Longitudinal Assessment of Inflammation in Recipients of Continuous-Flow Left Ventricular Assist Devices

doi:10.1016/j.cjca.2014.12.006

Canadian Journal of Cardiology

Volume 31, Issue 3, March 2015, Pages 348-356

https://doi.org/10.1016/j.cjca.2014.12.006 Get rights and content

Abstract

Background

The long-term effects of continuous-flow left ventricular assist device (CF-LVAD) support on trends of inflammatory markers over time are unknown. We examined the hypothesis that the levels of inflammatory markers in CF-LVAD recipients are higher than in healthy controls and that these levels increase over time with long-term CF-LVAD support.

Methods

We examined the levels of inflammatory markers longitudinally at baseline before CF-LVAD implantation and at 3, 6, and 9 months after implantation. We then compared the levels of inflammatory markers to those in a healthy control group.

Results

Compared with baseline values before CF-LVAD implantation, left ventricular end-diastolic diameter (LVEDd) and left ventricular end-systolic diameter (LVESd) decreased significantly at 3, 6, and 9 months after CF-LVAD implantation. Brain natriuretic peptide (BNP) levels dropped significantly after CF-LVAD implantation but did not normalize. Improvements in ejection fraction at 3, 6, and 9 months after CF-LVAD implantation did not reach significance. Monocyte chemoattractant protein-1, interferon γ-induced protein, and C-reactive protein levels were higher in the CF-LVAD recipients at each of the time points (baseline before CF-LVAD implantation and 3, 6, and 9 months after implantation) compared with levels in healthy controls. In CF-LVAD recipients, serum interleukin-8, tumour necrosis factor-α, and macrophage inflammatory protein-β increased significantly at 9 months, and macrophage-derived chemokine increased at 6 months after CF-LVAD implantation compared with baseline.

Conclusions

Despite improvements in LV dimensions and BNP levels, markers of inflammation remained higher in CF-LVAD recipients. High levels of inflammation in CF-LVAD recipients may result from heart failure preconditioning or the long-term device support, or both. Because inflammation may be detrimental to CF-LVAD recipients, future studies should determine whether inflammatory pathways are reversible.

Résumé

Introduction

Les effets à long terme d’un soutien par un dispositif d'assistance ventriculaire gauche à flux continu (CF-LVAD) sur les marqueurs inflammatoires en fonction du temps ne sont pas connus. Nous avons examiné l'hypothèse que les taux de marqueurs inflammatoires chez les bénéficiaires d’un CF-LVAD sont plus élevés que chez les témoins sains et que ces niveaux augmentent avec le temps lors d’un soutien à long terme d’un CF-LVAD.

Méthodes

Nous avons examiné les niveaux de marqueurs inflammatoires longitudinalement au niveau basal avant l’implantation d’un CF-LVAD et à 3, 6 et 9 mois après l'implantation. Nous avons ensuite comparé les niveaux de marqueurs inflammatoires à ceux d'un groupe témoin sain.

Résultats

Par rapport aux valeurs de base avant l’implantation d’un CF-LVAD, le diamètre ventriculaire gauche télédiastole (LVEDd) et le diamètre ventriculaire gauche en télésystole (LVESd) ont diminué de manière significative à 3, 6, et 9 mois après l'implantation d’un CF-LVAD. Les niveaux du peptide cérébral natriurétique sont sensiblement diminués après l'implantation du CF-LVAD mais ne retournent pas à la normale. Les améliorations de la fraction d'éjection à 3, 6 et 9 mois après implantation d’un CF-LVAD n’étaient pas significatives. Une protéine induite par l’interféron-γ : la Monocyte chemoattractant protein-1 (MCP-1), et les taux de protéine C-réactive étaient plus élevés chez les bénéficiaires d’un CF-LVAD à chacun des points temporels (ligne de base avant implantation de CF-LVAD et 3, 6 et 9 mois après l'implantation) par rapport aux niveaux des contrôles sains. Chez les bénéficiaires de CF-LVAD, l'interleukine-8 (ILK-8) sérique, le facteur de nécrose tumorale alpha (TNFα), et la protéine « macrophage inflammatory protein-β » sont augmentés de manière significative à 9 mois, et la chimiokine dérivée des macrophages est augmentée 6 mois après l'implantation du CF-LVAD par rapport à la ligne de base.

Conclusions

Malgré des améliorations dans les dimensions du ventricule gauche les niveaux du peptide cérébral natriurétique, les marqueurs de l'inflammation sont demeurés plus élevés chez les bénéficiaires de CF-LVAD que chez les témoins sains. Des niveaux élevés de l'inflammation chez les bénéficiaires de CF-LVAD peuvent résulter de préconditionnement dû à l'insuffisance cardiaque ou au soutien de l'appareil à long terme, ou les deux. Puisque l'inflammation peut être préjudiciable aux bénéficiaires de CF-LVAD, les futures études devraient déterminer si les voies inflammatoires sont réversibles.

Section snippets

Patients and study design

Patients with heart failure who were candidates for CF-LVADs as a bridge to cardiac transplantation or as a destination therapy were recruited from the Heart Function Clinic at the Toronto General Hospital. Healthy controls were recruited using posters. All eligible study participants were between 40 and 65 years of age. Informed consent was obtained from each patient before participation in the study. Healthy control individuals were free of any known disease, including cardiovascular disease,

Patient characteristics

Nine patients with heart failure (New York Heart Association [NYHA] class IV) who were candidates for CF-LVAD implantation and 9 healthy controls participated in the study. Six patients with heart failure were supported with the HeartMate II (Thoratec, Pleasanton, CA) and 3 patients were implanted with the HeartWare LVAD (HeartWare, Framingham, MA). The average patient age was 52.3 years and the average age of the healthy controls was 51.3 years. Body mass index was not significantly different

Discussion

Although LV dimensions and BNP levels improved after CF-LVAD implantation, levels of inflammatory mediators remained elevated. These elevated levels in CF-LVAD recipients may be related in part to the underlying heart failure syndrome, which persists in CF-LVAD recipients after device implantation. We found that MCP-1, IP-10, and CRP levels were higher in the CF-LVAD recipients at each of the time points—at baseline before CF-LVAD implantation and at 3, 6, and 9 months after

Conclusions

In conclusion, despite improvements in hemodynamic parameters after CF-LVAD implantation, inflammatory markers remained significantly elevated. Given the link between increased levels of cytokines/chemokines and adverse clinical outcomes, future studies should determine whether or not the increased levels of inflammatory biomarkers are reversible.

Acknowledgements

The authors are grateful to the study participants whose time and effort are critical to the success of our research program.

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Several prior reports demonstrated residual heightened levels of inflammation after LVAD or HT. Grossman-Rimon et al. showed that chemokines and other inflammatory biomarkers including TNF-α are elevated in LVAD patients when compared with HF patients and healthy subjects using both cross-sectional and longitudinal study designs.89,90 As with the LVAD population, chronic systemic inflammation (despite immunosuppression) has been observed up to 2 years after HT, as evidenced by increased levels of CRP and TNF-α.
Despite significant advances in therapies, heart failure (HF) remains a progressive disease that, once advanced, is associated with significant death and disability. Cardiac replacement therapies with left ventricular assist device (LVAD) and heart transplantation (HT) are the only treatment options for advanced HF, while lifesaving they can also be lifespan limiting due to the associated complications. Systemic inflammation is mechanistically important in HF pathophysiology and progression. However, directly targeting inflammation in HF has not been beneficial thus far. These failed attempts at therapeutics might be related to our limited understanding of the factors that cause inflammation in HF, and, therefore, to our inability to investigate these triggers in interventional studies. Observational studies have consistently demonstrated associations between alterations in the digestive (gut and oral) microbiome, inflammation and HF risk and progression. Additionally, recent data indicate that these microbial perturbations persist following LVAD and HT, along with residual inflammation and oxidative stress. Furthermore, there is rising recognition of the critical contribution of the microbiome to the metabolism of immunosuppressive drugs after HT. Cumulatively, these findings might posit a mechanistic link between microbiome alterations, systemic inflammation, and adverse outcomes in HF patients before and after cardiac replacement therapies. This review (1) provides an update on available data linking changes in digestive tract microbiota, inflammation, and oxidative stress, to HF pathogenesis and progression; (2) describes evolution of these relationships following LVAD and HT; and (3) outlines present and future intervention strategies that can manipulate the microbiome and possibly modify HF disease trajectory.
Clinical myocardial recovery in advanced heart failure with long term left ventricular assist device support
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Left ventricular assist-device (LVAD) implantation is a life-saving therapy for patients with advanced heart failure (HF). With chronic unloading and circulatory support, LVAD-supported hearts often show significant reverse remodeling at the structural, cellular and molecular level. However, translation of these changes into meaningful cardiac recovery allowing LVAD explant is lagging. Part of the reason for this discrepancy is lack of anticipation and hence promotion and evaluation for recovery post LVAD implant. There is additional uncertainty about the long-term course of HF following LVAD explant. In selected patients, however, guided by the etiology of HF, duration of disease and other clinical factors, significant functional improvement and LVAD explantation with long-term freedom from recurrent HF events has been demonstrated to be feasible in a reproducible manner. The identified predictors of myocardial recovery suggest that the elective therapeutic use of potentially less invasive VADs for reversal of HF earlier in the disease process is a future goal that warrants further investigation. Hence, it is prudent to develop and implement tools to predict HF reversibility prior to LVAD implant, optimize unloading-promoted recovery with guideline directed medical therapy and monitor for myocardial improvement. This review article summarizes the clinical aspects of myocardial recovery and together with its companion review article focused on the biological aspects of recovery, they aim to provide a useful framework for clinicians and investigators.
Gut microbiota, endotoxemia, inflammation, and oxidative stress in patients with heart failure, left ventricular assist device, and transplant
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Recent improvements in LVAD technology have reduced adverse events and improved quality of life, and LVAD now offers 2-year survival rates on par with HT.25,26 However, complications such as RV failure, stroke, and gastrointestinal bleeding remain25 and might be, in part, driven by the heightened levels of inflammation that persist after LVAD.27–32 Our results are consistent with previous observations that showed non-selective activation of several inflammatory pathways after LVAD or HT.
Gut microbial imbalance may contribute to endotoxemia, inflammation, and oxidative stress in heart failure (HF). Changes occurring in the intestinal microbiota and inflammatory/oxidative milieu during HF progression and following left ventricular assist device (LVAD) or heart transplantation (HT) are unknown. We aimed to investigate variation in gut microbiota and circulating biomarkers of endotoxemia, inflammation, and oxidative stress in patients with HF (New York Heart Association, Class I–IV), LVAD, and HT.
We enrolled 452 patients. Biomarkers of endotoxemia (lipopolysaccharide and soluble [sCD14]), inflammation (C-reactive protein, interleukin-6, tumor necrosis factor-α, and endothelin-1 adiponectin), and oxidative stress (isoprostane) were measured in 644 blood samples. A total of 304 stool samples were analyzed using 16S rRNA sequencing.
Gut microbial community measures of alpha diversity were progressively lower across worsening HF class and were similarly reduced in patients with LVAD and HT (p < 0.05). Inflammation and oxidative stress were elevated in patients with Class IV HF vs all other groups (all p < 0.05). Lipopolysaccharide was elevated in patients with Class IV HF (vs Class I–III) as well as in patients with LVAD and HT (p < 0.05). sCD14 was elevated in patients with Class IV HF and LVAD (vs Class I–III, p < 0.05) but not in patients with HT.
Reduced gut microbial diversity and increased endotoxemia, inflammation, and oxidative stress are present in patients with Class IV HF. Inflammation and oxidative stress are lower among patients with LVAD and HT relative to patients with Class IV HF, whereas reduced gut diversity and endotoxemia persist in LVAD and HT.
HFSA/SAEM/ISHLT Clinical Expert Consensus Document on the Emergency Management of Patients with Ventricular Assist Devices
2019, Journal of Cardiac Failure
Citation Excerpt :
Studies assessing body mass index are inconclusive in implicating a role for obesity in infectious complications.84 In translational work, susceptibility to infection in patients with durable LVADs has been linked to defects in cellular and humoral immune responses83 and increased level of proinflammatory cytokines.85,86 Many studies have estimated the incidence of VAD infections and related outcomes.
Mechanical circulatory support is now widely accepted as a viable long-term treatment option for patients with end-stage heart failure (HF). As the range of indications for the implantation of ventricular assist devices grows, so does the number of patients living in the community with durable support. Because of their underlying disease and comorbidities, in addition to the presence of mechanical support, these patients are at a high risk for medical urgencies and emergencies (Table 1). Thus, it is the responsibility of clinicians to understand the basics of their emergency care. This consensus document represents a collaborative effort by the Heart Failure Society of America, the Society for Academic Emergency Medicine, and the International Society for Heart and Lung Transplantation (ISHLT) to educate practicing clinicians about the emergency management of patients with ventricular assist devices. The target audience includes HF specialists and emergency medicine physicians, as well as general cardiologists and community-based providers.
HFSA/SAEM/ISHLT clinical expert consensus document on the emergency management of patients with ventricular assist devices
2019, Journal of Heart and Lung Transplantation
Mechanical circulatory support is now widely accepted as a viable long-term treatment option for patients with end-stage heart failure (HF). As the range of indications for the implantation of ventricular assist devices grows, so does the number of patients living in the community with durable support. Because of their underlying disease and comorbidities, in addition to the presence of mechanical support, these patients are at a high risk for medical urgencies and emergencies (Table 1). Thus, it is the responsibility of clinicians to understand the basics of their emergency care. This consensus document represents a collaborative effort by the Heart Failure Society of America, the Society for Academic Emergency Medicine, and the International Society for Heart and Lung Transplantation (ISHLT) to educate practicing clinicians about the emergency management of patients with ventricular assist devices. The target audience includes HF specialists and emergency medicine physicians, as well as general cardiologists and community-based providers.
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Left ventricular assist devices (LVADs) can serve as a bridge to transplant or destination therapy for patients with advanced heart failure. Implantation of LVADs is known to be associated with increases in anti-HLA antibodies, but less is known about how autoantibody levels change with the use of these devices.
Autoantibody levels were quantified with the use of customized antigen microarrays in 22 patients both before and after LVAD. We observed an increase (1.5- to 2-fold) in 14 IgG autoantibodies in the serum of patients after LVAD, including autoantibodies against cardiac proteins (myosin, troponin I, tropomyosin), DNA, and structural proteins (collagen, laminin). There was also a small but significant rise in total serum IgG after LVAD. Increases in autoantibodies after LVAD were positively associated with increases in calculated panel-reactive antibody class II (P = .05) and negatively correlated with age (r = −0.45; P < .05). Cytokines were evaluated to gain insights into the mechanism of antibody generation, and we observed a positive correlation between total IgG levels after LVAD and the level of monocyte chemoattractant protein 1 (r = 0.60; P < .05).
LVAD implantation is associated with increases in IgG autoantibodies, anti-HLA antibodies, and total IgG. Increases in IgG after LVAD implantation may relate to an inflammatory response triggered by these devices.

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Clinical ResearchLongitudinal Assessment of Inflammation in Recipients of Continuous-Flow Left Ventricular Assist Devices

Abstract

Background

Methods

Results

Conclusions

Résumé

Introduction

Méthodes

Résultats

Conclusions

Section snippets

Patients and study design

Patient characteristics

Discussion

Conclusions

Acknowledgements

J Am Coll Cardiol

Am J Cardiol

Ann Thorac Surg

J Heart Lung Transplant

J Thorac Cardiovasc Surg

Ann Thorac Surg

Kidney Int Suppl

Peptides

Ann Thorac Surg

Ann Thorac Surg

J Thorac Cardiovasc Surg

J Am Coll Cardiol

J Heart Lung Transplant

Cardiovasc Pathol

J Am Coll Cardiol

Int J Cardiol

Int J Cardiol

Atherosclerosis

Ann Thorac Surg

J Heart Lung Transplant

J Heart Lung Transplant

Inflammatory mediators in chronic heart failure: an overview

Heart

Inflammatory mediators and the failing heart: past, present, and the foreseeable future

Circ Res

Decrease of serum levels of the anti-inflammatory cytokine interleukin-10 in patients with advanced chronic heart failure

Clin Sci (Lond)

Elevated circulating levels of C-C chemokines in patients with congestive heart failure

Circulation

First clinical experience with the DeBakey VAD continuous-axial-flow pump for bridge to transplantation

Circulation

Long-term mechanical left ventricular assistance for end-stage heart failure

N Engl J Med

Advanced heart failure treated with continuous-flow left ventricular assist device

N Engl J Med

The artificial surface-induced whole blood inflammatory reaction revealed by increases in a series of chemokines and growth factors is largely complement dependent

J Biomed Mater Res A

Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update

Eur J Cardiothorac Surg

Clinical Research
Longitudinal Assessment of Inflammation in Recipients of Continuous-Flow Left Ventricular Assist Devices