Transcatheter Tricuspid Valve Edge-to-Edge Repair in Cardiac Wild-Type Transthyretin Amyloidosis

Abstract

Background

Cardiac transthyretin amyloidosis (ATTR-CM) is an infiltrative, restrictive cardiomyopathy leading to heart failure across all stages of the disease. While specific disease-modulating therapies evolve, interventional therapeutic approaches on atrioventricular valve dysfunction have not yet been investigated in this cardiomyopathy and remain subject to personalized strategy.

Case Summary

We present 2 patients with wild-type ATTR-CM who underwent successful transcatheter tricuspid valve edge-to-edge repair (T-TEER) for severe tricuspid regurgitation (TR) 2-4 years after initial diagnosis. T-TEER was successful, and patients presented with a considerable improvement of their functional status.

Discussion

T-TEER represents an important therapeutic strategy for patients with TR and ATTR-CM, in whom treatment options for symptomatic improvement are scarce.

Take-Home Messages

T-TEER might be considered in patients with TR and restrictive cardiomyopathy, such as ATTR-CM in its advanced stages. Short-term outcomes demonstrate a considerable improvement of functional capacity on top of optimal medical therapy for ATTR-CM.

Visual Summary

History of Presentation

Patient A

An 82-year-old male patient was referred to our clinic for further diagnostic work-up on severe tricuspid regurgitation (TR), slowly progressive dyspnea on exertion according to NYHA functional class III, and recurrent leg edema. In his past medical history, the patient was diagnosed with wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) at 78 years of age, based on endomyocardial biopsy. At that time, his condition was classified as stage I according to National Amyloidosis Centre staging system,¹ and specific treatment with transthyretin (TTR) stabilizer was initiated. Due to recurrent nonsustained ventricular tachycardia, he had received an implantable cardiac defibrillator for primary prophylactic reasons. Pacing-rate of up to 80% was reported. In his charts, mild-to-moderate tricuspid regurgitation (TR) had been reported at the time of ATTR-CM diagnosis. On physical examination, mild peripheral edema and abnormal jugular vein pulsation were noticed. Laboratory tests revealed elevated levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP), alkaline phosphatase, bilirubin, and gamma glutamyl transferase and signs of chronic kidney disease (Table 1). Medication at admission included tafamidis 61 mg, dapagliflozin 10 mg, and torasemide 20 mg once daily. Initial comprehensive transthoracic and transesophageal assessment revealed global left ventricular (LV) and right ventricular (RV) hypertrophy (Figure 1A), severe diastolic dysfunction, and preserved left ventricular ejection fraction. LV global longitudinal strain was impaired and depicted apical sparing typically found in ATTR-CM. TR was of functional, secondary nature and torrential (grade V/V) with complex multileaflet anatomy, morphologic type IV² with 2 septal, 3 anterior, and 2 posterior leaflets. Overall, a large central coaptation gap with anteroseptal and posteroseptal components (gap area: 0.93 cm²) was observed (Figures 1B to 1D, Video 1). There was no evidence of significant contribution of the implantable cardiac defibrillator lead to TR (Video 2).

Take-Home Messages

• •T-TEER might be considered in patients with TR and restrictive cardiomyopathy, such as ATTR-CM in its advanced stages.
• •Short-term outcomes demonstrate a considerable improvement of functional capacity on top of optimal medical therapy for ATTR-CM.

Table 1.

Laboratory Evaluation

	Reference Values	Patient A (82 y)			Patient B (79 y)
		Diagnosis of ATTR-CM	Preprocedural	Follow-Up (6 mo)	Diagnosis of ATTR-CM	Preprocedural	Follow-Up (6 mo)
High-sensitive troponin T, ng/mL	≤0.014	0.053	0.081	a	0.027	0.030	a
NT-proBNP, pg/mL	<623	2,328	3,037	2,552	2,497	1,529	2,494
eGFR, mL/min	≥60	70	30	34	52	44	37
Creatinine, mg/dL	0.5-1.0	1.0	2.0	1.8	1.3	1.5	1.7
Urea, mg/dL	17-49	37	117	118	44	49	62

Reference values for each parameter are indicated in parenthesis.

ATTR-CM = transthyretin amyloid cardiomyopathy; eGFR = estimated glomerular filtration rate; NT-proBNP = N-terminal pro-B-Type natriuretic peptide.

^aValue not investigated.

Figure 1.

Echocardiographic Evaluation of Severe TR in a Patient With ATTR-CM

TTE showed severe LV hypertrophy in parasternal long axis (A) and torrential TR in apical 4-chamber view focused on the RV (B). Using the transgastric window in transesophageal echocardiography, the complex multileaflet anatomy of the tricuspid valve (C) as well as prominent regurgitation jet regions (D) were documented in patient A. ATTR-CM = transthyretin amyloid cardiomyopathy; LV = left ventricular; RV = right ventricle; TR = tricuspid regurgitation; TTE = transthoracic echocardiography.

Patient B

A 79-year-old patient was electively admitted to our hospital for further diagnostic work-up of his continuous deterioration in cardiac functional capacity. He reported severe loss of endurance, which he measured based on regular cycling training and had experienced shortness of breath upon managing 1 flight of stairs (NYHA functional class III), recurrent bilateral leg edema, and chronic fatigue. He also mentioned rapid onset of sense of fullness, which had led him to eat less within the recent months. His past medical history included paroxysmal atrial fibrillation, and, due to chronotropic incompetence, beta-blocker had been withdrawn several years ago. Physical examination revealed mild bilateral ankle edema. Laboratory tests showed elevated NT-proBNP levels and a mild elevation of high-sensitive troponin T (Table 1). Estimated glomerular filtration rate indicated stage III kidney injury.³ His medication included Torasemide 10 mg/d. Comprehensive echocardiographic assessment demonstrated LV hypertrophy and a mildly reduced LV ejection fraction. The RV was dilated and the TR was classified as severe (grade III/V) with a central coaptation gap of 3-4 mm (gap area: 0.35cm²) (Table 2). The patient also underwent cardiac magnetic resonance tomography for multimodal imaging in 2022 and TR was reported with a fraction of 15% at that time point. Myocardial tissue characterization raised the suspicion of cardiac amyloidosis by insufficient nulling in inversion time, prolonged T1 relaxation times, as well as diffuse subendocardial and intramural late gadolinium enhancement in basal segments of the septal wall and RV anterior free wall (Figure 2).

Table 2.

Baseline and Follow-Up Echocardiographic Imaging

	Patient A (82 y)		Patient B (79 y)
	Preprocedural	Follow-Up (6 mo)	Initial Assessment	Preprocedural	Follow-Up (6 mo)
IVSd, mm (≤12 mm)	23	21	18	19	18
LVPWd, mm (≤11 mm)	17	14	13	14	14
RWT (≤0.42)	0.67	0.56	0.58	0.60	0.62
LVEDD, mm (≤59 mm)	51	50	45	47	45
LV ejection fraction, % (≥60%)	58	56	45	44	45
LV global longitudinal strain, % (≤−16%)	−6.7	−8.2	−7.4	−9.0	−10.5
RV end diastolic area, cm2 (8-20 cm2)	54.3	51.2	29.5	27.9	25.3
RV end systolic area, cm2 (3-11 cm2)	36.0	34.0	19.4	19.8	18.0
RV fractional area change, % (≥35%)	33.7	33.5	34.2	29.0	28.8
RV ejection fraction (3D), % (≥45%)	37.0	31.0	31.0	30.9	27.1
RV base end diastolic diameter, mm (≤41 mm)	71	69	47	45	45
RV free-wall longitudinal strain, % (≤−20%)	−21.3	−15.6	−15.4	−12.0	−14.6
RV free wall thickness, mm (≤9 mm)	8	10	9	10	9
TV annular diameter, mm (<40 mm)	68	65	44	46	43
TR max PG, mm Hg (≤39 mm Hg)	17	31	10	14	25
RV/PA coupling, mm/mm Hg	0.640	0.359	0.720	0.586	0.475
IVC diameter, mm (≤21 mm)	25	25	26	30	27
RA area, mm2 (≤18 mm2)	48	40	34	43	33
TAPSE, mm (≥17 mm)	16	14	18	17	19
RV systolic velocity max, cm/s (≥10 cm/s)	7.6	10.0	9.8	9.9	13.2

Reference values for each parameter are indicated in parenthesis.

IVC = inferior vena cava; IVSd = intraventricular end diastolic septal wall thickness; LV = left ventricle; LVEDD = left ventricular end diastolic diameter; LVPWd = left ventricular end diastolic posterior wall thickness; PG = pressure gradient; RA = right atrium; RV = right ventricle; RV/PA = right ventricular to pulmonary artery coupling; RWT = relative wall thickness; TAPSE = tricuspid annular plane systolic excursion; TR = tricuspid valve regurgitation; TV = tricuspid valve.

Figure 2.

Incidental Diagnosis of ATTR-CM on Cardiac MRI for Quantification of TR

Comprehensive assessment of TR included CMR in patient B. CMR was performed on a Magnetom Aera (1.5-T, Siemens Healthineers) scanner. The patient had pleural effusions, visible in the survey images (A). Besides TR (yellow arrow), LV hypertrophy (yellow star) and pericardial effusion (green star) were noticed in 4-chamber view (B). Further tissue characterization revealed typical signs of cardiac amyloidosis including elevated T1 maps (not shown), insufficient nulling of inversion recovery time in TI-scout (B) and diffuse, subendocardial, and intramural LGE (C) in the basal septum (red arrow) and RV free wall (blue arrow) (PSIR LGE images were obtained at TI of 280 ms). CMR = cardiac magnetic resonance tomography; LGE = late gadolinium enhancement; MRI = magnetic resonance imaging; other abbreviations as in Figure 1.

Further diagnostic work-up showed a positive tracer uptake (Perugini grade II) in Technetium-99m-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy, and monoclonal gammopathy could be excluded in the immunofixation of serum and urine, thus patient B was diagnosed with ATTR-CM and started on specific stabilizing therapy with Tafamidis.

Coronary angiography excluded coronary artery disease in both cases. Right-sided heart catheterization revealed elevated “v”-waves in the right atrium, moderately elevated end-diastolic pressure in RV with characteristics of restrictive cardiomyopathy such as a dip-plateau phenomena, and evidence of postcapillary pulmonary hypertension.

As cardiac MRI showed initially a mild-to-moderate TR⁴ in patient B, he was discharged with intensified heart failure medication (added medication: dapagliflozin 10 mg and eplerenone 25 mg once daily) for observation and close follow-up. Within 18 months, the patient reported ongoing lower limp edema and unchanged heart failure symptoms. Repeated transthoracic echocardiography (TTE) revealed a significant progression of TR (now grade IV/V) with progressive pressure RV/right atrium equilibration. Subsequently, he was readmitted for evaluation of tricuspid repair.

Management

Due to their high TRI-SCORE (Tricuspid Regurgitation Impact-Score)⁵ (8 of 12 points in patient A; 6 of 12 points in patient B) and predicted in-hospital mortality rates of 48% (patient A) and 22% (patient B), the interdisciplinary heart team opted for an interventional treatment approach. Anatomy was found to be suitable for transcatheter tricuspid edge-to-edge valve repair (T-TEER). In patient A, 3 clipping devices were implanted in the antero-septal, postero-septal, and antero-posterior direction, leading to a reduction of the TR from grade 5+ to grade 2+. Patient B received 2 devices positioned in antero-septal direction with a downgrading to the TR from grade 3+ to grade 1+. The postinterventional course was uneventful and both patients were discharged 2 days after T-TEER.

Outcomes

Both patients presented to the 6-month follow-up after T-TEER. Patient A denied any interim hospitalizations and reported a relevant improvement of his functional status (NYHA functional class II, previous NYHA functional class III) and quality of life. Walking distance within 6 min improved to 390 m (baseline: 240 m). Laboratory values showed an improvement in renal function and a reduction in NT-proBNP (Table 1).

Patient B also reported significant functional improvement (NYHA functional class I-II) and the absence of peripheral edema. He denied any interim hospitalization. Six-minute walking test improved (546 m; baseline: 407 m). Laboratory values showed stable biomarkers within the short duration of time (Table 1).

In both cases, there were no changes of medication, particularly of diuretic dose between baseline and follow-up. In TTEs, residual TR was grade 2+ (patient A) and grade 1+ (patient B) with no stenotic component, whereas RV function and dimensions showed no significant changes within the short period of time (Video 3).

Discussion

In the presented cases, we report the feasibility and good short-term outcomes of T-TEER in 2 patients with wild-type ATTR-CM and concomitant functional TR. Based on recent observations, moderate-to-severe TR can occur in up to one-third of ATTR-CM patients and is associated with increased risk of all-cause mortality and worsening heart failure independent of LV or RV function.⁶ However, mild TR is much more common, present in about 50% of ATTR-CM patients. Although destructive TTR infiltration of the valve apparatus has been reported,⁶ TR most likely results secondary to restrictive ventricular filling patterns, leading to morphologic alterations of the RV. Given that diastolic dysfunction is particularly prominent in the restrictive condition, an altered transtricuspid pressure gradient may be a common finding for TR in ATTR-CM. Thus, the continuous wave velocity profile presumably differs in size and shape, leading to an underestimation of regurgitation volumes and limiting the diagnostic accuracy of the echocardiographic regurgitation quantification.

At their time of ATTR-CM diagnosis and based on the biomarkers, both patients were in the early stages of their disease (National Amyloidosis Centre I) at the beginning of treatment and baseline transthoracic echocardiography already revealed mild-to-moderate TR. Over the course of their disease, symptoms of right-sided HF gradually worsened, leading to a decrease in functional capacity. Diuretic doses were adjusted accordingly. Despite being on specific stabilizing therapy—which has previously been associated with a reduction in of renal deterioration⁷—both patients exhibited a decrease in renal function within 2-4 years, thus attributed to an increasing impact of TR. Short-term observation after T-TEER showed stabilization of renal function, suggesting that ATTR-CM patients with TR may benefit from T-TEER in alleviating progressive cardio-renal syndrome. This effect has also been reported in the general population treated with T-TEER.⁸ However, the timing of TR intervention in this specific condition remains undefined because TR might indicate a progressive disease earlier than established biomarkers. From these 2 cases, it can be inferred that the need to increase diuretic dosage may signal the optimal timing for intervention. Close monitoring of morphologic and functional changes in RV should also be considered for decision-making. Finally, it is still unclear whether ATTR-CM patients experience significant and beneficial reverse remodeling of the RV after T-TEER if TTR infiltration also affects the RV.

Overall, our short-term observations indicated a significant improvement in 6-min walking distance (+105 m patient A to +139 m patient B), reflecting an effective maintenance of quality of life – a key objective in the treatment of ATTR-CM. Thus, T-TEER appears to be a promising approach for managing TR in ATTR-CM.

Conclusions

TR is a common manifestation in patients with ATTR-CM that can already be observed at diagnosis. Typically, despite targeted medical therapy, there is a progressive worsening of valve insufficiency as the disease advances. These cases demonstrate that in ATTR-CM intervention for TR using T-TEER is feasible and safe. However, future research should focus on multimodal identification of the optimal timing for intervention. Long-term data are warranted to clarify the ultimate benefit of T-TEER in ATTR-CM.

Visual Summary.

Multimodal approach on T-TEER in ATTR-CM

TR in ATTR-CM patients is common and associated with worse outcome. Our case series demonstrate feasibility, safety, and improvement of functional capacity (green hooks) in 2 patients undergoing T-TEER. Decision on T-TEER was based on interdisciplinary heart team consensus that considered a multimodal approach, including TTE and TEE, cardiac MRI, and RHC. Unmet needs (red question marks) remain with regard to T-TEER, such as timing of interventional therapeutic strategy, presence of remodeling, and long-term outcome. RHC = right-sided heart catheterization; T-TEER = transcatheter tricuspid valve edge-to-edge repair; TEE = transesophageal echocardiography; other abbreviations as in Figures 1 and 2.

Funding Support and Author Disclosures

Dr Schwarting has received speaker honoraria from Pfizer, Alnylam, and Bayer. Dr Stolz has received speaker honoraria from Edwards Lifesciences. Dr Näbauer has received speaker fees from Abbott Vascular and Edwards Lifesciences. Dr Hausleiter has received research support and speaker honoraria from Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Video 1

Transgastric Short-Axis Sweep View on TR for Leaflet and Anatomical Evaluation in 2 Planes

Video 2

Transgastric Short-Axis View on TR to Rule Out Contribution of the Implantable Cardiac Defibrillator Lead

Video 3

TTE With 4-Chamber View Focused on RV After T-TEER in ATTR-CM (Patient B)