CardioNerd Amit Goyal is joined by Dr. Erika Hutt (Cleveland Clinic general cardiology fellow), Dr. Aldo Schenone (Brigham and Women’s advanced cardiovascular imaging fellow), and Dr. Wael Jaber (Cleveland Clinic cardiovascular imaging staff and co-founder of Cardiac Imaging Agora) to discuss nuclear and complimentary multimodality cardiovascular imaging for the evaluation of myocardial viability. Show notes & #Tweetorial were created by Dr. Hussain Khalid (University of Florida general cardiology fellow and CardioNerds Academy fellow in House Thomas). To learn more about multimodality cardiovascular imaging, check out Cardiac Imaging Agora! 

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In response to ischemia the myocardium can dynamically change along a spectrum from myocardial stunning to myocardial hibernation to myocardial necrosis. The goals of viability testing are to identify patients who may benefit from revascularization as hibernating or stunned myocardium are potentially reversible causes of LV dysfunction. There are numerous imaging modalities available for the evaluation of myocardial viability. The broad range of ways in which myocardial viability is assessed speaks to the complexity of the disease spectrum and the difficulty in creating a unifying definition of viability to assess in clinical trials.  

Five Take Home Pearls

1. In response to an acute episode of ischemia with subsequent reperfusion, the myocardium can be exposed to a large flux of oxygen free radicals or calcium overload that affects the cellular membrane and contractile apparatus. This phenotypically results in decreased contractility of the affected region of myocardium that can persist for weeks, labeled myocardial stunning 

2. Repeated episodes of myocardial stunning or chronic low myocardial blood flow can lead to cellular changes such as resorption of the contractile apparatus in order to decrease oxygen demand and allow the myocardial cells to survive. Phenotypically, this might appear as regions of hypokinesis or akinesis at rest with a fixed perfusion defect on myocardial perfusion imaging. This is typically considered hibernating myocardium.  

3. The goal of myocardial viability testing is to be able to differentiate between stunned, hibernating and necrosed myocardium. In patients with known epicardial coronary disease, this differentiation allows us to identify who may benefit from revascularization with improved LV systolic function and overall survival.  

4. There are several imaging modalities that can be used in the assessment of myocardial viability. The most sensitive modalities are FDG-PET and CMR. The addition of Dobutamine or first pass perfusion with Gadolinium additionally increases the specificity of CMR. These modalities are more expensive and not as widely available.  

5. The dynamic nature of the myocardial hibernation and the lack of a unifying definition/phenotypic expression of myocardial hibernation and viability have made it difficult for clinical trials to show that re-establishing myocardial blood flow to hibernating myocardium is beneficial. As Dr. Jaber stated in the episode in his spin on the classic opening phrase from Leo Tolstoy’s masterpiece, Anna Karenina, “All normal hearts are normal in the same way, and all abnormal hearts are abnormal in different ways.” 

6. The PARR-2 trial was one of the few randomized, controlled trials of patients with LV systolic dysfunction and coronary artery disease who were randomized to either FDG-PET guided management or standard care with respect to whether to pursue revascularization. Overall, there was not a significant reduction in the primary composite endpoint between the FDG-PET arm and the standard care arm. However, not all patients received the revascularization strategy recommended by imaging. In patients whom the PDG-PET recommendation for revascularization was followed, there was a significant benefit compared to the standard care group.  

Quotable: 

“All normal hearts are normal in the same way, All abnormal hearts are abnormal in different ways”—0:54 

Detailed Show Notes

1. What is myocardial hibernation and myocardial stunning? How do these concepts fit into the discussion of myocardial viability?  
   • A common scenario encountered in clinical practice is the patient who has depressed LV systolic function and known obstructive epicardial coronary disease. For these patients, we may wonder if the myocardium supplied by the epicardial coronary arteries with obstructive lesions is living (viable) or dead(scarred), and whether there would be a benefit to revascularization. If the LV systolic function is decreased with hypokinesis or akinesis and perfusion deficits, then the myocardium is either dead (scarred), stunned, or hibernating! This is a spectrum. 
   • Stunned myocardium and hibernating myocardium were originally described in the late 1970s and popularized in the 1980s — stunned myocardium by Dr. Braunwald and Dr. Kloner and hibernating myocardium by Dr. Diamond and Dr. Rahimtoola. When first described, myocardial stunning was thought of as a “hit” (episode of severe ischemia), “run” (relief of ischemia before irreversible injury) and “stun” (a relatively long period of post-ischemia LV dysfunction). 
   • What are stunned myocardium and hibernating myocardium? When a region of myocardium becomes ischemic and that ischemia is severe and prolonged, myocardial necrosis occurs, there is no return of contractile function, and the myocardium is replaced by scar tissue. If, however, there is reperfusion and relief of the ischemia before necrosis occurs, the myocardium can become “stunned”. 
   • Myocardial stunning is a transient period of post-ischemic dysfunction that can persist for days to weeks prior to recovery of myocardial function. There are a variety of hypotheses as to why this occurs. Some of the leading hypotheses are: 
     • In response to ischemia, there can be a flux of oxygen free radicals that disrupt cellular membranes and the contractile apparatus of the cell. 
     • Calcium overload that affects myofilament responsiveness to calcium or leads to sarcoplasmic reticulum dysfunction. Phenotypically, this may manifest as hypokinesis or akinesis of the corresponding area of myocardium.    
   • If there are repetitive episodes of myocardial stunning or if there is chronic low myocardial blood flow to a region of the myocardium, this can lead to myocardial hibernation.  
     • Essentially, the myocardium undergoes metabolic adaptations and downregulation of function (e.g. resorption of the intracellular contractile apparatus) that allows the myocardium to survive by reducing myocardial oxygen demand. Phenotypically, this results in contractile abnormalities at rest that may manifest as hypokinesis or akinesis of the corresponding area of myocardium. This dysfunction may persist weeks to months even after revascularization as the contractile apparatus replenishes.  
     • As referenced in the episode, Dr. Rahimtoola popularized the concept of hibernating myocardium in a published report in the 1980s of a patient who had chronic angina, single vessel obstructive epicardial coronary disease in the LAD, depressed LV systolic function, and an anteroapical myocardial wall motion abnormality (WMA). After administration of nitroglycerin, the patients LV systolic function and WMA improved suggesting that this area of the myocardium was viable. The patient underwent coronary bypass surgery and their LV systolic function and wall motion eventually normalized—confirming that this area of myocardium was viable all along. 
     • As described by Dr. Kloner in a recent review, an analogy to hibernating myocardium is a broken arm that is casted. As the muscles are not being used, we can expect some atrophy and similarly with hibernating myocardium, the cardiac muscle is not contracting and some level of atrophy is not unexpected. As with a broken arm that is casted will need some time to recover near full function, revascularization will not lead to immediate normalization of cardiac function.  

1. What are our goals when it comes to viability testing? In which patients should we pursue viability testing (evaluation for myocardial stunning or myocardial hibernation)?   
   • The primary goals of viability testing are: 
     • To avoid attempting to revascularize dead myocardium as this  would unnecessarily expose them to the risks of an invasive procedure.  
     • To identify patients who may have an improvement in LV systolic function with revascularization. 
     • To potentially improve survival. 
   • There are certain patient populations in whom we should not pursue viability testing as the information provided by testing would not change our management: 
     • Patients who have normal coronary arteries or nonobstructive disease. 
     • Patients with obstructive epicardial coronary disease that is not amenable to revascularization. 
     • Patients with normal LV systolic function. 

• There are different modalities we can use to assess for myocardial viability. How can we conceptualize the different modalities and what are the advantages/disadvantages of each one? 
  • We can broadly differentiate the modalities used to assess for myocardial viability into those that are looking for “signs of life” (e.g., evidence of inducible contractility, cell membrane integrity, metabolic activity) and those that are looking for “signs of death” (e.g., myocardial wall thinning, presence of scar).  
  • How to look for signs of life: 
    • Dobutamine Stress Echocardiography 
      • With DSE, we are trying to prove that areas of the myocardium that are hypokinetic or akinetic have some reserve and contractile function. We start with low dose dobutamine, and as we increase the dose, the wall may start to contract better if it is viable. As we get to higher doses, the wall may become hypokinetic again due to ischemia and perfusion-contractile mismatch (e.g., the oxygen demand overwhelms the chronically hypoperfused area which has adapted to chronic ischemia by downregulating the intracellular contractile apparatus). 
      • This test has high specificity; however, sensitivity is ~70%. The positive predictive value of DSE is likely highest when there is a biphasic response: improvement at low dose dobutamine but worsening function at high dose. It is a good tool when you want to avoid radiation exposure or when you don’t have access to more advanced techniques. 
    • Nuclear Imaging 
      • Fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
        • FDG uptake by cells is an indirect marker of viability as it establishes the cells in this region are metabolically active. Myocardial segments with a fixed perfusion defect are dead (scarred), hibernating but viable, or an admixture of scarred and hibernating myocardium. Those areas which “light up” on FDG-PET are metabolically active (sign of life) and thus likely viable. 
        • FDG-PET sensitivity for assessment of myocardial viability is up to 92% but specificity is relatively low compared to other studies (<70%). 
        • In the setting of an acute myocardial infarction (MI), FDG-PET may overestimate viability as infarcting segments are inflamed such that FDG uptake does not necessarily imply viable myocardium. 
      • Thallium-Single-photon emission computerized tomography (SPECT) 
        • Thallium is a potassium analog and uses a sodium-potassium ATPase (Na+/K+ ATPase) transport protein embedded in the plasma membrane to enter the cell. It has a long half-life of around 3 days. 
        • This is an indirect marker of viability as it establishes that myocardial cells have intact cellular membranes. This often requires a two day protocol in which you obtain baseline images and then reimage the patient 24 hours later. The myocardium that “lights up” is presumably viable. The 24-hour waiting period allows further slower uptake by cells and areas that we can classify as hibernating myocardium. Alternatively, we can reinject thallium on the second day and assess whether we have more myocardial uptake than on the first day—this helps improve the specificity of the study. Sensitivity of this method to detect hibernation is modest (around ~87%); however, specificity is very high. 
        • Most centers have abandoned this method because the patient has to present on two consecutive days for the procedure, they are exposed to significantly higher radiation, and the sensitivity is low. The American Society of Nuclear Cardiology has discouraged the use of thallium to minimize radiation exposure. 
      • Technetium (99mTc) Sestamibi SPECT 
        • 99mTc Sestamibi uptake in the myocardium is an indirect marker of viability as it taken up by cells with intact plasma membranes and mitochondrial membranes.  
        • 99mTc Sestamibi is given at rest. Nitroglycerin is then given to vasodilate the vessels that were not vasodilated at rest. This may enhance myocardial blood flow in the segments that were not taking up 99mTc Sestamibi prior to nitroglycerin. We then look for areas of myocardium that “light up” and represent likely hibernating myocardium 
        • Very few centers utilize this approach for viability testing. 

1. So we talked about ways to “look for signs of life.” How do we look for “signs of death” on viability imaging?  
   • Resting Echocardiography 
     • The presence of end-diastolic wall thickness less than or equal to 6 mm with a hypo-contractile segment is highly specific for nonviable myocardium and would not likely benefit from revascularization. If this is seen, you likely do not need to order follow up PET or other modality for further assessment of viability. 
   • Cardiac Magnetic Resonance Imaging (CMR): 
     • Whereas with PET, you are looking for areas to “light up” that are viable, with CMR, you are looking at late gadolinium enhancement (LGE)—areas of the myocardium that “light up” due to presence of scar. Because we know that scar in ischemic heart disease progresses from subendocardium to epicardium, we can quantify not only the extent (how many segments involved) of scar, but also the “transumurality” of the scar (the percentage of the wall thickness that is scar). We can quantify this in quartiles. For any segment that has >50% LGE, the chances of that segment recovering after revascularization are very low (<10%). If LGE is <25% of the wall thickness, the chances of wall recovery after revascularization are good (>60%). If LGE is 25-50%, this is the grey zone. For these patient’s we must consider individual patient factors such as age and comorbidities and complexity of the intervention when deciding whether to attempt revascularization. Remember—always consider risk vs benefit and incorporate informed shared decision-making! 
     • CMR additionally provides information on wall segment contractility and function, and big-picture information such as overall LV wall thickness and LV volumes. With this additional big picture information we can get a better understanding of the overall health of the ventricle and weigh this against the extent of hibernating myocardium when we are making a decision about revascularization.  
     • You can also use Dobutamine stress with CMR. If you are unsure/on the edge for deciding whether to revascularize a patient with 25-50% LGE on CMR, you can give dobutamine and see if that portion of the LV has augmented contractility (sign of life). This can give you more confidence that myocardial segment will recover. 
     • Finally, you can also do stress testing with CMR by using first pass perfusion with the injection of Gadolinium. You can knock everything out in one test—assessment for ischemia and viability!  
     • CMR has sensitivities similar to PET in regard to identifying viable myocardium and with the addition of dobutamine stress, you can have increased specificity. 
     • In contrast to PET, in the setting of an acute MI, CMR can underestimate viability because LGE can appear in areas of inflammation rather than scar. 
     • Enjoy Ep #33 – CMR with Dr. Kown for more! 

1. What are some challenges in viability testing to assess for hibernating myocardium prior to revascularization? Is there any data to support this approach? 
   • As we discussed above, myocardial stunning, hibernation, and necrosis with scarring represent a spectrum of disease processes in response to ischemia. This spectrum is dynamic. Additionally, as we saw above, there is a plethora of phenotypic expressions and definitions of hibernation and viability that we assess by our different imaging modalities in looking for signs of life versus death (e.g., mismatch between perfusion and metabolic activity, contractile reserve, wall thickness, evidence of an intact cellular membrane, degree of scar, etc.).  
   • The dynamic nature of the disease process and the lack of a unifying definition/phenotypic expression of myocardial hibernation and viability have made it difficult for clinical trials to show that re-establishing myocardial blood flow to hibernating myocardium is beneficial.  
   • As Dr. Jaber stated in the episode in his spin on the classic opening phrase from Leo Tolstoy’s masterpiece, Anna Karenina, “All normal hearts are normal in the same way, and all abnormal hearts are abnormal in different ways.”  With that being said, there are some notable studies that have assessed the benefit of myocardial viability testing prior to revascularization: 
     • In a 2002 meta-analysis by Allman et. al, myocardial viability testing and the impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction was reviewed.  
       • This analysis consisted of >3000 patients w/CAD and LV systolic dysfunction. Viability testing was assessed using thallium perfusion SPECT, FDG metabolic imaging, or dobutamine echocardiography. In patients showing areas of viability, revascularization was associated with an annual mortality rate of 3.2% over 25 months compared to 16% in the medical treatment alone (no revascularization) groups p<0.0001—a 79.6% annual reduction in mortality. 
     • The PARR-2 trial was a randomized, controlled trial of 430 patients with LV systolic dysfunction and suspected coronary artery disease who were randomized to either FDG-PET guided management or standard care in regards to whether to pursue revascularization. The primary outcome was composite endpoint of cardiac death, MI, or recurrent hospital stay for cardiac cause, within 1 year. Overall, there was not a significant reduction in the primary composite endpoint between the FDG-PET arm and the standard care arm.  
       • However, for patients in the FDG-PET arm in whom the FDG-PET recommendation for revascularization was followed, there was a significant benefit compared to the standard care group.  
       • A substudy of the PARR-2 trial showed that in the FDG-PET group, the imaging study recommendation regarding whether to proceed with revascularization was not followed 25% of the time for a variety of reasons—persistent or resolved symptoms, renal failure, and anatomy not amenable to revascularization, for instance. In a post-hoc analysis of the 182 patients randomized to the FDG-PET arm of PARR-2 with LVEF <35% and CAD being considered for revascularization, a larger amount of hibernating myocardium was associated with improved outcomes following revascularization. 
     • The STITCH (Surgical Treatment for Ischemic Heart Failure) trial was a randomized controlled trial that enrolled 1212 patients with severe CAD and LVEF <35% to CABG + medical therapy vs. medical therapy alone. 610 of these patients had viability testing (SPECT and/or dobutamine stress echo). The primary endpoint was death from any cause.  
       • Overall, there was no survival benefit at 5 years of CABG + medical therapy compared to medical therapy alone and an 8% benefit at 10 years of the revascularization group.  
       • In a substudy analysis, viability testing did not identify patients who would have a survival benefit from CABG. 
       • Of note, patients were not randomized for assessment of hibernation (viability testing) in this trial. And importantly, FDG-PET and MRI were not used in the assessment of viability.  
     • The recently published International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial was not a trial designed to assess the value of assessing myocardial hibernation/viability and had very few FDG-PET or MRI assessments  

A patient w/ICM (LVEF 15%) p/w angina & DOE. SPECT shows a fixed defect & LHC shows LCx CTO.

…To revasc or not to revasc…

1st we need to know if the myocardium is dead or alive?! Check out this #Tweetorial on 🫀 viability to see how! pic.twitter.com/Y45F6vQnQL

Wael Jaber, MD, is a staff cardiologist in the Section of Cardiovascular Imaging, Robert and Suzanne Tomsich Department of Cardiovascular Medicine, at the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at Cleveland Clinic. Dr. Jaber specializes in cardiac imaging (both nuclear cardiology and echocardiography) and valvular heart disease. Dr. Jaber attended college at the American University in Beirut, graduating with a Bachelor of Science in biology. He then went on at the American University to receive his medical degree while making the Dean’s honor list. He completed his residency in internal medicine at the St. Luke’s-Roosevelt Hospital Center at Columbia University College of Physicians and Surgeons, where he also completed fellowships in cardiovascular medicine and nuclear cardiology. Dr. Jaber is currently is the Medical Director of the Nuclear Lab and of the Cardiovascular Imaging Core Laboratory in C5Research. He is fluent in English, French and Arabic. He is the author of Nuclear Cardiology review: A Self-Assessment Tool and cofounder of Cardiac Imaging Agora.

Dr. Aldo L Schenone is one of the current Chief Non-Invasive Cardiovascular Imaging Fellows at the Brigham and Women’s Hospital. He completed medical school at the University of Carabobo in Valencia, Venezuela, and then completed both his Internal Medicine residency and Cardiology fellowship at the Cleveland Clinic where he also served as a Chief Internal Medicine Resident.

Dr. Erika Hutt @erikahuttce is a cardiology fellow at the Cleveland Clinic. Erika was born and raised in Costa Rica, where she received her MD degree at Universidad de Costa Rica. She then decided to pursue further medical training in the United States, with the goal of becoming a cardiologist. She completed her residency training at Cleveland Clinic and went on to fellowship at the same institution. Her passions include infiltrative heart disease, atrial fibrillation, valvular heart disease and echocardiography among many. She is looking forward to a career in advanced cardiovascular imaging.

1. Allman KC. 18F-FDG PET and myocardial viability assessment: trials and tribulations. J Nucl Med. Apr 2010;51(4):505-506. 

2. 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. Apr 2002;39(7):1151-1158. 

3. Beanlands RS, Nichol G, Huszti E, et al. F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2). J Am Coll Cardiol. Nov 2007;50(20):2002-2012. 

4. Bonow RO, Maurer G, Lee KL, et al. Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med. Apr 2011;364(17):1617-1625. 

5. Cwajg JM, Cwajg E, Nagueh SF, et al. End-diastolic wall thickness as a predictor of recovery of function in myocardial hibernation: relation to rest-redistribution T1-201 tomography and dobutamine stress echocardiography. J Am Coll Cardiol. Apr 2000;35(5):1152-1161. 

6. D’Egidio G, Nichol G, Williams KA, et al. Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial. JACC Cardiovasc Imaging. Sep 2009;2(9):1060-1068. 

7. Dilsizian V, Smeltzer WR, Freedman NM, Dextras R, Bonow RO. Thallium reinjection after stress-redistribution imaging. Does 24-hour delayed imaging after reinjection enhance detection of viable myocardium? Circulation. Apr 1991;83(4):1247-1255. 

8. Gerber BL, Raman SV, Nayak K, et al. Myocardial first-pass perfusion cardiovascular magnetic resonance: history, theory, and current state of the art. J Cardiovasc Magn Reson. Apr 2008;10:18. 

9. Gunning MG, Kaprielian RR, Pepper J, et al. The histology of viable and hibernating myocardium in relation to imaging characteristics. J Am Coll Cardiol. Feb 2002;39(3):428-435. 

10. Kloner RA. Stunned and Hibernating Myocardium: Where Are We Nearly 4 Decades Later? J Am Heart Assoc. 02 2020;9(3):e015502. 

11. Medrano R, Lowry RW, Young JB, et al. Assessment of myocardial viability with 99mTc sestamibi in patients undergoing cardiac transplantation. A scintigraphic/pathological study. Circulation. Sep 1996;94(5):1010-1017. 

12. Rahimtoola S. Coronary bypass surgery for chronic angina–1981. A perspective. Circulation. 1982;65(2):225-241. 

13. Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med. Apr 2011;364(17):1607-1616. 

• Wael Jaber, MD