Evaluation of systemic impact of tricuspid regurgitation: an appeal for the notion of tricuspid regurgitation syndrome

Tricuspid regurgitation (TR) is an often encountered but undertreated valvular heart lesion. Unlike left-sided valvular diseases, it is estimated that only 5% of patients with significant TR were treated surgically, among which 86% were treated in combination with other major procedures.^[1] This unmet need partially resulted from the lack of prospective evidence on reduced mortality of severe TR benefiting from surgery, alongside a historical viewpoint that functional TR (being the etiology for the vast majority of TR) would be improved once problems in the left heart are corrected. However, untreated severe TR shows various symptoms and a poor prognosis, including increased early and late mortality and impaired quality of life.^[2] With the rapid development of catheter-based valve therapies, less invasive treatment options have been offered to the once forgotten tricuspid valve, further expanding the complexity of decision-making for TR intervention.

When should TR patients be intervened? One of the essential questions in the management of TR patients is the timing of intervention. Although the newly updated guideline has advocated early treatment, the indication largely relies on anatomical measurements with yet-to-be defined thresholds.^[3] There is currently only one Level I recommendation for TR, that is, patients with severe TR in stages C and D are recommended to undergo left-sided valve surgery. Other main indications include severe symptomatic primary TR in Stage D and progressive TR with tricuspid annulus end-diastolic diameter >4 cm or right-sided heart failure while undergoing left-sided valve surgery.^[4] TR is a progressive disease usually complicated with systemic manifestations at the end stage, which in our opinion should be considered as important components in the evaluation of TR. It has been shown in a report reflecting the contemporary trends in the use and outcomes of tricuspid valve surgery for TR that approximately 40% of patients underwent isolated TR surgery during a non-elective admission, a significant number of whom had chronic kidney (23%) and liver (11%) diseases.^[5] They presented a higher in-hospital morbidity and mortality than patients receiving TR surgery concomitant with other cardiac surgeries,^[5] suggesting that more severe TR-related symptoms and later stages of TR (as indicative of isolated TR surgery) may translate to worse outcomes after surgical treatment. The reluctance of correcting TR likely loses the best window for right ventricular functional recovery, while the involvement of other systems as TR progresses in turn minimizes treatment benefits. In terms of surgery, valve repair is preferable to replacement, but in the presence of a markedly dilated annulus or primary disease of the leaflets, replacement may be the option. TR patients now being treated with transcatheter devices are usually in a state of irreversible pathology, but transcatheter tricuspid valve intervention still yielded a survival benefit compared with medical therapy alone in a recent propensity-matched case-control study.^[6] The most widely used edge-to-edge repair technique has been shown to have achieved a durable reduction of TR to moderate or less in 71% of patients in one year.^[7] The promising results have enhanced the enthusiasm for developing algorithms to select the right patients for the right type of device, which involves a set of criteria for the quantification of TR and evaluation of tricuspid valve anatomy.^[1] However, the assessment of TR severity remains challenging by the Doppler methods established from left-sided valvular regurgitation, and symptomatic improvement does not necessarily correspond to the degree of TR reduction. Cardiac pathology is indeed crucial, but patient-level risk stratification, such as clinical symptoms and comorbidities, has been shown to be the main contributor to the risk score model for isolated TR surgery,^[8] which is currently not well categorized in TR interventions.

We thought to construct a framework of patient-centered risk stratification that can also serve as a scale of effectiveness after interventions. The framework intends to add a dimension for patient evaluation in the scope of TR. The proposed notion of TR syndrome incorporates systemic manifestations from hemodynamic disorders of severe TR, including those of cardiac, respiratory, hepatic and digestive, hematopoietic, renal, and skin issues [Figure 1]. The symptomatic progression of TR starts from pulmonary and central venous congestion to chronic right heart failure.^[1] Outside the heart, (1) pulmonary congestion and the increase in intra-abdominal pressure from liver congestion and ascites further impair vital capacity, which aggravates dyspnea. (2) Long-term central venous congestion induces hepatomegaly, together with portal hypertension from liver congestion and hepatocyte ischemia and hypoxia from the decreased cardiac output and abnormal oxygen exchange in the liver, resulting in cirrhosis and liver dysfunction. (3) Digestive disorders in TR may be divided into five grades: no symptoms, loss of appetite, nausea, vomiting, and gastrointestinal bleeding. (4) Portal hypertension leads to splenomegaly and hypersplenia, resulting in increased destruction of blood cells. Long-term venous congestion leads to decreased digestion and absorption and may also affect the function of bone marrow. Thus, TR patients in the end-stage can show pancytopenia. (5) The skin changes caused by TR can have two main types. One type only affects the lower extremities, manifested as lower extremity edema, pigmentation, and itching or sensory disturbance; the second type has generalized skin changes, manifested as itching in the trunk and lower limbs, often resulting in skin damages, bleeding, and other pathological changes from scratching. (6) Low cardiac output also leads to renal hypoperfusion and a drop in glomerular filtration, eventually resulting in renal dysfunction. The assessment of the syndrome enables physicians to semiquantitatively grade the impact of TR on patients. We propose that Stage 1 should be defined as no clinical symptoms, Stage 2 with solely cardiac symptoms, Stage 3 presenting with any extracardiac manifestations, and Stage 4 involving ≥2 extracardiac systems [Figure 1]. Although there is a lack of evidence of the proportions of patients in each stage, Stage 3/4 would not be a rare case considering the comorbidities reported in previous cohorts.^[9] Systemic manifestations can be improved when the pathological state is still reversible after TR interventions; thus, reassessment of the syndrome serves as a reliable indicator for the effectiveness of treatment.

Figure 1.

The proposed patient-centered framework for risk stratification and outcome assessment in TR patients. Numbers marked within the section of digestive disorders represent the grade of each symptom. TR: Tricuspid regurgitation.

In conclusion, the clinical presentation of severe TR varies from nonspecific symptoms to extensively impaired functional capacity and systemic involvement. The current timing for definitive treatment of TR might often be late, which adversely affects outcomes after interventions. Thus, more parameters are needed to better justify the appropriateness of interventions. The assessment of extracardiac manifestations helps to identify hemodynamic disorders secondary to TR and enables us to quantify the impact on patients. From the patient's point of view, the improvement of symptoms such as epigastric fullness outweighs the decrease in the grade of TR. The notion of TR syndrome puts the patient's perspective at the center of decision-making in TR intervention and adds another dimension to the care of TR patients.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81970325 and 82102129).

Conflicts of interest

None.