Transcatheter Mitral Edge-to-edge Repair in Patients with Transthyretin Cardiac Amyloidosis: A Four-case Series

Abstract

Cardiac amyloidosis is characterized by the deposition of amyloid fibrils, which cause complications such as mitral regurgitation (MR). The efficacy of transcatheter mitral edge-to-edge mitral repair (TEER) in patients with amyloidosis remains uncertain. We herein present four cases of TEER for transthyretin cardiac amyloidosis. TEER reduced the MR in all cases. However, two of the four individuals died within one year, and in one case, a recurrent MR deterioration occurred. Although TEER can reduce MR in individuals with cardiac amyloidosis, the long-term outcomes appear to be poor owing to disease progression or comorbidities, thereby underscoring the need for careful patient selection.

Introduction

Systemic amyloidosis is characterized by the extracellular deposition of misfolded amyloid fibrils, leading to organ dysfunction. In wild-type transthyretin cardiac amyloidosis (ATTRwt-CA), transthyretin deposits accumulate in the myocardium, with an increased prevalence with age and male sex, ultimately resulting in heart failure (HF) (1). Cardiac amyloidosis (CA) is also associated with valvular disease and significant mitral regurgitation (MR) may coexist (2). However, because ATTRwt-CA predominantly affects older individuals, surgical repair for severe MR is often challenging due to the high procedural risk, as seen in aortic stenosis where transcatheter aortic valve implantation is preferred (3). Percutaneous catheter-based mitral valve repair has been developed as a treatment option for individuals who are inoperable or at high surgical risk. Currently, the most widely used device is MitraClip^Ⓡ, which enables the catheter-based application of the edge-to-edge repair surgical technique. Therefore, transcatheter edge-to-edge repair is considered a potential treatment option for individuals with CA and coexisting MR. However, published reports remain limited, and an optimal treatment strategy has yet to be established. We herein present four cases in which transcatheter edge-to-edge repair (TEER) was performed for MR associated with ATTRwt-CA, and evaluated its effectiveness.

Case Reports

Case 1

An 84-year-old man with hypertension and dyslipidemia was referred to our hospital because of recurrent HF exacerbations (Table). Transthoracic echocardiography showed a left ventricular ejection fraction (LVEF) of 52% with concentric hypertrophy and moderate-to-severe MR, which was attributed to left atrial enlargement along with degeneration and shortening of the chordae tendineae, resulting in an impaired leaflet motion (Fig. 1A, B). The mitral valve exhibited thickening and shortening of both leaflets, which were more pronounced in the posterior leaflet. These complex pathologies produce mixed MR with tethering extending from the A1/P1 to A2/P2 segments. Pyrophosphate scintigraphy was positive, and a myocardial biopsy revealed amyloid deposition with no ATTR gene mutation, thus resulting in a diagnosis of wild-type ATTR amyloidosis. Transesophageal echocardiography (TEE) confirmed the anatomical suitability of MitraClip therapy (Fig. 1C, D). A single G2-NT clip was deployed laterally at the A2/P2 segment, reducing the MR from moderate to severe to mild (Fig. 1E-G). Postoperatively, dual antiplatelet therapy was administered for one month, after which it was switched to a single antiplatelet therapy. Subsequently, atrial fibrillation was detected, and the therapy was changed to direct oral anticoagulant (DOAC). No complications occurred within 30 days, and the New York Heart Association (NYHA) functional class improved to Class II. Tafamidis therapy was then initiated. On day 286, the patient experienced a mild cerebral infarction. Although MR progressed slightly to mild-to-moderate, no HF exacerbations occurred during the 2.5-year follow-up after transcatheter edge-to-edge repair (Fig. 1H, 2A).

Table.

Baseline Patient Characteristics, Procedural, and Post Procedural Data.

	Case 1	Case 2	Case 3	Case 4
Demographics
Age (years)	84	74	78	80
Sex	Male	Male	Male	Male
Hypertension	+	-	+	-
Diabetes	-	+	-	-
Coronary artery disease	-	-	+	+
Atrial fibrillation	-	Paroxysmal	Paroxysmal	Permanent
Medication
RAS inhibitor	+	-	-	-
Beta blocker	-	-	+	+
MRA	+	-	+	+
SGLT2-i	-	-	+	+
Biochemical data
Hemoglobin (g/dL)	13.2	13.0	9.4	12.6
Creatinine (mg/dL)	0.75	1.01	1.6	3.09
eGFR (mL/min/1.73 m2)	74.5	55.8	33.2	16.1
NT-pro BNP (ng/dL)	2,054	13,008	8,405	18,975
Troponin T (ng/mL)	0.070	0.193	0.070	0.170
Clinical parameter
NYHA class	III	IV	IV	IV
STS-PROM score	3.59	8.4	14.46	28.30
Gillmore stage	I	II	III	III
Echocardiographic parameters
LVDd (mm)	39	51	41	56
LVDs (mm)	30	38	33	52
IVST (mm)	15	15	16	13
LVPWT (mm)	15	15	15	15
LVEF (%)	52	50	40	23
LVEDV (mL)	105	155	116	157
LVESV (mL)	50	77	70	121
LAVI (mL/m2)	46	63	77	72
MR grade	3-4	4	4	4
MR etiology	Mixed	Mixed	Mixed	Mixed
MVG (mmHg)	1.4	2	1.6	1
MVA (cm2)	5.28	5.26	5.00	4.01
Vena contracta (mm)	8.5	13	8.0	9.0
Color jet area (%)	37	64	41	60
TR grade	0	2	2	4
TRPG (mmHg)	25	67	31	14
Procedural and postprocedural data
MVG at discharge (mmHg)	3.1	3.2	1.5	2.1
MR grade at discharge	1	2	1	1
TR grade at discharge	0	1	1	4
TRPG at discharge (mmHg)	21	27	25	20
MR grade (follow up)	2	4	2	No data

CABG: coronary artery bypass graft, CRT: cardiac resynchronization therapy, eGFR: estimated glomerular filtration rate, HF: heart failure, IVST: thickness of interventricular septum, LAVI: left atrial volume index, LVDd: left ventricular end-diastolic diameter, LVDs: left ventricular end-systolic diameter, LVEDV: left ventricular end-diastolic volume, LVEF: left ventricular ejection fraction, LVESV: left ventricular end-systolic volume, LVPWT: left ventricular posterior wall thickness, MR: mitral regurgitation, MRA: mineralocorticoid receptor antagonist, MVA: mitral valve area, MVG: mitral valve pressure gradient, NT-pro BNP: N-terminal pro-B-type natriuretic peptide, NYHA: New York Heart Association, RAS: renin-angiotensin system, SGLT2-I: sodium-glucose cotransporter 2 inhibiter, STS-PROM: the Society of Thoracic Surgeons predicted risk of mortality. TR: tricuspid regurgitation, TRPG: tricuspid regurgitant pressure gradient

Figure 1.

(A, B) Preoperative transthoracic echocardiographic findings. (C, D) Preoperative transesophageal echocardiographic findings. (E, F) Intraoperative transesophageal echocardiographic findings. (G) Immediate postoperative transthoracic echocardiographic findings. (H) Transthoracic echocardiographic findings at 6-month follow-up.

Figure 2.

Time-to-event overview.

Case 2

A 74-year-old man was referred to our hospital for worsening HF, resulting in a dobutamine-dependent state (Table). Pulmonary congestion worsened with mild exertion, and the MR severity increased during the handgrip maneuver, indicating its contribution to HF exacerbation. Atrial tachycardia was also detected, which further worsened the hemodynamics. Echocardiography revealed an LVEF of 50% with concentric hypertrophy and severe MR (Fig. 3A, B). In addition to left atrial enlargement, marked thickening and degeneration of the posterior leaflet with prolapse of the medial P2 segment were observed (Fig. 3C-E). Sclerosis and a shortening of the subvalvular apparatus, including the papillary muscles and chordae tendineae, caused leaflet tethering. Pyrophosphate scintigraphy was positive, and a myocardial biopsy revealed amyloid deposition with no ATTR gene mutation, thus resulting in a diagnosis of wild-type ATTR amyloidosis. TEE confirmed the anatomical suitability of MitraClip^Ⓡ therapy. A G4-NTW clip was implanted medially at the A2/P2 segment, reducing the MR from severe to mild (Fig. 3F, G). Perioperative antithrombotic therapy was continued, with DOAC that had been prescribed for atrial tachycardia. Before the procedure, the tricuspid regurgitation peak gradient was 67 mm Hg, indicating severe pulmonary hypertension. After the procedure, the tricuspid regurgitation peak gradient decreased to 27 mmHg, suggesting a reduction in left atrial pressure. In addition, the RV fractional area change increased from 15 to 29%, indicating that the reduction in left atrial pressure achieved by TEER may have contributed to the improvement of right heart failure by decreasing the right ventricular afterload. No complications occurred within 30 days, and the NYHA functional class improved to class II. Tafamidis therapy was then initiated. On day 230, echocardiography revealed recurrent severe MR on both sides of the clip (Fig. 3H). A recurrent MR jet was observed on both sides of the clip, and there were no issues regarding clip stability. The mechanism of MR recurrence was considered to be the progression of left atrial enlargement due to chronic atrial fibrillation, as well as myocardial impairment and valvular degeneration associated with amyloid infiltration. Although a second TEER was considered, the patient was deemed to be at high risk for mitral stenosis due to a small mitral valve area (3.0 cm²) (Fig. 3I), and repeat intervention was not pursued. Despite intensive medical therapy, he was hospitalized for HF approximately one year later (Fig. 2B).

Figure 3.

(A, B) Preoperative transthoracic echocardiographic findings. (C-E) Preoperative transesophageal echocardiographic findings. (F) Intraoperative transesophageal echocardiographic findings. (G) Immediate postoperative transthoracic echocardiographic findings. (H, I) Transthoracic echocardiographic findings at 1-year follow-up.

Case 3

A 78-year-old man presented with positive pyrophosphate scintigraphy and amyloid deposition on a myocardial biopsy. No ATTR gene mutation was detected, resulting in the diagnosis of wild-type ATTR amyloidosis, and tafamidis therapy was initiated (Table). However, during the same period, MR gradually worsened. The patient was later admitted to the hospital with recurrent syncope. His medical history included recurrent atrial fibrillation after catheter ablation, angina pectoris, gastric cancer, and chronic kidney disease. Transthoracic echocardiography showed an LVEF of 40% and moderate-to-severe MR widely distributed across the A2 and P2 segments (Fig. 4A, B). The etiology of MR was mixed, comprising functional MR secondary to left atrial enlargement and degenerative MR characterized by leaflet thickening and shortening (Fig. 4C, D). TEE confirmed the anatomical eligibility for MitraClip^Ⓡ therapy. A G4-NTW clip was deployed at the A2/P2 segment, reducing the MR to mild levels (Fig. 4E-G). Perioperative antithrombotic therapy was continued, with DOAC that had been prescribed for atrial fibrillation. On day 8 post-procedure, the patient developed a pulseless electrical activity after urination, requiring temporary pacemaker insertion. Subsequently, cardiac resynchronization therapy with defibrillator implantation was performed for a complete left bundle branch block and left ventricular dysfunction. Despite these interventions, recurrent syncope persisted, which was attributed to autonomic dysfunction from CA. No complications occurred within 30 days; however, the NYHA functional class IV persisted without any improvement. The patient was readmitted on day 111 after sustaining a cerebral contusion due to syncope, became bedridden, and died on day 203. Throughout this period, MR showed minimal progression and no HF exacerbation occurred (Fig. 4H, 2C).

Figure 4.

(A, B) Preoperative transthoracic echocardiographic findings. (C, D) Preoperative transesophageal echocardiographic findings. (E, F) Intraoperative transesophageal echocardiographic findings. (G) Immediate postoperative transthoracic echocardiographic findings. (H) Transthoracic echocardiographic findings at 2-month follow-up.

Case 4

An 80-year-old man with chronic kidney disease, atrial fibrillation, and complete atrioventricular block with prior cardiac resynchronization therapy was diagnosed with ATTRwt-CA by a myocardial biopsy, pyrophosphate scintigraphy, and genetic testing (Table). Although the patient was treated with pharmacotherapy and cardiac resynchronization therapy for symptomatic HF, the condition remained decompensated, and his functional status was classified as NYHA class IV. Echocardiography showed an LVEF of 20% and severe MR originating from the A2/P2 segments, attributed to combined left atrial and ventricular dilation with mild leaflet thickening (Fig. 5A-C). Spontaneous echo contrast in the left atrium was grade 3, and the left atrial appendage flow showed decreased velocities, with an emptying velocity of 13.0 cm/s and a filling velocity of 15.0 cm/s. A G4-NTW MitraClip^Ⓡ was placed at the A2/P2 segment, thus reducing the MR to a trivial level (Fig. 5D-F). Intraoperative transesophageal echocardiography after clip placement demonstrated severe spontaneous echo contrast without evidence of left atrial appendage thrombus, and perioperative antithrombotic therapy was continued with warfarin that had been prescribed for atrial fibrillation. On day 6, the patient experienced a cardioembolic stroke. Although the precise etiology was unclear, suspected causes included blood stasis within the left atrium and appendages secondary to MR reduction or clip-related thrombosis. The patient developed irreversible right hemiplegia and global aphasia and died on day 339 (Fig. 2D).

Figure 5.

(A, B) Preoperative transthoracic echocardiographic findings. (C) Preoperative transesophageal echocardiographic findings. (D, E) Intraoperative transesophageal echocardiographic findings. (F) Immediate postoperative transthoracic echocardiographic findings.

Discussion

We encountered four cases of ATTRwt-CA in which mitral TEER was performed. CA can cause MR via multiple mechanisms. Amyloid deposition is widespread and it involves the atria, ventricles, annulus, valvular tissue, and subvalvular apparatus. The deposition of both ventricles leads to wall thickening and stiffening, causing combined diastolic and systolic dysfunction. In the atria, amyloid infiltration results in biatrial enlargement, whereas annular dilation and stiffening contribute to leaflet tethering (4,5). Amyloid involvement of the mitral valve and subvalvular structures induces structural changes and a functional impairment including leaflet thickening and stiffening, papillary muscle degeneration, and posterior leaflet shortening, all of which restrict leaflet motion and exacerbate tethering. Increased mechanical stress may lead to chordal rupture, leaflet prolapse, or flail, and such cases have been reported (6). AF further promotes mitral annular dilation and worsens tethering. Collectively, these mechanisms contribute to the onset and progression of MR in patients with CA.

The treatment options for symptomatic MR include surgical intervention and TEER. TEER has been shown to reduce HF hospitalization and mortality in individuals with symptomatic functional MR despite receiving optimal medical therapy (7). Its efficacy has also been suggested for degenerative MR (8). As noted above, CA is common in older individuals with comorbidities and surgery for concomitant MR is often avoided. Therefore, expanding the evidence based on the indications and prognosis of TEER in CA is essential.

The first reported case of TEER for CA was published in 2016 (9), and only a limited number of cases have since been described. A comparative study of individuals with and without CA undergoing TEER demonstrated that both groups achieved a substantial acute MR reduction, with comparable procedural complication rates. However, at a median follow-up of 1.7 years, CA-related MR was associated with significantly higher rates of hospitalization for HF and mortality than MR without CA (10). In the present study, all four individuals were older men, with a mean age of 79 years. The mechanism of MR was mixed in all cases, comprising both primary and secondary components. TEER was technically and procedurally successful in all cases, thereby achieving an acute MR reduction. Consistent with prior reports, short-term MR control was favorable; however, the postoperative trajectories varied considerably. The severity of HF before TEER was the greatest in Case 4 and the mildest in Case 1, and these baseline differences strongly influenced the outcomes. In Case 1, TEER was performed relatively early during ATTRwt-CA, with no HF hospitalizations over 2.5 years of follow-up. In Case 2, MR recurred within approximately 1 year, leading to hospitalization for HF. Case 3 died from progressive disease, whereas Case 4 died from postoperative stroke. The latter had advanced HF and a severely compromised preoperative status, rendering any type of intervention as inherently high-risk. These observations suggest that earlier intervention may yield more favorable long-term outcomes, whereas the prognosis in advanced CA is largely determined by the disease progression and procedural risks.

In Case 2, MR was initially well controlled after TEER, but it later recurred as severe MR. The recurrence rate of MR within 1 year after otherwise successful TEER was estimated to be approximately 10%, with established predictors including flail leaflet, residual MR ≥2+, and left atrial enlargement (11). Given the progressive involvement of the myocardium and mitral apparatus in CA, the recurrence rates in this population may differ from those in MR without amyloidosis. Although tafamidis stabilize transthyretin tetramers and lower circulating transthyretin levels, they do not reverse the existing amyloid deposits or completely halt disease progression. In this case series, tafamidis was administered for 30 months in Case 1, for 15 months in Case 2, and for 11 months in Case 3, respectively. In Case 4, tafamidis was not administered because the patient was NYHA class IV with severe renal dysfunction; thus, meaningful therapeutic benefit was deemed unlikely. According to the ATTR-ACT clinical trial, the mortality-reducing effect of tafamidis was evident at approximately 18 months after treatment initiation (12). In Case 1, tafamidis was introduced relatively early, and it is likely that the patient benefited from treatment, with additional prognostic improvement achieved through TEER. In contrast, in Cases 2 and 3, the shorter duration of tafamidis therapy may have limited its potential effect on the prognosis. From this standpoint, early TEER intervention in CA-associated MR may improve the long-term outcomes. However, further studies are required to confirm this hypothesis.

Conclusion

CA causes MR via multiple mechanisms. Although TEER can reduce MR in individuals with CA, the long-term outcomes are often poor due to disease progression or comorbidities, thereby underscoring the need for careful patient selection.

The authors state that they have no Conflict of Interest (COI).