CLAUDIA GIDEA, MD

1. MYOCARDIAL VIABILITY CLAUDIA GIDEA, MD

3. Viable = myocardial cells that are alive: • cellular function • metabolic function • contractile function • Viable myocardium: • contractile myocardium • hypocontractile myocardium • Viability  ``contractile recovery`` • Dysfunctional viable myocardium: • hibernating myocardium • stunned myocardium

4. The requirements of cellular viability: • intact sarcolemmal function → to maintain electrochemical gradients across the cell membrane • preserved metabolic activity → to generate high-energy phosphates • adequate myocardial blood flow → to deliver substrate and washout the metabolites of the metabolic processes

6. irrespective of the resting flow → perfusion reserve (CFR) is always reduced in dysfunctional but viable myocardium • CFR is more severely reduced in the segments with low resting perfusion flow than in segments with normal resting perfusion flow • the severity of CFR reduction → impacts the ability of dysfunctional but viable myocardium to improve its contraction on inotropic stimulation → increased MVO2 and blood flow

7. CFR= the ability of a coronary vascular bed to increase coronary blood flow in response to stimuli that produce a maximal or near maximal hyperemic response CFR=maximal hyperemic / resting coronary  CFR = 2-5 in man Reactive hyperemia that follows transient coronary occlusion or the administration of pharmacologic agents

8. The patterns of chronic LV ischemic dysfunction

9. Stunned myocardium • total coronary artery occlusion for 5 to 15 minutes (a period not associated with cell death) • abnormality in regional LV wall motion that persisted for hours or days following reperfusion • stunned myocardium

10. Key elements of the stunned myocardium are: • short-term, total or near total reduction of coronary blood flow • reestablishment of coronary blood flow • subsequent LV dysfunction of limited duration

11. Hybernating myocardium • Original concept: • ↓resting flow (moderate levels of ischemia for couple of hours) • adaptive response to ischemia (without infarction) • ``short-term`` hibernation

12. Hibernating myocardium • ↓resting flow (moderate levels of ischemia for ≥ 12hours) • sub-endocardial necrosis and infarction

13. prolong perfusion-contraction matching = short-term adaptation → ``short-term`` hibernation • prolong perfusion-contraction matching ≠ long-term adaptation → chronic hibernation • repetitive ischemia distal to a severe stenosis ↔ chronic hibernation →↓resting flow is a result rather than the cause of hibernation

14. critical relation between the physiological severity of a coronary stenosis (CFR) and the developing of viable dysfunctional myocardium: • severe physiological coronary stenosis → chronic hibernation • less marked physiological coronary stenosis → chronically stunned myocardium

15. 2 concepts regarding hybernation: 1) downregulation of metabolic and contractile function 2) repetitive stunning

17. Histopathologic abnormalities at the cellular level demonstrated by biopsies of the hibernating segments taken at the time of surgery: • cellular dedifferentiation and embrionic phenotype • substantial loss of myofibrillar content • cellular swelling • increased glycogen content

18. 23 swine • 15-min partial occlusion of the LAD using the primary occluder → acute stunning → then the hearts were reperfused through a critical stenosis → that abolished the hyperemic response to a 20sec occlusion → yet allowed peak LAD flow to increase above the preocclusion value • microspheres assess the transmural distribution of flow: • at rest • during a transient total LAD occlusion (collateral flow) • after adenosine vasodilation • histological analysis performed • to identify changes characteristic for hibernating myocardium

19. The reduction of resting LAD flow developed despite the fact that hyperemic flow always exceeded the preocclusion value at rest (CFR was ~2) 24 hr= sustained stunning; 2 weeks = hibernation

20. Analog recordings at selected time points from a representative animal from the 2-week group. Dotted vertical lines depict end diastole and end systole. On day 1, a 15-minute partial LAD occlusion produced acute stunning. When reperfused with a critical limitation in flow reserve, function remained depressed when the animals were reevaluated 24 hours later (day 2), but resting flow was normal, consistent with myocardial stunning. Function continued to be depressed throughout the study, but resting flow became reduced, consistent with a progression to hibernating myocardium (day 17). Throughout the study, heart rate and systemic hemodynamics remained constant, with the exception of an increase in LV enddiastolic pressure. dPLV/dt represents the first derivative of LV pressure.

21. Serial measurements of LAD flow and wall thickening in animals in the 2-week study protocol. The initial (triangles) and final (squares) reactive hyperemic (RH) flows were reduced by the stenosis but always exceeded the preocclusion baseline flow at the beginning of the study (dotted line). LAD wall thickening was initially depressed with normal flow, consistent with chronic myocardial stunning. After a critical stenosis was applied for 8 days, resting flow (circles) became reduced. Thus, a critical coronary stenosis caused a rapid progression from stunned to hibernating myocardium with reductions in resting flow occurring in the presence of recruitable flow reserve.

22. Reduction in flow were indicative of reduction in tissue perfusion Microsphere measurements of resting flow in animals completing the 2-week protocol. Paired analysis of flow measurements in the LAD and normally perfused remote region were similar before occlusion (day 1) and in stunned myocardium after 24 hours (day 2). At the end of the study, LAD flow was significantly lower than flow in normally perfused myocardium in each myocardial layer. Flow was reduced in each myocardial layer and was consistent with a progression from stunned to hibernating myocardium. Endo, Mid, and Epi indicate subendocardial, midmyocardial, and subepicardial samples, and FT indicates full thickness.

23. Histopathologic findings of hibernating myocardium in pigs. Light and electron microscopy in hibernating LAD regions (upper row) were similar to those reported from human biopsy specimens. Both the remote normally perfused myocardium (middle row) and sham-operated controls (lower row) are shown to contrast the role of regional ischemia versus global factors. Hibernating myocardium exhibited regional increases in collagen (blue, first column) (Masson’s trichrome stain, 40) as well as myocyte hypertrophy (second column) (hematoxylin-eosin stain, 600) as a result of apoptosis induced myocyte loss. Changes in collagen and myocyte size in remote regions were similar to sham controls. In contrast to these regional changes, electron microscopy ( 8300) (third column) and periodic acid–Schiff staining ( 600) (fourth column) demonstrated that the myofibrillar loss and glycogen deposition occurred throughout the left ventricle. Thus the myofibrillar loss and glycogen deposition thought to be characteristic of hibernating myocardium actually reflect a global phenomenon that is not a direct result of repetitive ischemia.

24. Quantitative analysis of myofibrillar volume loss in subendocardial (black bars) and subepicardial (gray bars) regions. Myofibrillar loss was nearly 4-fold higher in hibernating myocardium than sham control myocardium. Myofibrillar loss began after 24 hours and increased after 2 weeks. Subepicardial and subendocardial values were similar. Furthermore, measurements in the LAD region subjected to ischemia were similar to those in the normal region. Thus,myofibrillar loss was global and was dissociated from regional differences in function and coronary flow reserve.

25. Patients with hibernating myocardium → high mortality rate in the absence of revascularization PET Medical therapy

27. cause-specific mortality data are limited • unclear whether death arise from: • progressive heart failure (possibly as a result of progressive cellular degeneration and fibrosis) • myocardial infarction (as a result of unstable plaque in the setting of global LV dysfunction) • sudden death (as a result of primary ventricular tachycardia and/or fibrillation)

28. Kaplan-Meier survival analysis of pigs with hibernating myocardium. Swine with hibernating myocardium had a progressive reduction in survival rate as a result of sudden death. There were no deaths in sham-operated control animals. By use of implantable Reveal Plus loop recorders, the mechanism of sudden death was usually ventricular tachycardia (VT) degenerating into ventricular fibrillation (VF) (inset). Postmortem analysis showed that more than 90% of the animals developing sudden death had no pathologic evidence of acute or healed infarction. Total coronary occlusion and physiologic features consistent with hibernating myocardium were demonstrated in a subset of animals studied several weeks before sudden death. These data indicate that the myocardial adaptive response to ischemia may be a double-edged sword. Though regionally protecting myocytes from acute ischemia, they may lead to a substrate characterized by electrical instability and a high risk of lethal ventricular arrhythmias.

29. in the porcine models of hibernating myocardium the deaths were almost entirely suddenly and not preceded by heart failure • myocardial sympathetic nerves are very sensitive to reversible ischemia → ``neural stunning`` → dysinnervation → sudden death • transmural distribution of norepinephrine uptake (I-131 MIBG) in hibernating myocardium → ↓↓ regionalNEuptakein hibernating myocardium with ↓↓↓↓ in the subendocardium.

30. C-11 HED and PET → assess the myocardial sympathetic innervation in vivo Imaging of sympathetic dysinnervation in hibernating myocardium. Short-axis (upper panel) and horizontal long-axis (lower panel) views compare metabolic viability with stimulated F-18 2-deoxyglucose (FDG) and regional myocardial norepinephrine uptake by use of C-11 hydroxyephedrine (11C-HED) in a pig with hibernating myocardium. Like the reductions in MIBG by ex vivo tissue counting, C-11 HED uptake was markedly reduced throughout the risk area distal to the LAD stenosis. Viability was confirmed by FDG as well as postmortem pathologic analysis. These findings demonstrate a C-11 HED/FDG mismatch in hibernating myocardium indicative of dysinnervated but viable myocardium.

31. hibernating myocardium exhibits inhomogeneity in sympathetic nerve function that is similar to that seen after myocardial infarction → promote the development of VT/ Vfib • cellular alteration in hibernating myocardium → spatial inhomogeneity in the electrophysiological properties of cardiac myocytes

32. Contractile reserve (CR) in hibernating myocardium • CR has a lower sensitivity to detect viable myocardium than nuclear imaging techniques but higher specificity to predict functional recovery after coronary revascularization • CR depends on the resting flow

33. CR is less in hibernating myocardium with reduced resting flow (32-46% of hibernating segments) compared to CR in stunned myocardium with normal resting flow • 88% of segments that show ``biphasic response `` with dobutamine echo had normal resting perfusion.

34. Viability imaging techniques • Nuclear imaging techniques • Stress-delayed thallium-201 imaging • Rest-delayed thallium –201 imaging • Technetium-99m-labeled sestamibi imaging • Positron Emmision Tomography

35. Viability imaging techniques • Echocardiography techniques • Low dose dobutamine • Full dobutamine protocol • MRI • Delayed contrast enhancement → assess the microcirculation • Dobutamine MRI → assess the contractilereserve

36. Prediction of functional recovery by viability testing

37. Viability imaging techniques • Nuclear imaging techniques • Stress-delayed thallium-201 imaging • Rest-delayed thallium –201 imaging • Technetium-99m-labeled sestamibi imaging • Positron Emmision Tomography

38. Concept of redistribution: 1) the initial myocardial extraction of the tracer reflects the distribution of blood flow at the time of injection 2) the delayed uptake after equilibrium has been reached is flow independent but it reflects an intact myocardial cell membrane and membrane potential

39. - because delayed uptake is flow independent, redistribution can still occur if a myocardial segment is chronically hypoperfuzed, even when the injection is performed at rest • Concept of reinjection: - tracer reinjection has 2 effects 1) adds more tracer to both normal and abnormal segments 2) adds more redistribution

41. Tl-201 reinjection imaging has an 88% concordance with FDG–PET imaging 49% of fixed defects normal Tl-201uptake

43. Survival free from cardiac events (cardiovascular death or heart transplantation) in relation to viability index (V.I.). Pagley et al

45. 42 31 27 27

46. The correlation between improvement in regional function after coronary bypass grafting and assessment of viability by preoperative rest-redistribution Tl-201 imaging in segments with severe asynergy (severe hypokinesis, akinesis, or dyskinesis). 62% 54% 23%

47. for revascularization to improve LVSF, the ventricle must be ischemic from a stenosis in an artery perfusing the dysfunctional territory (defect reversibility) • in the setting of a ventricle impaired by cellular dysfunction related to a cardiomyopathy despite satisfactory myocardial Tl-201 uptake, the revascularization would not be expected to improve function.

48. Influence of left ventricular ejection fraction (EF) on survival in patients with coronary artery disease. Data from the Duke database are shown for patients with normal left ventricular function (left), miId-to-moderate left ventricular dysfunction (center), and severe left ventricular dysfunction (right). For each subgroup, survival rates in patients undergoing coronary artery bypass surgery are compared with those in patients treated medicaIly. Although survival rates are higher with surgery compared with medical therapy across the spectrum of left ventricular function. the incremental benefit of surgery is greatest in patients with the most severe left ventricular dysfunction. (From Muhlbaier LH, Pryor DB, RankinjS. et al: Observational comparison of event-jree survival with medical and surgical therapy in patients with coronary artery disease. 20 years of follow-up. Circulation 86[5 supplj:II198-204, 1992.)

50. Viability imaging techniques • Nuclear imaging techniques • Stress-delayed thallium-201 imaging • Rest-delayed thallium –201 imaging • Technetium-99m-labeled sestamibi imaging • Positron Emmision Tomography