Reverse Remodeling in Infarct Cardiomyopathy

Corresponding Author

Heart failure–associated cardiogenic shock remains a morbid condition with mortality rates of 30% to 50%.¹ Temporary mechanical circulatory support device use is increasing as a bridge to transplant or recovery. There is growing evidence that high-capacity transvalvular pump use in patients with cardiogenic shock may improve outcomes.² However, the mechanisms underlying reverse remodeling and recovery are relatively unknown.

A current challenge in the field is a lack of consensus around the criteria defining ventricular reverse remodeling. Possible metrics include hemodynamic, structural, histopathologic, and cellular or molecular indexes.³ Myocardial recovery, rather, has largely been evaluated in the durable ventricular device space where, in some patients, goal-directed medical therapy can be reinitiated on support and the patient’s cardiomyopathy functionally recovered to such an extent that the ventricular assist device can be explanted. What hemodynamic and molecular mechanisms underlie this potential and whether this concept may translate to shorter-term unloading and temporary assist devices are relatively unknown and the subject of ongoing research.

In this issue of JACC: Basic to Translational Science, Meyns et al⁴ investigated whether 3 months of high-capacity transvalvular unloading induced reverse remodeling in a preclinical (ovine) model of dilated ischemic cardiomyopathy (ischemia-reperfusion injury via coronary ligation followed by 2 months of postinfarct remodeling).⁴ Animals with left ventricular ejection fraction ≤35% and left ventricular dilation were then randomized to sham or transvalvular pump implantation for 3 additional months. Reverse left ventricular remodeling was evaluated by invasive left ventricular pressure wire recordings, cardiac magnetic resonance imaging, and myocardial histopathologic analysis. After 3 months of unloading and immediately after removal of the transvalvular pump, left ventricular end-diastolic and -systolic volumes were reduced compared with sham control subjects.

In the remote (noninfarcted) left ventricle, there was an improvement in regional wall thickening, myocardial strain, and ejection fraction. The unloaded group also had less compensatory hypertrophy in the remote zone than sham control subjects. The authors concluded that 3 months of unloading induces favorable left ventricular remodeling in an ischemic cardiomyopathy model.

Overall, this study provides important novel mechanistic insight into the hemodynamic, functional, and pathologic observations associated with high-capacity transvalvular support in the subacute setting. Consistent with current understanding of the concept of transvalvular unloading, prolonged support reduced end-diastolic and -systolic left ventricular volumes.

However, that this is correlated with an improvement in the remote zone regional systolic function and reduction in cardiomyocyte hypertrophy, which could be potentially pathologic, is a novel finding. Notably, prolonged unloading initiated 2 months after infarction did not reduce infarct size relative to total left ventricular area, which is also consistent with prior reports that pre-emptive unloading (ie, before reperfusion) may be required to minimize ischemia reperfusion injury.⁵ Further interpretation of ischemic zone recovery is limited because several animals in this study required repeat coronary ligation and the relative area at risk was not evaluated.

Regarding hemodynamic effects, although left ventricular unloading has been previously shown to acutely reduce end-diastolic pressure,⁵ prolonged unloading at maximal pump flows did not significantly reduce end-diastolic pressure, potentially reflective of the wide variation in readings in control animals (6.3 ± 4.1 mm Hg vs 12.8 ± 12.7 mm Hg; P = 0.59). Additionally, though nonsignificant in the cohort analysis, immediately after pump removal the mean left ventricular end-systolic pressure in the unloaded group was 24-mm Hg lower than sham control subjects (61 ± 16 mm Hg vs 85 ± 12 mm Hg; P = 0.079), albeit with similar mean arterial pressures. Whether this translates to relative systemic hypoperfusion, may limit the ability to initiate goal-directed medical therapy and how to best wean off support once there is evidence of reverse remodeling is unknown.

The authors’ inclusion of regional wall stress as a remodeling target is intriguing. However, the interpretations must be cautioned given significant assumptions in the derivation of these values. Fundamentally, wall stress as a concept underlies our current pathophysiologic models of adverse remodeling; whether this also holds true for reverse remodeling is less clear.

Arts’ formula defines wall stress as directly proportional to left ventricular pressure and cavity volume and inversely proportional to wall volume. This relation is valid with the following assumptions: 1) presence of healthy ventricle muscle fibers; and 2) rotational symmetry where stress and strain are homogeneously distributed, thus allowing for approximation of fiber stress and strain by single values being valid for the whole wall.⁶ These assumptions are not valid for pathological states where there is regional variation in stress and strain, such as documented by imaging and deformational analysis in the current work. Thus, although relative changes between timepoints or differences in conditions are informative, accurate values of wall stress will differ from the values presented. On further inspection of Art’s formula, the finding of higher wall stress in the sham group depends not only on the larger cavity size in this group but also higher systolic pressures, as previously noted. This may be emphasized by the use of the remote end-systolic wall stress, whose effect appears to be primarily driven by lower left ventricular end-systolic pressure in the transvalvular pump group.

Given the dearth of data on mechanisms of remodeling and recovery in acute mechanical circulatory support, several important questions remain, including those highlighted by the authors. Additional hemodynamic and molecular evaluations are urgently needed, which are ideally suited for the preclinical setting. In particular, future studies must consider evaluation of ventricular energetics, including pressure-volume loop estimates of ventricular work, which is directly correlated to myocardial oxygen consumption.⁷ More detailed molecular and cellular pathway analysis evident in reverse remodeling and recovery must be elucidated. There is a need for new mitigation strategies for increasingly recognized adverse events associated with the use of mechanical circulatory support devices, ranging from ischemia to bleeding.² In the current study, in the unloaded group (n = 9), 3 pumps required revision (2 caused by primary pump issues including pump stop and pump failure) and 2 animals died (caused by postimplantation bleeding and unmonitored repeated suction events). Meyns et al⁴ suggest that temporary support devices may offer additional risk reduction compared with durable ventricular assist devices. A clear differentiator is the inability to leave the hospital with current temporary circulatory support technology, although there is significant untapped engineering potential anticipated in future.

What is the promise and challenge of temporary mechanical circulatory support in future clinical translation for ventricular remodeling and recovery? The investigations by Meyns et al⁴ and others are pushing the boundaries of our current scientific understanding of the mechanisms of unloading, which is a critical first step. Wider application of investigational and clinical use of quantitative indexes evaluating reverse remodeling on support throughout the disease course will be critical in advancing the science of recovery. For now, extension to other disease models, including volume overload and acute myocardial infarction cardiogenic shock, requires further investigation before translation of these concepts, as they are largely untested at these longer timescales of device use. Prospective investigations of temporary mechanical circulatory support to initiate goal-directed medical therapy and possibly facilitate myocardial remission and/or recovery are needed.

Funding Support and Author Disclosures

The author has reported that she has no relationships relevant to the contents of this paper to disclose.