Etiology, clinical features, and evaluation of tricuspid regurgitation

INTRODUCTION — Tricuspid regurgitation (TR) is a relatively common abnormality. Since this lesion is frequently asymptomatic and may not be detected on physical examination, it is often diagnosed solely by echocardiography. This topic will review the etiology, pathophysiology, and clinical features associated with regurgitation of the tricuspid valve [1].

Management and prognosis of TR and Ebstein anomaly of the tricuspid valve are discussed separately. (See "Management and prognosis of tricuspid regurgitation" and "Ebstein anomaly: Clinical manifestations and diagnosis".)

ETIOLOGY — A small degree of TR (trace) is present in approximately 80 percent of healthy adults [2]. On echocardiography, this "normal" or physiological degree of regurgitation is localized to a small region adjacent to valve closure, often does not extend throughout systole, and has a low signal strength [3].

Abnormal degrees of TR in adults are largely secondary (ie, related to tricuspid annular dilation and/or leaflet tethering in the setting of right ventricular [RV] pressure and/or volume overload) and much less often due to primary disorders of the valve apparatus [4-7]. The frequency of TR as well as valvular pathology was evaluated in a study of 5223 adults (predominantly male with a mean age of 67) who underwent echocardiography at three Veterans Affairs medical centers [4]. Moderate to severe TR was present in 819 (15.7 percent), but only 8 percent had primary tricuspid valve pathology.

Implantable device leads that cross the tricuspid valve may cause acute or chronic TR. The reported frequency of pacemaker lead-associated TR ranges from 7 to 45 percent, can be progressive, and is associated with an increased rate of adverse clinical outcomes [8-10]. The causes of pacer-associated TR include: effects of chronic RV pacing on RV geometry and systolic function, direct impingement on leaflet motion, foreign body inflammation and fibrosis of the leaflets, thrombosis, and endocarditis [11-14]. In a retrospective series of 239 patients undergoing first device implantation with either a pacer or cardioverter-defibrillator lead crossing the tricuspid valve, 38 percent developed significant lead-associated TR within 1 to 1.5 years [8,15].

Secondary TR — TR in adults is most commonly secondary (or functional), defined as regurgitation with apparently anatomically normal leaflets and chords.

The cause of secondary TR most likely is dilation of the right atrium and RV with dilation of the tricuspid annulus [16] and tethering of the tricuspid valve leaflets, although the mechanism of valve dysfunction has not been fully defined [6,17]. RV dilation, tricuspid annular dilation, and tricuspid leaflet tethering may result from any condition that directly involves the RV or causes elevation in RV systolic pressure often with pulmonary hypertension.

The association between TR and pulmonary hypertension was illustrated by an echocardiographic study of 242 patients with severe TR. TR was secondary in 219 patients (90 percent), most often (157/219 or 72 percent) in association with documented significant pulmonary hypertension (defined as pulmonary artery pressure >50 mmHg; causes unspecified) [5]. There were 58 patients (26 percent) with severe secondary TR who did not have documented significant pulmonary hypertension. However, approximately half of these patients had factors suggestive of undocumented pulmonary hypertension or occult tricuspid disease including primary mitral disease, severe left ventricular dysfunction, and/or severe secondary mitral regurgitation. In the 23 patients (2 percent) with severe secondary TR and no evidence of pulmonary hypertension, six had tricuspid valve malcoaptation and two had indeterminate coaptation. In the 15 patients with no evident cause of severe TR, 14 had a history of atrial fibrillation (AF; 7 percent of the total secondary TR group).

The disorders that induce pulmonary hypertension and secondary RV dilatation include the following:

●Left-sided heart failure

●Mitral stenosis or regurgitation

●Primary pulmonary disease – Cor pulmonale, pulmonary embolism, pulmonary hypertension of any cause

●Left to right shunt – Atrial septal defect, ventricular septal defect, anomalous pulmonary venous return

●Eisenmenger syndrome

●Stenosis of the pulmonic valve or pulmonary artery

●Hyperthyroidism (see "Cardiovascular effects of hyperthyroidism")

In other studies, severe secondary TR has been attributed to and/or associated with AF [18-20]. In a series of 87 patients with TR severe enough for consideration of intervention, mean age was 80 (56 percent female), nearly all were in AF (93 percent), and chronic kidney disease was common (64 percent) [21]. There was at least moderate RV dysfunction in 47 percent. Most of these patients (75 percent) did not undergo intervention. Overall, 30-day and one-year survival rates were 100 and 76 percent, respectively.

Patients undergoing surgery for severe TR do not reflect the larger population of patients in whom surgical intervention is not indicated or considered, as illustrated by the following study. In a series of 466 patients undergoing surgery for isolated severe TR, mean age was 60 years, 49 percent were female, 41 percent had hypertension, 40 percent were in atrial fibrillation, and 33 percent had renal insufficiency [22]. TR was secondary in 49 percent, with approximately one-half having previous left-sided valve surgery and one-half having annular dilation in the absence of left-sided valve disease.

Examples of RV diseases causing secondary TR include cardiomyopathies affecting one or both ventricles and ischemic heart disease, which may involve the RV myocardial and tricuspid papillary muscles [23].

Factors predictive of TR severity were evaluated in an echocardiographic review of 2139 patients without primary tricuspid valve disease [20].

●Severe TR was associated with higher pulmonary artery systolic pressure (PASP), AF, right atrial and RV enlargement, left ventricular dysfunction, and primary mitral valve disease.

●Moderate or severe TR was associated with most of these factors, as well as presence of an RV pacemaker lead, older age, and female sex.

●Although TR severity was associated with higher PASP, many patients with pulmonary hypertension had only mild TR (65 percent of patients with PASP 50 to 69 mmHg and 46 percent with PASP ≥70 mmHg).

Severe secondary TR is also associated with AF, but whether the effects of TR such as right atrial enlargement increase the likelihood of AF or whether chronic AF increases the likelihood of TR is not known [19,20].

Primary TR — TR in adults is less often due to processes that directly affect the tricuspid valve (primary or "organic" valve disease); for example, primary tricuspid valve disease was found in only 23 patients (10 percent) of 242 patients with severe TR [5].

Causes of primary TR include:

●Endovascular pacemaker defibrillator leads crossing a native or bioprosthetic tricuspid valve can cause or exacerbate TR by impingement on a valve leaflet, leaflet tethering to the lead, leaflet perforation, or entanglement of the lead with subvalvular chordae [9]. Transvalvular pacemaker leads also increase the risk of recurrent regurgitation after tricuspid valve repair [24]. Endomyocardial biopsy is another cause of tricuspid valve apparatus injury. (See "Cardiac implantable electronic devices: Long-term complications" and "Heart transplantation in adults: Diagnosis of allograft rejection", section on 'Endomyocardial biopsy'.)

However, in some patients with pacemakers, the TR is secondary to RV pacing (possibly related to RV dyssynchrony), rather than the pacer lead [12,25].

●Chest wall or deceleration injury trauma.

●Infective endocarditis.

●Ebstein anomaly, the most common form of congenital disease affecting the tricuspid valve. (See "Ebstein anomaly: Clinical manifestations and diagnosis".)

●Rheumatic valve disease. (See "Clinical manifestations and diagnosis of rheumatic heart disease".)

●Carcinoid syndrome. (See "Carcinoid heart disease".)

●Ischemic heart disease affecting the RV with papillary muscle dysfunction or rupture.

●Myxomatous degeneration associated with tricuspid valve prolapse, which occurs in as many as 40 percent of patients with prolapse of the mitral valve.

●Connective tissue disorder (eg, Marfan syndrome). (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".)

●Marantic endocarditis in systemic lupus erythematosus or rheumatoid arthritis. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults", section on 'Valvular disease'.)

●Drug-induced disease. There was an association between TR and the combined use of the anorectic drugs, fenfluramine and phentermine, in some studies. The dopamine agonist pergolide may induce TR by a mechanism similar to that with anorectic drugs and carcinoid syndrome [26,27]. (See "Valvular heart disease induced by drugs".)

The cause of primary TR in adolescents and young adults [7] usually is congenital, with Ebstein anomaly being most common. Acquired TR is rare in adolescents and young adults except for occasional cases due to trauma, infective endocarditis in intravenous drug users, and valve injury due to the jet through a small ventricular septal defect. (See "Ebstein anomaly: Clinical manifestations and diagnosis" and "Right-sided native valve infective endocarditis".)

PATHOPHYSIOLOGY — TR is characterized by the backflow of blood into the right atrium during systole. Since the right atrium is relatively compliant, there are often no major hemodynamic consequences with mild or moderately severe TR. However, when TR is severe, right atrial and venous pressures rise and can result in the signs and symptoms of right-sided heart failure (figure 1), including ascites and liver failure. In such patients, chronic RV pressure and/or volume overload frequently lead to RV systolic dysfunction and a low forward cardiac output [28]. (See "Hemodynamics of valvular disorders as measured by cardiac catheterization".)

Elevated central venous pressure in patients with severe TR may contribute to impaired renal function regardless of the etiology of the regurgitant lesion [29,30]. Studies have shown that increasing intra-abdominal or central venous pressure, which should also increase renal venous pressure, reduced glomerular filtration rate. Such an effect is not closely related to the cardiac output. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on 'Increased renal venous pressure'.)

CLINICAL MANIFESTATIONS

Symptoms — There are often no specific symptoms associated with mild or moderate TR alone. With severe disease, there may be a sensation of pulsation in the neck (from the distended and pulsatile jugular veins) and symptoms of right-sided heart failure (HF) such as painful hepatosplenomegaly, ascites, and peripheral edema. Some patients with severe TR remain asymptomatic for many years. It remains unclear why some patients tolerate this lesion and others do not.

Symptoms may also arise from the underlying cause of regurgitation. As an example, pulmonary hypertension (whether primary or secondary) may lead to symptoms of low cardiac output, including fatigue, weakness, shortness of breath, and exercise intolerance. Patients with carcinoid valve disease often present with symptoms of carcinoid syndrome with cardiac involvement only diagnosed after imaging studies. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Clinical features of carcinoid syndrome".)

Physical examination — The most prominent features of the physical examination in patients with TR are those related to the regurgitant murmur and the development of right-sided HF. With severe right HF, the patient often looks cachectic, chronically ill, cyanotic, and occasionally jaundiced (reflecting hepatic dysfunction). If TR is due to left ventricular dysfunction, signs of left-sided HF may dominate.

Jugular veins — Distended and prominent jugular veins are apparent and reflect the elevation in right atrial pressure (figure 2 and waveform 1). (See "Examination of the jugular venous pulse".)

●There is a distinct "c-v" (regurgitant) wave due to systolic regurgitation into the right atrium.

●The jugular vein is very pulsatile and may be confused with the carotid arterial pulse. (See "Examination of the jugular venous pulse".)

●Jugular venous distension may be more prominent with inspiration (Kussmaul sign), a result of the increase in venous return. This finding, however, may not be very obvious with marked venous distension.

●A systolic thrill may be felt over the jugular vein in patients with severe regurgitation.

Palpation — Palpation of the chest may reveal a dynamic RV heave due to the dilated RV. A dilated pulmonary artery may also be suggested by dullness and a prominent pulsation over the left second intercostal space, a finding most often observed with pulmonary hypertension. When the TR is very severe, a pulsation may be detected along the right sternal border due to flow into the right atrium.

Edema — Ascites and peripheral edema of variable severity may be present, and anasarca can occur in severe disease. There is frequent evidence of unilateral or bilateral pleural effusions, which are more common when the TR results from pulmonary hypertension secondary to a left-sided cardiac problem (valvular or myocardial).

Hepatomegaly — The liver is often enlarged and tender, and may be pulsatile in severe TR. Occasionally, the systolic murmur may be transmitted to and heard over the liver (with a thrill).

Cardiac auscultation

Murmur — TR is classically associated with a holosystolic murmur that is best heard at the right or left mid sternal border or at the subxiphoid area. When the RV is very enlarged, the murmur may even be appreciated at the apex. There is usually little radiation of the murmur, and a thrill is generally not palpable. However, the murmur of TR is often soft or absent, even when regurgitation is severe. (See "Auscultation of cardiac murmurs in adults".)

Diastolic murmurs are usually absent in TR, although a diastolic rumble may be heard particularly if there is associated tricuspid stenosis or when there is substantial blood flow across the tricuspid valve during diastole, which may occur with an atrial septal defect.

Maneuvers — Interventions that result in an increase in venous return (leg raising, exercise, hepatic compression) will augment the murmur of TR. The murmur may also become louder after a premature beat and prolonged diastole. On the other hand, reducing venous return (with standing) will diminish the intensity of the murmur. In patients with pulmonary hypertension, the intensity of the murmur may change with changes in pulmonary artery pressure. (See "Physiologic and pharmacologic maneuvers in the differential diagnosis of heart murmurs and sounds".)

Respiratory variation in the intensity and duration of the murmur (Rivero-Carvallo's sign) may be observed with mild to moderate TR. With inspiration, there is an increase in venous return to the RV; as a result, the murmur of TR becomes louder and may become longer (unless it is already holosystolic).

The respiratory variation may occasionally be augmented when the patient is standing and venous return is reduced. On the other hand, respiratory variation may not be appreciated in patients with severe TR or marked RV enlargement and dysfunction.

Heart sounds — An S3, which may vary in intensity and with inspiration, is often associated with an extremely dilated RV. An S4 may also be heard if there is significant RV hypertrophy. The intensity of P2 may be increased and splitting of S2 may be marked in patients with pulmonary hypertension. (See "Auscultation of heart sounds".)

When there are other associated cardiac abnormalities, auscultatory findings of these conditions also may be appreciated.

Initial tests — Electrocardiography and chest radiography are not required to diagnose TR but are commonly obtained in evaluating patients with TR. Electrocardiography and chest radiography may reveal findings reflective of right atrial and RV enlargement and concomitant left heart disease, if present.

Electrocardiogram — There are no electrocardiographic (ECG) changes characteristic of mild TR except for nonspecific ST and T wave abnormalities in the right precordial leads that reflect RV dysfunction. If the cause is RV infarction, there is often ECG evidence of an inferior or posterior wall myocardial infarction. In this setting, right-sided precordial leads may demonstrate Q waves, particularly in leads V3R to V5R (waveform 2). (See "Right ventricular myocardial infarction".)

When the cause for TR is pulmonary hypertension, the ECG may show evidence for RV hypertrophy with right axis deviation and tall R waves in V1 to V2 (R>S or R/S>1) (waveform 3). Incomplete (or rarely complete) right bundle branch block is occasionally present.

With severe pulmonary hypertension, right atrial hypertrophy and "P-pulmonale" may also be present. With P-pulmonale, the P wave is tall in amplitude, narrow in duration, and peaked; these changes are especially prominent in leads II, III, aVF, and V1 (waveform 4). In addition, the terminal negative component of the P wave is absent in lead V1 (see "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults"). If atrial fibrillation is present, the fibrillatory waves may be coarse and of increased amplitude (reflecting right atrial hypertrophy).

Changes of underlying left heart disease may be present when the cause of the TR is pulmonary hypertension secondary to an associated left-sided cardiac abnormality.

Chest radiograph — Chest radiographs of patients with severe TR reveal cardiomegaly due to RV enlargement. A prominent cardiac silhouette is observed on the right with the posteroanterior (PA) view, and the enlarged RV fills in the retrosternal space on the lateral film (image 1). Additional findings may include:

●Evidence of right atrial enlargement

●An azygos vein may be seen when the pressure is increased

●Pleural effusions and upward displacement of the diaphragm due to ascites may occasionally be observed

When the cause of the TR is pulmonary hypertension secondary to a left-sided cardiac abnormality, other radiographic findings may be seen, particularly prominent right and left pulmonary artery hilar segments.

DIAGNOSIS — Echocardiography is the main diagnostic modality for identification of TR and evaluation of its severity and cause [31]. Most cases of TR in adults are secondary, although there are a variety of acquired diseases involving the tricuspid valve. By contrast, most cases of TR due to valve disease in adolescents and young adults are congenital, with Ebstein anomaly being most common [7]. Evaluation of Ebstein anomaly is discussed separately. (See 'Etiology' above and "Ebstein anomaly: Clinical manifestations and diagnosis".)

Cardiovascular magnetic resonance (CMR) may be helpful if further quantitative evaluation of RV size and systolic function is indicated. (See 'Cardiovascular magnetic resonance' below.)

Cardiac catheterization is generally not required but may be helpful to evaluate pulmonary artery hypertension, with direct pressure measurements and evaluation of pulmonary vascular resistance. (See 'Cardiac catheterization and angiography' below.)

Echocardiography — Echocardiography is the main diagnostic tool for identification and evaluation of TR (movie 1). Echocardiographic evaluation of the tricuspid valve is discussed in detail elsewhere, but the major findings will be summarized here (table 1) [7]. (See "Echocardiographic evaluation of the tricuspid valve", section on 'Tricuspid regurgitation'.)

Echocardiographic findings include the following:

●Tricuspid valve leaflets and motion may be normal or abnormal. Characteristic primary valvular abnormalities include Ebstein anomaly, carcinoid heart disease, rheumatic valve disease, leaflet prolapse, flail leaflet, and endocarditis.

Echocardiography, particularly three-dimensional transesophageal echocardiography (3D TEE), is helpful for identifying and defining the mechanism of pacer-lead-related TR [9].

●The RV, tricuspid annulus, and right atrium are usually dilated in the presence of moderate to severe TR (unless the TR is acute) (figure 1 and movie 1 and movie 2 and movie 3 and movie 4).

●Severity of TR is determined by integration of several imaging and Doppler findings (movie 1 and movie 4 and movie 5).

•The major Doppler criteria for severe TR are a vena contracta width of 0.7 cm or greater and systolic flow reversal in the hepatic veins [3,7]. However, hepatic vein systolic flow reversal is not accurate unless sinus rhythm is present, because normal atrial filling during ventricular systole depends on a preceding normal atrial contraction (movie 6 and movie 7) [3].

•3D imaging with 3D Doppler may be helpful in some cases [32,33].

●Interventricular septal movement may be paradoxical, reflecting the increased volume within the RV (diastolic overload) or due to pulmonary hypertension in patients with secondary TR.

●RV function may be hyperdynamic, normal, or reduced, reflecting the underlying cause of TR and the degree of RV compensation. Normal RV systolic function is defined by several parameters, including tricuspid annular plane systolic excursion >16 mm, tricuspid valve systolic annular velocity >10.0 cm/s, and RV end-systolic area <20.0 cm² or fractional area change >35 percent. Other imaging modalities, such as 3D TEE, cardiovascular magnetic resonance imaging, and computed tomography, may provide more accurate information on the status of the RV. (See "Approach to evaluation of the right ventricle in adults" and "Echocardiographic assessment of the right heart".)

●The degree of pulmonary hypertension often can be accurately measured by estimating the RV to right atrial systolic gradient from the velocity of the TR jet (using the modified Bernoulli equation) and adding this gradient to an estimate of right atrial pressure. However, estimation of right atrial pressure may be inaccurate when TR is severe, leading to underestimation of pulmonary systolic pressure [34,35]. (See "Echocardiographic evaluation of the tricuspid valve", section on 'Continuous wave Doppler'.)

If Doppler echocardiographic data are inadequate or discordant, invasive measurement of pulmonary artery pressures and calculation of pulmonary vascular resistance may be helpful [36].

●Evaluation of the left heart may identify a cause for pulmonary hypertension and secondary TR, such as mitral stenosis, mitral regurgitation, LV systolic or diastolic dysfunction, or aortic valve disease. (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults".)

Cardiovascular magnetic resonance — CMR imaging may be helpful if echocardiographic evaluation is suboptimal or inconclusive for assessment of TR severity and RV size and function [3,37,38]. CMR enables quantitative assessment of tricuspid regurgitant volume, regurgitant fraction (the ratio of TR volume to stroke volume), RV volumes and ejection fraction, as well as evaluation of associated LV and mitral disease [39]. (See "Clinical utility of cardiovascular magnetic resonance imaging".)

Cardiac catheterization and angiography — Cardiac catheterization and contrast right ventriculography are not helpful for the diagnosis or evaluation of TR in most patients. However, right heart catheterization of measurement of pulmonary pressures and pulmonary vascular resistance is appropriate in patients with TR when clinical and noninvasive data regarding pulmonary pressures are discordant. Left heart catheterization may be helpful to assess potential causes of secondary TR (eg, left-sided valve or myocardial disease with an elevated left atrial pressure). (See "Hemodynamics of valvular disorders as measured by cardiac catheterization".)

Stages of tricuspid regurgitation — TR is staged as mild to moderate (or progressive, stage B), asymptomatic severe (Stage C), or symptomatic severe TR (Stage D) (table 1).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease".)

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SUMMARY AND RECOMMENDATIONS

●Tricuspid regurgitation (TR) in adults is most commonly secondary, caused by dilatation of the right atrium and right ventricle (RV) with dilation of the tricuspid annulus and tethering of the tricuspid valve leaflets. It is much less commonly caused by primary valve disease. (See 'Etiology' above.)

●Causes of primary acquired tricuspid valve disease leading to TR include valve injury from a permanent pacemaker or implantable cardioverter-defibrillator lead, chest trauma, endocarditis, rheumatic fever, carcinoid syndrome, ischemic disease affecting the RV, and myxomatous degeneration associated with tricuspid valve prolapse. Ebstein anomaly is the most common congenital cause of TR. (See 'Etiology' above and "Ebstein anomaly: Clinical manifestations and diagnosis".)

●Symptoms of severe TR are variable. They may include a sensation of pulsation in the neck and symptoms of right-sided heart failure such as painful hepatosplenomegaly and edema. However, some patients with severe TR remain asymptomatic for many years. (See 'Symptoms' above.)

●Physical findings that may be seen with severe TR include jugular venous distention, RV heave, peripheral edema, ascites, and hepatomegaly. A holosystolic murmur of TR may be heard but this may be soft or absent even when the TR is severe. (See 'Physical examination' above.)

●Electrocardiography and chest radiography may reveal findings reflective of right atrial and RV enlargement and concomitant left heart disease, if present. (See 'Initial tests' above.)

●Echocardiography is the main diagnostic modality for evaluation of TR. It enables evaluation of the severity of TR, valve morphology, right chamber sizes and RV function, estimation of pulmonary artery systolic pressure, as well as assessment of any concomitant left heart disease. Cardiovascular magnetic resonance imaging may be helpful if echocardiographic evaluation is suboptimal or inconclusive for assessment of TR severity and RV size and function.