Author + information
- Abdallah G. Kfoury, MD∗ ()
- ↵∗Address for correspondence:
Dr. Abdallah G. Kfoury, Intermountain Medical Center, 5121 South Cottonwood Street, LL1, Salt Lake City, Utah 84107.
Nearly 3 decades ago during my cardiology training in Salt Lake City, our young family would take regular weekend trips to national parks in Utah and neighboring states. These outings typically confined us to a small car for 4 to 6 h. No later than 30 to 45 min of being on the road, the predictable barrage of “how much longer?” and “are we there yet?” would come from our 2 little daughters in the back seat, who were somewhat indifferent to the breathtaking scenery outside. An assertive “we’re almost there” from the front seat would reinstate tranquility at least for the next little while. Almost, used at the time in its broadest possible sense was nebulous enough to allow for guilt-free parenting to carry on, and there was a clear-cut tangible destination.
The journey to cardiac recovery with mechanical unloading has been an evolution to behold. Initially intended for temporary use to bridge select patients with end-stage heart failure to transplantation, left ventricular assist devices (LVADs) were later applied as lifelong therapy. Today, that the failing human heart can have its function partially or fully restored with mechanical assistance enough to permit device removal is a reality that few would contest. However, the phenomenon of spontaneous or induced cardiac healing is not novel. The ability of the heart to overcome a variety of injuries is a daily occurrence in our cardiology practice; we see it following acute myocarditis or an ischemic insult, after a valve exchange, or after guideline-directed medical therapies in chronic systolic heart failure. Most of the time, it has become the expectation rather than the exception. It was in the early 1990s that clinicians and investigators started observing that unloading the left ventricle with mechanical support could be associated with myocardial recovery in humans and animal models. Small accounts of weaning and removal of LVADs from a handful of experienced centers ensued in the mid to late 1990s. This remarkable forward leap heralded the renaissance of the field. Explantations that were at first done out of necessity in patients with device complications are now planned as part of well-structured strategies. Small single-center observational anecdotes have made way for large prospective multicenter trials with rigorous protocols using the LVAD as a safety platform to deploy adjuvant therapies that enhance reverse remodeling and reconditioning of the heart and periphery. Concurrently, the preceding 20 years have witnessed a surge in the number and sophistication of published supportive data. The opportunity to explore full-thickness cardiac tissue at distinct timepoints in this journey from a failing heart (at LVAD implant) to transplantation and/or recovery (at LVAD explant) is truly unique to the field and has been a strong catalyst for progress. As a result, the realms of investigation have transitioned from the clinical arena to efforts directed toward changes in structure and ultrastructure, metabolism, and gene expression. On the other hand, quality of life and physical endurance have not to date been studied in depth.
In this issue of the Journal, Jakovljevic et al. (1) report on a multicenter cross-sectional study using cardiopulmonary exercise testing to evaluate cardiac and physical functional capacities in patients who had their LVAD explanted after a successful bridge-to-recovery protocol. The exercise performance of 16 such recovered subjects was compared with that of 18 patients with LVADs, 24 heart transplant candidates, and 97 healthy control subjects. The studied cohorts with an LVAD were consecutive patients from the investigators’ previously published studies. All recovered and explanted patients underwent a 2-step protocol of disease-altering pharmacological regimens. The first one, intended to enhance ventricular reverse remodeling, included an angiotensin-converting enzyme inhibitor, a nonselective β-blocker, a mineralocorticoid receptor antagonist, and an angiotensin receptor blocker, some at high doses. In the second step that came after echocardiographic evidence of left ventricular size reduction after LVAD, a selective β1-receptor blocker was substituted for the nonselective β-blocker, and the selective β2-agonist clenbuterol was added to promote reversal of atrophy in both cardiac and skeletal muscles. On transient minimal to no support, patients had to meet a number of structural, hemodynamic, and functional criteria before the LVAD was explanted. All patients completed a maximal graded metabolic exercise test. Vital signs, oxygen consumption (VO2), carbon dioxide production, minute ventilation, and cardiac output using the inert gas rebreathing method were continuously measured at rest and through peak exercise. Cardiac systolic function was denoted by peak cardiac power (the product of cardiac output and mean arterial pressure) and functional capacity by peak VO2. For ease of comparison, collected and/or computed data were also expressed as a percentage of the corresponding values from healthy control subjects. Except for a lower left ventricular ejection fraction (LVEF) in transplantation candidates, basic demographic and clinical properties were similar among the groups. All patients exhibited an adequate exertional effort (mean respiratory exchange ratio >1.10). In general, as a group, healthy individuals outperformed everyone else (peak cardiac power output: 5.35 W; peak VO2: 36.4 ml/kg/min). When compared in order, heart transplant candidates, and the LVAD implanted and LVAD explanted groups, a significant stepwise improvement in the indices of cardiac (peak cardiac power output: 1.31, 2.37, and 3.45 W, respectively; p < 0.05) and physical (peak VO2, 12.0, 20.5, and 29.8 ml/kg/min, respectively; p < 0.05) performance was observed. Of interest in these 3 groups, the extent of cardiac impairment appeared to exceed that of the physical limitation. Strikingly, 38% of LVAD explanted patients reached peak power cardiac output, and 69% reached peak VO2 values within those of the healthy control subjects.
The study has limitations, some inherent to its cross-sectional design. The noteworthy absence of women was not explained. Exclusion criteria pertaining to the ability to exercise might have introduced selection bias favoring fitter patients, and disclosure of the number of excluded patients from each group would have added depth to the study results. The duration of LVAD support in both implanted and explanted groups varied widely, but one particular observation raised a problematic question. In the context of the expected clinical characteristics of the studied population (chronic heart failure) and the recovery protocol involved, should not the LVAD explant that took place at 22 days have been excluded? While on support, the LVAD implant group had a surprising near-normal LVEF (range 45% to 68%) and it was not clear whether this was intentional. Was there an overlap in patients between the LVAD implant and explant groups, or did these seemingly recovered patients simply not meet the other criteria for explantation? If the latter is true, then LVAD explanted patients performed better even relative to the best LVAD implanted patients. A direct comparison with heart transplant recipients would have been a welcome addition, because transplantation has traditionally been regarded as the competing reference therapy. Despite the acknowledged shortfalls of their study, Jakovljevic et al. provided reasonably convincing evidence that a sizeable number of patients who had their LVADs explanted after recovery could attain cardiac and physical capacities near those of healthy individuals. This is not trivial. When pondering what determines acceptable benchmarks in the field, physical recovery has to be an imperative consideration in the general well-being of the patient.
As for the journey, it is well underway, but many questions are left unanswered. The divergence in reported rates of cardiac recovery after mechanical support needs to be reconciled, and large registries and incidental reports will not provide definitive answers. How is the propensity to recover influenced by heart failure etiology and duration before device implant? What extent and length of support are optimal for myocardial recovery? Can we identify patient characteristics that will reliably predict sustained recovery? More importantly, how will we, in the end, measure success? The field has made admirable strides in trying to complete that puzzle, and although many pieces are still missing, the picture is getting clearer. The impending results of the RESTAGE-HF (Remission from Stage D Heart Failure) trial (2) and the recent gathering of a working group at the National Heart, Lung, and Blood Institute (3) should help energize and advance the field. There, our ultimate destination should be to extrapolate what we learn in myocardial disease and recovery pathways with mechanical support to the broader heart failure population. Are we there yet? No, but almost.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Kfoury has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
- Jakovljevic D.G.,
- Yacoub M.H.,
- Schueler S.,
- et al.
- Birks E.J.,
- Rame E.,
- Patel S.,
- et al.
- ↵National Heart, Lung, and Blood Institute. NHLBI Working Group on Advancing the Science of Myocardial Recovery with Mechanical Circulatory Support. 2016. Available at: http://www.nhlbi.nih.gov/research/reports/nhlbi-working-group-advancing-science-myocardial-recovery-mechanical-circulatory-support. Accessed February 20, 2017.