Abstract
Background
Mitral regurgitation (MR) is the most common valvular heart disease worldwide with a 5-year mortality rate of 50 % with medical therapy alone. Several transcatheter mitral valve replacement (TMVR) devices are being investigated in clinical trials. Early evidence has demonstrated clinical benefits with a reduction in heart failure symptoms, low rates of residual MR, and reverse remodeling of the left ventricle (LV) over time. However, high anatomical screen failure rates limit its applicability. The primary reasons for the anatomical screen failure are risk of LV outflow tract obstruction, large mitral valve annulus size, and the presence of mitral annular calcification. Our clinical experiences using an atrial only fixation TMVR technology delivered via a transfemoral-transseptal approach is described.
Methods
Three consecutive patients with severe functional MR underwent TMVR implantation using an atrial only fixation technology and a low-profile transseptal delivery system.
Results
Technical success was achieved in 100 % of the patients with a clinically significant reduction in MR. Longer-term follow-up (up to 6-months) has demonstrated a sustained reduction in MR and significant improvement in quality of life for all patients.
Conclusions
Longer-term outcomes in our patients showed persistent reduction in MR, sustained implant performance, and notable improvements in NYHA Class and quality of life. There were no major adverse events. Follow-up CT data showed no evidence of device-related thrombosis, with stable valve position and integrity. The atrial fixation TMVR technology may have benefits in preserving the dynamics of the native mitral valve annulus thereby reducing the overall risk of LVOT obstruction.
Short Abstract
We present a single-center experience of three consecutive patients with severe functional MR treated with the AltaValve using a low-profile transseptal delivery system. A clinically significant reduction in mitral regurgitation was achieved in all patients, and longer-term follow-up has demonstrated sustained clinical benefits.
Keywords
Abbreviations
ALMMafter load mismatchAPanterior posteriorASDatrial septal defectCIcardiac indexCKDchronic kidney diseaseCOcardiac outputCTcomputed tomographyEFSEarly Feasibility StudyFMRfunctional mitral regurgitationIABPintra-aortic balloon pumpLVEDDleft ventricular end diastolic diameterLVEFleft ventricular ejection fractionLVESDleft ventricular end systolic diameterLVOTleft ventricular outflow tractLVOTOleft ventricular outflow tract obstructionMRmitral regurgitationNYHANew York Heart AssociationPASPpulmonary artery systolic pressurePVLparavalvular leakageRHCright heart catheterizationSLseptal lateralTAPSEtricuspid annular plane systolic excursionTEEtrans-esophageal echocardiographyTEERtranscatheter edge-to-edge repairTMVRtranscatheter mitral valve replacementTTEtrans-thoracic echocardiography
1. Introduction
Mitral regurgitation (MR) is the most common valvular heart disease worldwide, affecting over 2 % of the total population with a prevalence that increases with age [1]. The Euro Heart Survey estimated that 11 % of MR patients exhibit severe MR. [2] Despite a 5-year mortality rate of 50 % with medical therapy alone [3], many patients remain untreated.
Surgical treatment of MR – via replacement or repair – has shown predominantly benefits for younger patients and patients with primary MR, but this constitutes an estimated 2 % of eligible patients who require treatment [[3], [4], [5]]. For the remaining high or prohibitive surgical risk patients, the development of non-invasive transcatheter therapies is critical. Transcatheter edge-to-edge repair (TEER) therapies are commercially available in the US and Europe to treat patients at elevated risk for surgery. The safety of TEER is well established as a treatment option, however not all patients are eligible for TEER or achieve an adequate reduction in MR severity [6]. Furthermore, recent publications have shown the degree of residual MR after TEER has a direct impact on patient mortality rates [[7], [8], [9]].
In this context, the effectiveness of transcatheter mitral valve replacement (TMVR) to consistently reduce MR is well established. Several recent studies have demonstrated both short- and long-term clinical benefits such as low post procedural residual MR and transvalvular pressure gradients, sustained reduction in MR over time, remodeling of the left ventricle, and a reduction in heart failure symptoms [[10], [11], [12], [13]].
One of the major limitations of current TMVR technologies is related to the complexity of device design to treat a multitude of anatomies and etiologies of patients with severe MR. [14] This has resulted in high anatomical screen failure rates – reported anywhere from 50 % to 83 % [12,[15], [16], [17]]. The primary anatomical factors that impact the high screen failure rates are the risk of left ventricular outflow tract obstruction (LVOTO), and the dimensions of the native mitral valve annulus, and mitral annular calcification [12,16]. Early TMVR clinical experiences were limited to transapical (TA) TMVR, which is established to be invasive. To further minimize invasiveness, it is desired to establish a transseptal (TS) treatment option to treat these high-risk patients.
The AltaValve™ (4C Medical Technologies, Maple Grove, MN) has an atrial only fixation method without any active anchoring within the sub-valvular apparatus, which is unlike other TMVR devices. This distinct anchoring method has the potential to minimize the risk of LVOTO, avoid interference with the base of the left ventricle, and expand its application to treat larger mitral valve annuli. The implant may be delivered in situ using either a transapical or a transseptal approach. Herein, we present our first three (N = 3) consecutive patients with severe MR who were treated using the transseptal, low-profile (29-French) AltaValve delivery system at the European InterBalkan Medical Center (Thessaloniki, Greece).
2. Device & procedure overview
2.1. Device
The AltaValve (Fig. 1) is comprised of a self-expanding nitinol stent frame, which houses a 27 mm tri-leaflet bovine pericardial valve. The annular ring – the ventricular end of the implant that interacts with the native mitral annulus – is available in three sizes (40 mm, 46 mm, and 54 mm diameter) and is covered by a fabric skirt to minimize paravalvular leak (PVL). With these available sizes, native mitral valve annuli ranging from 29 to 51 mm in diameter can be treated. The transseptal delivery system consists of a sheath, dilator, delivery catheter (which houses the implant), and a stand for a controlled implant deployment.
Fig. 1. The AltaValve is comprised of a nitinol self-expanding stent frame that houses a 27 mm tri-leaflet bovine pericardial tissue valve. Its annular ring structure is covered in fabric to promote sealing against the native mitral annulus after implantation. The device is attached to the delivery catheter at the stent cap, which allows for device deployment and recapture in case of need.
2.2. Anatomical analysis
Anatomical eligibility was assessed using an echocardiogram and cardiac computed tomography (CT) (Table 1). Additionally, pelvic CT imaging of the patients was obtained for measurement of venous dimensions and tortuosity of the iliac veins and the inferior vena cava. CT analysis was completed using Mimics Medical (Materialise Inc., Belgium) for sizing of the left atrium and the mitral valve annulus. The height and width of the left atrium were measured in diastole and systole. The maximum volumetric change of the left atrium between cardiac cycles was measured as part of the anatomical screening process. There were no prescreening criteria for LVOT measurements given the atrial fixation of the technology. A minimum septal height of 30 mm above the native mitral annulus is recommended for the transseptal access during the procedure. In total, eight patients were submitted for compassionate use considerations using AltaValve at our site. All eight patients (100 %) were determined to be anatomically acceptable for treatment. Subsequently and prior to the first procedures, appropriate regulatory approvals for compassionate treatment were obtained for two patients who were most in need of treatment. Following the successful procedures, regulatory approval to initiate the AltaValve Early Feasibility Study (EFS) in Greece was obtained. Hence, the third patient reported in this series was treated as part of the clinical trial.
Table 1. Summary of patient CT and echo parameters at baseline for anatomical assessments.
AP: anterior posterior; SL: septal lateral; PASP: pulmonary artery systolic pressure; TAPSE: tricuspid annular plane systolic excursion; LVESD: LV end systolic diameter.
2.3. Procedure
A surgical cutdown was performed for right femoral venous access. The transseptal puncture was obtained using a BRK needle. Balloon dilation of the septum was completed using a 12 mm balloon for ease of access to the left atrium (Fig. 2A). Pre-dilation of the vein using a 20-Fr dilator was completed prior to the introduction of the AltaValve system.
Fig. 2. The five-step sequence of AltaValve transseptal deployment in illustrated (top panel) and corresponding fluoroscopic images (bottom panel) are provided. (A) Transseptal access is obtained and balloon septostomy is completed. (B) The delivery sheath is advanced through the interatrial septum to the left atrium. (C) The delivery catheter is advanced through the delivery sheath into the left atrium and navigated to a desired depth below the level of the mitral annulus. (D) Deployment of the AltaValve is initiated with the positioner (denoted by white arrow) used to maintain its position during device deployment. (E) The delivery catheter is released from the device and withdrawn from the patient.
The AltaValve sheath and dilator were tracked over a stiff guidewire (Amplatz Superstiff, Abbott Labs, IL) to the left atrium (Fig. 2B). Once sheath position within the left atrium was confirmed using TEE, the dilator was removed, and the delivery catheter was inserted and navigated to the desired depth below the mitral annulus (Fig. 2C). Valve deployment was initiated by unsheathing the stent frame, and the positioner (highlighted in blue and denoted by the white arrow, Fig. 2D) was used to maintain the implant annular ring at the targeted depth throughout the deployment. Pacing at 90–120 bpm was optionally used during the deployment of the implant. Once the implant was fully deployed, the valve position and hemodynamic performance was assessed prior to the release of the implant from the delivery catheter (Fig. 2E).
3. Patient demographics & presentation
Patient demographics and baseline assessments are summarized in Table 2. The average patient age was 75.7 ± 4.7 years. All patients presented with advanced heart failure symptoms (NHYA III or IV) and severe functional MR (FMR) with a reduced left ventricular ejection fraction (≤35 %) and advanced kidney disease (creatinine ≥ 1.7 mg/dL).
Table 2. Summary of patient demographics at baseline.
BMI: body mass index; eGFR: estimated glomerular filtration rate; CABG: coronary artery bypass graft.
3.1. Patient #1
The patient was a 72-year-old male with chronic kidney disease and ischemic cardiomyopathy (LVEF 35 %) status post coronary artery bypass (CABG) who presented with advanced heart failure symptoms (NYHA Class IV). Right heart catheterization (RHC) was notable for a cardiac index of 1.8 L/min/m2.
The patient was not a candidate for a TEER procedure due to a short posterior leaflet. Additionally, there was concern for LVOTO with other TMVR therapies. TEE showed pronounced septal hypertrophy as well as a long anterior leaflet – both of which are known as high risk anatomical factors for LVOTO. CT demonstrated a dilated left atrium with a measured volume of 137 cm3 in systole. The measured left atrial volume change was 10 % by CT and a mitral valve excursion of 8 mm between cardiac phases. The left ventricle was dilated with a left ventricular end diastolic diameter (LVEDD) of 67 mm, and the aorto-mitral angle was 134°. Measurements were appropriate for a medium sized AltaValve with the 46 mm annular ring size.
3.2. Patient #2
The patient was a 74-year-old male with chronic kidney disease, prior transcatheter aortic valve replacement (Evolut, Medtronic, Minneapolis USA), ischemic cardiomyopathy (LVEF 35 %) status post CABG who presented with advanced heart failure symptoms (NYHA IV). The left ventricle was severely dilated resulting in severe FMR. Echocardiography showed a short posterior leaflet with restricted motion resulting in an eccentric MR jet. The left ventricular apex was aneurysmal and akinetic.
The patient was not a candidate for a TEER procedure due to a short and restricted posterior leaflet or other TMVR therapies due to concerns of LVOTO. The left ventricle was dilated with a LVEDD of 65 mm, and an aorto-mitral angle was measured at 107°. The low aorto-mitral angle is known to be a high-risk anatomical factor for LVOTO. CT measurements showed the left atrium was dilated with a measured volume of 156 cm3 in systole and a volume change of 4 % throughout the cardiac cycle. Interestingly, the patient had a highly dynamic mitral valve annulus with a change in area of 43 % between cardiac cycles. Measurements were appropriate for a medium sized AltaValve with the 54 mm annular ring.
3.3. Patient #3
The patient was an 81-year-old female with heart failure and preserved ejection fraction who presented with advanced heart failure symptoms (NYHA III). The left ventricle was severely dilated resulting in severe FMR and an elevated PASP of 40 mm Hg. The left ventricle was dilated with a LVEDD of 50 mm, and an aorta-mitral angle of 137°. CT measurements showed the left atrium was dilated with a measured volume of 108 cm3 in systole and a volume change of 5 %. Her anatomical measurements were suitable for a small sized AltaValve stent with the 40 mm annular ring size.
4. Results
All procedures were completed in the cardiac catheterization lab with general anesthesia under fluoroscopic and TEE guidance. Prior to the procedure, a RHC was obtained (Table 3). All patients were discharged on Vitamin K antagonist therapy.
Table 3. Summary of procedural & follow up measurements.
4.1. Patient #1
The pre-procedural RHC showed a reduced cardiac index (1.8 L/min/m2). Given that the patient was dependent on coronary bypass grafts and had a low cardiac index, an intra-aortic balloon pump (IABP) was placed via the left femoral artery to provide procedural hemodynamic support. A temporary transvenous pacemaker wire was inserted in the right ventricle. The transseptal puncture was performed at 42 mm above the mitral annulus. Once the implant was successfully navigated to the mitral valve annulus, pacing at 100 bpm was initiated for deployment of the implant. At the completion of implant deployment, Doppler assessment showed good valve position and MR reduction from severe to none. A summary of procedural echocardiographic measurements is given in Table 3. The LVOT demonstrated laminar flow post valve deployment. Final hemodynamic check confirmed no para-valvular leakage (PVL) and a mean pressure gradient of 1.0 mm Hg across the implanted valve. Fluoroscopic imaging shows the final location of the AltaValve following deployment and release (Fig. 3A). Doppler assessment of the iatrogenic atrial septal defect demonstrated insignificant left-to-right shunting; thus closure was not performed.
Fig. 3. Case 1: Fluoroscopic image (A) showing deployed AltaValve, TTE imaging (B) and CT images obtained 30-days post procedure, show good device function and position, and apposition to the LA with widely patent LVOT (C). Case 2: Fluoroscopic image (D) showing AltaValve final deployment, TTE imaging (E) obtained at 30-days post procedure showing good device function and widely patent LVOT. Case 3: Fluoroscopic image (F) showing deployed AltaValve, and intra-procedural TEE (G) show good device function and no LVOTO.
At 30-days post implant, the TTE confirmed excellent valve function, no PVL, and no significant change in mitral valve pressure gradient (Fig. 3B). CT analysis showed good apposition of the implant to the left atrium. The systolic post implant LVOT area was 5.6 cm2. A summary of post procedural CT measurements obtained at 30-day follow up is given in Table 3. CT demonstrated stable valve position and no device related thrombosis (Fig. 3C). The patient showed remarkable improvement from NYHA Class IV to I, enhanced overall quality of life, and improved kidney function. Further follow up at 3 months and 6 months have confirmed sustained improvements in his quality of life as well as valve function.
4.2. Patient #2
Pre-procedure RHC showed a reduced cardiac index (1.9 L/min/m2) – hence, an intraprocedural IABP was placed via the left femoral artery to provide procedural hemodynamic support. A temporary pacemaker wire was placed for pacing during implant deployment. Transseptal puncture was performed at 40 mm above the mitral annulus. The delivery catheter was then navigated to the mitral valve annulus for valve deployment. Pacing at 120 bpm was used during the implant deployment within the left atrium. At the completion of deployment, Doppler assessments showed acceptable valve hemodynamics and subsequently the implant was released from the delivery catheter. A final hemodynamic assessment via TEE confirmed a clinically significant reduction in MR with mild PVL and a mean pressure gradient of 1.0 mm Hg across the valve. The fluoroscopic image of the AltaValve after implantation is shown in Fig. 3D. Doppler assessment of the iatrogenic atrial septal defect demonstrated insignificant left-to-right shunting; thus closure was not performed.
Thirty-day post procedure follow up assessments were completed using TTE, which showed the valve hemodynamics were maintained with a mild PVL and low-pressure gradient (Fig. 3E). The patient did not demonstrate any laboratory or clinical evidence of hemolysis. The patient continued to have poor kidney function at follow up with low eGFR and hence, a contrast CT was not obtained. His heart failure symptoms improved from NYHA Class from IV to II. Further follow up at 3 and 6 months have confirmed sustained valve function and improved heart failure symptoms.
4.3. Patient #3
A pre-procedure RHC was performed and demonstrated a cardiac index of 2.3 L/min/m2. Transseptal puncture was performed at 35 mm above the mitral valve. Pacing at 100 bpm was utilized during deployment once the implant depth was set at the target location below the mitral annulus. The device deployment was completed without issue (Fig. 3F). Final valve hemodynamics obtained using TEE confirmed absence of PVL and a mean pressure gradient of 0.7 mm Hg across the implant after device release from the delivery catheter (Fig. 3G). RHC measurements immediately post procedure showed an improvement of the cardiac index to 3.4 L/min/m2 and the cardiac output to 6.9 L/min. Doppler assessment of the iatrogenic atrial septal defect showed a clinically insignificant left to right shunt – hence, closure was not performed.
TTE and CT were completed at 30-days post implant. TTE confirmed good valve function with no PVL and the low-pressure gradient across the implant was maintained. CT analysis showed good apposition of the implant to the left atrium with a systolic post implant LVOT area of 4.9 cm2. Interestingly, post implant LVOT area in systole was greater than in diastole by an estimated 30 %. There was no evidence of device-related thrombosis, and the implant was well-seated. The patient showed improvement from NYHA Class III to I with an overall improvement in quality of life. Further follow-up at 3 months confirmed sustained improvements in quality of life and the patient continues to progress well.
5. Discussion & conclusion
We present our experience treating three consecutive patients with severe FMR using the AltaValve transseptal system. All patients demonstrated technical success with sustained valve performance in follow-up.
High screen failure rates associated with current TMVR technologies, as high as 69 %, is extensively discussed in literature [12]. The primary reasons for the anatomical screen failure are risk of LVOTO, large mitral valve annulus size, and the presence of mitral annulus calcification [12]. Anatomical factors that are linked to high risk of LVOTO include pronounced septal hypertrophy, low aorta mitral angle (<120°), and long anterior mitral leaflets.
Pre-procedural CT is utilized to evaluate the risk of LVOTO. Neo-LVOT area measurements that are predicted <1.5 cm2 are seldom treated due to this defined design risk. Adjunctive procedures and techniques such as leaflet laceration techniques, and alcohol septal ablation may be used to increase the size of the LVOT and decrease the risk of obstruction post implant. However, these adjunct procedures add time and raise the complexity of TMVR thereby increasing the overall risks to the patient.
In this patient series, we demonstrated successful treatment of two patients with known risk factors for LVOTO. Patient 1 was known to have a pronounced septal hypertrophy and long anterior leaflet and Patient 2 had a suboptimal aorta mitral angle of 107°. Both patients were treated without issues and laminar LVOT flow post implant. Interestingly, Patient 1 & Patient 3 demonstrated a greater post implant LVOT area in systole as compared to diastole by approximately 20 % and 30 % respectively. It mimics the dynamics of the native mitral valve wherein the LVOT area increases in systole vs. diastole – yet this is not a standard post implant observation for other TMVR technologies. Atrial fixation may have benefits in preserving the dynamics of the native mitral valve annulus – thereby, reducing the overall risk of LVOT obstruction as evidenced by our limited patient experiences. In comparison, other TMVR technologies that utilize active anchoring at the annular or sub-annular level (e.g., barbs, hooks, tethers etc.) may directly affect the annular mechanics and thus increase LVOTO risk.
We used three different annular ring sizes (40 mm, 46 mm, and 54 mm) for the treatment of MR in our patients. Of note, for all cases the same low profile transseptal delivery system was used, and the deployment steps remained the same. Additionally, post implant hemodynamics were similar across the annular ring sizes with a clinically significant reduction in MR and low-pressure gradients across the implants. Post implant CT analysis at 30 days shows the central valve geometry is maintained circular. Since the central valve size is the same across the three annular ring sizes, the data suggests that the central valve is isolated from the outer cage mechanics and maintains its geometry during function.
Longer term follow up in our patients showed sustained implant performance and notable improvements in quality of life. The follow-up CT data available for two of the patients showed no evidence of device thrombosis. The patients did not experience any conduction issues – specifically, new onset of atrial fibrillation or the worsening of existing atrial fibrillation post implant. The concept of atrial fixation for TMVR treatment is new, but this limited experience suggests no long-term impacts on the left atrium. This initial experience warrants future study of the performance of the implant in a larger cohort of patients to further the device’s potential benefits for the treatment of MR.
5.1. Limitations
The present case series is a single-center experience with consecutive, yet limited number of patients treated using the AltaValve transseptal delivery system. All patients presented in this series had severe FMR at baseline with reduced left ventricular ejection fraction. Future experiences with the technology in patients with primary MR, who are more prone to risks of LVOTO and are frequently rejected by other TMVR technologies, would be of interest. With the current technology, two primary anatomical limitations are size of the left atrium (>90 mm at baseline) and size of the mitral annulus (<29 mm in diameter). Due to low pre-operative CI and CO measurements in two patients, an IABP was utilized to provide temporary mechanical support to minimize the risk of post implant afterload mismatch. In patients with diffuse atherosclerosis in the iliac or femoral vessels, it may preclude placement of temporary mechanical support and contraindicate implantation of a TMVR device. Additionally, investigation into the applicability of this technology for the treatment of patients with a small left ventricle, mitral annular calcification, and mitral stenosis is warranted.
AltaValve’s atrial fixation minimizes the left ventricular profile of the implant, which may allow treatment of a greater number of patients. As the technology has no active fixation at the mitral annulus, it is our anticipation the device interaction with calcium may be “TAVR” like and present a treatment option for such patients, who are typically considered surgically prohibitive. Our initial experiences and results with the technology are highly encouraging, and a larger multi-center investigation is warranted to confirm the benefits of the technology for the broader MR population.
Funding
No funding disclosures.
CRediT authorship contribution statement
Vlasis Ninios: Conceptualization, Investigation. Ilias Ninios: Investigation, Visualization. Lauren S. Ranard: Writing – review & editing. Torsten P. Vahl: Writing – review & editing. Krzysztof Wrobel: Writing – review & editing.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Vlasis Ninios: Consultant and a medical proctor of 4C Medical.
Ilias Ninios: Nothing to disclose.
Lauren S. Ranard: Institutional funding to Columbia University Medical Center from Boston Scientific, and consulting fees from 4C Medical and Philips.
Torsten P. Vahl: Institutional funding to Columbia University Irving Medical Center from Boston Scientific, Edwards Lifesciences, JenaValve, and Medtronic, and he has received consulting fees from Abbott Vascular, JenaValve and 4C Medical.
Krzysztof Wrobel: Consultant and medical proctor of 4C Medical.