Growth Differentiation Factor-15 as a Predictor of Functional Capacity, Frailty, and Ventricular Dysfunction in Patients With Aortic Stenosis and Preserved Left Ventricular Ejection Fraction.

In aortic stenosis (AS), left ventricular (LV) remodeling often occurs before symptom onset, and early intervention may be beneficial. Risk stratification remains challenging and identification of biomarkers may be useful. We evaluated the association between growth differentiation factor-15 (GDF-15) and soluble suppression of tumorigenicity 2 (sST2) and known markers of poor prognosis in AS. Baseline plasma GDF-15 and sST2 levels were measured in 70 patients with moderate-severe AS (aortic valve area <1.5 cm2) and preserved LV ejection fraction (>45%). Patients were categorized into "low GDF-15" versus "high GDF-15" and "low sST2" versus "high sST2" groups. Groups were compared for differences in cardiovascular risk factors, 6-minute walk test, 5 m gait speed, cognitive function (Montreal Cognitive Assessment), and echocardiographic parameters. Overall, 44% of patients were deemed asymptomatic by New York Heart Association class, 61% had severe AS (aortic valve area <1 cm2) and all patients had preserved LV ejection fraction. GDF-15 levels were not predictive of AS severity. However, high GDF-15 (>1,050 pg/ml) was associated with LV dysfunction as shown by lower indexed stroke volume (p <0.01), worse LV global longitudinal strain (p = 0.04), greater mean E/e' (p = 0.02) and indexed left atrial volume (p <0.01). It was also associated with decreased functional capacity with shorter 6-minute walk test (p = 0.01) and slower 5 m gait speed (p = 0.02). Associations between sST2 levels and markers of poor prognosis were less compelling. In this study of patients with moderate to severe AS, elevated GDF-15 levels are associated with impaired functional capacity, poorer performance on fragility testing, and LV dysfunction. In conclusion, GDF-15 may integrate these markers of adverse outcomes into a single biomarker of poor prognosis.

Successful implantation of self-expanding valve for a failed stentless prosthesis.

Valve-in-valve transcatheter aortic valve implantation is currently used for failed bioprosthesis. The use of a transcatheter prosthesis in a regurgitant noncalcified root implanted Medtronic Freestyle prosthesis is particularly challenging. We present a successful transaxillary valve-in-valve implantation of a self-expandable transcatheter aortic valve prosthesis in a failed Freestyle bioprothesis implanted eleven years earlier. Tips and tricks are discussed.

Clinical outcomes and economic impact of transcatheter mitral leaflet repair in heart failure patients.

BACKGROUND: Mitral regurgitation (MR) is a common valvular heart disorder requiring intervention once it becomes severe. Transcatheter mitral repair with the MitraClip device is a safe and effective therapy for selected patients denied surgery. The authors sought to evaluate the clinical outcomes and economic impact of this therapy compared to medical management in heart-failure patients with symptomatic mitral regurgitation. METHODS AND RESULTS: The study was comprised of two phases; an observational study of patients with heart failure and mitral regurgitation treated with either medical therapy or the MitraClip, and an economic model. Results of the observational study were used to estimate parameters for the decision model, which estimated costs, and benefits in a hypothetical cohort of patients with heart failure and moderate-to-severe mitral regurgitation treated with either standard medical therapy or MitraClip. The cohort of patients treated with the MitraClip was propensity matched to a population of heart failure patients, and their outcomes compared. At a mean follow-up of 22 months, all-cause mortality was 21% in the MitraClip cohort and 42% in the medical management cohort (p = .007). The decision model demonstrated that MitraClip increased life expectancy from 1.87-3.60 years and quality-adjusted life years (QALY) from 1.13-2.76 years. The incremental cost was $52,500 Canadian dollars, corresponding to an incremental cost-effectiveness ratio (ICER) of $32,300.00 per QALY gained. Results were sensitive to the survival benefit. CONCLUSION: In heart failure patients with symptomatic moderate-severe mitral regurgitation, therapy with the MitraClip is associated with superior survival and is cost-effective compared to medical therapy.

Histopathological effects and evolution of transvenous ß-radiation applications in right and left atria: an animal study.

AIMS: ß-radiation is a novel potential energy source for the creation of myocardial lesions. While the feasibility of delivering ß-radiation via a deflectable transvenous catheter has been described, dose effects and the time course of histopathological changes have not been previously assessed. The purpose of this study was to characterize pathological aspects of cardiac lesions induced by ß-radiation in an animal model at various stages of evolution and in response to different dose exposures. METHODS AND RESULTS: Nine dogs and one pig were studied. The cavotricuspid isthmus, antrum of pulmonary veins (PVs), and mitral isthmus were irradiated (25, 50, 75, or 100 Gy) with strontium-yttrium-90, delivered via a deflectable catheter (cavotricuspid isthmus and mitral isthmus) or a double-loop catheter (antrum of PVs). Eighteen lesions were created. Animals were sacrificed at 2 weeks, 1 month, 3 months, or 6 months. Lesions were processed for morphometric histopathological analyses. Over the first month, lesions were characterized by inflammation, haemorrhage, and myocyte necrosis. Thereafter, fibrotic replacement was predominant. Transmurality of lesions was observed in 50% of cases, with no dose-response effect (P = 0.976). Surface fibrin thrombus was present in 50% of cases and was essentially limited to lesions assessed within the first month. No neighbouring injury or pulmonary venous stenosis was observed. CONCLUSIONS: Atrial lesions created by ß-radiation are characterized by an inflammatory phase with surface fibrin thrombosis during the first month and replacement fibrosis thereafter. No appreciable dose-response effect was noted within the 25-100 Gy range tested.

2-year follow-up of patients undergoing transcatheter aortic valve implantation using a self-expanding valve prosthesis.

OBJECTIVES: The purpose of this study was to evaluate the safety, device performance, and clinical outcome up to 2 years for patients undergoing transcatheter aortic valve implantation (TAVI). BACKGROUND: The role of TAVI in the treatment of calcific aortic stenosis evolves rapidly, but mid- and long-term results are scarce. METHODS: We conducted a prospective, multicenter, single-arm study with symptomatic patients undergoing TAVI for treatment of severe aortic valve stenosis using the 18-F Medtronic CoreValve (Medtronic, Minneapolis, Minnesota) prosthesis. RESULTS: In all, 126 patients (mean age 82 years, 42.9% male, mean logistic European System for Cardiac Operative Risk Evaluation score 23.4%) with severe aortic valve stenosis (mean gradient 46.8 mm Hg) underwent the TAVI procedure. Access was transfemoral in all but 2 cases with subclavian access. Retrospective risk stratification classified 54 patients as moderate surgical risk, 51 patients as high-risk operable, and 21 patients as high-risk inoperable. The overall technical success rate was 83.1%. Thirty-day all-cause mortality was 15.2%, without significant differences in the subgroups. At 2 years, all-cause mortality was 38.1%, with a significant difference between the moderate-risk group and the combined high-risk groups (27.8% vs. 45.8%, p = 0.04). This difference was mainly attributable to an increased risk of noncardiac mortality among patients constituting the high-risk groups. Hemodynamic results remained unchanged during follow-up (mean gradient: 8.5 ± 2.5 mm Hg at 30 days and 9.0 ± 3.4 mm Hg at 2 years). Functional class improved in 80% of patients and remained stable over time. There was no incidence of structural valve deterioration. CONCLUSIONS: The TAVI procedure provides sustained clinical and hemodynamic benefits for as long as 2 years for patients with symptomatic severe aortic stenosis at increased risk for surgery.

Description and assessment of a common reference method for fluoroscopic and transesophageal echocardiographic localization and guidance of mitral periprosthetic transcatheter leak reduction.

OBJECTIVES: This study sought to describe and compare a novel fluoroscopic method and a 2-dimensional transesophageal echocardiographic (TEE) method to localize mitral periprosthetic leaks (PPLs) for transcatheter reduction. BACKGROUND: Transcatheter reduction of significant regurgitation represents a modern and attractive alternative to surgery for the treatment of mitral PPL in high-risk patients. Accurate localization and precise communication between the echocardiographer and the interventional cardiologist are essential for procedural success. METHODS: We analyzed TEE and fluoroscopic studies of patients with mitral PPL who underwent multiplane 2-dimensional TEE-guided transcatheter reduction in our institution. Periprosthetic leaks were routinely localized using the "surgeon's-view" time-clock method during periprocedural TEE assessments. The 2-dimensional TEE examinations were later retrospectively reviewed by an echocardiographer blinded to procedural TEE findings. A corresponding surgeon's-view time-clock method was plotted for fluoroscopic PPL localization. Using this fluoroscopic method, offline fluoroscopic images were reviewed by an independent interventional cardiologist blinded to TEE results. Agreement between methods was evaluated. RESULTS: Complete imaging data were available for analysis in 20 patients who, between 2002 and 2009, underwent transcatheter reduction in which the defect was successfully crossed. There was excellent agreement between procedural TEE and retrospective TEE review for PPL localization (100%; p < 0.0001) and between fluoroscopic and procedural TEE localization (90%; 95% confidence interval [CI]: 77% to 100%; p = 0.0003). In the 2 cases where there was disagreement, fluoroscopic PPL localization was adjacent to TEE localization. CONCLUSIONS: The surgeon's-view time-clock method of localizing PPL using 2-dimensional TEE is highly reproducible and allows fluoroscopic localization using the same reference system with very good agreement.

Good outcome and valve function despite Medtronic-corevalve underexpansion.

An 80-year old nun with severe calcific aortic stenosis and a bicuspid aortic valve was referred for transcatheter aortic valve implantation. She was declined for conventional surgery on the basis of poor left ventricular function, frailty, and a logistic EuroSCORE of 29.66. A 29-mm Medtronic-Corevalve bioprosthesis was implanted by transfemoral route. The inflow portion of the stent frame was grossly underexpanded. However, aortic valve area at 1.3 cm(2) was more than satisfactory for a body surface area of 1.29 m(2) (indexed area 1.0 cm(2)/m(2), peak gradient 23, and mean 16 mmHg). There was an early sustained improvement in New York Heart Association (NYHA) status, and there was no change in valvular function at 2 year follow-up. This case highlights that gross underexpansion of the Medtronic-Corevalve stent frame is compatible with good bioprosthetic function and excellent symptomatic recovery.

Anatomo-pathological analysis after CoreValve Revalving system implantation.

AIMS: Significant technological improvements have made percutaneous aortic valve replacement (PAVR) simpler and safer, but the behaviour of the implanted valve over time remains unknown. We report the anatomo-pathological analysis of patients who died at different time intervals post PAVR with the CoreValve Revalving System. METHODS AND RESULTS: In our early experience, 21 patients underwent CoreValve implantation between 12/2005 and 02/2007. Among the 11 deaths at one year follow-up, four patients had an autopsy with macro and microscopic analysis. The device was divided in three parts during pathological assessment: the lower portion (area 1), the leaflets (area 2) and the upper part (area 3). The CoreValves were implanted for 3, 13, 104 and 350 days. Gross examination showed neointimal tissue covering most of the frame struts in contact with the aortic wall, but areas of high velocity blood flow were bare. Histopathology examination demonstrated fibrin deposition and inflammatory response early after valve implantation, followed by neointimal coverage with progressive regression of the inflammatory response over time. CONCLUSIONS: While waiting for results of longer term PAVR echocardiographic follow-up, the anatomic assessment is encouraging with neointimal coverage of the native valve site and no excessive pannus formation occurring over the valve leaflets.

Percutaneous suture edge-to-edge repair of the mitral valve.

AIMS: To describe a new approach to percutaneous mitral valve repair and an illustrative first-in-man experience, we introduce a suture mediated "double orifice", "edge-to-edge" procedure which can be an effective surgical therapy for mitral regurgitation (MR) in selected patient. METHODS AND RESULTS: We describe a novel percutaneous approach to double orifice mitral repair utilising an intra-cardiac suture based system. The procedure was performed in 15 patients in four international centres. Endovascular suture based double orifice mitral repair was feasible with an acute reduction in the severity of MR by > or = 1 grade in nine of 15 patients. At 30 days improvement in MR appeared durable in six patients. Clinical utility was limited by technical difficulties, the inadequacies of current imaging modalities and suture dehiscence. CONCLUSIONS: Percutaneous endovascular suture based cardiac repair is feasible. However, in utilising the current device clinical benefit was limited and the repair not durable. In the future, similar endovascular approaches may enable more complex cardiac repair.

1-year results of the hydroxyapatite polymer-free sirolimus-eluting stent for the treatment of single de novo coronary lesions: the VESTASYNC I trial.

OBJECTIVES: We sought to assess the safety and efficacy of the novel VESTAsync-eluting stent (MIV Therapeutics, Atlanta, Georgia) combining a stainless steel platform with a nanothin-microporous hydroxyapatite surface coating impregnated with a polymer-free low-dose of sirolimus (55 microg). BACKGROUND: Durable polymers in first-generation drug-eluting stents (DES) have been linked to local inflammatory reaction leading to a positive vessel remodeling, late incomplete stent apposition, and in some cases, stent thrombosis. The removal of the polymer from the DES system could increase the safety profile of this novel technology. METHODS: A total of 15 patients with single de novo lesions in native coronary arteries with 3.0- to 3.5-mm diameter and

Transcatheter mitral and pulmonary valve therapy.

As the percentage of seniors continues to rise in many populations around the world, the already challenging burden of valvular heart disease will become even greater. Unfortunately, a significant proportion of patients with moderate-to-severe valve disease are refused or denied valve surgery based on age and/or accompanying comorbidities. Furthermore, because of advances in pediatric cardiology, the number of adult patients with congenital heart disease is on the rise and over time, these patients will likely require repeat high-risk surgical procedures. The aim of transcatheter valve therapies is to provide a minimally invasive treatment that is at least as effective as conventional valve surgery and is associated with less morbidity and mortality. The objective of this review was to provide an update on the clinical status, applicability, and limitations of transcatheter mitral and pulmonary valve therapies.

Role of transesophageal echocardiography in percutaneous aortic valve replacement with the CoreValve Revalving system.

Percutaneous aortic valve replacement (PAVR) is an emerging therapy for nonsurgical patients with severe aortic stenosis (AS). We examined the role of transesophageal echocardiography (TEE) in PAVR. TEE was used initially to assess the native valve and aortic root, and served as a guide during PAVR. Following prosthetic valve deployment, TEE was used to assess valve function. Eleven patients aged 82 +/- 10 years with NYHA III-IV underwent PAVR. Periprocedural TEE gave immediate information on prosthetic position and function, LV function, mitral regurgitation, pericardium, and thoracic aorta anatomy. There was excellent visual agreement between fluoroscopic and TEE images of prosthetic positioning and deployment. TEE facilitated the detection and management of procedure-related complications. Compared with pre-PAVR, AV area (0.56 +/- 0.19 cm(2) vs. 1.3 +/- 0.4 cm(2); P < 0.001) and LVEF (49 +/- 17% vs. 56 +/- 11%; P < 0.001) increased. TEE provides key anatomical and functional information, and serves as a diagnostic guide for complications, which may arise during PAVR.

Transcatheter mitral valve repair for functional mitral regurgitation: coronary sinus approach.

Mitral regurgitation has become recognized as an important health problem. More specifically, functional mitral regurgitation is associated with worse outcomes in heart failure, postmyocardial infarction, and perioperative coronary artery bypass surgery patients. Many patients with severe mitral regurgitation are denied or refused mitral valve surgery. A less invasive procedure with possibly fewer potential complications may thus be attractive for patients with severe mitral regurgitation. Devices used for coronary sinus (CS) mitral annuloplasty are directed toward patients with functional mitral regurgitation. Because of its easy accessibility and close relationship to the posterior mitral annulus (MA), alterations of the CS geometry with percutaneous devices may translate to displacement of the posterior annulus and correct mitral leaflet coaptation. This review will focus on the contemporary CS annuloplasty devices: (1) Edwards MONARC system; (2) Cardiac Dimensions CARILLON; and (3) Viacor Shape Changing Rods system. In addition, important information obtained from recent imaging studies describing the relationship between the CS, MA, and coronary arteries will be reviewed.

Surgical aspects of endovascular retrograde implantation of the aortic CoreValve bioprosthesis in high-risk older patients with severe symptomatic aortic stenosis.

OBJECTIVES: Aortic stenosis is one of the most common forms of acquired valvular heart disease in adults, and the proportion of patients unsuitable for conventional surgery is increasing. Consequently, the development of new less-invasive techniques to treat severe aortic stenosis is crucially important. Current experience in percutaneous aortic valve replacement is limited to a few groups, and the search for an optimal technique continues. We report our experience with retrograde endovascular bioprosthesis implantation with brief cardiopulmonary bypass support in high-risk older patients. METHODS: The CoreValve pericardial bioprosthesis (CoreValve, Inc, Paris, France) is sutured on a nitinol frame and delivered in a 21F catheter. All procedures were performed under femoro-femoral cardiopulmonary bypass support consisting of an aortic balloon valvuloplasty followed by prosthesis deployment within the aortic annulus under fluoroscopy. Ten high-risk surgical patients underwent percutaneous valve replacement. RESULTS: Immediate improvement in aortic valve function was observed in all patients. The aortic valve area increased from 0.57 +/- 0.19 to 1.2 +/- 0.35 cm2 (P = .00001), the mean transaortic valve gradient decreased from 51 +/- 19 to 11 +/- 3 mm Hg (P < .001). The 30-day mortality was 20%: one patient died 5 days after the procedure of a massive ischemic stroke and 1 patient died at 20 days of a hemorrhagic stroke. The median New York Heart Association functional class improved from III to II (P = .01). CONCLUSIONS: Aortic valve replacement with the CoreValve bioprosthesis can be performed with favorable early technical results in high-risk patients. However, the morbidity and short-term mortality of such procedures remain significant.

Novel therapeutic aspects of percutaneous aortic valve replacement with the 21F CoreValve Revalving System.

AIMS: Percutaneous aortic valve replacement (PAVR) is an emerging therapy for nonsurgical patients with severe aortic stenosis (AS). We investigated whether novel therapeutic approaches may facilitate AVR outcomes for high-risk patients. METHODS AND RESULTS: Eleven patients [n = 6 (54%) men] aged 82 +/- 10 years underwent PAVR after being refused for open surgery. The mean+/-SD AV area and left ventricular ejection fraction (LVEF) of these patients was 0.56 +/- 0.19 cm(2) and 49 +/- 17%, respectively, with severe functional limitation (NYHA class III (n = 8) and IV (n = 3)). One patient underwent PAVR combined with simultaneous percutaneous coronary intervention (PCI). Two male patients needed left iliac artery angioplasty. A percutaneous ventricular assist device (PVAD) was used in the most recent case. Compared with pre-PAVR, mean AV area (1.3 +/- 0.4 cm(2); P < 0.001) and LVEF (56 +/- 11%; P < 0.001) increased. One man had a peri-procedural stroke and died 5 days post-PAVR. Four other patients died within 4 months of hospital discharge. The median duration of survival of the survivors was 305 (range 249-431) days. CONCLUSIONS: Novel percutaneous techniques facilitate CoreValve PAVR (21 Fr.). Future lower profile devices (e.g. 18 Fr. Generation III CoreValve) should permit inclusion of a broader spectrum of high-risk patients. PAVR may evolve toward a full percutaneous approach.

Implantation of the CoreValve percutaneous aortic valve.

Surgical aortic valve replacement is the only recommended treatment for significant aortic valve stenosis. Percutaneous aortic valve replacement appears to be a novel option for high-risk patients. We report the implantation of the ReValving system (CoreValve, Paris, France) in a 64-year-old woman who was refused aortic valve replacement surgery for critical aortic stenosis and left ventricular dysfunction because of severe pulmonary fibrosis. After anesthesia, the patient was put on femorofemoral cardiopulmonary bypass, and underwent a balloon valvuloplasty with subsequent retrograde aortic valve replacement by the ReValving system. Transesophageal echocardiographic monitoring of the patient's hemodynamics showed immediate improvements of the valvular area and left ventricular ejection fraction and only traces of paravalvular leaks. The patient was easily weaned from ventilation and resumed activity soon after the surgery. A multidisciplinary approach is presently necessary to offer a reliable and safe procedure.

Predictors of recurrent in-stent restenosis after beta-radiation: An analysis from the START 40/20 trial.

OBJECTIVE: The purpose of this study was to identify potential predictors, including clinical, procedural, angiographic, and intravascular ultrasound (IVUS) parameters, for recurrent in-stent restenosis (ISR) following beta-radiation 90Strontium/Yttrium (90Sr/Y) in a large multicenter trial. BACKGROUND: Although adjunct brachytherapy reduces recurrent ISR after primary catheter-based intervention, recurrence of stenosis after brachytherapy still occurs. METHODS: We analyzed 185 IVUS cohort patients in the STent And Restenosis Therapy (START) 40/20 trial where a 40-mm, 90Sr/Y, radioactive source train was exclusively used for treatment of ISR to be treatable with a 20-mm balloon. RESULTS: Thirty-nine patients underwent target lesion revascularization. Preliminary univariate analysis showed that age, smoking, balloon/artery ratio, geographic miss, minimum lumen diameter, and diameter stenosis at baseline were associated with target lesion revascularization, while none of IVUS variables were (minimum lumen area, minimum stent area, or residual plaque burden). The multivariate logistic regression analysis showed that younger age, lower balloon/artery ratio, and presence of geographic miss were independent predictors of target lesion revascularization. CONCLUSIONS: Even with adjunct beta-radiation therapy, initial mechanical optimization, such as appropriate balloon sizing and positioning, may be critical for the prevention of recurrent ISR.

Safety of beta radiation exposure to the non-target segment: an intravascular ultrasound dosimetric analysis.

BACKGROUND: The use of longer radioactive seed trains to avoid geographic miss may lead to greater radiation exposure to distal vasculature due to the natural tapering of coronary arteries. The aim of this study was to use IVUS-based dosimetric analysis to evaluate the effect of beta-radiation on angiographically normal, noninjured distal segments. METHODS: We analyzed 17 in-stent restenosis cases (stent length: 20 +/- 8 mm) treated with a 40 mm 90Sr/Y source train. The prescribed dose was 18.4 Gy (reference less than or equal to 3.3 mm) or 23 Gy (reference > 3.3 mm) at 2 mm from the source. Noninjured, but fully radiated, distal reference sites were determined by angiography. Based upon the three-dimensional vessel contours obtained at baseline, the minimum dose delivered to 90% of plaque volume (Dv90) was determined. Vessel, plaque and lumen volumes and Dv90 were computed in every 2 mm subsegment (n = 52). RESULTS: On average, no significant serial change was observed in plaque area (5.0 +/- 2.5 mm3/mm post-treatment to 5.6 +/- 3.1 mm3/mm at 8-month follow up; p = 0.09), vessel area (10.2 +/- 3.7 to 10.3 +/- 4.0 mm3/mm; p = 0.84), or lumen area (5.2 +/- 2.0 to 4.7 +/- 1.8 mm3/mm; p = 0.19). Subsegment analysis, however, revealed a wide range of dose distribution, with a significant positive correlation between Dv90 and plaque increase (p = 0.008), as well as vessel change (p < 0.001), representing dose-dependent positive vessel remodeling following beta radiation. Consequently, no significant relationship was observed between Dv90 and lumen change. CONCLUSIONS: Detailed IVUS-based dosimetric analysis demonstrated that beta radiation promoted positive remodeling, preventing lumen loss despite a mild increase in plaque mass on angiographically normal, noninjured distal segments.