Ischemic heart disease affects 1.7% of the global population and is the leading cause of death in many national statistics across genders, accounting for 9 million deaths annually worldwide. Among its diverse presentations, we focus here on ischemic dilated cardiomyopathy. This condition entails a reduction in the left ventricular ejection fraction (EF) alongside a process of myocardial remodeling that underlies ventricular dysfunction, predisposition to ventricular arrhythmias, and functional mitral valve impairment.

Ventricular remodeling has been described as an ongoing histological phenomenon occurring asynchronously across various myocardial territories. This process, underpinned by ischemia as an imbalance between metabolic demands of viable myocardium and the oxygen and nutrient supply from coronary circulation, leads to degenerative changes. Myocardial oxygen extraction from coronary blood flow is nearly maximal, so the primary means of adjusting supply to meet stress-related demands is through increased coronary blood flow, largely mediated by epicardial vessel vasodilation (nitric oxide-mediated) and precapillary coronary sphincter dilation. When these compensatory mechanisms are insufficient, ischemia occurs. Although microvascular pathology coexists with atherosclerotic disease and endothelial dysfunction, significant epicardial vessel lesions primarily drive the resistance to blood flow and decrease perfusion to specific myocardial territories.

Ischemia’s effects manifest both chronically and as abrupt events known as acute coronary syndromes. Acute ischemia is well-known for its ECG sequence of ischemia-injury-necrosis, resulting in myocardial damage over a short period. Necrotic zones are replaced with electrically and mechanically dysfunctional fibrous tissue. Chronic ischemia leads to a gradual, microscopic process of sarcomere unit loss, similarly replaced by fibrous tissue. However, an intermediate, potentially recoverable state also exists, comprising stunned and hibernating myocardium. Stunned myocardium often occurs in the surrounding “penumbral” area around infarcted zones—a term borrowed from stroke terminology—where necrosis may extend unless revascularization, typically through primary angioplasty of the culprit lesion, is achieved. Once necrosis is contained, a surrounding stunned area may remain, potentially recoverable over time with restored circulation from the tributary vessel or collateral supply from adjacent territories. It is worth noting that coronary circulation is terminal, offering little cross-supply between territories upon acute occlusion. However, collateral circulation often develops when ischemic episodes evolve gradually.

Chronic presentation of potentially recoverable myocardium relates to hibernation, a cellular metabolic adaptation reducing contractile activity to balance requirements with a blood supply sufficient only to maintain viability. In the context of these simultaneous phenomena, the feedback effect of functional mitral regurgitation and volume overload, which increase ventricular diameters, must also be integrated. Neurohormonal responses, such as sympathetic tone increase and upregulation of beta-receptor expression and the renin-angiotensin-aldosterone axis, aim for short-term hemodynamic compensation but contribute to further myocardial degeneration over time. Indeed, the so-called “eccentric hypertrophy” of the left ventricle adapts to reduced EF, maintaining the same volume per minute through tachycardia and ejection from an enlarged ventricular cavity, despite each beat’s ejected percentage being lower than in a functionally normal heart. This enlarged heart, with increased blood volume, elevates ventricular pressures during diastolic filling (end-diastole), which may compromise myocardial perfusion and aggravate ventricular dysfunction and dilation. Tension forces (tenting) on the mitral valve during ventricular contraction may exacerbate mitral regurgitation. This process of hemodynamic deterioration continues in a steady decline, even without acute decompensation or ischemic events, which would only worsen the situation further. Mention should be made of the role of natriuretic peptides, which have long-term beneficial effects and represent therapeutic targets, such as sacubitril and SGLT-2 inhibitors, two major protagonists in modern pharmacotherapy.

Viability assessment has evolved through the proposal of four complementary studies, each providing unique perspectives on the same phenomenon; likely, a multimodal approach offers a closer approximation than any single test alone. Dobutamine stress echocardiography assesses contractile reserve, identifying viable zones (thick and contractile), non-viable zones (thin akinetic scars), and, to some extent, potentially recoverable zones (thick, hypocontractile or akinetic). Additionally, it can induce ischemia to complete the functional analysis. Another ischemia-inducing technique is PET, assessing myocardial metabolic function. However, discrepancies arise, as metabolic activity may suggest viability but not necessarily contractile improvement with dobutamine testing. The remaining two studies do not induce ischemia but instead provide better tissue resolution. SPECT evaluates cellular membrane integrity, disrupted in fibrotic zones, while MRI, the gold standard for ventricular function assessment, is especially valuable with gadolinium, enhancing myocardial perfusion and highlighting fibrotic, non-viable areas. Discrepancies can occur in potentially recoverable zones, where the crux of ventricular dysfunction-viability-revascularization resides.

Within this sea of ideas, various studies—discussed below—have shaped the classical paradigm in this patient subset. When viable myocardium is present, indicated by 4 or more ventricular segments (of 17), revascularization plus optimized medical therapy improves left ventricular function, prevents acute events (heart failure decompensation and ischemia), and enhances patient functional capacity and survival.

COMMENTARY:

Several observational studies have focused on myocardial viability’s role as a guide in therapeutic strategies, especially regarding coronary revascularization. Although outcomes varied, data aggregation in some meta-analyses indicated that viable myocardium correlates with a nearly 80% reduction in annual mortality post-revascularization. However, these studies often introduced biases due to retrospective design, protocol heterogeneity, and selective revascularization in patients with better viability. Confounding factors were not always adjusted for, and treatment options at the time of these studies were more limited than today.

Clinical trials began in 2000 and have continued into the current decade. The PARR-2 trial (2000–2004) enrolled 430 patients with EF <35%, assessing viability through PET. The HEART study (2002–2004) aimed for 800 patients but only enrolled 138 before premature termination, all with EF <35% and varied viability protocols. Both compared surgical revascularization with optimal medical therapy, showing no survival or major cardiac event benefits for revascularization guided by viability assessment.

The STICH trial (2002–2007) included 1212 patients with EF <35% and provided 10-year follow-up data. Revascularization reduced mortality compared to optimal medical therapy (58.9% vs. 66.1%; p = 0.02). This trial generated numerous sub-analyses, including one evaluating viability’s role in treatment allocation among 601 patients who underwent SPECT or dobutamine stress echocardiography, with no significant interaction observed. The trial coined the “4 of 17 segments” criterion for sufficient viability, which applied to nearly all patients analyzed. Additional STICH post-hoc analyses offered varying conclusions:

Patients with and without inducible ischemia on dobutamine stress echocardiography showed no survival differences at 5 and 10 years. Similarly, ischemia presence or extent did not affect cardiac events with surgical revascularization versus conservative management. EF improvement at 4 years was associated with viable myocardium, achievable with medical therapy rather than surgical revascularization. Increased remodeling, with worse EF and larger ventricular diameters, did not correlate with more frequent infarcts, though clinically, tolerance was lower in such cases due to reduced functional reserve. Revascularization reduced fatal infarcts and sudden death.

Following the STICH study’s initial impact (favoring surgical revascularization but not viability studies), new questions arose due to poorly designed post-hoc interpretations. These studies had limited statistical power, with inconsistent viability thresholds and imaging protocols. New pharmacologic therapies eventually rendered these studies obsolete until the Revived-BICS2 study (2013–2020). This trial randomized 700 patients with EF <35% to percutaneous revascularization versus optimal medical therapy, using modern agents. Viability assessment used dobutamine stress echocardiography or MRI, again requiring >4 viable segments for revascularization. However, with a median follow-up of 41 months, interventionism showed no survival benefit over medical therapy, nor did viability analysis significantly interact with treatment choice.

Thus, the authors question the classic paradigm, suggesting a new approach where viable territories and revascularization feasibility of tributary vessels must align. Only then might revascularization yield benefits for left ventricular function, cardiac events, and survival. However, this assertion remains speculative, as no study to date supports it. A new STICH study using current medical therapy would be invaluable, yet even the Revived-BICS2 study provides no interventional support. We argue that this view oversimplifies surgical revascularization and underestimates the potential for myocardial recovery previously discussed. Surgical revascularization promotes collateral formation and offers the best option for suitable patients, particularly those needing additional procedures (mitral valve repair/replacement) and/or with diabetes. Indeed, this new paradigm seems based on two flawed assumptions:

The Revived-BICS2 study focused on interventionism, where vessel viability mismatch may occur, as closed vessels might prevent complete revascularization. However, this limitation does not apply to coronary bypass surgery. The SYNTAX study established the concept of complete revascularization, showing that clinical benefit requires comprehensive revascularization. The ISCHEMIA trial, previously discussed in the blog, had inappropriate conclusions extrapolating medical versus interventional results to all revascularization, disregarding surgery’s unique advantages, which were underrepresented in the invasive cohort.

Ultimately, we still lack clarity on viability studies’ role and surgical revascularization’s advantage over optimal medical therapy. Until new evidence emerges, a win-win strategy—complete revascularization plus advanced medical therapy—appears to offer the best prognosis for these patients.

REFERENCE:

Isath A, Panza JA. The Evolving Paradigm of Revascularization in Ischemic Cardiomyopathy: from Recovery of Systolic Function to Protection Against Future Ischemic Events. Curr Cardiol Rep. 2023 Oct 24. doi: 10.1007/s11886-023-01977-5.