PHYSIOLOGICAL BASIS OF

CORONARY

REVASCULARISATIONChairperson -Prof.(Dr.) S. Mukherjee

Speaker -Dr. Abhishek Das, PGT

AREAS OF DISCUSSION

• Coronary physiology

• Myocardial viability and its assessment

• Coronary revascularisation

CONTROL OF CORONARY BLOOD FLOW• SYSTOLIC AND DIASTOLIC VARIATIONS OF-

1. ARTERIAL INFLOW

2. VENOUS OUTFLOW

Basic Principles• myocardial cells have to do only 2 things: contract and relax; both are

aerobic, O2 requiring processes

• oxygen extraction in the coronary bed is maximal in the baseline state; therefore to increase O2 delivery, flow must increase

• large visible epicardial arteries are conduit vessels not responsible for resistance to flow (when normal)

• small, distal arterioles make up the major resistance to flow in the normal state

• atherosclerosis (an abnormal state) affects the proximal, large epicardialarteries

• once arteries are stenotic (narrowed) resistance to flow increases unless distal, small arterioles are able to dilate to compensate

Myocardial Ischemia:Occurs when myocardial oxygen demand exceeds

myocardial oxygen supply

Coronary Blood FlowProportional to perfusion pressure / resistance

• Coronary Perfusion pressure

=

Diastolic blood pressure, minus LVEDP

• Coronary Vascular resistance

external compression

intrinsic regulation Local

metabolites(Adenosine,O2,Lactate,ADP)

Endothelial factors(NO, Prostacyclin, EDHF, Endothelin)

Neural factors (esp. sympathetic nervous system)

CORONARY AUTOREGULATION

• Regional coronary blood flow remains constant at a wide range

• Resting flow- .7-1 ml/min/g

• May increase upto 5 times

• Flow in maximally vasodilated heart depends on coronary pressure

• CORONARY RESERVE- ability to increase flow above baseline in response to pharmacological vasodilatation.

• Maximum flow and coronary reserve are reduced-

1. Diastolic time for subendocardial perfusion decreased (tachycardia)

2. Compressive determinants of diastolic perfusion (preload) increased

3. Increased resting flow- d/t increased MVO2 or decreased arterial O2 supply( anemia, hypoxia)

CORONARY AUTOREGULATION

SUBENDOCARDIAL VS SUBEPICARDIAL FLOW•Greater shortening/ thickening, higher wall tension--- increased MVO2

•Greater Compressive resistance

•Reduced perfusion pressure

•Less collateral

•NET RESULT- More compensatory arterial vasodilation at baseline, therefore reduced CFR

Principle of flow through stenosed artery •Follows Bernoulli’s principle(30%-90%)

•Total pressure drop= viscous loss+ separation loss+ turbulence

•Resistance inversely proportional to square of cross sectional area

•Separation losses determine the steepness of prss-flo relationship

•no significant pressure drop across a stenosis or stenosis-related alteration in maximal myocardial perfusion until stenosisseverity exceeds a 50% diameter reduction (75% cross-sectional area).

•Above a value of 70% diameter reduction, small increases in stenosis severity are accompanied by further increases in stenosispressure drop

•A critical stenosis, one in which subendocardial flow reserve is completely exhausted at rest( >90% stenosis)

Coronary Flow Reserve• Arteriolar autoregulatory vasodilatory capacity in response to increased MVO2 or

pharmacologic agents

• Expressed as a ratio of Maximum flow / Baseline flow• ~ 4-5 / 1 (experimentally)• ~ 2.25 - 2.5 (when measured clinically)

• Stenosis in large epicardial (capacitance) vessel decreased perfusion pressure arterioles downstream dilate to maintain normal resting flow

• As stenosis progresses, arteriolar dilation becomes chronic, decreasing potential to augment flow and thus decreasing CFR

• Endocardial CFR < Epicardial CFR

• As CFR approaches 1.0 (vasodilatory capacity “maxxed out”), any further decrease in PP or increase in MVO2 ischemia

Microcirculatory coronary flow reserveLV hypertrophy

Impaired NO mediated Vasodilatation

Coronary collateral circulation• Following a total cor. occlusion residual perfusion persists through coll.

• Mechanisms-

1. Arteriogenesis- Proliferation of collaterals in response to repetitive stress induced ischemia.

(stenosis> 70%-resting distal coronary pressure consistently falls- interarterial pressure gradient increases-endothelial shear stress in smaller collaterals(200µm)- NO synthase and VEGF mediated enlargement of collaterals)

Most functional collaterals from arteriogenesis exist in epicardial anastomosis

2. Angiogenesis - de novo sprouting of smaller capillary like structures from pre-existing blood vessels

May provide nutritive collateral flow when develop in borders of ishaemic and non ischemic zones.

• Scope of experimental interventions to improve collateral flow (recombinant growth factor, in vivo gene transfer, endothelial progenitor cells)

Clinical implications

•Useful prognostic marker in coronary artery disease

•Reduces infarct size

•Retrograde angioplasty in Chronic Total Occlusion( CTO) through collaterals

Myocardial viability and its assessment

Metabolic and functional consequences of ischaemiaAerobic metabolism stops

Onset of anaerobic glycolysis

Accumulation of lactate, reduced ATP

Development of tissue acidosis

Irreversible injury and myocyte death-

>20 min of coronary occlusion in the absence of significant collaterals

Subendocardium to subepicardium

Increased MVO2( tachycardia) or reduced O2 delivery( anemia, hypotension) accelerates progression.

Repetitive reversible ischaemia reduce irreversible injury.

Residual coronary flow is an important determinant.

Reversible ischaemia

• More frequent• Supply induced vs. demand induced

• Sequence of events- Regional contractile dysfunction within 1 min Reduction in global LV contractility(dP/dT) Progressive increase in LV end diastolic pressure with reduced SBP Chest pain occurs last in the sequence

• On restoring perfusion- chest pain resolution first Followed by resolution of haemodynamic changes Regional contraction remain depressed (stunned)

Myocardial viability

• Myocardium that demonstrates contractile dysfunction that shows functional improvement after revascularisation.

So, it comprises of-

Dysfunctional myocardium subtended by diseased coronary arteries

Limited or absent scarring

Potential for functional recovery

Preconditioning

Acute preconditioning-• Brief reversible ischemia preceding a coronary artery occlusion reduces

myocyte necrosis.• Endogenous mechanism to delay evolution of irreversible myocyte injury• Induced pharmacologically ( adenosine A1 receptor stimulation, agonists

of PKC or opening of K+ ATP channels)• Clinical relevance- during angioplasty, reduced subjective and objective

ischemia during subsequent coronary occlusions

Delayed preconditioning-• Develops in a chronic basis, persist upto 4 days• Reduce myocardial infarct size and protects heart from ischaemia induced

stunning• Mechanism- Protein synthesis, upregulation of iNOS,COX2, opening of

K+ATP channel

Postconditioning

• Final protective mechanism

• Cardioprotection by producing intermittent ischaemia and pharmacological agonists at the time of reperfusion

• Less extensively studied

• Greater potential to affect irreversible injury as it has induced after myocardial ischemia is established.

STUNNED MYOCARDIUM• Heyndrickx et al 1978

• Prolonged and fully reversible contractile dysfunction of the ischemic heart that persists after reperfusion

• Transient period of ischemia f/b reperfusion- depressed function at rest , but preserved perfusion

• Affected area responsive to inotropes, e.g. beta adrenergic agonists

• Time course not altered by inotropes- usually resolves by a week

• Duration of stunning depends on duration and severity of ischemia and adequacy of arterial flow

• Areas of stunning may co exist with irreversibly injured myocardium

Mechanism of stunning-

1. Calcium hypothesis- reduced myofilament Ca2+ sensitivity

2. Oxyradical hypothesis- ROS during reperfusion impairs Ca2+ handling

Clinical relevance-

1. Exercise induced ischemia2. Acute coronary syndrome3. Angioplasty balloon inflation4. Post cardiopulmonary bypass

Myocardial hibernation

• Diamond et al 1978

• Persistent LV contractile dysfunction when myocardial perfusion is chronically reduced but sufficient to maintain viability of tissue

• Depressed function and perfusion at rest

• Progressively reversible after revascularisation

• Time to restoration-– Months to one year– Depend on duration and severity of flow reduction &

ultrastructural changes

Mechanisms

• Smart heart hypothesis-

– Myocardial function &metabolism reduced to match a reduction in blood flow

• Repetitive stunning hypothesis-

– Repetitive episodes of ischemia reperfusion from supply demand mismatch leading to sustained depression of contractile function

Cellular mechanisms• Apoptosis prominent during transition to hibernation-

30%cell loss

• Compensatory regional myocyte hypertrophy-to maintain normal wall thickness

• Increase in interstitial connective tissue,myolysis,increasedglycogen deposition,minimitochondria

• Cell survival programme-downregulation of glycogen synthase kinase,increase anti apoptotic proteins

• Downregulation of beta adrenergic adenylyl cyclase

Clinical assessment

• Heart failure and active angina– Directly angiography – Viability study may have a role in planning revascularisation

strategy once coronary anatomy known

• Heart failure and no angina– Class 1 recommendation for assessment of viability in pts

with CAD and LVD – Class 2a rec.for assessment of co-presence of CAD

• STEMI– Class2a rec. for viability assessment 4 to 10 days after STEMI

in hemodynamically & electrically stable pts.to define potential effect of revascularisation

• Strong association b/w myocardial viability and improved survival after revascularization in pts with chronic CAD and LV dysfunction.– Allmann KC et al;JACC 2002

• Pts with viability-revascularization a/w 79% reduction in mortality (16% vs. 3.2%) as compared to conserv.Rx

• Pts without viability-no significant difference in revasc. Vs medical therapy (7.7% vs. 6.2%)

Techniques for assessment of viability

• Myocardial glucose utilisation-PET FDG

• Cell membrane integrity-SPECT Thallium

• Intact mitochondria-SPECT Tc

• Contractile reserve-dob.echo and dob.MRI

• Scar tissue-DEMRI,MSCT

ECHOCARDIOGRAPHY

•ASSESS RWMA

•Thickness>= 6 cm considered viable

•THIN ecodensesegment(fibrotic) considered scarred

Dobutamine stress echo• Low-dose dobutamine (5–10 μg/kg/min)

– Increase contractility in viable myocardium

• High-dose dobutamine(upto 40 μg/kg/min)

– Biphasic response –initial improvement F/B worsening –underperfused but viable tissue-most specific sign of improvement after revasc.

– Uniphasic response-sustained improvement-myocardial damage with subsequent reperfusion-less predictive of improvement after revasc.

– Deterioration of wall motion without initial improvement-severe ischemia

– No change in wall motion-scar

• Sensitivity(84%),specificity(81%)for recovery of function

SPECT-Th-201

• K+ analogue utilizes active cellular transport system-relies on intact cell

• Uptake depends on viability &regional perfusion

• Redistribution-gradual accumulation of tracer in hypoperfused areas ,rapid washout from normally perfusedareas

• Segments with tracer uptake >60%-viable

• Subendocardial scar tissue may be labelled as viable-lower specificity

• Rest redistribution protocols-

– Defects in initial images that improve in 4 hour image-viable myocardium

– Additional 24 hr image if fixed defects in 4 hr image

– S/L NTG prior to injection

– Less sensitive-86%,specificity 47%

PET

• Positron emitting isotopes releasing 2 photons at angle180,detected by camera by coincidence counting to give a higher resolution

• Perfusion tracers-N13 ammonia,Rb 82,O15 water

• Metabolic tracers- F18DG,C11acetate,C11 palmitate

• FDG taken up by viable cells,phoshorylated&trapped inside

• Poor uptake in diabetics

Interpretation

• Normal perfusion-viability

• Flow metabolism mismatch-reduced perfusion with intact metabolism-hibernating viable myocardium

• Flow metabolism match-impaired FDG uptake with reduced perfusion-scar

• Gold standard for assessment of viability

Perfusion metabolism mismatch-apex,anterioranterolateral wall

Limitations of non invasive testing

•Diagnostic accuracy not optimal- esp not in intermediate stenosis

•Limited spatial resolution- esp in pts with more complex disease-

Multivessel disease

Several stenosis within same artery

Uncertainty about exact perfusion territories

• No discrimination between epicardial vs microvasculardisease or local stenosis vs diffuse epicardial disease

REPERFUSION THERAPY

General concepts

• Spontaneous reperfusion- usually late

• Pharmacological- fibrinolysis

• PCI

Fibrinolysis

•Recannalisation of the infarct related artery

•Timely reperfusion essential

•TIMI Flow grade- TIMI grade 3 is the goal

•TIMI frame count- more quantitative

Myocardial perfusion

‘myocardial no reflow’ –

1. Microvascular damage

2. Reperfusion injury

Assess myocardial perfusion-

1. ECG- ST resolution

2. Cardiac biomarkers

3. Echocardiography

4. Others-doppler flow wire,CMR,PET

5. CAG- TIMI myocardial perfusion grade(myocardial blush)-TMP

Choice of reperfusion strategy

• Time from the onset of symptoms to initiation of reperfusion therapy

• Risk of death after STEMI.

• Risk of bleeding

• Time required for transportation to a skilled PCI center

PCI• Indications- stable angina,ACS

• STEMI- Primary PCI, Rescue PCI, Facilitated PCI, PCI after successful thrombolysis

• Consider-

1. Extent of jeopardized myocardium2. Baseline lesion morphology(SCAI)- CTO, Bifurcation

lesion,calcification3. Underlying cardiac function(LV function,rhythm, valve)4. Associated renal dysfunction5. Pre existing medical comorbidities

Choice..

•Balloon angioplasty

•Coronary atherectomy devices

•Thrombectomy and aspiration devices

•Embolic protection devices- e.g. filters

•Stents

•Drug eluting stents

Reperfusion Injury• Reperfusion, although beneficial in terms of myocardial salvage, may come at a cost

because of a process known as reperfusion injury.

• Types of reperfusion injury

• (1) lethal reperfusion injury—reperfusion-induced death of cells that were still viable at the time of restoration of coronary blood flow

• (2) vascular reperfusion injury—progressive damage to the microvasculature so that there is an expanding area of no reflow and loss of coronary vasodilatory reserve

• (3) stunned myocardium—salvaged myocytes display a prolonged period of contractile dysfunction following restoration of blood flow because of abnormalities of intracellular metabolism leading to reduced energy production

• (4) reperfusion arrhythmias—bursts of ventricular tachycardia and, on occasion, ventricular fibrillation—that occur within seconds of reperfusio

• Increased incidence of hemorrhagic infarct , esp with fibrinolytic therapy

Protection against reperfusion injury

(1) Preservation of microvascular integrity by using antiplatelet agents and antithrombins to minimize embolization of atheroembolic debris

(1) Prevention of inflammatory damage

(3) Metabolic support of the ischemic myocardium.

• The effectiveness of agents directed against reperfusion injury rapidly declines the later they are administered after reperfusion; eventually, no beneficial effect is detectable in animal models after 45 to 60 minutes of reperfusion has elapsed.

• Postconditioning, which involves introducing brief repetitive episodes of ischemia alternating with reperfusion. This appears to activate a number of cellular protective mechanisms centering around prosurvival kinases.

THANK YOU