Dr. Zeeshan Mansuri writes about valvular heart disease and the use of prosthetic heart valves in patients, the different options available, special considerations for patients taking oral vitamin K antagonists and valve dysfunction.

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Valvular heart disease is an increasingly common cause of morbidity and mortality in the Indian population. Both stenotic (occlusive) and regurgitant (insufficiency) type of lesions can be seen in valvular heart disease. Causes of valvular heart diseases include rheumatic heart disease, degenerative heart diseases (sclerodegenerative aortic stenosis, mitral annular calcification with mitral regurgitation, aortic regurgitation), congenital heart diseases (mitral valve prolapse, bicuspid aortic valve, parachute mitral valve, congenital pulmonary stenosis), ischaemic heart diseases (acute mitral regurgitation due to chordal rupture or myocardial infarction), cardiomyopathy with functional mitral regurgitation, infective endocarditis, traumatic injury to heart etc.

All four heart valves can be affected of which left-sided valves (mitral and aortic) are more commonly involved because the left-sided heart deals with higher blood pressure as well as higher systemic vascular resistance. Depending upon clinical and echocardiographic severity of valvular dysfunction (stenosis or regurgitation), patients may have to undergo valve replacement surgery with removal of diseased native valve and replacement with a prosthetic heart valve.

Prosthetic heart valves are mainly classified into three general categories; mechanical, bioprosthetic and homograft.

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Mechanical prosthetic heart valve

It comprises of three basic elements; occluder, occluder restraint, and a sewing ring. The first mechanical prosthetic valve was invented by Dr. Charles Hufnagel in 1952 who created a ball valve prosthesis to be implanted in descending aorta. Dr. Albert Star and Dr. Lowell Edwards created starr-edwards ball & cage valve in 1960. Soon, other types of mechanical valve prostheses were invented and brought into clinical practice. Different types of mechanical prosthetic valves include ball & cage valves, disk valves (tilting or non-tilting disk) and bi-leaflet valves.

Some examples of all three types are as follows.

• Ball & cage valves: Hufangel prosthetic valve, Starr-edwards ball & cage valve
• Disk valves: Medtronic hall, Bjork-Shiley, TTK chitra
• Bi-leaflet valves: St.jude, Carbomedics, On-X

Bioprosthetic heart valves

They are composed of three leaflets made up of xenograft tissue either from porcine valve leaflets or from bovine pericardium. These tissues are treated with gluteraldehyde as it inhibits collagen denaturation and hence reduces the risk of thromboembolism. Bioprosthetic heart valves can be either of the two types; stented and non-stented. In stented bioprosthesis, the tissue leaflets are sewn into a metallic support structure covered with dacron. Non-stented bioprosthesis require to be sewn directly to the native valvular annulus. Bioprosthetic heart valves produce better haemodynamics than mechanical protheses but they generate higher trans-valvular pressure due to smaller annular size.

Examples of bioprosthetic heart valves are as follows;

• Porcine aortic bioprosthetic valve: Carpentier-Edwards, Hancock
• Bovine pericardial bioprosthetic valve: Carpentier-Edwards, Perimount
• Stentless porcine: Toronto stentless
• Bioprosthetic heart valves used for trans catheter aortic replacement: Edward Sapiens (bovine), Medtronic Core valve (porcine)

Homografts

These are cadaveric tissue valves taken from same species. They are used in conjunction with the autograft as in ross procedure. In ross procedure, the patient’s own pulmonic valve is re-implanted in aortic position and a homograft tissue is implanted in pulmonary position. They are used infrequently nowadays.

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Selection of prosthetic heart valves

Choosing the correct type of valve is an essential process in order to improve quality of life post surgery. Important criteria include patient’s preference, age, life expectancy, indication/contra indication for oral anticoagulation and co-morbidities.

A mechanical prosthesis is preferred if:

• the patient has long life expectancy
• the patient is already on oral anticoagulation or has indication for anticoagulation
• the patient is at high risk for bioprosthesis structural valve deterioration (young age, hyperparathyroidism, renal insufficiency)

Bioprosthetic heart valve is chosen as per,

• the patient’s preference
• if the patient is a woman of childbearing age
• there is no other indication for anticoagulation or having contraindication of oral anticoagulation
• old age (more than 70 years)
• short life expectancy

Bioprostheses degenerate rapidly in young patients and in pregnancy. Hence, female patients in the third or fourth decade of life (who have completed a family) should be offered mechanical prosthetic valves.

Historically, open heart surgery and surgical valve replacement has been the gold standard of treatment in most of the valvuar heart disease. However, since the inception of trans catheter aortic valve replacement (TAVR) in 2002, the balance has now shifted to less invasive and safer trans catheter procedures. TAVR can be performed for sclerodegenerative aortic stenosis, aortic regurgitation, as well as bioprosthetic valve dehiscence/degeneration in aortic position (valve-in-valve). Initially performed for high-risk surgical AVR candidates, TAVR has evolved and is now a non-inferior option in low-moderate risk candidates for aortic valve replacement.

1. For mitral valve replacement surgeries, it is recommended that chordae tendinae should be preserved as it helps in maintaining geometry of left ventricle and prevents post-operative left ventricular dysfunction.
2. For bioprosthetic valve dehiscence/ degeneration in any position, trans catheter valve in valve implantation is a feasible option in suitable patients but, it requires high operator expertise and increases the treatment cost.

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Post-operative anticoagulation and follow up

All patients with mechanical prosthesis, atrial fibrillation, history of thromboembolism and high-risk for thromboembolism require oral anticoagulation with vitamin k antagonists. Warfarin and acenocoumarol are traditionally used for this purpose.

A few studies have tried to evaluate newer oral anticoagulants (NOACs) for patients with prosthetic heart valves but they all showed increased thromboembolic complications as well as increased rate of major and minor bleeding when compared to warfarin. Hence, warfarin/acenocoumarol remains the mainstay of oral anticoagulant treatment of choice.

For patients with bioprosthetic heart valves, oral anticoagulation is recommended for the first 3 to 6 months after which they can be switched over to single anti-platelet (aspirin).

Patients with oral anticoagulation need to maintain their prothrombin time with INR in therapeutic range so the valve can work smoothly and efficiently.

Various mechanical prostheses have different recommended therapeutic INR and it is as follows. [1]

Prosthesis type & position	Target INR
Mechanical MVR	3.0 (range 2.5 - 3.5)
Mechanical AVR with bileaflet or new generation titlting disk valve with no other risk factors for thromboembolism	2.5 (range 2 - 3)
Mechanical AVR with old generation titlting disk valve or with other risk factors for thromboembolism	3.0 (range 2.5 - 3.5)
Mechanical AVR with On-X aortic heart valve	1.5 – 2.0

Risk factors for thromboembolism: atrial fibrillation, h/o thromboembolism, lv dysfunction, hypercoagulable state

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It is recommended to prescribe 75 to 100 mg of aspirin to all patients receiving prosthetic heart valve.

Patients receiving bioprosthetic heart valves should be given vitamin K antagonist for first 3 to 6 months and thereafter continued as per their risk of recurrent thromboembolism.

Patients should be closely followed after surgery till therapeutic INR is achieved and necessary dose adjustments are made after which patients can be followed every 3 to 6 months. Echocardiography should be done every monthly until therapeutic INR is achieved and yearly thereafter in asymptomatic patients.

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Special considerations for patients taking oral vitamin K antagonists

Diet: Patients receiving vitamin K antagonists should avoid green leafy vegetables, cabbage, brocolli, green tea, green apple, cranberry juice etc. As it affects metabolism of vitamin K antagonists and can alter their anticoagulation status.

Drug interactions: Many a times, patients on oral anticoagulation develop common cold, flu, fever or other symptoms for which their physician might prescribe them some remedies or even patients may directly go to chemists and ask for any over the counter medicines which may interact with vitamin K antagonists in the body, and patients may develop adverse reactions due to under- or over-anticoagulation.

Some of these interactions are listed below;

Drugs increasing warfarin effect	Drugs decreasing warfarin effect
Allopurinol	Carbamazepine
Amiodarone	Naficillin
Azithromycin	Pentobarbital
Capecitabine	Phenobarbital
Cepahalosporins	Primidone
Chloramphenicol	Rifabutin
Choral hydrate	Rifampicin
Cimetidine	Secobarbital
Ciprofloxacin
Clarithromycin
Clotrimazole
Danazol
Duloxetine
Efavirenz
Erythromycin
Escitalopram
Fenofibrate
Fluconazole
Fluoxetine
Imatinib
Itraconazole
Ketoconazole
Levothyroxine
Metronidazole
Nitazoxanide
Oxandrolone
Paroxetine
Piperacillin
Quinine
Sertraline
Sulphonamides
Tamoxifen
Trazodone
Voriconazole

Pregnancy: It is recommended that female patients at child-bearing age should receive bioprosthetic heart valves so that anticoagulation can be stopped in pregnancy. However, sometimes a female patient may have received a mechanical prosthesis or might be on oral anticoagulation for other reasons. It becomes difficult to manage her anticoagulation status with ongoing pregnancy.

It is ideal to stop warfarin as soon as pregnancy is known so as to avoid the teratogenic effects of warfarin which is maximum if warfarin is taken during 6 to 12 weeks of gestation. Patients should be switched over to unfractionated heparin (UFH) or low molecular weight heparin (LMWH), which should be continued until term and then all patients should be switched over to UFH which is stopped 6 hours prior to elective cesarean section. Recent studies have shown that if the patient is on warfarin dose <5 mg/day, it is safe to continue warfarin till term and then switch to heparin prior to delivery.

Dental extraction and cataract removal surgeries: It is recommended that vitamin K antagonists should be continued with therapeutic INR in any patients undergoing dental extractions and cataract removal surgeries in which bleeding is less and easily controlled.

Major invasive surgeries: Any patient with prosthetic heart valve undergoing major invasive surgery should stop vitamin K antagonists for 3 to 4 days before surgery and confirm that INR has dropped to near normal prior to surgery. However, during this time period patient must be put on UFH or LMWH injections which are to be stopped 6 and 12 hours before the surgery respectively.

Oral anticoagulation-related bleeding (warfarin toxicity): Patients may present with overt bleeding such as haematuria, epistaxis, hematemesis or may have benign presentation such as purpura, ecchymosis, or may just present with elevated INR without manifest bleeding.

• For patients with elevated INR >5 with ongoing bleeding, fresh frozen plasma (FFP) or prothrombin complex concentrates should be given to counter the anticoagulant effect of warfarin
• For patients with no bleeding, if INR is <9, then warfarin needs to be stoppped for 3 to 5 days and frequent monitoring of INR is recommended. Once INR is below 3 then warfarin can be re-started
• For patients with no bleeding, if INR is >9, then prothrombin complex concentrates and/or FFP should be given pre-emptively to avoid any major bleeding

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Prosthetic heart valve dysfunction

Prosthetic heart valve dysfunction can be due to patient prosthesis mismatch (PPM), structural valve deterioration (SVD), prosthetic valve obstruction (thrombosis/pannus), prosthetic valve regurgitation/para valvular regurgitation, haemolysis and prosthetic valve infective endocarditis.

Patient prosthesis mismatch (PPM)

PPM occurs when the effective orifice area (EOA) of a normally functioning prosthesis is too small in relation to the body size of the patient, resulting in abnormally high trans valvular gradient.

Indexed EOA per body surface area of the patient (i-EOA) is calculated for diagnosis of PPM. [2]

	Mild PPM	Moderate PPM	Severe PPM
Aortic position (i-EOA)	>0.85 cm2/m2	0.85 – 0.65 cm2/m2	<0.65 cm2/m2
Mitral position (i-EOA)	>1.2 cm2/m2	0.90 – 1.2 cm2/m2	<0.90 cm2/m2

PPM is associated with less improvement in symptom class, exercise intolerance, less improvement in cardiac reserve, less regression of cardiac remodelling, and more adverse cardiac events.

Every effort should be made to avoid PPM in patients undergoing AVR or MVR especially in patients with severe LV hypertrophy, pre-existing LV dysfunction, age <65 years, intense physical activity etc. Projected i-EOA should be calculated pre-operatively to prevent PPM.

Structural valve deterioration (SVD)

1. Mechanical prosthetic valves have greater durability than bioprosthetic heart valves, however, mechanical failure may occur due to leaflet escape, strut fracture or occluder dysfunction.
2. Bioprosthetic heart valve tissue does not have regenerative capabilities and hence they start to erode or degenerate after 7 to 8 years. Clinically they manifest as valvular regurgitation or stenosis depending upon the position of leaflets.

Risk factors for SVD include young age, hyper-parathyroidism, renal insufficiency, mitral position, hypertension, and LV dysfunction. Stented bioprosthetic heart valves are less prone to SVD than stentless valves.

Bioprosthetic heart valves are pre-treated with gluteraldehyde so as to reduce its antigenicity and immune reaction. This predisposes the bioprosthetic valves to higher risk of structural deterioration as gluteraldehyde fixation leads to calcium influx as a result of membrane damage which provides an environment prone to calcium crystal formation which in collaboration with the immune reaction towards the valve tissue and native atherosclerotic process, eventually leads to cuspal thickening or tear and bioprosthetic valve deterioration.

Patients with clinically evident SVD may require repeat surgery with implantation of new prosthetic heart valve. Nowadays, trans catheter valve in valve implantation is also possible in case of bioprosthetic valve degeneration or dehiscence.

Prosthetic heart valve obstruction (PHVO) (thrombus/pannus)

Prosthetic heart valve obstruction is generally due to impeded leaflet movement of mechanical prosthetic valves and may present with acute or chronic valve failure.

• Acute PHVO can be due to thrombus or vegetation obstructing the laminar haemodynamics and forward flow through the prosthesis
• Chronic PHVO can be due to pannus ingrowth from the peri annular tissue onto the leaflets and leading to restricted opening/closure of the leaflets

Acute PHVO also known as prosthetic heart valve thrombosis (PHVT) is generally due to sub-therapeutic INR leading to pro-thrombotic milieu which leads to thrombus formation in the mechanical prosthesis.

Clinical features of acute PHVO/PHVT resemble that of heart failure with pulmonary oedema; the patient may also present with sudden cardiac death.

PHVO can be diagnosed on the basis of 2D echocardiography, trans oesophageal echocardiography (TEE), cine-fluoroscopy.

• 2D echocardiography shows increased trans valvular gradient and may also show large size thrombus or vegetation
• TEE shows the thrombus clearly and may also help in differentiating thrombus from vegetation or pannus.
• Cine-fluoroscopy may show restricted or absent movement of leaflet and is best used for bi-leaflet mechanical valve prosthesis

Treatment includes fibrinolysis, repeat surgery with replacement of affected prosthesis, or de-clotting. Measures to reduce pulmonary congestion (i.e. diuretics, non-invasive ventilation) are to be provided as per routine care.

Fibrinolysis is generally done with streptokinase, urokinase, or alteplase with an intravenous bolus followed by slow continuous infusion.

Surgery may include declotting procedure and thrombectomy or may also require removal of old mechanical prosthesis and implantation of a new one.

Decision regarding fibrinolysis and surgery is a crucial one and should always be considered by the heart team as per the guideline as shown below. [3]

Favouring surgery	Favouring fibrinolysis
Readily available surgical expertise	No surgical expertise available
Low surgical risk	High surgical risk
Contraindication to fibrinolysis	No contraindication to fibrinolysis
Recurrent PHVT	First episode of PHVT
NYHA class IV	NYHA class I-III
Large clot (>0.8 cm2)	Small clot (<0.8 cm2)
Left atrial thrombus	No left atrial thrombus
Concomitant coronary artery disease in need of revascularisation	No or mild coronary artery disease
Other valve disease	No other valve disease
Pannus	Thrombus visualised
Patient choice	Patient choice

Patients with history of PHVT should have their therapeutic INR range revised and higher therapeutic INR targeted.

Chronic PHVO may present with exertional dyspnoea, exercise intolerance, paroxysmal noctural dyspnoea (PND) and may be detected on routine annual echocardiography due to elevated trans valvular gradients. They require treatment as per their symptomatic status and depending upon the aetiology (thrombus vs pannus), they may also require fibrinolysis and/or surgery.

Bioprosthetic valves may also present with acute obstructive PHVT and may require fibrinolysis and/or repeat surgery. However, bioprosthetic heart valve thrombosis is very rare.

Prosthetic valve para valvular regurgitation

Regurgitation of blood through gap between prosthetic annular sewing ring and native annular tissue is called as para valvular regurgitation.

A small degree of para valvular regurgitation is seen in one-fourth of patients undergoing valve replacement surgeries but it is minimal and does not cause any symptoms/harm.

Causes of significant para valvular regurgtation include infection, suture dehiscence, fibrosis or calcification of native annular tissue leading to inadequate contact between sewing ring and annular tissue.

Mild paravalvular regurgitation may be visible immediately after surgery and may resolve over a few days during the convalescent period. However, moderate to severe para valvular regurgitation may lead to symptoms of heart failure, haemolysis and/or progressive LV dysfunction.

Patients with para valvular regurgitation may require repeat surgery with re-suturing of sewing ring into the annulus. Sometimes para valvular regurgitation can also be treated with percutaneous device closure (amplatzer septal occluder or amplatzer duct occluder) if the anatomy is suitable.

Haemolysis

Metallic mechanical prosthetic heart valves can produce hemolysis when RBCs come in contact with metal surface. This is aggravated when there is a paravalvular regurgitation which augments haemodynamic turbulence at the valvular interface.

Blood tests for haemolysis i.e. lactate dehydrogenase (LDH) should be done routinely on follow-up. More than 50% of patients with mechanical valves have some degree of intravascular haemolysis. However, anaemia caused by hemolysis is rare unless prosthetic para valvular regurgitation has occurred.

Patients with mild to moderate anaemia can generally be treated conservatively with iron and folate, β-blockers, and erythropoietin.

Repeat surgery or repair of a paravalvular regurgitation may be needed when prosthetic valve haemolysis is associated with severe refractory anaemia.

Prosthetic valve infective endocarditis

Prosthetic valves are at an increased risk for infective endocarditis than native heart vlaves due to altered haemodynamics, foreign material and incomplete attachment with the native annular tissue providing a nidus for infection.

Prosthetic valve infective endocarditis can present with vegetation over the valve leaflets or sewing ring, annular or peri-annular abscess and new onset para valvular regurgitation.

Staphylococcus aureus, coagulase-negative staphylococci (S.epidermidis and S.lugdunensis), streptococci and candidial species are all aetiologic agents for prosthetic valve infective endocarditis.

Diagnosis requires echocardiogrpahic (2D and/or TEE) demonstration of vegetation or abscess and blood cultures for detecting the culprit bacteria and for sensitivity testing.

Prosthetic valve infective endocarditis requires a longer course of antibiotics than native valve infections, sometimes, severe para valvular regurgitation or large vegetation may also require surgical intervention.

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The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr. Zeeshan Mansuri is an Interventional Cardiologist at Ahmedabad.