Ciammaichella M. M.

Dirigente Medico
Responsabile UAS “Trombosi Venosa Profonda ed Embolia Polmonare”
Responsabile CDF BLSD IRC “Emersan Lateranum”
U.O.C. Medicina Interna I° per l’Urgenza

(Direttore: Dott. G. Cerqua)
A.C.O. S. Giovanni - Addolorata - Roma

MITRAL REGURGITATION

KEY-WORDS: Mitral regurgitation

INTRODUCTION
CLINICAL
WORKUP
TREATMENT
MEDICATION
FOLLOW-UP
BIBLIOGRAPHY

INTRODUCTION

Background: Mitral regurgitation is a common entity seen in the emergency department in the acute and chronic decompensated states. It is critical that the emergency physician understand the underlying etiologies and pathophysiology to direct appropriate treatment for the patient.

Pathophysiology: Mitral regurgitation is a common entity seen in the emergency department in the acute and chronic decompensated states. It is critical that the emergency physician understand the underlying etiologies and pathophysiology to direct appropriate treatment for the patient.

Pathophysiology: Mitral regurgitation can be divided into three stages, acute, chronic compensated and chronic decompensated.

In the acute stage, which usually occurs with spontaneous chordae tendinae rupture secondary to myocardial infarction, there is a sudden volume overload on an unprepared left ventricle and left atrium. The volume overload on the the left ventricle increases left ventricular stroke work. Increased left ventricular filling pressures, combined with transfer of blood from the left ventricle to left atrium during systole, results in elevated left atrial pressures. This pressure is transmitted to the lungs, resulting in acute pulmonary edema and symptoms of dyspnea.

If the patient can tolerate the acute phase, he or she enters the chronic compensated phase, which results in eccentric left ventricular hypertrophy. The combination of increased preload and hypertrophy produces increased end-diastolic volumes, which, over time, results in left ventricular muscle dysfunction. This impairs emptying of ventricle during systole, which increases regurgitant volume and elevation of left atrial pressures, causing pulmonary congestion.

Frequency:

In the U.S.: Chronic rheumatic heart disease used to be the most common cause of acquired mitral valve disease in the Western world. More recently, however, mitral valve prolapse has replaced it. This entity is responsible for 45% of cases of mitral regurgitation. Mitral valve prolapse has been estimated to be present in 4% of the normal population. Significant regurgitation in this population occurs only in those with abnormalities of the valve.
Internationally:In the rest of the world, rheumatic heart disease remains the leading cause of mitral regurgitation

Mortality/Morbidity: The prognosis of patients with mitral regurgitation depends on the underlying etiologies and the state of the left ventricular function. In acute regurgitation, the course is often complicated by acute pulmonary edema and sometimes cardiogenic shock. The operative mortality in these cases approaches 80%. A patient with a ruptured tendinae and minimal symptoms has a much better prognosis.

With chronic regurgitation, volume overload is tolerated very well for years before symptoms of failure develop. Left atrial enlargement predisposes patients to the onset of atrial fibrillation which can further be complicated by embolization. In addition, patients remain succeptible to endocarditis. Survival of patients with chronic regurgitation, in a study with randomly selected patients, revealed that 80% were alive at five years and 60% at 10 years.

The majority of patients with mitral valve prolase are asymptomatic. Prolapse in those greater than 60 years of age is frequently associated with chest pain, arrythmias and heart failure. Although the prognosis remains good, sudden death, endocarditis and progressive regurgitation are infrequent complications.
When ischemic heart disease is the mechanism for regurgitation, the extent of anatomic disease and left ventricular performance are prognostic determinants. Complicating events include sudden death and myocardial infarction.

.Sex:

Male > Female (under 20 years of age)

Male = female (after age 20 years)
Males are more severely affected after 50 years of age.

Age: Of those cases caused by prior rheumatic disease, the mean age is 36 +/- 6 years.

CLINICAL

PATHOPHYSIOLOGY

History:

Mitral regurgitation can be tolerated for many years.

The initial symptoms of dyspnea and fatigue can rapidly progress to orthopnea and paroxysmal nocturnal dyspnea.

Patients with anginal type pain may have underlying ischemia.

Atypical chest pain can be associated with mitral valve prolapse syndrome.

In those with mitral valve prolapse, palpitations and atypical chest pain are the most frequent complaints. Two-thirds of these patients are female, often with underlying panic disorder.

In patients with underlying coronary artery disease (CAD), regurgitation is usually associated with symptoms of angina pectoris.

Regurgitation can also develop acutely with myocardial infarction secondary to papillary muscle rupture.

CAD is often accompanied by dyspnea, fatigue, othopnea and fluid retention. Chest pain is usually minimal in these patients.

When mitral regurgitation is due to left ventricular dilatation and altered valve function, patients often have chronic left-sided heart failure.
In acute mitral regurgitation from sudden disruption of the valve, the symptoms are of acute pulmonary edema.

Physical:

The classic murmur of mitral regurgitation is a high-pitched holosystolic murmur beginning with the first heart sound and extending to the second heart sound.

The intensity is usually constant throughout systolic ejection, often radiating to the axilla.

The volume of the murmur does not correlate with the magnitude of the valvular defect.

Those patients with severe disease often have a third heart sound, indicative of the large ventricular filling volume ejected into the left ventricle under higher than normal pressure.

Patients with mitral valve prolapse often have a mid- to late systolic click and a late systolic murmur. These patients are usually female and often have orthostatic hypotension.

Patients with CAD can have the murmur any time during systole, accompanied by an atrial gallop.

In acute mitral regurgitation, the exam is usually consistent with acute pulmonary edema and left ventricular failure.

Usually the heart size is normal often with an audible systolic thrill.
The murmur is often harsh, heard over the back of the neck, vertebra and sacrum, radiating to the axilla, back and left sternal border.

Causes:

Acute rheumatic heart disease still remains a significant consideration in patients less than 40 years of age with mitral regurgitation.

Mitral valve prolapse (often called myxomatous degeneration) accounts for approximately 45% of the cases in the Western world.

The causative agent is unknown in this condition.

Myxomatous degeration is often a slow process, with rupture of the chordae tendinae a complication.

Acute regurgitation, as mentioned earlier, can be caused by chordae tendinae rupture or papillary muscle dysfunction.

The literature now seems to suggest that mitral valve prolapse has become the most common cause in the adult population.

In addition, mitral valve prolapse and coronary artery disease have become major mechanisms for incompetence of the mitral valve.

Ischemia is responsible for 3-25% of mitral regurgitation.

The severity is directly proportional to the amount of left ventricular hypokinesis.

Mitral annular calcification can contribute to regurgitation. Impaired constriction of the annulus results in poor valve closure.

Left ventricular dilatation and heart failure can also produce annular dilatation and poor valve closure resulting in mitral regurgitation.

Tendinae rupture can be due to endocarditis, myocardial infarction or trauma.

Papillary muscle dysfunction is usually caused by infarction.

Other Causes:

Ehlers-Danlos

Marfan's

Osteogenesis imperfecta
Systemic lupus erythematosus (SLE)

WORKUP

Imaging Studies:

Chest X-Ray (CXR):

The cardiac silouhette is often normal in patients with mitral valve prolapse.

In patients with chronic mitral regurgitation, left ventricular and left atrial enlargement are present.

The left atrium can be so large as to cause elevation of the left mainstem bronchus.

Occasionally, there is what is called the double density sign along the right heart border, which is the wall of the dilated left atrium.

In patients with coronary artery disease (CAD), the heart size can range from normal to significant dilatation of the left ventricle and left atrium.

In patients with acute mitral regurgitation, when secondary to rupture of valve apparatus, mitral regurgitation will present with acute pulmonary edema and a normal cardiac silhouette.

Two Dimensional Echocardiography:

There is evidence of posterior motion of valve leaflet during mid-systole in patients with mitral valve prolapse.

Annular calcifications are seen in patients with CAD. In addition, there is evidence of posterior or inferior wall motion abnormalities.

In patients with acute mitral regurgitation, the ruptured chordae or papillary can be visualized as well as a perforated interventricular septum.

The left atrium and ventricle will be of normal size.
Transesophageal echo will give a better estimate of severity of damage.

Other Tests:

Electrocardiogram (ECG):

Chronic Mitral Regurgitation:

Atrial fibrillation is often present due to a severely dilated left atrium.

The ECG shows evidence of left ventricular hypertrophy and left atrial enlargement.

Coronary Artery Disease (CAD): There may be evidence of Q waves inferiorly and posteriorly, indicating prior infarction.

Mitral Valve Prolapse (MVP):

Patients will most commonly have ST and T wave changes, with T wave inversions in the inferior leads.

It may reveal an underlying arrythmia, such as sinus arrythmia, sinus arrest, atrial fibrillation and premature ventricular contractions.
Acute Mitral Regurgitation: May reveal evidence of an acute myocardial infarction, more commonly inferior or posterior.

Procedures:

Cardiac Catheterization:

Angiography is considered to be the gold standard in the assessment of the severity of the disease.

It is usually graded on a scale from 0, none, 1, mild, 2, moderate, 3, moderately severe and 4, severe.

The severity is based on the opacity of the left atrium.

The regurgitant volume can be calculated based on information from the catheterization.
In addition, this test will identify those with underlying CAD.

TREATMENT

Emergency Department Care:

Acute mitral regurgitation is a specific case where immediate intervention in the emergency department can make a difference.

If the cause is a myocardial infarction, infusion of thrombolytics may re-establish blood flow to the papillary muscle and restore function.

The mainstay of medical treatment in most other cases of mitral regurgitation is reduction of afterload.

This will decrease the impedance to left ventricular ejection and, as a result, decrease the regurgitant volume.

The treatment of pulmonary edema should include oxygen, diuretics, nitrates and early intubation for respiratory failure.

These individuals can benefit from afterload reduction with nitroprusside, even in the setting of a normal blood pressure.

Avoid trying to alleviate tachycardia with beta-blockers. Mild to moderate tachycardia is beneficial in these patients in that it allows less time for the heart to have backfill, thus, lowering regurgitant volume.

Rapid atrial fibrillation secondary to chronic mitral regurgitation should be rate-controlled with either digoxin or diltiazem.
One should consider cardioversion in refractory or unstable patients but, if effective, the restored sinus rhythm is usually transient since the left atrium is severely dilated.

Consultations:

In the setting of acute regurgitation secondary to an acute myocardial infarction, a cardiologist should be involved early to perform an echo, looking for papillary muscle rupture. Interventional cardiology for emergency angioplasty as an alternative to thrombolysis should be obtained as per protocol in institutions with such capability.
A cardiothoracic surgeon should be notified for highly suspicious cases, before the echo is done, to mobilize surgical team for repair.

MEDICATION

The mainstay of treatment is preload and afterload reduction, particularly in the setting of mitral regurgitation with pulmonary edema.

Drug Category: Diuretics - These agents are used reduce preload and the left ventricular volume.

Drug Name	Furosemide - It is an excellent preload reducer. It increases the excretion of water by interfering with the chloride-binding cotransport system which in turn inhibits the reabsorption of sodium and chloride in the ascending loop of Henle and distal renal tubule. The dose must be individualized to the patient. Depending on the response, administer at increments of 20-40 mg, no sooner than 6-8 h after the previous dose, until the desired diuresis occurs. When treating infants, titrate with 1 mg/kg/dose increments until a satisfactory effect is achieved.
Adult Dose	IV, PO: 1 mg/kg with a range of 20-120 mg
Pediatric Dose	IV, PO: 2 mg/kg
Contraindications	Avoid use in patients with documented hypersensitivity to this drug, sulfonylureas, or related products and those diagnosed with hepatic coma, anuria, or are in a state of severe electrolyte depletion.
Interactions	Metformin decreases furosemide concentrations. Conversely, furosemide interferes with the hypoglycemic effect of antidiabetic agents. It also antagonizes the muscle relaxing effect of tubocurarine. Auditory toxicity appears to be increased with concurrent use aminoglycosides and furosemide. Hearing loss of varying degrees may occur. The anticoagulant activity of warfarin may be enhanced, when taken concurrently with this medication. Increased plasma lithium levels and toxicity are possible when taken concurrently with this medication.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Loop diuretics may increase the urinary excretion of magnesium and calcium.

Drug Category: Nitrates - These agents are useful in preload reduction and as anti-anginal.

Drug Name	Nitroglycerin - It causes relaxation of the vascular smooth muscle via stimulation of intracellular cyclic guanosine monophosphate production causing a decrease in blood pressure.
Adult Dose	SL: 0.4mg Spray: 1-2 sprays per dose Paste: 1- 2 inches of paste q8h IV: 50 mg in 250 cc D5W start at 5 ug/min and titrate to effect up to 200 ug/min, watching for hypotension.
Pediatric Dose	Safety and efficacy in children have not been established.
Contraindications	Avoid use in patients with documented hypersensitivity to this medication or related products and those diagnosed with severe anemia, shock, postural hypotension, head trauma, closed angle glaucoma, or cerebral hemorrhage.
Interactions	Aspirin may increase nitrate serum concentrations. Marked symptomatic orthostatic hypotension may occur when administered concurrently with calcium channel blockers and an adjustment in the dose of either agent may be necessary.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Exercise caution in patients with coronary artery disease, and low systolic blood pressure.

Drug Name	Aztreonam - It is a monobactam that inhibits cell wall synthesis during bacterial growth. It is active against aerobic gram-negative bacilli.
Adult Dose	2.0 g q8h
Pediatric Dose	IV, IM: 90-120 mg/kg/d divided q6-8h
Contraindications	Avoid use in patients with documented hypersensitivity to this medication or related products.
Interactions	Tetracyclines may reduce the effects of this medication.
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust the dose in patients diagnosed with renal insufficiency.

Drug Name	Nitroprusside - It has an effect in afterload reduction but has some effect on preload. It produces vasodilation and increases the inotropic activity of the heart. In addition, it reduces peripheral resistance by acting directly on arteriolar and venous smooth muscle. It is the drug of choice for afterload reduction.
Adult Dose	50 mg in 250cc D5W, start at 0.3ug/kg/min up to 10 ug/kg/min.
Pediatric Dose	Safety and efficacy in children have not been established.
Contraindications	Avoid using in patients with documented hypersensitivity to sulfites or related products and those diagnosed with subaortic stenosis, idiopathic hypertrophic and atrial fibrillation or flutter.
Interactions	No significant drug-interactions have been documented with this medication.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use with caution in patients with increased intracranial pressure, hepatic failure, severe renal impairment, and hypothyroidism. In renal or hepatic insufficiency, nitroprusside levels may increase and can cause cyanide toxicity. Sodium nitroprusside has the ability to lower blood pressure and thus should be used only in those patients with mean arterial pressures greater than 70 mm Hg.

Drug Category: Anti-arrythmics - These agents are used for the control of atrial fibrillation in the setting of chronic mitral regurgitation.

Drug Name	Digoxin - It is the drug of choice in rate-control of atrial fibrillation. It is a cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system.
Adult Dose	Loading dose: 0.25 IV q6h up to 1 mg Maintenance dose: 0.125-0.25 mg IV, PO qd
Pediatric Dose	Digitalization must be individualized
Contraindications	Avoid use in patients with documented hypersensitivity to this medication or related products and those diagnosed with beriberi heart disease, ventricular fibrillation, idiopathic hypertrophic subaortic stenosis, or constrictive pericarditis, or carotid sinus syndrome.
Interactions	Medications that may increase digoxin levels include alprazolam, benzodiazepines, bepridil, captopril, cyclosporine, propafenone, propantheline, quinidine, diltiazem, aminoglycosides, oral amiodarone, anticholinergics, diphenoxylate, erythromycin, felodipine, flecainide, hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine, ibuprofen, indomethacin, esmolol, tetracycline, tolbutamide, and verapamil. Medications that may decrease serum digoxin levels include aminoglutethimide, antihistamines, cholestyramine, neomycin, penicillamine, aminoglycosides, oral colestipol, hydantoins, hypoglycemic agents, antineoplastic treatment combinations (including carmustine, bleomycin, methotrexate, cytarabine, doxorubicin, cyclophosphamide, vincristine, procarbazine), aluminum or magnesium antacids, rifampin, sucralfate, sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Toxicity develops more quickly in those with renal impairment. Hypokalemia may reduce the positive inotropic effect of digitalis. Calcium, if administered IV, may produce dysrhythmias in digitalized patients. Hypercalcemia predisposes the patient to digitalis toxicity and hypocalcemia can make digoxin ineffective until serum calcium levels are normal. Magnesium replacement therapy must be instituted in patients with hypomagnesemia to prevent digitalis toxicity. Patients diagnosed with incomplete A-V Block may progress to complete block when treated with digoxin. Exercise caution in patients diagnosed with hypothyroidism, hypoxia, and acute myocarditis.

Drug Name	Diltiazem - It is useful as the second line of therapy in rate-control of atrial fibrillation in chronic mitral regurgitation. During the depolarization, it inhibits the calcium ion from entering the slow channels or the voltage-sensitive areas of the vascular smooth muscle and myocardium.
Adult Dose	Bolus 0.25 mg/kg up to 20 mg IV over 2 min, Rebolus with 25 mg or 0.35 mg/kg if needed, then start infusion of 5-15 mg/h.
Pediatric Dose	Safety and efficacy in children have not been established.
Contraindications	Avoid use in patients with documented hypersensitivity to this drug or related products and in those diagnosed with severe CHF, sick sinus syndrome or second- or third-degree AV block, and hypotension (Less than 90 mm Hg systolic).
Interactions	Diltiazem may increase carbamazepine, digoxin, and cyclosporine levels when administered concurrently. Diltiazem, when administered concurrently with amiodarone, can cause bradycardia and a decrease in cardiac output. Similarly, diltiazem when administered concurrently with beta blockers may increase cardiac depression. Cimetidine may increase diltiazem levels. Diltiazem may increase theophylline levels.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Exercise caution when administering to patients with impaired renal or hepatic function. Diltiazem may increase LFTs and hepatic injury may occur.

FOLLOW-UP

Further Outpatient Care:

The definitive treatment for mitral regurgitation remains surgery.

The risk:benefit ratio must be looked at carefully in each situation prior to a decision to replace the valve.

There are two basic operations, mitral valve replacement and mitral valve repair.

If treated early enough, mitral valve repair is the optimal choice (i.e., lower risk of infectious endocarditis and better post-operative left ventricular function).

Repair is usually available only to those whose cause is nonrheumatic, noninfectious and nonischemic, which leaves few candidates.

Valve replacement should not be done in asymptomatic patients.

It is crucial that even minimal symptoms be picked up early to preserve as much left ventricular function as possible.

The reason for this is that chordal transection during replacement surgery will result in some impairment of LV function.
Thus, the more preserved the LV is prior to surgery, the better the outcome.

Complications:

Those patients with acute mitral regurgitation secondary to infarction who require valve replacement emergently, have a 60-80% mortality if they present in severe pulmonary edema.

Major Complications From Chronic Regurgitation:

Severe LV dysfunction

Chronic congestive heart failure

Atrial fibrillation and its complications (e.g., LA thrombus, stroke).
Sudden death, ruptured chordae tendinae and endocarditis remain infrequent complications of regurgitation secondary to longstanding prolapse.

Prognosis:

The extent of left ventricular dysfunction from underlying ischemia is the primary prognostic determinant in those with regurgitation secondary to coronary artery disease.

Patient Education:

Patients must be clearly educated on the warning signs and symptoms of congestive heart failure, chest pain, etc. as well as seeing their physician early, before symptoms progress.

BIBLIOGRAPHY

Carabello BA : Mitral Valve Disease. Current Problems in Cardiology 1993; 18(7) July: 423-478.
Carabello BA: Management of Valvular Regurgitation. Current Opinion in Cardiology 1995; 10(2) March: 124-127.
Fenster MS, Feldman MD: Mitral Regurgitation: An Overview. Current Problems in Cardiology 1995; 20(4) April: 198-268.
Gaasch WH, Eisenhauer AC: The Management of Mitral Valve Disease. Current Opinions in Cardiology 1996; 11(2) March: 114-119.
Schon HR: Medical Treatment of Chronic Valvular Regurgitation. Journal of Heart Valve Disease 1995; 4 Suppl 2: 170-174.
Wisenbaugh T: Mitral Valve Disease. Current Opinion in Cardiology 1994; 9(2) March: 146-151.