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.

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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 ValveThe 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 DiseaseCongenital 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.

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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.

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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.

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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) scanThe 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 resultsIf 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 resultsAn 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.

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4 Valve Replacement and Repair4.1 Mechanical Valve Replacement

Aortic 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.

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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 outcomeChordal 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 AortoplastyAortic 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.

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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 Patients5.1 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 mediaPatients 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

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Aortaplasty

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 SurgeryAVR 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.

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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 re-operation 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.

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Actuarially Determined Complication Rates of Mechanical Valves for all patient types, % March 2000:

Aortic Mitral10 y 20 y 30 y 10 y 20 y 30 y

Mortality 25-55 40-78 52-100 25-55 40-77 52-100Thrombo embolism 26 41 47 39 52 54Bleeding 13 24 26 15 25 26Endocarditis 4 7 11 4 7 9

Reoperation (explant) 10 15 19 9 21 24

6.1 Papworth ScoresThe 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

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7 Recovery after heart surgery7.1 Care of your incisionYou 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 painSome 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 legsYou 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. (Note- recliners 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 MedicationsYou 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 DrivingYour 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 ActivityFor the first six to eight weeks:

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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 DietYou 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 SleepIt 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 WorkYou 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 TherapyImprovements 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 - Warfarin8.1.1 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.

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8.1.2 Drugs Inhibiting the Effect of WarfarinFew 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 – StatinsHMG 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 CholesterolStatins lower total cholesterol 18% to 26%, lower undesirable Low Density Lipoprotein-Cholesterol (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 Initial: 10 mg 35%-40% Maximum: 80 mg 50%-60%Fluvastatin Initial: 20 mg 20%-25% Maximum: 40 mg 30%-35%Lovastatin Initial: 20 mg 25%-30% Maximum: 80 mg 35%-40%Mevacor Initial: 20 mg 25%-30% Maximum: 80 mg 35%-40%Pravastatin Initial: 40 mg 30%-35% Maximum: 80 mg 35%-40%Rosuvastatin Initial: 10 mg 40%-45% Maximum: 40 mg 50%-60%Simvastatin Initial: 20 mg 35%-40% Maximum: 80 mg 45%-50%

8.2.2 NONLIPID EFFECTS OF STATINSSome 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

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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/RhabdomyolysisCYP3A4 Inhibitors/Substrates Others

Cyclosporine, tacrolimus DigoxinMacrolides (azithromycin, clarithromycin, erythromycin) Fibrates (gemfibrozil)Azole antifungals (itraconazole, ketoconazole) NiacinCalcium antagonists (mibefradil, diltiazem, verapamil)NefazodoneProtease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir)SildenafilWarfarin

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8.2.3.3 Statin Associated FDA Reports of Rhabdomyolysis

Statin Frequency of

Reports/Unique Cases No. of Cases Associated With Potentially

Interacting Drugs* (n)

Simvastatin 321/215 Mibefradil (48) Azole antifungals (4)Fibrates (33) Chlorzoxazone (2)Cyclosporine (31) Nefazodone (2)Warfarin (12) Niacin (2)Macrolide antibiotics (10) Tacrolimus (1)Digoxin (9) Fusidic acid (1)

Cerivastatin 231/192 Fibrates (22)Digoxin (7)Warfarin (6)Macrolide antibiotics (2)Cyclosporine (1)Mibefradil (1)

Atorvastatin 105/73 Mibefradil (45)Fibrates (10)Macrolide antibiotics (13)Warfarin (7)Cyclosporine (5)Digoxin (5)Azole antifungals (2)

Pravastatin 98/71 Fibrates (6)Macrolide antibiotics (6)Warfarin (5)Cyclosporine (2)Digoxin (2)Mibefradil (1)Niacin (1)

Lovastatin 51/40 Cyclosporine (12) Digoxin (2)Macrolide antibiotics (11) Nefazodone (2)Azole antifungals (6) Niacin (1)Fibrates (5) Warfarin (1)Mibefradil (3)

Fluvastatin 11/10 Fibrates (4)Warfarin (2)Digoxin (1)Mibefradil (1)

Rosuvastatin No Data N/A

*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 warfarinThe 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

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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 Fluvastatin

XL Lovastatin Pravastatin Rosuvastatin Simvastatin

Tmax (h) 2–3 0.5–1 4 2–4 0.9–1.6 3 1.3–2.4Cmax (ng/mL) 27–66 448 55 10–20 45–55 37 10–34Bioavailability (%)

12 19–29 6 5 18 20 5

Lipophilicity Yes Yes Yes Yes No No YesProtein binding (%)

80–90 >99 >99 >95 43–55 88 94–98

Metabolism CYP3A4 CYP2C9 CYP2C9 CYP3A4 Sulfation CYP2C9, 2C19 (minor)

CYP3A4

Metabolites Active Inactive Inactive Active Inactive Active (minor) ActiveTransporter protein substrates

Yes No No Yes Yes/No Yes Yes

T1/2(h) 15–30 0.5–2.3 4.7 2.9 1.3–2.8 20.8 2–3Urinary excretion (%)

2 6 6 10 20 10 13

Fecal excretion (%)

70 90 90 83 71 90 58

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.

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8.2.5 Human Cytochrome P450 Isoenzymes that Oxidize DrugsCYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP2E1 CYP3A4

Acetaminophen Alprenolol Diazepam Amitriptyline Acetaminophen AmiodaroneCaffeine Diclofenac Ibuprofen Codeine Etanol AtorvastatinTheophylline Fluvastatin Mephenytoin Debrisoquine Halothane Clarithromycin

Hexobarbital Methylphenobarbital Flecainide CyclosporinePhenytoin Omeprazole Imipramine Diltiazem

Rosuvastatin Phenytoin Metoprolol ErythromycinTolbutamide Proguanyl Mibefradil Itraconazole

Warfarin Rosuvastatin Nortriptyline KetoconazolePherexiline Lacidipine

Propafenone LovastatinPropranolol MibefradilSparteine Midazolam

Thioridazine NefazodoneTimolol Nifedipine

Protease inhibitorsQuinidineSildenafil

SimvastatinTerbinafineVerapamilWarfarin

8.2.6 Inhibitors/Inducers of Cytochrome P450 Enzymatic PathwayCYP Substrates (Statins) Inducers Inhibitors

CYP3A4Atorvastatin, Lovastatin, Simvastatin

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

CYP2C9Fluvastatin, Rosuvastatin (2C19-minor)

Rifampin, phenobarbital, phenytoin, troglitazone

Ketoconazole, fluconazole, sulfaphenazole

8.3 Angiotensin Converting Enzyme (ACE) Inhibitors TherapyThe 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

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8.4 Alcohol TherapyThere 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-to-moderate 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.

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