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pulmonary capillary wedge pressure, and exercise
intolerance. Dhakal et al.3 found that a peripheral
limitation was the most important cause of reduced aerobic capacity, whereas impaired cardiac
output had less impact. This finding is consistent
with other studies that indirectly estimated oxygen
extraction.
In an accompanying editorial comment, William C. Little, MD, and Barry A. Borlaug, MD,
noted that the delivery of oxygen to contracting
muscles is essential to perform aerobic exercise.4
Optimum oxygen delivery requires oxygenation
of the blood in the lungs, normal oxygen carrying capacity of the blood, adequate cardiac output
that is appropriately distributed to match regional
demands, and adequate tissue extraction of oxygen
from the blood. Normal adults can increase oxygen
consumption (Vo2) more than six-fold during
exercise by increasing cardiac output (because of a
faster heart rate and enhanced stroke volume) and
by augmenting oxygen extraction producing a fall
in mixed venous oxygen content, thereby increasing the difference between arterial and venous
oxygen content. Measuring Vo2 during exercise
provides a powerful method to objectively assess
the degree of functional limitation and prognosis

in patients with HFrEF. The study by Dhakal et al.
confirms that the cause of the reduction in peak
Vo2 in patients with HFpEF is predominantly (but
not exclusively) because of an inadequate increase
in cardiac output during exercise.
Thus, the evidence suggests that improving
abnormal O2 extraction—for example, through exercise—might be an important therapeutic target
in the notoriously difficult-to-treat patients with
HFpEF. And it seems exercise is the key; while
most studies have looked at aerobic exercise, resistance training as been evaluated, too, although
there is really not enough evidence available at the
present time to say one is superior to the other.
Little and Borlaug added, the data also suggest
other approaches to therapy: For example, “inorganic nitrates can improve vascular conductance
and oxygen delivery to skeletal muscle during
exercise. An alternative approach might be to
modify the allosteric regulation of hemoglobin
to allow for greater oxygen dissociation in the
muscle. In addition, training may enhance exercise
tolerance in HFpEF without producing an improvement in systolic or diastolic function. It may be
that exercise testing can be used to identify the
primary mechanisms of exercise intolerance in the

individual patient, potentially allowing for more
tailored therapies in HFpEF.”
Here is how Dr. Litwin interprets the data:
there are intrinsic abnormalities of skeletal
muscle structure, biochemistry and metabolism
in HFpEF. Exercise increases muscle oxygen
uptake, perhaps via mitochondrial biogenesis,
muscle fiber type, increased oxidative enzymes,
and increased capillary density.
Put another way, a heart-centric view has not
been helpful in the treatment of HFpEF, with failure
to benefit from angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone
antagonists, beta-blockers, digoxin, phosphodiesterase type 5 inhibitors, and nitrates. Therefore, when
considering HFpEF, think outside the heart. ■
REFERENCES:
1. Pandey A, Parashar A, Kumbhani DJ, et al. Circ Heart Fail.
2015;8:33-40.
2. Fujimoto N, Prasad A, Hastings JL, et al. Am Heart J.
2012;164:869-77.
3. Dhakal BP, Malhotra R, Murphy RM, et al. Circ Heart Fail.
2015;8:286-94.
4. Little WC, Borlaug BA. Circ Heart Fail. 2015;8:233-5.

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