Multiple trials and epidemiologic surveys have demonstrated that patients with ischemic cardiomyopathy (ICM) have decreased survival compared to patients with nonischemic dilated cardiomyopathy (NIDCM).1–5 Increased age, multivessel arteriopathy, potent neurohormonal stimulation, and arrhythmias associated with sudden death predispose patients with ICM to greater morbidity and mortality compared to patients with NIDCM.6–10
Myocardial response to left ventricular assist device (LVAD) therapy has been of particular interest. Left ventricular (LV) unloading is characterized by changes in proteomic expression with subsequent improvement in contractile functions of cardiomyocytes, normalization of LV geometry, and neurohormonal function,11–16 a process termed reverse remodeling. These changes are more likely to occur in the dysfunctional, yet viable, myocardium of patients with NIDCM. The observed improvement in LV function with LVAD therapy led to patients being explanted. Unfortunately, myocardial recovery at cellular and molecular level has not been associated with analogous bridge to recovery rates.
The effect that heart failure etiology may have on patients with continuous-flow LVADs as a bridge to transplantation (BTT) or destination therapy (DT) has not been fully investigated. The term NIDCM includes various subtypes of cardiomyopathy including idiopathic dilated, hypertrophic, restrictive, postpartum, and viral.17 From this group of NIDCM, LVADs at our institution were only implanted for idiopathic dilated cardiomyopathy (IDCM). Thus, the aim of our study was to compare outcomes following continuous-flow LVAD implantation between patients with ICM and NIDCM.
Our health system’s Institutional Review Board approved this retrospective study. We reviewed our institutions’ LVAD dataset and analyzed patients who underwent continuous-flow LVAD implantation as a BTT or a DT from March 2006 to February 2012. A total of 100 patients were identified and formed the cohort of this study. They received either HeartMate II (n = 93; Thoratec Corp., Pleasanton, CA) or HeartWare (n = 7; HeartWare Inc., Framingham, MA) LVADs. Patients were stratified into two groups (ICM and NIDCM) based on the etiology of heart failure. Stratification of ICM versus NIDCM was based on a history of angina or myocardial infarction, coronary angiography findings, and echocardiography results.
Patient demographics included age, gender, race, body surface area, body mass index (BMI), previous sternotomy, days in hospital prior to LVAD implantation, preoperative creatinine, liver function tests, and associated comorbidities—hypertension (HTN), diabetes mellitus, chronic renal insufficiency (CRI), dialysis, chronic obstructive pulmonary disease (COPD), and peripheral vascular disease (PVD). CRI was defined as glomerular filtration rate < 60 mls/min/m2. Operative characteristics analyzed were type of device (HeartMate II or HeartWare), cardiopulmonary bypass (CPB) time, and indication (BTT or DT). Hemodynamic and echocardiographic data included pre- and post-LVAD (at 1 and 6 months) central venous pressure, pulmonary artery (PA) pressure, pulmonary capillary wedge pressure (PCWP), LV ejection fraction (LVEF), cardiac output (CO), cardiac index, left ventricular end diastolic diameter and right ventricular end diastolic diameter (LVEDD/RVEDD), and mitral regurgitation and tricuspid regurgitation (MR/TR). Outcome variables were complications; postoperative survival at 1 month, 6 months, and 1 year; intensive care unit (ICU) and overall length of stay; transplantation; reoperation for aortic insufficiency (AI); readmission rates; and cause of death. Complications included reexploration for bleeding, driveline infections, pocket infections, pneumonia, right ventricular (RV) failure, postoperative right ventricular assist device (RVAD) implantation, dialysis, ventilator-dependent respiratory failure (VDRF), tracheostomy, hemorrhagic or ischemic stroke, and gastrointestinal bleeding (GIB). RV failure was defined as 1) need for inotropic support for more than 1 week, or 2) need for RVAD support. VDRF was defined as inability to wean from the ventilator for at least 1 week.
Patient Selection and Timing of LVAD Implantation
Timing of LVAD implantation relies heavily on the surgeon’s clinical judgment and experience. Patients in refractory heart failure (inotrope dependent, recurrent ventricular arrhythmias, worsening renal and hepatic function, and worsening hemodynamics and mental status) or cardiogenic shock are considered for LVAD implantation. Every effort is made preoperatively to optimize the patient’s condition (diuresis, improve peripheral perfusion, protect against RV ischemia, and correct coagulopathy). The general criteria for LVAD implantation at our institution include the following: patients not candidates for heart transplantation (only DT patients), with ejection fraction < 25%, New York Heart Association class 4 for 3 months or 30 days with inotrope dependence, peak exercise oxygen consumption < 12 mls/kg/min, and BMI between 18 and 40. The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) scores for our patients were as follows: class 1: 7/100 (7%), class 2: 40/100 (40%), class 3: 26/100 (26%), class 4: 20/100 (20%), class 5: 5/100 (5%), and class 6: 2/100 (2%). The average waiting time for heart transplantation for our BTT patients is 125 days ± 52 when they are listed as status 1B.
Patient demographics, operative characteristics, postoperative complications, and hemodynamic data were compared between the two groups in a univariate analysis. Continuous variables were reported as mean, standard deviation, minimum, and maximum and were compared using two-sided two-sample t-tests. Alternatively, Wilcoxon rank-sum tests were used if normality could not be assumed. Categorical variables were reported as count and percent, and were compared using χ2 tests. Alternatively, Fisher’s exact tests were used if expected cell counts were not sufficiently large. Survival at 30 days, 180 days, and 360 days were compared between ICM and IDCM using a log-rank test. Once patients were transplanted, they were censored from the survival plot. Variables were placed in a multiple Cox proportional hazards model with 30 day, 180 day, and 360 day survival as the outcome. Variables included in the model were restricted to those that had at least 95% non-missing values. A backward selection process was used to restrict each of the models to contain all significant predictors. Adjusted hazard ratios and 95% confidence intervals for hazard ratios were reported. Tests were considered significant at p < 0.05. All analyses were performed using SAS 9.2.
Comparison of ICM and NIDCM LVAD Recipients
We identified 34 patients (34%) with ICM and 66 (66%) patients with NIDCM. Mean age for ICM patients was 59.5 + 6.5 years (range 48–72 years) compared to 49.3 + 12.6 years (range 18–75 years) for NIDCM patients (p < 0.001). In the ICM subgroup, 79.4% (27/34) were men and 20.6% (7/34) women compared to 69.7% (46/66) (p = 0.22) men and 30.3% (20/66) women in the NIDCM subgroup (p = 0.3). Among patients implanted as a BTT (n = 68), 35.2% (24/68) had ICM and 64.7% (44/68) NIDCM (p = 0.215). Within the BTT cohort, 29.1% (7/24) of patients with ICM received a heart transplant compared to 31.8% (21/44) of patients with NIDCM (p = 0.236). ICM was present in 31.2% (10/32) of patients implanted for DT compared to 68.7% (22/32) with NIDCM. The average duration of support in the ICM group was 414.4 days ± 335.3 vs. 426 days ± 320 in the nonischemic cardiomyopathy (NICM) group (p = 0.505). None of our patients were explanted (bridged to recovery). Additional demographics and comorbidities are summarized by etiology of cardiomyopathy in Table 1. In addition to being younger, patients with NIDCM were more likely to be African–American (p = 0.035). Patients in the ICM subgroup had higher rates of HTN (91.2% vs. 84.8%; p = 0.021), CRI (38.2% vs. 25.8%; p < 0.001), and PVD (11.8% vs. 10.6%; p = 0.015), and were more likely to have undergone previous cardiac surgery (58.8% vs. 13.6%; p < 0.001).
Effect of Heart Failure Etiology on Post-LVAD Survival
Survival was similar for both groups with 30 day, 6 month, and 1 year survivals of 94.1%, 85.3%, and 82.4%, respectively, for ICM patients versus 95.5%, 92.4%, and 89.4%, respectively, for NIDCM patients (p = 0.743; Figure 1).
Length of ICU and Overall Hospital Stay
Postoperative outcomes are compared in Table 2. Postoperative ICU stay (13.0 + 16.7 days for ICM vs. 11.5 + 9.3 days for NIDCM; p = 0.772), and overall length of hospital stay (24.9 + 21.5 days for ICM vs. 21.3 + 13.7 days for NIDCM; p = 0.755) were similar for both groups. Additionally, readmission rates within 30 days of discharge were similar for both groups (20.6% for ICM vs. 25.8% for NIDCM; p = 0.566).
Comparison of Postoperative Complications Between ICM and NIDCM Patients
Complication rates were similar for both groups, although there was a trend toward an increased rate of reexploration for bleeding in ICM patients (14.7% vs. 4.5%; p = 0.076).
Comparison of Postoperative Hemodynamics and Echocardiographic Data
Hemodynamic variables are compared in Table 3. Patients with NIDCM had greater LVEDD (73.5 vs. 67.8 mm; p = 0.04) and were more likely to have preoperative severe MR (69.8% vs. 46.9%; p = 0.029), and severe TR (58.7% vs. 35.5%; p = 0.034). In both groups, LVEDD, LVEF, CO, cardiac index, PA pressures, PCWP, RVEDD, severity of MR, and TR significantly improved after 1 month of LVAD therapy.
Cox Multivariate Logistic Regression Analysis: Effect of Heart Failure Etiology on Survival
All variables were placed in a multiple Cox proportional hazards with postoperative survival as the outcome. Stepwise logistic regression analysis demonstrated that etiology of heart failure was not an independent predictor of 30 day (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.41–1.32, p = 0.315), 180 day (OR 0.4, 95% CI 0.37–1.41, p = 0.446), or 360 day (OR 0.35, 95% CI 0.29–1.46, p = 0.511) survival. Preoperative aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significant predictors of 30 day survival (p < 0.001). Survival at 30 days was 0.6% greater with every one unit decrease in ALT and AST. Age, HTN, CRI, and preoperative intubation were independent significant predictors of 180 day survival (p = 0.012, p = 0.011, p = 0.004, and p = 0.045, respectively). Survival at 180 days was 10% greater with every 1 year decrease in age, 88% lower for patients with HTN, 27 times lower for patients with CRI, and approximately 21 times lower for patients intubated preoperatively. At 360 days, AST/ALT and CRI were independent predictors of survival. For each 1 unit decrease in AST/ALT, 360 day survival was 0.6% greater. Risk of death within 360 days of LVAD implantation was 7.1 times greater for patients with CRI (Table 4).
This study was undertaken to investigate whether etiology of heart failure impacts outcomes in LVAD patients. Our analysis demonstrated that etiology of heart failure did not affect perioperative or mid-term survival up to at least 1 year postoperatively, and possibly two. Survival was similar for patients with ICM and NIDCM, despite ICM patients being significantly older and having an increased incidence of HTN, CRI, PVD, and previous cardiac surgery. Additionally, there was no significant difference in the incidence of LVAD-related complications, such as infections, stroke, respiratory failure, renal failure, right heart failure, and GIB between ICM and NIDCM patients. There was, however, a trend toward significance for a higher incidence of postoperative bleeding requiring reexploration for ICM patients. This was likely due to the higher incidence of previous cardiac surgery in these patients and is consistent with additional operative dissection and adhesions as well as the longer CPB time and possible coagulopathy associated with this.
In addition, there was a trend for higher rates of tracheostomy and need for dialysis in the ICM group. This may simply represent the older age of patients with ICM. COPD was also more common in the ICM, which may also explain the need for more tracheostomies in this cohort. Paradoxically, more patients had CRI in the NICM, although more patients with ICM required dialysis. We must point out though that the two patients with ICM and one patient with NICM who required postoperative dialysis were actually on dialysis preoperatively. Reoperation for AI also occurred more often in the ICM group. With continuous-flow LVADs, as the left ventricle is decompressed, there is little or no opening of the aortic valve. As a result, the aortic valve leaflets can fuse, resulting in AI. This creates a closed circulatory loop, as blood from the proximal ascending aorta regurgitates into the left ventricle and back into the inflow cannula, causing poor peripheral perfusion and potentially shock. It may be that HTN, which was more common in patients with ICM, worsens regurgitation, necessitating a reoperation by either replacing the valve, or by performing partial closure of the leaflets with a single central stitch or by oversewing all of the leaflets, thus completely closing the valve.
Several studies have demonstrated that ICM patients have decreased survival compared to NIDCM patients. Bart et al.18 demonstrated that the overall risk adjusted 5-year mortality was significantly higher for patients with ICM compared to NIDCM patients (p < 0.0001). Likoff et al.7 studied 201 patients with ICM and NIDCM and reported significantly higher mortality at 6 months and 12 months for patients with ICM (24% and 36%, respectively; p < 0.001). Stevenson et al.6 demonstrated that an ischemic etiology for heart failure was an independent predictor of adverse outcomes and recommended that patients with ICM be considered for priority listing for heart transplantation.
The two etiologies of heart failure are also associated with differing LV responses to medical therapy. Freedman et al.8 in a cohort of 168 patients (90 ICM vs. 78 NICM), demonstrated that younger NIDCM patients were more likely to exert reverse remodeling and improvement in symptomatology with medical therapy compared to patients with ICM. Both the Cardiac Insufficiency Bisoprolol Study II of Bisoprolol1 and the Metoprolol Controlled Release / Extended Release (CR/XL) Randomized Intervention Trial in Congestive Heart Failure Study of Metoprolol CR/XL3 revealed that NIDCM was associated with a greater survival benefit with medical therapy.
What is unique about the process or consequences of implanting an LVAD that neutralizes the presumed survival advantage of NIDCM over ICM patients? One potential explanation is that there is equivalent improvement in systemic perfusion, albeit through an artificial mechanism, that supersedes the underlying pathophysiologic mechanisms associated with poorer outcomes in patients with ICM. This is compounded by the rigorous pre-LVAD workup that assesses a patient’s compliance, confirms cessation of smoking and other high-risk behaviors, and ensures that patients have appropriate psychosocial and family support as well as access to medical care postoperatively. Finally, the intense and thorough multidisciplinary long-term follow-up that each LVAD patient receives may contribute to improved outcomes for patients.
The improvements in right and left heart catheterization measurements as well as echocardiographic parameters in our cohort of LVAD patients were a result of LVAD-associated LV decompression in conjunction with optimal medical therapy for heart failure. Concomitant medical therapy is an important factor in reversing the neurohormonal response of the failing heart and has been demonstrated to be a significant factor in augmenting CO19 in patients on LVAD support.
To our knowledge, this is the first study that compared clinical outcomes in LVAD patients with ICM and NIDCM. However, there have been studies that have identified differences in ventricular unloading and reverse remodeling on the cellular level between ischemic and nonischemic ventricles. De Weger et al.20 reported significant downregulation of 16 proteins after LVAD therapy in patients with NIDCM versus 38 proteomic downregulations and 12 upregulations in the ICM patients. Additionally, the types of proteins that were down- or upregulated were different in the ICM and NICM groups. Other studies16,21,22 have identified differences in structural myocardial remodeling after LVAD therapy when comparing patients with ischemic and nonischemic etiologies. Despite possible differences in reverse remodeling on the cellular level, our study demonstrated equivalent clinical outcomes, including survival, incidence of postoperative complications, hemodynamic measurements, and echocardiographic parameters, for patients with ICM and NIDCM who underwent LVAD implantation for long-term mechanical circulatory support.
Our study has several limitations. First, it was an observational, non-randomized study and is subject to limitations inherent to any retrospective study. Second, statistical tests may have been insufficiently powered due to our relatively small sample size. Third, the duration of follow-up was relatively short. Fourth, the potential inaccuracy of data retrieved from medical records. Finally, it was a single institutional study and selection bias may have been introduced.
In conclusion, we presented a retrospective, single institutional analysis that compared outcomes of patients with ICM and NIDCM who underwent implantation of continuous-flow LVADs. Survival at 30 days, 180 days, and 360 days was similar for both groups. Additionally, the incidence of LVAD-related complications was similar for both groups. Older age along with a higher rate of several comorbidities, including HTN, CRI, and PVD, as well as a higher incidence of reoperative sternotomy, did not translate into diminished outcomes for patients with ICM. Although published reports suggest that patients with NIDCM exhibit improved myocardial reverse remodeling compared to patients with ICM, our analysis demonstrated similar hemodynamic and echocardiographic improvements for both etiologies of heart failure. Additional studies with larger numbers of patients would be useful to corroborate these findings.
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left ventricular assist device; cardiomyopathy; etiology of heart failure; reverse remodeling; outcomes