Tricuspid Regurgitation: State-of-the-Art Insights

Introduction: The (Not So) Forgotten Tricuspid Valve

Tricuspid regurgitation (TR), historically overshadowed by left-sided valvular diseases, is increasingly recognized as a significant contributor to heart failure (HF) symptoms, hospitalizations, and mortality. Despite its prevalence, TR often remains undiagnosed or untreated until advanced stages, exacerbating patient morbidity and diminishing quality of life (QoL).

TR arises from diverse mechanisms, broadly categorized into primary TR (stemming from intrinsic structural abnormalities like prolapse or myxomatous degeneration) and secondary TR (caused by functional impairments such as annular dilation, atrial enlargement, or ventricular dysfunction). Adding complexity, cardiac implantable electronic devices (CIEDs) can induce TR by interfering with valve apparatus, causing leaflet tethering or perforation.

Advances in therapies, particularly transcatheter tricuspid valve interventions (TTVI), are reshaping TR management. However, leveraging these innovations requires a thorough understanding of the mechanisms, phenotypes, and challenges of TR, which this blog aims to explore, thereby establishing the groundwork for a deeper exploration of TTVI in the subsequent blog.

Mechanisms and Challenges in TR: Decoding Complexity

Unique Anatomy Challenges

The tricuspid valve's anatomy, with its thin leaflets and crescent-shaped right ventricle (RV), poses distinct challenges compared to left-sided valves. The RV depends heavily on longitudinal shortening for contraction, making it more vulnerable to dysfunction in TR. These anatomical features complicate imaging, diagnosis, and therapeutic interventions, particularly for severe TR.

Mechanisms of TR

• Primary TR: Results from structural abnormalities such as leaflet prolapse, carcinoid disease, or myxomatous degeneration.
• Secondary TR: Driven by annular dilation, atrial fibrillation (AF), or ventricular dysfunction.
• CIED-Related TR: Arises from mechanical interference by pacemaker or defibrillator leads, causing leaflet damage or misalignment.

Advances in Quantifying Severe tR

Modern imaging modalities, including 3D echocardiography and computed tomography (CT), allow precise assessments of leaflet tethering, annular dilation, and jet location, aiding in the evaluation and treatment planning of massive or torrential TR.

Hemodynamics of TR: Balancing Pressure and Volume

TR disrupts RV performance by increasing preload and reducing forward cardiac output, leading to systemic congestion and RV dysfunction. Key tools for assessment include:

• Pressure-Volume (PV) Loops: These loops provide critical insights into RV function, showing how TR increases stroke volume and stroke work while lowering afterload. However, these compensatory changes can mask underlying RV dysfunction as forward stroke work does not equate to total stroke work, underlining the importance of comprehensive assessment​.
• RV-Pulmonary Artery (PA) Coupling: Measures the RV’s adaptation to PA loading conditions. High coupling suggests effective RV function, while low coupling indicates dysfunction, often predictive of poor outcomes post-TTVI.

Understanding and evaluating these hemodynamic principles is essential for tailoring interventions to TR-related right HF.

Advances in TR Imaging: Bridging Diagnostic Gaps

As emphasized during the recent discussions at TCT 2024, "there is nothing moderate about moderate TR", reflects the need for better criteria to guide clinical decisions​. RV enlargement, characterized by increases in end-diastolic volume (EDV) and end-systolic volume (ESV), often precedes overt decompensation. Imaging can detect these changes early, providing critical insights into the compensatory mechanisms and eventual failure of the right heart. Therefore, imaging plays a pivotal role in diagnosing and managing TR, offering detailed insights into disease severity and RV function.

• Echocardiography: 2D vs. 3D Imaging: While 2D transthoracic echocardiography (TTE) remains the practical choice for TR evaluation, 3D imaging significantly improves accuracy in assessing regurgitant volume and leaflet morphology. Key Metrics for RV Function: Indicators like tricuspid annular plane systolic excursion (TAPSE), systolic velocity (S’), and fractional area change (FAC) are standard for evaluating RV function. However, these metrics often fail to detect early or subclinical dysfunction. Early Detection Needs: Declines in TAPSE, FAC, and right ventricular free wall strain (RVFWS) signal subclinical dysfunction and decompensation, underscoring the need for refined thresholds and advanced diagnostic metrics.
• Cardiac Magnetic Resonance (CMR): Provides superior accuracy in quantifying regurgitant volume and phenotyping TR by its hemodynamic burden.
• Emerging Modalities: Techniques such as strain imaging and CT are improving early detection and risk stratification.

Standardization of imaging criteria and broader adoption of advanced modalities remain critical to improving diagnostic accuracy.

Clinical Phenotypes of TR: Diversity in Presentation and Prognosis

TR manifests in a spectrum of phenotypes, each with distinct etiologies, clinical manifestations, and implications for management:

• Low-risk TR: Minimal comorbidities, less severe TR, and preserved RV function.
• High-risk TR: Severe TR, significant RV enlargement, atrial fibrillation, and comorbidities such as congestive heart failure (CHF).
• TR with Lung Disease: Driven by pulmonary hypertension secondary to lung conditions like chronic obstructive pulmonary disease (COPD).
• TR with Coronary Artery Disease (CAD): Linked to ischemic cardiomyopathy and reduced left ventricular ejection fraction.
• TR with Renal Disease: Marked by chronic kidney disease, often with systemic complications influencing outcomes.

Recent studies suggest clustering patients by phenotypes improves risk stratification, treatment optimization and prognoses, highlighting the importance of tailored management strategies and identifying (and stratifying) responders for TTVI.

Potential Emerging Phenotype: Chronic Venous Insufficiency (CVI)
Although current data is lacking, patients with chronic venous insufficiency (CVI) could represent an important emerging TR phenotype. Limited data may stem from economic or geographic barriers preventing these patients from accessing care early or being included in outcome studies. As innovations targeting venous disease become more widely available, this subgroup warrants attention. Future research and surveillance are essential to better understand their unique characteristics, disease progression, and responses to evolving therapies.

Management of Patients with Right Heart Failure: Strategies and Outcomes

Pathophysiology and Challenges

TR exacerbates right heart failure by increasing right atrial pressure, causing systemic venous congestion, and impairing cardiac output. The interdependence of the left and right ventricles further complicates management, as dysfunction in one chamber impacts the other. Consequently, TR-induced right heart failure presents unique challenges, requiring a mix of medical and interventional therapies:

Therapeutic Approaches

1. Medical Management: Diuretics and pulmonary vasodilators alleviate symptoms and improve hemodynamics but do not address underlying structural issues.
2. Interventional Therapies: TTVI, including edge-to-edge repair (TEER) and transcatheter tricuspid valve replacement (TTVR), are increasingly preferred for patients unsuited for surgery.

Timing and Selection of Interventions

Emerging tools like the TRI-SCORE guide patient selection for TTVI by predicting outcomes. Early intervention is critical to prevent irreversible RV remodeling and improve survival.

Future Directions: Research and Clinical Trials for Advancing TR Care

TR presents unique challenges and opportunities for innovation. The following recommendations highlight key areas of ongoing and future research, clinical practice, and technology development to improve outcomes and transform TR management.

1. Strengthen Hemodynamic Assessments to Prevent RV Dysfunction

• • Expand RV-PA Coupling Research: Metrics like end-systolic elastance (Ees) and effective arterial elastance (Ea) derived from PV loops reveal changes in systolic and diastolic performance. Refinement of these metrics and RV-PA coupling ratio thresholds can help identify patients at higher risk of poor outcomes following TTVI.
  • Incorporate Molecular Biomarkers: Pair hemodynamic assessments with advanced biomarkers (viz., genes like ADORA2B and GALNT13), to better detect early RV dysfunction and chronic TR progression.
  • Refine Risk Estimation Tools: Enhance predictive models like TRI-SCORE by integrating biomarkers and advanced imaging metrics for improving patient selection for TTVI and tailoring risk-based management strategies.

2. Advance Imaging Modalities and Standardization

• • Leverage Emerging Imaging Trends: Transition from 2D to 3D echocardiography for more accurate volumetric assessments and improved visualization of tricuspid valve geometry.
  • Adopt Molecular Imaging: Use advanced techniques, such as molecular imaging in conjunction with standard imaging modalities like echocardiography or CMR imaging, to explore valvular and myocardial tissue health, refining phenotyping, and patient stratification.
  • Standardize Imaging Protocols: Collaborate with KOLs from high volume centers on guidelines for imaging parameters to improve consistency in diagnosis, staging, and treatment planning.

3. Enhance Phenotyping for Personalized Therapy

• • Refine Patient Selection: Use advanced imaging, biomarkers, and phenotyping tools to identify TR patients most likely to benefit from specific therapies, such as TTVR or TEER.
  • Cluster Patients by Phenotype: Expand the application of phenotypic clustering to optimize tailored management strategies and survival outcomes.

4. Tailor Therapeutic Approaches Based on Disease Mechanisms

• • Address Annular Dilation: Develop hybrid therapies that combine annular reshaping with leaflet repair to address complex cases of dilation-related TR.
  • Manage CIED-Related TR: Conduct targeted studies on lead repositioning and device modifications to reduce interference with valve function.
  • Explore Adjunctive Therapies: Investigate neurohormonal and anti-inflammatory therapies to complement mechanical interventions and address systemic contributors to TR progression.

5. Drive Innovation in Device Development and Durability

• • Evaluate Long-Term Outcomes: Conduct long-term studies on the durability, safety, and hemodynamic performance of transcatheter devices, focusing on hybrid approaches.
  • Foster Device Innovation: Encourage development of advanced materials and designs to enhance TTVR device durability, biocompatibility, and function in challenging anatomies.

6. Promote Rigorous and Comparative Clinical Trials

• • Compare Therapeutic Approaches: Design trials comparing transcatheter and surgical therapies across phenotypes to define optimal treatment pathways.
  • Focus on Patient-Centered Outcomes: Incorporate metrics like QoL, functional status, and exercise capacity to ensure therapies align with patient priorities.
  • Assess Adjunctive Treatments: Evaluate the benefits of combining mechanical therapies with medical management, such as pulmonary vasodilators or neurohormonal modulators.

7. Advance Risk Stratification and Early Intervention

• • Develop Early Detection Tools: Use imaging advancements and biomarkers to identify patients at risk of RV decompensation before structural changes become irreversible.
  • Expand Access to TTVI: Refine criteria for TTVI candidacy to include patients with moderate disease, ensuring interventions occur before advanced RV dysfunction.

8. Focus on Multivalvular and Comorbid Disease Management

• • Integrate Multivalvular Care Pathways: Address TR in the context of multivalvular disease, ensuring comprehensive evaluation and treatment strategies.
  • Personalize Care for Comorbidities: Incorporate tailored approaches for patients with concurrent conditions such as lung disease, CAD, or renal dysfunction.

To put it in a nutshell, collaborative efforts and innovative trial designs will bridge knowledge gaps and drive progress in TR management.

Conclusion: Shaping the Future of Tricuspid Regurgitation Care

TR is no longer an overlooked condition as it has emerged from the shadows as a critical focus in cardiovascular care. Advances in imaging, phenotyping, and interventional therapies are not only transforming how we diagnose and treat TR but also redefining the possibilities for patient outcomes. These innovations are paving the way for a more personalized, effective, and compassionate approach to managing right-sided heart disease.

The path forward demands a multifaceted strategy. Precision diagnostics, including enhanced imaging and molecular biomarkers, are essential for understanding the diverse phenotypes of TR and tailoring treatments accordingly. Refined risk stratification tools like TRI-SCORE, and novel technologies, such as 3D echocardiography/CMR, offer clinicians the means to intervene earlier and with greater confidence. Meanwhile, collaborative research efforts and rigorously designed clinical trials are key to optimizing therapeutic pathways, improving device durability, and exploring complementary medical therapies.

By integrating these advances into a cohesive, patient-centered model, the care of TR can be transformed from reactive to proactive. This evolution promises not just better survival rates and functional outcomes but also a marked improvement in QoL for patients. The future of TR care lies in this holistic, collaborative approach, where cutting-edge science meets compassionate clinical practice to redefine the standard of care for right-sided heart disease.

Key Takeaways:

• TR is increasingly recognized as a critical contributor to heart failure and mortality, requiring early detection and management.
• Advanced imaging modalities like 3D echocardiography and CMR are revolutionizing diagnosis and treatment planning.
• Innovative therapies such as TTVI offer promising outcomes, especially for patients unsuitable for surgery.
• Personalized strategies, including phenotyping and risk stratification tools like TRI-SCORE, are essential for optimal care.
• Collaborative research and device development are paving the way for improved patient outcomes and quality of life.