Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study).

RATIONALE: Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure. OBJECTIVE: To compare the safety and efficacy of 2 doses of allogeneic bone marrow-derived human mesenchymal stem cells identically delivered in patients with ischemic cardiomyopathy. METHODS AND RESULTS: Thirty patients with ischemic cardiomyopathy received in a blinded manner either 20 million (n=15) or 100 million (n=15) allogeneic human mesenchymal stem cells via transendocardial injection (0.5 cc per injection × 10 injections per patient). Patients were followed for 12 months for safety and efficacy end points. There were no treatment-emergent serious adverse events at 30 days or treatment-related serious adverse events at 12 months. The Major Adverse Cardiac Event rate was 20.0% (95% confidence interval [CI], 6.9% to 50.0%) in 20 million and 13.3% (95% CI, 3.5% to 43.6%) in 100 million (P=0.58). Worsening heart failure rehospitalization was 20.0% (95% CI, 6.9% to 50.0%) in 20 million and 7.1% (95% CI, 1.0% to 40.9%) in 100 million (P=0.27). Whereas scar size reduced to a similar degree in both groups: 20 million by -6.4 g (interquartile range, -13.5 to -3.4 g; P=0.001) and 100 million by -6.1 g (interquartile range, -8.1 to -4.6 g; P=0.0002), the ejection fraction improved only with 100 million by 3.7 U (interquartile range, 1.1 to 6.1; P=0.04). New York Heart Association class improved at 12 months in 35.7% (95% CI, 12.7% to 64.9%) in 20 million and 42.9% (95% CI, 17.7% to 71.1%) in 100 million. Importantly, proBNP (pro-brain natriuretic peptide) increased at 12 months in 20 million by 0.32 log pg/mL (95% CI, 0.02 to 0.62; P=0.039), but not in 100 million (-0.07 log pg/mL; 95% CI, -0.36 to 0.23; P=0.65; between group P=0.07). CONCLUSIONS: Although both cell doses reduced scar size, only the 100 million dose increased ejection fraction. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action and enhance planning of pivotal Phase III trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02013674.

Alternative access for transcatheter aortic valve replacement in older adults: A collaborative study from France and United States.

BACKGROUND: We examined the outcomes of older adults undergoing nontrans-femoral (non-TF) transcatheter aortic valve replacement (TAVR) procedures including trans-apical (TA), trans-aortic (TAo), trans-subclavian (TSub), and trans-carotid (TCa) techniques. METHODS AND RESULTS: This is an observational study of all consecutive older patients who underwent non-TF TAVR for symptomatic severe AS with Edwards Sapien (ES), Medtronic CoreValve, ES3 or Lotus Valve at three centers in France and the United States from 04/2008 to 02/2017. Baseline characteristics and clinical outcomes were defined according to VARC-2 criteria. Of 857 patients who received TAVR, 172 (20%) had an alternative access procedure. Of these, 45 (26%) were TA, 67 (39%) TAo, 17 (10%) TSub, and 43 (25%) TCa procedures. The preference for non-TF access site was different between the two countries (US: TA 39%, TAo 52%, TSub 9%; TCa 0% vs. France: TA 9%, TAo 23%, TSub 11%, and TCa 57%, P-value < .001). Most patients who underwent TAo TAVR were older women (median age: TA 82, TAo 84, TSub 81, TCa 81, P-value = 0.043; female gender: TA 32 (27%), TAo 30 (55%), TSub 10 (41%), TCa 27 (37%), P-value = .021). The predicted Society of Thoracic Surgery risk of mortality was similar among groups (TA 7%, TAo 7%, TSub 6%, TCa 7%, P-value= .738). No differences were observed in the frequency of para-valvular leak, intra-procedural bleeding, vascular complications, conversion to open-heart surgery, or development of acute kidney injury. The highest in-hospital mortality was observed in the TAo group (TA 2%, TAo 15%, TSub 0%, TCa 2%, P-value = .014). However, hospital length of stay, one-month, and one-year mortality were similar among non-TF techniques. CONCLUSION: Although regional differences exist in the choice of alternative access techniques, centers with high technical expertise can provide a safe alternative to traditional TF TAVR. TAo TAVR was associated with higher in-hospital mortality than other non-TF approaches, and this may have reflected patient rather than procedural factors. All alternative access techniques had similar mortality rates and clinical outcomes at one-year follow-up. Trans-carotid access is safe and feasible compared to other non-TF access techniques.

Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial.

RATIONALE: Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis. OBJECTIVE: To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects. METHODS AND RESULTS: Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4 ± 1.7%, P=0.0002) and decreased scar mass (-47.5 ± 8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93 ± 0.07), whereas revascularized (0.5 ± 0.21) and nontreated segments (-0.07 ± 0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments). CONCLUSIONS: Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.

Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally?: An analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial.

RATIONALE: Transendocardial stem cell injection (TESI) with mesenchymal stem cells improves remodeling in chronic ischemic cardiomyopathy, but the effect of the injection site remains unknown. OBJECTIVE: To address whether TESI exerts its effects at the site of injection only or also in remote areas, we hypothesized that segmental myocardial scar and segmental ejection fraction improve to a greater extent in injected than in noninjected segments. METHODS AND RESULTS: Biplane ventriculographic and endocardial tracings were recorded. TESI was guided to 10 sites in infarct-border zones. Sites were mapped according to the 17-myocardial segment model. As a result, 510 segments were analyzed in 30 patients before and 13 months after TESI. Segmental early enhancement defect (a measure of scar size) was reduced by TESI in both injected (-43.7 ± 4.4%; n=95; P<0.01) and noninjected segments (-25.1 ± 7.8%; n=148; P<0.001; between-group comparison P<0.05). Conversely, segmental ejection fraction (a measure of contractile performance) improved in injected scar segments (19.9 ± 3.3-26.3 ± 3.5%; P=0.003) but not in noninjected scar segments (21.3 ± 2.6-23.5 ± 3.2%; P=0.20; between-group comparison P<0.05). Furthermore, segmental ejection fraction in injected scar segments improved to a greater degree in patients with baseline segmental ejection fraction <20% (12.1 ± 1.2-19.9 ± 2.7%; n=18; P=0.003), versus <20% (31.7 ± 3.4-35.5 ± 3.3%; n=12; P=0.33, between-group comparison P<0.0001). CONCLUSIONS: These findings illustrate a dichotomy in regional responses to TESI. Although scar size reduction was evident in all scar segments, scar size reduction and ventricular functional responses preferentially occurred at the sites of TESI versus non-TESI sites. Furthermore, improvement was greatest when segmental left ventricular dysfunction was severe.

Elective or Emergency Use of Mechanical Circulatory Support Devices During Transcatheter Aortic Valve Replacement.

OBJECTIVE: Evaluate the use of mechanical circulatory support (MCS) devices in high-risk patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: The use of MCS devices in elderly patients with multiple comorbidities undergoing TAVR is underexplored. METHODS: All patients undergoing TAVR at a single tertiary academic center who required MCS during index procedure between 2008 and 2015 were included in a prospective database. RESULTS: MCS was used in 9.4% (54/577) of all TAVRs (n = 52 Edwards Sapien and n = 2 CoreValves) of which 68.5% (n = 37) were used as part of a planned strategy, and 31.5% (n = 17) were used in emergency "bail-out" situations. IABP was the most commonly used device (87%) followed by Impella and ECMO (6% each). Among the MCS group, 22% required cardiopulmonary resuscitation during the procedure (n = 4 elective [11%] vs. n = 8 emergent [47%]) and 15% upgrade to a second device (Impella or CPB after IABP; n = 5 elective [14%] vs. n = 3 emergent [18%]). Median duration of support was 1-day. Device related complications were low (4%). In-hospital mortality in this extremely high-risk population was 24% (13/54) (11% [4/37] for elective cases and 53% [9/17] for emergency cases). Cardiogenic shock (50%) was the most common cause of in-hospital death. Cumulative all-cause 1-year mortality was 35% (19/54) (19% 97/370 for elective and 71% [12/17] for emergency cases). CONCLUSION: Emergent use of MCS during TAVR in extremely high-risk population is associated with high short and long-term mortality rates. Early identification of patients at risk for hemodynamic compromise may rationalize elective utilization of MCS during TAVR.

Multimodality image guidance with Dyna-CT for transcatheter treatment of paravalvular leak of a stentless valve.

The transcatheter treatment of paravalvular leaks (PVL) are technically challenging procedures; they pose increasing difficulty in cases where there is a stentless valve, without the usual fluoroscopic landmarks. Hence, there is limited experience in treating this defect percutaneously. We present a case of a patient with an aortic PVL of a stentless valve and how the integrated use of multi-imaging modalities (transesophageal echocardiography, computed tomography and rotational angiography) allowed the demarcation of landmarks onto live fluoroscopy and guided the transcatheter occlusion of the PVL.

Long-term outcomes associated with the transaortic approach to transcatheter Aortic valve replacement.

OBJECTIVE: We investigated the long-term safety, efficacy and clinical outcomes associated with transaortic (TAO) transcatheter aortic valve replacement (TAVR) in the United States. BACKGROUND: We previously reported the technical feasibility and short-term safety of TAO TAVR. Compared to transapical (TAP) access, the TAO approach was associated with shorter median intensive care unit (ICU) length of stay (LOS) and more favorable technical learning curve. However, outcomes data beyond 30 days were lacking and the longer-term clinical consequences of this strategy were unknown. METHODS: Mortality outcomes at 1 year (and longer) of 44 consecutive patients who underwent TAO TAVR in our institution were compared with that of 76 consecutive patients who underwent TAP TAVR at our site. Risk-adjusted analysis was performed in propensity-matched patients (25 from each group) to account for baseline differences. RESULTS: TAO TAVR was associated with a trend towards lower all-cause mortality at 1 year compared to TAP TAVR (18% vs. 34%, P=0.09 in the overall sample; 12% vs. 40%, P=0.05 in the matched cohort). The higher probability of survival with TAO TAVR persisted after a median follow-up period of 23 months (hazard ratio [HR]=1.96, P=0.06 in the overall sample; HR=3.4, P=0.01 in the matched cohort). Cardiovascular mortality at 1 year was lower with TAO TAVR (2% vs. 22%, P=0.01 in the overall sample; 4% vs. 28%, P=0.05 in the matched cohort). ICU LOS (shorter in the TAO group) and implantation of second prosthetic valve (higher incidence in the TAP group) were independent predictors of long-term mortality. CONCLUSION: The outcomes associated with TAO TAVR compare favorably with TAP TAVR. Our results appear to corroborate the long-term safety and efficacy of the TAO approach in TAVR patients with inadequate iliofemoral access.

Management of transcatheter aortic valve embolization into the left ventricle.

Embolization of transcatheter aortic valve replacement (TAVR) prostheses is a rare and serious procedural complication. While embolization into the aorta can sometimes be managed by transcatheter techniques, embolization into the left ventricle (LV) often requires immediate open heart surgery. We report three TAVR cases complicated by LV embolization. In each case, successful implantation of a second transcatheter prosthesis was accomplished, followed by surgical removal of the first embolized device.

Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction.

BACKGROUND: Because mesenchymal stem cells (MSCs) induce proliferation and differentiation of c-kit(+) cardiac stem cells (CSCs) in vivo and in vitro, we hypothesized that combining human (h) MSCs with c-kit(+) hCSCs produces greater infarct size reduction compared with either cell administered alone after myocardial infarction (MI). METHODS AND RESULTS: Yorkshire swine underwent balloon occlusion of the left anterior descending coronary artery followed by reperfusion and were immunosuppressed after MI with cyclosporine and methylprednisolone. Intramyocardial combination hCSCs/hMSCs (1 million cells/200 million cells, n=5), hCSCs alone (1 million cells, n=5), hMSCs alone (200 million cells, n=5), or placebo (phosphate-buffered saline; n=5) was injected into the infarct border zones at 14 days after MI. Phenotypic response to cell therapy was assessed by cardiac magnetic resonance imaging and micromanometer conductance catheterization hemodynamics. Although each cell therapy group had reduced MI size relative to placebo (P<0.05), the MI size reduction was 2-fold greater in combination versus either cell therapy alone (P<0.05). Accompanying enhanced MI size reduction were substantial improvement in left ventricular chamber compliance (end-diastolic pressure-volume relationship; P<0.01) and contractility (preload recruitable stroke work and dP/dtmax; P<0.05) in combination-treated swine. Ejection fraction was restored to baseline in cell-treated pigs, whereas placebo pigs had persistently depressed left ventricular function (P<0.05). Immunohistochemistry showed 7-fold enhanced engraftment of stem cells in the combination therapy group versus either cell type alone (P<0.001). CONCLUSIONS: Combining hMSCs and hCSCs as a cell therapeutic enhances scar size reduction and restores diastolic and systolic function toward normal after MI. Taken together, these findings illustrate important biological interactions between c-kit(+) CSCs and MSCs that enhance cell-based therapeutic responses.

Clinical outcomes with on-label and off-label use of the transcatheter heart valve in the United States.

OBJECTIVE: We explored the efficacy, safety, and clinical consequences of on-label and off-label transcatheter aortic valve replacement (TAVR) in the real-world setting. BACKGROUND: The transcatheter heart valve (THV) was initially approved only for transfemoral (TF) delivery (on-label use) during TAVR in inoperable patients with severe aortic stenosis (AS). Because of lack of alternative options in TAVR-eligible patients with inadequate TF access, other routes have been utilized for THV implantation (off-label use), outcomes of which were previously unknown. METHODS: Consecutive patients with severe inoperable AS who underwent clinical TAVR at our site were enrolled in a prospective database. Fifty subjects underwent TF-TAVR (on-label group), while non-TF routes were utilized in 60 subjects (off-label group). Procedural events, 30-day clinical outcomes, and 1-year all-cause mortality data were analyzed. RESULTS: Technical device success was similar between on-label and off-label groups (88% vs. 87%, respectively; P = 0.92), as was the incidence of procedural complications and 30-day clinical events. The on-label group had lower 1-year all-cause death rate (12%) compared to the off-label group (32%; P = 0.02). The 1-year all-cause mortality in the off-label group was comparable to published clinical trial and registry data on TAVR, and appeared lower than historical outcomes with conservative medical therapy. CONCLUSION: On-label use of the THV in the real-world setting was associated with favorable survival outcomes compared to off-label TAVR and historical data. Off-label use of the THV appeared to be safe and effective when used in select patients with inoperable AS who are not eligible for TAVR via TF approach.

Impact of CMS coverage decision on access to transcatheter aortic valve replacement.

OBJECTIVES: To assess the impact of the Centers for Medicare and Medicaid Services (CMS) national coverage determination (NCD) on access for patients with aortic stenosis (AS) with transcatheter aortic valve replacement (TAVR) in a tertiary care center. BACKGROUND: TAVR has given hope to patients with AS who are deemed inoperable. The effects of the NCD on access to patients with AS has not been evaluated. MATERIALS AND METHODS: A total of 94 inoperable AS patients were evaluated and treated from December 2011 through June of 2012 with TAVR. Patients who underwent transfemoral (TF) vs. non-TF access were compared. The CMS NCD was released on May 1, 2012 and on July 1, 2012, the nontransfemoral access program was put on hold due to lack of reimbursement. RESULTS: Patients in the TF (n = 33) and non-TF access (n = 61) groups were similar in age (85.2 ± 6.3 vs. 84.8 ± 6.6 P = 0.74) and STS mortality (9.38 ± 5.33 vs. 7.91 ± 3.69, P = 0.074). The iliofemoral arteries were larger diameter in the TF group (7.72 ± 1.49 vs. 6.21 ± 1.78, P < 0.001) and males (7.39 ± 1.81 vs. 6.1 ± 1.61 P < 0.001). More women underwent valve implantation via non-TF access (73 vs. 23%, P = 0.03). After the NCD, 21 patients who previously qualified for non-TF TAVR would not be reimbursed by CMS. Four died soon after. CONCLUSIONS: After the NCD, the proportion of inoperable patients with severe AS that can be treated with TAVR was greatly reduced due the lack of reimbursement for TAVR via non-TF access. This effect is particularly pronounced in women. © 2014 Wiley Periodicals, Inc.

Optimizing rotational atherectomy in high-risk percutaneous coronary interventions: insights from the PROTECT ΙΙ study.

OBJECTIVE: To study rotational atherectomy (RA) outcomes in patients undergoing high-risk PCI randomized to receive hemodynamic support using either IABP or Impella 2.5 in the PROTECT II trial. BACKGROUND: RA of heavily calcified lesions is often necessary for complex PCI but can be associated with slow-flow, hypotension, and higher risk of periprocedural MI. METHODS: We compared baseline, angiographic, procedural characteristics, and outcomes of patients treated with and without RA. We examined also RA technique and outcomes. RESULTS: RA was used in 52 of 448 patients (32 with Impella vs 20 with IABP, P = 0.08). RA patients were older (72 vs. 67 yo, P = 0.0009), more likely to have prior CABG (48 vs. 32%, P = 0.017), higher STS (8.1 vs. 5.7, P = 0.012) and higher SYNTAX scores (37 vs. 29, P < 0.0001). At 90 days, RA use was associated with higher incidence of MI but no mortality difference. RA was used more aggressively with Impella resulting in higher rate of periprocedural MI (P < 0.01), with no difference in mortality between groups (P = 0.78). Repeat revascularization occurred less frequently with Impella (P < 0.001). There were no differences in 90-day major adverse events between IABP and Impella in patients undergoing RA (P = 0.29). In patients not treated with RA, fewer MAEs were observed with Impella compared with IABP (P = 0.03). CONCLUSIONS: Patients who were treated with RA had more comorbidities, and more complex and extensive coronary artery disease. In patients with Impella, more aggressive RA use resulted in fewer revascularization events but higher incidence of periprocedural MI.

The use of vascular closure devices and impact on major bleeding and net adverse clinical events (NACEs) in balloon aortic valvuloplasty: a sub-analysis of the BRAVO study.

OBJECTIVE: To determine the impact of suture-mediated vascular closure devices (VCDs) on net adverse clinical events (NACEs) after balloon aortic valvuloplasty (BAV). BACKGROUND: Ischemic and bleeding complications are common following transfemoral BAV; however, previous studies have been single center and limited by varying definitions of major bleeding. METHODS: The Effect of Bivalirudin on Aortic Valve Intervention Outcomes (BRAVOs) study was a retrospective observational study conducted at two high-volume academic centers over a 6-year period designed to compare the effect of bivalirudin versus unfractionated heparin. This is a subanalysis of 428 consecutive patients who underwent BAV (with 10-13 French sheaths) to compare the effect of hemostasis with VCDs versus manual compression utilizing standardized definitions. NACE was defined as the composite of major bleeding and major adverse clinical events (MACEs). All events were adjudicated by an independent clinical events committee who were blinded to antithrombin use. RESULTS: Preclosure was performed in 269 (62.8%) of patients. While bivalirudin was used more frequently in those with pre-closure (60.6% vs. 37.7%, P < 0.001), a history of prior BAV (11.1% vs. 3.6%, P = 0.04) and peripheral vascular disease (30.7% vs. 19.7%, P = 0.01) was more common in those not undergoing preclosure (n = 159, 37%). Other clinical and demographic features were well balanced between groups. Vascular closure was associated with a significant reduction in NACE (24.5% vs. 10.0% P < 0.001). Results remained significant after adjusting for baseline differences and bivalirudin use (OR 0.38, 95% CI: 0.21-0.68; P = 0.001). CONCLUSIONS: Our study suggests that suture-mediated vascular closure is associated with a substantial reduction in NACE after transfemoral BAV. Large randomized clinical trials should be conducted to confirm our results.

Transfemoral aortic valve replacement in failing aortic root homografts.

Transcatheter aortic valve implantation (TAVI) for failing aortic root and valve homografts has been described primarily via a transapical approach. We report the successful treatment of two patients with failing homografts by transfemoral (TF) TAVI. In both cases, TF TAVI was accomplished without technical difficulty and with good clinical outcomes.

Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial.

IMPORTANCE: Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. OBJECTIVE: To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. DESIGN, SETTING, AND PATIENTS: A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. INTERVENTIONS: Injections in 10 LV sites with an infusion catheter. MAIN OUTCOMES AND MEASURES: Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. RESULTS: No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95% CI, -15.7% to 1.7%; within-group, P = .11) or placebo (-5.2%; 95% CI, -16.8% to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95% CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95% CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. CONCLUSIONS AND RELEVANCE: Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00768066.

Emergent use of retrograde left ventricular support in patients after transcatheter aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) is currently a therapeutic alternative to open aortic valve replacement for high-risk patients with severe symptomatic aortic valve stenosis. The procedure is associated with some life-threatening complications including circulatory collapse which may require temporary hemodynamic support. We describe our experience with the use of the Impella 2.5 system to provide emergent left ventricular support in cases of hemodynamic collapse after TAVR with the Edwards SAPIEN prosthesis.

Management of paravalvular regurgitation after Edwards SAPIEN transcatheter aortic valve replacement: management of paravalvular regurgitation after TAVR.

BACKGROUND: With the expansion in the use of transcatheter valve therapies for aortic stenosis, the incidence of hemodynamically significant paravalvular regurgitation (PVR) has become a clinical challenge. METHODS: The study population consisted of those patients with either acute significant PVR immediately post-Edwards SAPIEN (ES) aortic valve implantation, requiring additional maneuvers during the index transcatheter aortic valve replacement (TAVR) or symptomatic PVR requiring treatment by transcatheter closure at a later date. All the patients were assessed within 24 hrs, 30 days, 3 months, 6 months and 12 months after the procedure. RESULTS: A total of 100 consecutive patients underwent ES TAVR (62% with 23 mm and 38% with 26 mm valve), of them 27% (27/100) were identified to have hemodynamically significant PVR requiring additional percutaneous interventions during or after the index procedure. Patient's mean age was 85 ± 12 years and 74% (20/27) were male. The mean Society of Thoracic Surgeon Score was 11.3% (range 4.6-17.6%), 59% had a 23 mm and 41% had a 26 mm ES valve. There was no difference in the occurrence of PVR between a) two valve sizes-23 mm (16/62) vs. 26 mm (11/38) (P = 0.817) and b) the two approaches-transfemoral (15/48) vs. transapical (TA) (12/52) (P = 0.37). A total of 32 procedures were performed on the 27 patients: one patient required four and two required two procedures each. There were 19 repeat ballooning, seven valve in valve and six transcatheter device closure procedures. The approach was retrograde in 66%, antegrade transeptal in 6% and antegrade TA in 28%. The procedural success rate was 90.6%, the total 30-day, 3 months and 6 months mortality rate was 7.4, 18.5, and 22% respectively. At the time of final analysis a total of 56% (15/27) had completed a 12 month follow-up. CONCLUSION: The management of PVR in the TAVR era is a technical challenge. We present our experience and propose a management approach.

Transseptal antegrade transcatheter aortic valve replacement for patients with no other access approach - a contemporary experience.

OBJECTIVE: To assess the feasibility and outcomes in patients undergoing transvenous transseptal (TS) transcatheter aortic valve replacement (TAVR). BACKGROUND: TS approach for TAVR was abandoned in favor of retrograde transfemoral, transaortic, or transapical approaches. TS TAVR may still be warranted in patients for whom no other approach is feasible. METHODS: Observational consecutive case series at a single center, to evaluate technical outcomes in inoperable patients with aortic stenosis who had contraindications for other approaches and who underwent TAVR via a transvenous TS antegrade approach using the Edwards-Sapien (ES) valve. RESULTS: Over a 4-month period, 9 patients underwent TS TAVR with 26 mm (n = 4) and 23 mm (n = 5) ES valves. Mean age was 84.5 ± 6.6 years and Society of Thoracic Surgeons predicted risk of mortality was 7.8 ± 2.8%. Specific contraindications for other access included iliofemoral arterial diameter <7 mm in 9 (100%), porcelain aorta in 6 (66%) patients, multiple (≥2) sternotomies in 2 (22%) patients, severe pulmonary disease in 3 (33%), extreme frailty in 1 (11%), spinal stenosis with impaired ability to rehabilitate postsurgery in 1 (11%) and apical left ventricular thrombus in 1 (11%) patient. Antegrade deployment of the ES prosthetic valve was technically feasible in 8 patients. Major bleeding occurred in 4 patients, two patients suffered acute kidney injury without need for dialysis and one patient required a permanent pacemaker. The median (25th, 75th percentiles) fluoroscopy time was 49 (34, 81) minutes and contrast volume was 150 (120, 225) ml. No patient had hemodynamically significant post-TAVR aortic insufficiency nor damage to the mitral valve. At 6 months follow-up, there were no cerebrovascular events or rehospitalizations and mean NYHA Class improved from 3.4 to 1.7. CONCLUSIONS: The antegrade TS approach to TAVR is a technically feasible option for "no-access" patients. Prospective assessment of the safety and efficacy of this approach in the current era warrants further study.

Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling.

RATIONALE: Transcatheter, intramyocardial injections of bone marrow-derived cell therapy produces reverse remodeling in large animal models of ischemic cardiomyopathy. OBJECTIVE: We used cardiac MRI (CMR) in patients with left ventricular (LV) dysfunction related to remote myocardial infarction (MI) to test the hypothesis that bone marrow progenitor cell injection causes functional recovery of scarred myocardium and reverse remodeling. METHODS AND RESULTS: Eight patients (aged 57.2±13.3 years) received transendocardial, intramyocardial injection of autologous bone marrow progenitor cells (mononuclear or mesenchymal stem cells) in LV scar and border zone. All patients tolerated the procedure with no serious adverse events. CMR at 1 year demonstrated a decrease in end diastolic volume (208.7±20.4 versus 167.4±7.32 mL; P=0.03), a trend toward decreased end systolic volume (142.4±16.5 versus 107.6±7.4 mL; P=0.06), decreased infarct size (P<0.05), and improved regional LV function by peak Eulerian circumferential strain in the treated infarct zone (-8.1±1.0 versus -11.4±1.3; P=0.04). Improvements in regional function were evident at 3 months, whereas the changes in chamber dimensions were not significant until 6 months. Improved regional function in the infarct zone strongly correlated with reduction of end diastolic volume (r(2)=0.69, P=0.04) and end systolic volume (r(2)=0.83, P=0.01). CONCLUSIONS: These data suggest that transcatheter, intramyocardial injections of autologous bone marrow progenitor cells improve regional contractility of a chronic myocardial scar, and these changes predict subsequent reverse remodeling. The findings support the potential clinical benefits of this new treatment strategy and ongoing randomized clinical trials.

Percutaneous retrograde left ventricular assist support for interventions in patients with aortic stenosis and left ventricular dysfunction.

OBJECTIVES: To evaluate feasibility and technical outcomes in patients with aortic stenosis (AS) who have undergone high-risk procedures with continuous flow left ventricular (LV) assist, with the Impella 2.5 system (Abiomed, Danvers, MA). BACKGROUND: In preparation for transcatheter aortic valve implantation, an increasing number of high-risk patients with severe AS and left ventricular dysfunction are currently considered for percutaneous coronary interventions (PCI) and balloon aortic valvuloplasty (BAV). Hemodynamic support may be required in some patients. METHODS: We reviewed procedural and clinical findings and 30-day outcomes in patients with symptomatic AS who underwent high-risk percutaneous procedures supported by the Impella 2.5 system. All patients carried a high-risk of operative mortality. Impella was used during PCI, BAV, and for hemodynamic support during emergencies. RESULTS: Over a 14-month period, 21 patients with AS underwent insertion of Impella prior to high-risk PCI (n = 3), BAV with subsequent PCI (n = 8), BAV alone (n = 7), or during cardiac arrest immediately following BAV (n = 3). The mean Society of Thoracic Surgeons (STS) predicted mortality risk was 14% (range 7.3-24.7%). Impella was inserted successfully in all patients attempted. Retrograde advancement of two catheters across the aortic valve (for concomitant BAV in 15 patients) was technically feasible. Retrograde continuous flow LV assist produced a reduction in LV end-diastolic pressure and an increase in arterial pressure. Periprocedural complications occurred in 19% (n = 4) patients, with no periprocedural deaths. Mortality at 30 days was 14.2%. CONCLUSION: Our data suggests that continuous flow LV assist with Impella 2.5 can be used in high-risk patients with severe AS who require periprocedural hemodynamic support.