NOBEL PRIZE SYMPOSIUM

Pathophysiology of Chronic Systolic Heart Failure

A View from the Periphery
Stuart D. Katz
Leon H. Charney Division of Cardiology, New York University School of Medicine, New York University Langone Health, New York,
New York
ORCID ID: 0000-0003-2340-2021 (S.D.K.).

Abstract failure. Reduced metabolic vasodilation limits delivery of available

Heart failure is a common form of heart disease associated with
progressive exercise intolerance and high risk of adverse clinical
outcome events. The pathophysiology of chronic systolic heart
failure is fundamentally determined by the failure of the circulatory
system to deliver oxygen sufficient for metabolic needs, and
it is best explained by a complex interplay between intrinsic
abnormalities of ventricular pump function and extracardiac factors
that limit oxygen use in metabolically active tissues. This brief review
highlights the role of extracardiac factors (peripheral factors) that
may impact exercise capacity in patients with chronic systolic heart
cardiac output reserve to skeletal muscle during exercise, and it
is associated with reduced peak oxygen capacity. Abnormal substrate
use in skeletal muscle due to reduced skeletal muscle mass, change
in skeletal muscle fiber type, and mitochondrial dysfunction reduces
work efficiency and submaximal exercise endurance capacity in
patients with systolic heart failure. These extracardiac peripheral
mechanisms of impaired exercise tolerance in chronic heart failure
may be targets for novel therapeutic development in this patient
population.
Keywords: vasodilation; skeletal muscle; exercise

(Received in original form October 11, 2017; accepted in final form January 5, 2018 )
Correspondence and requests for reprints should be addressed to Stuart D. Katz, M.D., M.S., Leon H. Charney Division of Cardiology, New York University
Langone Health, 530 First Avenue, Skirball 9R, New York, NY 10016. E-mail: stuart.katz@nyumc.org.
Ann Am Thorac Soc Vol 15, Supplement 1, pp S38–S41, Feb 2018
Copyright © 2018 by the American Thoracic Society
DOI: 10.1513/AnnalsATS.201710-789KV
Internet address: www.atsjournals.org

Heart failure affects 6 million persons in the
United States and is associated with high
rates of hospitalization (1.1 million/yr), high
health care costs (.$30 billion/yr in
Medicare costs), and high mortality risk
(30 to 50% over 5 yr) (1, 2). Heart failure
due primarily to systolic dysfunction (also
known as heart failure with reduced
ejection) accounts for approximately 50% of
the heart failure cases. Although there is
some overlap in the pathophysiology of
heart failure related to primary systolic or
diastolic dysfunction, this review is focused
on a discussion of chronic systolic heart
failure. The pathophysiology of chronic
systolic heart failure is fundamentally
determined by the failure of the circulatory
system to deliver sufficient oxygen for
metabolic needs, and it is best explained
by a complex interplay between intrinsic
abnormalities of ventricular pump function
and extracardiac factors that limit oxygen
use in metabolically active tissues (3–6).
Exercise intolerance at both maximal and
submaximal effort is the hallmark of
progressive heart failure, and it is associated
with worsened quality of life and increased
risk of adverse clinical outcomes. This
brief review considers the role of two
extracardiac factors (“peripheral factors”)—
abnormal metabolic vasodilation in skeletal
muscle and abnormal skeletal muscle
substrate use—in the pathogenesis of
exercise intolerance at maximal and
submaximal effort in patients with chronic
systolic heart failure (7, 8).
According to the Fick equation, peak
oxygen uptake during exercise is determined
by the product of the peak oxygen cardiac
output and the peak arteriovenous
oxygen difference (9). Cardiac output
reserve is reduced in patients with heart
failure in proportion to the severity of
functional impairment (10). However, there
are several lines of evidence which suggest
that reduced cardiac output reserve is not
the primary limitation of peak oxygen
uptake. Acute and chronic pharmacological
interventions that increase cardiac output
reserve during exercise are not associated
with the expected increase in peak oxygen
uptake in patients with chronic heart
failure (11, 12). Patients with more severe
reduction in functional capacity (New York
Heart Association class III) also manifest
an abnormal response to combined upper
and lower extremity exercise (13). In
contrast to normal control subjects or
patients with chronic systolic heart failure
with more well-preserved functional

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 NOBEL PRIZE SYMPOSIUM
capacity, patients with more severe
impairment of functional capacity
demonstrate a marked increase in peak
oxygen uptake when arm ergometry
exercise is combined with maximal leg
ergometry exercise, suggesting that
maximal leg ergometry alone does not
exhaust cardiac output reserve in these
patients. Taken together with the findings
of studies with acute and chronic
pharmacological interventions, it appears
that maximal lower extremity exercise in
patients with chronic systolic heart failure
is limited not by cardiac output reserve,
but rather by reduction of delivery of
available cardiac output to the active
skeletal muscle in the lower extremity.
Reduced delivery of cardiac output
during exercise in patients with chronic
heart failure is attributable to reduced
metabolic vasodilation in the skeletal
muscle circulation. Zelis and colleagues
first described impaired response to
numerous vasodilatory stimuli, including
pharmacological agents and transient limb
ischemia in patients with chronic heart
failure due primarily to rheumatic heart
disease (14). Subsequent investigations
demonstrated that the reduction in
postischemic metabolic vasodilation in the
calf circulation is proportional to the
reduction in peak oxygen uptake (15). The
mechanisms contributing to reduced
metabolic vasodilation have not been fully
characterized. Sympathetic activation
during exercise is not a contributing factor,
because pharmacological a-adrenergic
blockade does not increase limb blood flow
during exercise or after transient limb
ischemia in patients with chronic heart
failure (14, 16). Vascular wall edema may
play a role, because treatment with loop
diuretics is associated with improved
postischemic limb vasodilation in patients
with chronic systolic heart failure (17).
Vascular endothelium–dependent, nitric
oxide–mediated vasodilation is abnormal
in conduit arterial vessels of patients
with chronic systolic heart failure, but the
role of endothelial dysfunction in metabolic
vasodilation in the skeletal muscle
microcirculation has not been determined
(18). The observation that minimal vascular
resistance after a maximal ischemic
vasodilation stimulus is increased in
chronic heart failure when compared with
control subjects without heart failure
suggests that remodeling of the skeletal
muscle microcirculation (either rarefaction,
Katz: Pathophysiology of Chronic Heart Failure
reduction in maximal arteriolar lumen size, compared with control populations
or both) is a determinant of reduced (6, 8, 21–27). Endurance performance at
skeletal muscle blood flow during exercise. submaximal exercise levels is determined
The remodeling process in skeletal by the efficiency of mitochondrial
muscle microcirculation appears to be a conversion of oxygen to adenosine
dynamic process that can be partially triphosphate and efficiency of the
reversed with interventions that reduce conversion of adenosine triphosphate to
neurohormonal activation and therefore physical work (28–31). Decreased work
is a potential target for novel therapeutics efficiency during submaximal exercise has
development in patients with chronic been reported in subjects with chronic
systolic heart failure (19, 20). systolic heart failure when compared with
Submaximal exercise endurance control subjects without heart failure (32).
capacity is determined by factors that link The etiology of abnormal skeletal
oxygen delivery, substrate use, and muscle structure and function has not been
ventilation in response to increased definitively characterized, but it is thought
metabolic demand during exercise (9). to be potentially related to effects of chronic
In patients with chronic systolic heart neurohormonal activation, chronic
failure, available evidence suggests that inflammation, and increased oxidative stress
submaximal exercise is limited not by in heart failure; however, there is little
reduced nutritive blood flow, but rather interventional study data for assessment
by impaired substrate use in skeletal of causality (33, 34). Many of the described
muscle. Patients with chronic heart failure abnormalities in patients with heart failure
demonstrate reduced percentage of are concordant with skeletal muscle
type I (oxidative slow-twitch) muscle changes associated with deconditioning,
fibers, reduced skeletal muscle aerobic chronic lung disease, and aging. Physical
enzyme activity, reduced skeletal muscle training in patients with chronic systolic
mitochondrial volume density, reduced heart failure increased skeletal muscle
skeletal muscle mass, and reduced skeletal mitochondrial volume density and the
muscle mitochondrial oxidative capacity proportion of type I muscle fibers when
independent of nutrient blood flow when compared with a nontrained control group (35).
Myocardial Injury or Overload
Abnormal Cardiac Pump Function
Reduced Cardiac Output Reserve
Neurohormonal Activation
Increased Cardiac Filling Pressures
Reduced Skeletal Muscle Mass
Impaired Metabolic Vasodilation
Mitochondrial Dysfunction
Reduced Oxygen Utilization
Reduced Work Efficiency
Reduced Exercise Capacity
Figure 1. Pathophysiology of exercise intolerance in patients with chronic systolic heart failure. A
combination of hemodynamic factors related to impaired cardiac pump function (reduced cardiac
output reserve, neurohormonal activation, and increased cardiac filling pressures) and extracardiac
factors that limit skeletal muscle oxygen use (impaired metabolic vasodilation, reduced skeletal
muscle mass, and mitochondrial dysfunction) contribute to impairment of both submaximal and
maximal exercise capacity in patients with chronic systolic heart failure.
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Iron deficiency is common in chronic heart
failure and may be an important
determinant of abnormal skeletal muscle
mitochondrial function in this population
(36–38). Experimental iron deficiency
in rats is associated with evidence of
mitochondrial dysfunction and reduced
exercise capacity (39–44). In most human
subject studies of iron deficiency, an
increase in maximal exercise performance
in response to iron repletion therapy
is closely linked to hemoglobin levels,
but some field reports and submaximal
exercise data suggest that iron repletion
may result in change in skeletal muscle
efficiency and metabolism independent of
hemoglobin effects (45). Previous studies
have demonstrated that intravenous iron
administration is associated with evidence
of clinical improvement in patients with
heart failure with iron deficiency, with or
without anemia (46–49). In the majority
of studies, detection of a potential
effect of iron replacement on skeletal
muscle function is confounded by
increases in hemoglobin levels. However,
some randomized clinical trials have
demonstrated that iron repletion with
intravenous ferric carboxymaltose
was associated with improvement in
submaximal exercise capacity and quality-
of-life scores when compared with placebo
independent of the initial hemoglobin
or ferritin levels and without change in
hemoglobin level in response to therapy
(50). Further investigation is need to
determine links between iron stores,
mitochondrial function, and exercise
capacity in patients with chronic systolic
heart failure without anemia who
have evidence of functional iron
deficiency.
In conclusion, the exercise intolerance
in patients with chronic systolic heart failure
is determined by a combination of abnormal
cardiac hemodynamics, as elegantly
described by Dr. Cournand and Dr.
Richards in their Nobel Prize–winning
investigations (51, 52), and extracardiac
peripheral factors including impaired
skeletal muscle metabolic vasodilation and
skeletal muscle mitochondrial dysfunction
that limit oxygen use during submaximal
and maximal exercise (Figure 1). This
complex pathophysiology may provide
targets for development of novel
therapeutic interventions to improve
exercise capacity and quality of life
in patients with chronic systolic heart
failure. n
Author disclosures are available with the text
of this article at www.atsjournals.org.

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