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.

     

Left ventricular assist device as a bridge to recovery in a young woman admitted with peripartum cardiomyopathy

Left ventricular assist devices (LVAD) are an effective therapeutic option for end-stage heart failure patients as a bridge to cardiac transplantation in those who deteriorate despite maximal therapy and when a donor heart is not ready available. In some patients, cardiac recovery has been reported while supported by an LVAD. In this case report, we describe a 29-year-old female who was admitted to our centre because of peripartum cardiomyopathy (PPCM). Despite intensive treatment with intravenous inotropes and intra-aortic balloon counter-pulsation she had a persisting low cardiac index and an LVAD was implanted. In the months following implantation the left ventricular systolic function improved and the left ventricular dimensions normalised. Eventually the LVAD could be ex-planted nine months after implantation. At this moment, three years after explantation, echo-cardiography shows a normal-sized left ventricle and almost completely recovered systolic function. (Neth Heart J 2008;16:426-8).     

Linear regression and two-class classification with gene expression data

MOTIVATION: Using gene expression data to classify (or predict) tumor types has received much research attention recently. Due to some special features of gene expression data, several new methods have been proposed, including the weighted voting scheme of Golub et al., the compound covariate method of Hedenfalk et al. (originally proposed by Tukey), and the shrunken centroids method of Tibshirani et al. These methods look different and are more or less ad hoc. RESULTS: We point out a close connection of the three methods with a linear regression model. Casting the classification problem in the general framework of linear regression naturally leads to new alternatives, such as partial least squares (PLS) methods and penalized PLS (PPLS) methods. Using two real data sets, we show the competitive performance of our new methods when compared with the other three methods.     

Left ventricular assist device for end-stage heart failure: results of the first LVAD destination program in the Netherlands

PurposeMechanical circulatory support with a continuous-flow left ventricular assist device (LVAD) may be a valuable treatment in end-stage heart failure patients for an extended period of time. The purpose of this study was to evaluate the safety and efficacy of implantation of a continuous-flow LVAD in end-stage heart failure patients within the first destination program in the Netherlands.MethodsA third-generation LVAD was implanted in 16 heart failure patients (age 61 ± 8; 81 % male; left ventricular ejection fraction 20 ± 6 %) as destination therapy. All patients were ineligible for heart transplant. At baseline, 3 and 6 months, New York Heart Association (NYHA) functional class, quality-of-life and exercise capacity were assessed. Clinical adverse events were registered.ResultsSurvival at 30 days and 6 months was 88 and 75 %, respectively. In the postoperative phase, 6 (38 %) patients required continuous veno-venous haemofiltration for renal failure and 2 (13 %) patients required extracorporeal membrane oxygenation because of severe right ventricular failure. During follow-up, NYHA functional class and quality-of-life improved from 3.7 ± 0.1 to 2.3 ± 0.1 and 57 ± 5 to 23 ± 3 at 6 months (P < 0.001), respectively. The 6 min walking distance improved from 168 ± 42 m to 291 ± 29 m at 6 months (P = 0.001).ConclusionContinuous-flow LVAD therapy is a promising treatment for patients with end-stage heart failure ineligible for heart transplant.     

Remote monitoring of pulmonary artery pressures with CardioMEMS in patients with chronic heart failure and NYHA class III: first experiences in the Netherlands

We report the first patient experiences with the CardioMEMS device in the Erasmus MC Thorax Center in the Netherlands. In line with clinical trial evidence, the device is applicable in patients with chronic heart failure in functional New York Heart Association class III with at least 1 admission for heart failure in the past 12 months. CardioMEMS has been shown to be safe and reliable, and effective in reducing the number of hospitalisations for heart failure by guided therapy based on pulmonary artery pressures.     

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.     

Regularized estimation in the accelerated failure time model with high-dimensional covariates

We consider two regularization approaches, the LASSO and the threshold-gradient-directed regularization, for estimation and variable selection in the accelerated failure time model with multiple covariates based on Stute's weighted least squares method. The Stute estimator uses Kaplan-Meier weights to account for censoring in the least squares criterion. The weighted least squares objective function makes the adaptation of this approach to multiple covariate settings computationally feasible. We use V-fold cross-validation and a modified Akaike's Information Criterion for tuning parameter selection, and a bootstrap approach for variance estimation. The proposed method is evaluated using simulations and demonstrated on a real data example.     

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.     

In vitro endothelial cell activation and inflammatory responses in end-stage heart failure.

BACKGROUND: vascular endothelial cell activation and dysfunction are observed in patients with severe heart failure and may contribute to systemic manifestations of this syndrome. It remains unknown whether inflammatory activation of these cells occurs in these patients because of increased circulating proinflammatory mediators. Aim: to determine whether the serum from patients with heart failure possesses a net proinflammatory bioactivity to active proinflammatory pathways in cultured endothelial cells. METHODS: serum was obtained from stable patients with end-stage heart failure undergoing elective cardiac transplantation (Tx) and severely decompensated patients with heart failure requiring emergency left ventricular assist device (LVAD) implantation. Net proinflammatory bioactivity of serum was investigated by monitoring IkappaBalpha degradation and E-selectin expression in cultured human pulmonary artery endothelial cells (HPAEC) following incubation with serum samples. Serum cytokine concentrations were measured by ELISA and neutralizing antibodies were used to determine the role of specific factors in the observed bioactivity. RESULT: serum from both patient groups induced HPAEC IkappaBalpha degradation. Low basal HPAEC E-selectin expression significantly increased following treatment with Tx but not LVAD serum. Serum tumor necrosis factor-alpha (TNF-alpha) and IL-10 concentrations were higher in patients with LVAD than those with Tx, and soluble TNF-alpha receptor expression was high in both groups. Neither TNF-alpha nor IL-10 blocking experiments altered either bioassay result. CONCLUSION: activation of a specific profile of pro- and anti-inflammatory mediators is associated with heart failure resulting in HPAEC nuclear factor (NF)-kappaB activation. However, E-selectin expression is further regulated by unidentified factors. TNF-alpha is upregulated but appears to play no part in NFkappaB activation in these patients. These findings could have important therapeutic implications.     

Incorporating prior knowledge of predictors into penalized classifiers with multiple penalty terms

MOTIVATION: In the context of sample (e.g. tumor) classifications with microarray gene expression data, many methods have been proposed. However, almost all the methods ignore existing biological knowledge and treat all the genes equally a priori. On the other hand, because some genes have been identified by previous studies to have biological functions or to be involved in pathways related to the outcome (e.g. cancer), incorporating this type of prior knowledge into a classifier can potentially improve both the predictive performance and interpretability of the resulting model. RESULTS: We propose a simple and general framework to incorporate such prior knowledge into building a penalized classifier. As two concrete examples, we apply the idea to two penalized classifiers, nearest shrunken centroids (also called PAM) and penalized partial least squares (PPLS). Instead of treating all the genes equally a priori as in standard penalized methods, we group the genes according to their functional associations based on existing biological knowledge or data, and adopt group-specific penalty terms and penalization parameters. Simulated and real data examples demonstrate that, if prior knowledge on gene grouping is indeed informative, our new methods perform better than the two standard penalized methods, yielding higher predictive accuracy and screening out more irrelevant genes.     

Use of partial least squares regression to impute SNP genotypes in Italian Cattle breeds

Background

The objective of the present study was to test the ability of the partial least squares regression technique to impute genotypes from low density single nucleotide polymorphisms (SNP) panels i.e. 3K or 7K to a high density panel with 50K SNP. No pedigree information was used.

Methods

Data consisted of 2093 Holstein, 749 Brown Swiss and 479 Simmental bulls genotyped with the Illumina 50K Beadchip. First, a single-breed approach was applied by using only data from Holstein animals. Then, to enlarge the training population, data from the three breeds were combined and a multi-breed analysis was performed. Accuracies of genotypes imputed using the partial least squares regression method were compared with those obtained by using the Beagle software. The impact of genotype imputation on breeding value prediction was evaluated for milk yield, fat content and protein content.

Results

In the single-breed approach, the accuracy of imputation using partial least squares regression was around 90 and 94% for the 3K and 7K platforms, respectively; corresponding accuracies obtained with Beagle were around 85% and 90%. Moreover, computing time required by the partial least squares regression method was on average around 10 times lower than computing time required by Beagle. Using the partial least squares regression method in the multi-breed resulted in lower imputation accuracies than using single-breed data. The impact of the SNP-genotype imputation on the accuracy of direct genomic breeding values was small. The correlation between estimates of genetic merit obtained by using imputed versus actual genotypes was around 0.96 for the 7K chip.

Conclusions

Results of the present work suggested that the partial least squares regression imputation method could be useful to impute SNP genotypes when pedigree information is not available.     

Predicting patient survival from microarray data by accelerated failure time modeling using partial least squares and LASSO

We consider the problem of predicting survival times of cancer patients from the gene expression profiles of their tumor samples via linear regression modeling of log-transformed failure times. The partial least squares (PLS) and least absolute shrinkage and selection operator (LASSO) methodologies are used for this purpose where we first modify the data to account for censoring. Three approaches of handling right censored data-reweighting, mean imputation, and multiple imputation-are considered. Their performances are examined in a detailed simulation study and compared with that of full data PLS and LASSO had there been no censoring. A major objective of this article is to investigate the performances of PLS and LASSO in the context of microarray data where the number of covariates is very large and there are extremely few samples. We demonstrate that LASSO outperforms PLS in terms of prediction error when the list of covariates includes a moderate to large percentage of useless or noise variables; otherwise, PLS may outperform LASSO. For a moderate sample size (100 with 10,000 covariates), LASSO performed better than a no covariate model (or noise-based prediction). The mean imputation method appears to best track the performance of the full data PLS or LASSO. The mean imputation scheme is used on an existing data set on lung cancer. This reanalysis using the mean imputed PLS and LASSO identifies a number of genes that were known to be related to cancer or tumor activities from previous studies.     

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.     

Mitochondrial respiratory control and early defects of oxidative phosphorylation in the failing human heart

Heart failure is a consequence of progressive deterioration of cardiac performance. Little is known about the role of impaired oxidative phosphorylation in the progression of the disease, since previous studies of mitochondrial injuries are restricted to end-stage chronic heart failure. The present study aimed at evaluating the involvement of mitochondrial dysfunction in the development of human heart failure. We measured the control of oxidative phosphorylation with high-resolution respirometry in permeabilized myocardial fibres from donor hearts (controls), and patients with no or mild heart failure but presenting with heart disease, or chronic heart failure due to dilated or ischemic cardiomyopathy. The capacity of the phosphorylation system exerted a strong limitation on oxidative phosphorylation in the human heart, estimated at 121 pmol O(2)s(-1)mg(-1) in the healthy left ventricle. In heart disease, a specific defect of the phosphorylation system, Complex I-linked respiration, and mass-specific fatty acid oxidation were identified. These early defects were also significant in chronic heart failure, where the capacities of the oxidative phosphorylation and electron transfer systems per cardiac tissue mass were decreased with all tested substrate combinations, suggesting a decline of mitochondrial density. Oxidative phosphorylation and electron transfer system capacities were higher in ventricles compared to atria, but the impaired mitochondrial quality was identical in the four cardiac chambers of chronic heart failure patients. Coupling was preserved in heart disease and chronic heart failure, in contrast to the mitochondrial dysfunction observed after prolonged cold storage of cardiac tissue. Mitochondrial defects in the phosphorylation system, Complex I respiration and mass-specific fatty acid oxidation occurred early in the development of heart failure. Targeting these mitochondrial injuries with metabolic therapy may offer a promising approach to delay the progression of heart disease.     

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.     

气象因素对心力衰竭的影响

目的:相关性分析近两年上海的气象因素及心力衰竭发病患者之间的关系,探讨影响心力衰竭高发的天气气候条件,为开展疾病预防和干预提供了理论和实践依据。方法:前瞻性统计2011年1月-2012年12月上海市胸科医院急诊的心力衰竭人数,并与同期气温,气压,湿度等气象资料进行相关性分析。结果:温度、气压、湿度对心衰的发生具有显著的影响。心力衰竭数与平均气温、最高气温、最低气温呈显著负相关,而与日平均气压呈显著正相关。前期相对湿度变化与心衰数显著相关。温度对心力衰竭数的影响具有滞后效应。结论:气温、气压及湿度与心力衰竭发病有明显相关,揭示了急性呼吸系统感染高发的天气气候条件,为开展疾病预防和干预提供了理论和实践依据。     

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。     

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.     

Formulas predicting survival in patients with heart transplantation

Kirklin et al. (J Heart Transpl, 7 (1988) 331–336) reported survival data in 132 patients who underwent heart transplantation. Survival was evaluated by using the product-limit method of Kaplan-Meier and maximum likelihood method. In addition, the effect of pulmonary vascular resistance on survival was estimated by using multivariate analysis. A microcomputer program in BASIC for predicting the survival probability after transplantation in patients with heart transplantation is designed. The formula used in this program is derived from the survival data reported by Kirklin et al. (J Heart Transpl, 7 (1988) 331–336). A mathematical model of the ‘probacent’-probability equation and a computer program previously published by the author are employed in this study. Analysis of the computer-assisted predicted values and the data reported by Kirklin et al. (J Heart Transpl, 7 (1988) 331–336) indicates that the program is accurate and reliable with a complete agreement in expressing survival probability as a function of time after heart transplantation. The computer-assisted predictive formula can determine the relationship between the time and the survival probability and may be of value for prognostic evaluation of patients. The computer-assisted mathematical model of the ‘probacent’-probability equation may be proposed as a general approximation method to make useful predictions of probable outcomes in various biomedical phenomena.