Epidemiology, Etiology, and Natural History of Tricuspid Regurgitation
- Luigi P. Badano, MD, PhD
- Karima Addetia, MD
- Denisa Muraru, MD, PhD
- Karima Addetia, MD
With respect to heart valve diseases, until recently tricuspid valve regurgitation has received less attention than aortic or mitral valve lesions and therefore has been referred to as the “forgotten valve.” Although trivial or mild tricuspid regurgitation may be detected in 80% to 90% of normal subjects undergoing modern echocardiography and is usually benign, hemodynamically significant tricuspid regurgitation can lead to debilitating symptoms and is associated with poor prognosis in a number of cardiovascular diseases.
Today, diagnostic techniques and appropriate management strategies for patients with tricuspid regurgitation are established and continually refined. Therefore, it is important that clinicians consider assessing the severity of tricuspid regurgitation, understand its pathophysiology, choose appropriate imaging techniques, and refer patients for timely intervention to prevent clinical deterioration and subsequent adverse consequences.
Epidemiology
Using echocardiography, the Framingham Heart Study investigators found a prevalence of moderate or severe tricuspid regurgitation of 0.8% and an increased prevalence with aging. Overall, the prevalence of significant tricuspid regurgitation was 4.3 times greater in females than in males. Tricuspid regurgitation is frequently present in patients with mitral valve disease, and more than one third of patients with mitral stenosis have at least moderate tricuspid regurgitation. Severe tricuspid regurgitation has been reported in 23% to 37% of patients after mitral valve replacement for rheumatic valve disease. In the majority of patients, tricuspid regurgitation is not related to any primary valve pathology and is defined as “functional.” Functional tricuspid regurgitation is frequently observed in the advanced stage of left-sided valvular heart disease or myocardial disease. In 14% of patients, tricuspid regurgitation may occur in the absence of structural tricuspid valve alterations, pulmonary hypertension, or left heart dysfunction ( Fig. 120.1 ).
Finally, the development of hemodynamically significant tricuspid regurgitation has been reported in 27% of patients who had only mild tricuspid regurgitation at the time of left-sided valve surgery. In most cases, tricuspid regurgitation is diagnosed late after mitral valve replacement, 10 years on average, but can appear as late as 24 years after the initial surgery. Matsunaga and Duran reported moderate or severe tricuspid regurgitation in 74% of patients who had undergone surgical repair of ischemic mitral regurgitation 3 years previously.
Etiology and mechanisms of tricuspid regurgitation
The etiology of tricuspid regurgitation is generally divided into primary (or intrinsic) valve disease and secondary (or functional) valve dysfunction ( Box 120.1 ). Primary tricuspid regurgitation results from structural abnormalities of valve apparatus, may be congenital or acquired, and accounts for only 8% to 10% of all severe tricuspid regurgitations ( Fig. 120.2 ). Secondary or functional tricuspid regurgitation is usually due to tricuspid annulus dilatation caused by right ventricular dilatation and dysfunction, which may be primary or secondary to left heart diseases resulting in pulmonary hypertension ( Fig. 120.3 ). However, despite the fact that pulmonary arterial hypertension from any cause is known to be associated with the occurrence of secondary or functional tricuspid regurgitation, not all patients with pulmonary hypertension develop significant tricuspid regurgitation because its mechanisms are multifactorial. Mutlak and colleagues assessed the determinants of tricuspid regurgitation severity in a large cohort (2139 patients) with mild (< 50 mm Hg), moderate (50-70 mm Hg), or severe (> 70 mm Hg) elevation of pulmonary artery systolic pressure. In this population, elevated pulmonary artery systolic pressure was associated with more severe tricuspid regurgitation (odds ratio 2.26 per 10 mm Hg increase). However, a large number of patients with elevated pulmonary artery systolic pressure showed only mild tricuspid regurgitation (65.4% of patients with moderate and 45.6% of patients with severe pulmonary hypertension, respectively). These authors showed that other factors such as atrial fibrillation, pacemaker leads, and right ventricular remodeling were also significant determinants of the severity of tricuspid regurgitation. Among them, remodeling of the right heart in response to the increase in pulmonary artery systolic pressure was the most powerful predictor of tricuspid regurgitation. These data confirm earlier observations that annular dilatation, right ventricular dilatation, or tricuspid valve tenting and not pulmonary hypertension itself are the main determinants of functional tricuspid regurgitation (see Fig. 120.3 ).
Functional (morphological normal leaflets with annular dilatation) (75%)
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Left heart diseases (left ventricular dysfunction or valve diseases) resulting in pulmonary hypertension
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Primary pulmonary hypertension
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Secondary pulmonary hypertension (e.g., chronic lung disease, pulmonary thromboembolism, left-to-right shunt)
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Right ventricular dysfunction from any cause (e.g., myocardial diseases, ischemic heart disease)
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Atrial fibrillation
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Cardiac tumors (particularly right atrial myxomas)
Structural abnormality of the tricuspid valve (25%)
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Rheumatic
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Prolapse
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Congenital
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Ebstein anomaly
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Tricuspid valve dysplasia
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Tricuspid valve hypoplasia
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Tricuspid valve cleft
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Double-orifice tricuspid valve
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Unguarded tricuspid valve orifice
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Endocarditis
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Endomyocardial fibrosis
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Carcinoid disease
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Traumatic (blunt chest injury, laceration)
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Iatrogenic
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Pacemaker/defibrillator lead interference
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Right ventricular biopsy
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Drugs (e.g., exposure to fenfluramine-phentermine, or methysergide)
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Radiation
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Even in the absence of pulmonary hypertension, tricuspid annular dilatation may cause significant regurgitation. In patients with chronic pulmonary thromboembolic hypertension and in patients with mitral stenosis in whom tricuspid regurgitation resolved after successful pulmonary thromboendoarterectomy or mitral balloon valvuloplasty, there was no change in tricuspid annulus diameter after the resolution of pulmonary hypertension. These observations suggest that tricuspid annulus dilatation could be irreversible and might be the mechanism of late tricuspid regurgitation encountered in mitral valve diseases. Once tricuspid regurgitation has become significant, progressive right ventricular remodeling and dysfunction due to chronic volume overload result in papillary muscle displacement and leaflet tethering, which worsen tricuspid regurgitation and lead to further right ventricular dilatation. On the other hand, the dilated right ventricle may also compress the left ventricle via chamber interdependence, leading to an increase of pulmonary pressure which, in turn, will worsen tricuspid regurgitation.
Particular cases of tricuspid regurgitation are those developing after blunt chest trauma or as a consequence of pacemaker or defibrillator leads, which may directly interfere with leaflet coaptation while crossing the valve from the right atrium to the right ventricle. Tricuspid regurgitation is a rare complication of blunt chest trauma, most frequently of high-energy road traffic accidents. If the acute rise in right intraventricular cavity pressure happens when the valve is closed, it may result in chordal rupture ( Fig. 120.4 ); however, both anterior papillary muscle rupture and leaflet tears (primarily the anterior leaflet) have also been reported. In the acute phase of the injury, the traumatic lesion can go undetected. In the chronic phase, many patients remain asymptomatic, whereas others exhibit symptoms and signs of right heart failure.
Tricuspid regurgitation due to endocardial lead implantation or removal of permanent pacemakers or implantable cardioverter-defibrillators is a known complication of these procedures. Conflicting data have been reported about the incidence of tricuspid regurgitation related to endocardial lead implantation. The reported incidence of at least moderate tricuspid regurgitation ranged between 7% and 39%. However, there are significant limitations in these reports: Most of them were retrospective, the number of enrolled patients was limited, the length of follow-up was not predefined, and the methods used to assess the severity of tricuspid regurgitation were quite different and mainly qualitative. The mechanisms by which a right ventricular lead may induce tricuspid regurgitation remain to be clarified. Several investigators have documented a mechanical interference of the lead with the valve leaflets leading to impaired valve closure , ( Fig. 120.5 ). Others have found that delayed right ventricular activation and/or alteration in right ventricular geometry and/or right ventricular dyssynchrony induced by active right ventricular pacing may cause tricuspid valve malfunction and regurgitation. The mechanical (lead interference) and functional (valve malfunction induced by active right ventricular pacing) mechanisms may also coexist, but the relative contribution of the two remains to be defined. Sakai and associates studied 26 paced hearts at autopsy and reported an interference of the pacemaker lead with the valve leaflets in 42% of cases (interference with leaflet motion in 2 patients, entanglement of valve chordae in 4 patients, and coexistence of the two in 5 patients). Lin and colleagues, in a retrospective study of 41 patients, identified four mechanisms by which right ventricular lead led to severe tricuspid regurgitation: perforation of valve leaflets, entanglement of the lead with subvalvular apparatus, impingement of the tricuspid valve leaflets, and lead adherence to the tricuspid valve.
The time course for tricuspid regurgitation development/progression after pacemaker implantation also remains to be defined. Pathologic studies have detected major inflammatory changes within the heart only few days after lead implantation. It has been postulated that progression of inflammation over weeks to months may lead to the formation of fibrous tissue involving the pacemaker lead and resulting in lead fusion and adherence to the various components of the tricuspid valve apparatus, causing regurgitation. This has important implications for management because early detection of catheter-related tricuspid regurgitation may be solved by lead repositioning only if it is performed shortly after lead implantation, but the procedure can be difficult, if not impossible, during the chronic stage.
Finally, tricuspid regurgitation may be iatrogenic. Franceschi and co-workers performed a prospective study during which they removed 237 catheters in 208 patients implanted around 46 months earlier. New tricuspid regurgitation occurred in 19 patients (9.1%) and was severe in 14. Three independent risk factors of traumatic tricuspid regurgitation were identified: use of laser sheath, use of both laser sheath and lasso, and female gender. However, the strongest risk factor appears to be related to the use of specific extraction tools, due to the failure of simple traction. The anatomic substrate is related to the fibrous growth around the whole length of the lead, with attachments to surrounding structures including the tricuspid valve.
Another cause of iatrogenic, traumatic tricuspid regurgitation is represented by repeated endomyocardial biopsies. Tricuspid regurgitation is the most frequent valvular abnormality that occurs after cardiac transplantation. Mielniczuk and colleagues found histologic findings of chordal tissue in 47% of endomyocardial biopsy specimens from heart transplant patients in whom a significant tricuspid regurgitation was detected. These findings suggest that chordal damage at the time of endomyocardial biopsy leading to tricuspid valve prolapse is the cause of tricuspid regurgitation in these patients ( Fig. 120.6 ). In 101 patients who underwent orthotopic cardiac transplantation and survived more than 1 year, Nguyen and associates reported that 25% developed a severe tricuspid regurgitation (4% required valve replacement for refractory right-sided heart failure). In their series, there was no case of severe tricuspid regurgitation in those patients who underwent fewer than 18 biopsies; conversely, the incidence of severe tricuspid regurgitation was 60% in those who underwent more than 31 endomyocardial biopsies.
Tricuspid regurgitation is also a dynamic phenomenon that shows respiratory changes of large magnitude and complex pathophysiology which are independent on severity and pathogenesis of the regurgitation and degree of associated pulmonary hypertension. Topilsky and colleagues performed a quantitative echo-Doppler study to elucidate the mechanics of respiratory variations of tricuspid regurgitation. They observed marked right ventricular (and not right atrial) changes in size and shape during inspiration, particularly right ventricular widening. Right ventricular widening was associated with inspiratory annular enlargement, leading to less systolic annular coverage by tricuspid leaflets and increased valvular tenting, both of which contribute to coaptation loss and increase in effective regurgitant orifice. Therefore, despite a decline in regurgitant gradient, a large increase in effective regurgitant orifice occurs during inspiration, causing a notable increase in regurgitant volume.
Natural history
Some patients with isolated chronic severe tricuspid regurgitation may remain asymptomatic for some time, whereas others may experience fatigue and decreased exercise tolerance as a result of reduced cardiac output. As the right atrial pressure increases, patients may experience the classic symptoms caused by right-sided heart failure: peripheral edema, abdominal fullness, ascites, hepatomegaly, and decreased appetite. As the right atrium enlarges, the incidence of atrial fibrillation increases, leading itself to further right atrial and tricuspid annulus dilatation and clinical deterioration. If left untreated, severe tricuspid regurgitation will determine right ventricular failure, which will result in severe peripheral edema, ascites, and severe functional limitation. It has been reported that increasing severity of tricuspid regurgitation is associated with worsening prognosis, independently from left ventricular function or pulmonary pressure.
Quantification of Tricuspid Regurgitation
- Luigi P. Badano, MD, PhD
- Karima Addetia, MD
- Denisa Muraru, MD, PhD
- Karima Addetia, MD
Two-dimensional echocardiography combined with spectral and color flow Doppler evaluation provides the most accurate laboratory test in detection and quantification of tricuspid regurgitation (TR). “Physiological” TR is associated with normal valve leaflet morphology and normal right ventricular and atrial size ( Fig. 121.1 ).
When a “pathologic” TR is detected at color Doppler, a complete understanding of leaflet morphology and of the pathophysiological mechanisms underlying TR is mandatory (see Chapter 123 ). In these cases, a more comprehensive assessment of the morphology of the tricuspid valve apparatus using transthoracic three-dimensional echocardiography provides important clues to the underlying etiology and mechanisms of valve dysfunction.
Secondary TR is characterized by annular dilatation (> 40 mm) and tethering of the leaflets, with a tenting distance greater than 8 mm. In most severe cases, the leaflets fail to coapt, resulting in a wide-open regurgitation ( Fig. 121.2 ).
Color flow Doppler and spectral Doppler are sensitive for the detection of TR and generally accurate for a semiquantitative assessment of its severity.
TR using color flow imaging can be detected using both the parasternal (tricuspid inflow view and short-axis view at great vessels level), and apical or subcostal (four-chamber view) approaches ( Fig. 121.3 ). Regurgitant jet area correlates roughly with the severity of regurgitation, being less than 5 cm 2 in mild, 6 to 10 cm 2 , in moderate, and greater than 10 cm 2 in severe cases. In clinical practice, a visual estimate rather than actual planimetry is used. Detection of a large eccentric jet adhering, swirling, and reaching the posterior wall of the right atrium is in favor of significant TR. Conversely, small thin central jets usually indicate mild TR. However, the color Doppler method is a source of many errors, is limited by several technical and hemodynamic factors, and therefore is not recommended to assess TR severity. A more accurate estimate may be obtained by using jet vena contracta width and proximal isovelocity surface area (PISA) measurements.
Vena contracta represents the cross-sectional area of the blood column as it leaves the regurgitant orifice; it reflects thus the regurgitant orifice area. The vena contracta of the TR jet is typically imaged in the apical four-chamber view using a careful probe angulation to optimize the flow image, an adapted Nyquist limit (color Doppler scale, 40 to 70 cm/sec) to perfectly identify the neck of the jet, and a narrow sector scan coupled with the zoom mode to maximize temporal resolution and measurement accuracy ( Fig. 121.4 ). Averaging measurements over at least two or three beats is recommended. A vena contracta diameter larger than 6.5 mm is usually associated with severe TR (see Fig. 121.4 , right panel). Intermediate values are not accurate for distinguishing moderate from mild TR. However, when measuring the vena contracta, one should take into account the fact that the regurgitant orifice geometry is complex and not necessarily circular ( Fig. 121.5 ). This may explain the poor correlation found between the vena contracta width at two-dimensional color Doppler and the three-dimensional echo assessment of the effective regurgitant orifice area. Particular caution should be used in assessing eccentric jets. With three-dimensional color Doppler echo, an effective regurgitant orifice area greater than 75 mm 2 has been associated with severe TR.
PISA radius measurement is by itself a good indicator of severity of regurgitation, but the method should be properly performed ( Fig. 121.6 ). Qualitatively, a TR PISA radius greater than 9 mm at a Nyquist limit of 28 cm/sec has been associated with the presence of significant TR (corresponding to an effective regurgitant orifice area ≥ 40 mm 2 and a regurgitant volume ≥ 45 mL, the quantitative thresholds for severe TR), whereas a radius less than 5 mm suggests mild regurgitation. However, the PISA method also faces several limitations. Eccentric jets may represent a challenge in alignment with the beam of ultrasound. The most challenging issue is the fact that leaflets that are tenting are often not flat and the outer angle formed by these should be accounted for in the calculation of regurgitant flow. It is also crucial to account for the expected respiratory variation of TR and to average measurements performed during inspiration (largest flow convergence, lowest TR velocity) and expiration (smallest flow convergence, highest TR velocity) to provide an average severity over the respiratory cycle to the clinician ( Fig. 121.7 ). Finally, we must take into account the extreme load dependency of the tricuspid regurgitant volume and its changes during cardiac systole ( Fig. 121.8 ). Changes in patient’s position, diuretic therapy, and lack of standardization of timing in measuring severity of TR are among the most frequent causes of inter-technique and day-to-day variability of severity of TR.
