Myocardial Viability

Etiology

Myocardial Hibernation due to Ischemic Cardiomyopathy

Chronic reversible ischemia due to obstructive coronary artery disease leads to a reduction in resting blood flow and subsequent downregulation in metabolism and contractility. This myocardium is viable and recovers partially or fully upon revascularization.

Myocardial Stunning due to Acute Coronary Syndrome

An acute coronary syndrome due to plaque rupture leads to an ischemic cascade downstream and subsequent impairment in LV contractility. The contractile dysfunction persists despite early revascularization and before irreversible myocardial injury sets. Duration of transient post-ischemic dysfunction or stunning is the function of the duration of ischemia. It is believed to be caused by acute ischemia followed by reperfusion injury.

Myocardial Stunning Post-Cardiac Surgery

On-pump cardiac surgical procedures like CABG involve the institution of cardiopulmonary bypass machines, aortic cross-clamping, and cardioplegia, which lead to an interruption in coronary artery blood flow. This leads to ischemia, initially followed by reperfusion injury once the heart is restarted, resulting in reversible post-ischemic systolic dysfunction.[4] This may require using vasopressors and inotropes, mechanical circulatory assist devices like ECMO, thus prolonging the hospital stay.

Left Atrial Stunning Post Cardioversion

Conversion of atrial fibrillation or flutter to sinus rhythm by either electrical or pharmacological cardioversion leads to transient left atrial and left atrial appendage contractile dysfunction lasting about 4 to 6 weeks. A stunned atrium and appendage can be a nidus for thrombus formation; hence, patients should be on anticoagulation for at least four weeks.

Myocardial Stunning in Resuscitated Cardiac Arrest

Myocardial dysfunction may result after the return of spontaneous circulation following a cardiac arrest. It manifests as global myocardial hypokinesis with a severe reduction in ejection fraction, reduction in cardiac output, and hypotension.[5] Studies have shown that myocardial blood flow is not reduced during the period of dysfunction, and myocardial recovery occurs in about 72 hours in survivors.[6]

Epidemiology

In developed countries, ischemic cardiomyopathy due to atherosclerotic coronary artery disease accounts for about 70% of HFrEF patients. Studies have shown that 50% of patients with coronary artery disease and heart failure with reduced ejection have a significant volume of viable myocardium.[7] 

The overall mortality in patients with HFrEF due to ischemic cardiomyopathy is 39%, which is lower in patients with viable myocardium than with non-viable myocardium, ie, 37% vs. 51%.[8]

Pathophysiology

Atherosclerosis leads to lipid-rich plaque accumulation in the coronary artery's intima.[9] Plaques with thin fibrous caps, increased macrophage activity, large necrotic lipid-rich cores, and superficial microcalcifications are considered vulnerable as they easily get eroded by exogenous shear stresses leading to plaque fissuring, rupture, destabilization, and exposing the underlying thrombogenic and proinflammatory necrotic core. This leads to the initiation of the coagulation cascade and superimposed thrombosis leading to downstream myocardial ischemia, fatal myocardial infarction, and sudden cardiac death.[10]

Myocardial ischemia follows a temporal sequence of events called an ischemic cascade, a function of the duration of ischemia. It begins with a reduction in perfusion, leading to flow disparity and, thus, impairment of the Na/K ATPase pump, followed by diastolic dysfunction, systolic dysfunction, electrocardiographic changes, and angina. The extent of myocardial ischemia is the function of the duration of obstruction and the area of myocardium subtended by the diseased vessel.

Partial occlusion for more than 5 hours causes patchy infarction, whereas complete occlusion for more than 20 minutes causes irreversible myocyte death, termed transmural infarction. The cascade of irreversible myocardial injury begins from the endocardium and then progresses to the myocardium. If reperfusion is established before the onset of irreversible damage after myocardial infarction, stunning develops, and the time required for recovery depends on the duration of ischemia.

In chronic stunning, oxygen-free radicals released when interrupted blood flow damages the myocytes and cause myocardial stunning. The sequential evolution of the extent of myocardial injury from ischemia depends on the duration of ischemia, residual blood flow from collateral circulation, location of the occlusion, and myocardial oxygen consumption.[2] 

Ischemic pre- and post-conditioning are the adaptive responses believed to reduce infarct size. Brief reversible ischemic episodes followed by reperfusion preceding the major ischemic event are cardioprotective as it is believed to reduce the extent of myocardial necrosis. This is called ischemic preconditioning; preconditioned myocytes can tolerate ischemia better than naive myocytes.[11] 

Myocardial post-conditioning is when intermittent episodes of ischemia and reperfusion during reperfusion therapy are believed to be cardioprotective by reducing reperfusion injury and infarct size. Complex endogenous second messenger systems like Protein Kinase C, inducible Nitric oxide (iNOS), COX-2, and mitochondrial K channels are believed to be active.[2]

Studies suggest hibernation and stress-induced ischemia without angina are common in patients with HFrEF, and revascularization may improve resting blood flow and left ventricular contractility.[12] Thus, both chronic stunning and hibernation present with reversible systolic dysfunction, but the resting blood flow is normal in myocardial stunning, whereas it is critically reduced in hibernation.[13] 

The resting myocardium uses beta-oxidation of fatty acids as a metabolic fuel to produce high-energy phosphates like ATP to power myocardial contraction. However, the ischemic myocardium switches its energy metabolism from fatty acids to anaerobic glycolysis. Hence, glucose uptake is upregulated in ischemic and viable myocardium, and this phenomenon is utilized to assess myocardial viability in 18F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET).[2]

History and Physical

History: Patients with left ventricular dysfunction may be asymptomatic or present with exertional fatigue, palpitation, angina, paroxysmal nocturnal dyspnea, or orthopnea. Sudden cardiac arrest or sudden cardiac death may be the initial presentation. 

Physical: General physical examination varies with the stage of the disease and may reveal respiratory distress, cyanosis, elevation in JVP, bilateral pitting pedal edema, or congestive hepatomegaly. The precordial examination may reveal a displaced apex beat or pan systolic murmur of secondary mitral regurgitation.

Evaluation

The physiology of the ischemic cascade is fundamental for a stress test and myocardial viability assessment, as different imaging modalities utilize different stages of the cascade. The following imaging modalities are commonly used in the evaluation of myocardial viability.

Dobutamine Stress Echocardiography

Dobutamine stress echocardiography is used to assess the myocardial viability in patients with resting systolic dysfunction before revascularization. It is based on the principle that viable myocardium will undergo augmentation in contractility in response to beta-adrenergic stimulation, whereas non-viable myocardium will not. Dobutamine is infused at a rate of 2.5 to 10 micrograms/kg/min.

Improvement in contractility at low dose followed by diminished wall motion at high dose (10 to 40 micrograms/kg/min) is termed a biphasic response and suggests viable myocardium. A biphasic response is predictive of recovery in myocardial contractility after revascularization.[14] This phenomenon is explained by an increase in myocardial flow and contractility at low doses but significant myocardial oxygen demand and supply mismatch during the high dose of dobutamine infusion.

Radionuclide Techniques

Radiotracers used in the viability study are the analogs of our endogenous second messenger system and metabolites used in cell signaling and metabolism. Quantitative analysis of these radiotracers' uptake thus yields indirect evidence of intact cellular function and the cell membrane and subcellular organelles' integrity. These tracers have unstable nuclei and electrons, which emit characteristic radiation after being taken up by the myocardial cells, which are converted to photons and imaged by a camera system.

The degree of uptake is proportional to myocardial blood flow. The strength of the emitted radiation correlates with the degree of uptake and, thus, the extent of viability. The infarcted myocardium does not take up tracers; hence, no radiation is emitted by this portion of the myocardium. The images show perfusion defects in that area. Radiotracer perfusion study thus aims to study the flow disparity component of the ischemic cascade, which is the early stage. The areas with normal perfusion are viable, but those with perfusion defects may be infarcted or hibernating.

Metabolic tracers like 18F-FDG, as well as delayed imaging with Thallium-201, help differentiate this. The following imaging protocols are commonly used for viability assessment:

• Thallium-201 Single Photon Emission Computed Tomography (SPECT) Study: Thallium-201 is a potassium analog, and its uptake via Na/K ATPase is evidence of intact cell membrane and, thus, cellular viability. Thallium-201 has a high first-pass myocardial extraction of about 85% after the intravenous injection. The initial myocardial uptake after intravenous injection is a function of blood flow, and hence uptake will be high in normal myocardium and low in ischemic myocardium. Thallium has a unique property of late redistribution from the myocardium to the blood pool, which depends on its concentration difference between the myocardium and blood pool, and not on blood flow. Since the concentration difference between the blood pool and ischemic myocardium is low, washout is low, retaining more TI-201 activity, while washout is high in normal myocardium. This phenomenon of differential washout is utilized in the viability study. The rest or stress images are taken 15 to 20 minutes after injection, and then redistribution images are obtained after 3 to 4 hours. The presence of perfusion defect in the initial images followed by improvement in redistribution images is the hallmark of myocardial viability. The specificity of this study can be further improved by enhancing redistribution by reinjecting the tracer during the redistribution stage or taking late distribution images at 24 to 48 hours later, thus allowing more time for redistribution and improving positive predictive value for improvement in LV function.[15]
• Technetium 99m Sestamibi SPECT: Tc-99m Sestamibi is a cation that diffuses across the cell membrane and then into the mitochondria, and positive uptake is suggestive of viable myocardial cells. The protocols used are rest-stress and rest protocol with nitrate enhancement to promote uptake.[16] Normal uptake is consistent with viable myocardium, moderate uptake is consistent with a mixture of infarct and viable tissue, and absent uptake is consistent with an infarct.
• 18F-Fluorodeoxyglucose (FDG) PET Scan: 18F-FDG is an analog of glucose tagged with a radiotracer, taken up by mitochondria, phosphorylated in the stage of glycolysis, and gets trapped in this state without further metabolism. In hibernating myocardium, GLUT receptors are overexpressed; hence, the myocardium is FDG avid. In ischemic myocardium, beta-oxidation of fatty acids is suppressed by hypoxia, so cells switch to anaerobic glycolysis for energy metabolism. Viable tissue characteristically shows flow-metabolism mismatch. The first component tests for the perfusion using PET radiotracers like rubidium-82, 13-N ammonia, and hibernating myocardium exhibit perfusion defects. The metabolic component of the test consists of keeping the patient in a fasting state for 6 hours, followed by a glucose load, insulin infusion, and finally, radiotracer F-FDG. The uptake in hibernating and normal myocardium is thus facilitated by insulin, and an image with uniform uptake is shown in a PET scanner.[17] The absence of uptake is consistent with an infarct.

Contrast-Enhanced Cardiac Magnetic Resonance (CMR) 

The initial method of viability assessment using CMR is quantifying end-diastolic wall thickness (EDWT). A myocardial thickness of less than 6 mm is likely a 'scar' and less likely to improve after revascularization. One of the fundamental histologic changes in necrotic myocardium is extracellular volume expansion and death of myocytes. This change enables the high uptake and retention of high-density gadolinium-based contrast agents in the cell as well as extracellular space, termed late gadolinium enhancement (LGE) and forms the basis for a viability study with contrast-enhanced CMR.[17] 

The LGE starts from the endocardium (subendocardial infarct) and then progresses transmurally (transmural infarct) in the segments supplied by the coronary artery. The degree of LGE correlates with the extent of viability and potential benefit from revascularization. The myocardial segment with >50% LGE is non-viable and will not improve after revascularization, <25% is viable and will benefit from revascularization, and 25 to 50% LGE needs to be further investigated for inotropic contractile reserve by a dobutamine infusion and assessment of wall motion in echocardiography or CMR.[18][19]

Figure 1 shows a transmural LGE in the right coronary artery consistent with transmural infarction and lack of viability. Dobutamine stress CMR can be used to assess viability. A dysfunctional but viable myocardium will exhibit an increased systolic thickening of over 2 mm on low-dose dobutamine stress.

Treatment / Management

Identifying patients with ischemic cardiomyopathy who would benefit from revascularization in addition to guideline-directed medical therapy (GDMT) is important. All patients with HFrEF should be on optimal medical therapy, irrespective of the presence or absence of viable myocardium.

Medical Therapy

Beta-Blockers: Selected beta-blockers carvedilol, metoprolol, and bisoprolol in maximum tolerated doses have proven mortality and morbidity benefit in HFrEF patients. (ACC/AHA Class IA).

ACEIs/ARBs/Angiotensin-Neprlisyn inhibitors (ARNI): RAAS inhibitors (particularly Enalapril) and ARNI (Sacubitril-Valsartan) also have a mortality benefit (ACC/AHA Class IA). ACEI and ARNIs should not be used together, and a washout period of at least 36 hours should be given before transitioning from ACEI to ARNI. (ACC/AHA Class IA ) 

Mineralocorticoid Receptor Antagonists (MRA): Spironolactone and eplerenone are proven to reduce mortality and morbidity and are recommended with LOR Class IA by ACC/AHA for NYHA Class II-IV heart failure and LVEF <35%. (ACC/AHA Class IA)

Hydralazine and isosorbide dinitrate: The combination reduces mortality and morbidity and is used predominantly in African American patients with NYHA Class III-IV HFrEF despite receiving beta-blockers and ACEI (Class IA). These drugs can be used as alternative preload and afterload-reducing agents in patients who cannot be on ACEI/ARBs/ARNI due to hypersensitivity, hypotension, and renal failure.

Sodium-Glucose Cotransporter 2 (SGLT2i) Inhibitors: SGLT2i (empagliflozin and dapagliflozin) are shown to reduce heart failure-related hospitalization and cardiovascular mortality in patients with symptomatic HFrEF irrespective of the presence of type 2 diabetes (ACC/AHA Class I).[20]

Coronary Artery Revascularization

CABG surgery is done for the left main disease, triple vessel disease, complex coronary artery disease, and patients with CAD and reduced left ventricular ejection fraction. Percutaneous coronary intervention with balloon angioplasty and stent placement is done for uncomplicated single or two-vessel disease.

Device-Based Therapies for Cardiomyopathy-Related Arrhythmias

An implantable cardioverter defibrillator (ICD) is used in patients with end-stage cardiomyopathy with non-viable myocardium as a prevention against sudden cardiac arrest from malignant ventricular arrhythmias. Cardiac resynchronization therapy (CRT) synchronizes LV and RV contraction in HFrEF, prevents heart failure progression, and improves symptoms.

ICD is indicated for the primary prevention of sudden cardiac death in patients with LVEF <35%, NYHA class II/III heart failure who have been on maximally tolerated doses of beta blocker, ACEI/ARNI, and MRA for 90 days, and with survival for more than a year. Patients with LBBB with a QRS duration of 150 msec or more and NYHA Class II, III symptoms on GDMT benefit from its upgrade to a CRT device.

Differential Diagnosis

Stress-induced cardiomyopathy: Any form of myocardial stress, like sepsis, and emotional and physical trauma, can lead to catecholaminergic surge, microvascular spasm, and myocardial dysfunction. This is characterized by reversible distal myocardial hypo-contractility with basal hyper-contractility in echocardiography. Its presentation is similar to acute coronary syndrome, and it is a diagnosis of exclusion. Obstructive coronary artery disease needs to be ruled out by cardiac catheterization. 

LV Systolic dysfunction due to myocarditis: Myocarditis due to viruses like Coxsackie and Parvovirus B19 can lead to transient reversible myocardial dysfunction.

Tachycardia-induced cardiomyopathy: Any tachycardia like atrial fibrillation with a rapid ventricular response, supraventricular tachycardia, and atrial flutter with rapid ventricular response can cause reversible myocardial systolic dysfunction. Myocardial function recovers after the rate is controlled.

Peripartum cardiomyopathy: Peripartum cardiomyopathy is defined by the development of congestive heart failure in the last month of pregnancy or within five weeks of puerperium. It is thought to be due to the hemodynamic stress of pregnancy on the heart. LV systolic function often improves with time.

Pertinent Studies and Ongoing Trials

Extensive landmark studies assessing the mortality benefits of revascularization in a viable myocardium are not available, and studies are ongoing. Small- and moderate-sized studies showed no mortality benefits with revascularization and medical therapy versus medical therapy only in patients with viable myocardium. But these studies were statistically underpowered and had many confounding factors. In a sub-analysis of the STICH (Surgical Treatment for Ischemic Heart Failure) trial, 601 patients underwent a viability study before revascularization; about half received optimal medical therapy with CABG, and half received optimal medical therapy only. The arm with CABG and medical therapy had lower mortality, but it was statistically insignificant.[2] 

The STICH trial additionally showed that the increase in ejection fraction was more in patients with viable myocardium. Still, this increase was similar in both CABG with medical therapy and medical therapy-only groups. PARR-2 (FDG-PET assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial) study showed PET viability imaging did not demonstrate survival benefits with revascularization compared to medical therapy.[21] 

The most important benefit mechanism from revascularization may be an improvement in ejection fraction and prevention of future coronary events, as the patients who benefitted most in the STICH trial were those with multivessel disease and severely reduced ejection fraction.[22] 

The benefits of CABG can be extrapolated from survival benefits to improving quality of life and exercise tolerance in patients with ischemic cardiomyopathy.[23] The revascularized myocardium is electrically stable and less likely to be a source of malignant ventricular arrhythmias.

Prognosis

It is essential to diagnose hibernating myocardium in patients with ischemic cardiomyopathy because symptoms of chronic LV dysfunction may not always be from necrotic and scarred myocardium from previous MIs, but rather from reversible ischemia. Hibernating myocardium may be the predominant etiology of chronic heart failure in patients with a history of known or suspected coronary artery disease, and the degree of cardiac dysfunction may not be solely accounted for by previous MIs.

The prognosis of ischemic cardiomyopathy with scarred myocardium due to previous MIs is dismal, and ventricular assist devices and cardiac transplant may be the only alternatives ultimately.[8] However, the prognosis of patients with hibernating myocardium presenting as chronic heart failure may be better with revascularization. ACC/AHA recommends myocardial viability testing in chronic ischemic cardiomyopathy with Class IIa level of recommendation (LOR).

Complications

Untreated myocardial dysfunction may lead to: 

• End-stage heart failure
• Multi-organ failure
• Heart failure hospitalization
• Arrhythmia hospitalization
• Sudden cardiac death
• Need for device-based therapy/left ventricular assist devices.
• Need for cardiac transplantation