Download Structure and Function of the Aortic Valve

1 Your Heart & Valves
Cardiac valves are structures that are designed to work like one-way doors. They let blood
flow in from one chamber or vessel to another, and then close to prevent the blood from
regurgitating backward. There are four valves within your heart. They are the mitral, tricuspid,
aortic and pulmonic valve.
The mitral valve and tricuspid valve lie between the atria (upper heart chambers) and the
ventricles (lower heart chambers). The aortic valve and pulmonic valve lie between the
ventricles and the major blood vessels leaving the heart.
As blood leaves each chamber of the heart, it passes through a valve. Your heart valves
make sure that blood flows in only one direction through your heart.
1 of 19 24/06/2017 at 18:32
1.1
A closer looks at what valves look like.
Mitral Valve Closed
Aortic Valve Open
The valve is made of strong, thin pieces or flaps of tissue called leaflets.
Mitral Valve Open
Aortic Valve Closed
The leaflets are attached to and supported by a ring of tough fibrous tissue called the
annulus. The annulus helps to provide support and maintain the proper shape of the valve.
The valve leaflets can be compared to doors opening and closing. While the annulus
functions as the door frame.
The leaflets of the mitral and tricuspid valve are also supported by tough, fibrous strings
called chordae tendineae. These are similar to the strings supporting a parachute. The
chordae tendineae extend from the valve leaflets to small muscles, called papillary muscles,
which are part of the inside walls of the ventricles. The chordae tendineae and papillary
muscles keep the leaflets stable against any backward flow of blood.
1.2
Structure and Function of the Aortic Valve
The aortic valve consists of 3 half-moon-shaped pocket-like flaps of delicate tissue, referred to
as cusps. When the aortic valve is closed, the cusps are perfectly aligned and separate the
large pumping chamber of the heart (the left ventricle) from the large artery (aorta) that
supplies blood to the body. During the period when the left ventricle contracts and pumps the
blood (systole), the aortic valve opens widely and blood flows freely from the left ventricle to
the aorta. When the left ventricle then relaxes (diastole), the aortic valve closes completely so
that the blood remains in the aorta. During diastole, blood flows into the left ventricle from the
lungs through the left atrium across the mitral valve, thus refilling the ventricle for the next
contraction.
2 Congenital Valve Disease
Congenital Valve Disease is an abnormality that develops before birth. It may be related to
improper valve size, malformed leaflets, or an irregularity in the way the leaflets are attached.
This most often affects the aortic or pulmonic valve.
 Bicuspid aortic valve disease
is a congenital valve disease that affects the aortic valve. Instead of the normal three
leaflets or cusps, the bicuspid aortic valve has only two. Without the third leaflet, the
valve may be:
Bicuspid aortic valve disease affects about 2 percent of the population.
2 of 19 24/06/2017 at 18:32
Clinical diagnosis of a bicuspid aortic valve condition was unsatisfactory before the
widespread use of cross sectional echocardiography approximately 15 years ago.
Because bicuspid aortas have familial clustering (37% of which males are affected in
a ration of 4:1) it might also be appropriate to screen first-degree relatives, especially
brothers and sons. A bicuspid aortic valve is detected in only about 35% of patients
using echocardiograms.
BAV is associated with accelerated degeneration of the aortic media (dilatation,
aneurysm formation, degradion of elasticity, and dissection), indicating that BAV
disease is an ongoing pathological process, not a discrete developmental event.
If a bicuspid aortic valve is left untreated, once symptoms start death occurs within 2
to 4 years.


Stenotic - stiff valve leaflets that can not open or close properly
Leaky - not able to close tightly
This occurs more frequently in some family members. About 1/4 of patients may have
some enlargement of the aorta above the valve.
3 of 19 24/06/2017 at 18:32
3 Diagnosis of valve disease
Once onset of symptoms occurs they will increase at the rate of 6% per year or progressive
left ventricular dilation of 3% to 4% per year
Performing diagnostic tests help your cardiologist evaluate the extent of your valve disease,
its effect on the function of your heart, and the best form of treatment for you. Tests may
include:
3.1
Echocardiogram (echo)
An "echo" is a graphic outline of the heart's movement. A sound-wave transducer wand is
placed on the surface of the chest. High frequency sound-waves are used to provide pictures
of the heart's valves and chambers and to look at the pumping action of the heart. Echo is
often combined with Doppler ultrasound and color Doppler to detect changes in the blood flow
across the heart valves and pressures within the chambers. An echocardiogram can be
performed at rest or during exercise, down the throat (more accurate) or externally.
3.2
Electrocardiography (ECG)
Electrocardiography (ECG) is a quick, simple, painless procedure in which electrical impulses
flowing through the heart are amplified and recorded on a moving strip of paper. This record,
the electrocardiogram (the ECG), provides information about the part of the heart that triggers
each heartbeat (the pacemaker), the nerve conduction pathways of the heart, and the rate
and rhythm of the heart.
An electrocardiogram (ECG) represents the electrical current moving through the heart during
a heartbeat. The current's movement is divided into parts, and each part is given an
alphabetic designation in the ECG.
Each heartbeat begins with an impulse from the heart's pacemaker (sinus or sinoatrial node).
This impulse activates the upper chambers of the heart (atria). The P wave represents
activation of the atria.
Next, the electrical current flows down to the lower chambers of the heart (ventricles). The
QRS complex represents activation of the ventricles.
4 of 19 24/06/2017 at 18:32
The electrical current then spreads back over the ventricles in the opposite direction. This
activity is called the recovery wave, which is represented by the T wave.
Many kinds of abnormalities can be seen on an ECG. For example, the heart rhythm may be
abnormal: too fast, too slow, or irregular. By reading an ECG, doctors can usually determine
where in the heart the abnormal rhythm starts and can begin to determine its cause.
3.3
Multiple-gated acquisition (MUGA) scan
The MUGA scan measures the heart's function and the flow of blood through it. The strongest
chamber in the heart is the left ventricle, which serves as the main pump of blood through the
body. The MUGA scan is the most accurate, non-invasive test available to assess the heart's
ventricles.
MUGA is a nuclear heart scan, which means that it involves the use of a radioactive isotope
that targets the heart and a radionuclide detector that traces the absorption of the radioactive
isotope. The isotope is injected into a vein and absorbed by healthy tissue at a known rate
during a certain time period. The radionuclide detector, in this case a gamma scintillation
camera, picks up the gamma rays emitted by the isotope.
The MUGA scan is not dangerous. The technetium is completely gone from the body within a
few days of the test. The scan itself exposes the patient to about the same amount of
radiation as a chest x ray. The patient can resume normal activities immediately after the test.
Normal results
If the patient's heart is normal, the technetium will appear to be evenly distributed in the
scans. In a stress MUGA, patients with normal hearts will exhibit an increase in ejection
fraction or no change.
Abnormal results
An uneven distribution of technetium in the heart indicates that the patient has coronary artery
disease, a cardiomyopathy, or blood shunting within the heart. Abnormalities in a resting
MUGA usually indicate a heart attack, while those that occur during exercise usually indicate
ischemia. In a stress MUGA, patients with coronary artery disease may exhibit a decrease in
ejection fraction.
3.4
Cardiac Catheterization (Cardiac Cath or Angiogram)
A catheter (inserted into your arm or leg) is guided to your heart, contrast dye is injected and
x-rays of your coronary arteries, heart chambers, and heart valves are taken.
Additional tests, such as the exercise stress echocardiogram, radionuclide scans, and
magnetic resonance imaging (MRI) may also be used.
5 of 19 24/06/2017 at 18:32
4 Valve Replacement and Repair
4.1
Aortic
Mechanical Valve Replacement
Mitral
Mechanical valves are made totally of mechanical parts, which are non-reactive and tolerated
well by the body. The bileaflet valve is used most often. It consists of two pyrolite (qualities
similar to a diamond) carbon leaflets in a ring covered with polyester knit fabric.
Advantages:
Mechanical valves are very sturdy. They are designed to last a lifetime. Re-operations for
mechanical failures or tissue in-growth are uncommon.
Drawbacks:
Due to the artificial material involved, patients who receive these valves will need to take a
blood-thinner (anticoagulant) medication for the rest of their lives. Blood thinners are
medications (such as warfarin or Coumadin) that delay the clotting action of the blood. They
help prevent clots from forming on the valve prosthesis; such clots can cause a heart attack
or stroke and disturb the valve function.
Bi Technology valve prosthesis. After the examination of 33 mechanical prostheses over 264
months (mean, 72 months), the overall causes of failure modes included paravalvular leak
15%, thrombosis 7%, tissue overgrowth 8%, degeneration or mechanical failure 43%, and
endocarditis 19%.
No clear failure mode predominates with mechanical valve prostheses, although some
designs have specific inherent limitations.
Tri Technology valve prosthesis has a high risk of structural failure; leaflet escape caused by
a leaflet’s pivoting system fracture is usually fatal.
6 of 19 24/06/2017 at 18:32
4.2
Mitral valve repair
Mitral valve repair is the procedure of choice for most patients with mitral regurgitation (a
leaky valve). When the leak is caused by mitral valve prolapse (degenerative mitral valve
disease), a variety of repair techniques may be employed. Quadrangular resection is the
technique used most frequently for posterior leaflet prolapse. Mitral valve repair is superior to
replacement. If repair is not feasible, the subvalvular apparatus should be preserved. Early
surgery before the development of severe symptoms and demonstrable left ventricular
impairment is also needed to optimize outcome
Chordal transfer to correct anterior leaflet prolapse. Posterior leaflet chordae are transferred
to the unsupported free edge of the anterior leaflet. The posterior leaflet is repaired as after a
quadrangular resection.
Gor-Tex chord for correction of anterior leaflet prolapse.
Chordae may be constructed from Gore-Tex sutures. A premeasured loop of Gore-Tex is
affixed to the head of the papillary muscle with a pledgetted suture. The loop is then attached
to the free edge of the unsupported anterior leaflet, providing support.
Long-term durability is excellent. The new chordae do not rupture or elongate.
4.3
Aortic Wrapping and Aortoplasty
Aortic Wrapping of the ascending aorta is a procedure that is carried out to prevent dissection
occurring with or without Valve replacement.
Aortic wrapping with or without aortoplasty may have a beneficial effect not only in dilated
ascending aorta but also in all non-dilated BAV patients. Ascending aorta wrapping in BAV
patients may preserve the endothelial lining and prevent further dilatation, aneurysm
formation, and dissection. Less elastic tissue in the aortas of BAV patients may explain the
anecdotal increase in aortic fragility and propensity for aortic dissection, but at this time the
suspected portion of the aorta will generally be replaced with a dacron graft, a more
established procedure with good data on long term durability. Wrap procedures have met with
variable success.
7 of 19 24/06/2017 at 18:32
Aortaplasty
The wrapping of the supracoronary-ascending aorta during AVR should not increase the
surgical risk. Fixing the Dacron wrap to the aorta with decreasing diameter prevents
dislocation of the wrap and therefore erosion of the aorta.
It is very important for anticipatory surgery for dilatation of the ascending aorta in
patients with bicuspid aortic valves compared with patients with tricuspid aortic
valves.
5 Risk Factors for Patients
5.1
Bicuspid Aortic Valve
BAV itself is reported as a risk factor for aortic dissection after AVR. Studies have confirmed
the higher risk of late ascending aorta aneurysm or dissection (a tear of the aorta causing
blood to flow between the layers of the wall of the aorta and dissects the layers) in patients
with BAV, and reinforce the importance of appropriate timing of ascending aorta replacement
in cases of AVR or other cardiac procedures in these patients.
Dissection of the ascending aorta is likely in 50% of patients where there is a coexisting
bicuspid aortic valve. Research has shown a greater incidence of sudden death and
aortic events in the BAV patients (5 times more likely).
Regardless of a seemingly normal ascending aorta at surgery the occurrence of
ascending aortic alterations during follow-up could not be predicted at the time of the first
operation and was independent of the ascending aorta diameter. In post mortems the
dissection entrance tear was always in the ascending aorta, which usually had severe
loss of elastic fibres in its media
Patients with BAV seem to have a severe alteration of the aortic wall, which is
potentially capable of evolving into acute aortic pathology or progressive dilation of
the ascending aorta, independent of valve surgery. Currently there are no diagnostic tests
that enable a prediction of which patients with BAV will develop ascending aorta pathology.
Most patients who experience acute aortic syndrome die. Operations for acute aortic
dissection or ascending aorta aneurysm after AVR have very high perioperative mortality and
morbidity.
5.2
Aortic Left Ventricular Ejection Fraction (LVEF)
The left ventricular ejection fraction (LVEF) is an important clinical indicator of the cardiac
function and long-term outcome for patients with coronary artery disease.
The left ventricular is assessed by measuring the amount of blood pumped with each
heartbeat (the ejection fraction), ventricle filling, and the blood flow into the pumping chamber.
A normal ejection fraction is 50% or more. The heart's ejection fraction is one of the most
8 of 19 24/06/2017 at 18:32
important measures of its performance. Although a marker of survival, ejection fraction looses
its prognostic value when it dips under 25% and is above 40-45%.
5.3
Aortic Insufficiency (AI, Regurgitation)
Aortic Insufficiency (regurgitation) occurs when there is a leakage of the valve backward into
the left ventricle during diastole. This can be caused by structural abnormalities of the valve,
similar to those seen in aortic stenosis. Enlargement of the aorta can stretch the valve cusps
and produce aortic regurgitation. The acute onset of aortic regurgitation can occur when there
is an infection of the aortic valve (called infective endocarditis) or a tear in the aorta.
Chronic aortic regurgitation may be present for decades before any symptoms occur. The left
ventricle is able to compensate for the large volume of blood that flows backward by enlarging
the cavity and increasing the thickness of the muscle. This mechanism allows the heart to
pump out both the amount of blood required by the body and the blood that has gone
backward into the left ventricle. When symptoms do occur, patients usually experience
shortness of breath or chest discomfort. Long-standing aortic regurgitation may result in
irreversible damage to the muscle of the left ventricle, even in the absence of
symptoms.
An aortic valve replacement operation should be performed whenever there is severe aortic
regurgitation and the patient develops symptoms. Even in the absence of symptoms, aortic
valve replacement may be necessary in some patients to prevent the irreversible damage to
the heart muscle caused by the extra volume load. If surgery is performed before damage to
the heart muscle becomes irreversible, the outlook is excellent, and most patients can return
to a normal lifestyle.
5.4
Atrial Fibrillation (AF)
Atrial Fibrillation (AF) decreases relative survival substantially. The liability of left
ventricular dysfunction with regard to diminished long-term survival is not completely reversed
by valve operation. If operation is not performed before left ventricular dysfunction develops,
postoperative medical treatment of these dilated, remodelled ventricles should be considered.
The presence of moderate or severe valvular calcification, together with a rapid increase in
aortic-jet velocity, identifies patients with a very poor prognosis.
Long term follow up studies consistently report better survival rates in patients undergoing
aortic rather than mitral valve replacement. Atrial Fibrillation usually results in the fitting of a
pacemaker as the condition worsens.
6 Prognosis after Valve Replacement Surgery
AVR should be considered palliative because the valve prosthesis introduces the patient to a
new disease process in which complications include thromboembolism, anticoagulant-related
bleeding, infection, and structural deterioration. Significant refinements in valve prostheses
have reduced but not eliminated these problems. Furthermore, improvements in surgical
technique and myocardial preservation continue to decrease the risks.
AVR is generally performed with low hospital mortality and complication rates, and significant
symptomatic improvement can be expected. Aortic valve recipients have a favourable
prognostic outcome.
Risk factors that determine long-term survival can be identified pre-operatively;
Bicuspid Aortic Valve Vs. Tricuspid, exercise capacity, peak heart rate, peak systolic blood
pressure and peak early diastolic velocity (reflecting both systolic and diastolic function) are
all better in survivors than in non-survivors. Non-survivors have considerably larger hearts.
Post operatively, small increases in exercise capacity are expected and ejection fraction
increases among survivors. No such changes are seen in non-survivors.
9 of 19 24/06/2017 at 18:32
After valve replacement The Post Operative survivals are:
Long-Term Survival Factors for Bicuspid Aortic Valve:
 “Patient self calculated Euro Score” 4.63%. (Surgery mortality).
 Atrial fibrillation
 Aortic Insufficiency (AI, Regurgitation) Mod/Severe
 Ejection Fraction (EF force of muscle) 53% Normal
 BAV - Dissection of the Ascending Aorta
 Blood pressure at the first postoperative visit.

Post Operative survival 98+/-2%, valve related complications include
thromboembolism, bleeding, deterioration of the prosthetic valve requiring reoperation and infective endocarditisis 1% per year.
 In-hospital survivability (first 6 – 10 days) was 94-98%.
 Major complication 21.7% of patients have one or more.
 One month survival including the operative survivability is approximately 92 to 95%,
 One year survival was 90-93%,
 5 year survival, see graph above.
The prognosis for postoperative valve-related events; life expectancy and event-free life
expectancy were 22 and 16 years in males aged 35 years respectively,
The presence of a bicuspid aortic valve increases the risk of postoperative dissection nine fold
and occurs in patients with BAV at about 54 Vs 62 years in TAV. In a study of Aortic
complications, dissection of the ascending aorta in patients with BAV replacements always
occurred within 10 to 14 years of initial surgery and was usually fatal.
10 of 19 24/06/2017 at 18:32
Actuarially Determined Complication Rates of Mechanical Valves for all patient types,
% March 2000:
Aortic
Mitral
10 y
20 y
30 y
10 y
20 y
30 y
Mortality
25-55 40-78 52-100 25-55 40-77 52-100
Thrombo embolism
26
41
47
39
52
54
Bleeding
13
24
26
15
25
26
Endocarditis
4
7
11
4
7
9
Reoperation (explant)
6.1
10
15
19
9
21
24
Papworth Scores
The dot is actual death rate. The horizontal line shows the 95% confidence interval around
the actual death rate. The cross shows the predicted death rate for patients.
This 1st chart shows that Papworth has performed better than predicted in all cardiac surgery,
coronary artery bypass grafting and valve surgery.
Cardiac Mortality by procedure 1st April 2004 - 31st March 2005
The 2nd chart shows no single surgeon in Papworth performs less well than that predicted by
EuroSCORE.
All Cardiac Surgery by Surgeon 1st April 2004– 31st March 2005
11 of 19 24/06/2017 at 18:32
7 Recovery after heart surgery
7.1
Care of your incision
You will be told how to care for your incision(s) before you leave the hospital. It is important
to:
o Keep your incision(s) clean and dry.
o Use only soap and water to cleanse the area.
o Bathing:
 When showers and baths are permitted, they should be limited to 10 minutes.
The water temperature should be warm - not too hot or cold. Extreme water
temperatures can cause faintness.
o Do not apply ointments, oils, salves or dressings to your incision unless specifically told to
do so.
o Eat a healthy diet to help healing.
o Call your doctor if signs of infection appear:
 Increased drainage or oozing from incision Increased opening of the incision line
 Redness or warmth around the incision
 Increased opening of the incision line
 Increased body temperature (greater than 101 degrees Fahrenheit or 38 degrees
Celsius)
7.2
Relief of pain
Some muscle or incision discomfort, itching, tightness and/or numbness along your incision
are normal after surgery. You should not have pain in your chest similar to what you had
before surgery. You will be given a prescription for a pain medication before you leave the
hospital.
If you had bypass surgery, you may have more pain in your legs than around your chest
incision if saphenous vein grafts were used. Walking, daily activities, and time will help to
lessen leg discomfort and stiffness.
Call your doctor if your sternum feels like it moves, or it pops or cracks with
movement.
7.3
Swelling - for those with vein grafts taken from their legs
You may return home with some swelling in your legs and feet, especially if you had vein
graphs taken from your legs. If you notice swelling:
Place your feet up higher than your heart level when resting. One way to do this is to lie
on your bed or couch and put several pillows under your legs. Or, you may lie on the floor and
place your feet on the couch. Try this three times a day for one hour to relieve swelling. (Noterecliners do not adequately elevate your feet).
o Do not cross your legs
o Walk daily even if your legs are swollen
o Hospital support hose may be suggested
o Call your doctor if swelling in your leg(s) become worse or painful and/or associated with
increased fatigue and/or shortness of breath.
7.4
Medications
You may need medications after surgery. Your doctor will tell you if you need these
medications until you recover from heart surgery or lifelong. Make sure you understand the
names of your medications, what they are for, and what times to take them. Only take the
medications that are prescribed when you are discharged from the hospital. If you want to
take medications you were previously on for other conditions, discuss this with your doctor
first.
7.5
Driving
Your doctor will tell you when you may resume driving. This usually occurs about six to eight
weeks after surgery, however, time may be shorter if you had minimally invasive surgery.
During this time, you may be a passenger as often as you like.
7.6
Activity
For the first six to eight weeks:
12 of 19 24/06/2017 at 18:32
Gradually increase your activity. You may do light household chores, but do not stand in one
place longer than 15 minutes.
Do not lift objects greater than 20 pounds (your doctor may give you a different number if
appropriate). Also, do not push or pull heavy objects.
It is OK to perform activities above shoulder level, such as reaching for an object or brushing
your hair. But, do not hold your arms above shoulder level for a longer period of time.
You may climb steps unless they have been restricted by your doctor. You may need to rest
part of the way if you become tired. Do not climb up and down stairs several times during the
day, especially when you first arrive home. It is better to plan activities to go downstairs in the
morning and back upstairs when it is time for bed.
Pace yourself - spread your activities throughout the day. If you become tired, rest and
schedule unfinished activities for another time.
Walk daily. Your doctor or cardiac rehabilitation specialist will give you guidelines for walking
when you return home.
Check with your doctor to confirm activity guidelines.
7.7
Diet
You should eat a healthy diet to help you heal. Your doctor will tell you if you should follow
any special diet instructions. It is common after surgery to have a poor appetite at first. If this
is the case, try to eat smaller, more frequent meals. Your appetite should return within the first
few weeks. If it does not, contact your doctor.
7.8
Sleep
It is important to get enough rest or you may feel overtired and irritable. Unfortunately, many
people complain of having trouble sleeping for some time after surgery. Normal sleep
pattern`s should return within a few months. Call your doctor if lack of sleep begins causing
changes in behavior or if normal sleep patterns do not return.
7.9
Work
You will need to take time to recover; usually about six to eight weeks (may be earlier with
minimally invasive surgery). Your doctor will tell you when you can return to work. If you have
the flexibility at your job, ease back to your work schedule. If possible, start back at half-time
and gradually increase back to your normal routine.
8 Drug Therapy
Improvements in long-term survival after valve surgery will most likely be achieved through the
earlier recognition and correction of significant valve lesions, pacemaker implantation and
controlled multiple drug therapy.
8.1 Anticoagulation Therapy - Warfarin
8.1.1 Drugs Potentiating the Effect of Warfarin
Antibiotics drugs:
There is highly probable evidence for; cotrimoxazole, erythromycin, isoniazid, fluconazole,
miconazole, and metronidazole. There is some evidence for; ciprofloxacin, itraconazole, and
tetracycline.
Cardiac drugs:
There is highly probable evidence for; amiodarone, clofibrate, propafenone, propranolol, and
sulfinpyrazone. Sulfinpyrazone's effect was biphasic, which means that an initial potentiation
of effect was noted, followed by inhibition of the effect. There is some evidence for; Quinidine,
simvastatin, fluvastatin, and acetylsalicylic acid.
Anti-inflammatory or analgesic drugs:
There is highly probable evidence for; phenylbutazone, piroxicam, acetylsalicylic acid,
acetaminophen, and dextropropoxyphene.
Other medications with highly probable or probable evidence were cimetidine, omeprazole,
alcohol (only if concomitant liver disease was present), chloral hydrate, disulfiram, phenytoin
(late effect of inhibition), tamoxifen, anabolic steroids, and influenza vaccines.
It is possible that diltiazem, tobacco, and vancomycin do interact with warfarin because the
evidence for no interaction was doubtful.
13 of 19 24/06/2017 at 18:32
8.1.2 Drugs Inhibiting the Effect of Warfarin
Few drugs inhibited the effect of warfarin, but there are a proportion with good evidence.
There is highly probable evidence for nafcillin, rifampin, griseofulvin, cholestyramine,
barbiturates, carbamazepine, chlordiazepoxide, sucralfate, high vitamin K content in enteral
feeds or in the diet, and large amounts of avocado. There is probable evidence for
dicloxacillin. Reported interactions for four other drugs in addition to the consumption of large
amounts of broccoli were considered possible evidence.
8.1.3 Drugs with No Effect on Warfarin
It is highly probable that several cardiac and gastrointestinal drugs do not interact with
warfarin. These drugs included atenolol, bumetanide, felodipine, metoprolol, moricizine,
antacids, famotidine, nizatidine, psyllium, and ranitidine. Seven other drugs also have highly
probable evidence: enoxacin, diflunisal, ketorolac, naproxen, alcohol (when not taken to levels
inhibiting normal liver function), nitrazepam, and fluoxetine. In addition there is probable
evidence for ketoconazole, ibuprofen, and ketoprofen.
8.2
HMG CoA Reductase Inhibitors Therapy – Statins
HMG CoA reductase inhibitors (statins) retard the progression of both coronary disease and
of aortic stenosis. In some studies, this retardation is related to a fall in low density lipoprotein
(LDL), cholesterol, but in others, retardation has occurred without a consistent relationship to
cholesterol, suggesting that statin agents may have effects other than simple cholesterol
lowering to account for their effects on the aortic valve. Although aortic valve replacement and
its timing have been the major foci of the therapy of aortic stenosis, it is possible that in the
future, aggressive therapy with statins and other agents might block or slow the progression
of the valve lesion, forestalling or even preventing the need for aortic valve replacement.
8.2.1 Statin - Effects on Cholesterol
Statins lower total cholesterol 18% to 26%, lower undesirable Low Density LipoproteinCholesterol (LDL-C) 20% to 60%, raised desirable High-Density Lipoprotein-Cholesterol
(HDL-C) 5% to 7%, and lowered triglycerides 11% to 17%.
8.2.1.1 FDA-Approved Drug Daily Dosage and Usual Decrease in LDL
Cholesterol
Atorvastatin
Fluvastatin
Lovastatin
Mevacor
Pravastatin
Rosuvastatin
Simvastatin
Initial: 10 mg 35%-40%
Initial: 20 mg 20%-25%
Initial: 20 mg 25%-30%
Initial: 20 mg 25%-30%
Initial: 40 mg 30%-35%
Initial: 10 mg 40%-45%
Initial: 20 mg 35%-40%
Maximum: 80 mg 50%-60%
Maximum: 40 mg 30%-35%
Maximum: 80 mg 35%-40%
Maximum: 80 mg 35%-40%
Maximum: 80 mg 35%-40%
Maximum: 40 mg 50%-60%
Maximum: 80 mg 45%-50%
8.2.2 NONLIPID EFFECTS OF STATINS
Some pathophysiologic data suggest that statins are also beneficial in the acute setting. For
example, in the short term (weeks to months) statins have been shown to:
 Decrease thrombus formation
 Increase fibrinolysis
 Inhibit platelet reactivity and aggregation
 Reduce thromboxane A production
 Improve endothelial function in patients with coronary artery disease
 Possibly stabilize plaques and make atheromas less susceptible to rupture by
reducing cholesterol synthesis by macrophages, decreasing inflammatory cells,
reducing matrix metalloproteinase activation, and promoting collagen accumulation in
the fibrous cap
 Reduce levels of C-reactive protein, an inflammatory marker and predictor of adverse
cardiovascular outcomes.
8.2.3 Adverse Events when taking Statins with Multiple Drugs –
Avoiding the concomitant use of drugs with the potential to inhibit CYP-dependent metabolism
may decrease the risk of statin-associated myopathy. Alternatively, if drug therapy with a
14 of 19 24/06/2017 at 18:32
potent CYP inhibitor is inevitable, choosing a statin without relevant CYP metabolism (eg,
pravastatin) should be considered.
8.2.3.1 General Statin interactions with drug regimes.
Simvastatin, (35.8%); cerivastatin, (31.9%); atorvastatin, (12.2%); pravastatin, (11.8%);
lovastatin, (6.7%); and fluvastatin, (1.7%). Statins are the primary cause of 72% of FDA
reported cases and suspected secondary cause in 28% of cases. In clinical trials and post
marketing surveillance, there are three statins that are not metabolised by the cytochrome
P450 3A4 system (fluvastatin, rosuvastatin and pravastatin) and have exhibited very low
propensities to elicit myopathy when combined with other agents. These agents should be
considered initially when contemplating combination lipid-lowering regimens for coronary
prevention.
FDA reports of rhabdomyolysis/Myopathy, the breakdown of muscle fibers resulting in the
release of muscle fiber contents into the circulation, that may be manifested by muscle pain
and in extreme cases dark or cola coloured urine without significant elevations in serum
creatine phosphokinase (CPK) levels, thus pointing out the inadequacy of CK testing for
statin-associated myopathy. Rhabdomyolysis/Myopathy is generally observed between 1-2
weeks and 4 months after initiation of therapy. Myalgias and weakness resolve within days to
4 weeks after discontinuation.
8.2.3.2 Drugs Increasing Risk of Myopathy/Rhabdomyolysis
CYP3A4 Inhibitors/Substrates
Others
Cyclosporine, tacrolimus
Macrolides (azithromycin, clarithromycin, erythromycin)
Azole antifungals (itraconazole, ketoconazole)
Calcium antagonists (mibefradil, diltiazem, verapamil)
Digoxin
Fibrates (gemfibrozil)
Niacin
Nefazodone
Protease inhibitors
saquinavir)
Sildenafil
(amprenavir,
indinavir,
nelfinavir,
ritonavir,
Warfarin
15 of 19 24/06/2017 at 18:32
8.2.3.3 Statin Associated FDA Reports of Rhabdomyolysis
Statin
Frequency of
Reports/Unique Cases
Simvastatin
321/215
Cerivastatin
231/192
Atorvastatin
105/73
Pravastatin
98/71
Lovastatin
51/40
Fluvastatin
11/10
Rosuvastatin
No Data
No. of Cases Associated With Potentially
Interacting Drugs* (n)
Mibefradil (48)
Fibrates (33)
Cyclosporine (31)
Warfarin (12)
Macrolide antibiotics (10)
Digoxin (9)
Fibrates (22)
Digoxin (7)
Warfarin (6)
Macrolide antibiotics (2)
Cyclosporine (1)
Mibefradil (1)
Mibefradil (45)
Fibrates (10)
Macrolide antibiotics (13)
Warfarin (7)
Cyclosporine (5)
Digoxin (5)
Azole antifungals (2)
Fibrates (6)
Macrolide antibiotics (6)
Warfarin (5)
Cyclosporine (2)
Digoxin (2)
Mibefradil (1)
Niacin (1)
Cyclosporine (12)
Macrolide antibiotics (11)
Azole antifungals (6)
Fibrates (5)
Mibefradil (3)
Fibrates (4)
Warfarin (2)
Digoxin (1)
Mibefradil (1)
N/A
Azole antifungals (4)
Chlorzoxazone (2)
Nefazodone (2)
Niacin (2)
Tacrolimus (1)
Fusidic acid (1)
Digoxin (2)
Nefazodone (2)
Niacin (1)
Warfarin (1)
*Each case may be associated with 1 or more potentially interacting drugs.
Adapted from Omar MA, Wilson JP. Ann Pharmacother. 2002;36:288–295.
8.2.3.4 Statin interactions with warfarin
The interactions between statins and warfarin are complex. Warfarin goes through several
different CYP450 pathways, any of which might serve as a source of interactions with statins.
However, whereas most of the interactions previously described result in inhibited statin
metabolism, interactions with warfarin tend to work in the opposite direction and inhibit
warfarin metabolism. The clinical result is an increase in the international normalized ratio
(INR), a standardized measure of prothrombin time. The CYP3A4-dependent statins
(simvastatin, lovastatin, and atorvastatin) all have the potential to raise the INR in patients
taking warfarin; the effect is variable, and monitoring INR is important to determine whether
the warfarin dosage must be adjusted. Fluvastatin, metabolized through the CYP2C9
pathway, can also interfere with warfarin metabolism and raise the INR. Rosuvastatin can
raise the INR without raising warfarin concentrations, which implies that its effect is not
mediated through the CYP450 system but is more likely caused by a partial displacement of
16 of 19 24/06/2017 at 18:32
warfarin from its protein-bound state in circulation. For patients taking multiple medications, it
is especially important to select agents that are least likely to incur an additional risk of
interaction; for patients who require the addition of lipid-lowering pharmacotherapy to a drug
regimen that is already complex, the preferred agents would be the statins that are least
dependent on the CYP450 system in general and on CYP3A4 in particular. Pravastatin is
unique among the statins in that it produces no change in the INR in patients taking warfarin,
which demonstrates its lack of involvement in the CYP450 pathways and an absence of
effects on warfarin protein binding, but it has caused an increased INR when combined with
the anticoagulant fluindione. Clinicians should monitor the INR closely after starting statin
therapy in any patient receiving anticoagulation therapy; rabdomyolysis and renal failure can
occrred within days
8.2.4 Statin Clinical Pharmacokinetics
Parameter
Atorvastatin Fluvastatin
Tmax (h)
2–3
Cmax (ng/mL)
27–66
Bioavailability
12
(%)
Lipophilicity
Yes
Protein
80–90
binding (%)
Metabolism
CYP3A4
CYP2C9
Metabolites
Inactive
Active
Fluvastatin
XL
Lovastatin Pravastatin Rosuvastatin Simvastatin
0.5–1
448
19–29
4
55
6
2–4
10–20
5
0.9–1.6
45–55
18
3
37
20
1.3–2.4
10–34
5
Yes
>99
Yes
>99
Yes
>95
No
43–55
No
88
Yes
94–98
CYP2C9 CYP3A4
Sulfation
CYP3A4
Inactive
Inactive
CYP2C9,
2C19
(minor)
Active
(minor)
Yes
Active
Active
Transporter
Yes
No
No
Yes
Yes/No
Yes
protein
substrates
T1/2(h)
15–30
0.5–2.3
4.7
2.9
1.3–2.8
20.8
2–3
Urinary
2
6
6
10
20
10
13
excretion (%)
Fecal
70
90
90
83
71
90
58
excretion (%)
Based on a 40-mg oral dose, with the exception of fluvastatin XL (80 mg).Adapted from data in
Corsini A, et al. Pharmacol Ther. 1999;84:413–428, and White CM. J Clin
Pharmacol.2002;42:963–970.
17 of 19 24/06/2017 at 18:32
8.2.5 Human Cytochrome P450 Isoenzymes that Oxidize Drugs
CYP1A2
CYP2C9
CYP2C19
CYP2D6
CYP2E1
CYP3A4
Acetaminophen Alprenolol
Diazepam
Amitriptyline Acetaminophen Amiodarone
Caffeine
Diclofenac
Ibuprofen
Codeine
Etanol
Atorvastatin
Theophylline
Fluvastatin
Mephenytoin
Debrisoquine Halothane Clarithromycin
Hexobarbital Methylphenobarbital Flecainide
Cyclosporine
Phenytoin
Omeprazole
Imipramine
Diltiazem
Rosuvastatin
Phenytoin
Metoprolol
Erythromycin
Tolbutamide
Proguanyl
Mibefradil
Itraconazole
Warfarin
Rosuvastatin
Nortriptyline
Ketoconazole
Pherexiline
Lacidipine
Propafenone
Lovastatin
Propranolol
Mibefradil
Sparteine
Midazolam
Thioridazine
Nefazodone
Timolol
Nifedipine
Protease
inhibitors
Quinidine
Sildenafil
Simvastatin
Terbinafine
Verapamil
Warfarin
8.2.6 Inhibitors/Inducers of Cytochrome P450 Enzymatic Pathway
CYP
Substrates
(Statins)
Inducers
Inhibitors
Phenytoin, phenobarbital,
barbiturates, rifampin,
dexamethasone,
cyclophosphamide,
carbamazepine, troglitazone,
omeprazole
Ketoconazole, itraconazole, fluconazole,
erythromycin, clarithromycin, tricyclic
antidepressants, nefazodone, venlafaxine,
fluvoxamine, fluoxetine, sertraline,
cyclosporine A, tacrolimus, mibefradil,
diltiazem, verapamil, protease inhibitors,
midazolam, corticosteroids, grapefruit juice,
tamoxifen, amiodarone
Rifampin, phenobarbital,
phenytoin, troglitazone
Ketoconazole, fluconazole, sulfaphenazole
CYP3A4
Atorvastatin,
Lovastatin,
Simvastatin
CYP2C9
Fluvastatin,
Rosuvastatin
(2C19-minor)
8.3
Angiotensin Converting Enzyme (ACE) Inhibitors Therapy
The narrowing of the vessels increases the pressure within the vessels and can cause high
blood pressure (hypertension). Angiotensin II is formed from angiotensin I in the blood by the
enzyme, angiotensin converting enzyme (ACE). ACE inhibitors are medications that slow
(inhibit) the activity of the enzyme, which decreases the production of angiotensin II. As a
result, the blood vessels enlarge or dilate, and the blood pressure is reduced. This lower
blood pressure makes it easier for the heart to pump blood and can improve the function of a
failing heart. In addition, the progression of kidney disease due to high blood
18 of 19 24/06/2017 at 18:32
8.4
Alcohol Therapy
There is compelling epidemiological evidence suggesting that regular light-to-moderate
alcohol intake is associated with reduced atheromatous morbidity and mortality. It is
interesting to note that while atherogenesis takes many decades, the beneficial effects of
alcohol accrue only in later life. The reasons for this are uncertain but the effects may be a
combination of plaque stabilisation, analogous to the effects of some cholesterol lowering
drugs which affect coronary endpoints relatively quickly, and an antithrombotic effect.
To prove causation requires the correct temporal sequence, an ability to control for
confounders, plausible biological explanations, and a consistent and specific effect (ischaemic
heart disease appears to be one of the few diseases alcohol benefits). It is only the relatively
small apparent benefit that precludes definitive statements on causation; it is possible that an
as yet unrecognised confounding variable could explain the findings. In addition, over
30 years of research has not revealed a definite alternative explanation.
Alcohol, especially in excess, does have detrimental effects, which in many groups outweigh
its benefits. Indeed, other interventions, including dietary modification, are far more effective
at reducing cardiovascular endpoints. The vast majority of those who abstain do so for a
reason, which would preclude advising them to take up alcohol, for example, dislike of the
taste/effects, past/family history of alcohol abuse, medical contraindication, or
moral/ethical/religious objections. However, one can reassure our patients that regular light-tomoderate alcohol intake, especially in those at risk, whose diet is steadfastly Western will, at
the very least, do no harm and almost certainly lead to benefit.
Is there evidence to enable us to advise what to drink? Although the epidemiological evidence
suggests not, there are at least theoretical reasons why red wines rich in flavonoids and
resveratrol may hold extra benefit.
Flavonoids, being found particularly in grape skins, occur in the highest concentrations in
grape varieties with thick skins grown in hot climates. Cabernet sauvignon based wines from
Australia, South America, and the southern Mediterranean are particularly rich sources. Syrah
(shiraz) and merlot are good too.
Wines from this grape form Burgundy, Sancerre, New Zealand, and the north west United
States are particularly rich in resveratrol. Merlot, gammay, syrah, zinfandel, and pinotage
wines may also be too.
19 of 19 24/06/2017 at 18:32