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)

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

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 Interpretation Rest / Baseline Low dose stress Peak & post stress Normal Hyper dynamic Ischemic Normal / severe ischemia – new RWMA Decreased Scar WMA No change Hibernating Improved Worsens Stunned

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 Hibernating Myocardium : PHYSIOLOGICAL REVIEWS Vol. 78, No. 4, October 1998 Clinical assessment of myocardial hibernation Heart 2005;91;111-117

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