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Mechanical circulatory support (MCS) with an implantable left ventricular assist device (LVAD) is an established therapeutic option for advanced heart failure. Most of the currently used LVADs generate a continuous stream of blood that decreases arterial pulse pressure. This study investigated whether a change of the pulse pressure during different pump speed settings would affect cerebral autoregulation and thereby affect cerebral blood flow (CBF). The study included 21 haemodynamically stable outpatients with a continuous-flow LVAD (HeartMate II, Abbott, USA) implanted a median of 6 months before the study (interquartile range 3 to 14 months). Arterial blood pressure (measured by finger plethysmography) was recorded simultaneously with CBF (measured by transcranial Doppler ultrasound) during baseline pump speed (8900 rpm [IQR 8800; 9200]) and during minimum and maximum tolerated pump speeds (8000 rpm [IQR 8000; 8200] and 9800 rpm [IQR 9800; 10 000]). An increase in LVAD pump speed by 800 rpm [IQR 800; 1000] from the baseline lead to a significant decrease in arterial pulse pressure and cerebral blood flow pulsatility (relative change -24 % and -32 %, both p < 0.01), but it did not affect mean arterial pressure and mean CBF velocity (relative change 1 % and -1.7 %, p=0.1 and 0.7). In stable patients with a continuous-flow LVAD, changes of pump speed settings within a clinically used range did not impair static cerebral autoregulation and cerebral blood flow. [ABSTRACT FROM AUTHOR]

The hemocompatible HeartMate3 (HM3) LVAD has demonstrated near-elimination of pump thrombosis but bleeding adverse events (AE) persist. We previously demonstrated safety of lower intensity anticoagulation targetsin the MAGENTUM 1 study and now explored complete withdrawal of anticoagulation in the MAGENTUM 2 trial. The prospective, single-center study was designed as a trial of vitamin K antagonist (VKA) withdrawal in HM3 patients. Stable patients who did not suffer a hemocompatibility event at 6 months post implant were enrolled. Exclusion criteria included absence of aortic valve opening, presence of intracardiac/aortic root thrombosis or a functional left atrial appendage with atrial fibrillation. Patients were transitioned to monotherapy with Aspirin.The primary endpoint was survival free of pump thrombosis, ischemic stroke and major bleeding at 6 months after VKA withdrawal. We enrolled 11 HM3 LVAD patients (mean age 62.3 (45-72) years, 10 men, 8 ischemic etiology [72%]) with 5 as bridge to transplant, 5 destination therapy (DT) and in 1 as bridge to candidacy. All patients met the primary endpoint for success at a median follow-up of 551 days (73-1168) accruing 16.6 pt years of experience. No mortality or hemocompatibility AE occured during follow-up. One patient with recurrent driveline infection developed abrupt pump flow drop after 319 days suspected as outflow graft twist however perioperatively, deep pump pocket infection was observed and pump inspection revealed obstructive Streptococcus vegetations corroborated by histology and microbiology. After pump exchange, VKA was resumed and uneventful transplant ensued. The MAGENTUM 2 Study supports the potential safety of VKA withdrawal in highly selected patients pointing to a signal of intrinsic thromboresistence with the HM3 pump. These observations set the stage for exploring a use of alternative strategies or novel anticoagulant regimens with the HM 3 LVAD. [ABSTRACT FROM AUTHOR]

Microparticles are small circulating vesicles originating from circulatory system and vascular wall cells released during their activation or damage. They possess different roles in regulation of endothelial function, inflammation, thrombosis, angiogenesis, and in general, cellular stress. Microparticles are the subject of intensive research in pulmonary hypertension, atherosclerotic disease, and heart failure. Another recently emerging role is the evaluation of the status of vasculature in end-stage heart failure patients treated with implantable ventricular assist devices. In patients implanted as destination therapy, assessment of the long-term effect of currently used continuous-flow left ventricular assist devices (LVADs) on vasculature might be of critical importance. However, unique continuous flow pattern generated by LVADs makes it difficult to assess reliably the vascular function with most currently used methods, based mainly on ultrasound detection of changes of arterial dilatation during pulsatile flow. In this respect, the measurement of circulating microparticles as a marker of vascular status may help to elucidate both short- and long-term effects of LVADs on the vascular system. Because data regarding this topic are very limited, this review is focused on the advantages and caveats of the circulating microparticles as markers of vascular function in patients on continuous-flow LVADs. [ABSTRACT FROM AUTHOR]

Left ventricular assist devices (LVAD), currently used in treatment of terminal heart failure, are working on principle of rotary pump, which generates continuous blood flow. Non-pulsatile flow is supposed to expose endothelial cells to high stress and potential damage. Therefore, we investigated longitudinal changes in concentration of circulating endothelial microparticles (EMP) as a possible marker of endothelial damage before and after implantation of LVAD. Study population comprised 30 patients with end-stage heart failure indicated for implantation of the Heart Mate II LVAD. Concentrations of microparticles were measured as nanomoles per liter relative to phosphatidylserine before and 3 months after implantation. At 3 months after implantation we observed significant decrease in concentration of EMP [5.89 (95% CI 4.31-8.03) vs. 3.69 (95% CI 2.70-5.03), p=0.03] in the whole group; there was no difference observed between patients with ischemic etiology of heart failure (n=18) and with heart failure of non-ischemic etiology (n=12). In addition, heart failure etiology had no effect on the rate of EMP concentration decrease with time. These results indicate possibility that LVAD do not cause vascular damage 3 months after implantation. Whether these results suggest improvement of vascular wall function and of endothelium is to be proved in long-term studies. [ABSTRACT FROM AUTHOR]

Attenuation of physiological pulsatility after continuous flow left ventricular assist device (LVAD) implantation has been reported as a contributor to alteration of aortic wall morphology and function. MicroRNAs are non-coding RNAs that act to regulate translation of messenger RNA (mRNA) into proteins and are fine-tuners of gene expression in response to pathophysiological stimuli. Differences in gene expression (mRNA) and in post-transcriptional regulators (microRNAs) could reflect biological response to exposure to the low pulsatile environment. We hypothesized that pulsatility deficit caused by LVAD may influence miRNA/mRNA expression in aortic tissue. The aim of the study was to detect miRNA/mRNA associations in the aortic tissue during LVAD support. Aortic samples were collected at the time of LVAD implant and at heart transplantation in 16 patients (mean age 49.6±16.8 years; 3 females) and examined for miRNA/mRNA profiling. QuantSeq 3′ mRNA-Sequencing was used to examine differences in gene expression. Using human miRNome panels a profile of 752 miRNAs was identified. A total of 277 mRNAs were dysregulated after LVAD support (p adj <0.05). 5 most up-regulated genes (all p<0.0001) were COL1A2, CMKLR1, S100A4, ELN, and COL3A1. The most down-regulated genes (all p<0.0001) included SLC12A2, PDK4, ID1, ARGLU1 and MALAT1. Of 68 differently expressed miRNAs the most increased were let-7, miR-181, -29, 149 and -99 (all p<0.01), decrease was found in miR-19-, -654, -664, -885, and -511 (all p<0.01). Gene analysis identified genes involved in extracellular matrix (ECM) and collagen organization. MiRNA/mRNA analysis showed that miRNA downregulated in explanted samples affected expression of genes involved in myeloid leukocyte activation and cell activation during immune response. The study provides additional insight in pathophysiology of vascular changes after LVAD implantation. A significant regulation of mRNAs involved in ECM and collagen fibers organization in response to implantation of LVAD was observed, which may suggest infliction of ECM homeostasis resulting in changes of intrinsic properties of vascular wall and arterial stiffness. Downregulation of miRNAs involved in molecular processes related to immune response, could implicate dysregulation in inflammatory processes after LVAD implantation. [ABSTRACT FROM AUTHOR]

A pulsatility decrement caused by implantation of continuous flow left ventricular assist device (LVAD) has been corroborated as an additive factor further compromising aortic wall morphology and function. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression which could reflect individual biologic adaptation to exposure to the low pulsatile environment. We hypothesized that pulsatility deficit caused by CF-LVAD implantation may influence miRNAs expression in aortic wall and that the miRNA profiles may differ between devices with different pulsatility profiles, such as speed modulated artificial pulse wave in HeartMate3. Paired aortic samples obtained at the time of LVAD implantation and at the time of Heart transplantation from CF-LVAD patients were examined for miRNA profiling in ten patients (3 females; mean age 55±13.8 years, ischemic cardiomyopathy 40%; HeartMateII(n=4), HeartMate3 (n=6). Human miRNome profile (miRCURY LNA miRNA PCR panels) of 752 miRNAs using qPCR on QuantStudio6 RT-PCR instrument was performed in all samples. The mean support duration was 383.5±222.4 days (range 162 to 887 days). 25 differently expressed multifunctional miRNAs that contribute to the regulation of multiple signaling pathways were identified. The most significant differences in miRNAs expression between implant/explant samples were found in miR-99b-5p; -144-3p; -23b-3p; -30e-3p and let-7d-5p (all p<0.002) which all play important role in differentiation of endothelial cells, vascular smooth muscle cells, or inflammation. No differences were observed between different types of CF-LVAD. The study provides additional evidence on a negative effect of suppressed physiologic pulsatility amplitude in CF-LVAD patients. Negative changes predominantly in miRNAs participating in vascular tissue engineering in aortic wall and pro-inflammatory changes of miRNA profiles during LVAD duration were observed. Our observations suggest that a programmed artificial pulsatility in HeartMate3 does not provide mitigation of continuous flow effect on aortic wall. Moreover, the most up-expressed miR-99b which target ENO2 gene, a marker of neuronal injury, was detected after explant of LVAD. Larger scale adverse events matched clinical trials are warranted. [ABSTRACT FROM AUTHOR]

Purpose Heart failure is associated with impaired endothelial function including peripheral vessels. A pulsatility decrement once continuous flow left ventricular assist device (CF-LVAD) implanted has been consistently corroborated as an additive factor further compromising peripheral vascular function in such patients. EndoPAT 2000 is a FDA approved, operator independent device for assessment of endothelial function allowing for serial examination of reactive hyperemia index (RHI; as a measure of endothelial responsiveness; cutoff < 1.67 indicative of an endothelial dysfunction) and peripheral augmentation index (AI; as a measure of arterial stiffness). We hypothesized that a documented detrimental impact of a pulsatility deficit may be mitigated by a presence of speed modulated artificial pulse wave in fully magnetically levitated CF-LVAD HeartMate3. Methods Thirty-two patients implanted with HeartMate3 LVAS (5 females; mean age 55±13.8 years, ischemic cardiomyopathy 43.75%) were longitudinally examined by EndoPAT 2000 prior to the procedure and subsequently at 3rd and 6th month after implantation. Results Mean RHI was substantially impaired and below the norm already at a baseline (1.33±0.63). Temporal analysis revealed highly significant worsening at 3rd (RHI = 0.5±0.64) and 6th (RHI = 0.67±0.59) month post implantation (both p < 0.0001). Conversely, the arterial stiffness expressed as AI significantly increased at 3rd [(-3.4)±27.1] and 6th [(-0.9)±34.5] month after implantation relative to baseline [(-32.2)±25.2]; (p = 0.003 and p <0.0001 respectively). Additive functional worsening was most prominent within the first time interval and plateaued within a pre-specified follow up (RHI p=0.58; AI p=0.55). Conclusion The study provides additional evidence on a negative effect of suppressed physiologic pulsatility amplitude in CF-LVAD patients. Despite restored central hemodynamics, peripheral vascular function after implantation is further compromised based on serial assessment by EndoPAT 2000. Our observations suggest that a novel feature of programmed artificial pulsatility in HeartMate3 does not provide a sufficient pulse amplitude to avert further progression of peripheral vascular dysfunction due to continuous flow circulatory pattern. Larger scale adverse events matched clinical trials are warranted. [ABSTRACT FROM AUTHOR]

Left ventricular assist devices (LVADs) play a fundamental role in treating end-stage heart failure. Outflow graft stenosis (OGS) represents a serious complication that can occur at a variable time point after the implantation, although typically of the order of months to years. Different types of OGS, both intrinsic and external, were described. Notwithstanding the etiology, this clinical scenario poses a life and health-threatening complication requiring timely and precise diagnosis followed by appropriate intervention. We present a case of a 72-years-old woman on LVAD HeartMate II (HM II) support. Three years after the index implantation, she presented with clinical symptoms of outflow graft stenosis. The patient was admitted to the hospital due to"low-flow" alarms of HMII. The CT scan revealed distal outflow graft stenosis suggestive of kinking of the graft. Subsequent percutaneous transluminal stenting of the graft was performed. However, after the intervention, signs of hemodynamic compromise persisted. Both angiography and repeated CT scans verified peculiar pattern of the proximal shift of the stenotic segment relative to the implanted stent. Given this specific feature, a diagnosis was reclassified as a previously reported pattern of the outflow graft twist scenario, and surgical subxiphoid approach reexploration was indicated. On inspection, after disconnecting the bend relief from the pump body massive"gelly mass" plasma transudate located in the interspace between the graft and the bend relief was observed. Immediately after removing compressing gelly mass, hemodynamic and pump parameters promptly resolved, and the bend relief was re-attached. Further patient follow-up remains uneventful to the date. Our observation suggests that the diagnostic assessment of the outflow graft stenosis may be confusing and challenging. As plasma transudate likely develops over an extended period of time once a distal orifice of the bend relief already gets entrapped within the adjacent adhesion, the outflow graft may become contained within incompressible interspace while limited by tight connection to the pump body. That said, the graft constriction migration upon stenting can easily get misdiagnosed as a pattern suggestive of the intrinsic twist instead of correct"pseudotwist" diagnosis associated with the external contained compartment compression. [ABSTRACT FROM AUTHOR]