Publications by authors named "Daniel Sürder"

33 Publications

Impact of mitral regurgitation aetiology on MitraClip outcomes: the MitraSwiss registry.

EuroIntervention 2020 06 12;16(2):e112-e120. Epub 2020 Jun 12.

Division of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerland.

Aims: The Swiss national registry on percutaneous mitral valve interventions (MitraSwiss) was established in 2011 to monitor safety/efficacy of percutaneous mitral valve repair (PMVR) with the MitraClip device. The aim of this analysis was to report the outcome after PMVR in a real-world, all-comers population and its predictors after inclusion of more than 1,200 patients, stratifying the results according to mitral regurgitation (MR) aetiology. Here we report the in-hospital, short and midterm outcomes of all patients prospectively enrolled.

Methods And Results: Since 2011, MitraSwiss has enrolled 1,212 patients with moderate and severe MR of functional (FMR) or degenerative (DMR) aetiology treated with PMVR in 10 centres. Pre-specified endpoints included clinical, echocardiographic and functional parameters with follow-up planned up to five years. Outcomes are compared according to MR aetiology. Acute procedural success was achieved in 91.5% of cases, with no differences between FMR and DMR and sustained good midterm results. NYHA class and pulmonary pressure improved significantly in both cohorts. Cumulative probability of death at five years was 54% (95% CI: 45-63) in FMR and 45% (95% CI: 37-54) in DMR (HR 1.15, p=0.009). Age, anaemia, impaired renal function and reduced left ventricular ejection fraction resulted in being independent predictors of death at five years.

Conclusions: In a large contemporary cohort of non-surgical patients with severe MR, the safety and effectiveness of PMVR have been confirmed. At midterm follow-up, mortality and MACE were lower in DMR patients, though MR aetiology was not directly and independently associated with outcome.
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http://dx.doi.org/10.4244/EIJ-D-19-00718DOI Listing
June 2020

Intractable coronary fibromuscular dysplasia leading to end-stage heart failure and fatal heart transplantation.

ESC Heart Fail 2020 04 29;7(2):714-720. Epub 2020 Jan 29.

Cardiovascular Research, Hospital of San Giovanni, Bellinzona, 6500, Switzerland.

Coronary fibromuscular dysplasia is uncommon, and even rarer its unstable and recurrent course. We present the unique case of a 52-year-old woman who underwent in total 12 coronary angiographies and three percutaneous coronary intervention within 24 months because of repetitive acute coronary syndromes due to refractory spasm, dissection, restenosis all leading to end-stage heart failure, and heart transplantation. The patient died 12 days after the heart transplantation complicated by intraoperative acute thrombotic occlusion of left anterior descending artery of the graft despite normal pretransplant coronary angiography. Autopsy of the recipient heart confirmed coronary fibromuscular dysplasia with massive intimal hyperplasia and restenosis.
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http://dx.doi.org/10.1002/ehf2.12626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160508PMC
April 2020

Closure of Large Percutaneous Femoral Venous Access Using a Modified "Figure-of-Eight" Suture.

Innovations (Phila) 2018 Mar/Apr;13(2):147-151

Recent advances in different percutaneous treatments made insertion of large-caliber sheaths in the femoral veins more common. Venous punctures are historically managed by initial manual compression with subsequent application of a compression bandage and bed rest. We describe a modified "figure-of-eight" suture technique for minimizing the risk of accidental puncture of the vein while grabbing the subcutaneous tissue. We examined the safety and feasibility of this technique combined with early mobilization in a real-world setting. We performed a retrospective analysis on 56 consecutive patients undergoing percutaneous mitral valve repair using large femoral venous access. The patient population was heterogeneous and bleeding risk characteristics were common. Bleeding Academic Research Consortium Consensus (BARC)-classifiable bleeding complications occurred in eight patients (14%), BARC of two events or more in five patients (8.9%), and BARC of three or more event in only one patient (1.8%), which is a comparable success rate to large venous access closure with suture-mediated closure devices. No BARC Type 3b or BARC Type 5 bleeding occurred. During routine clinical follow-up, no groin-related problems were reported in all patients. Closure of large femoral venous access using a modified temporary subcutaneous figure-of-eight suture in combination of a light compression bandage and bed rest for 2 to 4 hours provides a safe and low-cost alternative to closure devices for early mobilization.
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http://dx.doi.org/10.1097/IMI.0000000000000488DOI Listing
October 2018

Evaluation of a protocol for same-day discharge after radial lounge monitoring in a southern Swiss referral percutaneous coronary intervention centre.

J Cardiovasc Med (Hagerstown) 2017 Aug;18(8):590-595

Fondazione Cardiocentro Ticino, Lugano, Switzerland.

Aims: The aim of the study was to retrospectively evaluate safety and patient satisfaction of same-day discharge after elective radial coronary angiography/percutaneous coronary intervention (PCI) after the implementation of a radial lounge facility.

Methods: All patients admitted to our radial lounge with a planned same-day discharge after an uncomplicated coronary angiography/PCI, having a co-living caregiver, were day enrolled in the study. Rates of same-day discharge, unplanned overnight stay, and in-hospital and first complications [death, myocardial infarction (MI), unplanned coronary angiography, access site hematoma, bleedings requiring hospitalization] were analysed; satisfaction was also evaluated through a questionnaire.

Results: From February 2015 to January 2016, 312 patients with a mean age of 66.6 ± 10.8 years were admitted to the radial lounge (coronary angiography, n = 232; PCIs, n = 80). Of them, 245 (78.5%) were discharged the same day. Mean radial lounge monitoring was 6:35 h (interquartile range 5:30-7:30 h). No episodes of death/MI/unplanned coronary angiography were observed both in same-day discharged and postponed patients. Reasons to postpone discharge were: PCI deemed to need prolonged monitoring in 31, patient's preference in 14, femoral shift in 13, surgery in four, chest pain in four, and bleeding in one. At day 1, 11 access site hematoma and one hospitalization for access site bleeding were reported. Patients reported complete satisfaction in 97% of cases. Unplanned overnight stay was common among PCIs patients (RR 6.2, 95% CI 3.9-9.9, P < 0.001).

Conclusion: A low rate of minor complications was observed in elective radial coronary angiography and PCIs showing the feasibility and safety of the development of an institutional protocol for same-day discharge after the implementation of a radial lounge facility.
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http://dx.doi.org/10.2459/JCM.0000000000000519DOI Listing
August 2017

The relation between local repolarization and T-wave morphology in heart failure patients.

Int J Cardiol 2017 Aug 22;241:270-276. Epub 2017 Feb 22.

Maastricht University, Maastricht, The Netherlands. Electronic address:

Background: Both duration and morphology of the T-wave are regarded important parameters describing repolarization of the ventricles. Conventionally, T-wave concordance is explained by an inverse relation between the time of depolarization (TD) and repolarization (TR). Little is known about T-wave morphology and TD-TR relations in patients with heart failure.

Methods: Electro-anatomic maps were obtained in the left (LV) and right ventricle (RV) and in the coronary sinus (CS) in patients with heart failure with narrow (nQRS, n=8) and wide QRS complex with (LBBB, n=15) and without left bundle branch block (non-LBBB, n=7). TD and TR were determined from the thus acquired electrograms.

Results: In nQRS and non-LBBB patients, TD-TR relations had a slope between 0 and +1, indicating that repolarization followed the sequence of depolarization. In LBBB patients, repolarization occurred significantly earlier in the RV than in the LV, fitting with the idea that the discordant T-waves in LBBB are secondary to the abnormal depolarization sequence. However, the slopes of the TD-TR relations in the LV and CS were not significantly different from zero, indicating no major spatial gradient in LV repolarization, despite a considerable gradient in depolarization. Remarkable was also the large (~100ms) transseptal gradient in repolarization. Values of the slopes of the TD-TR relation overlapped between the three patient groups, despite a difference in T-wave morphology between LBBB (all discordant) and nQRS patients (all flat/biphasic).

Conclusions: Discordant T-waves in LBBB patients are explained by interventricular dispersion in repolarization. T-wave morphology is determined by more factors than the TD-TR relation alone.
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http://dx.doi.org/10.1016/j.ijcard.2017.02.056DOI Listing
August 2017

SYNTAX score II in patients with coronary artery disease undergoing percutaneous mitral repair with the MitraClip.

Int J Cardiol 2017 Jun 24;236:375-380. Epub 2017 Feb 24.

University Heart Center, University Hospital Zurich, Switzerland. Electronic address:

Background: Percutaneous mitral valve repair (PMVR) using the MitraClip™ system has become a valuable alternative in patients with severe mitral regurgitation (MR) and high surgical risk. We sought to evaluate the prognostic value of the SYNTAX II score (SSII) in patients with concomitant coronary artery disease (CAD) undergoing a Mitraclip procedure.

Methods: In seventy-five consecutive patients who underwent PMVR at the University Heart Center Zürich and the Cardiocentro Ticino, the SSSII was calculated at baseline. Clinical endpoints comprised of all-cause mortality, mitral valve surgery due to failure of PMVR or reoperation, hospitalization for congestive heart failure, heart transplantation and the composite of all four endpoints.

Results: Patients were followed for a median of 271days. And were divided in tertiles of SSII: SSII low ≤46.5 (n=25), SSII mid 46.6-54.4 (n=25) and SSII high ≥54.5 (n=25). Patients in the highest SSII tertile had a lower left ventricular ejection fraction (33% vs. 40% vs. 53%) with a higher log-BNP (3.6 vs. 3.45 vs. 3.16) when compared to SSII mid and SSII low, respectively. However, the anatomical syntax score (SS) did not differ significantly within the tertiles (9.1±6.3 (SSII Low) vs 9.5±7.6 (SSII Mid) vs 10.2±6.7(SSII High), p=0.837). The primary endpoint occurred in 33% of patients (n=25). By multivariate analysis patients in the high SSII tertile (OR=6.12, 95% confidence interval, [CI] 1.45-25.86, p=0.014) and patients with a history of MI (OR=3.57, 95% confidence interval, [CI] 1.17-10.88, p=0.025) were at significantly higher risk of experiencing adverse events. Furthermore, in a combined outcome ROC curve analysis, the SSII showed good discrimination with an AUC of 0.73, p=0.001. A cutoff SSII >49 has been identified to have a sensitivity of 83% and specificity of 53% with approximately 45% of the patients experiencing an event during follow-up.

Conclusion: Using SSII in CAD patients undergoing PMVR is feasible and of prognostic significance hence widening its clinical utility in valvular heart disease.
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http://dx.doi.org/10.1016/j.ijcard.2017.02.049DOI Listing
June 2017

Effect of Bone Marrow-Derived Mononuclear Cell Treatment, Early or Late After Acute Myocardial Infarction: Twelve Months CMR and Long-Term Clinical Results.

Circ Res 2016 Jul 6;119(3):481-90. Epub 2016 Jun 6.

From the Department of Cardiology, Cardiovascular Center (D.S., R.M., M.Z., I.B., P.E., T.F.L., R.C.) and Clinic for Cardiac Surgery, Cardiovascular Center (M.Y.E.), University Hospital Zurich, Zurich, Switzerland; Department of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerland (D.S., T.M., V.L.C., S.S., L.T., M.R.); Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland (R.M., S.K.); IRCCS Fondazione Policlinico San Matteo, Servizio di Biometria e Statistica, Pavia, Italy (C.K.); Department of Cardiology, Cantonal Hospital, Lucerne, Switzerland (M.Z., P.E.); and Department of Cardiology, Bern University Hospital, Bern, Switzerland (S.W., A.M.).

Rationale: Intracoronary delivery of autologous bone marrow-derived mononuclear cells (BM-MNC) may improve remodeling of the left ventricle (LV) after acute myocardial infarction (AMI).

Objective: To demonstrate long-term efficacy of BM-MNC treatment after AMI.

Methods And Results: In a multicenter study, we randomized 200 patients with large AMI in a 1:1:1 pattern into an open-labeled control and 2 BM-MNC treatment groups. In the BM-MNC groups, cells were either administered 5 to 7 days (early) or 3 to 4 weeks (late) after AMI. Cardiac magnetic resonance imaging was performed at baseline and after 12 months. The current analysis investigates the change from baseline to 12 months in global LV ejection fraction, LV volumes, scar size, and N-terminal pro-brain natriuretic peptide values comparing the 2 treatment groups with control in a linear regression model. Besides the complete case analysis, multiple imputation analysis was performed to address for missing data. Furthermore, the long-term clinical event rate was computed. The absolute change in LV ejection fraction from baseline to 12 months was -1.9±9.8% for control (mean±SD), -0.9±10.5% for the early treatment group, and -0.7±10.1% for the late treatment group. The difference between the groups was not significant, both for complete case analysis and multiple imputation analysis. A combined clinical end point occurred equally in all the groups. Overall, 1-year mortality was low (2.25%).

Conclusions: Among patients with AMI and LV dysfunction, treatment with BM-MNC either 5 to 7 days or 3 to 4 weeks after AMI did not improve LV function at 12 months, compared with control. The results are limited by an important drop out rate.

Clinical Trial Registration Information: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00355186.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.308639DOI Listing
July 2016

Thrombus formation in the left ventricle after large myocardial infarction – assessment with cardiac magnetic resonance imaging.

Swiss Med Wkly 2015 22;145:w14122. Epub 2015 Jun 22.

Department of Cardiology, Cardiovascular Centre, University Hospital Zurich, Switzerland, and Institute for Biomedical Engineering, University and ETH Zurich, Switzerland.

Introduction: Left ventricular thrombus (LVT) formation may worsen the post-infarct outcome as a result of thromboembolic events. It also complicates the use of modern antiplatelet regimens, which are not compatible with long-term oral anticoagulation. The knowledge of the incidence of LVT may therefore be of importance to guide antiplatelet and antithrombotic therapy after acute myocardial infarction (AMI).

Methods: In 177 patients with large, mainly anterior AMI, standard cardiac magnetic resonance imaging (CMR) including cine and late gadolinium enhancement (LGE) imaging was performed shortly after AMI as per protocol. CMR images were analysed at an independent core laboratory blinded to the clinical data. Transthoracic echocardiography (TTE) was not mandatory for the trial, but was performed in 64% of the cases following standard of care. In a logistic model, 3 out of 61 parameters were used in a multivariable model to predict LVT.

Results: LVT was detected by use of CMR in 6.2% (95% confidence interval [CI] 3.1%-10.8%). LGE sequences were best to detect LVT, which may be missed in cine sequences. We identified body mass index (odds ratio 1.18; p = 0.01), baseline platelet count (odds ratio 1.01, p = 0.01) and infarct size as assessed by use of CMR (odds ratio 1.03, p = 0.02) as best predictors for LVT. The agreement between TTE and CMR for the detection of LVT is substantial (kappa = 0.70).

Discussion: In the current analysis, the incidence of LVT shortly after AMI is relatively low, even in a patient population at high risk. An optimal modality for LVT detection is LGE-CMR but TTE has an acceptable accuracy when LGE-CMR is not available.
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http://dx.doi.org/10.4414/smw.2015.14122DOI Listing
March 2016

Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data.

Circ Res 2015 Apr 19;116(8):1346-60. Epub 2015 Feb 19.

Rationale: The meta-Analysis of Cell-based CaRdiac study is the first prospectively declared collaborative multinational database, including individual data of patients with ischemic heart disease treated with cell therapy.

Objective: We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI), including individual patient data from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252).

Methods And Results: The primary end point was freedom from combined major adverse cardiac and cerebrovascular events (including all-cause death, AMI recurrance, stroke, and target vessel revascularization). The secondary end point was freedom from hard clinical end points (death, AMI recurrence, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions. Secondary efficacy end points included changes in end-diastolic volume, end-systolic volume, and ejection fraction, analyzed with random-effects meta-analyses and ANCOVA. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on major adverse cardiac and cerebrovascular events (14.0% versus 16.3%; hazard ratio, 0.86; 95% confidence interval, 0.63-1.18) or death (1.4% versus 2.1%) or death/AMI recurrence/stroke (2.9% versus 4.7%) was identified in comparison with controls. No changes in ejection fraction (mean difference: 0.96%; 95% confidence interval, -0.2 to 2.1), end-diastolic volume, or systolic volume were observed compared with controls. These results were not influenced by anterior AMI location, reduced baseline ejection fraction, or the use of MRI for assessing left ventricular parameters.

Conclusions: This meta-analysis of individual patient data from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01098591.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.304346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509791PMC
April 2015

Comparison of clinical and angiographic prognostic risk scores in elderly patients presenting with acute coronary syndrome and referred for percutaneous coronary intervention.

Swiss Med Wkly 2015 6;145:w14049. Epub 2015 Feb 6.

Fondazione Cardiocentro Ticino, Lugano, Switzerland.

Background: Multiple risk prediction models have been validated in all-age patients presenting with acute coronary syndrome (ACS) and treated with percutaneous coronary intervention (PCI); however, they have not been validated specifically in the elderly.

Methods: We calculated the GRACE (Global Registry of Acute Coronary Events) score, the logistic EuroSCORE, the AMIS (Acute Myocardial Infarction Swiss registry) score, and the SYNTAX (Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery) score in a consecutive series of 114 patients ≥75 years presenting with ACS and treated with PCI within 24 hours of hospital admission. Patients were stratified according to score tertiles and analysed retrospectively by comparing the lower/mid tertiles as an aggregate group with the higher tertile group. The primary endpoint was 30-day mortality. Secondary endpoints were the composite of death and major adverse cardiovascular events (MACE) at 30 days, and 1-year MACE-free survival. Model discrimination ability was assessed using the area under receiver operating characteristic curve (AUC).

Results: Thirty-day mortality was higher in the upper tertile compared with the aggregate lower/mid tertiles according to the logistic EuroSCORE (42% vs 5%; odds ratio [OR] = 14, 95% confidence interval [CI] = 4-48; p <0.001; AUC = 0.79), the GRACE score (40% vs 4%; OR = 17, 95% CI = 4-64; p <0.001; AUC = 0.80), the AMIS score (40% vs 4%; OR = 16, 95% CI = 4-63; p <0.001; AUC = 0.80), and the SYNTAX score (37% vs 5%; OR = 11, 95% CI = 3-37; p <0.001; AUC = 0.77).

Conclusions: In elderly patients presenting with ACS and referred to PCI within 24 hours of admission, the GRACE score, the EuroSCORE, the AMIS score, and the SYNTAX score predicted 30 day mortality. The predictive value of clinical scores was improved by using them in combination.
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http://dx.doi.org/10.4414/smw.2015.14049DOI Listing
September 2015

Two-year outcomes after percutaneous mitral valve repair with the MitraClip system: durability of the procedure and predictors of outcome.

Open Heart 2014;1(1):e000056. Epub 2014 Apr 8.

Cantonal Hospital Lucerne , Lucerne , Switzerland ; University Hospital Zurich , Zurich , Switzerland.

Objective: Analyse 2-year outcomes after MitraClip therapy and identify predictors of outcome.

Methods: Consecutive patients (n=74) undergoing MitraClip therapy were included in the MitraSWISS registry and followed prospectively.

Results: A reduction of mitral regurgitation (MR) to ≤ mild was achieved in 32 (43%) patients and to moderate in 31 (42%) patients; 16/63 (25%) patients with initially successful treatment developed recurrent moderate to severe or severe MR during the first year and only 1 patient did so during the second year. At 2 years, moderate or less MR was more frequently present in patients with a transmitral mean gradient <3 mm Hg at baseline (73% vs 23%, p < 0.01) and in patients with a left atrial volume index (LAVI) <50 mL/m(2) at baseline (86% vs 52%, p=0.03). More than mild MR post MitraClip, N-terminal probrain natriuretic peptide ≥5000 ng/L at baseline, chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD) were associated with reduced survival.

Conclusions: A mean transmitral gradient <3 mm Hg at baseline, an LAVI <50 mL/m(2), the absence of COPD and CKD, and reduction of MR to less than moderate were associated with favourable outcome. Given a suitable anatomy, such patients may be excellent candidates for MitraClip therapy. Between 1 and 2 years follow-up, clinical and echocardiographic outcomes were stable, suggesting favourable, long-term durability of the device.
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http://dx.doi.org/10.1136/openhrt-2014-000056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195933PMC
October 2014

Bone marrow-derived cells for cardiovascular cell therapy: an optimized GMP method based on low-density gradient improves cell purity and function.

J Transl Med 2014 Sep 27;12:276. Epub 2014 Sep 27.

Background: Cardiovascular cell therapy represents a promising field, with several approaches currently being tested. The advanced therapy medicinal product (ATMP) for the ongoing METHOD clinical study ("Bone marrow derived cell therapy in the stable phase of chronic ischemic heart disease") consists of fresh mononuclear cells (MNC) isolated from autologous bone marrow (BM) through density gradient centrifugation on standard Ficoll-Paque. Cells are tested for safety (sterility, endotoxin), identity/potency (cell count, CD45/CD34/CD133, viability) and purity (contaminant granulocytes and platelets).

Methods: BM-MNC were isolated by density gradient centrifugation on Ficoll-Paque. The following process parameters were optimized throughout the study: gradient medium density; gradient centrifugation speed and duration; washing conditions.

Results: A new manufacturing method was set up, based on gradient centrifugation on low density Ficoll-Paque, followed by 2 washing steps, of which the second one at low speed. It led to significantly higher removal of contaminant granulocytes and platelets, improving product purity; the frequencies of CD34+ cells, CD133+ cells and functional hematopoietic and mesenchymal precursors were significantly increased.

Conclusions: The methodological optimization described here resulted in a significant improvement of ATMP quality, a crucial issue to clinical applications in cardiovascular cell therapy.
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http://dx.doi.org/10.1186/s12967-014-0276-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4189603PMC
September 2014

Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis.

Eur Heart J 2014 Apr 11;35(15):989-98. Epub 2013 Sep 11.

Department of Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.

Aims: The objective of the present analysis was to systematically examine the effect of intracoronary bone marrow cell (BMC) therapy on left ventricular (LV) function after ST-segment elevation myocardial infarction in various subgroups of patients by performing a collaborative meta-analysis of randomized controlled trials.

Methods And Results: We identified all randomized controlled trials comparing intracoronary BMC infusion as treatment for ST-segment elevation myocardial infarction. We contacted the principal investigator for each participating trial to provide summary data with regard to different pre-specified subgroups [age, diabetes mellitus, time from symptoms to percutaneous coronary intervention, infarct-related artery, LV end-diastolic volume index (EDVI), LV ejection fraction (EF), infarct size, presence of microvascular obstruction, timing of cell infusion, and injected cell number] and three different endpoints [change in LVEF, LVEDVI, and LV end-systolic volume index (ESVI)]. Data from 16 studies were combined including 1641 patients (984 cell therapy, 657 controls). The absolute improvement in LVEF was greater among BMC-treated patients compared with controls: [2.55% increase, 95% confidence interval (CI) 1.83-3.26, P < 0.001]. Cell therapy significantly reduced LVEDVI and LVESVI (-3.17 mL/m², 95% CI: -4.86 to -1.47, P < 0.001; -2.60 mL/m², 95% CI -3.84 to -1.35, P < 0.001, respectively). Treatment benefit in terms of LVEF improvement was more pronounced in younger patients (age <55, 3.38%, 95% CI: 2.36-4.39) compared with older patients (age ≥ 55 years, 1.77%, 95% CI: 0.80-2.74, P = 0.03). This heterogeneity in treatment effect was also observed with respect to the reduction in LVEDVI and LVESVI. Moreover, patients with baseline LVEF <40% derived more benefit from intracoronary BMC therapy. LVEF improvement was 5.30%, 95% CI: 4.27-6.33 in patients with LVEF <40% compared with 1.45%, 95% CI: 0.60 to 2.31 in LVEF ≥ 40%, P < 0.001. No clear interaction was observed between other subgroups and outcomes.

Conclusion: Intracoronary BMC infusion is associated with improvement of LV function and remodelling in patients after ST-segment elevation myocardial infarction. Younger patients and patients with a more severely depressed LVEF at baseline derived most benefit from this adjunctive therapy.
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http://dx.doi.org/10.1093/eurheartj/eht372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271100PMC
April 2014

Combined delivery of bone marrow-derived mononuclear cells in chronic ischemic heart disease: rationale and study design.

Clin Cardiol 2013 Aug 29;36(8):435-41. Epub 2013 May 29.

Division of Cardiology, Ticino Cardiac Center Foundation, Lugano, Switzerland; Cell Therapy Unit, Ticino Cardiac Center, Lugano, Switzerland.

Background: Treatment with bone marrow-derived mononuclear cells (BM-MNC) may improve left ventricular (LV) function in patients with chronic ischemic heart disease (IHD). Delivery method of the cell product may be crucial for efficacy.

Hypothesis: We aimed to demonstrate that the combination of intramyocardial and intracoronary injection of BM-MNC is safe and improves LV function in patients with chronic IHD.

Methods: After a safety/feasibility phase of 10 patients, 54 patients will be randomly assigned in a 1:1:1 pattern to 1 control and 2 BM-MNC treatment groups. The control group will be treated with state-of-the-art medical management. The treatment groups will receive either exclusively intramyocardial injection or a combination of intramyocardial and intracoronary injection of autologous BM-MNC. Left ventricular function as well as scar size, transmural extension, and regional wall-motion score will be assessed by cardiac magnetic resonance imaging studies at baseline and after 6 months. The primary endpoint is the change in global LV ejection fraction by cardiac magnetic resonance from 6 months to baseline.

Results: The results, it is hoped, will have important clinical impact and provide essential information to improve the design of future regenerative-medicine protocols in cardiology.

Conclusions: As cell delivery may play an important role in chronic IHD, we aim to demonstrate feasibility and efficacy of a combined cell-delivery approach in patients with decreased LV function.
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http://dx.doi.org/10.1002/clc.22148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649397PMC
August 2013

Intracoronary injection of bone marrow-derived mononuclear cells early or late after acute myocardial infarction: effects on global left ventricular function.

Circulation 2013 May 17;127(19):1968-79. Epub 2013 Apr 17.

Department of Cardiology, Cardiovascular Center, University Hospital Zurich, 8091 Zürich, Switzerland.

Background: Intracoronary administration of autologous bone marrow-derived mononuclear cells (BM-MNC) may improve remodeling of the left ventricle (LV) after acute myocardial infarction. The optimal time point of administration of BM-MNC is still uncertain and has rarely been addressed prospectively in randomized clinical trials.

Methods And Results: In a multicenter study, we randomized 200 patients with large, successfully reperfused ST-segment elevation myocardial infarction in a 1:1:1 pattern into an open-labeled control and 2 BM-MNC treatment groups. In the BM-MNC groups, cells were administered either early (i.e., 5 to 7 days) or late (i.e., 3 to 4 weeks) after acute myocardial infarction. Cardiac magnetic resonance imaging was performed at baseline and after 4 months. The primary end point was the change from baseline to 4 months in global LV ejection fraction between the 2 treatment groups and the control group. The absolute change in LV ejection fraction from baseline to 4 months was -0.4±8.8% (mean±SD; P=0.74 versus baseline) in the control group, 1.8±8.4% (P=0.12 versus baseline) in the early group, and 0.8±7.6% (P=0.45 versus baseline) in the late group. The treatment effect of BM-MNC as estimated by ANCOVA was 1.25 (95% confidence interval, -1.83 to 4.32; P=0.42) for the early therapy group and 0.55 (95% confidence interval, -2.61 to 3.71; P=0.73) for the late therapy group.

Conclusions: Among patients with ST-segment elevation myocardial infarction and LV dysfunction after successful reperfusion, intracoronary infusion of BM-MNC at either 5 to 7 days or 3 to 4 weeks after acute myocardial infarction did not improve LV function at 4-month follow-up.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00355186.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.112.001035DOI Listing
May 2013

[Pecutaneous mitral valve repair].

Praxis (Bern 1994) 2013 Feb;102(5):265-71

Fondazione Cardiocentro Ticino, Lugano.

Over four million Europeans and a similar number Americans suffer from significant mitral regurgitation (MR). Approximately 250,000 new patients are diagnosed with the disease annually. The disorder generally evolves insidiously over many years because the heart compensates for the regurgitant volume by left atrial enlargement, left ventricular (LV) volume overload, and progressive (LV) dilatation. The most common causes of MR include ischemic heart disease, non-ischemic heart disease, and valve degeneration. Mitral valve surgery has long been the only treatment available with proven efficacy for MR. It alleviates clinical symptoms and prevents ventricular dilatation and heart failure, or attenuates further progression of this process. Surgical valve repair significantly improves clinical outcomes compared with valve replacement, reducing mortality by approximately 70%. However, patients with heart failure have both higher acute risk and significant rates of late MR recurrence after surgical repair of ischemic MR. Recently, a number of percutaneous modalities of mitral valve repair have been developed. Most of these techniques are still at early stages of clinical evaluation. The MitraClip System consists of a percutaneous edge-to-edge attachemnt system that mimics the surgical procedure. This technique creates a bridge between the anterior and posterior leaflet by means of a clip deployed through trans-septal catheterization. The growing experience show that percutaneous edge-to-edge repair using the MitraClip system is feasible, safe and, in overall, effective, with very promising clinical results when performed in carefully selected patients, The new technique does not represent a general alternative to conventional surgical valve repair, which remains the gold standard particularly in the patients with degenerative MR. However, it offers a valid option in patients unsuitable for surgery and those with functional MR secondary to advanced heart failure, where the surgical approach still remains empiric.
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http://dx.doi.org/10.1024/1661-8157/a001199DOI Listing
February 2013

Real-time left ventricular pressure-volume loops during percutaneous mitral valve repair with the MitraClip system.

Circulation 2013 Mar 1;127(9):1018-27. Epub 2013 Feb 1.

Andreas Grüntzig Cardiac Catheterization Laboratories, University Hospital Zurich, Zurich, Switzerland.

Background: Percutaneous mitral valve repair with the MitraClip device has emerged as an alternative to surgery for treating severe mitral regurgitation. However, its effects on left ventricular loading conditions and contractility have not been investigated yet.

Methods And Results: Pressure-volume loops were recorded throughout the MitraClip procedure using conductance catheter in 33 patients (mean age, 78±10 years) with functional (45%), degenerative (48%), or mixed (6%) mitral regurgitation. Percutaneous mitral valve repair increased end-systolic wall stress (WSES; from [median] 184 mm Hg [interquartile range (IQR), 140-200 mm Hg] to 209 mm Hg [IQR, 176-232 mm Hg]; P=0.001) and decreased end-diastolic WS (WSED; from 48 mm Hg [IQR, 28-58 mm Hg] to 34 mm Hg [IQR, 21-46 mm Hg]; P=0.005), whereas the end-systolic pressure-volume relationship was not significantly affected. Conversely, cardiac index increased (from 2.6 L·min(-1)·m(-2) [IQR, 2.2-3.0 L·min(-1)·m(-2)] to 3.2 L·min(-1)·m(-2) [IQR, 2.6-3.8 L·min(-1)·m(-2)]; P<0.001) and mean pulmonary capillary wedge pressure decreased (from 15 mm Hg [IQR, 12-20 mm Hg] to 12 mm Hg [IQR, 10-13 mm Hg]; P<0.001). Although changes in WSES were not correlated with changes in cardiac index, changes in WSED correlated significantly with changes in mean pulmonary capillary wedge pressure (r=0.63, P<0.001). Total mechanical energy assessed by the pressure-volume area remained unchanged, resulting in a more favorable index of forward output (cardiac index) to mechanical energy (pressure-volume area) after mitral valve repair. On follow-up (153±94 days), New York Heart Association functional class was reduced from 2.9±0.6 to 1.9±0.5 (P<0.001) at 3 months, and echocardiographic follow-up documented a stepwise reduction in end-diastolic volume (from 147 mL [IQR, 95-191 mL] to 127 mL [IQR, 82-202 mL]; P=0.036).

Conclusions: Percutaneous mitral valve repair improves hemodynamic profiles and induces reverse left ventricular remodeling by reducing left ventricular preload while preserving contractility. In nonsurgical candidates with compromised left ventricular function, MitraClip therapy could be considered an alternative to surgical mitral valve repair.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.112.135061DOI Listing
March 2013

Predictors for efficacy of percutaneous mitral valve repair using the MitraClip system: the results of the MitraSwiss registry.

Heart 2013 Jul 23;99(14):1034-40. Epub 2013 Jan 23.

Department of Cardiology, University Hospital Zurich, Zürich, Switzerland.

Background: Percutaneous mitral valve repair (MVR) using the MitraClip system has become a valid alternative for patients with severe mitral regurgitation (MR) and high operative risk.

Objective: To identify clinical and periprocedural factors that may have an impact on clinical outcome.

Design: Multi-centre longitudinal cohort study.

Setting: Tertiary referral centres.

Patients: Here we report on the first 100 consecutive patients treated with percutaneous MVR in Switzerland between March 2009 and April 2011. All of them had moderate-severe (3+) or severe (4+) MR, and 62% had functional MR. 82% of the patients were in New York Heart Association (NYHA) class III/IV, mean left ventricular ejection fraction was 48% and the median European System for Cardiac Operative Risk Evaluation was 16.9%.

Interventions: MitraClip implantation performed under echocardiographic and fluoroscopic guidance in general anaesthesia.

Main Outcome Measures: Clinical, echocardiographic and procedural data were prospectively collected.

Results: Acute procedural success (APS, defined as successful clip implantation with residual MR grade ≤2+) was achieved in 85% of patients. Overall survival at 6 and 12 months was 89.9% (95% CI 81.8 to 94.6) and 84.6% (95% CI 74.7 to 91.0), respectively. Univariate Cox regression analysis identified APS (p=0.0069) and discharge MR grade (p=0.03) as significant predictors of survival.

Conclusions: In our consecutive cohort of patients, APS was achieved in 85%. APS and residual discharge MR grade are important predictors of mid-term survival after percutaneous MVR.
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http://dx.doi.org/10.1136/heartjnl-2012-303105DOI Listing
July 2013

Sustained improvement in left ventricular function after bone marrow derived cell therapy in patients with acute ST elevation myocardial infarction. A 5-year follow-up from the Stem Cell Transplantation in Ischaemic Myocardium Study.

Swiss Med Wkly 2012 25;142:w13632. Epub 2012 Jul 25.

Fondazione Cardiocentro Ticino, Lugano, Switzerland.

Background: Intracoronary injection of autologous bone marrow-derived mononucleated cells (BM-MNC) may improve LV function shortly after acute ST elevation myocardial infarction (STEMI), but little is known about the long-term durability of the treatment effect.

Methods: In a single-centre trial a total of 60 patients with acute anterior STEMI, successful reperfusion therapy and a left ventricular ejection fraction (LVEF) of <50% were screened for the study. 23 patients were actively treated with intracoronary infusion of BM-MNC within a median of 3 days. The open-label control group consisted of 19 patients who did not consent to undergo BM-MNC treatment but agreed to undergo regular clinical and echocardiographic follow-up for up to 5 years after AMI.

Results: Whereas at 4 months there was no significant difference between the increase in LVEF in the BM-MNC group and the control group (+7.0%, 95%CI 3.6; 10.4) vs. +3.9%, 95%CI -2.1; 10), the absolute increase at 5 years remained stable in the BM-MNC but not in the control group (+7.95%, 95%CI 3.5; 12.4 vs. -0.5%, 95%CI -5.4; 4.4; p for interaction between groups = 0.035).

Discussion: In this single-centre, open-labelled study, intracoronary administration of BM-MNC is feasible and safe in the short term. It is also associated with sustained improvement of left ventricular function in patients with acute myocardial infarction, encouraging phase III studies to examine the potential BM-MNC effect on clinical outcome.
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http://dx.doi.org/10.4414/smw.2012.13632DOI Listing
January 2013

The SYNTAX score predicts early mortality risk in the elderly with acute coronary syndrome having primary PCI.

J Invasive Cardiol 2011 Dec;23(12):505-10

Department of Cardiology, CardioCentro Ticino, Via Tesserete, Lugano, Switzerland.

Background: The SYNTAX score (SXscore), an angiographic score reflecting coronary lesion complexity, predicts clinical outcomes in patients with left main or multivessel disease, and in patients with ST-segment elevation myocardial infarction undergoing primary PCI. The clinical SXscore (CSS) integrates the SXscore and clinical variables (age, ejection fraction, serum creatinine) into a single score. We analyzed these scores in elderly patients with acute coronary syndrome (ACS) undergoing primary PCI. The purpose of this analysis was not to decide which patients should undergo PCI, but to predict clinical outcomes in this population.

Methods: The SXscore was determined in a consecutive series of 114 elderly patients (mean age, 79.6 ± 4.1 years) undergoing primary PCI for ACS. Outcomes were stratified according to SXscore tertiles: SXLOW ≤15 (n = 39), 15< SXMID <23 (n = 40), and SXHIGH ≥23 (n = 35). The primary endpoint was all-cause mortality at 30 days. Secondary endpoints were nonfatal major adverse cardiac and cerebrovascular events (MACCE) at 30 days, and 1-year outcomes in patients discharged alive.

Results: Mortality at 30 days was higher in the SXHIGH group compared with the aggregate SXLOW+MID group (37.1% vs 5.1%; P<.0001), and in the CSSHIGH group compared with the aggregate CSSLOW+MID group (25.5% vs 1.4%; P=.0001). MACCE rates at 30 days were similar among SXscore tertiles. The CSS predicted 1-year MACCE rates (12.1% for CSSHIGH vs 3.1% for CSSLOW+MID; P=.03).

Conclusions: The SXscore predicts 30-day mortality in elderly patients with ACS undergoing primary PCI. In patients discharged alive, the CSS predicts risk of MACCE at 1 year.
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December 2011

Acute haemodynamic changes after percutaneous mitral valve repair: relation to mid-term outcomes.

Heart 2012 Jan 7;98(2):126-32. Epub 2011 Oct 7.

Andreas Gruntzig Laboratories, Cardiovascular Center, University Hospital Zurich, Ramistrasse 100, Zurich, Switzerland.

Background: Percutaneous mitral valve repair (MVR) using the Evalve MitraClip has been recently introduced as a potential alternative to surgical MVR.

Objective: To assess immediate haemodynamic changes after percutaneous MVR using right heart catheterisation. Design Single-centre longitudinal cohort study.

Setting: Tertiary referral centre.

Patients: Fifty consecutive non-surgical patients (age 74±14 years, EuroSCORE 26±14) with moderate to severe (3+) and severe (4+) mitral regurgitation (MR) due to functional (56%), degenerative (30%) or mixed (14%) disease were selected.

Interventions: MitraClip implantation was performed under general anaesthesia with fluoroscopy and echocardiographic guidance. Haemodynamic variables were obtained before and after MVR using standard right heart catheterisation and oximetry.

Main Outcome Measures: Haemodynamic changes immediately before and after MVR.

Results: Acute procedural success (reduction in MR to grade 2+ or less) was achieved in 46 (92%) patients. Mitral valve clipping reduced mean pulmonary capillary wedge pressure (mPCWP) (from 17±7 to 12±5 mm Hg), PCWP v-wave (from 24±11 to 16±7 mm Hg) and mean pulmonary artery pressure (mPAP) (from 29±12 to 24±6 mm Hg), and increased the cardiac index (CI) (from 3.1±1.0 to 3.9±1.1 l/min/m(2)) (all p<0.05). On Cox univariate regression analysis, mPCWP, PCWP v-wave- and mPAP-changes were associated with death, open-heart surgery for MR and/or hospitalisation for heart failure on follow-up.

Conclusion: In a heterogeneous population with predominantly functional MR, percutaneous MVR with the Evalve MitraClip system lowers mPCWP, PCWP v-wave and mPAP by 20%, 20% and 8%, respectively, and increases the CI by 32%.
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http://dx.doi.org/10.1136/heartjnl-2011-300705DOI Listing
January 2012

Autologous bone marrow mononucleated cell preparation for the clinical treatment of acute myocardial infarction and peripheral arterial disease.

Cytotherapy 2011 Oct;13(9):1031-5

Laboratory of Advanced Cellular Therapies, Department of Hematology, S. Bortolo Hospital, Vicenza, Italy.

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http://dx.doi.org/10.3109/14653249.2011.605620DOI Listing
October 2011

Primary percutaneous coronary intervention for unprotected left main disease in patients with acute ST-segment elevation myocardial infarction the AMIS (Acute Myocardial Infarction in Switzerland) plus registry experience.

JACC Cardiovasc Interv 2011 Jun;4(6):627-33

Division of Cardiology, CardioCentro Ticino, Lugano, Switzerland.

Objectives: This study sought to assess outcomes in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (PCI) for unprotected left main (LM) disease.

Background: Limited data are available on outcomes in patients with ST-segment elevation myocardial infarction undergoing LM PCI.

Methods: Of 9,075 patients with ST-segment elevation myocardial infarction enrolled in the AMIS (Acute Myocardial Infarction in Switzerland) Plus registry between 2005 and June 30, 2010, 6,666 underwent primary PCI. Of them, 348 (5.2%; mean age: 63.5 ± 12.6 years) underwent LM PCI, either isolated (n = 208) or concomitant to PCI for other vessel segments (n = 140). They were compared with 6,318 patients (94.8%; mean age: 61.9 ± 12.5 years) undergoing PCI of non-LM vessel segments only.

Results: The LM patients had higher rates of cardiogenic shock (12.2% vs. 3.5%; p < 0.001), cardiac arrest (10.6% vs. 6.3%; p < 0.01), in-hospital mortality (10.9% vs. 3.8%; p < 0.001), and major adverse cardiac and cerebrovascular events (12.4% vs. 5.0%; p < 0.001) than non-LM PCI. Rates of mortality and major adverse cardiac and cerebrovascular events were highest for concurrent LM and non-LM PCI (17.9% and 18.6%, respectively), intermediate for isolated LM PCI (6.3% and 8.3%, respectively), and lowest for non-LM PCI (3.8% and 5.0%, respectively). Rates of mortality and major adverse cardiac and cerebrovascular events for LM PCI were higher than for non-LM multivessel PCI (10.9% vs. 4.9%, p < 0.001, and 12.4% vs. 6.4%, p < 0.001, respectively). LM disease independently predicted in-hospital death (odds ratio: 2.36; 95% confidence interval: 1.34 to 4.17; p = 0.003).

Conclusions: Emergent LM PCI in the context of acute myocardial infarction, even including 12% cardiogenic shock, appears to have a remarkably high (89%) in-hospital survival. Concurrent LM and non-LM PCI has worse outcomes than isolated LM PCI.
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http://dx.doi.org/10.1016/j.jcin.2011.04.004DOI Listing
June 2011

MitraClip® therapy in patients with end-stage systolic heart failure.

Eur J Heart Fail 2011 May 6;13(5):569-76. Epub 2011 Apr 6.

Department of General and Interventional Cardiology, University Heart Centre, Hamburg, Germany.

Aims: To assess the feasibility, short-term durability and clinical outcomes of MitraClip® therapy for mitral regurgitation (MR) in patients with end-stage heart failure and a severely reduced left ventricular (LV) ejection fraction.

Methods And Results: We analysed retrospectively collected data from seven European centres. Included in the study were 50 heart failure patients [mean age 70 ± 11 years, 38 men (76%)] with a LV ejection fraction ≤25% and MR of at least grade 3+. All patients had functional MR, were in New York Heart Association (NYHA) functional class III or IV, and their mean logistic EuroSCORE was 34%. The patients underwent a total of 53 MitraClip® procedures; one or more clips were implanted in 50 procedures (48 patients), for an acute procedural success rate of 94%. Severity of MR was reduced in all successfully treated patients, 44 (92%) were discharged with MR ≤2+. Thirty-day mortality was 6%; cumulative survival at 6 months was 81.2%. Clinical and echocardiographic 6-month follow-up data were obtained from 32 and 31 successfully treated patients, respectively. At 6 months, MR ≤2+ was present in 27 (87%) of 31 patients, and 23 (72%) of 32 patients were in NYHA functional class I or II. Six-minute walk distance improved significantly, and significant reductions in LV volumes indicative of reverse LV remodelling were concordant with significant reductions in N-terminal pro-brain natriuretic peptide plasma levels.

Conclusion: MitraClip® therapy reduces functional MR in patients with end-stage heart failure and marked LV dysfunction and entails clinical benefit at 6 months.
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http://dx.doi.org/10.1093/eurjhf/hfr029DOI Listing
May 2011

Acute, subacute, and chronic myocardial infarction: quantitative comparison of 2D and 3D late gadolinium enhancement MR imaging.

Radiology 2011 Jun 5;259(3):704-11. Epub 2011 Apr 5.

Department of Diagnostic Radiology, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland.

Purpose: To assess a late gadolinium enhancement (LGE) single-breath-hold three-dimensional (3D) inversion recovery magnetic resonance (MR) imaging sequence for the quantification of myocardial scar mass and transmurality in comparison with a clinically established two-dimensional (2D) sequence.

Materials And Methods: All patients gave written informed consent to participate in this institutional review board-approved study. Ninety patients (84 men; mean age, 54.4 years ± 10.8 [standard deviation]) with acute (n = 30), subacute (n = 30), or chronic (n = 30) myocardial infarction were included. Imaging was performed by using a 1.5-T clinical MR imaging system. Spatial resolution was identical for 3D and 2D images (1.5 × 1.5 mm(2); section thickness, 8 mm; no section gap). Quantitative comparisons of myocardial mass (in grams), scar mass (in grams), and scar transmurality (on a five-point scale) were performed by using the Pearson correlation and Bland-Altman analysis (for myocardial and scar mass) or κ statistics (for transmurality).

Results: There were no significant differences between 2D and 3D data sets in terms of mean myocardial mass (2D: 148.3 g ± 35.1; 3D: 148.1 g ± 34.6; P = .76) and scar tissue mass (2D: 31.8 g ± 14.6; 3D: 31.6 g ± 15.5; P = .39), with strong and significant correlation regarding both myocardial mass (r = 0.982; P < .001) and scar tissue mass (r = 0.980; P < .001). Bland-Altman analysis showed a mean difference of 0.21 g ± 6.64 (range, -19.64 to 18.44 g) for myocardial mass and a mean difference of 0.26 g ± 2.88 (range, -7.15 to 7.74 g) for scar mass between the 2D and 3D data sets. Agreement regarding scar transmurality was good (κ = 0.75). Acquisition time was significantly shorter for 3D data sets (26.7 seconds ± 4.4 vs 367.7 seconds ± 56.4; P < .001).

Conclusion: Three-dimensional LGE MR imaging enables quantitative evaluation of scar tissue mass and transmurality in patients with acute, subacute, or chronic myocardial infarction at significantly reduced acquisition times compared with 2D LGE MR imaging.
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http://dx.doi.org/10.1148/radiol.11102216DOI Listing
June 2011

Percutaneous double valve intervention.

Eur Heart J 2011 Mar 23;32(5):636. Epub 2010 Nov 23.

Andreas Grüntzig Cardiac Catheter Laboratories, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1093/eurheartj/ehq378DOI Listing
March 2011

Stem cell update: highlights from the 2010 Lugano Stem Cell Meeting.

J Cardiovasc Transl Res 2011 Apr 30;4(2):192-9. Epub 2010 Oct 30.

Swiss Stem Cell Foundation, Lugano, Switzerland.

The 2010 edition of the Lugano Stem Cell Meeting, under the auspices of the Swiss center of excellence in cardiovascular diseases "Cardiocentro Ticino" and the Swiss Stem Cell Foundation, offered an update on clinical, translational, and biotechnological advances in regenerative science and medicine pertinent to cardiovascular applications. Highlights from the international forum ranged from innate mechanisms of heart repair, safety, and efficacy of ongoing and completed clinical trials, novel generations of stem cell biologics, bioengineered platforms, and regulatory processes. In the emerging era of regenerative medicine, accelerating the critical path from discovery to product development will require integrated multidisciplinary teams to ensure timely translation of new knowledge into validated algorithms for practice adoption.
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http://dx.doi.org/10.1007/s12265-010-9232-4DOI Listing
April 2011

Cell-based therapy for myocardial repair in patients with acute myocardial infarction: rationale and study design of the SWiss multicenter Intracoronary Stem cells Study in Acute Myocardial Infarction (SWISS-AMI).

Am Heart J 2010 Jul;160(1):58-64

Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.

Background: Recent studies report that intracoronary administration of autologous bone marrow mononucleated cells (BM-MNCs) may improve remodeling of the left ventricle after acute myocardial infarction (AMI). Subgroup analysis suggest that early treatment between days 4 and 7 after AMI is probably most effective; however, the optimal time point of intracoronary cell administration has never been addressed in clinical trials. Furthermore, reliable clinical predictors are lacking for identifying patients who are thought to have most benefit from cellular therapy.

Study Design: In a multicenter trial, 192 patients with AMI successfully treated by percutaneous coronary intervention (PCI) of the infarct-related artery will be randomized in a 1:1:1 pattern to 1 control and 2 BM-MNC treatment groups. The control group will be treated with state-of-the-art medical management. The treatment groups will receive intracoronary administration of autologous BM-MNC at 5 to 7 days or 3 to 4 weeks after the initial event, respectively. Left ventricular function as well as scar size, transmural extension, and regional wall motion score will be assessed by cardiac magnetic resonance (CMR) studies at baseline and after 4 and 12 months.

Methods: Fifty milliliters of bone marrow will be harvested by aspiration from the iliac crest and then carried by courier to a centralized cell processing facility. The mononucleated cell fraction will be isolated by density gradient centrifugation, washed, and resuspended in 10 mL of injection medium. The cells will be characterized by fluorescence-activated cell sorting analysis and tested for sterility and potency both "in vitro" and "in vivo." Bone marrow MNC will then be reinfused directly in the infarct-related coronary artery.

End Points: The primary end point is the change in global left ventricular (LV) ejection fraction by CMR at 4 months as compared to baseline. Comparisons will then be made between each of the prespecified therapy subgroups (early and late after AMI) and the control group. Secondary end points include change in infarct size, change in regional myocardial thickness, and wall motion at 4 and 12 months compared to baseline. Infarct extension (size and transmural extension), time delay to PCI, and coronary flow characteristics after PCI will be assessed as potential predictors of LV remodeling and change after cell therapy. Major adverse cardiac events (MACE) (death, myocardial infarction, coronary revascularization, rehospitalization for heart failure) will be assessed at 4, 12, and 24 months and time to MACE will be estimated.

Discussion: With the present study, we aim to determine the optimal time point of intracoronary administration of autologous BM-MNC after AMI on LV remodeling.
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http://dx.doi.org/10.1016/j.ahj.2010.03.039DOI Listing
July 2010

Bone marrow derived stem cells in regenerative medicine as advanced therapy medicinal products.

Am J Transl Res 2010 May 15;2(3):285-95. Epub 2010 May 15.

Cell Therapy Unit, Foundation Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland.

Bone marrow derived stem cells administered after minimal manipulation represent an important cell source for cell-based therapies. Clinical trial results, have revealed both safety and efficacy of the cell reinfusion procedure in many cardiovascular diseases. Many of these early clinical trials were performed in a period before the entry into force of the US and European regulation on cell-based therapies. As a result, conflicting data have been generated on the effectiveness of those therapies in certain conditions as acute myocardial infarction. As more academic medical centers and private companies move toward exploiting the full potential of cell-based medicinal products, needs arise for the development of the infrastructure necessary to support these investigations. This review describes the regulatory environment surrounding the production of cell based medicinal products and give practical aspects for cell isolation, characterization, production following Good Manufacturing Practice, focusing on the activities associated with the investigational new drug development.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892405PMC
May 2010

A practical approach for the validation of sterility, endotoxin and potency testing of bone marrow mononucleated cells used in cardiac regeneration in compliance with good manufacturing practice.

J Transl Med 2009 Sep 8;7:78. Epub 2009 Sep 8.

The Cell Therapy Unit, Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland.

Background: Main scope of the EU and FDA regulations is to establish a classification criterion for advanced therapy medicinal products (ATMP). Regulations require that ATMPs must be prepared under good manufacturing practice (GMP). We have validated a commercial system for the determination of bacterial endotoxins in compliance with EU Pharmacopoeia 2.6.14, the sterility testing in compliance with EU Pharmacopoeia 2.6.1 and a potency assay in an ATMP constituted of mononucleated cells used in cardiac regeneration.

Methods: For the potency assay, cells were placed in the upper part of a modified Boyden chamber containing Endocult Basal Medium with supplements and transmigrated cells were scored. The invasion index was expressed as the ratio between the numbers of invading cells relative to cell migration through a control insert membrane. For endotoxins, we used a commercially available system based on the kinetic chromogenic LAL-test. Validation of sterility was performed by direct inoculation of TSB and FTM media with the cell product following Eu Ph 2.6.1 guideline.

Results And Discussion: The calculated MVD and endotoxin limit were 780x and 39 EU/ml respectively. The 1:10 and 1:100 dilutions were selected for the validation. For sterility, all the FTM cultures were positive after 3 days. For TSB cultures, Mycetes and B. subtilis were positive after 5 and 3 days respectively. The detection limit was 1-10 colonies. A total of four invasion assay were performed: the calculated invasion index was 28.89 +/- 16.82% (mean +/- SD).

Conclusion: We have validated a strategy for endotoxin, sterility and potency testing in an ATMP used in cardiac regeneration. Unlike pharmaceutical products, many stem-cell-based products may originate in hospitals where personnel are unfamiliar with the applicable regulations. As new ATMPs are developed, the regulatory framework is likely to evolve. Meanwhile, existing regulations provide an appropriate structure for ensuring the safety and efficacy of the next generation of ATMPs. Personnel must be adequately trained on relevant methods and their application to stem-cell-based products.
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http://dx.doi.org/10.1186/1479-5876-7-78DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753319PMC
September 2009