Identification of differentially expressed transcripts and pathways in blood one week and six months following implant of left ventricular assist devices.
ABSTRACT: 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.
Project description:Left ventricular assist devices (LVADs) improve survival and quality of life in patients with advanced heart failure. Despite these benefits, combined post- and precapillary pulmonary hypertension can be particularly problematic in patients on LVAD support, often exacerbating right ventricular (RV) dysfunction. Both persistently elevated pulmonary vascular resistance and RV dysfunction are associated with adverse outcomes, including death after LVAD. These observations have led to significant interest in the use of pulmonary vasodilators to treat pulmonary hypertension and preserve RV function among LVAD-supported patients. Although pulmonary vasodilators are commonly used for the treatment of pulmonary hypertension and RV dysfunction in LVADs, the benefits of this practice remain unclear. The purpose of this review is to highlight the current challenges in managing pulmonary vascular disease and RV dysfunction in patients with heart failure on LVAD support.
Project description:Importance:Left ventricular assist devices (LVADs) are widely used both as a bridge to heart transplant and as destination therapy in advanced heart failure. Although heart failure is common in patients with end-stage renal disease (ESRD), little is known about outcomes after LVAD implantation in this population. Objective:To determine the utilization of and outcomes associated with LVADs in nationally representative cohorts of patients with and without ESRD. Design, Setting and Participants:We described LVAD utilization and outcomes among Medicare beneficiaries after ESRD onset (defined as having received maintenance dialysis or a kidney transplant) from 2003 to 2013 based on Medicare claims linked to data from the United States Renal Data System (USRDS), a national registry for ESRD. We compared Medicare beneficiaries with ESRD to a 5% sample of Medicare beneficiaries without ESRD. Exposures:ESRD (vs no ESRD) among patients who underwent LVAD placement. Main Outcomes and Measures:The primary outcome was survival after LVAD placement. Results:Among the patients with ESRD, the mean age was 58.4 (12.1) years and 62.0% (96) were male. Among those without ESRD, the mean age was 62.2 (12.6) years and 75.1% (196) were male. From 2003 to 2013, 155 Medicare beneficiaries with ESRD (median and interquartile range [IQR] days from ESRD onset to LVAD placement were 1655 days [453-3050 days]) and 261 beneficiaries without ESRD in the Medicare 5% sample received an LVAD. During a median follow-up of 762 days (IQR, 92-3850 days), 127 patients (81.9%) with and 95 (36.4%) without ESRD died. more than half of patients with ESRD (80 [51.6%]) compared with 11 (4%) of those without ESRD died during the index hospitalization. The median time to death was 16 days (IQR 2-447 days) for patients with ESRD compared with 2125 days (IQR, 565-3850 days) for those without ESRD. With adjustment for demographics, comorbidity and time period, patients with ESRD had a markedly increased adjusted risk of death (hazard ratio, 36.3; 95% CI, 15.6-84.5), especially in the first 60 days after LVAD placement. Conclusions and Relevance:Patients with ESRD at the time of LVAD placement had an extremely poor prognosis, with most surviving for less than 3 weeks. This information may be crucial in supporting shared decision-making around treatments for advanced heart failure for patients with ESRD.
Project description:Left ventricular assist devices (LVADs) offer effective therapy for severe heart failure (HF) as bridge to transplantation or destination therapy. Rarely, the sustained unloading provided by the LVAD has led to cardiac reverse remodelling and recovery, permitting explantation of the device. We describe the clinical course of a patient with severe peri-partum cardiomyopathy (PPCM) rescued with a continuous flow LVAD, who experienced recovery and explantation. We discuss assessment of and criteria for recovery.
Project description:For almost half a century, cardiac transplant has been the only long-term treatment for patients with end-stage heart failure. Implantable left ventricular assist devices (LVADs) have emerged as a new treatment option for advanced heart failure as destination therapy for patients either too old or not suitable for transplant. A meta-analysis presenting head-to-head comparisons of cardiac transplant versus LVAD as destination therapy (LVAD-DT) found no difference in 1-year mortality rates between LVAD-DT and cardiac transplant (OR 1.49; 95% CI [0.48-4.66]; I2=82.8%). Moreover, a recent subanalysis from the Interagency Registry for Mechanically Assisted Circulatory Support found similar outcomes after LVAD-DT implantation in both transplant and non-transplant centres. The time is right for LVAD-DT in non-transplant centres, provided multidisciplinary heart failure teams and expertise are in place.
Project description:The increasing adoption of left ventricular assist devices (LVADs) into clinical practice is related to a combination of engineering advances in pump technology and improvements in understanding the appropriate clinical use of these devices in the management of patients with advanced heart failure. This review intends to assist the clinician in identifying candidates for LVAD implantation, to examine long-term outcomes and provide an overview of the common complications related to use of these devices.
Project description:AIMS: Left ventricular assist devices (LVADs) are implanted to support the circulation of patients with advanced heart failure. Patients approaching death, or their surrogates, may request withdrawal of LVAD support. We sought to study the attitudes and practices of heart failure clinicians regarding withdrawal of LVAD support in patients approaching death. METHODS AND RESULTS: Using internet-based and secure methods, we surveyed members of the European Society of Cardiology-Heart Failure Association (ESC-HFA), the International Society for Heart and Lung Transplantation (ISHLT), and the Heart Failure Society of America (HFSA) to assess their attitudes and practices regarding LVAD withdrawal for patients approaching death. The results indicated that clinicians have varied attitudes and practices regarding withdrawing LVAD support in these patients. Furthermore, ESC-HFA clinicians (primarily European) and ISHLT and HFSA clinicians (primarily North American) differed in their attitudes and practices regarding withdrawal of LVAD support, particularly its ethical and legal permissibility. For example, more European clinicians than North American clinicians regarded withdrawing LVAD support as a form of euthanasia. CONCLUSION: Opinions and level of comfort with LVAD withdrawal vary among clinicians. Clinicians should be aware of suggested approaches or guidelines for managing requests for withdrawal of LVAD therapy.
Project description:Left ventricular assist devices (LVADs) are used increasingly as a bridge to transplantation or as destination therapy in end-stage heart failure patients who do not respond to optimal medical therapy. Many of these patients have end-organ dysfunction, including advanced kidney dysfunction, before and after LVAD implantation. Kidney dysfunction is a marker of adverse outcomes, such as increased morbidity and mortality. This review discusses kidney dysfunction and associated management strategies during the dynamic perioperative time period of LVAD implantation. Furthermore, we suggest potential future research directions to better understand the complex relationship between renal pathophysiology and mechanical circulatory support.
Project description:Nonsurgical bleeding is the most common adverse event in patients with continuous-flow left ventricular assist devices (LVADs) and is caused by arteriovenous malformations. We hypothesized that deregulation of an angiogenic factor, angiopoietin-2 (Ang-2), in patients with LVADs leads to increased angiogenesis and higher nonsurgical bleeding.Ang-2 and thrombin levels were measured by ELISA and Western blotting, respectively, in blood samples from 101 patients with heart failure, LVAD, or orthotopic heart transplantation. Ang-2 expression in endothelial biopsy was quantified by immunofluorescence. Angiogenesis was determined by in vitro tube formation from serum from each patient with or without Ang-2-blocking antibody. Ang-2 gene expression was measured by reverse transcription-polymerase chain reaction in endothelial cells incubated with plasma from each patient with or without the thrombin receptor blocker vorapaxar.Compared with patients with heart failure or those with orthotopic heart transplantation, serum levels and endothelial expression of Ang-2 were higher in LVAD patients (P=0.001 and P<0.001, respectively). This corresponded to an increased angiogenic potential of serum from patients with LVADs (P<0.001), which was normalized with Ang-2 blockade. Furthermore, plasma from LVAD patients contained higher amounts of thrombin (P=0.003), which was associated with activation of the contact coagulation system. Plasma from LVAD patients induced more Ang-2 gene expression in endothelial cells (P<0.001), which was reduced with thrombin receptor blockade (P=0.013). LVAD patients with Ang-2 levels above the mean (12.32 ng/mL) had more nonsurgical bleeding events compared with patients with Ang-2 levels below the mean (P=0.003).Our findings indicate that thrombin-induced Ang-2 expression in LVAD patients leads to increased angiogenesis in vitro and may be associated with higher nonsurgical bleeding events. Ang-2 therefore may contribute to arteriovenous malformation formation and subsequent bleeding in LVAD patients.
Project description:BACKGROUND:Left ventricular assist devices (LVADs) are an established treatment for end stage heart failure patients. As LVADs do not currently respond to exercise demands, attention is also directed towards improvements in exercise capacity and resulting quality of life. The aim of this study was to explore hemodynamic responses observed during maximal exercise tests to infer underlying patient status and therefore investigate possible diagnostics from LVAD derived data and advance the development of physiologically adaptive LVAD controllers. METHODS:High resolution continuous LVAD flow waveforms were recorded from 14 LVAD patients and evaluated at rest and during maximum bicycle exercise tests (n = 24). Responses to exercise were analyzed in terms of an increase (?) or decrease (?) in minimum (QMIN), mean (QMEAN), maximum flow (QMAX) and flow pulsatility (QP2P). To interpret clinical data, a cardiorespiratory numerical simulator was used that reproduced patients' hemodynamics at rest and exercise. Different cardiovascular scenarios including chronotropic and inotropic responses, peripheral vasodilation, and aortic valve pathologies were simulated systematically and compared to the patients' responses. RESULTS:Different patients' responses to exercise were observed. The most common response was a positive change of ?QMIN? and ?QP2P? from rest to exercise (70% of exercise tests). Two responses, which were never reported in patients so far, were distinguished by QMIN? and QP2P? (observed in 17%) and by QMIN? and QP2P? (observed in 13%). The simulations indicated that the QP2P? can result from a reduced left ventricular contractility and that the QMIN? can occur with a better left ventricular contractility and/or aortic insufficiency. CONCLUSION:LVAD flow waveforms determine a patients' hemodynamic "fingerprint" from rest to exercise. Different waveform responses to exercise, including previously unobserved ones, were reported. The simulations indicated the left ventricular contractility as a major determinant for the different responses, thus improving patient stratification to identify how patient groups would benefit from exercise-responsive LVAD control.
Project description:A cohort of heart failure (HF) patients receiving left ventricular assist devices (LVADs) has decoupling of their diastolic pulmonary artery pressure and pulmonary capillary wedge pressure. However, the clinical implications of this decoupling remain unclear.In this prospective study, patients with LVADs underwent routine invasive hemodynamic ramp testing with right heart catheterization, during which LVAD speeds were adjusted. Inappropriate decoupling was defined as a >5 mm?Hg difference between diastolic pulmonary artery pressure and pulmonary capillary wedge pressure. The primary outcomes of survival and heart failure readmission rates after ramp testing were assessed. Among 63 LVAD patients (60±12 years old and 25 female [40%]), 27 patients (43%) had inappropriate decoupling at their baseline speed. After adjustment of their rotation speed during ramp testing, 30 patients (48%) had inappropriate decoupling. Uni/multivariable Cox analyses demonstrated that decoupling was the only significant predictor for the composite end point of death and heart failure readmission during the 1 year following the ramp study (total of 18 events; hazards ratio, 1.09; 95% confidence interval, 1.04-1.24; P<0.05). Furthermore, normalization of decoupling (n=8) during ramp testing was significantly associated with higher 1-year heart failure readmission-free survival rate compared with the non-normalized group (n=19, 100% versus 53%; P=0.035).The presence of inappropriate decoupling was associated with worse outcomes in patients with LVADs. Prospective, large-scale multicenter studies to validate the result are warranted.