The role of long-term mechanical circulatory support in patients with advanced heart failure

In patients with end-stage heart failure, advanced therapies such as heart transplantation and long-term mechanical circulatory support (MCS) with a left ventricular assist device (LVAD) have to be considered. LVADs can be implanted as a bridge to transplantation or as an alternative to heart transplantation: destination therapy. In the Netherlands, long-term LVAD therapy is gaining importance as a result of increased prevalence of heart failure together with a low number of heart transplantations due to shortage of donor hearts. As a result, the difference between bridge to transplantation and destination therapy is becoming more artificial since, at present, most patients initially implanted as bridge to transplantation end up receiving extended LVAD therapy. Following LVAD implantation, survival after 1, 2 and 3 years is 83%, 76% and 70%, respectively. Quality of life improves substantially despite important adverse events such as device-related infection, stroke, major bleeding and right heart failure. Early referral of potential candidates for long-term MCS is of utmost importance and positively influences outcome. In this review, an overview of the indications, contraindications, patient selection, clinical outcome and optimal time of referral for long-term MCS is given.

     

Impact of left ventricular assist device (LVAD) support on the cardiac reverse remodeling process

With improved technology and expanding indications for use, left ventricular assist devices (LVADs) are assuming a greater role in the care of patients with end-stage heart failure. Following LVAD implantation with the intention of bridge to transplant, it became evident that some patients exhibit substantial recovery of ventricular function. This prompted explantation of some devices in lieu of transplantation, the so-called bridge-to-recovery (BTR) therapy. However, clinical outcomes following these experiences are not always successful. Patients treated in this fashion have often progressed rapidly back to heart failure. Special knowledge has emerged from studies of hearts supported by LVADs that provides insights into the basic mechanisms of ventricular remodeling and possible limits of ventricular recovery. In general, it was these studies that spawned the concept of reverse remodeling now recognized as an important goal of many heart failure treatments. Important examples of myocardial and/or ventricular properties that do not regress towards normal during LVAD support include abnormal extracellular matrix metabolism, increased tissue angiotensin levels, myocardial stiffening and partial recovery of gene expression involved with metabolism. Nevertheless, studies of LVAD-heart interactions have led to the understanding that although we once considered the end-stage failing heart of patients near death to be irreversibly diseased, an unprecedented degree of myocardial recovery is possible, when given sufficient mechanical unloading and restoration of more normal neurohormonal milieu. Evidence supporting and unsupporting the notion of reverse remodeling and clinical implications of this process will be reviewed.     

Computational fluid dynamics analysis of surgical adjustment of left ventricular assist device implantation to minimise stroke risk

Background. Currently, mechanical support is the most promising alternative to cardiac transplantation. Ventricular assist devices (VADs) were originally used to provide mechanical circulatory support in patients awaiting planned heart transplantation (‘bridge-to-transplantation’ therapy). The success of short-term bridge devices led to clinical trials evaluating the clinical suitability of long-term support (‘destination’ therapy) with left ventricular assist devices (LVADs). The first larger scale, randomised trial that tested long-term support with an LVAD reported a 44% reduction in the risk of stroke or death in patients with an LVAD. In spite of the success of LVADs as bridge-to-transplantation and long-term support, patients managed by these devices are still at risk of several adverse events. The most devastating complication is caused by embolisation of thrombi formed within the LVAD or inside the heart into the brain. Prevention of thrombi formation is attempted through anticoagulation management and by improving LVADs design; however, there is still significant occurrence of thromboembolic events in patients. Investigators have reported that the incidence of thromboembolic cerebral events ranges from 14% to 47% over a period of 6–12 months.

Methods and approach. An alternative method to reduce the incidence of cerebral embolisation is proposed by the co-authors, and the hypothesis is that it is possible to minimise the number of thrombi flowing into the carotid and vertebral arteries by an optimal placement of the LVAD outflow conduit, with or without the addition of aortic bypass connecting the ascending aorta and the innominate artery (IA), or left carotid artery. This paper presents the computational fluid dynamics (CFD) analysis of the aortic arch haemodynamics using a representative geometry of the human aortic arch with or without an alternative aortic bypass. In order to study the trajectory of the thrombi within the aortic arch bed, the CFD code, Fluent 6.3, is utilised to resolve the flow field and to solve the Lagrangian particle tracking of thrombi released randomly at the inlet of the LVAD cannula.

Results. Results are presented for simulations of thrombi in the range of 2–5 mm. The percentage of individual diameter as well as aggregate diameter thrombi flowing to the carotid and vertebral arteries as a function of LVAD conduit placement and aortic bypass implantation is reported. The influence of the LVAD conduit implantation and bypass reveals a nearly 50% variation in predicted cerebral embolism rates.

Conclusions. The adjustment of the location of the anastomosis of the LVAD outflow cannula as well as its angle of incidence plays a significant role in the level of thromboembolisms. By proper adjustment in this CFD study of a synthetic model of an aortic arch bed, we found that nearly a 50% reduction in cerebral embolism could be achieved for a configuration consisting of a shallow angle of implantation over a baseline normal incidence of the LVAD cannula. Within the limitations of our model, we have established that the LVAD implantation geometry is an important factor and should be taken into consideration when implanting an LVAD. It is possible that other parameters such as distance of the LVAD outflow cannula to the root of the IA could affect the thrombi embolisation probabilities. However, the results of this study suggest that the risk of stroke may be significantly reduced by as much as 50% by tailoring the VAD implantation by a simple surgical manoeuvre. The results of this line of research may ultimately lead to techniques that can be used to estimate the optimal LVAD configuration in a patient-specific manner by pre-operative imaging.     

Identification of Differentially Expressed Transcripts and Pathways in Blood One Week and Six Months Following Implant of Left Ventricular Assist Devices

Introduction

Continuous-flow left ventricular assist devices (LVADs) are an established therapy for patients with end-stage heart failure. The short- and long-term impact of these devices on peripheral blood gene expression has not been characterized, and may provide insight into the molecular pathways mediated in response to left ventricular remodeling and an improvement in overall systemic circulation. We performed RNA sequencing to identify genes and pathways influenced by these devices.

Methods

RNA was extracted from blood of 9 heart failure patients (8 male) prior to LVAD implantation, and at 7 and 180 days postoperatively. Libraries were sequenced on an Illumina HiSeq2000 and sequences mapped to the human Ensembl GRCh37.67 genome assembly.

Results

A specific set of genes involved in regulating cellular immune response, antigen presentation, and T cell activation and survival were down-regulated 7 days after LVAD placement. 6 months following LVAD placement, the expression levels of these genes were significantly increased; yet importantly, remained significantly lower than age and sex-matched samples from healthy controls.

Conclusions

In summary, this genomic analysis identified a significant decrease in the expression of genes that promote a healthy immune response in patients with heart failure that was partially restored 6 months following LVAD implant.     

Third-generation continuous flow left ventricular assist devices

Tremendous advances have been made in the treatment of end-stage heart failure patients with left ventricular assist devices (LVADs). An important factor playing a role in the improved clinical outcomes is the development of continuous flow, rotary LVADs. New technology using magnetic levitation and hydrodynamic suspension to eliminate contact bearings offers the potential of more durable and efficacious mechanical circulatory blood pumps. Clinical trials evaluating these novel "third-generation" LVADs are in progress.     

Cardiac Health Risk Stratification System (CHRiSS): A Bayesian-Based Decision Support System for Left Ventricular Assist Device (LVAD) Therapy

This study investigated the use of Bayesian Networks (BNs) for left ventricular assist device (LVAD) therapy; a treatment for end-stage heart failure that has been steadily growing in popularity over the past decade. Despite this growth, the number of LVAD implants performed annually remains a small fraction of the estimated population of patients who might benefit from this treatment. We believe that this demonstrates a need for an accurate stratification tool that can help identify LVAD candidates at the most appropriate point in the course of their disease. We derived BNs to predict mortality at five endpoints utilizing the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database: containing over 12,000 total enrolled patients from 153 hospital sites, collected since 2006 to the present day, and consisting of approximately 230 pre-implant clinical variables. Synthetic minority oversampling technique (SMOTE) was employed to address the uneven proportion of patients with negative outcomes and to improve the performance of the models. The resulting accuracy and area under the ROC curve (%) for predicted mortality were 30 day: 94.9 and 92.5; 90 day: 84.2 and 73.9; 6 month: 78.2 and 70.6; 1 year: 73.1 and 70.6; and 2 years: 71.4 and 70.8. To foster the translation of these models to clinical practice, they have been incorporated into a web-based application, the Cardiac Health Risk Stratification System (CHRiSS). As clinical experience with LVAD therapy continues to grow, and additional data is collected, we aim to continually update these BN models to improve their accuracy and maintain their relevance. Ongoing work also aims to extend the BN models to predict the risk of adverse events post-LVAD implant as additional factors for consideration in decision making.     

A fluid dynamics study in a 50 cc pulsatile ventricular assist device: influence of heart rate variability

Although left ventricular assist devices (LVADs) have had success in supporting severe heart failure patients, thrombus formation within these devices still limits their long term use. Research has shown that thrombosis in the Penn State pulsatile LVAD, on a polyurethane blood sac, is largely a function of the underlying fluid mechanics and may be correlated to wall shear rates below 500 s(-1). Given the large range of heart rate and systolic durations employed, in vivo it is useful to study the fluid mechanics of pulsatile LVADs under these conditions. Particle image velocimetry (PIV) was used to capture planar flow in the pump body of a Penn State 50 cubic centimeters (cc) LVAD for heart rates of 75-150 bpm and respective systolic durations of 38-50%. Shear rates were calculated along the lower device wall with attention given to the uncertainty of the shear rate measurement as a function of pixel magnification. Spatial and temporal shear rate changes associated with data collection frequency were also investigated. The accuracy of the shear rate calculation improved by approximately 40% as the resolution increased from 35 to 12 μm/pixel. In addition, data collection in 10 ms, rather than 50 ms, intervals was found to be preferable. Increasing heart rate and systolic duration showed little change in wall shear rate patterns, with wall shear rate magnitude scaling by approximately the kinematic viscosity divided by the square of the average inlet velocity, which is essentially half the friction coefficient. Changes in in vivo operating conditions strongly influence wall shear rates within our device, and likely play a significant role in thrombus deposition. Refinement of PIV techniques at higher magnifications can be useful in moving towards better prediction of thrombosis in LVADs.     

Importance of realistic LVAD profiles for assisted aortic simulations: evaluation of optimal outflow anastomosis locations

Left ventricular assist devices (LVADs) are carefully designed, but the significance of the implantation configuration and interaction with the vasculature is complex and not fully determined. The present study employs computational fluid dynamics to investigate the importance of applying a realistic LVAD profile when evaluating assisted aortic flow fields and subsequently compares a number of potential anastomosis locations in a patient-specific aortic geometry. The outflow profile of the Berlin Heart INCOR? device was provided by Berlin Heart GmbH (Berlin, Germany) and the cannula was attached at a number of locations on the aorta. Simulations were conducted to compare a flat profile against the real LVAD profile. The results illustrate the importance of applying an LVAD profile. It not only affects the magnitude and distribution of oscillatory shear index, but also the distribution of flow to the great arteries. The ascending aorta was identified as the optimal location for the anastomosis.     

Treatment options in end-stage heart failure: where to go from here?

Chronic heart failure is a major healthcare problem associated with high morbidity and mortality. Despite significant progress in treatment strategies, the prognosis of heart failure patients remains poor. The golden standard treatment for heart failure is heart transplantation after failure of medical therapy, surgery and/or cardiac resynchronisation therapy. In order to improve patients' outcome and quality of life, new emerging treatment modalities are currently being investigated, including mechanical cardiac support devices, of which the left ventricular assist device is the most promising treatment option. Structured care for heart failure patients according to the most recent international heart failure guidelines may further contribute to optimal decision-making. This article will review the conventional and novel treatment modalities of heart failure.     

Intraventricular flow patterns and stasis in the LVAD-assisted heart

Left ventricular assist device (LVAD) support disrupts the natural blood flow path through the heart, introducing flow patterns associated with thrombosis, especially in the presence of medical devices. The aim of this study was to quantitatively evaluate the flow patterns in the left ventricle (LV) of the LVAD-assisted heart, with a focus on alterations in vortex development and stasis. Particle image velocimetry of a LVAD-supported LV model was performed in a mock circulatory loop. In the Pre-LVAD flow condition, a vortex ring initiating from the LV base migrated toward the apex during diastole and remained in the LV by the end of ejection. During LVAD support, vortex formation was relatively unchanged although vortex circulation and kinetic energy increased with LVAD speed, particularly in systole. However, as pulsatility decreased and aortic valve opening ceased, a region of fluid stasis formed near the left ventricular outflow tract. These findings suggest that LVAD support does not substantially alter vortex dynamics unless cardiac function is minimal. The altered blood flow introduced by the LVAD results in stasis adjacent to the LV outflow tract, which increases the risk of thrombus formation in the heart.     

心力衰竭动物模型研究进展

心力衰竭是一种复杂的临床症候群,它是各种心脏病的终末阶段,发病率及病死率均较高,严重危害着人类健康,为了广泛深入地研究和治疗心力衰竭,迫切需要建立该病的动物模型。本综述复习了近年来文献,介绍目前较为成熟的心力衰竭动物模型的应用,同时比较之间的优缺点。     

ONTOLOGY OR PHENOMENOLOGY? HOW THE LVAD CHALLENGES THE EUTHANASIA DEBATE

This article deals with the euthanasia debate in light of new life‐sustaining technologies such as the left ventricular assist device (LVAD). The question arises: does the switching off of a LVAD by a doctor upon the request of a patient amount to active or passive euthanasia, i.e. to ‘killing’ or to ‘letting die’? The answer hinges on whether the device is to be regarded as a proper part of the patient's body or as something external. We usually regard the switching off of an internal device as killing, whereas the deactivation of an external device is seen as ‘letting die’. The case is notoriously difficult to decide for hybrid devices such as LVADs, which are partly inside and partly outside the patient's body. Additionally, on a methodological level, I will argue that the ‘ontological’ arguments from analogy given for both sides are problematic. Given the impasse facing the ontological arguments, complementary phenomenological arguments deserve closer inspection. In particular, we should consider whether phenomenologically the LVAD is perceived as a body part or as an external device. I will support the thesis that the deactivation of a LVAD is to be regarded as passive euthanasia if the device is not perceived by the patient as a part of the body proper.     

Implantation of the Syncardia Total Artificial Heart

With advances in technology, the use of mechanical circulatory support devices for end stage heart failure has rapidly increased. The vast majority of such patients are generally well served by left ventricular assist devices (LVADs). However, a subset of patients with late stage biventricular failure or other significant anatomic lesions are not adequately treated by isolated left ventricular mechanical support. Examples of concomitant cardiac pathology that may be better treated by resection and TAH replacement includes: post infarction ventricular septal defect, aortic root aneurysm / dissection, cardiac allograft failure, massive ventricular thrombus, refractory malignant arrhythmias (independent of filling pressures), hypertrophic / restrictive cardiomyopathy, and complex congenital heart disease. Patients often present with cardiogenic shock and multi system organ dysfunction. Excision of both ventricles and orthotopic replacement with a total artificial heart (TAH) is an effective, albeit extreme, therapy for rapid restoration of blood flow and resuscitation. Perioperative management is focused on end organ resuscitation and physical rehabilitation. In addition to the usual concerns of infection, bleeding, and thromboembolism common to all mechanically supported patients, TAH patients face unique risks with regard to renal failure and anemia. Supplementation of the abrupt decrease in brain natriuretic peptide following ventriculectomy appears to have protective renal effects. Anemia following TAH implantation can be profound and persistent. Nonetheless, the anemia is generally well tolerated and transfusion are limited to avoid HLA sensitization. Until recently, TAH patients were confined as inpatients tethered to a 500 lb pneumatic console driver. Recent introduction of a backpack sized portable driver (currently under clinical trial) has enabled patients to be discharged home and even return to work. Despite the profound presentation of these sick patients, there is a 79-87% success in bridge to transplantation.     

Modeling the relationship between LVAD support time and gene expression changes in the human heart by penalized partial least squares

MOTIVATION: Heart failure affects more than 20 million people in the world. Heart transplantation is the most effective therapy, but the number of eligible patients far outweighs the number of available donor hearts. The left mechanical ventricular assist device (LVAD) has been developed as a successful substitution therapy that aids the failing ventricle while a patient is waiting for the donor heart. We obtained genomics data from paired human heart samples harvested at the time of LVAD implant and explant. The heart failure patients in our study were supported by the LVAD for various periods of time. The goal of this study is to model the relationship between the time of LVAD support and gene expression changes. RESULTS: To serve the purpose, we propose a novel penalized partial least squares (PPLS) method to build a regression model. Compared with partial least squares and Breiman's random forest method, PPLS gives the best prediction results for the LVAD data.     

Severity of oxidative stress and inflammatory activation in end-stage heart failure patients are unaltered after 1 month of left ventricular mechanical assistance

This study investigates the impact of early left ventricular (LV)-mechanical unloading on systemic oxidative stress and inflammation in terminal heart failure patients and their impact both on multi organ failure and on intensive care unit (ICU) stay. Circulating levels of urinary 15-isoprostane-F(2t) (8-epi-PGF2(α)) and pro-inflammatory markers [plasma interleukin (IL)-6, IL-8, and urinary neopterin, a monocyte activation index] were analyzed in 20 healthy subjects, 22 stable end-stage heart failure (ESHF) patients and in 23 LV assist device (LVAD) recipients at pre-implant and during first post-LVAD (PL) month. Multi-organ function was evaluated by total Sequential Organ Failure Assessment (tSOFA) score. In LVAD recipients the levels of oxidative-inflammatory markers and tSOFA score were higher compared to other groups. After device implantation 8-epi-PGF2(α) levels were unchanged, while IL-6, and IL-8 levels increased during first week, and at 1month returned to pre-implant values, while neopterin levels increased progressively during LVAD support. The tSOFA score worsened at 1 PL-week with respect to pre-implant value, but improved at 1 PL-month. The tSOFA score related with IL-6 and IL-8 levels, while length of ICU stay related with pre-implant IL-6 levels. These data suggest that hemodynamic instability in terminal HF is associated to worsening of systemic inflammatory and oxidative milieu that do not improve in the early phase of hemodynamic recovery and LV-unloading by LVAD, affecting multi-organ function and length of ICU stay. This data stimulate to evaluate the impact of inflammatory signals on long-term outcome of mechanical circulatory support.     

Stem cell therapy for heart failure:Medical breakthrough,or dead end?

Heart failure continues to be one of the leading causes of morbidity and mortality worldwide.Myocardial infarction is the primary causative agent of chronic heart failure resulting in cardiomyocyte necrosis and the subsequent formation of fibrotic scar tissue.Current pharmacological and non-pharmacological therapies focus on managing symptoms of heart failure yet remain unable to reverse the underlying pathology.Heart transplantation usually cannot be relied on,as there is a major discrepancy between the availability of donors and recipients.As a result,heart failure carries a poor prognosis and high mortality rate.As the heart lacks significant endogenous regeneration potential,novel therapeutic approaches have incorporated the use of stem cells as a vehicle to treat heart failure as they possess the ability to self-renew and differentiate into multiple cell lineages and tissues.This review will discuss past,present,and future clinical trials,factors that influence stem cell therapy outcomes as well as ethical and safety considerations.Preclinical and clinical studies have shown a wide spectrum of outcomes when applying stem cells to improve cardiac function.This may reflect the infancy of clinical trials and the limited knowledge on the optimal cell type,dosing,route of administration,patient parameters and other important variables that contribute to successful stem cell therapy.Nonetheless,the field of stem cell therapeutics continues to advance at an unprecedented pace.We remain cautiously optimistic that stem cells will play a role in heart failure management in years to come.     

Chinese society of cardiology expert consensus statement on the diagnosis and treatment of adult fulminant myocarditis

Fulminant myocarditis is primarily caused by infection with any number of a variety of viruses. It arises quickly, progresses rapidly, and may lead to severe heart failure or circulatory failure presenting as rapid-onset hypotension and cardiogenic shock, with mortality rates as high as 50%–70%. Most importantly, there are no treatment options, guidelines or an expert consensus statement. Here, we provide the first expert consensus, the Chinese Society of Cardiology Expert Consensus Statement on the Diagnosis and Treatment of Fulminant Myocarditis, based on data from our recent clinical trial (NCT03268642). In this statement, we describe the clinical features and diagnostic criteria of fulminant myocarditis, and importantly, for the first time, we describe a new treatment regimen termed life support-based comprehensive treatment regimen. The core content of this treatment regimen includes (i) mechanical life support (applications of mechanical respirators and circulatory support systems, including intraaortic balloon pump and extracorporeal membrane oxygenation, (ii) immunological modulation by using sufficient doses of glucocorticoid, immunoglobulin and (iii) antiviral reagents using neuraminidase inhibitor. The proper application of this treatment regimen may and has helped to save the lives of many patients with fulminant myocarditis.

     

Hemocompatibility and hemodynamic comparison of two centrifugal LVADs: HVAD and HeartMate3

Mechanical circulatory support using ventricular assist devices is a common technique for treating patients suffering from advanced heart failure. The latest generation of devices is characterized by centrifugal turbopumps which employ magnetic levitation bearings to ensure a gap clearance between moving and static parts. Despite the increasing use of these devices as a destination therapy, several long-term complications still exist regarding their hemocompatibility. The blood damage associated with different pump designs has been investigated profoundly in the literature, while the hemodynamic performance has been hardly considered. This work presents a novel comparison between the two main devices of the latest generation–HVAD and HM3–from both perspectives, hemodynamic performance and blood damage. Computational fluid dynamics simulations are performed to model the considered LVADs, and computational results are compared to experimental measurements of pressure head to validate the model. Enhanced performance and hemocompatibility are detected for HM3 owing to its design incorporating more conventional blades and larger gap clearances.

     

Gender differences in adult congenital heart disease

Objective. To assess gender differences in morbidity, mortality and patient management among adults born with a heart defect. Methods and results. The database of the European Heart Survey on adult congenital heart disease was explored. This contains data on 4110 patients with one of eight congenital heart defects followed retrospectively for a median of 5.1 years. The existence of gender differences was assessed by considering mortality and a few ‘overall’ measures of morbidity. Adjusting for type of defect and age, it was found that cumulative mortality was greater in the male population (hazard ratio 1.63 (95% CI 1.12 to 2.38); p=0.011)). A significantly greater proportion of females had functional limitations (NYHA functional class >1; 37% vs. 29% of men; p=0.003). However, males were more likely to be on chronic medication during follow-up (59% vs. 55% of women; p=0.001), and males underwent diagnostic procedures more frequently (1.58/patient-year vs. 1.48/patient-year for women; p<0.02). There was no significant difference in the proportions of patients who underwent at least one intervention during follow-up, and rates of outpatient (re-)visits were not different between the sexes. Conclusion. This exploratory assessment of a large international database found evidence that gender differences exist in morbidity and mortality among adult patients with congenital heart disease, as well as in medical management. Future studies in adult congenital heart disease should always take into account the effects of gender. (Neth Heart J 2009; 17:414–7.)     

Early signatures of bleeding and mortality in patients on left ventricular assist device support: novel methods for personalized risk-stratification

Background: Left ventricular assist devices (LVADs) provide support for patients with end-stage heart failure. The aims of this study were to determine whether baseline analysis and early trends in routine laboratory data, platelet activity, and thromboinflammatory biomarkers following LVAD implantation reveal trends that predict personalized risks of one-year gastrointestinal (GI) bleeding, stroke, pump thrombosis, drive-line infections and mortality in patients on LVAD support.

Methods: We performed an observational study at the University of Kentucky with 61 participants who underwent first-time LVAD implantation. Blood was collected at baseline and post-op days 0, 1, 3 and 6 as well as clinical follow-up. Demographics, clinical characteristics, one-year adverse events and routine laboratory data were collected from electronic medical records. Platelet function and plasma biomarkers were profiled.

Results: Evaluation of routine laboratory results revealed that sustained thrombocytopenia and increased mean platelet volume (MPV) were associated with development of GI bleeding and mortality. Platelet function at follow-up visit predicted one-year bleeding events. Thrombotic biomarker sCD40L strongly predicted one-year GI bleeding at baseline before implantation and within the first week following LVAD implant.

Conclusions: Early trends in routine bloodwork and platelet function may serve as novel signatures of patients at risk to experience adverse events.