Endothelial Function in Mechanical Circulatory Support
Condition: Heart Failure With Reduced Ejection Fraction; Endothelial Dysfunction; LVAD
MeSH terms: Heart Failure
Study type: Observational

Summary: 
      The pathophysiology of HF is highly variable, with overlapping pathogenic mechanisms that
      complicates any attempt to create a simple and unified conceptual model. Left ventricular
      (LV) ejection fraction (EF), assessed as the fraction of the end-diastolic volume that is
      ejected upon contraction, has been the cornerstone metric for characterization of LV systolic
      function in patients with HF. LVEF demonstrates a strong inverse relationship with clinical
      outcomes in HF in patients with reduced EF (HFrEF). Current management options for the
      treatment of HFrEF include medical management, mechanical circulatory support, and cardiac
      transplantation. In the setting of refractory end stage HFrEF, the standard of care is heart
      transplantation. Since limited organ procurement is a significant constraint to the treatment
      of patients with advanced disease, durable mechanical circulatory support (MCS) with left
      ventricular assist devices (LVAD) were developed as a safe and efficacious treatment strategy
      for patients with advanced HF that is refractory to medical therapy.

      The advances in LVAD engineering and design, tailored towards defined physiological goals,
      have resulted in the creation of much smaller continuous-flow (CF) pumps that possess
      technical superiority, pump durability, and ease of implantation compared to the older and
      larger pulsatile-flow pumps. The addition of speed modulation algorithms to the next
      generation centrifugal CF LVADs, has decreased the incidence of device related adverse
      events.

      Our interest lies in the impact of continuous flow hemodynamics on endothelial function and
      the cardiac and end-organ responses to this novel therapy. Current knowledge of the impact of
      these specific advances in LVAD therapy is however limited by the relative youth of the
      field. Thus, the goal of this research project is to study human LVAD patients and to
      determine the impact of speed modulation algorithms in CF physiology on microvascular and
      endothelial function and its association with cardiac and peripheral organ function.

      The investigators hypothesize that restoration of cardiac output using an LVAD with modern
      speed modulation algorithm improves vascular endothelial function. In addition, these changes
      would have a positive correlation with functional outcomes.
    

Detailed description: 
      The advances in LVAD engineering and design, tailored towards defined physiological goals,
      have resulted in the creation of much smaller CF pumps that possess technical superiority,
      pump durability, and ease of implantation compared to the older and larger PF pumps. The
      addition of artificial pulsatility to the next generation centrifugal CF LVADs, has decreased
      the incidence of device related adverse events. However, given the recent nature of these
      advances, the physiologic impact has yet to be fully elucidated. LVADs in general have
      demonstrated good outcomes and are rapidly gaining traction towards becoming standard therapy
      for refractory end stage HF. The investigators are in a position to study this new technology
      and the impact of the resultant altered physiologic state.

      Our interest lies in the impact of continuous flow hemodynamics on endothelial function and
      the cardiac and end-organ responses to this novel therapy. Basal homeostatic properties of
      healthy endothelium are in part based on the effects of hemodynamic forces such as
      hydrostatic pressure, cyclic stretch, and fluid shear stress, which occur as a consequence of
      blood pressure and pulsatile blood flow in the vasculature. Under ambient conditions, these
      forces are generally atheroprotective and increase the expression of nitric oxide synthase
      (eNOS) to generate nitric oxide (NO), decrease reactive oxidative species (ROS) and oxidative
      stress, decrease expression of proinflammatory adhesion molecules, and maintain an
      antithrombotic surface. Increases in shear stress stimulate compensatory expansion of the
      vessels and thereby return shear forces to basal levels. Likewise, a decrease in shear stress
      can narrow the lumen of the vessel in an endothelium-dependent manner. In essence, the vessel
      remodels itself in response to long-term changes in flow, such that the luminal diameter is
      reshaped to maintain a constant predetermined level of shear stress. The capacity of the
      endothelium to sense shear stress is therefore an important determinant of luminal diameter
      and overall vessel structure. Failure to adapt to pathophysiological stimuli may lead to
      maladaptive responses that result in seemingly permanent alterations in endothelial phenotype
      and promote endothelial dysfunction. This phenomenon plays an integral role in several
      cardiovascular disease processes. Endothelial dysfunction (of both microvascular and conduit
      arteries) is a component of chronic heart failure and correlates with severity of disease.
      Improvement in cardiac function, whether via medical therapy or cardiac output augmentation,
      can improve endothelial function and benefit patients through better peripheral vascular
      reactivity. However, much of the improvement in endothelial function is thought to be related
      to the pulsatile laminar flow that occurs in majority of vascular beds. With the increasing
      use of CF pumps, it has become clear that the lack of pulsatility adversely affects the
      endothelium by decreasing vessel wall shear stress; reducing cyclic stretch that affects
      vascular cell proliferation; disrupting endothelium-dependent vasodilation; activating
      extrinsic pathway of thrombosis; and heightening vascular inflammation. The reintroduction of
      pulsatility through flow modulation control strategies could help mitigate these device
      specific issues and help promote endothelial recovery. Our knowledge of the impact of these
      specific advances in LVAD therapy is however limited by the relative youth of the field.
      Thus, the goal of this research project is to study human LVAD patients to determine the
      impact of artificial pulsatility in CF physiology on microvascular and endothelial function
      and its association with cardiac and peripheral organ function.
    

Intervention name(s): Exposure of interest - Use of left ventricular assist device (LVAD)
Intervention type(s): Other
Intervention description(s): Mechanical circulatory support devices such as left ventricular assist device is used as a treatment option for patients with end-stage heart failure.
Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        End-stage heart failure patients at an academic medical center who are scheduled for LVAD
        implantation, will be screened for their candidacy in this study.
      
Biospecimen description: 
      Urine specimen - 1 sample per subject taken over a period of 1 day for urine pregnancy test.
      Up to a total of 60 (20 x 3 visits) samples for the duration of the project.

      Blood specimen - 1 sample per subject taken over a period of 1 day for measurement of blood
      nitric oxide levels. Up to a total of 60 (20 x 3 visits) samples for the duration of the
      project.
    
Keywords: Observational; Pilot study