https://orcid.org/0000-0002-5993-4487
The growing interest in transcatheter tricuspid valve treatment marks a major shift in managing severe tricuspid regurgitation (TR). Since the advent of transcatheter tricuspid interventions (TTVIs), several devices have gained CE mark approval, aimed at either repairing or replacing the regurgitant valve or mitigating the haemodynamic effects of TR. The recent publication of the first randomized clinical trial in TTVI1 raises a critical question: who are the right patients for TR treatment? To answer this, it is crucial to understand the pathophysiological impact of severe TR, including forward and backward failure as well as ventricular interaction (Figure 1).
Pathophysiological consequences of haemodynamically relevant tricuspid regurgitation
Forward failure
The incompetent tricuspid valve allows a portion of the stroke volume generated by the right ventricle (RV) to leak back into the right atrium (RA). This leakage reduces the effective stroke volume, leading to diminished cardiac output (CO) at rest.2 Exercise intolerance and shortness of breath are frequently observed in patients with TR mainly due to limited CO reserve, explaining why improvements in New York Heart Association functional class are often seen over a broad range of patients after TTVI.3–7 In more advanced stages of TR, forward failure might occur, marked by decreased systemic vascular resistance, resulting in reduced organ perfusion and oxygen delivery, including the coronary arteries and other vital organs.
Markers of hepatocellular injury, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), should be monitored as they are sensitive markers of severely impaired CO due to TR and they portend a dismal prognosis.6,8 Reduced perfusion can worsen RV function and exacerbate TR, contributing to further systemic complications. Transcatheter tricuspid intervention has been shown to improve forward stroke volume and CO,3,4 making these factors valuable for assessing the success of TTVI beyond focusing solely on the tricuspid valve.
Ventricular interaction
Ventricular interaction arises due to the interplay of the four heart chambers in the finite pericardial space. In advanced TR, the RV and RA dilate, occupying most of this space and displacing the left ventricle (LV).2,3 Especially in patients with heart failure with preserved ejection fraction (HFpEF), this displacement leads to septal flattening or even a shift towards the LV during early diastole, due to increased RV filling and volume overload. As a result, LV transmural pressures decrease, reducing LV filling despite elevated LV end-diastolic pressure (LVEDP). The rise in LVEDP can cause postcapillary pulmonary hypertension, adding further strain on the RV and increasing the likelihood of ventricular TR. Additionally, elevated LVEDP stresses the left atrium, promoting atrial fibrillation and possibly exacerbating atrial TR.
Transcatheter tricuspid intervention has been proposed to counteract this vicious cycle by increasing LV filling while maintaining filling pressures.3 However, the relationship between HFpEF and TR remains complex. Traditionally, HFpEF has been viewed as a cause of TR, but recent evidence suggests TR might elevate LVEDP, mimicking a HFpEF phenotype. Some patients with TR and initially elevated LVEDP experience normalized filling pressures after TTVI, leading to the proposal of a TR-HFpEF phenotype induced by TR, which might be potentially treatable by addressing TR.3 Thus, normalization of LV filling pressures, restoration of intraventricular septum movement, and significant reductions in RV volumes are positive indicators of successful TTVI.
Backward failure
The hallmark of TR is backward failure, characterized by chronic venous congestion due to elevated RA pressures, which are driven by both loading conditions and regurgitant volume. This chronic congestion leads to conditions such as congestive nephropathy, hepatopathy, gastropathy, and intestinal oedema, resulting in malabsorption.8
It also increases glomerular efferent pressure, activating the renin–angiotensin–aldosterone system, which raises total blood volume and contributes to diuretic resistance.9 Hepatic congestion results in sinusoidal dilation, fibrosis, and hepatocyte atrophy, leading to the release of vasoactive substances that lower systemic vascular resistance and worsen organ perfusion, contributing to a high CO TR phenotype, which resembles a phenotype frequently observed among patients with primary liver disease and counteracts some effects of forward failure.7 In contrast to AST and ALT, which represent markers of ischaemic hepatic injury due to low CO, gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) are more susceptible to backward failure and can positively be influenced by improving TR through TTVI.8 Malabsorption further exacerbates symptoms of right heart failure, such as anasarca and ascites, through nutritional deficiencies and hypoalbuminemia.8
Yet, simply reducing TR may not fully reverse backward failure. Patients with signs of hepatopathy undergoing TTVI have worse prognosis compared to those without.6 Interestingly, RA pressure reduction is often minimal even after successful TR treatment in patients with congestive hepatopathy or high CO states, despite expectations that reducing TR would lower RA pressures.7 This suggests that treating TR alone may be insufficient in patients with advanced congestive hepato- and nephropathy. This might be explained by the concept of unstressed and stressed blood volume (SBV). Stressed blood volume plays a critical role in right heart failure and severe TR. Stressed blood volume representing effective circulating blood volume elevates due to reduced venous capacitance—a key feature of heart failure. In severe TR, increased SBV is associated with greater congestion, renal and hepatic dysfunction, larger RV size, worsened RV function, higher LVEDP, and poorer outcomes.9 While linked to high CO, SBV influences outcomes independently, highlighting two main drivers of backward failure: high CO and elevated SBV.
Who is the ideal candidate for the treatment of tricuspid regurgitation?
Considering the three main haemodynamic effects of TR, it becomes clear that the therapeutic response can vary significantly depending on the extent of haemodynamic derangements, even with similar reductions in TR. In early stages, where forward failure and exercise intolerance predominates and the venous system compensates for increased backward flow, TR treatment restores CO reserve. Improvements in physical activity and shortness of breath have been observed consistently in TTVI patients.3,4,8 Where unfavourable ventricular interaction is present, TR reduction brings benefits beyond restoring CO, potentially improving LV diastolic function, reducing filling pressures and therefore pulmonary congestion further alleviating symptoms of dyspnoea, and reducing the strain on both the LV and RV.
Patients in advanced disease stages with severe renal, hepatic, and gastrointestinal involvement may require additional treatments, which are yet to be explored, to address systemic effects and improve outcomes.
Recent evidence shows that patients in early- and late-stage TR experience diminished survival benefits from TTVI compared to those in intermediate stages.10 This clinical observation has been supported by invasive haemodynamic data, revealing that patients without evident congestion or with isolated left-sided congestion have better prognoses and procedural outcomes. Conversely, the presence of right-sided congestion, regardless of left-sided involvement, is associated with poorer outcomes and procedural success. Differentiating between left- and right-sided congestion using invasive haemodynamics can help identify patients who may need additional treatment beyond TTVI.5
In conclusion, TR is a complex disease with multiple haemodynamic consequences, including forward and backward failure, and ventricular interaction. Recognizing the pathophysiological nuances of each aspect may help tailor therapy for severe TR, leading to novel therapeutic approaches and better timing of interventions.
Declarations
Disclosure of Interest
P.L. has received institutional fees and research grants from Abbott Cardiovascular, Edwards Lifesciences, and ReCor; has received honoraria from Edwards Lifesciences, Abbott Medical, Innoventric, ReCor, Boehringer Ingelheim, and Daiichi Sankyo; and has stock options with Innoventric. E.Z. reports no conflicts of interest. K.-P.K. is a consultant to Edwards Lifesciences and ReCor.
