MYOCARDIAL STUNNING AND HIBERNATION

Dr Binjo J Vazhappilly.SR , Cardiology Dept.

Calicut Medical College

Stunning

• Definition : Prolonged and fully reversible dysfunction of

the ischemic heart that persists despite the normalization of blood flow.

• 1st described by Heyndrickx et al in 1975 in conscious dogs undergoing brief coronary occlusions.

• In that study regional contractile dysfunction lasted for 6 hrs following 5 min and > 24 hrs following 15 min of ischemia.

Features of stunning

• Normal perfusion.• Depressed myocardial function.• Dissociation of usual relationship between

subendocardial flow and function.• Reversible . • Function improves with inotropic agents.

Brief total occlusion

Prolonged partial occlusion

• Stunning occurs in a wide variety of settings that differ from one another in several aspects

• At experimental level it can occur during 1. Single , completely reversible episode of regional ischemia (< 20 min ) 2. Multiple, completely reversible episodes of regional ischemia 3. Partly reversible plus partly irreversible ischemia in vivo ( > 20 min & < 3 hrs)

4. After global ischemia in vitro (isolated heart preparations) 5. After global ischemia in vivo (cardioplegic arrest) 6. After exercise-induced ischemia

Clinical Relevance• In the clinical setting stunning can occur 1. Brief period of total coronary occlusion: pts with angina due to spasm 2. Global ischemia after cardiopulmonary bypass. 3. In combination : Subendocardium is infarcted and overlying subepicardium reversibly injured in MI 4. Following exercise in presence of a flow limiting stenosis 5. Ischemic bout that is induced by PCI

Mechanisms of Stunning

• There is no unified view of pathogenesis of stunning

• Most plausible hypotheses are Oxyradical hypothesis : oxidant stress secondary to the generation of ROS. Calcium hypothesis : results from disturbance of cellular calcium homeostasis.

Oxyradical Hypothesis

• Role of ROS in pathogenesis of stunning is proven• Its role in all settings of stunning is unclear• ROS-mediated injury responsible for stunning occurs

in initial moments of reperfusion• Antioxidant therapies alleviate stunning whether

begun before ischemia or just prior to reperfusion• But ineffective when begun after reperfusion • None of the antioxidant therapies completely

prevented myocardial stunning

Calcium hypothesis

• Transient Ca2+ overload activates Ca2+-dependent proteases which degrades and induces covalent modifications of myofilaments.

• It results in ↓ responsiveness to Ca2+, manifested by a decrease in maximal force of contraction.

Myocardial Hibernation

• Term hibernation is borrowed from zoology and implies an adaptive reduction of energy expenditure through reduced activity in situation of reduced energy supply.

• In CAD myocardial hibernation refers to adaptive reduction of myocardial contractile function in response to reduction of myocardial blood flow.

• Diamond et al. in 1978 1st used the word hibernation in ischemic dog myocardium.

• Its importance was recognized by Rahimtoola in early 1980s.

Mechanisms of hibernation

• Smart heart hypothesis : Myocardial metabolism and function are reduced to

match concomitant reduction in coronary blood flow which prevents necrosis.

• Repetitive stunning hypothesis: Repetitive episodes of ischemia results in sustained depression of contractile function.

• Genomics of Survival Maintained viability in hibernation suggests

possibility of genomic adaptation.

Major survival genes (antiapoptotic, cytoprotective & growth-promoting genes) and their corresponding proteins are up regulated in hibernating myocardium.

Natural history of hibernation

Histological Features

• Myolysis• Glycogen accumulation• Increased interstitial fibrosis

Clinical Relevance

• 20 to 50 % of pts with chronic ischemic LV dysfunction have significant amount of viable hibernating myocardium.

• They improve with revascularization.

ASSESSMENT OF MYOCARDIAL VIABILITY

• ECG : gives little information.• Dobutamine stress echocardiography.• SPECT with thallium-201 or technetium-99 m.• PET • MRI

Characteristics of dysfunctional but viable myocardium

• ECG No clear correlation between Q waves on ECG and

presence of viability.

Pts with preserved QT dispersion are likely to have viable myocardium.

Pts with high QT dispersion have predominantly non-viable scar tissue.

Dobutamine Stress Echocardiography

• Hypokinetic or akinetic regions improving during low dose dobutamine infusion (5–10 µg/kg/min) is indicative of viable tissue.

• At higher doses (upto 40 µg/kg/min plus atropine) wall motion may improve or diminish, reflecting inducible ischemia.

• Biphasic response is highly predictive of recovery of function after revascularization.

Stress Echo InterpretationInterpretation Rest /

BaselineLow dose stress Peak & post

stressNormal Normal Normal Hyper dynamic

Ischemic Normal Normal / severe ischemia – new RWMA

Decreased

Scar WMA No change No change

Hibernating WMA Improved Worsens

Stunned WMA Improved Improved

• Advantage of Echo based techniques Safety , low cost , widespread availability of

equipment .

• Disadvantage Spatial resolution is relatively low. High interobserver variability. Diagnostic accuracy is reduced in pts with poor acoustic window.

SPECT

• Thallium-201 Early uptake is proportional to regional blood

flow & delayed uptake indicates preserved Na+ K+ pump and an intact cell membrane.

Defects on initial images that improve later are viable.

• Technetium 99 lipophilic molecules and their intracellular

retention requires intact mitochondrial function.

Gating allow simultaneous assessment of myocardial perfusion & contractile function.

• SPECT has higher sensitivity & lower specificity than techniques based on contractile reserve.

PET• Glucose utilization is evaluated with FDG and regional

perfusion assessed with N13-ammonia, rubidium-82, or O15- labeled water.

• A normal perfusion and FDG uptake or reduced perfusion with enhanced FDG uptake indicates viable myocardium.

• Concordant reduction in FDG uptake and myocardial perfusion is indicative of scar tissue.

• PET is regarded as gold standard for viability assessment.

Hibernation in LAD occlusion

FDG SPECT

Magnetic resonance imaging

• Three techniques are being used: 1.Resting MRI to measure end diastolic wall

thickness. 2. Dobutamine MRI to evaluate contractile reserve 3. Contrast enhanced MRI to detect extent

and transmurality of scar tissue.

• Resting MRI End diastolic wall thickness < 6 mm represent transmural scar. • Dobutamine MRI Evaluate contractile reserve. Increased resolution of MRI avoid subjective variation of echo. Has sensitivity of 89% & specificity of 94% to predict

improvement after revascularization.

• Contrast enhanced MRI Allows precise detection of scar tissue. Extent & transmurality of scar can be assessed. Can detect subendocardial scar. Similar to FDG PET in detecting scar.

Accuracy of non-invasive techniques to assess myocardial viability

Impact of Revascularization on LV Function

• Studies shows LV ejection fraction improves significantly (ie ≥ 5%) after revascularization in 60% of patients (range 38% to 88%).

• To predict 5% improvement in LVEF, at least 25% of LV should be viable using DSE and ≈38% using conventional nuclear medicine and PET.

• In dyskinetic and akinetic segments, absence of scar or a transmural extension of scar of <25% have PPV of 88% and NPV 89% for functional recovery.

Treatment and Survival Rates

• Meta-analysis that pooled data of 3,088 pts from 24 studies demonstrated improved survival after revascularization in pts with hibernation.

• Revascularization resulted in 79.6% reduction in mortality (16% vs 3.2%)

• In absence of hibernation, no significant difference in mortality with revascularization (7.7% vs 6.2%).

Summary• Stunning and hibernation are 2 causes for LV

dysfunction. • Both conditions imply presence of viable

myocardium and are reversible.

References

• HURST’S THE HEART 13TH EDITION• BRAUNWALD’S HEART DISEASE NINTH EDITION• Medical and Cellular Implications of Stunning,

Hibernation, and Preconditioning :Circulation. 1998;97:1848-1867

• Stunning, Hibernation and Assessment of Myocardial Viability : Circulation.2008;117:103-114

• Molecular and Cellular Mechanisms of Myocardial Stunning :PHYSIOLOGICAL REVIEWS Vol. 79, No. 2, April 1999

• Hibernating Myocardium : PHYSIOLOGICAL REVIEWS Vol. 78, No. 4, October 1998

• Clinical assessment of myocardial hibernation Heart 2005;91;111-117

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