Monocyte Phenotypic Changes in Heart Failure

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.

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