Attenuation in Peripheral Endothelial Function After Continuous Flow Left Ventricular Assist Device Therapy Is Associated With Cardiovascular Adverse Events

Hasin, Tal; Matsuzawa, Yasushi; Guddeti, Raviteja; Aoki, Tatsuo; Kwon, Taek Geun; Schettle, Sarah; Lennon, Ryan J.; Chokka, Ramesh G.; Lerman, Amir; Kushwaha, Sudhir S.

doi:10.1253/circj.cj-14-1079

Cited by 46 publications

(32 citation statements)

References 49 publications

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“…In addition, these chronic HFrEF patients would be expected to have endothelial dysfunction involving the coronary arteries or systemic vasculature, conditions that would further contribute to the patients’ morbidity, exercise intolerance, and mortality. 124–127,155,156…”

Section: Dream-hf Trial: Key Phase III Trial Design Aspects For Evalumentioning

confidence: 99%

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Borow

Yaroshinsky

Greenberg

et al. 2019

Circulation Research

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Advanced heart failure (HF) is a progressive disease characterized by recurrent hospitalizations and high risk of mortality. Indeed, outcomes in late stages of HF approximate those seen in patients with various aggressive malignancies. Clinical trials assessing beneficial outcomes of new treatments in patients with cancer have used innovative approaches to measure impact on total disease burden or surrogates to assess treatment efficacy. Although most cardiovascular outcomes trials continue to use time-to-first event analyses to assess the primary efficacy end point, such analyses do not adequately reflect the impact of new treatments on the totality of the chronic disease burden. Consequently, patient enrichment and other strategies for ongoing clinical trial design, as well as new statistical methodologies, are important considerations, particularly when studying a population with advanced chronic HF. The DREAM-HF trial (Double-Blind Randomized Assessment of Clinical Events With Allogeneic Mesenchymal Precursor Cells in Advanced Heart Failure) is an ongoing, randomized, sham-controlled phase 3 study of the efficacy and safety of mesenchymal precursor cells as immunotherapy in patients with advanced chronic HF with reduced ejection fraction. Mesenchymal precursor cells have a unique multimodal mechanism of action that is believed to result in polarization of proinflammatory type 1 macrophages in the heart to an anti-inflammatory type 2 macrophage state, inhibition of maladaptive adverse left ventricular remodeling, reversal of cardiac and peripheral endothelial dysfunction, and recovery of deranged vasculature. The objective of DREAM-HF is to confirm earlier phase 2 results and evaluate whether mesenchymal precursor cells will reduce the rate of nonfatal recurrent HF-related major adverse cardiac events while delaying or preventing progression of HF to terminal cardiac events. DREAM-HF is an example of an ongoing contemporary events-driven cardiovascular cell–based immunotherapy study that has utilized the concepts of baseline disease enrichment, prognostic enrichment, and predictive enrichment to improve its efficiency by using accumulating data from within as well as external to the trial. Adaptive enrichment designs and strategies are important components of a rational approach to achieve clinical research objectives in shorter clinical trial timelines and with increased cost-effectiveness without compromising ethical standards or the overall statistical integrity of the study. The DREAM-HF trial also presents an alternative approach to traditional composite time-to-first event primary efficacy end points. Statistical methodologies such as the joint frailty model provide opportunities to expand the scope of events-driven HF with reduced ejection fraction clinical trials to utilize time to recurrent nonfatal HF-related major adverse cardiac events as the primary efficacy end point without compromising the integrity of the statistical analyses for terminal cardiac events. In advanced chronic HF...

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Section: Dream-hf Trial: Key Phase III Trial Design Aspects For Evalumentioning

confidence: 99%

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Borow

Yaroshinsky

Greenberg

et al. 2019

Circulation Research

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“…WSS is a very important hemodynamic factor believed to have critical effects on regulating the structure and function of endotheliocytes. For instance, Hasin et al reported that the endothelial function showed a significant and persistent decline under excessive WSS condition [ 27 ]. Uzarski et al reported that the excessive shear stress magnitude could elicit phenotypic changes relevant to their critical roles in thrombosis, hemostasis, and inflammation [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Helical Flow Component of Left Ventricular Assist Devices (LVADs) Outflow Improves Aortic Hemodynamic States

2018

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BackgroundAlthough LVADs are confirmed to have strong effects on aortic hemodynamics, the precise mechanisms of the helical flow component of LVAD outflow are still unclear.Material/MethodsTo clarify these effects, 3 cases – normal case, flat flow case, and realistic flow case – were designed and studied by using the CFD approach. The normal case denoted the normal aorta without LVAD support, and the flat flow case represented the aorta with the outflow cannula. Similarly, the realistic flow case included the aortic model, the model of outflow cannula, and the model of LVAD. The velocity vector, blood streamline, distribution of wall shear stress (WSS), and the local normalized helicity (LNH) were calculated.ResultsThe results showed that the helical component of LVAD outflow significantly improved the aortic hemodynamics. Compared with the flat flow case, the helical flow eliminated the vortex near the outer wall of the aorta and improved the blood flow transport (normal case 0.1 m/s vs. flat flow case 0.14 m/s vs. realistic flow case 0.30 m/s) at the descending aorta. Moreover, the helical flow was confirmed to even the distribution of WSS, reduce the peak value of WSS (normal case 0.92 Pa vs. flat flow case 7.39 Pa vs. realistic flow case 5.2Pa), and maintain a more orderly WSS direction.ConclusionsThe helical flow component of LVAD outflow has significant advantages for improving aortic hemodynamic stability. Our study provides novel insights into LVAD optimization.

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“…Similarly, Templeton et al reported that vascular compliance was impaired by the use of LVAD support [ 30 ]. In addition, Hasin et al found that the peripheral endothelial function was attenuated after LVAD therapy [ 31 ]. From the hemodynamic view point, the changes in hemodynamic states, especially in the swirling flow characteristic, play an important role in these complications.…”

Section: Discussionmentioning

confidence: 99%

Effect of Different Rotational Directions of BJUT-II VAD on Aortic Swirling Flow Characteristics: A Primary Computational Fluid Dynamics Study

2016

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BackgroundThe BJUT-II VAD is a novel left ventricular assist device (LVAD), which is thought to have significant effects on the characteristics of aortic swirling flow. However, the precise mechanism of the rotational direction of BJTU-II VAD in the aortic swirling flow is unclear.Material/MethodsA patient-specific aortic geometric model was reconstructed based on the CT data. Three pump’s output flow profiles with varied rotational direction, termed “counterclockwise”, “flat profile”, and “clockwise”, were used as the boundary conditions. The helicity density, area-weighted average of helicity density (Ha), localized normalized helicity (LNH), wall shear stress (WSS), and WSS spatial gradient (WSSG) were calculated to evaluate the swirling flow characteristics in the aorta.ResultsThe results demonstrated that the swirling flow characteristics in the aorta and 3 branches are directly affected by the output blood flow of BJUT-II VAD. In the aortic arch, the helicity density, supported by the clockwise case, achieved the highest value. In the 3 branches, the flat profile case achieved the highest helicity density, whereas the maximum WSS and WSSG generated by clockwise case were lower than in other cases.ConclusionsThe outflow of the BJUT-II VAD has significant effects on the aortic hemodynamics and swirling flow characteristics. The helical blood profiles can enhance the strength of aortic swirling flow, and reduce the areas of low WSS and WSSG regions. The clockwise case may have a benefit for preventing development of atherosclerosis in the aorta.

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Attenuation in Peripheral Endothelial Function After Continuous Flow Left Ventricular Assist Device Therapy Is Associated With Cardiovascular Adverse Events

Cited by 46 publications

References 49 publications

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Helical Flow Component of Left Ventricular Assist Devices (LVADs) Outflow Improves Aortic Hemodynamic States

Effect of Different Rotational Directions of BJUT-II VAD on Aortic Swirling Flow Characteristics: A Primary Computational Fluid Dynamics Study

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