7.6.1 The Clinical–Molecular Interface: Congestive Heart
Failure and the Na+/K+ATPase Transporter ProteinCongestive heart failure (CHF) is a common clinical problem in which an abnormality
of myocardial function (myocardiumis the muscle tissue that constitutes the heart)
is responsible for the inability of the heart to deliver adequate quantities of blood to
the tissues of the body at rest or during normal activity. Thus, CHF occurs when the
cardiac output is inadequate to provide the oxygen and nutrients required by the body
for its normal metabolism. It occurs because of the heart’s failure to act as an efficient
mechanical pump, with the primary defect residing at the level of the heart’s excitation–
contraction coupling machinery. CHF is a serious medical problem with a 5-year
mortality of 50%. Its clinical manifestations are varied. The inability of the heart to
effectively handle the fluids and blood, which it normally pumps, produces the char-
acteristic clinical symptoms of CHF. Since the heart is overwhelmed by fluid, it “backs
up” fluid into the lungs, producing dyspnea(shortness of breath) and orthopnea(short-
ness of breath when in the recumbent position). This backed-up fluid in the lungs
can be heard with a stethoscope (as wet-sounding pulmonary rales) or seen on a
chest X-ray. The person with CHF will also experience edemaas both a symptom
and a sign, either in the legs (in ambulatory patients) or over the sacral region at the
base of the back (in bed-bound patients). The inability of the heart to meet the perfu-
sional demands of the body will result in symptoms in which the afflicted individual
will have fatigue, weakness,anorexia, confusion, and other relatively nonspecific
complaints.
At the molecular level, the Na+/K+ATPase molecule is a key player in the signs,
symptoms, and treatment of CHF. Na+/K+ATPase is a membrane-bound transporter
protein, often referred to as the “sodium pump.” Although transmembrane in structure,
much of the Na+/K+ATPase protein extends from the extracellular surface. Na+/K+
ATPase is a dimer constructed from two catalytic αsubunits and two inert βsubunits,
with the βsubunits seemingly functioning by holding the αsubunits in a bioactive con-
formation. Several different forms of this protein, each consisting of multiples of αand
βsubunits, have been identified; the binding sites for Na+,K+and ATP all exist on the
αsubunit. In addition, different isoforms of the subunits have also been identified (three
α,two β), thus providing different versions of the molecule with varying affinities in
various tissues in the body.
The Na+/K+ATPase protein functions as an enzyme crucial to cardiac physiology.
During each contraction of the heart, there is an influx of Na+ion and an efflux of K+
ion at the cellular level (analogous to the molecular events during generation of an
action potential within neurons, described in chapter 4). Before the next contraction of
the heart, Na+/K+ATPase must restore the ionic concentration gradient by pumping Na+
back into the cell against a concentration gradient; this action requires energy which is
obtained from the hydrolysis of adenosine triphosphate (ATP) to adenosine diphosphate
(ADP), also accomplished by Na+/K+ATPase. Thus, Na+/K+ATPases operate to “pump
out” Na+ions that have entered or leaked into a cell and to “pump in” K+ions that have
leaked out of the cell; through this molecular function, the Na+/K+ATPase protein main-
tains the transmembrane gradients for K+and Na+ions and thus the normal electrical
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