Author + information
- Received April 12, 2016
- Revision received July 7, 2016
- Accepted July 12, 2016
- Published online October 18, 2016.
- James Wever-Pinzon, MDa,
- Craig H. Selzman, MDa,b,
- Greg Stoddard, MPH, MBAa,
- Omar Wever-Pinzon, MDa,
- Anna Catino, MDa,
- Abdallah G. Kfoury, MDa,
- Nikolaos A. Diakos, MDa,b,
- Bruce B. Reid, MDa,
- Stephen McKellar, MDa,b,
- Michael Bonios, MD, PhDa,
- Antigone Koliopoulou, MDa,
- Deborah Budge, MDb,
- Aaron Kelkhoff, MDa,
- Josef Stehlik, MDa,
- James C. Fang, MDa and
- Stavros G. Drakos, MD, PhDa,b,∗ ()
- aUtah Transplantation Affiliated Hospitals Cardiac Transplant Program, University of Utah Health Sciences Center, Intermountain Medical Center, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah
- bUniversity of Utah Molecular Medicine Program, Salt Lake City, Utah
- ↵∗Reprint requests and correspondence:
Dr. Stavros G. Drakos, Division of Cardiovascular Medicine, University of Utah, 15 North 2030 East, Room 4420, Salt Lake City, Utah.
Background Small-scale studies focused mainly on nonischemic cardiomyopathy (NICM) have shown that a subset of left ventricular assist device (LVAD) patients can achieve significant improvement of their native heart function, but the impact of ischemic cardiomyopathy (ICM) has not been specifically investigated. Many patients with acute myocardial infarction are discharged from their index hospitalization without heart failure (HF), only to return much later with overt HF syndrome, mainly caused by chronic remodeling of the noninfarcted region of the myocardium.
Objectives This study sought to prospectively investigate the effect of ICM HF etiology on LVAD-associated improvement of cardiac structure and function using NICM as control.
Methods Consecutive patients (n = 154) with documented chronic and dilated cardiomyopathy (ICM, n = 61; NICM, n = 93) requiring durable support with continuous-flow LVAD were prospectively evaluated with serial echocardiograms and right heart catheterizations.
Results In patients supported with LVAD for at least 6 months, we found that 5% of subjects with ICM and 21% of subjects with NICM achieved left ventricular ejection fraction ≥40% (p = 0.034). LV end-diastolic and end-systolic volumes and diastolic function were significantly and similarly improved in patients with ICM and NICM.
Conclusions LVAD-associated unloading for 6 months resulted in a substantial improvement in myocardial structure, and systolic and diastolic function in 1 in 20 ICM and 1 in 5 NICM patients. These specific incidence and timeline findings may provide guidance in clinical practice and research design for sequencing and prioritizing advanced HF and heart transplantation therapeutic options in patients with ICM and NICM.
- cardiac recovery
- ischemic cardiomyopathy
- left ventricular assist device
- mechanical unloading
- myocardial function
- myocardial structure
Left ventricular assist devices (LVADs) are increasingly used in the management of patients with advanced heart failure (HF) nonresponsive to traditional therapeutic modalities, as a bridge to transplant or as permanent therapy (1). LVADs improve symptoms, exercise tolerance, quality of life, and survival in this population. Furthermore, the intriguing observation that some patients with advanced chronic HF undergoing LVAD support can experience reverse remodeling and significant improvement of myocardial function suggests that LVAD-associated mechanical unloading of the failing heart may be a plausible therapeutic strategy aimed at myocardial recovery and device removal, avoiding the need for heart transplantation (2–6).
The availability of myocardial tissue collected at the time of LVAD implantation and explantation has allowed characterization of individuals who experienced significant recovery of myocardial function during mechanical unloading. The genetic, molecular, cellular, and structural bases of this observed phenomenon are now being unveiled (7–10). However, the optimal approach to prospectively identify patients who would benefit from elective LVAD insertion as a bridge to recovery remains unknown. The impact of the etiology of HF on the potential for myocardial recovery is not well understood. The field has primarily focused on patients with nonischemic cardiomyopathy (NICM), reasoning that patients with chronic ischemic cardiomyopathy (ICM) would have experienced irreversible scarring following myocardial infarction (MI) that would hamper their chances for recovery. However, a large number of patients with acute MI, even some with large anterior wall MI, are discharged from their index hospitalization without HF symptoms to return later with overt HF syndrome, mainly caused by chronic remodeling of the noninfarcted regions of the myocardium (11,12).
A few studies suggested a low incidence of myocardial recovery in ICM (13,14), but lack a pre-specified protocol to monitor for structural and functional changes serially. We aimed to prospectively evaluate the effect of mechanical unloading on myocardial structure and function in a large cohort of patients with chronic end-stage cardiomyopathy supported with continuous-flow LVADs, and to assess the effects and natural history of mechanical unloading on patients with ICM in relation to patients with NICM using a serial and systematic approach.
Patients with end-stage cardiomyopathy who underwent implantation of a continuous-flow LVAD as a bridge to transplant or as destination therapy between 2008 and 2014 at the institutions comprising the Utah Transplantation Affiliated Hospitals Cardiac Transplant Program (i.e., University of Utah Health Science Center, Intermountain Medical Center, and the Veterans Administration Salt Lake City Health Care System) were enrolled after obtaining informed consent. Patients with acute forms of HF, defined by symptoms <3 months of duration with no evidence of LV dilation, were prospectively excluded. Subjects with hypertrophic or infiltrative cardiomyopathies were also excluded from this study. The study was approved by the institutional review board of the participating institutions.
Chronic ICM was defined as a left ventricular ejection fraction (LVEF) <40% and any of the following: 1) a history of MI or revascularization; 2) a history of angina or chest pain and evidence of scarring in noninvasive imaging studies corresponding to previous MI; 3) presence of ≥75% stenosis of the left main or proximal left anterior descending artery; or 4) presence of ≥75% stenosis of ≥2 epicardial vessels in a patient with unexplained cardiomyopathy. Patients with a LVEF <40% and nonobstructive coronary artery disease without evidence of prior MI or revascularization were considered to have NICM.
Medical management was at the discretion of the treating physicians within the Utah Transplantation Affiliated Hospitals Cardiac Transplant Program. The use of beta-blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists (i.e., standard HF drug therapy) after device implantation was encouraged.
Clinically relevant data were collected within 1 week preceding LVAD implantation. Right heart catheterization was performed within 1 week preceding LVAD implantation and within 6 to 8 weeks after implantation to document adequacy of left ventricular pressure unloading. As per our clinical protocol, cardiac resynchronization therapy was discontinued in all study subjects.
Before patients were discharged home, the effect of LVAD unloading on cardiac size, shape, and function was assessed by echocardiography. The device speed was adjusted to achieve adequate flows and optimal LV and right ventricle decompression with positioning of the interventricular and interatrial septa in the midline plus minimum mitral valve regurgitation. Aortic valve opening was desirable but considered of lower priority compared with the conditions outlined previously. Subsequent adjustments of the speed were made as indicated by patients’ symptoms or clinical events.
Assessment of cardiac recovery
Surveillance for functional recovery was undertaken using a protocol developed and tested at the Utah Cardiac Recovery Program (15). Briefly, we performed transthoracic echocardiograms within 2 weeks preceding LVAD implantation, and then at months 1, 2, 3, 4, 6, 9, and 12 after implantation. Echocardiographic measurements were made at full and reduced support or turn-down study (30 min after reducing speed to the lowest recommended by manufacturer). Turn-down studies were not performed in patients with a history of stroke, transient ischemic attack, LVAD thrombosis, hemolysis, or with subtherapeutic international normalized ratio. Complete 2-dimensional, M-mode, and Doppler images were recorded from standard views in accordance with current American Society of Echocardiography guidelines (16,17), and as we previously described (15).
Standard summary descriptors were used (e.g., frequencies, percentages, and means). Measures of variation were presented in the form of SD and SEM. Patient characteristic comparisons between ICM and NICM groups were made with a chi-square test or Fisher exact test, as appropriate for unordered categorical variables, with a Wilcoxon-Mann-Whitney test for ordered categorical variables, and with an independent sample Student t test for continuous variables.
For the comparison between groups, the primary outcome was defined as LVEF at 6 months post-LVAD, based on our previous results where peak of functional improvement after LVAD implantation was achieved at 6 months (15). All other outcomes and time points are secondary comparisons. In this primary-secondary framework, there is no need to apply a multiple comparison procedure to adjust the p values, because only 1 comparison is required (18,19).
Separately, for each of the ischemic and nonischemic patients, to describe changes from baseline to specific follow-up times, we used a paired sample Student t test. Because they are secondary endpoints describing the natural history of improvement, no adjustment for multiple comparison was made.
To estimate the effect size of the etiology of the cardiomyopathy on the chances for experiencing meaningful recovery of cardiac function during LVAD support, we created an operational definition of sustained recovery where all of the following conditions needed to be met: the presence of 2 or more consecutive post-LVAD LVEF ≥40% at any follow-up time, and no LVEF <40% after the initial LVEF ≥40%. To adjust for confounding, we performed a propensity score analysis in 2 steps. In the first step, we used 9 potential confounders (age at LVAD implantation, body mass index, diabetes mellitus, history of hypertension, LVAD indication, baseline LVEF, left ventricular end-diastolic dysfunction [LVEDD], serum sodium, and creatinine levels). We identified these variables through analysis of pre-LVAD baseline characteristics of both groups as predictor variables for ischemic status in a multivariable logistic regression, using an interactive backward variable selection until 6 of these variables confounders remained in the model with p < 0.20. The predicted probability of ICM status was obtained from this logistic model to represent the propensity score. In the derivation of the propensity score, we used hotdeck imputation of missing values, as 1 variable (LVEDD) was missing 6.5% of its values, 2 variables were missing 4.5% of their values (serum sodium and creatinine levels), and the remainder missing either 1 or 2 values. In the second step, we fit a logistic regression model with sustained recovery as the outcome (1 = recovered; 0 = not recovered), ischemic status as the primary predictor, and the propensity score as a covariate.
All analyses were performed using STATA software version 14 (StataCorp LP, College Station, Texas).
Characteristics of patients before LVAD implantation
A total of 169 patients underwent LVAD implantation during the study period. We prospectively excluded subjects with acute forms of HF, including acute MI, acute myocarditis, and post-cardiotomy cardiogenic shock (n = 13). By doing so we eliminated a group of patients with a likely higher propensity for natural cardiac recovery. We also excluded 2 patients with hypertrophic and infiltrative cardiomyopathies. The remaining 154 subjects with chronic advanced cardiomyopathy were prospectively enrolled after obtaining informed written consent. The baseline characteristics of patients with ICM and NICM at the time of LVAD implantation are shown in Table 1. The ICM group was older (mean age, 63 vs. 52 years) and had a significantly higher prevalence of diabetes and hypertension when compared with the NICM group. As expected, given our inclusion and exclusion criteria, both groups had long duration of HF symptoms and LV dilation. The mean duration of symptoms was 7 years in the ICM group and 6 years in the NICM group (p = 0.48). The mean LVEDD was 6.5 cm in the ICM group and 7.0 cm in the NICM group (p < 0.01). There was no significant difference between groups in terms of severity of HF symptoms, use of temporary mechanical support, or LVAD indication.
Hemodynamic and biochemical profile of subjects before LVAD implantation
Table 2 shows invasive hemodynamic data and biochemical data of ICM and NICM groups before LVAD implantation. There were no significant differences between groups in terms of baseline hemodynamic or biochemical profile. Both groups had elevated right and left heart filling pressures, blood urea nitrogen, creatinine, and total bilirubin.
Degree of LV mechanical unloading and drug therapy post-LVAD implant
Table 2 shows invasive, hemodynamic, and echocardiographic data 2 months after LVAD implant. There were no significant differences in the degree of LV unloading achieved early post-LVAD between the ICM and NICM groups, as demonstrated by similar filling pressures, cardiac index, and aortic valve opening. Also, there was no significant difference between groups in the proportion of patients receiving axial versus centrifugal continuous-flow pumps (Online Table 1).
A similar proportion of patients with ICM and NICM were treated with beta-blockers (51% vs. 59%; p = 0.31), angiotensin-converting enzyme inhibitors (28% vs. 41%; p = 0.10), and angiotensin receptor blockers (7% vs. 13%; p = 0.21). Fifty percent of patients with NICM and 33% of patients with ICM were treated with aldosterone antagonists during LV mechanical unloading (p = 0.03). There was no significant difference between groups in the proportion of patients treated with combined renin-angiotensin-aldosterone system inhibition (i.e., concomitant administration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonist, either all 3 concomitantly or 2 of the 3 drugs) or in the proportion of patients treated with other vasodilators.
Effects of LVAD unloading on structure and systolic function
Table 3 shows the time course and magnitude of the changes in structure and function in patients with ICM and NICM during LVAD mechanical unloading. Overall, LVEF significantly increased from 20% to 24% by 6 months in the ICM group (p = 0.03), and from 17% to 27% by 9 months in the NICM group (p < 0.01). The LV end-diastolic and end-systolic volumes decreased significantly in both groups as early as 30 days after LVAD implantation. LV mass index also decreased in both groups, from 133 g/m2 in the ICM and 135 g/m2 in the NICM groups at the time of implant to 92 and 95 g/m2 at 1-year after implant, respectively (p < 0.01 for both comparisons). This change was also evident as early as 30 days after LVAD implant. Notably, this decrease was not beyond the normal LV mass index reference range (43 to 115 g/m2) (15), a finding that might have suggested hypertrophy regression to the point of myocardial atrophy.
Adjusted for baseline LVEF, the maximum LVEF reached during the post-LVAD follow-up in the ischemic group (adjusted mean, 25%; 95% confidence interval [CI]: 22% to 28%) and in the nonischemic group (adjusted mean, 28%; 95% CI: 25% to 30%) were not significantly different (p = 0.14).
Effect of LV unloading on diastolic function
Table 4 shows the serial changes in diastolic function echocardiographic parameters. After LVAD implantation, a significant and sustained decrease in left atrial volume index occurred in patients with ICM and NICM. Improvement of the restrictive filling pattern present at baseline in both groups occurred gradually, achieving normalization of the E/A ratio and E wave deceleration time at 4 months post-LVAD. Both groups experienced significant improvement in septal E’ and decrease in the septal E/E’ ratio after LVAD implantation that was sustained during the follow-up period.
Assessment of function during increased loading conditions
Echocardiographic parameters were also recorded during serial turn-down echocardiograms. Decrease of the LVAD speed resulted in reduced flow through the LVAD and increased LV loading. The increased loading was confirmed by our assessment of aortic valve opening during the turn-down echocardiographic studies. During full LVAD support, the aortic valve opened rarely, whereas during the LVAD turn-down examinations, the aortic valve opened with every beat. The improvement in LV structure and systolic function was sustained in the ICM and NICM groups under increased loading conditions during turn-down echocardiographic studies and is described in detail in Online Table 2. Similarly, the improvement in the diastology observed in both groups was sustained during increased LV loading conditions induced during turn-down echocardiographic studies (Online Table 3).
Effect of duration of LVAD unloading
Taking into consideration that, as shown in Table 3, the peak of improvement of myocardial function in our cohort occurred approximately at 6 months, we examined the incidence of cardiac recovery in the subset of LVAD patients who completed at least 6 months of LVAD unloading, excluding patients with shorter duration of support that could have been considered inadequate to attest the full effects of mechanical unloading (Figure 1). In this analysis, 5% of subjects with ICM and 21% of subjects with NICM supported with LVAD for 6 months or more achieved a LVEF ≥40% (p = 0.034).
We also compared the LVEF of both groups at different time points, adjusting for their baseline differences using a regression model. Figure 2 shows the absolute LVEF increase from baseline in both groups at each time point. Numerically, the NICM group showed a higher degree of LVEF improvement at all time points; however, the difference did not achieve statistical significance at 6 months post-LVAD in this analysis.
Effect of time from index MI to LVAD implant
We identified 3 groups of patients with ICM based on the duration of time from their index MI to the date of LVAD implant: <2 years (group 1, n = 7), 2 to 10 years (group 2, n = 11), and ≥10 years (group 3, n = 23). The mean highest LVEF achieved by each group was 26% in group 1, 28% in group 2, and 26% in group 3 (p = 0.82). Mean ages were 60.4 years, 63.2 years, and 64.2 years in the 3 groups, respectively (p = 0.89). There was no significant difference between groups regarding pre-LVAD LVEF (mean LVEF: 22% in group 1, 21% in group 2, and 19% in group 3; p = 0.58). There were no differences between groups regarding severity of symptoms at baseline (p = 0.32) and Interagency Registry for Mechanically Assisted Circulatory Support profile (p = 0.16).
Patients with greatest systolic functional improvement
In the group of patients with NICM that achieved an LVEF ≥40% (n = 15) during the follow-up period, mean pre-LVAD LVEF was 19% and mean pre-LVAD LVEDD was 6.4 cm. Ten subjects had idiopathic dilated cardiomyopathy, 3 had chemotherapy-induced HF, and 2 had peripartum cardiomyopathy. Seventy-four percent of subjects had New York Heart Association functional class IV symptoms and 2 required extracorporeal membrane oxygenation support before LVAD implant. Bridge to transplant was the LVAD indication in 13 (87%) patients. Compared with the rest of the patients (that did not respond with improving their LVEF ≥40%) we found that the responder patients were younger (37.1 vs. 54.9 years; p < 0.01) and had shorter duration of HF symptoms (1.6 vs. 7.2 years; p < 0.01).
In the group of patients with ICM that achieved an LVEF ≥40% (n = 4) during LVAD mechanical unloading, mean age was 68.2 years, mean duration of HF symptoms was 5.9 years, mean pre-LVAD LVEF was 27%, and mean pre-LVAD LVEDD was 6.0 cm. Two patients had New York Heart Association functional class III symptoms and none of them required temporary mechanical circulatory support as a bridge to LVAD. Three of these subjects had their LVAD implanted as a bridge to transplant.
Incidence of sustained recovery
When we focused on those subjects that met our operational definition of sustained recovery (see Statistical Analysis section), we found that 11 patients from the NICM group and 5 from the ICM group showed sustained recovery during our follow-up period. The ICM was less likely to experience sustained recovery than the NICM (unadjusted odds ratio: 0.67; 95% CI: 0.22 to 2.04; p = 0.49), although the difference did not reach statistical significance, even after adjusting for covariates with a propensity model (odds ratio: 0.77; 95% CI: 0.22 to 2.69; p = 0.68).
Impact of study design on reported LVAD-induced cardiac improvement outcomes
The extremely low incidence of cardiac recovery observed in retrospective studies (3,20–24) and post hoc queries of large multicenter LVAD trials and registries (i.e., original study design focused on other indications, such as bridge-to-transplant/destination therapy) (1,13,25) versus the higher incidence observed in prospective studies with a specific bridge-to-recovery study design (2,4–6,15,26–32) has created confusion in the field. The results of these different types of studies have been recently grouped together and analyzed (33). The differences in the incidence of cardiac recovery between these different categories of studies should have been anticipated, especially when the investigation of the LVAD bridge-to-recovery phenomenon requires a battery of diagnostic and therapeutic protocols (also analyzed in reference ). Specifically, most programs included in national LVAD registries and multicenter trials do not have an LVAD bridge-to-recovery research program because of other research priorities in those institutions. Therefore, those programs do not include their LVAD patients in research protocols to: 1) serially assess the function of the mechanically unloaded heart; 2) use aggressive adjuvant antiremodeling pharmacological therapy that may have synergistic effects with hemodynamic unloading; or 3) standardize the criteria to define myocardial recovery/LVAD explantation (10,33). In most advanced HF centers for a bridge-to-transplant or destination therapy patient who is doing well as an outpatient, clinicians usually do not focus on the potential for cardiac recovery unless the patient is experiencing a serious LVAD complication (e.g., pump thrombosis, infection) in hopes of a potential device explantation. Therefore, most centers report near zero cardiac recovery rates, and the fact that the observed overall bridge-to-recovery rate in multicenter registry and trial datasets is dismal, at around 1%, is quite understandable. For all of these reasons, we think that studies based on multicenter trials and registry data (e.g., United Network for Organ Sharing and Interagency Registry for Mechanically Assisted Circulatory Support) focused on other LVAD indications, such as bridge-to-transplant or destination therapy, are inherently flawed in their capacity to accurately evaluate the incidence of LVAD-induced cardiac recovery (and to reliably investigate this phenomenon) and we should avoid using them to derive conclusions about its incidence (10,33). The prospective design of our study and the use of serial post-LVAD hemodynamic and echocardiographic monitoring allowed us to more accurately assess the time course and the true incidence of myocardial functional and structural improvement in ICM and NICM. We also observed that the improvement in myocardial function was not an “all or none” phenomenon but rather a continuum, similar to other biological phenomena.
Impact of HF etiology on recovery
The effect of HF etiology on the potential for reverse remodeling and improvement of myocardial function during mechanical unloading with a long-term LVAD is not completely understood. A limited number of studies have directly compared patients with LVAD with ICM and NICM. Most of those studies were lacking prospective cardiac functional assessment protocols and also they were focused on myocardial tissue and molecular changes but not on myocardial functional outcomes (13,26,34–37).
Importantly, the rate of cardiac improvement in patients with NICM reported in our study (21% in the patients with NICM that were supported for at least 6 months) is consistent with the NICM recovery/LVAD explantation rate reported in the largest reported bridge-to-recovery series. In this work from the Berlin Heart Center, recovery/LVAD explantation rate of 24.4% was reported in a group of 131 patients with NICM (28). The clinical features of the patients with NICM that experienced improvement of LVEF >40% in our study (younger age and shorter duration of HF symptoms) were factors that have also been previously reported to predict functional recovery during LVAD mechanical unloading (13,14,28).
Compared with NICM, patients with ICM are typically considered to have a worse “substrate” for LVAD-induced myocardial recovery because of extensive LV scarring. However, a large number of patients with acute MI, even some with large anterior wall MI, are discharged from their index hospitalization without HF symptoms, only to return later with overt HF syndrome caused by chronic remodeling of the noninfarcted regions of the myocardium, and without a new MI (11,12). It has also been suggested that although in ICM the initial insult to the myocardium is usually well recognized and limited, in NICM the process leading to progressive ventricular remodeling and HF remains uncertain and most likely persists despite an initial improvement, and this process might recur after termination of LVAD support (27,28). Our study suggests that although a greater number of patients with NICM tended to achieve significant myocardial improvement (LVEF >40%), both patients with NICM and ICM have the potential for significant recovery with chronic mechanical unloading (Central Illustration). We therefore propose that patients with ICM who have experienced MI and have large areas of noninfarcted myocardium that remodeled over time could also be considered candidates for myocardial recovery protocols (27). This concept deserves further investigation and could combine the excision of scarred myocardium, using LV reconstruction techniques (e.g., Dor operation), with LVAD unloading. It can be argued that with this approach the initial insult that triggered the cascade of cardiac remodeling progression (i.e., the post-MI scar) has been eliminated (27).
Interestingly, the subset of patients with ICM with the highest functional response in our study were not younger and did not have shorter time from index MI to LVAD implant or shorter duration of HF symptoms (as found for the patients with NICM). We believe improvement of myocardial function in ICM may depend on other factors. For example, up to 50% of patients with advanced ICM have hibernating myocardium (38–42), but do not undergo revascularization for several reasons. LVAD support in this population offers a stable platform to test the viable and jeopardized myocardium at risk as a potential therapeutic target to induce reverse remodeling and myocardial recovery. Although we could not establish a relationship between functional improvement and viability/hibernating myocardium at baseline, the number of patients with ICM that had viability testing before LVAD implant was small (less than one-third) and this is a limitation of our study. Prospective studies with pre-specified protocols to test for viability before and after LVAD implant maybe warranted.
Impact of duration of LVAD unloading
Our study showed that peak LVEF in ICM and NICM subjects is achieved approximately 6 months after LVAD implantation (Central Illustration). These findings suggest that, just as many other cardiac-specific therapies need a reasonable amount of time before exerting their curative effect, a critical duration of mechanical unloading may be necessary to induce reverse remodeling and functional improvement. Translational LVAD studies have also attempted to identify this optimal time when maximal potentiation of myocardial recovery occurs (26,43,44). In comparison with those studies the peak of recovery in our study was achieved later during mechanical support and with no sign of regression subsequently. However, it is likely that the optimal duration of mechanical support may vary among patients, because it could be affected by underlying patient characteristics (e.g., age, duration of HF symptoms, HF etiology, comorbidities) or even device characteristics (pulsatile vs. continuous flow, centrifugal vs. axial flow, and so forth). This argument could explain individual variations in the time to highest LVEF achieved after LVAD support within a single study. A long-standing question directly related to the sustainability of LVAD-induced cardiac improvement is whether prolonged LVAD unloading induces regression of cardiac hypertrophy to the point of atrophy and degeneration. Our results show that the LV mass decreased in ICM and NICM with continuous-flow LVAD unloading, but remained within the normal reference range during the 1-year follow-up period. These findings are in agreement with our prior findings that demonstrated no histological, microstructural, molecular, and metabolic evidence of induced atrophy in an LVAD population (45).
The reliability of LVAD turn-down studies to predict long-term sustainability of myocardial recovery (e.g., after device explantation) has not been established and as such this is a limitation of our study. The protocol to induce increased loading conditions on the LV used in our study is similar to published protocols used in bridge-to-recovery LVAD studies that led to sustained myocardial recovery post-LVAD explant (2,4,28). In the largest series reported so far this protocol was associated with a 5-year freedom of HF recurrence of 69% (28). More importantly, our findings that during LVAD turn-down studies some failing human hearts can substantially improve in structure and function, whereas other similarly sick hearts undergoing the same LVAD chronic unloading do not show any improvement, strongly suggest that the observed reverse remodeling and structural and functional improvement during mechanical unloading is a real phenotype (and not a universal acute phenomenon attributed to the acute removal of load). These results invite further clinical and translational investigations that could significantly advance the field of cardiac recovery.
The number of observations at each pre-specified time point decreased gradually as subjects got transplanted or as some died from their disease or complications. Online Table 4 shows the frequencies of fatalities and heart transplants. To reduce the impact of a decreasing number of individuals, either because of death of “sicker” patients or because of heart transplantation in the healthier subset, we studied changes in the outcome variables from baseline to specific time points using paired sample Student t test analysis. In addition, we reported on and emphasized the outcomes of the subset of patients that was supported with a LVAD for at least 6 months.
Our study did not assign LVAD patients to standard HF drug therapy versus no HF drug therapy so we cannot reliably determine the contribution of medical therapy during LVAD support to the observed degree of cardiac improvement (randomizing LVAD patients to no HF drug therapy would have been inappropriate given the current national and international HF and mechanical circulatory support guidelines). However, a similar proportion of patients with ICM and NICM were treated with beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers or their combination. We did not include the average dose of medications in each group and this is a limitation of our study.
Our research protocol did not include routine cardiopulmonary testing in this population and, therefore, we cannot correlate structural and functional changes with exercise response and peak oxygen consumption.
In a significant subset of patients with NICM and a smaller subset of patients with ICM, continuous-flow LVAD unloading induced early improvement in myocardial structure and systolic and diastolic function. These improvements plateaued after approximately 6 months of support with no evidence of subsequent improvement regression. Future studies are needed to prospectively investigate which characteristics specific to ICM (myocardial scar size, viability, or others) and NICM can help predict durable cardiac recovery after device explantation. In addition, considering that the observed improvement was induced in patients with end-stage cardiomyopathy, these prospective findings demonstrate the clinical and translational potential of the field of mechanical unloading and cardiac recovery for the broader, less ill HF populations.
COMPETENCY IN MEDICAL KNOWLEDGE: The improvement of myocardial function after mechanical unloading in patients with end-stage heart failure is not restricted to nonischemic cardiomyopathy, but also occurs in those with chronic ischemic cardiomyopathy.
TRANSLATIONAL OUTLOOK: Future research should explore the mechanisms by which mechanical unloading enhances cardiac recovery in patients with end-stage ischemic cardiomyopathy.
For supplemental tables, please see the online version of this article.
This work was funded by the American Heart Association CVGPS Discovery Grant (15CVGPSD27690000, to Dr. Drakos), the Doris Duke Foundation Clinical Scientist Development Grant (7/2013, to Dr. Drakos), National Institutes of Health National Center for Research Resources grant that supports the Center for Clinical Translational Sciences (UL1-RR025764 and C06-RR11234 to Drs. Drakos and Kfoury), Deseret Foundation/Intermountain Research and Medical Foundation (00571, to Drs. Drakos and Kfoury), and the American Heart Association HF Strategically Focused Research Network - Clinical Project 1 (to Dr. Drakos). Dr. Stehlik has received research support from St. Jude Medical; and speaker honoraria from St. Jude Medical and Heartware. Dr. Drakos has received research support from Abiomed; and is a consultant for Heartware. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- confidence interval
- heart failure
- ischemic cardiomyopathy
- left ventricle
- left ventricular assist device
- left ventricular end-diastolic diameter
- left ventricular ejection fraction
- myocardial infarction
- nonischemic cardiomyopathy
- Received April 12, 2016.
- Revision received July 7, 2016.
- Accepted July 12, 2016.
- American College of Cardiology Foundation
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