REVASCULARIZATION IN HEART FALIURE

DR. ANKIT JAINREVASCULARIZATION IN HEART FALIURE

CORONARY ARTERY DISEASE

ACUTE CORONARY SYNDROME

Undergo revascularization procedures

Improved survivalIncreased number of patients with residual LV dysfunction undergoing progressive LV remodeling and congestive heart failure

In these patients, coronary revascularization may lead to symptomatic and prognostic improvementThese clinical benefits are accompanied by evidence of reverse LV remodeling

In the early 1980s, Rahimtoola et al reviewed the results of coronary bypass surgery trials and identified patients with CAD and chronic LV dysfunction that improved by revascularizationCASS (coronary artery surgery study) REGISTRY

Data from the coronary artery surgery study (CASS) registry for patients with LVEF < 35% involved 651 patients.

The five year survival was significantly better in surgical patients (68%) than in the medical group (54%).

The contrast was even more in patients with LVEF < 26% whose five year survival was 63% with surgery, but 43% with medical treatment

Thus came the concept of myocardial viability and with it came the new terms such as hibernation and stunning

VIABILITYViable myocardium must have the following characteristics

The ability to generate ATP have an intact sarcolemma, to maintain ionic/electrochemical gradients, and Have sufficient perfusionThe term viable implies nothing with regard to contractile state

There are two tissue states that exhibit sustained contractile dysfunction despite meeting the three criteria

Stunned myocardium &Hibernating myocardium.

MYOCARDIAL STUNNINGFirst documented by Heyndrickx et al. in the mid- 1970s

They concluded that brief periods of coronary occlusion resulted in prolonged depression of myocardial function in the ischemic zone.

While regional electrograms return to normal within seconds and the coronary flow restored rapidly, functional derangement lasts for several hours.

Published October, 1975

Definition Brief period of ischemia followed by restoration of perfusionSubsequent LV dysfunction of limited duration Perfusion-contraction mismatchNormal resting perfusionDecreased MBF reserveBolli R. Mechanism of myocardial stunning. Circulation 1990;82: 7238. Hearse DJ, Bolli R. Reperfusion induced injury: manifestations, mechanisms and clinical relevance. Cardiovasc Res1992;26:1018.

PATHOGENESISThere are 2 major hypotheses for myocardial stunning: a oxygen-free radical hypothesis and a calcium overload hypothesis

Dysfunction may persist as long as 6 weeks post-insultDuration and severity of ischemia determine the duration of post-ischemia/reperfusion dysfunction

Normal cardiac contraction depends on the maintenance of calcium cycling and homeostasis across the mitochondrial membrane and sarcoplasmic reticulum during each cardiac cycle.

Brief ischemia followed by reperfusion- accumulation of calcium and a partial failure of normal beat to beat calcium cycling - damages Ca2+pump and ion channels of the sarcoplasmic reticulum.

This results in the electromechanical uncoupling of energy generation from contraction that characterizes myocardial stunning

HIBERNATING MYOCARDIUMIs a state of persistently impaired myocardial function at rest due to reduced coronary blood flow

The physiology of hibernation involves reduced myocardial blood flow, particularly to the subendocardium

Resting blood flow may be reduced at rest but coronary flow reserve is always reduced

Rahimtoola SH The hibernating myocardium Am Heart 1989;117:211-221

Ultra structural changesCirculation1998;98:1151-1156

Alteration of structural proteins & metabolism to a more fetal form - Smart heart hypothesis Apoptosis and fibrosisDisorganization of the cytoskeletonLoss of myofilamentsOccurrence of large areas filled with glycogenIonic instability

Stenosis and flow relationship

Coronary stenosis between 40 50% percent does not alter resting MBF and coronary flow reserveBetween 40 and 80 percent stenosis, resting MBF is normal, but MBF reserve flow is diminishedA stenosis greater than 80 percent is associated with a reduction in resting blood flow

Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol 1974;33:8794.

Recent data suggest that myocardial blood flow in hibernation may not be decreased at rest to an extent that would account for the degree of cardiac dysfunction

It is now believed that hibernating myocardium is a manifestation of repeated myocardial stunning as a result of impaired coronary flow reserve

In severe coronary disease, the limited flow reserve causes repeated myocardial ischemia repeated stunning Hibernation

Gerber BLJL, Vanoverschelde JL, Bol A, et al. Myocardial blood flow, glucose uptake and recruitment of inotropic reserve in chronic left ventricular ischaemic dysfunction

SUSPECT HM Unstable and stable anginaAcute myocardial infarctionLeft-ventricular dysfunction +_congestive heart failureAnomalous left coronary artery from the pulmonary artery

Myocardial viability Nearly 50-60% of pts with Ischemic HF have substantial viable myocardium

Substantial viable myocardium means presence of viability in at least 25% of LV myocardium ( 4 segments)

Revascularization in such patients is likely to lead to a significant in LVEF (by 5%)Schinkel et al. Am J Cardiol 2001;88:561-4Bax et al. J Am Coll Cardiol 1999;34:163-9

Why should viable myocardium be Revascularized?Improvement of regional and global LV systolic functionRemodeling is reversed Survival is increasedDecrease of the composite of myocardial infarction, heart failure, and unstable angina Ferrari R. Myocardial hibernation. An adaptive phenomenon? In: Yellon DM, Rahimtoola SH, Opic LH, New IschemicSyndromes. New York, NY: Authors Publishing House, 1997:20414Rahimtoola SH, La Canna G, Ferrari R. Hibernating myocardium: another piece of the puzzle falls into place. J Am Coll Cardiol 2006;47:97880.

The role of viability testingObservational series suggest that viability testing is useful to identify patients likely to benefit from revascularization

In a meta-analysis of 24 studies of viability testing in 3088 patients with CAD and systolic dysfunction (Tl-201 SPECT (n- 6) FDG-PET (n-11), or DbE (n - 8) to assess HM)

In Patients with viability 1-year mortality was 16% in the OMT patient and 3.2% in patients who had revascularization

There was no difference in mortality among the patients who did not had viability

Allman KC, Shaw LJ, Hachamovitch R, Udelson JE: Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: A meta-analysis. J Am Coll Cardiol 39:1151, 2002.)

Allman KC, Shaw LJ, Hachamovitch R, Udelson JE: Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: A meta-analysis. J Am Coll Cardiol 39:1151, 2002.)

RESULTSExcess death in the population with hibernating myocardium is to a large extent sudden, presumably arrhythmic death Scar formation and a reduction and inhomogeneity of connexin 43 expression in HM may contribute to alterations in electrical impulse propagation and reentryIsolated myocytes from HM are hypertrophied and have striking prolongation of the action potential and EADBito V, Heinzel FR et al. Cellular mechanisms of contractile dysfunction in hibernating myocardium. Cellular remodeling in hibernation.Circ Res 94:

How much of LV should be viable?Target is to improve LV function by at least 5%

25% of the LV should be viable using DSE

38% using conventional nuclear medicine and PET

Bax JJ, Maddahi J, Poldermans D, Elhendy A, Schinkel A, Boersma E, Valkema R, Krenning EP, Roelandt JR, van der Wall EE. Preoperative comparison of different noninvasive strategies for predicting improvement in left ventricular function after coronary artery bypass grafting. Am J Cardiol. 2003;92:1 4

Techniques to assess myocardial viability

ECG and viability60% of regions with Q waves have viable myocardium as detected by imaging techniques

ST-segment elevation at rest in leads with Q waves is associated with non viable scarred myocardium

Exercise-induced Q wave prolongation is demonstrated in patients with recent MI who shows viabilityAssessment of residual myocardial viability in regions with chronic electrocardiographic Q-wave infarction. Am Heart J 2002;144:865869 Bodi V, Sanchis J, Llacer A et al. ST-segment elevation in Q leads at rest and during exercise: relation with myocardial viability and left ventricular remodelling within the first 6 months after infarction. Am Heart J 1999;137:110715.

CONTD..ST elevation developing during exercise or dobutamine stress is a marker of maintained viabilityThe combination of ST elevation and reciprocal ST depression increases the accuracy for detection of viable myocardiumInducible perfusion abnormalities assessed by SPECT have been seen In 94% of patients with exercise- induced ST elevation In 50% with pseudonormalisation of the T wave but without ST elevation

2D EchoDo improveLV end-diastolic wall thickness 0.5 to 0.6 cm Hypokinetic rather than akinetic or dyskinetic

Don t improveLV (end-diastolic volume greater than twice the upper limit of normal) The involvement of 4 ventricular wall segments by scarringRahimtoola et al. J Am col cardio : c a r d i o v a s c u l a r i m a g i n g , 1 (4), 2 0 0 8 : 5 3 6 5 5

DSEThe augmentation of contractility (contractile reserve) in response to dobutamine stress is the basis for the use of stress echocardiography

Dysfunctional myocardium that is able to show a transient improvement in systolic function in response to dobutamine (contractile reserve) is considered viable

Predictive value of DSEE/o myocardial viability on low dose DSE is a strong predictor of both long term survival and functional recovery in Ischemic HF patients

Biphasic response has highest predictive value

Segments with a biphasic response has a specificity and sensitivity of 80% to 90% for prediction ofglobal functional recoveryCurr Probl Cardiol 2001;26:14186

Myocardial Contrast echoMyocardial perfusion by CE is evaluated qualitatively, and segments visually classified as :Viable (normal or patchy perfusion ) OrNonviable ( absent perfusion)

Micro vascular density and the capillary area correlates inversely with the extent of fibrosis

MCE has a primary role in assessing the quality of reperfusion following STEMI (No reflow)

Heart 2003;89:139144 Circulation 2002;106:9506

MCE for prediction of viabilitySensitivity and specificity of 89% and 51% to predict functional recovery

High NPV for recovery of function and residual viability

3 viable segments on MCE: high likelihood of improvement in global LV function post-revascularizationJ Am Coll Cardiol 1997;29:98593

201Thallium SPECTThe most widely used method for assessing myocardial viability

Initial uptakedependent on myocardial blood flow

Retention 3 to 4 hours after injection is an active, energy-requiring process that is a function of cell membrane integrity and tissue viability

Markers of viability on ThalliumReversible defects on rest-redistribution imaging

Rest-redistribution, an uncommon observation, is highly predictive of hibernation when seen

The recommended SPECT imaging is stress-redistribution-reinjection It provides information about viability and ischemia

Lomboy CT, Schulman DS, Grill HP et al. Rest-redistribution thallium-201 scintigraphy to determine myocardial viability early after myocardial infarction. J Am Coll Cardiol 1995;25:2107.Marin Neto JA, Dilsizian V, Arrighi JA et al. Thallium reinjection demonstrates viable myocardium in regions with reverse redistribution. Circulation 1993;88:173645.

Technetium-99m sestamibiEmits higher energy photonsHas better tissue penetration Shorter T1/2 Uptake depends on both perfusion and viability

No redistribution The most widely reported technetium agent is Tc- 99m-sestamibi

Markers of viabilityViability is considered to be present when in dysfunctional segments: tracer uptake is normal or shows reversible defect or mild-to-moderate fixed defects (>50-60% of normal region)

Pretreatment with nitrates may enhance the accuracy for detection of viabilitySciagra R, Bisi G et al J Nucl Cardiol 1996;3: 22130.

Prediction of outcomeOverall sensitivity - 81%, specificity - 66%, PPV-71%, and a NPV- 77% in predicting post-revascularization improvement of regional ventricular function

Curr Probl Cardiol 2001;26:14186

Nuclear imaging Vs DSE

Bax et al. Curr Probl Cardiol. 2001;26:141-188

Limitations of nuclear scansThe relatively poor spatial resolution Detection of subendocardial scar is difficultFalse negative in TVD with uniform in perfusion ( global ischemia effect)Radiation burden

Positron Emission Tomography

Allows simultaneous assessment of perfusion and metabolic status of myocardial tissue

Imaging with high spatial and temporal resolution

Estimations of myocardial perfusion have been performed with 13NH3 and H215O

Metabolism by FDG

Can quantify MBF

FDG- PETIn the fasting state, the heart predominantly uses free fatty acids as a source of fuel

During conditions of ischemia, the myocyte switches to glucose as its predominant source of energy glycogenolysis glycolysis mitochondrial metabolism FFA uptake

FDG- PETAs there should be no uptake of glucose by infarcted myocardiumwhich is metabolically inertnonviable myocardium will appear as a region of low-FDG concentration

In areas of reversibly injured myocardium, glucose utilization is normal and even above normal

Thus, stunned or hibernating myocardium may be indistinguishable from normal tissue in an FDG PET image

PET Classification of Dysfunctional MyocardiumTissue typePerfusionMetabolismRecovery with revascularizationStunned NormalNormal YesHibenatingReducedIncreased relative to perfusionYesTransmural infarctionReduced Reduced NoNon transmural infarctionPartially reduced Partially reduced Varies

Curr Opin Cardiol 21:464468 2001

PET in Viability assessmentLess radiation burden

Significantly higher sensitivity than Tl-201 rest-redistribution imaging

Spatial resolution superior to SPECT but inferior to MRI

Meta-analyses suggest sensitivity around 90% and specificity of 60% to 70%

CMRMost promising modalityProvides information on anatomy, function and perfusion, with high spatial resolutionThe minimum amount of myocardium that can be imaged is 1 g with a spatial resolution of 2 mmReliable and accurate assessment of myocardial scar burden and contractile reserve by CMR Overall sensitivity and specificity of 81% and 80%

LGE

DEMRI-Bright means deadMost promising MR parameter for viabilityDemonstrates nonviable tissue as "hyperenhanced" or bright signal-DE-MRI assesses viability as a continuum based on transmural thickness of hyperenhancement

Jonathan W. Weinsaft et al Magn Reson Imaging Clin N Am 15 (2007) 505525

ADVANTAGE OF CMRA major advantage of DE-MRI is that it can visualize the transmural extent of both alive (viable) and dead (nonviable) myocardium

Low dose Dobutamine stress MRI DS MRI is less sensitive but more specific with respect to recovery of contractile function after revascularization

sensitivity and specificity of dobutamine MRI for the diagnosis of myocardial viability is 81 and 95%.

MODALITYSENSITIVITY (%)MEAN (95% CI)SPECIFICITY (%)MEAN (95% CI)Dobutamine echocardiography76 (72-80)81 (77-84)Delayed enhancement by MRI97 (91-100)68 (51-85)FDG PET89 (85-93)57 (51-63)SPECT89 (84-93)68 (61-75)

COMPARISION OFDIFFERENT TECHNIQUESCirculation 117:103, 2008.

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REVASCULARIZATION IN ICMRevascularization in ICM refers to revascularization of not only of dysfunctional but viable myocardium but also of remote, normally contracting myocardium (at rest) but subtended by flow limiting stenosis

REVASCULARIZATION IN HMFunctional recovery after revascularization is more prolonged and dependent on new protein synthesis and myocyte repair

In the absence of revascularization, repetitive ischemia may progress to myocyte necrosis or apoptosis and fibrosis indicating that hibernating myocardium is not fully adapted to chronic hypo perfusion

Consequently, if revascularization is to succeed, it must be applied early

EARLY REVASCULARIZATIONWhen the dyskinetic region occupies more than 10% of the total myocardial mass , the left ventricle progressively enlarges This causes subendocardial ischemia in the remote myocardium and progressive ventricular remodeling occur

After severe ventricular dilitation revascularization is less likely to be successful even in the presence of HM

Revascularization should be done early before irreversible LV remodeling and myocardial fibrosis occur

CONTD..LVEDD more then 70 mm predicts poor prognosis after revascularizationIt indicates the presence of multiple segments of scarred myocardiumIf such degree of LV remodeling and these ventricular dimensions are present , even if viability is documented, revascularization is not improve clinical outcomes

Rahimtoola SH et al. Chronic ischemic left ventricular dysfunction: from pathophysiology to imaging and its integration into clinical practice. JACC Imaging. 2008

REVASCULARIZATIONRevascularization is associated with increased risk in patients with low LVEF, And not all patients with ischemic cardiomyopathy show improvement in contractile function

So a careful selection of patients who may benefit from revascularization procedures appears to be warranted

The evidence supporting the clinical benefit of surgical coronary revascularization is based on observational data

Duke Cardiovascular Disease Databank They reported 25-year experience of 1391 patients with systolic dysfunction and ischemic heart disease

1052 patients were treated medically

339 underwent CABG

CABG-treated patients had a significantly lower mortality

The survival advantage was present regardless EF, age or NYHA class

RESULTS

Results for 1, 2 or TVD

Subgroup analysis

Surgical Treatment for Ischemic Heart Failure Trial (STICH)In patients with HF, LVD and CAD amenable to surgical revascularization, CABG added to intensive MED will decrease all-cause mortality compared to MED alone INCLUSION CRITERIASLVEF 35%, CAD suitable for CABGMED eligibleAbsence of left main CAD as defined by an intraluminal stenosis of 50%Absence of CCS III angina or greater (angina markedly limiting ordinary activity)

RESULTS1212 Patients were randomized CABG 610Medical Therapy 602In patients randomized to STICH, there was no statistically significant difference in all-cause mortality between medical therapy alone and medical therapy with CABG Although CABG reduces cardiovascular mortality and morbidity compared to medical therapy alone

N Engl J Med 2011; 364:1607-1616

LIMITATIONSThe mean age was just 60 years60% predominantly suffered angina pectoris and, 60% were in NYHA class I or II HF means ,patients were less sickThe clinical HF was not necessary for trial enrolmentTrial excluded patients with significant left main stem diseaseIntention-to-treat analysis did not demonstrate a beneficial impact of revascularization, the as-treated analysis did show significant benefit for CABG over OMTA 19% reduction in cardiovascular mortality was observed

RESULTSInclusion criteria was LVEF