This review provides a comprehensive overview of the past 25+ years of research into the development of left ventricular assist device (LVAD) to improve clinical outcomes in patients with severe ...end-stage heart failure and basic insights gained into the biology of heart failure gleaned from studies of hearts and myocardium of patients undergoing LVAD support. Clinical aspects of contemporary LVAD therapy, including evolving device technology, overall mortality, and complications, are reviewed. We explain the hemodynamic effects of LVAD support and how these lead to ventricular unloading. This includes a detailed review of the structural, cellular, and molecular aspects of LVAD-associated reverse remodeling. Synergisms between LVAD support and medical therapies for heart failure related to reverse remodeling, remission, and recovery are discussed within the context of both clinical outcomes and fundamental effects on myocardial biology. The incidence, clinical implications and factors most likely to be associated with improved ventricular function and remission of the heart failure are reviewed. Finally, we discuss recognized impediments to achieving myocardial recovery in the vast majority of LVAD-supported hearts and their implications for future research aimed at improving the overall rates of recovery.
Primary graft dysfunction (PGD) is one of the most common causes of early death after orthotopic heart transplantation. Mechanical circulatory support devices are required for severe forms of PGD. ...Venoarterial extracorporeal membrane oxygenation (VA-ECMO) and temporary ventricular assist device (VAD) support have both been reported to be useful for severe PGD.
Between January 2007 and December 2015, 597 patients received a heart transplant at our center. Of those, severe PGD developed in 44 patients (7.4%), and they received a continuous-flow external VAD (n = 17) or VA-ECMO (n = 27) support within 24 hours after transplant. We compared early and late outcomes between groups.
Baseline characteristics were similar between groups. Implantation of the temporary VAD required longer cardiopulmonary bypass time compared with VA-ECMO (323 ± 86 minutes vs 216 ± 65 minutes, p < 0.0001). Patients who received a VAD were more likely to have longer support time (14 ± 17 days vs 5.2 ± 3.9 days, p = 0.011), a higher incidence of major bleeding requiring chest reexploration (77% vs 30%, p = 0.0047), and a higher incidence of renal failure requiring renal replacement therapy (53% vs 11%, p = 0.0045) after surgery. Overall hospital mortality was 27%. In-hospital mortality for VAD and VA-ECMO patients were 41% and 19%, respectively (p = 0.16). Ten patients (59%) were weaned from VAD support, and 24 (89%) were weaned from VA-ECMO support after adequate graft function recovery (p = 0.03). The 3-year post-transplant survival was 41% in the VAD group and 66% in the VA-ECMO group (p = 0.13).
For severe PGD, support with VA-ECMO appears to result in better clinical outcomes compared with VAD.
This study assessed characteristics and outcomes of patients who are not dependent on dialysis receiving simultaneous heart kidney transplantation versus heart transplantation alone (HTA) to identify ...optimal eGFR threshold where combined transplant strategy may be superior.
This study retrospectively analyzed 7896 adult patients with estimated glomerular filtration rate (eGFR) <60 mL/minute from the United Network for Organ Sharing database who received HTA or simultaneous heart kidney transplant between 2005 and 2021, excluding those who received pretransplant dialysis. Subjects were further stratified into 3 groups based on chronic kidney disease stage at time of transplant: Stage 3A (eGFR 45-59 mL/minute; n = 5044), Stage 3B (eGFR 30-44 mL/minute; n = 2193), and Stage 4 or 5 (eGFR <30 mL/minute; n = 659). Outcomes of interest were all-cause mortality, cardiac allograft failure, and freedom from chronic dialysis or renal transplant following heart transplant.
Simultaneous heart kidney transplant and HTA recipients differed in various baseline characteristics. Simultaneous heart kidney transplant recipients with eGFR <45 mL/minute had greater short- and long-term overall survival and cardiac allograft survival compared with HTA, as well as greater long-term freedom from chronic dialysis or renal transplant. These results were consistent with both propensity matched analyses and multivariable Cox regression analysis of 10 year outcomes. Optimal cutoff value for pretransplant eGFR in predicting elevated risk of renal failure in recipients of heart transplant alone was found to be eGFR ∼45 mL/minute.
Similar to patients with eGFR <30 mL/minute, patients with eGFR 30 to 44 mL/minute who underwent simultaneous heart kidney transplant had superior outcomes compared with HTA, suggesting possible benefit of combined transplant strategy for this subset of heart transplant candidates.
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Many patients listed for transplant require temporary or durable mechanical circulatory support (MCS) devices for bridging to cardiac transplantation. The choice of device for bridging to heart ...depends on a number of factors including level of support desired and patient-device hemocompatibility.
The authors summarize the current heart transplant landscape including the new UNOS listing criteria as well as indications for bridging to transplant with MCS devices. The authors also review the characteristics of commonly used MCS devices and discuss the limited evidence supporting their use in cardiogenic shock and specifically as a bridge to heart transplant.
The new UNOS heart organ allocation policy has resulted in a growth in the use of temporary MCS devices as bridge to transplantation for patients with cardiogenic shock, while bridging with durable MCS devices has become more challenging. Patients supported on temporary MCS devices should be routinely assessed for potential of myocardial recovery prior to urgent transplantation. Emerging machine learning algorithms may help better identify individuals who are likely to recover on temporary or durable MCS therapy. Modifications to the current heart allocation policy may facilitate bridging of patients with durable left ventricular assist devices.
Stroke is one of the leading complications during continuous flow-left ventricular assist device (CF-LVAD) support. Risk factors have been well described, although less is known regarding treatment ...and outcomes. We present a large single-center experience on stroke outcome and transplant eligibility by stroke sub-type and severity in CF-LVAD patients.
Between January 1, 2008, and April 1, 2015, 301 patients underwent CF-LVAD (266 HeartMate II HM I, Thoratec Corp, Pleasanton, CA; 35 HeartWare HVAD, HeartWare International Inc, Framingham, MA). Stroke was defined as a focal neurologic deficit with abnormal neuroimaging. Intracerebral hemorrhage (ICH) definition excluded sub-dural hematoma and hemorrhagic conversion of an ischemic stroke (IS). Treatment in IS included intra-arterial embolectomy when appropriate; treatment in ICH included reversal of coagulopathy. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). Outcomes were in-hospital mortality and transplant status.
Stroke occurred in 40 patients: 8 ICH (4 HM II, 4 HVAD) and 32 IS (26 HM II, 6 HVAD). Among 8 ICH patients, there were 4 deaths (50%), with NIHSS of 18.8 ± 13.7 vs 1.8 ± 1.7 in survivors (p = 0.049). Among 32 IS patients, 12 had hemorrhagic conversion and 5 were treated with intra-arterial embolectomy. There were 9 deaths (28%), with NIHSS of 16.2 ± 10.8 vs 7.0 ± 7.6 in survivors (p = 0.011). Among the 32 IS patients, 12 underwent transplant, and 1 is awaiting transplant. No ICH patients received a transplant.
In-hospital mortality after stroke is significantly affected by the initial neurologic impairment. Patients with IS appear to benefit the most from in-hospital treatment and often make sufficient recovery to be able to progress to transplant.
The pulmonary artery pulsatility index (PAPi), defined as the ratio of pulmonary artery pulse pressure to right atrial pressure, emerged as a powerful predictor of right ventricular (RV) failure in ...patients with acute inferior myocardial infarction and those undergoing left ventricular assist device placement; however, its prognostic utility in the advanced heart failure population remains largely unknown.
We comparatively analyzed PAPi with traditional indices of RV function including RV stroke work index and right atrial/pulmonary capillary wedge pressure ratio (RAP/PCWP) in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial. Median PAPi score was 2.35 in 190 patients. PAPi was significantly associated with clinical (jugular venous distention, ascites, edema), echocardiographic (right atrial size, vena cava size, tricuspid regurgitation velocity), and hemodynamic signs of RV failure (RAP, PCWP); all P < .05. In addition, PAPi was associated with the measures of left ventricular function, including ejection fraction, cardiac index, and PCWP (all P < .05). In Cox regression analysis, PAPi was an independent predictor of primary endpoint of death or hospitalization at 6 months (hazard ratio 0.91 95% confidence interval 0.84–0.99, P = .022), whereas RA pressure, RV stroke work index, or RA/PCWP were not.
PAPi serves as a marker of RV dysfunction and strongly predicts adverse clinical events in patients with advanced heart failure. Incorporating PAPi into existing risk models can substantially improve patient selection for advanced therapies and clinical outcomes in this population.
Microarrays have been used extensively to profile transcriptome remodeling in failing human heart, although the genomic coverage provided is limited and fails to provide a detailed picture of the ...myocardial transcriptome landscape. Here, we describe sequencing-based transcriptome profiling, providing comprehensive analysis of myocardial mRNA, microRNA (miRNA), and long noncoding RNA (lncRNA) expression in failing human heart before and after mechanical support with a left ventricular (LV) assist device (LVAD).
Deep sequencing of RNA isolated from paired nonischemic (NICM; n=8) and ischemic (ICM; n=8) human failing LV samples collected before and after LVAD and from nonfailing human LV (n=8) was conducted. These analyses revealed high abundance of mRNA (37%) and lncRNA (71%) of mitochondrial origin. miRNASeq revealed 160 and 147 differentially expressed miRNAs in ICM and NICM, respectively, compared with nonfailing LV. Among these, only 2 (ICM) and 5 (NICM) miRNAs are normalized with LVAD. RNASeq detected 18 480, including 113 novel, lncRNAs in human LV. Among the 679 (ICM) and 570 (NICM) lncRNAs differentially expressed with heart failure, ≈10% are improved or normalized with LVAD. In addition, the expression signature of lncRNAs, but not miRNAs or mRNAs, distinguishes ICM from NICM. Further analysis suggests that cis-gene regulation represents a major mechanism of action of human cardiac lncRNAs.
The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support. These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.
MicroRNAs (miRNAs) are endogenous, short (~22 nucleotide), evolutionarily conserved, non-coding RNAs that regulate gene expression at the post-transcriptional level. Recent evidence suggests that ...miRNAs are differentially expressed in the failing myocardium and play an important role in progression of heart failure by targeting genes that govern diverse functions in cardiac remodeling process including myocyte hypertrophy, excitation-contraction coupling, increased myocyte loss, and myocardial fibrosis. In addition to their role in adverse cardiac remodeling, miRNAs hold promise as biomarkers of disease progression in heart failure given their presence in circulation and enhanced stability. Further development of miR-based therapeutics may allow for modulation of cardiac and/or systemic levels of specific miRNAs in patients with heart failure . Here, we summarize current knowledge of miRNAs in relation to their role in regulating various aspects of the cardiac remodeling process and discuss their potential use as biomarkers and/or therapeutic targets in heart failure.
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