Project

HIT-LVAD Project

Goal: To characterise arterial haemodynamics in LVAD patients and determine their role in relation to clinical outcomes.

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Barry J. McDonnell
added 2 research items
Background In the general population, increased aortic stiffness is associated with an increased risk of cardiovascular events. Previous studies have demonstrated an increase in aortic stiffness in continuous-flow left ventricular assist device (CF-LVAD) patients. However, the association between aortic stiffness and common adverse events is unknown. Methods 40 HeartMate II (HMII) pts (51±8 years, 32% female, 25% ischemic) implanted between January 2011 and September 2017 were included. Two-dimensional transthoracic echocardiograms of the ascending aorta, obtained prior to HMII placement and early after heart transplant, were analyzed to calculate Aortic-Stiffness Index (AO-SI). The study cohort was divided into patients who had an increased vs. reduced AO-SI following LVAD support. A composite outcome of gastrointestinal bleeding, stroke, and pump thrombosis was defined as the primary endpoint and compared between the groups. Results While median AO-SI increased significantly following HMII support (AO-SI: 4.4 to 6.5, p=0.012), 16 patients had reduced AO-SI. Patients with increased (n=24) AO-SI had a significantly higher rate of the composite end-point (58% vs 12%, OR 9.8, p<0.01). Similarly, those with increased AO-SI tended to be on LVAD support for a longer duration, had higher LVAD speed and reduced use of angiotensin-converting-enzyme inhibitors or angiotensin-II-receptor blockers. Conclusions Increased aortic stiffness in HMII patients is associated with significantly higher rates of adverse events. Further studies are warranted to determine the causality between aortic stiffness and adverse events, as well as the effect of neurohormonal modulation on the conduit vasculature in CF-LVAD patients. Subject terms Heart Failure; Vascular Disease
BACKGROUND While rates of stroke have declined with the HeartMate3 (HM3) continuous flow (CF) left ventricular assist device (LVAD), the impact of non-pulsatile flow and artificial pulse physiology on cerebrovascular function is not known. We hypothesized that improved hemodynamics and artificial pulse physiology of HM3 patients would augment cerebrovascular metabolic reactivity (CVR) compared with HeartMate II (HMII) CF-LVAD and heart failure (HF) patients. METHODS Mean, peak systolic and diastolic flow velocities (MFV, PSV, MinFV, respectively) and cerebral pulsatility index (CPI) were determined in the middle cerebral artery (MCA) before and after a 30s breath-hold challenge in 90 participants: 24 healthy controls; 30 HF, 15 HMII, and 21 HM3 patients. RESULTS In HM3 patients, breath-holding increased MFV (Δ8±10 cm/s, P<0.0001 vs. baseline) to levels similar to HF patients (Δ9±8 cm/s, P>0.05), higher than HMII patients (Δ2±8 cm/s, P<0.01) but lower than healthy controls (Δ13±7 cm/s, P<0.05). CF-LVAD altered the proportion of systolic and diastolic flow responses as reflected by a differential CPI (P=0.03). Baseline MFV was not related to CVR (r²=0.0008, P=0.81). However, CF-LVAD pump speed was strongly inversely associated with CVR in HM II (r²=0.51, P=0.003) but not HM3 patients (r²=0.01, P=0.65). CONCLUSIONS Compared with HMII, HM3 patients have a significantly improved CVR. However, CVR remains lower in HM3 and HF patients than in healthy controls, therefore suggesting that changes in cerebral hemodynamics are not reversed by CF-LVAD therapy. Further research on the mechanisms and the long-term impact of altered cerebral hemodynamics in this unique patient population are warranted.
Barry J. McDonnell
added a research item
Left ventricular assist devices (LVADs) are associated with major vascular complications including stroke and gastrointestinal bleeding (GIB). These adverse vascular events may be the result of widespread vascular dysfunction resulting from pre-LVAD abnormalities or continuous flow during LVAD therapy. We hypothesized that pre-existing large artery atherosclerosis and/or abnormal blood flow as measured in carotid arteries using ultrasonography are associated with a post-implantation composite adverse outcome including stroke, GIB, or death. We retrospectively studied 141 adult HeartMate II patients who had carotid ultrasound duplex exams performed before and/or after LVAD surgery. Structural parameters examined included plaque burden and stenosis. Hemodynamic parameters included peak-systolic, end-diastolic, and mean velocity as well as pulsatility index. We examined the association of these measures with the composite outcome as well as individual subcomponents such as stroke. After adjusting for established risk factors, the composite adverse outcome was associated with pre-operative moderate-to-severe carotid plaque (OR 5.08, 95% CI 1.67–15.52) as well as pre-operative internal carotid artery stenosis (OR 9.02, 95% CI 1.06–76.56). In contrast, altered hemodynamics during LVAD support were not associated with the composite outcome. Our findings suggest that pre-existing atherosclerosis possibly in combination with LVAD hemodynamics may be an important contributor to adverse vascular events during mechanical support. This encourages greater awareness of carotid morphology pre-operatively and further study of the interaction between hemodynamics, pulsatility, and structural arterial disease during LVAD support.
Eric J. Stöhr
added 5 research items
Background: The MOMENTUM3 trial1 has revealed superiority of the novel HeartMate3 (HM3) left ventricular assist device (LVAD) compared with the HM2, with a significantly reduced occurrence of cerebrovascular accidents. Thus, cerebral autoregulation may be improved in HM3 compared with HM II patients, possibly because of altered microcirculatory haemodynamics associated with the in-built speed modulation (‘pulsatility’) of the HM3 device. Methods: Angle-corrected Doppler ultrasound images of the middle cerebral artery (MCA) were recorded before and at the end of a 30s breathhold test in healthy controls (n = 17), heart failure (HF n = 18), HM2 (n = 10) and HM3 (n = 17) patients. Microcirculatory haemodynamics as represented by the central retinal artery (CRA) were also quantified (Controls = 33, HF = 27, HM2 = 23, HM3 = 31). Data were analysed for Time-Averaged Maximum flow velocity (TAMAX), peak flow velocity (Vmax), minimum flow velocity (Vmin), Pulsatility Index (PI) and Resistance Index (RI, Table 1). Table 1Haemodynamics in the middle cererbral artery (MCA) and the central retinal artery (CRA) between HeartMate2 and HeartMate3 patients Healthy controls (n = 33) Heart failure (n = 27) HeartMate II (n = 23) HeartMate3 (average) (n = 31) HeartMate3 (no speed modulation) (n = 31) HeartMate3 (with speed modulation) (n = 31) Middle Cerebral Artery TAMAX (cm/s) 58 ± 15 48 ± 13 45 ± 15 48 ± 19 48 ± 19 46 ± 18 Vmax (cm/s) 92 ± 22 78 ± 20 55 ± 19*# 55 ± 21*# 54 ± 21*# 55 ± 22*# Vmin (cm/s) 39 ± 12 29 ± 11 37 ± 16 39 ± 14 44 ± 16# 32 ± 13 Pulsatility index 0.88 ± 0.18 1.05 ± 0.31* 0.40 ± 0.24*# 0.34 ± 0.14*# 0.21 ± 0.12*#$ 0.56 ± 0.24*# Resistance index 0.57 ± 0.07 0.60 ± 0.11 0.29 ± 0.14*# 0.16 ± 0.09*#$ 0.17 ± 0.10*#$ 0.14 ± 0.09*#$ Central retinal artery TAMAX (cm/s) 6 ± 1 5 ± 2 6 ± 3 7 ± 3 7 ± 4 6 ± 4 Vmax (cm/s) 12 ± 3 11 ± 6 8 ± 4* 8 ± 4* 8 ± 4* 8 ± 4* Vmin (cm/s) 3 ± 1 3 ± 1 5 ± 2 5 ± 3 6 ± 3*# 4 ± 4 Pulsatility index 1.60 ± 0.45 1.42 ± 0.40 0.58 ± 0.26*# 0.49 ± 0.21*# 0.32 ± 0.17*# 0.79 ± 0.35*# Resistance index 0.75 ± 0.09 0.70 ± 0.11 0.38 ± 0.15*# 0.22 ± 0.11*#$ 0.24 ± 0.12*#$ 0.20 ± 0.13*#$ *p < 0.05 compared with healthy controls; #p < 0.05 compared with Heart Failure; $p < 0.05 compared with HeartMate II. Results: Breathhold significantly increased TAMAX, Vmax and Vmin in all groups except HM II patients (Figure 1A). Conversely, PI decreased slightly in all groups while RI was maintained. The greater breathhold response in HM3 compared with HM2 patients was not attributable to the in-built pump-speed modulation (Figure 1B), however, HM3 had a consistently lower RI in the MCA and CRA. Figure 1(A) Time-averaged maximum flow velocity in the middle cerebral artery of healthy controls and patient groups in response to a 30-s breathhold test. (B) Breakdown of the responses in HM3 patients, comparing beats with and without added pulsatility. Conclusion: Although reduced compared with healthy controls, HF and HM3 patients have a significantly greater metabolic cerebral vasoreactivity compared with HM2 patients. The 60% greater diastolic flow velocity in the microcirculation of both LVAD groups compared to healthy controls may alter gas exchange in the microcirculation. Future studies should examine the role of altered RI in HM3 patients.
New findings: Advanced heart failure patients who are implanted with left ventricular assist devices (LVADs) have a unique circulation that is characterised by a reduced or even absent arterial pulse. The remarkable survival of these patients is accompanied by circulatory complications, including stroke, gastro-intestinal bleeding and right-heart failure. Understanding the mechanisms related to the complications in LVAD patients will help the patients and also advance our fundamental understanding of the human circulation in general. Abstract: Some humans with chronic, advanced heart failure are surgically implanted with a left ventricular assist device (LVAD). Because the LVAD produces a continuous flow, a pulse is often absent in these patients. This allows for a unique investigation of the human circulation and a controversy around the 'need' for a pulse. This medical debate also generates a more generic, fundamental discussion into what is 'normal' arterial physiology & health. The comprehensive study and understanding of the arterial responses to drastically altered haemodynamics due to CF-LVADs, at rest and during activity, presents an opportunity to significantly increase our current understanding of the fundamental components of arterial regulation (flow, blood pressure, sympathetic activity, endothelial function, pulsatility) in a way that could never have been studied previously. In a series of four articles, we summarise the talks presented at the symposium entitled "Bionic Women and Men - Physiology lessons from implantable cardiac devices" during the 2019 Annual Meeting of The Physiological Society in Aberdeen, Scotland. The articles highlight the novel questions generated by physiological phenomena observed in LVAD patients and proposes future areas of interest within the field of cardiovascular physiology. This article is protected by copyright. All rights reserved.
New findings: LVAD patients are predisposed to hypertension which may increase the risk of stroke. Hypertension may result from markedly elevated levels of sympathetic nerve activity, which occurs through a baroreceptor-mediated pathway in response to chronic exposure to a non-physiologic (and reduced) pulse. Cerebral autoregulatory processes appear to be preserved in the absence of a physiologic pulse. Nevertheless, the rate of ischemic/embolic and hemorrhagic stroke is unacceptably high and is a major cause of morbidity and mortality in these patients. Despite normalization of a resting cardiac output, LVAD patients suffer from persistent, severe reductions in functional capacity. Abstract: Current generation left ventricular assist devices (LVADs) have led to significant improvements in survival compared to medical therapy alone, when used for management of patients with advanced heart failure. However, there are a number of side-effects associated with LVAD use, including hypertension, gastrointestinal bleeding, stroke, as well as persistent and severe limitations in functional capacity despite normalization of a resting cardiac output (Qc). These issues are, in large part, related to chronic exposure to a non-physiologic pulse, which contributes to a hyperadrenergic environment characterized by markedly elevated levels of sympathetic nerve activity through a baroreceptor-mediated pathway. In addition, these machines are unable to participate in, or contribute to, normal cardiovascular/autonomic reflexes that attempt to modulate flow through the body. Efforts to advance device technology and develop biologically sensitive devices may resolve these issues, and lead to further improvements in quality-of-life, functional capacity, and ultimately, survival, for the patients they support. This article is protected by copyright. All rights reserved.
Barry J. McDonnell
added a research item
Purpose Blood flow through the left ventricular assist device (LVAD) is dependent on the rotation speed of the impeller, and inversely dependent on the differential pressure across the LVAD (HQ relationship). We developed a novel approach to estimate intraventricular pressure difference (IVPD) in patients with LVAD and assess the change of IVPD according to pump speed during ramp study. Methods We developed in-house code of 1-dimensional incompressible Euler equation written in MATLAB (MathWorks, Natick, MA, USA) which allows us to measure IVPD by analyzing transesophageal echocardiographic images. Color M-mode images in mid-esophageal long axis view were obtained at 3 different pump speeds (low, optimized, high) in 10 patients who had LVAD implant (Figure). The optimal rotation speed was defined by stable hemodynamic conditions and the septal shape on transesophageal imaging. Pairwise comparison between each group was performed using Steel-Dwass analysis. Results Images were successfully obtained in all patients. Median IVPD values were 0.88 mmHg [IQR 0.73 - 1.02] at pre-LVAD implant, 1.86 mmHg [IQR 1.50 - 2.15] at low speed, 2.12 mmHg [IQR 1.72 - 2.71] at optimal speed, 2.09 mmHg [IQR1.72 - 2.31] at high speed, respectively (figure). There was significant difference between pre-implantation and the remaining 3 groups (p<0.005). IVPD was highest at optimal speed in 7 cases, at high speed in 2 cases, and at low speed in 1 case. Conclusion These data illustrate a novel approach to estimate IVPD during early diastole in patients with LVAD. Importantly, data suggests that setting of pump speed can be informed by analyzing IVPD during early diastole.
Eric J. Stöhr
added a project goal
To characterise arterial haemodynamics in LVAD patients and determine their role in relation to clinical outcomes.
 
Barry J. McDonnell
added 2 research items
Purpose It has been proposed that the high prevalence of bleeding events in continuous-flow left ventricular assist device (CF-LVAD) patients may be lowered by increasing von Willebrand factor-release via augmented peripheral pulsatility (PI). However, the hemostatic effects of increased PI may be offset by concomitant increases in local wall shear stress (WSS) - which is known to stimulate the endothelial release of anti-thrombotic factors (NO, prostacyclin, thrombomodulin). Hypothesis Higher pulsatility in the middle cerebral artery of CF-LVAD patients will be significantly associated with increased local WSS. Methods Video loops of color Doppler recordings from the middle cerebral artery were obtained in 8 HeartMate II (HM II) patients and 8 healthy controls. Data were analyzed offline with validated vector flow mapping software. WSS was calculated as: viscosity*(du/dy), according to Newton's law. Viscosity was corrected by using individuals’ hematocrit. Importantly, we determined not only peak WSS but also WSS per beat (area under the curve) and WSS/min (WSS/beat * heart rate). PI was measured from angle-corrected pulsed-wave Doppler velocities. Results Peak WSS and WSS/beat were lower in HM II (P = 0.05) but WSS/min was not different (P > 0.05). Supporting our hypothesis, WSS and pulsatility index (PI) were strongly correlated non-linearly in HM II patients (r² = 0.94) and shared a common linear slope with healthy controls between a PI of ∼0.45 and ∼0.90 (Fig. 1). Conclusion In CF-LVAD patients, a strong curvilinear relationship was noted between cerebral PI and WSS, with linear increases in WSS shown above a PI of ∼0.45. These data suggest a threshold for PI and its interaction with endothelium-dependent hemostatic and anti-thrombotic activity. Future work is warranted to investigate whether alteration of the PI-WSS relationship will influence the release of hemostatic or anti-thrombotic factors and reduce cerebral bleeding in CF-LVAD patients.
Purpose In advanced heart failure (HF) patients, a normal cardiac output is restored after continuous-flow left ventricular assist device (CF-LVAD) implantation. Previous studies have suggested that cerebral autoregulation is preserved. However, it is not known whether CF-LVAD therapy affects the cerebrovascular reactivity to a metabolic challenge. Hypothesis CF-LVAD patients will have a similar cerebrovascular response to a CO2-retention challenge compared with HF patients and healthy controls. Methods Angle-corrected Doppler ultrasound images of the middle cerebral artery (MCA) were recorded immediately before and at the end of a 30s breathhold in 10 healthy controls, 4 HF and 7 CF-LVAD (HM II) patients. Time-averaged maximum blood velocity (TAMAX), peak flow velocity (Vmax), Pulsatility Index (PI) and Resistance Index (RI) were determined by tracing of the blood velocity envelope. Statistical differences were determined with 2-way ANOVA (% change is illustrated graphically). Results In the MCA, significant baseline differences in TAMAX, Vmax, PI and RI existed between groups (all P < 0.05). Breathhold increased TAMAX and Vmax, although the difference was significantly greater in healthy controls (P = 0.04). Conversely, the CO2-retention challenge did not affect PI or RI in any group (Fig. 1 & 2). Conclusion A metabolic challenge has a differential impact on cerebrovascular hemodynamics of HF and CF-LVAD patients compared with healthy controls. The pilot data suggest that cerebrovascular reserve may be altered already in HF and not further modulated after CF-LVAD implantation.
Barry J. McDonnell
added 2 research items
An increasing number of end-stage heart failure patients are now implanted with continuous-flow left ventricular assist devices (CF-LVADs). Although this therapeutic approach is associated with improved clinical outcomes, continuous flow physiology reduces arterial pulse pressure and pulsatility to an extent that is unique to this population. Recent data suggest that high blood pressure (BP) contributes to life-threatening complications such as pump thrombosis and stroke of CF-LVAD patients. However, limited understanding of the distinct hemodynamics of these pumps makes measurement and, consequently, medical management of BP quite challenging. Here, we review the evolution of LVAD design, the impact of CF-LVAD flow, and “artificial pulse” technology on hemodynamics and BP measurement, as well as suggest new approaches for the assessment and interpretation of the unique physiology of modern LVADs.