Monocyte Phenotypic Changes in Heart Failure

There are many treatments that can improve how long and how well people live with heart failure when they are outside the hospital. However, the investigators know less about how to effectively treat hospitalized heart failure patients so that they do not have to return to the hospital after they go home. Part of the problem is that the investigators don't understand all of the causes of worsening heart failure.

Previous studies by other researchers suggest that white blood cells called monocytes are over-active in heart failure. Under normal conditions monocytes help fight infections in the body, but over-active monocytes release chemicals that could cause abnormal function of the heart and blood vessels. The investigators' research group believes that over-active monocytes may be an important reason that heart failure worsens before hospitalization.

In this study the investigators will collect blood samples on the day a patient comes into the hospital, the day they return home, and the day they come back to the clinic for a follow-up appointment. The investigators will measure the inflammation in the bloodstream and the activity of monocytes from the patients' blood to see if there are changes in these measurements as heart failure improves. The investigators will also call each patient several times after they return home to ask questions about how they are doing.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Decompensated Heart Failure

Detailed Description

With over 5 million Americans having heart failure (HF) today and an incidence approaching 10 per 1000 population among persons over the age of 65, HF is a major source or morbidity and mortality and a significant public health concern facing developed nations. In the US, decompensated heart failure is the most common reason for hospital admission among persons older than 65. Yet despite significant advances in the treatment of chronic heart failure, currently there are very few evidence-based strategies to treat acutely decompensated heart failure. The incidence of heart failure will likely continue to rise with the increasing prevalence of HF risk factors (advanced age, hypertension, obesity, diabetes, and other metabolic diseases). Accordingly, substantial efforts are underway to identify and treat populations at risk and to understand the molecular drivers of this heterogeneous disease.

The investigators understanding of the pathophysiology of heart failure has evolved from a 'cardiocentric' view focused on mechanical dysfunction to a more global view. Heart failure is now understood as a complex blend of structural, functional, and neurohormonal abnormalities manifested both locally and systemically. More recently, several groups have demonstrated abnormalities in the inflammatory cascade associated with both the initiation and the progression of heart failure. The innate immune system appears to modulate the inflammatory component of HF through several mechanisms including the production of inflammatory cytokines (tumor necrosis factor-α,TNFα; interleukin-6, IL6), reactive oxygen species, activation of the complement system, as well as through functional modification of endothelial cells and myeloid cell trafficking.

Monocytes and macrophages are two of the key myeloid mediators of acute and chronic inflammatory responses. Myeloid dysregulation has been implicated in the pathogenesis of diverse diseases including diabetes, tumor metastasis, pulmonary fibrosis, myocardial infarction, and atherosclerosis. Accumulating evidence suggests that myeloid subsets have distinct functional properties reflecting their polarization patterns and their interaction with the local microenvironment. As a framework to study their role in models of clinical diseases, myeloid populations have been broadly categorized as "inflammatory" and "anti-inflammatory" based on specific surface markers, cytokine potential, and other functional properties.

Although the role of myeloid populations in inflammatory disease is now appreciated, the molecular mechanisms linking these cells to clinical heart failure syndromes remain largely unknown. The investigators hypothesize that distinct myeloid subsets drive different phases of acute and chronic heart failure syndromes, and that identification of these subsets and their functional properties will provide further insight into the pathophysiology of clinical heart failure.

In order to initially characterize the roles that monocytes play across the spectrum of heart failure, the investigators will obtain whole-blood samples from acutely decompensated patients on the date of hospitalization, the date of transfer from the intensive care unit (ICU) to the general-care telemetry floor (if relevant), the date of hospital discharge, and at their first outpatient follow-up visit. Subjects will be recruited from the University of Michigan inpatient heart failure service, which admits approximately 75 patients for decompensated heart failure each month. Once the samples are obtained, the investigators will perform flow cytometry to characterize monocyte subsets and their flux in response to treatment. The investigators will also look at the production of reactive oxygen species by monocytes and will examine how cytokines and chemokines skew monocyte population subsets and their gene expression profiles. The investigators will also investigate the energetic state and flux (aerobic vs. anaerobic metabolic status) of the monocytes.

• Study Type: Observational
• Enrollment (Actual): 60

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Heart failure inpatients and age-matched controls

Description

Inclusion Criteria: Heart Failure Patients:

• 18 years of age or older
• Patients must be diagnosed with heart failure
• Patients must be hospitalized at the University of Michigan Hospital for treatment of heart failure symptoms.

Exclusion Criteria: Heart Failure Patients:

• Heart attack or other active problem with coronary artery disease
• Severe kidney failure or need for dialysis
• An active infection or inflammatory condition
• A need for treatment that affects the immune system (e.g. systemic steroids, immunomodulatory therapies)
• A planned surgery during this hospital admission, including heart transplant or other heart surgery

Inclusion Criteria: Healthy Control Patients:

- Must be greater than or equal to 65 years of age

Exclusion Criteria: Healthy Control Patients:

• Diabetes
• High blood pressure
• Active cancer
• Heart disease
• Lung disease
• Liver disease
• Kidney disease
• Active smoker

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Heart Failure; Heart Failure patients admitted to the ICU or Heart Failure Service. No changes in service-directed plan of care for patients.
Healthy Control; Healthy, age-matched controls.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in IL-6 between hospital admission and discharge	Cytokine	All scheduled blood draws - hospital admission, discharge (3-14 days after admission), and first post-discharge appointment (5-10 days following discharge)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lys6c Hi and Lo, Mannose Receptor	Cell Surface Markers	All scheduled blood draws - hospital admission, discharge (3-14 days after admission), and first post-discharge appointment (5-10 days following discharge)
IL-10, IL-13	Cytokine	All scheduled blood draws - hospital admission, discharge (3-14 days after admission), and first post-discharge appointment (5-10 days following discharge)
Gene Expression (iNOS, CCL2, Ym1, Fizz, VEGF, MMP2/9)	Monocyte gene expression	All scheduled blood draws - hospital admission, discharge (3-14 days after admission), and first post-discharge appointment (5-10 days following discharge)
microRNA	miR155, let7, mir-33a	All scheduled blood draws - hospital admission, discharge (3-14 days after admission), and first post-discharge appointment (5-10 days following discharge)
Monocyte/macrophage morphology	Macrophages/monocytes will be classified based on their morphology	All scheduled blood draws - hospital admission, discharge (3-14 days after admission), and first post-discharge appointment (5-10 days following discharge)
Serum F-2 Isoprostanes	Oxidative stress marker	All scheduled blood draws - hospital admission, discharge (3-14 days after admission), and first post-discharge appointment (5-10 days following discharge)
TNF-alpha	Marker of inflammation	All scheduled blood draws - hospital admission, discharge (3-14 days after admission), and first post-discharge appointment (5-10 days following discharge)

Collaborators and Investigators

• Sponsor: University of Michigan
• Investigators: Principal Investigator: Scott Hummel, MD MS, University of Michigan; Principal Investigator: Adam Stein, MD, University of Michigan; Principal Investigator: Sascha Goonewardena, MD, University of Michigan

Publications and helpful links

General Publications

• Seidler S, Zimmermann HW, Bartneck M, Trautwein C, Tacke F. Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults. BMC Immunol. 2010 Jun 21;11:30. doi: 10.1186/1471-2172-11-30.
• Polidori MC, Pratico D, Savino K, Rokach J, Stahl W, Mecocci P. Increased F2 isoprostane plasma levels in patients with congestive heart failure are correlated with antioxidant status and disease severity. J Card Fail. 2004 Aug;10(4):334-8. doi: 10.1016/j.cardfail.2003.11.004.
• Colombo PC, Banchs JE, Celaj S, Talreja A, Lachmann J, Malla S, DuBois NB, Ashton AW, Latif F, Jorde UP, Ware JA, LeJemtel TH. Endothelial cell activation in patients with decompensated heart failure. Circulation. 2005 Jan 4;111(1):58-62. doi: 10.1161/01.CIR.0000151611.89232.3B. Epub 2004 Dec 20.
• Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990 Jul 26;323(4):236-41. doi: 10.1056/NEJM199007263230405.
• Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation. 2001 Apr 24;103(16):2055-9. doi: 10.1161/01.cir.103.16.2055.
• Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, van Veldhuisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004 Apr 6;109(13):1594-602. doi: 10.1161/01.CIR.0000124490.27666.B2. Epub 2004 Mar 15.
• Aukrust P, Ueland T, Lien E, Bendtzen K, Muller F, Andreassen AK, Nordoy I, Aass H, Espevik T, Simonsen S, Froland SS, Gullestad L. Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1999 Feb 1;83(3):376-82. doi: 10.1016/s0002-9149(98)00872-8.

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): June 23, 2022
• Study Completion (Actual): June 23, 2022

Study Registration Dates

• First Submitted: March 19, 2012
• First Submitted That Met QC Criteria: December 15, 2016
• First Posted (Estimated): December 20, 2016

Study Record Updates

• Last Update Posted (Actual): May 8, 2024
• Last Update Submitted That Met QC Criteria: May 6, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Endothelial Function; Oxidative Stress; Congestive Heart Failure; Monocyte
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: HUM00049322

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No