Percutaneous mitral annuloplasty with the Carillon device: Outcomes in proportionate and disproportionate functional mitral regurgitation.

BACKGROUND: It has been suggested that the disparity of outcomes between the studies of transcutaneous edge-to-edge repair (TEER) for functional mitral regurgitation (FMR) in heart failure with reduced ejection fraction (HFrEF) could be due to systematic differences in the populations studied. One proposal is that there are 2 broad groups: those with proportional FMR who respond less favorably, and those in whom the FMR is greater than expected (disproportionate) FMR where edge-to-edge TEER seems to be more effective. Whether this grouping is relevant for other percutaneous interventions for FMR is unknown. OBJECTIVES: We sought to compare clinical and echocardiographic outcomes of patients with HFrEF and proportionate and disproportionate FMR treated with indirect annuloplasty using the Carillon device. METHODS: This is a pooled analysis from 3 trials of patients with FMR. Key patient eligibility in these trials specified persistent grade 2+ to 4+ FMR with >5.5 cm left ventricular (LV) end-diastolic diameter (LVEDD) and reduced ejection fraction. Patients with an effective regurgitant orifice area/LV end-diastolic volume (EROA/LVEDV) ratio under 0.15 were assigned to the proportionate FMR group (n = 74;65%) and those with a ratio above 0.15 were classed as having disproportionate FMR (n = 39;35%). RESULTS: At 12 months following treatment, both groups showed improvements in all MR variables including regurgitation volume, EROA and vena contracta. Moreover, in patients with proportionate MR there were clinically relevant and statistically significant improvements in LV volumes and diameters. There was no independent relationship between the degree of proportionality as a continuous variable and the remodeling response to Carillon therapy (change in LVEDV r = 0.17; change in LVESV r = 0.14). CONCLUSION: Percutaneous mitral annuloplasty with the Carillon device reduces MR in patients with both proportionate and disproportionate FMR, and also results in LV reverse remodeling in those with proportionate FMR. The effect on remodeling remains to be verified in a large-scale trial.

A randomized double-blind trial of an interventional device treatment of functional mitral regurgitation in patients with symptomatic congestive heart failure-Trial design of the REDUCE FMR study.

The Carillon Mitral Contour System has been studied in 3 nonrandomized trials in patients with symptomatic congestive heart failure and functional mitral regurgitation. The REDUCE FMR study is a uniquely designed, double-blind trial evaluating the impact of the Carillon device on reducing regurgitant volume, as well as assessing the safety and clinical efficacy of this device. Carillon is a coronary sinus-based indirect annuloplasty device. Eligible patients undergo an invasive venogram to assess coronary sinus vein suitability for the Carillon device. If the venous dimensions are suitable, they are randomized on a 3:1 basis to receive a device or not. Patients and assessors are blinded to the treatment assignment. The primary end point is the difference in regurgitant volume at 1 year between the implanted and nonimplanted groups. Other comparisons include clinical parameters such as heart failure hospitalizations, 6-minute walk test, Kansas City Cardiomyopathy Questionnaire (KCCQ), and other echocardiographic parameters. An exercise echo substudy will also be included.

Biotechnology Based Process for Production of a Disulfide-Bridged Peptide.

A disulfide-bridged peptide drug development candidate contained two oligopeptide chains with 11 and 12 natural amino acids joined by a disulfide bond at the N-terminal end. An efficient biotechnology based process for the production of the disulfide-bridged peptide was developed. Initially, the two individual oligopeptide chains were prepared separately by designing different fusion proteins and expressing them in recombinant E. coli. Enzymatic or chemical cleavage of the two fusion proteins provided the two individual oligopeptide chains which could be conjugated via disulfide bond by conventional chemical reaction to the disulfide-bridged peptide. A novel heterodimeric system to bring the two oligopeptide chains closer and induce disulfide bond formation was designed by taking advantage of the self-assembly of a leucine zipper system. The heterodimeric approach involved designing fusion proteins with the acidic and basic components of the leucine zipper, additional amino acids to optimize interaction between the individual chains, specific cleavage sites, specific tag to ensure separation, and two individual oligopeptide chains. Computer modeling was used to identify the nature and number of amino acid residue to be inserted between the leucine zipper and oligopeptides for optimum interaction. Cloning and expression in rec E. coli, fermentation, followed by cell disruption resulted in the formation of heterodimeric protein with the interchain disulfide bond. Separation of the desired heterodimeric protein, followed by specific cleavage at methionine by cyanogen bromide provided the disulfide-bridged peptide.

Role of three-dimensional echocardiography in management of acquired intracardiac shunts.

Gerbode defect and sinus of Valsalva aneurysm fistula are congenital and acquired forms of intracardiac shunt. The increasing prevalence of invasive, recurrent cardiovascular procedures cause tissue damage and has led to more iatrogenic and acquired cases of predominantly congenital shunt over time. We report 2 cases of acquired intracardiac fistula precisely defined by Real time three-dimensional transesophageal echocardiography (3DTEE). The first case is a 70-year-old male with Gerbode defect after second aortic valve replacement surgery due to prosthetic valve endocarditis and the other case is a 41-year-old male with sinus of Valsalva aneurysm fistula between aorta and right atrium post subclinical infective endocarditis. Advanced cardiac imaging techniques such as cardiac computerized tomography, MRI and Real time three-dimensional (3D) echocardiography help to precisely detect intracardiac fistula and provide detailed anatomic and physiologic information. The relatively low cost, lack of radiation exposure, portability and guiding characteristic make real time 3DTEE an imaging technique with arguably the most advantages. Surgical repair is the usual treatment for intracardiac shunt, and percutaneous catheter-based closure is a less invasive alternative.

The CINCH-FMR postmarket registry: Real-world long-term outcomes with percutaneous mitral valve repair with the Carillon Mitral Contour System®.

BACKGROUND: The Carillon® Mitral Contour System® has been studied in 4 prospective controlled studies in the treatment of functional mitral regurgitation (FMR) where it has been found to reduce mitral regurgitation, reduce left ventricular and atrial volumes, and be associated with improvements in clinical parameters. AIMS: The CINCH post-market registry is designed to evaluate immediate, mid-term and long-term outcomes from a post-approval study of the Carillon® device evaluated in real-world practice. METHODS: The CINCH post-market registry is a single-arm study of percutaneous mitral annuloplasty with the Carillon device in patients with functional (secondary) mitral regurgitation and symptomatic congestive heart failure when utilized in real-world conditions. Patient selection, echocardiographic hemodynamic measurements, and patient follow-up requirements were performed per standard of care at each institution. RESULTS: A total of 101 patients treated with the Carillon device at 13 sites in Germany were enrolled in the CINCH registry. The mean age was 75 ± 9 years, 57 % were male, and patient presentation included primarily NYHA class III (69 %) with MR grade 3 (68 %). Over 5 years of follow-up, all-cause mortality was 40.1 %, the incidence of HFH was 53.9 %, and the composite outcome of HFH or death was 66.4 %. At each follow-up interval through 5 years, statistically significant reductions in NYHA class (p < 0.05) and MR grade (p < 0.01) were reported. CONCLUSIONS: In this "real world" registry of the Carillon Mitral Contour System, procedural safety and medium-term follow-up outcomes is similar to the outcomes seen in the prospective, controlled clinical trials, despite being used in populations of patients that extend outside of those studied in the trials. The use of this therapy in patients with atrial functional mitral regurgitation, and heart failure with preserved ejection fraction, was notable, since these types of patients were excluded from the prospective, controlled trials. This supports possible additional patient populations who might benefit from this type of mechanical therapy. The safety profile of this therapy in this registry and in the earlier trials may support a potential role in earlier forms of secondary mitral regurgitation.

The Society for Cardiovascular Angiography and Interventions Structural Heart Disease Early Career Task Force survey results: endorsed by the Society for Cardiovascular Angiography and Interventions.

Over the last decade, structural heart disease interventions have emerged as a new field in interventional cardiology. Currently, the Accreditation Council for Graduate Medical Education accredited interventional cardiology fellowship programs in the United States provide high-quality and well established training curriculum in coronary and peripheral interventions, but training in structural interventions remains in its infancy. The current survey seeks to collect relevant information and assess the opinion of interventional cardiology program directors in ACGME-accredited institutions that are actively involved in structural interventional training. Our study describes the actual number of structural procedures performed by interventional cardiology fellows in ACGME-accredited programs, the form of the structural training today and the suggestions from program directors who are actively trying to integrate structural training in the interventional cardiology fellowship programs.

Treating symptoms and reversing remodelling: clinical and echocardiographic 1-year outcomes with percutaneous mitral annuloplasty for mild to moderate secondary mitral regurgitation.

AIMS: To determine the effects of percutaneous mitral annuloplasty on symptoms, walk distance and left ventricular (LV) structure and function in patients with mild or moderate secondary mitral regurgitation (SMR). METHODS AND RESULTS: This was a pooled analysis of patients (n = 68) who, despite guideline-directed medical therapy had symptomatic heart failure (HF) with mild (n = 25) or moderate (n = 43) SMR treated with percutaneous mitral annuloplasty as part of the TITAN, TITAN II, or REDUCE-FMR trials. Primary outcomes were changes in symptoms, 6-min walk distance, and quality of life assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) after 1 year. Secondary analyses included changes in LV structure and function. At 1 year, New York Heart Association class status was maintained (48%) or improved (46%) in most patients, mean KCCQ scores increased from baseline by 10 units [95% confidence interval (CI) 3 to17; P < 0.01] and mean 6-min walk test distance increased by 34 m (95% CI 12 to 57; P < 0.01). SMR grade improved in 25% of patients and was maintained in 58% of patients with changes in mean regurgitant volume of -7 mL (95% CI -11 to -3; P < 0.001), vena contracta -0.11 cm (95% CI -0.20 to -0.02; P < 0.05), and effective regurgitant orifice area -0.03 cm2 (95% CI -0.06 to -0.01; P < 0.05). There were non-significant improvements in LV ejection fraction and volumes. Survival over 1 year was 89% with no difference between mild (96%) and moderate (86%) SMR (log-rank P = 0.22). Progression-free survival was 70% (82% in mild vs. 63% in moderate SMR; P = 0.16). Freedom from HF hospitalization was 73% (87% in mild SMR vs. 66% in moderate SMR; P = 0.07). CONCLUSION: Among patients with symptomatic HF and mild or moderate SMR on guideline-directed medical therapy, percutaneous mitral annuloplasty was associated with improvements in symptoms, SMR, a stabilization of LV structure and function, and high survival rates.

Percutaneous mitral valve interventions: overview of new approaches.

The percutaneous management of valvular heart disease has recently been receiving a great deal of interest as an area of great potential. Innovative technologies are now being developed to treat mitral regurgitation. Although there are established surgical techniques for treating organic mitral regurgitation, the surgical management of functional mitral regurgitation remains controversial, and such patients have a poor prognosis. Therefore, a percutaneous treatment for functional mitral regurgitation holds great clinical potential. Having a nonsurgical approach available may be attractive to patients with organic mitral valve regurgitation as well. Several approaches and devices have been designed to treat specifically functional mitral regurgitation, and some of these have been applied to humans in early-stage evaluations. The MitraClip device (Abbott Laboratories, Abbott Park, IL) has been used to treat both functional and degenerative mitral valve regurgitation and has been compared to surgery in the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study II) randomized trial. Although the field of percutaneous management of mitral regurgitation is at an early stage, it has been demonstrated that percutaneous approaches can reduce mitral regurgitation, suggesting there is a great deal of potential for clinical benefit to patients with mitral regurgitation.

Long-term prognosis of patients treated by coronary sinus-based percutaneous annuloplasty: single centre experience.

AIMS: This study aims to report long-term mortality, echocardiographic, and clinical outcomes of patients receiving treatment for functional mitral regurgitation (FMR) with the Carillon device. METHODS AND RESULTS: This was a single centre analysis of prospectively collected data from patients treated with the Carillon Mitral Contour System for symptomatic congestive heart failure despite guideline-directed medical therapy, who were included from a single centre from the TITAN II study. All patients presented with New York Heart Association (NYHA) class 2 or greater symptoms, grade 2+ to 4+ FMR, left ventricular enlargement, and reduced ejection fraction. Surviving patients were evaluated for long-term follow-up post-procedure, averaging 6.9 years. Fifteen (15) patients (mean age 72 years, 60% male, 100% NYHA class III or IV, 50% MR grade 3+ or 4+) were treated with the Carillon device. The Kaplan-Meier mortality rate was 40% at 6 years of follow-up. Long-term survival through 6 years was associated with echocardiographic improvement in mitral regurgitation (change in effective regurgitant orifice area in survivors versus non-survivors from baseline to 1 year follow-up, -9.0 ± 5.6 vs. -1.7 ± 1.5, P = 0.02) and clinical status at 12 months (difference in NYHA at 1 year follow-up between survivors versus non-survivors, P = 0. 05) which was sustained throughout follow-up. All patients at 6 year follow-up had ≤2+ MR, with 6 of 7 having 0-1+ MR. Left ventricular end-diastolic volume was reduced from 154.0 ± 65.7 mL at baseline to 104.5 ± 59.2 mL at 6 year follow-up, P = 0.03 in survivors with both measurements. CONCLUSIONS: Among patients with congestive heart failure treated with the Carillon device, long-term survival is associated with favourable 1 year and sustained improvements in mitral regurgitation, left ventricular volume, ejection fraction, and clinical status.

Long-Term Survival Following Transcatheter Mitral Valve Repair: Pooled Analysis of Prospective Trials with the Carillon Device.

PURPOSE: To report long-term survival and to identify potential determinants of survival among patients receiving treatment for functional mitral regurgitation (FMR) with the Carillon device. METHODS: This was a post hoc analysis in which we pooled prospectively collected data from three studies of the Carillon device with available long-term vital status data. Patient eligibility in these trials specified symptomatic congestive heart failure despite guideline-directed medical therapy, grade 2 to 4 FMR, left ventricular enlargement, and reduced ejection fraction. Echocardiographic parameters were available through the 12-month visit and vital status was available through 5 years. The association of patient characteristics and changes in echocardiographic parameters at 6 and 12 months with long-term survival was analyzed using Cox proportional hazards regression. RESULTS: A total of 74 patients (mean age 67 years, 72% male, 59% MR grade 3 or 4) were treated with the Carillon device. Over 1 year of follow-up, the New York Heart Association (NYHA) class decreased in 64% of patients, distance on the 6-minute walk test increased, and echocardiographic measures indicated significant decreases in MR grade and favorable left ventricular remodeling. The Kaplan-Meier survival rate was 83.6% at 1 year, 73.1% at 2 years, 67.9% at 3 years, and 56.2% at 4 and 5 years of follow-up. Primary determinants of long-term survival were a decrease in NYHA class, an increase in 6-minute walk test distance, and a decrease in regurgitant volume during the first year of follow-up. CONCLUSIONS: Among patients with congestive heart failure and grade 2 to 4 FMR who were symptomatic despite guideline-directed medical therapy, transcatheter mitral valve repair with the Carillon device resulted in a favorable 5-year survival rate. The survival benefit was greatest among patients with improvement in clinical and hemodynamic parameters during the first year of follow-up.

Cardiac resynchronization therapy following Carillon® annuloplasty device for symptomatic heart failure and functional mitral regurgitation: a case report.

BACKGROUND: Symptomatic patients with significant left ventricular systolic dysfunction (LVSD) require a tailored treatment approach. Both functional mitral regurgitation (FMR) and left bundle branch block (LBBB) can develop, contributing to clinical deterioration, and worse prognosis despite optimal medical therapy (OMT). CASE SUMMARY: We report the case of a symptomatic 60-year-old man on OMT with LVSD and significant FMR. His symptoms and FMR initially improved following transvenous mitral annuloplasty using the Carillon® Mitral Contour System® annuloplasty device. However, he subsequently developed LBBB with associated reduction in exercise capacity, for which he underwent cardiac resynchronization therapy, and ensuing symptom improvement and stabilization. DISCUSSION: Our case describes how targeted device interventions can be combined synergistically to optimize patient symptoms.

The REDUCE FMR Trial: A Randomized Sham-Controlled Study of Percutaneous Mitral Annuloplasty in Functional Mitral Regurgitation.

OBJECTIVES: This study sought to evaluate the effects of the Carillon device on mitral regurgitation severity and left ventricular remodeling. BACKGROUND: Functional mitral regurgitation (FMR) complicates heart failure with reduced ejection fraction and is associated with a poor prognosis. METHODS: In this blinded, randomized, proof-of-concept, sham-controlled trial, 120 patients receiving optimal heart failure medical therapy were assigned to a coronary sinus-based mitral annular reduction approach for FMR or sham. The pre-specified primary endpoint was change in mitral regurgitant volume at 12 months, measured by quantitative echocardiography according to an intention-to-treat analysis. RESULTS: Patients (69.8 ± 9.5 years of age) were randomized to either the treatment (n = 87) or the sham-controlled (n = 33) arm. There were no significant differences in baseline characteristics between the groups. In the treatment group, 73 of 87 (84%) had the device implanted. The primary endpoint was met, with a statistically significant reduction in mitral regurgitant volume in the treatment group compared to the control group (decrease of 7.1 ml/beat [95% confidence interval [CI]: -11.7 to -2.5] vs. an increase of 3.3 ml/beat [95% CI: -6.0 to 12.6], respectively; p = 0.049). Additionally, there was a significant reduction in left ventricular volumes in patients receiving the device versus those in the control group (left ventricular end-diastolic volume decrease of 10.4 ml [95% CI: -18.5 to -2.4] vs. an increase of 6.5 ml [95% CI: -5.1 to 18.2]; p = 0.03 and left ventricular end-systolic volume decrease of 6.2 ml [95% CI: -12.8 to 0.4] vs. an increase of 6.1 ml [95% CI: -1.42 to 13.6]; p = 0.04). CONCLUSIONS: The Carillon device significantly reduced mitral regurgitant volume and left ventricular volumes in symptomatic patients with functional mitral regurgitation receiving optimal medical therapy. (Carillon Mitral Contour System for Reducing Functional Mitral Regurgitation [REDUCE FMR]; NCT02325830).

Coronary Sinus-Based Approach to Mitral Regurgitation.

Functional, or secondary, mitral regurgitation (FMR) is clinically important because patient with congestive heart failure with FMR have worse clinical outcomes and associated higher risks than patients without FMR. There is interest in finding repair techniques which may modify the mitral valve dysfunction and reduce the clinical impact. Although several devices have taken advantage of the close anatomical relationship between the coronary sinus and the posterior annulus of the mitral valve, in order to provide a cinching force on the mitral annulus, only the Carillon device is currently in use in humans. A double blind randomized trial is currently being done to evaluate the value of this therapy, building upon the favorable result of three prior safety and efficacy trials, which have led to European approval of the device.