Endothelial Function in Mechanical Circulatory Support

Sponsor

Medical College of Wisconsin (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT04539093

Collaborator

(none)

Enrollment

Location

41.9

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure With Reduced Ejection Fraction Endothelial Dysfunction LVAD	Other: Exposure of interest - Use of left ventricular assist device (LVAD)

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.

Study Design

Study Type:

Observational

Anticipated Enrollment :

20 participants

Observational Model:

Case-Only

Time Perspective:

Prospective

Official Title:

Assessment of Endothelial Function in Patients With Advanced Heart Failure Requiring Mechanical Circulatory Support

Actual Study Start Date :

Jan 1, 2022

Anticipated Primary Completion Date :

Jun 30, 2022

Anticipated Study Completion Date :

Jun 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
End-stage heart failure patients requiring lvad support Patients with end-stage heart failure with reduced ejection fraction, requiring mechanical circulatory support.	Other: Exposure of interest - Use of left ventricular assist device (LVAD) Mechanical circulatory support devices such as left ventricular assist device is used as a treatment option for patients with end-stage heart failure.

Arm

Intervention/Treatment

End-stage heart failure patients requiring lvad support

Patients with end-stage heart failure with reduced ejection fraction, requiring mechanical circulatory support.

Other: Exposure of interest - Use of left ventricular assist device (LVAD)

Mechanical circulatory support devices such as left ventricular assist device is used as a treatment option for patients with end-stage heart failure.

Outcome Measures

Primary Outcome Measures

Evaluation of endothelial function [9 months]
Measurement of blood nitric oxide levels will be used to evaluate vascular endothelial function. Flow-mediated dilation technique will then be used as a barometer of nitric oxide availability. The concentration of nitric oxide levels and degree of flow-mediated dilation would correlate with endothelial function.
Evaluation of microvascular function [9 months]
Contrast enhanced ultrasound of the peripheral skeletal muscle of lower extremities will be used to evaluate microvascular function. Blood flow quantified using the ultrasound images would correlated with microvascular function.

Secondary Outcome Measures

Functional outcomes - Quality of Life [9 months]
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item self-administered questionnaire that helps quantify the impact of heart failure on quality of life. This score will be used to determine correlations with endothelial function.
Functional outcomes - Mobility [9 months]
The six-minute walk test (6MWT) is an index of physical function in patients with heart failure. The walking distance achieved by the 6MWT will be used to determine correlations with endothelial function.
Functional outcomes - Handgrip [9 months]
Handgrip strength (HGS) measured by using a handheld dynamometer is a simple and effective means of assessing peripheral muscle strength. The degree of HGS will be used to determine correlations with endothelial function.
Functional outcomes - Lower extremity strength [9 months]
The Five-repetition sit-to-stand test (FRSTST) is a widely used measure of lower extremity strength in clinical research and practice. The time taken to complete the test will be used to determine correlations with endothelial function.
Functional outcomes - Ventilation and gas exchange [9 months]
The Cardiopulmonary Exercise Test (CPET) provides breath-by-breath gas exchange measures of 3 variables: O2 uptake (VO2), carbon dioxide output (VCO2), and ventilation (VE). These 3 measures will be used to determine correlations with endothelial function.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

• Patients over the age of 18 years, deemed to be candidates for LVAD implantation. All ethnicities will be included in this study.

Exclusion Criteria:

Age < 18 years or > 85 years.
Presence of intra-cardiac shunt - safety concern for use of Echo contrast.
Patient requiring temporary MCS - high acuity; may not be feasible to perform baseline assessment.
Severe peripheral vascular disease - potential confounding bias during ultrasound assessment.
Skeletal muscle disorder - not feasible to assess functional outcomes.
Underlying/genetic vascular disease, i.e. vasculitis - potential for confounding bias during ultrasound assessment.
Pregnant women - potential risk to fetus.
Non-English Speaking.
Active alcohol or illicit substance use.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

Medical College of Wisconsin

Investigators

Principal Investigator: Nicole L Lohr, MD PhD, Medical College of Wisconsin

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Nicole Lohr, Associate Professor, Medical College of Wisconsin

ClinicalTrials.gov Identifier:

NCT04539093

Other Study ID Numbers:

PRO00038133

First Posted:

Sep 4, 2020

Last Update Posted:

Apr 5, 2022

Last Verified:

Apr 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Undecided

Plan to Share IPD:

Undecided

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Nicole Lohr, Associate Professor, Medical College of Wisconsin

Observational

Pilot study

Additional relevant MeSH terms:

Heart Failure

Study Results

No Results Posted as of Apr 5, 2022