in the placebo group (hazard ratio:
0.82; 95% CI: 0.69 to 0.99;0.82; 95% CI: 0.69 to 0.99; P=0.035P=0.035
 Disodium EDTA, particularly when infused too rapidly, mayDisodium EDTA, particularly when infused too rapidly, may
cause hypocalcemia, renal failure, and death.cause hypocalcemia, renal failure, and death.

50.  Despite these positive findings, the TACT investigatorsDespite these positive findings, the TACT investigators
did not recommend the routine use of chelation therapydid not recommend the routine use of chelation therapy
to reduce symptoms or cardiovascular complications forto reduce symptoms or cardiovascular complications for
all patients with SIHD, given the modest overall benefit,all patients with SIHD, given the modest overall benefit,
high proportion of patient withdrawals (18% lost tohigh proportion of patient withdrawals (18% lost to
follow-up), absence of adequate scientific basis for thefollow-up), absence of adequate scientific basis for the
therapy.therapy.
 Changed from class lll to class llb in 2014 SIHD focusedChanged from class lll to class llb in 2014 SIHD focused
update.update.

51. NeurostimulationNeurostimulation
 It is for the palliation of angina by interruption or modification of the afferentIt is for the palliation of angina by interruption or modification of the afferent
neural signals through which pain is perceived.neural signals through which pain is perceived.
 Different surgical techniques have been used to interrupt the innervation ofDifferent surgical techniques have been used to interrupt the innervation of
the heart, including autotransplantation, sympathectomy and plexectomy.the heart, including autotransplantation, sympathectomy and plexectomy.
 More recent studies using transcutaneous electrical nerve stimulationMore recent studies using transcutaneous electrical nerve stimulation
(TENS) and spinal cord stimulation (SCS) have produced the most(TENS) and spinal cord stimulation (SCS) have produced the most
promising results.promising results.
 Mannheimer first described the beneficial effects of TENS in early 1980s.Mannheimer first described the beneficial effects of TENS in early 1980s.
 In TENS, two electrodes are applied to the chest—one in the dermatomeIn TENS, two electrodes are applied to the chest—one in the dermatome
with the highest intensity of projected pain and the other in the contralateralwith the highest intensity of projected pain and the other in the contralateral
dermatome. The stimulus intensity is adjusted to just below the individual’sdermatome. The stimulus intensity is adjusted to just below the individual’s
pain threshold.pain threshold.
 They act by reducing the activation of central pain receptors. In addition,They act by reducing the activation of central pain receptors. In addition,
there is a reduction in sympathetic discharge, leading to a decrease inthere is a reduction in sympathetic discharge, leading to a decrease in
cardiac work load and myocardial oxygen demand.cardiac work load and myocardial oxygen demand.

52. SPINAL CORD STIMULATIONSPINAL 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

53.  Spinal cord stimulation appears to be the most promisingSpinal cord stimulation appears to be the most promising
neurostimulatory technique for refractory angina.neurostimulatory technique for refractory angina.
 It is performed under local anaesthesia. In SCS, the epiduralIt is performed under local anaesthesia. In SCS, the epidural
space is punctured at the level of the fourth or sixth thoracicspace is punctured at the level of the fourth or sixth thoracic
vertebra, and Tuohy-type needle was advanced in the midlinevertebra, and Tuohy-type needle was advanced in the midline
through the intervertebral spaces into the epidural space anthrough the intervertebral spaces into the epidural space an
electrode is introduced to the level of the first or secondelectrode is introduced to the level of the first or second
thoracic vertebra.thoracic vertebra.
 An electrode stimulator is then placed subcutaneously in theAn electrode stimulator is then placed subcutaneously in the
upper left abdomen.upper left abdomen.
 The device has an epidural lead, extension wire, and pulseThe device has an epidural lead, extension wire, and pulse
generator.generator.

54.  An extension lead is tunneled subcutaneously to theAn extension lead is tunneled subcutaneously to the
midline incision and connected to the electrode.midline incision and connected to the electrode.
 The pulse generator is telemetrically programmed .The pulse generator is telemetrically programmed .
 The pulse generator is turned on or off when the patientThe pulse generator is turned on or off when the patient
quickly touches the skin over the pulse generator with anquickly touches the skin over the pulse generator with an
external magnet.external magnet.
 It is used for at least 2 hours four times daily.It is used for at least 2 hours four times daily.
 The patient can also use the magnet to switch betweenThe patient can also use the magnet to switch between
the two preset stimulation strengths.the two preset stimulation strengths.

55.  Angina pectoris often results from ischemic episodes that exciteAngina pectoris often results from ischemic episodes that excite
chemosensitive and mechanoreceptive receptors in the heart.chemosensitive and mechanoreceptive receptors in the heart.
 Ischemic episodes release a collage of chemicals, including adenosineIschemic episodes release a collage of chemicals, including adenosine
and bradykinin, that excites the receptors of the sympathetic and vagaland bradykinin, that excites the receptors of the sympathetic and vagal
afferent pathways.afferent pathways.
 Sympathetic afferent fibers from the heart enter the upper thoracic spinalSympathetic afferent fibers from the heart enter the upper thoracic spinal
cord and synapse on cells of origin of ascending pathways. Excitation ofcord and synapse on cells of origin of ascending pathways. Excitation of
spinothalamic tract cells in the upper thoracic and lower cervical segments,spinothalamic tract cells in the upper thoracic and lower cervical segments,
contributes to the anginal pain experienced in the chest and arm.contributes to the anginal pain experienced in the chest and arm.
 Cardiac vagal afferent fibers synapse in the nucleus tractus solitarius ofCardiac vagal afferent fibers synapse in the nucleus tractus solitarius of
the medulla and then descend to excite upper cervical spinothalamic tractthe medulla and then descend to excite upper cervical spinothalamic tract
cells. This innervation contributes to the anginal pain experienced in thecells. This innervation contributes to the anginal pain experienced in the
neck and jaw.neck and jaw.
 The spinothalamic tract projects to the medial and lateral thalamus and,The spinothalamic tract projects to the medial and lateral thalamus and,
activates several cortical areas, including the anterior cingulate gyrus,activates several cortical areas, including the anterior cingulate gyrus,
lateral basal frontal cortex, and the mesiofrontal cortex.lateral basal frontal cortex, and the mesiofrontal cortex.

56.  Mechanism of action -both anMechanism of action -both an antalgic effectantalgic effect, mainly due to, mainly due to
modulation of pain signal in the spinal cord and change inmodulation of pain signal in the spinal cord and change in
metabolism of beta-endorphine .metabolism of beta-endorphine .
 antiischemic effectantiischemic effect expressed by decrease in the serumexpressed by decrease in the serum
catecholamine level, exerted by reducing sympathetic tonecatecholamine level, exerted by reducing sympathetic tone
leading to decrease in myocardial oxygen consumption at aleading to decrease in myocardial oxygen consumption at a
comparable level of cardiac work. Redistribution of bloodcomparable level of cardiac work. Redistribution of blood
from non-ischaemic to ischaemic areas is also proposed.from non-ischaemic to ischaemic areas is also proposed.
 The effect of transcutaneous electrical nerve stimulationThe effect of transcutaneous electrical nerve stimulation
(TENS) on coronary flow was not accomplished in patients(TENS) on coronary flow was not accomplished in patients
with a heart transplant which suggests that neurostimulationwith a heart transplant which suggests that neurostimulation
employs its effect through neural mechanisms employed atemploys its effect through neural mechanisms employed at
the microcirculatory level.the microcirculatory level.

57. Contraindications to this therapy include,Contraindications to this therapy include,
 Unstable anginaUnstable angina
 Unfavorable physical conditionUnfavorable physical condition
 Cardiac pacemaker or ICDCardiac pacemaker or ICD
 Lack of patient complianceLack of patient compliance
 Obvious infection, allergic or immune responseObvious infection, allergic or immune response
to implanted materialsto implanted materials
 Anticoagulation that might increase bleeding atAnticoagulation that might increase bleeding at
the implantation site.the implantation site.

59. Randomized Trial of SCS vs. CABG For Patients withRandomized Trial of SCS vs. CABG For Patients with
Refractory AnginaRefractory Angina
14.6 15.2
16.2
13.7
4.4 4.1
5.2
3.1
0
2
4
6
8
10
12
14
16
18
Anginal attacks NTG
consumption
Anginal attacks NTG
consumption
Mean
number
per
week
Baseline
6 months
Spinal cord stimulation (n=53) CABG (n=51)
*P < 0.0001
****
(Mannheimer, et al. Circulation 1998;97:1157)
104 Patients with refractory angina, not suitable for PCI and
high risk for re-op (3.2% of patients accepted for CABG)
No difference in symptom relief between SCS and CABG

60.  It is frequently complicated by persistent skin irritation,It is frequently complicated by persistent skin irritation,
which makes adequate continuation of therapy difficult.which makes adequate continuation of therapy difficult.
 Meanwhile, SCS has a rather high incidence ofMeanwhile, SCS has a rather high incidence of cathetercatheter
dislodgementdislodgement requiring repositioning,requiring repositioning, painpain at the deviceat the device
site andsite and device migrationdevice migration may occur in a large proportionmay occur in a large proportion
of patients; furthermore,of patients; furthermore, infectioninfection of the device systemof the device system
may also occur.may also occur.

61. Safety and Efficacy of theSafety and Efficacy of the
Coronary Sinus ReducerCoronary Sinus Reducer
in Patients with Refractoryin Patients with Refractory
Angina: the COSIRA TrialAngina: the COSIRA Trial
((Coronary Sinus ReducerCoronary Sinus Reducer
for Treatment of Refractoryfor Treatment of Refractory
Angina)Angina)

62. The reducerThe reducer
 Stainless steel balloon expandable stentStainless steel balloon expandable stent
 Hourglass shapedHourglass shaped
 Mid portion diameter 3mmMid portion diameter 3mm
 At ends can reach diameter of 7-13 mm using inflation pressure of 2-4 barsAt ends can reach diameter of 7-13 mm using inflation pressure of 2-4 bars
 Introduced in coronary sinus through right IJVIntroduced in coronary sinus through right IJV
 Creates controlled narrowing to modulate flow and elevate CS pressureCreates controlled narrowing to modulate flow and elevate CS pressure
which increaseswhich increases endocardial perfusionendocardial perfusion providing relief of ischemia and anginaproviding relief of ischemia and angina

63. Implantation of the reducer stent in coronary sinusImplantation of the reducer stent in coronary sinus

64. mechanism of action...mechanism of action...
 The Reducer creates a slight increase in CS pressure whichThe Reducer creates a slight increase in CS pressure which
results in dilatation of the capillaries and arterioles andresults in dilatation of the capillaries and arterioles and
improves perfusion of ischemic sub-endocardial myocardiumimproves perfusion of ischemic sub-endocardial myocardium
 In the setting of obstructive CAD –increased CS pressureIn the setting of obstructive CAD –increased CS pressure
can lead to:can lead to:
 Redistribution of collateral blood flow from non-ischemic intoRedistribution of collateral blood flow from non-ischemic into
ischemic territories of the myocardiumischemic territories of the myocardium
 Redistribution of arterial blood from sub-epicardial to sub-Redistribution of arterial blood from sub-epicardial to sub-
endocardial vessels, with normalization of the endocardial/endocardial vessels, with normalization of the endocardial/
epicardialblood flow ratioepicardialblood flow ratio
 Redistribution of arterial blood significantly reducingRedistribution of arterial blood significantly reducing
myocardial ischemiamyocardial ischemia

65. StudyStudy
 AIM-To examine whether implantation of the Reducer couldAIM-To examine whether implantation of the Reducer could
effectively and safely improve angina symptoms in patients witheffectively and safely improve angina symptoms in patients with
obstructive CAD, CCS class 3 or 4, having concomitant evidence ofobstructive CAD, CCS class 3 or 4, having concomitant evidence of
reversible myocardial ischemia and unsuitable for revascularizationreversible myocardial ischemia and unsuitable for revascularization
 STUDY-Prospective, phase-II, randomized, double-blind, sham-STUDY-Prospective, phase-II, randomized, double-blind, sham-
controlled, multi-center clinical trial to test the safety and efficacy ofcontrolled, multi-center clinical trial to test the safety and efficacy of
the Reducer in 104 patientsthe Reducer in 104 patients
 RESULTS-RESULTS- Primary endpoint: CCS ≥ 2 class ImprovementPrimary endpoint: CCS ≥ 2 class Improvement
35% (18/52) of the patients in the Reducer group vs.15% (8/52) of35% (18/52) of the patients in the Reducer group vs.15% (8/52) of
patients in the sham-control group improved by ≥2 CCS classespatients in the sham-control group improved by ≥2 CCS classes
(p =0.024)(p =0.024)

66. The resultsThe results

67. summarysummary
 The COSIRA trial evaluated the CS Reducer as a new therapy forThe COSIRA trial evaluated the CS Reducer as a new therapy for
patients with refractory anginapatients with refractory angina
 Reducer implantation was significantly better than a sham interventionReducer implantation was significantly better than a sham intervention
to improve angina symptoms in patients with advanced coronaryto improve angina symptoms in patients with advanced coronary
artery disease unsuitable for revascularization and treated with optimalartery disease unsuitable for revascularization and treated with optimal
medical therapymedical therapy
 The improvement of ≥2 angina CCS classes (the primary end point)The improvement of ≥2 angina CCS classes (the primary end point)
occurred 2.3 times more frequently in the Reducer group,occurred 2.3 times more frequently in the Reducer group,
demonstratinga clinically meaningful difference (P =0.024)demonstratinga clinically meaningful difference (P =0.024)
 Based on these findings, percutaneous transvenous implantation ofBased on these findings, percutaneous transvenous implantation of
the CS Reducer is a safe and effective treatment for patients withthe CS Reducer is a safe and effective treatment for patients with
refractory angina who are not suitable for coronary revascularizationrefractory angina who are not suitable for coronary revascularization
despite maximally tolerated therapydespite maximally tolerated therapy

68. GENE THERAPYGENE THERAPY
 Clinical experience with protein growth factors and genes encoding forClinical experience with protein growth factors and genes encoding for
those growth factors to enhance myocardial angiogenesis primarilythose growth factors to enhance myocardial angiogenesis primarily
involves vascular endothelial growth factor (VEGF)and fibroblast growthinvolves vascular endothelial growth factor (VEGF)and fibroblast growth
factor(FGF)factor(FGF)
 Multiple delivery methods (protein alone, plasmid, and adenoviralMultiple delivery methods (protein alone, plasmid, and adenoviral
vectors) and routes (intravenous, intracoronary, intramyocardial) havevectors) and routes (intravenous, intracoronary, intramyocardial) have
been used in clinical trials.been used in clinical trials.
 Although the promise of angiogenesis is great, randomized placebo-Although the promise of angiogenesis is great, randomized placebo-
controlled trials demonstrate excellent safety but only modest efficacycontrolled trials demonstrate excellent safety but only modest efficacy
based on secondary angina and quality-of-life .based on secondary angina and quality-of-life .
 Plasids (small, circular DNA pieces) represent a relatively inefficientPlasids (small, circular DNA pieces) represent a relatively inefficient
means of delivering a gene protein. They are taken up inefficiently bymeans of delivering a gene protein. They are taken up inefficiently by
most cells and are unprotected against cellular defense mechanisms.most cells and are unprotected against cellular defense mechanisms.

69.  Losordo et al. * published the first randomized, phase-1 clinicalLosordo et al. * published the first randomized, phase-1 clinical
trial testing the safety of intramyocardial delivery of VEGFtrial testing the safety of intramyocardial delivery of VEGF
plasmid in humans with myocardial ischemia.plasmid in humans with myocardial ischemia.
 Using a left anterior thoracotomy, the plasmid VEGF DNA wasUsing a left anterior thoracotomy, the plasmid VEGF DNA was
directly injected into the myocardium at risk in five patients withdirectly injected into the myocardium at risk in five patients with
symptomatic angina in whom conventional therapy had failed.symptomatic angina in whom conventional therapy had failed.
 Dobutamine SPECT showed evidence of reduced ischemia inDobutamine SPECT showed evidence of reduced ischemia in
all five patients after 30 and 60 days. Rentrop collateral flowall five patients after 30 and 60 days. Rentrop collateral flow
was increased in all five patients after 60 days.was increased in all five patients after 60 days.
** Losordo DW, Vale PR, Symes JF, et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of ph VEGF 165 asLosordo DW, Vale PR, Symes JF, et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of ph VEGF 165 as
sole therapy for myocardial ischemia. Circulation 1998;98:2800–4sole therapy for myocardial ischemia. Circulation 1998;98:2800–4..

70. Adenovirus GENe Therapy (AGENT) trialAdenovirus GENe Therapy (AGENT) trial
 First randomized, double-blinded, placebo-controlled trial of gene therapyFirst randomized, double-blinded, placebo-controlled trial of gene therapy
enrolling 79 patients with documented CAD by angiography, objectiveenrolling 79 patients with documented CAD by angiography, objective
evidence of ischemia . Sixty patients received direct injection of recombinantevidence of ischemia . Sixty patients received direct injection of recombinant
adenovirus 5 FGF-4 and 19 patients received placebo.adenovirus 5 FGF-4 and 19 patients received placebo.
 Follow-up treadmill tests were performed at 4 and 12 weeks, and the activeFollow-up treadmill tests were performed at 4 and 12 weeks, and the active
treatment group had a greater improvement in exercise duration and a 30%treatment group had a greater improvement in exercise duration and a 30%
increase in exercise tolerance time, as compared with the placebo group.increase in exercise tolerance time, as compared with the placebo group.
 It should be noted that the placebo group showed marked improvementIt should be noted that the placebo group showed marked improvement
from baseline, demonstrating the importance of double-blinded, placebo-from baseline, demonstrating the importance of double-blinded, placebo-
controlled trials in this population.controlled trials in this population.
Grines C. Late breaking trial results: the AGENT trial. Presented at: American College of Cardiology, 50th Annual Scientific Sessions, March 2001, Orlando, FLGrines C. Late breaking trial results: the AGENT trial. Presented at: American College of Cardiology, 50th Annual Scientific Sessions, March 2001, Orlando, FL..

71. ESMR (Extracorporeal Shockwave MyocardialESMR (Extracorporeal Shockwave Myocardial
Revascularization)Revascularization)
 It is a breakthrough in management of refractory anginaIt is a breakthrough in management of refractory angina
pectorispectoris
 The treatment is performed using a special generator thatThe treatment is performed using a special generator that
produces low intensity shockwaves, a kind of sound wavesproduces low intensity shockwaves, a kind of sound waves
similar to, but of lower strength than Extracorporeal Shocksimilar to, but of lower strength than Extracorporeal Shock
Wave Lithotripsy (ESWL) that is used in the treatment ofWave Lithotripsy (ESWL) that is used in the treatment of
kidney stones .kidney stones .
 These waves stimulate the formation of new blood vessels inThese waves stimulate the formation of new blood vessels in
the heart.the heart.
 The shock wave schedule consists of three 20-minuteThe shock wave schedule consists of three 20-minute
sessions per week over nine weeks.sessions per week over nine weeks.

72.  The patient must first undergo cardiac SPECT (single photonThe patient must first undergo cardiac SPECT (single photon
emission computed tomography) testing to identify the locationemission computed tomography) testing to identify the location
of the ischemic areas.of the ischemic areas.
 Afterwards a handheld device called a transducer is placedAfterwards a handheld device called a transducer is placed
over the skin and shockwaves will then be delivered directly toover the skin and shockwaves will then be delivered directly to
the ischemic region under echocardiographic guidance.the ischemic region under echocardiographic guidance.
 ESMR is an alternative therapy for patients who have angina,ESMR is an alternative therapy for patients who have angina,
even though they take medicine, and are not suitableeven though they take medicine, and are not suitable
candidates for coronary angioplasty or bypass surgerycandidates for coronary angioplasty or bypass surgery
 Nishida T,Shimokawa H et al. Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo. CirculationNishida T,Shimokawa H et al. Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo. Circulation
2004;110: 3055-3061.2004;110: 3055-3061.
 [ Faber L, Lindner O, Prinz C, Fricke E, Hering D, Burchert W, Horstkotte D. Echo guided extracorporeal shockwave therapy for refractory angina improves regional[ Faber L, Lindner O, Prinz C, Fricke E, Hering D, Burchert W, Horstkotte D. Echo guided extracorporeal shockwave therapy for refractory angina improves regional
myocardial blood flow as assessed by PET imaging. J. Am. Coll. Cardiol. 2010;55:A120.E1125myocardial blood flow as assessed by PET imaging. J. Am. Coll. Cardiol. 2010;55:A120.E1125
 Caspari GH, Erbel R. Revascularization with extracorporeal shock wave therapy: first clinical results. Circulation 1999;100(Suppl 18):84-89.Caspari GH, Erbel R. Revascularization with extracorporeal shock wave therapy: first clinical results. Circulation 1999;100(Suppl 18):84-89.

73. PERCUTANEOUS IN SITUPERCUTANEOUS IN SITU
CORONARY VENOUS ARTERIALIZATIONCORONARY VENOUS ARTERIALIZATION
 Percutaneous in situ coronary venous arterialization (PICVA) isPercutaneous in situ coronary venous arterialization (PICVA) is
a percutaneous approach to CABG that redirects arterial blooda percutaneous approach to CABG that redirects arterial blood
flow from the occluded, offending artery into an adjacentflow from the occluded, offending artery into an adjacent
coronary vein, thereby arterializing the vein and providingcoronary vein, thereby arterializing the vein and providing
retroperfusion to ischemic myocardium.retroperfusion to ischemic myocardium.
 Even in the most severe cases of CAD, the venous system isEven in the most severe cases of CAD, the venous system is
generally free of atherosclerosis, and the individual veins aregenerally free of atherosclerosis, and the individual veins are
dispensable, owing to a redundant venous system.dispensable, owing to a redundant venous system.
 Percutaneous in situ coronary artery bypass (PICAB) is anPercutaneous in situ coronary artery bypass (PICAB) is an
advancing technology for this group of patients with refractoryadvancing technology for this group of patients with refractory
angina.angina.

74.  The procedure requires that the occluded artery and correspondingThe procedure requires that the occluded artery and corresponding
great vein be imaged. A needle is advanced proximal to thegreat vein be imaged. A needle is advanced proximal to the
occlusion in the artery and into the adjacent vein under ultrasoundocclusion in the artery and into the adjacent vein under ultrasound
guidance. A connector is then placed in between the structures, andguidance. A connector is then placed in between the structures, and
a plug is placed proximal to the coronary sinus so that venousa plug is placed proximal to the coronary sinus so that venous
retroperfusion may occur.retroperfusion may occur.

75.  Arterial blood flow is redirected from a diseased artery to an adjacentArterial blood flow is redirected from a diseased artery to an adjacent
coronary vein, and then rerouted back to the artery after the lesion .coronary vein, and then rerouted back to the artery after the lesion .
 Thus, the coronary vein acts as an in situ coronary bypass conduitThus, the coronary vein acts as an in situ coronary bypass conduit
rather than as a means of retroperfusion.rather than as a means of retroperfusion.
 It requires two arteriovenous fistulae to be created—one on either sideIt requires two arteriovenous fistulae to be created—one on either side
of the artery blockage—and that the vein be blocked both distally andof the artery blockage—and that the vein be blocked both distally and
proximally.proximally.
 Oesterle et al. * reported the first successful case of PICVA in a 53-Oesterle et al. * reported the first successful case of PICVA in a 53-
year-old diabetic German man diagnosed with CCS class IV anginayear-old diabetic German man diagnosed with CCS class IV angina
refractory to medical therapy and not a good candidate for CABG orrefractory to medical therapy and not a good candidate for CABG or
PCIPCI
 Currently it must be considered experimental only.Currently it must be considered experimental only.
**Oesterle SN, Reifart N, Hauptmann E, et al. Percutaneous in situ coronary venous arterialization: report of the first human catheterbased coronaryOesterle SN, Reifart N, Hauptmann E, et al. Percutaneous in situ coronary venous arterialization: report of the first human catheterbased coronary
artery bypass. Circulation 2001;103:2539–43.artery bypass. Circulation 2001;103:2539–43.

76. HEART TRANSPLANTHEART TRANSPLANT
 For patients who have disabling angina and in whom allFor patients who have disabling angina and in whom all
conventional and alternative treatment modalities haveconventional and alternative treatment modalities have
failed, heart transplantation should be considered.failed, heart transplantation should be considered.
 Heart transplants are severely limited in number, withHeart transplants are severely limited in number, with
only 3,000 transplantations being performed worldwide.only 3,000 transplantations being performed worldwide.
 Heart transplantation remains a final option for theseHeart transplantation remains a final option for these
patients.patients.

77. Alternative Therapies for Relief of Symptoms inAlternative Therapies for Relief of Symptoms in
Patients With Refractory Angina: RecommendationPatients With Refractory Angina: Recommendation

79. CONCLUSIONCONCLUSION
 End-stage angina pectoris refractory to conventionalEnd-stage angina pectoris refractory to conventional
medical therapy and not amenable to either CABG or PCImedical therapy and not amenable to either CABG or PCI
represents a truly desperate and frustrating condition forrepresents a truly desperate and frustrating condition for
both the patient and physician.both the patient and physician.
 There is no suggestion that any of the alternativeThere is no suggestion that any of the alternative
treatments for refractory angina may improve prognosis.treatments for refractory angina may improve prognosis.
 The choice of treatment should be mainly based on aThe choice of treatment should be mainly based on a
careful assessment of the balance between the benefits forcareful assessment of the balance between the benefits for
the disabling symptoms of patients and the risk associatedthe disabling symptoms of patients and the risk associated
with the different treatment options.with the different treatment options.

80. THANK YOUTHANK YOU..........

81. Current pharmacologicCurrent pharmacologic
antianginal strategiesantianginal strategies
 New mechanistic approaches to anginaNew mechanistic approaches to angina
 Rho kinase inhibition (Rho kinase inhibition (fasudilfasudil))
 Metabolic modulation (Metabolic modulation (trimetazidinetrimetazidine))
 Preconditioning (Preconditioning (nicorandilnicorandil))
 Sinus node inhibition (Sinus node inhibition (ivabradineivabradine))
 Late Na+ current inhibition (Late Na+ current inhibition (ranolazineranolazine))

82. Rho kinase inhibition: FasudilRho kinase inhibition: Fasudil
 Rho kinase triggers vasoconstriction throughRho kinase triggers vasoconstriction through
accumulation of phosphorylated myosinaccumulation of phosphorylated myosin
Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8.
Ca2+
Ca2+
PLC
SR Ca2+
Receptor
Agonist
Myosin
Myosin-P
Myosin phosphatase
PIP2
IP3
MLCK
VOC ROC
Ca2+
Calmodulin
Rho
Rho kinase
Fasudil

83. Metabolic modulation (pFOX):Metabolic modulation (pFOX):
TrimetazidineTrimetazidine
 O2 requirement ofO2 requirement of
glucose pathway isglucose pathway is
lower than FFAlower than FFA
pathwaypathway
 During ischemia,During ischemia,
oxidized FFA levelsoxidized FFA levels
rise, blunting therise, blunting the
glucose pathwayglucose pathway
FFA Glucose
Acyl-CoA
Acetyl-CoA
Pyruvate
Energy for contraction
Myocytes
β-oxidation
Trimetazidine
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.
pFOX = partial fatty acid oxidation
FFA = free fatty acid

84. Preconditioning: NicorandilPreconditioning: Nicorandil
Nitrate-associated effects
• Vasodilation of coronary epicardial arteries
Activation of ATP-sensitive K+
channels
• Ischemic preconditioning
• Dilation of coronary resistance arterioles
IONA Study Group. Lancet. 2002;359:1269-75.
Rahman N et al. AAPS J. 2004;6:e34.
N O
O NO2
HN

85. Late Na+ current inhibition:Late Na+ current inhibition:
RanolazineRanolazine
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.
Myocardial ischemia
↑ Late INa
Na+
Overload
Ca2+
Overload
Mechanical dysfunction
↑ LV diastolic tension
↓ Contractility
Electrical dysfunction
Arrhythmias
Ranolazine

86. Understanding Angina at theUnderstanding Angina at the
Cellular LevelCellular Level
 Ischemia impairs cardiomyocyteIschemia impairs cardiomyocyte
sodium channel functionsodium channel function
 Impaired sodium channel functionImpaired sodium channel function
leads to:leads to:
 Pathologic increased late sodiumPathologic increased late sodium
currentcurrent
 Sodium overloadSodium overload
 Sodium-induced calcium overloadSodium-induced calcium overload
 Calcium overload causes diastolicCalcium overload causes diastolic
relaxation failure, which:relaxation failure, which:
 Increases myocardial oxygenIncreases myocardial oxygen
consumptionconsumption
 Reduces myocardial blood flowReduces myocardial blood flow
and oxygen supplyand oxygen supply
 Worsens ischemia and anginaWorsens ischemia and angina
Ranolazine
Ischemia
↑ Late INa
Na+
Overload
Diastolic relaxation failure
Extravascular compression
Ca++
Overload
aitman BR. Circulation. 2006;113:2462-2472

87. Na+/Ca2+ overload andNa+/Ca2+ overload and
ischemiaischemia
Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.
↑ Late Na+
current
↑ Diastolic wall tension (stiffness)
Intramural small vessel compression
(↓ O2 supply)
↑ O2 demand
Na+
overload
Ca2+
overload
Myocardial
ischemia

88. Ischaemia
(↓ oxygen supply/↑ Demand)
∀↑ late Na+
current
∀↑ Na+
/Ca++
exchange
pump activation
[Ca2+
] overload
↑ Diastolic wall
tension (stiffness)
↑ Vascular
compression
↑ [Na+
]i
RanolazineRanolazine

89. Metabolic modulation (pFOX)Metabolic modulation (pFOX)
and ranolazineand ranolazine
 Clinical trials showed ranolazine SR 500–Clinical trials showed ranolazine SR 500–
1000 mg bid (~2–6 µmol/L) reduced angina1000 mg bid (~2–6 µmol/L) reduced angina
 Experimental studies demonstrated thatExperimental studies demonstrated that
ranolazine 100 µmol/L achieved only 12%ranolazine 100 µmol/L achieved only 12%
pFOX inhibitionpFOX inhibition
 Ranolazine does not inhibit pFOX substantially atRanolazine does not inhibit pFOX substantially at
clinically relevant dosesclinically relevant doses
 Fatty acid oxidation Inhibition is not a majorFatty acid oxidation Inhibition is not a major
antianginal mechanism for ranolazineantianginal mechanism for ranolazine
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.
pFOX = partial fatty acid oxidation

90. Ranolazine: Key conceptsRanolazine: Key concepts
 Ischemia is associated with ↑ Na+ entry intoIschemia is associated with ↑ Na+ entry into
cardiac cellscardiac cells
 Na+ efflux by Na+/Ca2+ exchange results in ↑Na+ efflux by Na+/Ca2+ exchange results in ↑
cellular [Ca2+]i and eventual Ca2+ overloadcellular [Ca2+]i and eventual Ca2+ overload
 Ca2+ overload may cause electrical andCa2+ overload may cause electrical and
mechanicalmechanical dysfunctiondysfunction
 ↑↑ Late INa is an important contributor to theLate INa is an important contributor to the
[Na+]i - dependent Ca2+ overload[Na+]i - dependent Ca2+ overload
 Ranolazine reduces late INaRanolazine 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.

91. MedicationMedication
ClassClass
ImpactImpact
on HRon HR
ImpactImpact
on BPon BP
PhysiologicPhysiologic
MechanismMechanism
BetaBeta
BlockersBlockers
Decrease pumpDecrease pump
functionfunction
CalcCalc
ChannelChannel
BlockersBlockers
Decrease PumpDecrease Pump
function + Vaso-function + Vaso-
dilitationdilitation
NitratesNitrates Vaso-dilitationVaso-dilitation
RanolazineRanolazine OO OO Reduced CardiacReduced Cardiac
StiffnessStiffness
Pharmacologic Classes for
Treatment of Angina