Cardiopoietic Stem Cell Therapy in Heart Failure Bartunek, Jozef, MD, PhD; Behfar, Atta, MD, PhD; Dolatabadi, Dariouch, MD ...
Journal of the American College of Cardiology,
06/2013, Volume:
61, Issue:
23
Journal Article
Peer reviewed
Open access
Objectives This study sought to evaluate the feasibility and safety of autologous bone marrow–derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in ...patients with chronic heart failure. Background In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling. Methods The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy. Results Mesenchymal stem cell cocktail–based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume (−24.8 ± 3.0 ml vs. −8.8 ± 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. −15 ± 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. Conclusions The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238 ).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives The aim of this study was to determine the risk of major clinical and thromboembolic events after cardioversion for atrial fibrillation in subjects treated with apixaban, an oral factor Xa ...inhibitor, compared with warfarin. Background In patients with atrial fibrillation, thromboembolic events may occur after cardioversion. This risk is lowered with vitamin K antagonists and dabigatran. Methods Using data from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, we conducted a post-hoc analysis of patients undergoing cardioversion. Results A total of 743 cardioversions were performed in 540 patients: 265 first cardioversions in patients assigned to apixaban and 275 in those assigned to warfarin. The mean time to the first cardioversion for patients assigned to warfarin and apixaban was 243 ± 231 days and 251 ± 248 days, respectively; 75% of the cardioversions occurred by 1 year. Baseline characteristics were similar between groups. In patients undergoing cardioversion, no stroke or systemic emboli occurred in the 30-day follow-up period. Myocardial infarction occurred in 1 patient (0.2%) receiving warfarin and 1 patient receiving apixaban (0.3%). Major bleeding occurred in 1 patient (0.2%) receiving warfarin and 1 patient receiving apixaban (0.3%). Death occurred in 2 patients (0.5%) receiving warfarin and 2 patients receiving apixaban (0.6%). Conclusions Major cardiovascular events after cardioversion of atrial fibrillation are rare and comparable between warfarin and apixaban. (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation ARISTOTLE; NCT00412984 )
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSCs) into a cardiac progenitor phenotype and assess therapeutic benefit in chronic myocardial ...infarction. Background Adult stem cells, delivered in their naïve state, demonstrate a limited benefit in patients with ischemic heart disease. Pre-emptive lineage pre-specification may optimize therapeutic outcome. Methods hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of transforming growth factor-beta1 , bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-6 was formulated to engage hMSC into cardiopoiesis. Derived hMSC were injected into the myocardium of a nude infarcted murine model and followed over 1 year for functional and structural end points. Results Although the majority of patient-derived hMSC in their native state demonstrated limited effect on ejection fraction, stem cells from rare individuals harbored a spontaneous capacity to improve contractile performance. This reparative cytotype was characterized by high expression of homeobox transcription factor Nkx-2.5, T-box transcription factor TBX5, helix–loop–helix transcription factor MESP1, and myocyte enhancer factor MEF2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared with unguided counterparts, cardiopoietic hMSC delivered into infarcted myocardium achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric, and gap junction content along with induction of myocardial cell cycle activity. Conclusions Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived hMSC in chronic ischemic cardiomyopathy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives The aim of this study was to investigate the correlation between myocardial ischemia detected by myocardial perfusion imaging (MPI) with single-photon emission computed tomography with ...intracoronary pressure-derived fractional flow reserve (FFR) in patients with multivessel coronary disease at angiography. Background Myocardial perfusion imaging can underestimate the number of ischemic territories in patients with multivessel disease. However, there are limited data comparing MPI and FFR, a highly accurate functional index of myocardial ischemia, in multivessel coronary disease. Methods Sixty-seven patients (201 vascular territories) with angiographic 2- or 3-vessel coronary disease were prospectively scheduled to undergo within 2 weeks MPI (rest/stress adenosine) and FFR in each vessel. Results In 42% of patients, MPI and FFR detected identical ischemic territories (mean number of territories 0.9 ± 0.8 for both; p = 1.00). In the remaining 36% MPI underestimated (mean number of territories; MPI: 0.46 ± 0.6, FFR: 2.0 ± 0.6; p < 0.001) and in 22% overestimated (mean number of territories; MPI: 1.9 ± 0.8, FFR: 0.5 ± 0.8; p < 0.001) the number of ischemic territories in comparison with FFR. There was poor concordance between the ability of the 2 methods to detect myocardial ischemia on both a per-patient (κ = 0.14 95% confidence interval: −0.10 to 0.39) and per-vessel (κ = 0.28 95% confidence interval: 0.15 to 0.42) basis. Conclusions Myocardial perfusion imaging with single-photon emission computed tomography has poor concordance with FFR and tends to underestimate or overestimate the functional importance of coronary stenosis seen at angiography in comparison with FFR in patients with multivessel disease. These findings might have important consequences in using MPI to determine the optimal revascularization strategy in patients with multivessel coronary disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives This study was designed to investigate: 1) relationships between serum ST2 levels and hemodynamic/neurohormonal variables; 2) myocardial ST2 production; and the 3) expression of ST2, ...membrane-anchored ST2L, and its ligand, interleukin (IL)-33, in myocardium, endothelium, and leukocytes from patients with left ventricular (LV) pressure overload and congestive cardiomyopathy. Background Serum levels of ST2 are elevated in heart failure. The relationship of ST2 to hemodynamic variables, source of ST2, and expression of ST2L and IL-33 in the cardiovascular system are unknown. Methods Serum ST2 (pg/ml; median 25th, 75th percentile) was measured in patients with LV hypertrophy (aortic stenosis) (n = 45), congestive cardiomyopathy (n = 53), and controls (n = 23). ST2 was correlated to N-terminal pro-brain natriuretic peptide, C-reactive protein, and hemodynamic variables. Coronary sinus and arterial blood sampling determined myocardial gradient (production) of ST2. The levels of ST2, ST2L, and IL-33 were measured (reverse transcriptase-polymerase chain reaction) in myocardial biopsies and leukocytes. The ST2 protein production was evaluated in human endothelial cells. The IL-33 protein expression was determined (immunohistochemistry) in coronary artery endothelium. Results The ST2 protein was elevated in aortic stenosis (103 65, 165 pg/ml, p < 0.05) and congestive cardiomyopathy (194 69, 551 pg/ml, p < 0.01) versus controls (49 4, 89 pg/ml) and correlated with B-type natriuretic peptide (r = 0.5, p < 0.05), C-reactive protein (r = 0.6, p < 0.01), and LV end-diastolic pressure (r = 0.38, p < 0.03). The LV ST2 messenger ribonucleic acid was similar in aortic stenosis and congestive cardiomyopathy versus control (p = NS). No myocardial ST2 protein gradient was observed. Endothelial cells secreted ST2. The IL-33 protein was expressed in coronary artery endothelium. Leukocyte ST2L and IL-33 levels were highly correlated (r = 0.97, p < 0.001). Conclusions In human hypertrophy and failure, serum ST2 correlates with the diastolic load. Though the heart, endothelium, and leukocytes express components of ST2/ST2L/IL-33 pathway, the source of circulating serum ST2 is extra-myocardial.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Long-Term Follow-Up After Fractional Flow Reserve–Guided Treatment Strategy in Patients With an Isolated Proximal Left Anterior Descending Coronary Artery Stenosis Olivier Muller, Fabio Mangiacapra, ...Argyrios Ntalianis, Katia M. C. Verhamme, Catalina Trana, Michalis Hamilos, Jozef Bartunek, Marc Vanderheyden, Eric Wyffels, Guy R. Heyndrickx, Frank J. A. van Rooij, Jacqueline C. M. Witteman, Albert Hofman, William Wijns, Emanuele Barbato, Bernard De Bruyne The aim of the study was to assess the long-term clinical outcome of 730 patients with an angiographically intermediate left anterior descending coronary artery (LAD) stenosis in whom the revascularization strategy was based on fractional flow reserve (FFR). The 5-year survival estimate was 92.9% in the medical group (FFR ≥0.8) versus 89.6% in the controls (age- and sex-matched reference population, p = 0.74) versus 87.4% in the revascularization group (FFR <0.8) (p = 0.03). Medical treatment of patients with a hemodynamically nonsignificant stenosis (FFR ≥0.80) in the proximal LAD is associated with an excellent long-term clinical outcome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background Fractional flow reserve (FFR)–guided percutaneous revascularization (percutaneous coronary intervention PCI) of intermediate stenosis in native coronary artery is safe and associated with ...better clinical outcomes as compared with an angiography-guided PCI. It is unknown whether this applies to coronary artery bypass grafts (CABGs). Methods We included 223 patients with CABG and with stable or unstable angina and an intermediate stenosis involving an arterial or a venous graft. Patients were divided into 2 groups: FFR guided (n = 65, PCI performed in case of FFR ≤0.80) and angio guided (n = 158, PCI performed based on angiographic evaluation). Primary end point was major adverse cardiac and cerebrovascular event, defined as death, myocardial infarction, target vessel failure, and cerebrovascular accident (CVA). Results The 2 groups were similar in terms of demographic and clinical characteristics. Percutaneous coronary intervention was performed in 23 patients (35%) of the FFR-guided group and 90 patients (57%) of the angio-guided group ( P < .01). In the FFR-guided group, PCI was more often performed in arterial grafts as compared with the angio-guided group (16 70% vs 12 13%, respectively; P < .01). Follow-up was obtained in 96% of patients at a median of 3.8 years (1.6-4.0 years). At multivariate analysis, major adverse cardiac and cerebrovascular event rate was significantly lower in the FFR-guided group as compared with the angio-guided group (18 28% vs 77 51%, hazard ratio 0.33 0.11-0.96, P = .043. Procedure costs were overall reduced in the FFR-guided group (€2240 ± €652 vs €2416 ± €522, P = .03). Conclusions An FFR-guided PCI of intermediate stenosis in bypass grafts is safe and results in better clinical outcomes as compared with an angio-guided PCI. This clinical benefit is achieved with a significant overall reduction in procedural costs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objectives This study investigated the influence of intracoronary enalaprilat on coronary microvascular function and peri-procedural outcome measures in patients with stable angina undergoing ...percutaneous coronary intervention (PCI). Background Intracoronary angiotensin-converting enzyme inhibitors have been shown to relieve myocardial ischemia in stable patients and to improve epicardial flow in patients with ST-segment elevation myocardial infarction. Yet, it is still unclear whether these effects are mediated by a modulation of the coronary microcirculation. Methods We randomly assigned 40 patients to receive either an intracoronary bolus of enalaprilat (50 μg) or placebo before elective PCI. The index of microvascular resistance was measured at baseline, 10 minutes after study drug administration, and after PCI. High-sensitivity cardiac troponin T was measured as a marker of myocardial injury. Results Infusion of enalaprilat resulted in a significant reduction in index of microvascular resistance (27 ± 11 at baseline vs. 19 ± 9 after drug vs. 15 ± 8 after PCI), whereas a significant post-procedural increase in index of microvascular resistance levels was observed in the placebo group (24 ± 15 at baseline vs. 24 ± 15 after drug vs. 33 ± 19 after PCI). Index of microvascular resistance levels after PCI were significantly lower in the enalaprilat group (p < 0.001). Patients pre-treated with enalaprilat also showed lower peak values (mean: 21.7 ng/ml, range: 8.2 to 34.8 ng/ml vs. mean: 32.3 ng/ml, range: 12.6 to 65.2 ng/ml, p = 0.048) and peri-procedural increases of high-sensitivity cardiac troponin T (mean: 9.9 ng/ml, range: 2.7 to 19.0 ng/ml vs. mean: 26.6 ng/ml, range: 6.3 to 60.5 ng/ml, p = 0.025). Conclusions Intracoronary enalaprilat improves coronary microvascular function and protects myocardium from procedure-related injury in patients with coronary artery disease undergoing PCI. Larger studies are warranted to investigate whether these effects of enalaprilat could result into a significant clinical benefit.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Fractional flow reserve (FFR) has never been investigated in patients with aortic stenosis (AS). From 2002 to 2010, we identified 106 patients with AS and coronary artery disease with at least one ...intermediate lesion treated according to FFR guidance. We matched 212 contemporary control patients with AS in which revascularization was decided on angiography only. More patients in the FFR-guided group underwent percutaneous coronary intervention (24% vs 13%; p = 0.019), whereas there was a trend toward less coronary artery bypass grafting (CABG) performed. After FFR, the number of diseased vessels was downgraded within the FFR-guided group (from 1.85 ± 0.97 to 1.48 ± 1; p <0.01) and compared with the angio-guided group (1.48 ± 1 vs 1.8 ± 0.97; p <0.01). Less aortic valve replacement was reported in the FFR-guided group (46% vs 57%; p = 0.056). In patients who underwent CABG, less venous conduits (0.5 ± 0.69 vs 0.73 ± 0.76; p = 0.05) and anastomoses (0.61 ± 0.85 vs 0.94 ± 1; p = 0.032) were necessary in the FFR-guided group. Up to 5 years, we found no difference in major adverse cardiac events (38% vs 39%; p = 0.98), overall death (32% vs 31%; p = 0.68), nonfatal myocardial infarction (2% vs 2%; p = 0.79), and revascularization (8% vs 7%; p = 0.76) between the 2 groups. In conclusion, FFR guidance impacts the management of selected patients with moderate or severe AS and coronary artery disease by resulting into deferral of aortic valve replacement, more patients treated with percutaneous coronary intervention, and in patients treated with CABG, into less venous grafts and anastomoses without increasing adverse event rates up to 5 years.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Objectives The aim of this study was to investigate the impact of rs5065 atrial natriuretic peptide (ANP) gene variant on coronary artery disease (CAD) and its outcomes and to gain potential ...mechanistic insights on the association with CAD. Background Either modified ANP plasma levels or peptide structural alterations have been involved in development of cardiovascular events. Methods Three hundred ninety-three control subjects and 1,004 patients undergoing coronary angiography for suspected CAD (432 stable angina SA, 572 acute coronary syndrome ACS) were genotyped for rs5065 ANP gene variant. Data in SA and ACS groups were replicated in an independent population of 482 stable angina patients (rSA) and of 675 ACS patients, respectively. Clinical follow-up was available for both SA and rSA patients. Plasma N-terminal-proANP, myeloperoxidase, lipoprotein-associated phospholipase A2, and oxidized low-density lipoprotein were assessed in a subgroup of rSA patients. Results rs5065 minor allele (MA) was an independent predictor of ACS (odds ratio: 1.90; 95% confidence interval: 1.40 to 2.58, p < 0.001). At follow-up, rs5065 MA was independently associated with a significantly higher rate of major adverse cardiovascular events in the SA group, p < 0.001. Data were replicated in the rSA group at follow-up (p = 0.008). Cox proportional hazard analysis tested by 4 models confirmed higher major adverse cardiovascular events risk in rs5065 MA carriers in both SA and rSA cohorts. Significantly higher myeloperoxidase levels were detected in rs5065 MA carriers (n = 597 345 to 832 μg/l vs. n = 488 353 to 612 μg/l, p = 0.038). No association of rs5065 was observed with N-terminal-proANP levels. Conclusions The MA of rs5065 ANP gene variant associates with increased susceptibility to ACS and has unfavorable prognostic value in CAD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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