Primary versus Secondary Right-Sided Valve Disease

Differentiation of primary valve abnormalities from valve dysfunction secondary to pulmonary hypertension or primary right heart disease is an important first step in the evaluation of patients with tricuspid or pulmonic valve disease. Primary anatomic abnormalities of the tricuspid and pulmonic valves are often congenital and are usually diagnosed in childhood. In adults, right-sided valve disease is more commonly secondary to pulmonary hypertension, which in turn is often due to left-sided heart disease.

Response of the Right Heart to Pressure and/or Volume Overload

In the setting of chronic tricuspid or pulmonic regurgitation, the right ventricle dilates in response to chronic volume overload, which is visualized on echocardiography predominantly as enlargement in the short axis rather than in the longitudinal axis dimension.1,2 Right ventricular volume overload is also associated with abnormal or “paradoxic” ventricular septal motion, because the septum moves toward the center of the right ventricle in systole and moves rapidly posteriorly in diastole—a pattern opposite of normal.^3–5 The reversed curvature of the septum is most marked in end-diastole, in contrast to pressure overload in which the maximum reversed curvature is more evident and occurs early in diastole. ⁶

In chronic right ventricular volume overload, right ventricular systolic dysfunction occurs earlier in the disease course than is typical for left-sided volume overload conditions.7,8 As with left-sided valve disease, right ventricular volume and systolic function typically improve after intervention for valvular regurgitation unless an irreversible decline in contractility has occurred.

The response of the right ventricle to chronic pressure overload, such as pulmonary hypertension or pulmonic stenosis, also differs from that of the left ventricle. Although the initial response is an increase in wall thickness, ventricular dilation may occur and depends on the acuteness and severity of the pressure overload state. With a gradual increase in right ventricular pressure, right ventricular size and systolic function may remain normal with a compensatory increase in right ventricular wall thickness. ⁹ After intervention, such as relief of pulmonic stenosis, an improvement in right ventricular hypertrophy and systolic function is expected because of the decreased right ventricular afterload. Although few studies have analyzed the extent of improvement in right ventricular function after relief of pulmonic stenosis, the improvement in right ventricular dimensions and systolic function in most patients after lung transplantation supports the concept that systolic function improves with decreased afterload.^10,11

In contrast, with an acute increase in right ventricular pressure, for example with acute pulmonary embolism, decreased right ventricular systolic function and clinical right heart failure may be seen with mean pulmonary pressures of only 20 to 40 mm Hg. ¹² Acute or subacute right ventricular pressure overload often results in right ventricular dilation with secondary annular dilation and tricuspid regurgitation. This combination superimposes a volume overload state, engendering a vicious circle of right ventricular dilation and worsening tricuspid regurgitation.

Principles of Diagnosis

Etiology

Tricuspid regurgitation that is at least moderate or greater in severity is most frequently “functional” or secondary in nature. Secondary tricuspid regurgitation by definition is not due to primary tricuspid leaflet pathology but is secondary to another disease process causing right ventricular dilation, distortion of the subvalvular apparatus, tricuspid annular dilation, or a combination of these problems. Causes of clinically significant tricuspid regurgitation are listed in Table 24-1. Furthermore, a moderate or greater degree of tricuspid regurgitation, regardless of etiology, usually engenders worsening tricuspid regurgitation owing to adverse hemodynamic consequences of right ventricular volume overload, resulting in a slow and inexorable clinical and hemodynamic deterioration.

Tricuspid regurgitation secondary to pulmonary hypertension is seen in patients with significant left-sided heart disease, those with primary pulmonary hypertension, and those with pulmonary disease leading to cor pulmonale. ²² As a general rule, when systolic pulmonary artery pressures increase beyond 55 mm Hg, tricuspid regurgitation can occur despite anatomically normal tricuspid leaflets, whereas more than mild tricuspid regurgitation occurring in the setting of lower systolic pulmonary pressures (<55 mm Hg) likely reflects a structural abnormality of the valve leaflets or the subvalvular apparatus.^23,24 Secondary tricuspid regurgitation also results from tricuspid annular dilation in patients with right ventricular enlargement resulting from right ventricular infarction, dilated cardiomyopathy, or chronic left-to-right shunt due to an atrial septal defect or anomalous pulmonary venous drainage.^25–27

Primary tricuspid valve pathology leading to tricuspid regurgitation may result from blunt trauma, iatrogenic injury, or specific diseases. When it is caused by permanent pacemaker or internal cardiac defibrillator leads, the mechanism of valve injury is variable, related to lead entrapment in the tricuspid apparatus, direct leaflet perforation, fibrotic adhesion of the lead to the leaflet, or avulsion or laceration of the tricuspid valve leaflets upon lead removal. ²⁸ Because leaflet injury may be underappreciated, a high clinical index of suspicion is warranted, particularly when the patient with such an injury later presents with worsening right heart failure. Echocardiography, including 3D imaging, may be useful in localizing the leads relative to the tricuspid valve leaflets ( Figure 24-2). The device leads can be visualized on computed tomography, ²⁹ but because of artifact from the leads, their position relative to the tricuspid valve leaflets can be difficult to determine. Tricuspid valve repair or replacement may be required in symptomatic patients; ²⁸ the role of pacemaker or defibrillator extraction to improve tricuspid regurgitation in patients without infection is less clear.

Direct tricuspid valve leaflet or chordal trauma may occur from transvenous endomyocardial biopsy, particularly in patients who have undergone cardiac transplantation who have repeated biopsies for rejection surveillance ³⁰ ( Figure 24-3). Echocardiographic guidance using real-time three-dimensional imaging during the biopsy may prevent damage to the tricuspid valve or subvalvular apparatus. ³¹

The tricuspid leaflets and supporting structures may be damaged by blunt chest trauma, most often after a motor vehicle accident resulting in papillary muscle, valve, or chordal rupture. Affected patients may be asymptomatic and remain so for years following the trauma, and the murmur of tricuspid regurgitation is often not initially recognized. ³² Conduction abnormalities, including right and left bundle branch block and left anterior hemiblock, occur in more than 90% of patients with traumatic tricuspid regurgitation. Severe tricuspid regurgitation due to a flail leaflet is associated with adverse outcomes favoring early surgical repair (see natural history discussion). ³⁰

Damage to the tricuspid valve may also occur as a result of infective and marantic endocarditis.30,33 Right-sided infective endocarditis is usually a manifestation of intravenous drug abuse, indwelling dialysis or chemotherapy venous catheters, or infected pacemakers or implantable cardioverter defibrillators^24,34–38 ( Figure 24-4). Staphylococcus aureus accounts for 80% of these tricuspid valve infections, although in pacemaker- or defibrillator-associated endocarditis, coagulase-negative staphylococcus may be more common.^24,35,36 In cases of implantable cardiac device or indwelling catheter infections, early device extraction reduces mortality, and in most cases, the pacemaker or defibrillator can be explanted safely even with large vegetations.^36,39 Infrequently, marantic or noninfective endocarditis occurs in the setting of systemic lupus erythematosus, rheumatoid arthritis, or antiphospholipid antibody syndrome. ⁴⁰ The tricuspid valve may also be affected in up to 30% to 50% of patients with rheumatic valve disease. ⁴¹

Serotonin-active drugs can induce fibroproliferative changes to the tricuspid valve leaflets, which are mediated by the 5-HT_2B receptor. ⁴² These changes result in pathologic and echocardiographic features similar to those seen in carcinoid heart disease, with thickened tethered leaflets leading to tricuspid regurgitation. This association was first described with the ergot alkaloids, ergotamine and methysergide, used for migraine therapy. ⁴³ The anorectic agents fenfluramine and dexfenfluramine were subsequently implicated and have since been withdrawn from the market. ⁴⁴ Pergolide and cabergoline, dopamine agonists used in the treatment of Parkinson disease and restless leg syndrome, induce valve thickening and regurgitation by a similar mechanism and have also been withdrawn.^45–47

Carcinoid heart disease is a rare but distinctive form of valve disease affecting primarily the right-sided cardiac valves. Carcinoid tumors arise from argentaffin cells; the primary tumor is usually located in the small bowel and metastasizes to the liver. Serotonin produced by the primary tumor and metastases is recognized to be an agent involved in the development and progression of valve disease in patients with carcinoid syndrome. ⁴⁸ Carcinoid heart disease involves a combination of tricuspid regurgitation ( Figure 24-5) with rare stenosis as well as pulmonic stenosis and regurgitation. Left-sided valvular involvement occurs in approximately 10% of patients with carcinoid, generally in relation to right-to-left shunting of serotonin-rich blood through a patent foramen ovale or primary lung metastases. ⁴⁹ Rarely, carcinoid valve disease occurs in patients without hepatic metastases; an ovarian carcinoid tumor should be sought in this setting. ⁵⁰

Mediastinal irradiation can directly damage the tricuspid leaflets ( Figure 24-6). The associated post-inflammatory fibrosis and calcification, which usually manifest 5 years or longer after the radiation insult, result in distortion of the leaflets, causing tricuspid regurgitation.^24,51,52 Assessment and treatment of tricuspid regurgitation in this setting may be complicated by concomitant dysfunction of other cardiac valves as well as pericardial, myocardial, and coronary artery involvement.

Endomyocardial fibrosis, which is prevalent in tropical Africa, causes fibrosis of the papillary muscle tip and thickening and shortening of the leaflets and chordae, leading to regurgitation. This process may affect both mitral and tricuspid valves.

Congenital causes of tricuspid regurgitation are rare and include congenital tricuspid valve prolapse, which may occur as an isolated abnormality or may be associated with mitral valve prolapse and other connective tissue disorders.53,54 The most common congenital cause of tricuspid regurgitation is Ebstein anomaly ⁵⁵ ( Figure 24-7). In this entity there is apical displacement of the septal and posterior tricuspid valve leaflets into the right ventricle and variable tethering of the anterior leaflet as well as variability in the severity of tricuspid regurgitation. A patent foramen ovale or atrial septal defect occurs in more than 50% of patients. Other associated defects include accessory conduction pathways, pulmonic stenosis, and ventricular septal defect. ⁵⁶

Diagnosis

The course and presentation of tricuspid regurgitation are variable; moderate to severe tricuspid regurgitation is often well tolerated, and patients can remain asymptomatic for years. Symptoms depend on the acuity and chronicity of valve dysfunction and resultant right chamber dilation, and they are usually related to hemodynamic changes that occur as a result of elevated right atrial pressure due to tricuspid regurgitation. Chronic, severe tricuspid regurgitation leads to right heart failure and low cardiac output, resulting in fatigue and decreased exercise tolerance. Peripheral edema and hepatic congestion with associated anorexia and abdominal fullness can occur, and eventually, ascites and anasarca may develop.

Physical examination findings are characterized by jugular venous distention with a visible systolic v wave in 35% to 75% of patients.25–27 Hepatomegaly is present in 90% of patients, but palpable systolic pulsation of the liver is less common. Classically the holosystolic murmur of tricuspid regurgitation is heard along the left sternal border with radiation to the hepatic region and increases in intensity with inspiration because of increased systemic venous return. ²⁶ However, the murmur is often inaudible and can be auscultated in fewer than 20% of patients with documented tricuspid valve regurgitation.^25–27 In addition, many patients have atrial fibrillation, which further confounds interpretation of the characteristic respiratory variation in murmur intensity.^25–27,57

As many as 80% to 90% of patients referred for echocardiography have some degree of tricuspid regurgitation. ⁵⁸ Tricuspid regurgitation can be qualitatively graded with use of color-flow Doppler imaging according to the extent of the systolic color-flow disturbance in the right atrium and semiquantitatively from the density of the continuous wave Doppler echocardiography signal ( Figure 24-8A). Severe tricuspid regurgitation is characterized by a dense and dagger-shaped continuous wave Doppler signal appearance due to rapid equalization of pressures between the right atrium and right ventricle ( Figure 24-8B). Ancillary echocardiographic findings in patients with severe tricuspid regurgitation include inferior vena cava dilation of more than 2 cm and systolic flow reversals in the hepatic veins^59–62 ( Figure 24-8C).

The effective regurgitant orifice area can be estimated by measuring the vena contracta on color-flow Doppler imaging; a vena contracta larger than 0.7 cm indicates severe tricuspid regurgitation.24,61–63 Quantitative Doppler assessment is also feasible with use of the proximal isovelocity surface area (PISA) method, although this requires angle correction. ⁶¹ As with auscultation of the tricuspid regurgitant murmur, respiratory changes occur that may impact Doppler quantification of tricuspid regurgitation. Both the effective regurgitant orifice and the regurgitant volume significantly increase with inspiration, independent of both the severity and pathophysiology of tricuspid regurgitation and the degree of pulmonary hypertension. ⁶⁴

Natural History

The natural history of severe tricuspid regurgitation is often one of a prolonged latent period with eventual progressive right ventricular and later right atrial volume overload. Atrial arrhythmias are common secondary to right atrial enlargement and may be difficult to treat in the presence of persistent tricuspid regurgitation. Initially symptoms of right heart failure and volume overload can be palliated with diuretics, but as hepatic congestion and resultant anorexia develop, patients may become nutritionally depleted.

Tricuspid valve regurgitation has an important impact on clinical outcome and survival in patients with cardiovascular disease. Mortality is higher in patients with tricuspid regurgitation regardless of ejection fraction or severity of pulmonary hypertension. ⁶⁵ Severe tricuspid regurgitation following percutaneous mitral balloon valvotomy has a negative effect on survival, ⁶⁶ and as in patients who have undergone mitral valve replacement, subsequent severe tricuspid regurgitation is associated with a significant reduction in exercise capacity. ⁶⁷

Tricuspid regurgitation from flail leaflets is associated with an increased risk of atrial fibrillation, heart failure, need for surgery, or death. ³⁰ The natural history of tricuspid regurgitation due to flail tricuspid valve leaflets was demonstrated in a cohort of 60 patients at Mayo Clinic, half of whom underwent operative intervention (27 tricuspid valve repair, 6 tricuspid valve replacement). In this series, operative risk was low, and symptomatic improvement was noted in 88% of operated patients. Unoperated patients experienced higher than expected mortality (4.5% yearly; P <0.01) than a matched U.S. population. Right-sided chamber enlargement, even in asymptomatic patients, was associated with a marked increase in morbidity. Unfortunately, risk of atrial arrhythmia may persist even after successful repair.

Medical and Surgical Treatment

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