The role of nutritional deficiencies in chronic heart failure

Despite improvements in chronic heart failure (HF) treatment, mortality and
morbidity rates remain high. Also, daily activities of many patients stay
behind. Exercise intolerance is a cardinal feature of HF, and is related to a
poor quality of life and an heightened risk of morbidity and mortality. In
addition, comorbidities, such as anemia are common in chronic HF and might
further contribute to impaired exercise capacity. Despite the focus on anemia
as a target for therapy in HF, the cause of anemia in chronic HF patients is a
matter of ongoing debate. Similarly, the mechanism by which the presence of
anemia contributes to an adverse outcome in these patients, is often complex
and multifactorial.

In regard to the etiology of anemia in chronic HF, there is growing evidence
that nutritional deficiencies, in particular iron deficiency (ID), play a role
in chronic HF. Iron deficiency is the most common nutritional disorder,
affecting more than one-third of the general population. Traditionally, ID has
been considered to have clinical consequences only in the presence of anemia.
Alternatively, a reduced hemoglobin level can be viewed as the end result of a
process beginning with the gradual depletion of iron stores. Even if patients
are not anemic, ID may already be common in HF.

In the past few years, it has been recognized that chronic HF patients are
prone to develop ID or other nutritional deficiencies. For ID, this may result
from either an absolute deficiency of iron, due to the result of a gradual
depletion of iron stores (absolute ID), causing iron deficiency anemia.
Alternatively, ID may be *relative* or *functional*, the result of inflammatory
process and the sustained elevation of pro-inflammatory cytokines, including
interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα). An increase in
these cytokines causes a decrease in erythropoietin (EPO) production and a
reduced erythropoietic response of the bone marrow to increased EPO levels.
Also, IL-6 increases the synthesis of hepcidin, a liver derived protein.
Hepcidin, in return, causes reduced iron absorption and dysregulation of iron
homeostasis and accumulation of iron in cells of the reticuloendothelial
system, which is a characteristic feature of anemia of chronic disease.

However, not much is known about the prevalence of ID and other nutritional
deficiencies (e.g. vitamin B12, folate) in chronic HF. Also, they relationship
between these nutritional deficiencies and exercise capacity or outcome has not
been fully explored. For that reason, we want to investigate the prevalence of
ID, vitamin B12 deficiency (VB12D) and folate deficiency (FD) and examine their
relation with exercise capacity and outcome.

Primary Objective:
• To investigate the relationship between ID, VB12D or FD and outcome (HF
hospitalization and all-cause mortality) in patients with chronic HF.

Secondary Objectives:
• To investigate the prevalence of ID, VB12D or FD in chronic HF.
• To investigate the relationship between ID, VB12D or FD and exercise capacity
in chronic HF patients.
• To investigate possible differences in blood markers (e.g. NTproBNP, renal
function, inflammatory markers) between chronic HF patients
with/without ID, VB12D or FD.
• To describe differences in chronic HF patients with/without ID, VB12D or FD
regarding echocardiographic parameters and non-invasive
cardiac index (Nexfin).

This protocol concerns a non-interventional study, in which previous stored
blood samples from all patients, who participated in the BENFICIAL (A
double-Blind, placEbo-coNtrolled, randomized trial Evaluating the efFICacy and
safety of ALagebrium (ALT-711) in patients
with chronic heart failure) trial, will be analyzed. All assessments will be
done at the University Medical Center Groningen (UMCG) in Groningen, the
Netherlands.

In 2010 the BENEFICIAL trial ended. This prospective, randomized, double-blind,
placebo-controlled, phase II trial studied the effects of the advanced
glycation end-product (AGE) breaker Alagebrium (ALT-711) on the severity of
chronic HF. 15,16 102 patients with stable chronic HF and a reduced left
systolic function (left ventricular ejection fraction < 45%) were included in
this study. One of the main conclusions of this study was that adding
Alagebrium to the treatment of chronic HF patients did not improve exercise
capacity (measured by 2 cardiopulmonary aerobic capacity tests). During this
study, blood samples from all patients were frozen and stored (for a period of
15 years) to perform additional analysis on in the future.

Rationale for choosing patients from the BENEFICIAL trial
Nutritional deficiencies, in particular ID, have been associated with chronic
systolic HF. It has also been suggested that ID also predicts impaired exercise
capacity in these patients.9,11 To further investigate these findings, we will
use stored blood and data from patients, who participated in the BENEFICIAL
trial. This trial included only patients with a reduced left systolic function
and who performed two cardiopulmonary aerobic capacity tests during this study
to objectify the exercise capacity of these patients.

Blood sample analysis:
Once written informed consent has been obtained by the principal investigator,
blood sample analysis will take place. Approximately 5 mL aliquots of the
stored blood samples will be taken. Validated methods will be used to analyze
multiple blood markers by the laboratory of the University Medical Center
Groningen, the Netherlands. Hematological blood markers that will be assessed
include (but are not limited to): vitamin B12 and folate. Markers that reflect
iron status that will be assessed include (but are not limited to): ferritin,
serum iron, total iron binding capacity, transferrin and soluble transferrin
receptor. Contributors of ID (IL-6, TNFα, hepcidin and growth differentiation
factor 15) will be assessed. Blood samples that are not used will stay frozen
and stored for the remaining period of the 15 years (which started when
patients participated in the BENFICIAL trial). Patients will have to give their
informed consent again to enable possible future analyses on their blood.


ID will be defined as ferritin < 100 µg/L or 100-299 µg/L in combination with a
transferrin saturation of < 20%.
VB12D will be defined as a vitamin B12 level < 142 pmol/L.
FD will be defined as a folate level < 13.6 nmol/L when supplemented and as a
folate level < 6.8 nmol/L when not supplemented.

There are no burdens or risks associated with this study. Only frozen and
stored blood samples from all patients, who participated in the BENEFICIAL
trial (NL16287.042.07), will be used for analysis.