608
UNIT FOUR
A Metabolic Block
Sometimes inherited heart disease strikes early
in life. Jim D. died at four days of age, two days
after suF
ering cardiac arrest. Two years later, his
parents had another son. Like Jim, Kerry seemed
normal at birth, but when he was thirty-six hours
old, his heart rate plummeted, he had a seizure,
and he stopped breathing. He was resuscitated. A
blood test revealed excess long-chain fatty acids,
indicating inability to use fatty acids. Hunger trig-
gered the symptoms because the boys could not
use fatty acids for energy, as healthy people do.
Kerry survived for three years by following a diet
low in fatty acids and eating frequently. Once he
became comatose because he missed a meal.
Eventually, he died of respiratory failure.
Jim and Kerry had inherited a de±
ciency of a
mitochondrial enzyme that processes long-chain
fatty acids. This is a primary energy source for car-
diac muscle, so their tiny hearts failed.
Controlling Cholesterol
Low-density lipoprotein (LDL) receptors on liver
cells admit cholesterol into the cells, keeping the
A
variety of inherited and environmental
factors contribute to causing cardiovas-
cular disease, including poor diet and
sedentary lifestyle, against a backdrop of genetic
predisposition. Disorders of the heart and blood
vessels caused by single genes are rare, but
understanding how they arise can provide
insights useful in developing treatments for more
prevalent forms of disease. ²or example, widely
used cholesterol-lowering drugs called statins
were developed based on understanding famil-
ial hypercholesterolemia, an inherited condition
that aF
ects one-in-a-million children.
A Connective Tissue Defect
Just after midnight on June 8, 2004, ²lorida State
University basketball player Ronalda Pierce lay in
bed watching TV. At about 2
A
.
M
., her roommate
heard sounds of disturbed breathing—Pierce
could not be roused. The nineteen-year-old ath-
lete died within an hour of reaching the hospital.
Her aorta had burst. Pierce had
Marfan syndrome,
an inherited condition that also caused the char-
acteristics that led her to excel in her sport—her
great height and long fingers. In Marfan syn-
drome, an abnormal form of a connective tissue
protein called fibrillin weakens the aorta wall,
dilating the aortic root (±
gure 15K).
Ronalda Pierce had a strong family history
of heart disease, but Marfan syndrome had never
been diagnosed. Identifying the mutation can
make it possible to locate and surgically repair a
weakened aorta, or take a drug that can slow the
effect of the disease on the aorta. This can pre-
vent a tragic ±
rst symptom—sudden death.
A Myosin Defect
Each year, one or two seemingly healthy young
people die suddenly during a sports event, usu-
ally basketball. The cause of death is often
famil-
ial hypertrophic cardiomyopathy,
an inherited
overgrowth of the heart muscle. The defect in
this disorder is diF
erent from that behind Marfan
syndrome. It is an abnormality in one of the myo-
sin chains that comprise cardiac muscle. Again,
detecting the responsible gene can alert aF
ected
individuals to their increased risk of sudden
death. They can adjust the type of exercise they
do to avoid stressing the cardiovascular system.
lipid from building up in the bloodstream and
occluding arteries. When LDL receptors bind cho-
lesterol, they activate a negative feedback system
that temporarily halts the cell’s production of
cholesterol. In the severe form of
familial hyper-
cholesterolemia,
a person inherits two defective
copies of the gene encoding the LDL receptors.
Yellowish lumps of cholesterol can be seen
behind the knees and elbows, and heart failure
usually causes death in childhood. People who
inherit one defective gene have a milder form of
the illness. They develop coronary artery disease
in young adulthood, but can delay symptoms by
following a heart-healthy diet and regularly exer-
cising. These people have half the normal num-
ber of LDL receptors.
In Niemann-Pick type C disease, a defective
protein disturbs the fate of cholesterol inside
cells. Normally, the protein escorts cholesterol out
of a cell’s lysosomes, which triggers the negative
feedback mechanism that shuts off cholesterol
synthesis. When the protein is absent or malfunc-
tions, the cell keeps producing cholesterol and
LDL receptors. Coronary artery disease develops,
and is typically fatal in childhood.
15.7
CLINICAL APPLICATION
Molecular Causes of Cardiovascular Disease
Heart in Marfan syndrome
Aneurysm
Auricle
of right
atrium
Right ventricle
Vena cava
Aorta
Left
ventricle
Pulmonary
artery
Normal heart
Auricle
of right
atrium
Right ventricle
Vena cava
Aorta
Left
ventricle
Pulmonary
artery
FIGURE 15K
The symptoms of Marfan syndrome, including a progressive dilation of the
aortic root, arise from an abnormal form of the connective tissue protein ±
brillin that in turn
increases signaling by a protein called transforming growth factor B (TG²-B). A drug usually used
to treat hypertension, losartan, lowers levels of TG²-B and has been shown in preliminary clinical
trials to slow the life-threatening ballooning out of the ascending aorta. Surgery can replace the
aF
ected part of the aorta with a synthetic graft.
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