Anweshan Samanta

Adult Bone Marrow Cell Therapy for Ischemic Heart Disease: Evidence and Insights from Randomized Controlled Trials

RATIONALE Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. OBJECTIVE To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. METHODS AND RESULTS Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91-3.92; P<0.00001), reduced infarct size (-2.25%; 95% confidence interval, -3.55 to -0.95; P=0.0007) and LV end-systolic volume (-6.37 mL; 95% confidence interval, -8.95 to -3.80; P<0.00001), and tended to reduce LV end-diastolic volume (-2.26 mL; 95% confidence interval, -4.59 to 0.07; P=0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (<48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. CONCLUSIONS Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up.Rationale: Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. Objective: To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. Methods and Results: Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91–3.92; P <0.00001), reduced infarct size (−2.25%; 95% confidence interval, −3.55 to −0.95; P =0.0007) and LV end-systolic volume (−6.37 mL; 95% confidence interval, −8.95 to −3.80; P <0.00001), and tended to reduce LV end-diastolic volume (−2.26 mL; 95% confidence interval, −4.59 to 0.07; P =0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (<48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. Conclusions: Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up. # Novelty and Significance {#article-title-77}

Adult Bone Marrow Cell Therapy for Ischemic Heart DiseaseNovelty and Significance: Evidence and Insights From Randomized Controlled Trials

RATIONALE Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. OBJECTIVE To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. METHODS AND RESULTS Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91-3.92; P<0.00001), reduced infarct size (-2.25%; 95% confidence interval, -3.55 to -0.95; P=0.0007) and LV end-systolic volume (-6.37 mL; 95% confidence interval, -8.95 to -3.80; P<0.00001), and tended to reduce LV end-diastolic volume (-2.26 mL; 95% confidence interval, -4.59 to 0.07; P=0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (<48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. CONCLUSIONS Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up.Rationale: Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. Objective: To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. Methods and Results: Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91–3.92; P <0.00001), reduced infarct size (−2.25%; 95% confidence interval, −3.55 to −0.95; P =0.0007) and LV end-systolic volume (−6.37 mL; 95% confidence interval, −8.95 to −3.80; P <0.00001), and tended to reduce LV end-diastolic volume (−2.26 mL; 95% confidence interval, −4.59 to 0.07; P =0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (<48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. Conclusions: Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up. # Novelty and Significance {#article-title-77}

Use of contact force sensing technology during radiofrequency ablation reduces recurrence of atrial fibrillation: A systematic review and meta-analysis

The suboptimal outcomes of atrial fibrillation (AF) ablation have been attributed to lack of transmural lesions during pulmonary vein isolation. The advent of contact force (CF) sensing technology enables real-time assessment of the applied force at the catheter-tissue interface and increases the chances of transmural lesions. We sought to perform a meta-analysis of data from eligible studies to delineate the true impact of CF technology. Database searches through April 2015 identified 9 eligible studies (enrolling 1148 patients). The relative risk of AF recurrence at follow-up was used as the primary end point and assessed with random-effects meta-analysis. Radiofrequency (RF) duration, total procedure length, and fluoroscopy exposure were assessed as secondary outcomes using weighted mean difference with the random-effects model. Compared with standard technology, the use of CF technology showed a 37% reduction (relative risk 0.63; 95% confidence interval 0.44-0.91; P = .01) in AF recurrence at a median follow-up of 12 months and a 7.3-minute reduction (95% confidence interval -14.05 to -0.55; P = .03) in RF use during ablation. There was no significant difference in total procedure length and fluoroscopy exposure between the 2 groups. In conclusion, this meta-analysis shows that the use of CF technology decreases AF recurrence at a median follow-up of 12 months and also led to decreased use of RF during ablation. There was no difference in total procedure length and fluoroscopy exposure.

Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction

RATIONALE The role of interleukin (IL)-6 in the pathogenesis of cardiac myocyte hypertrophy remains controversial. OBJECTIVE To conclusively determine whether IL-6 signaling is essential for the development of pressure overload-induced left ventricular (LV) hypertrophy and to elucidate the underlying molecular pathways. METHODS AND RESULTS Wild-type and IL-6 knockout (IL-6(-/-)) mice underwent sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiograms and terminal hemodynamic studies revealed attenuated LV hypertrophy and superior preservation of LV function in IL-6(-/-) mice after TAC. The extents of LV remodeling, fibrosis, and apoptosis were reduced in IL-6(-/-) hearts after TAC. Transcriptional and protein assays of myocardial tissue identified Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and signal transducer and activator of transcription 3 (STAT3) activation as important underlying mechanisms during cardiac hypertrophy induced by TAC. The involvement of these pathways in myocyte hypertrophy was verified in isolated cardiac myocytes from wild-type and IL-6(-/-) mice exposed to prohypertrophy agents. Furthermore, overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation, and exposure of H9c2 cells to IL-6 resulted in STAT3 activation that was attenuated by CaMKII inhibition. Together, these results identify the importance of CaMKII-dependent activation of STAT3 during cardiac myocyte hypertrophy via IL-6 signaling. CONCLUSIONS Genetic deletion of IL-6 attenuates TAC-induced LV hypertrophy and dysfunction, indicating a critical role played by IL-6 in the pathogenesis of LV hypertrophy in response to pressure overload. CaMKII plays an important role in IL-6-induced STAT3 activation and consequent cardiac myocyte hypertrophy. These findings may have significant therapeutic implications for LV hypertrophy and failure in patients with hypertension.

Induced Pluripotent Stem Cell (iPSC)-Derived Extracellular Vesicles Are Safer and More Effective for Cardiac Repair than iPSCs

Rationale: Extracellular vesicles (EVs) are tiny membrane-enclosed droplets released by cells through membrane budding or exocytosis. The myocardial reparative abilities of EVs derived from induced pluripotent stem cells (iPSCs) have not been directly compared with the source iPSCs. Objective: To examine whether iPSC-derived EVs can influence the biological functions of cardiac cells in vitro and to compare the safety and efficacy of iPSC-derived EVs (iPSC-EVs) and iPSCs for cardiac repair in vivo. Methods and Results: Murine iPSCs were generated, and EVs isolated from culture supernatants by sequential centrifugation. Atomic force microscopy, high-resolution flow cytometry, real-time quantitative RT-PCR, and mass spectrometry were used to characterize EV morphology and contents. iPSC-EVs were enriched in miRNAs and proteins with proangiogenic and cytoprotective properties. iPSC-EVs enhanced angiogenic, migratory, and antiapoptotic properties of murine cardiac endothelial cells in vitro. To compare the cardiac reparative capacities in vivo, vehicle, iPSCs, and iPSC-EVs were injected intramyocardially at 48 hours after a reperfused myocardial infarction in mice. Compared with vehicle-injected mice, both iPSC- and iPSC-EV–treated mice exhibited improved left ventricular function at 35 d after myocardial infarction, albeit iPSC-EVs rendered greater improvement. iPSC-EV injection also resulted in reduction in left ventricular mass and superior perfusion in the infarct zone. Both iPSCs and iPSC-EVs preserved viable myocardium in the infarct zone, whereas reduction in apoptosis was significant with iPSC-EVs. iPSC injection resulted in teratoma formation, whereas iPSC-EV injection was safe. Conclusions: iPSC-derived EVs impart cytoprotective properties to cardiac cells in vitro and induce superior cardiac repair in vivo with regard to left ventricular function, vascularization, and amelioration of apoptosis and hypertrophy. Because of their acellular nature, iPSC-EVs represent a safer alternative for potential therapeutic applications in patients with ischemic myocardial damage.

Remote Ischemic Preconditioning for Cardiac Surgery Reflections on Evidence of Efficacy

Effect of remote ischemic preconditioning on clinical outcomes in patients undergoing coronary artery bypass graft surgery: the ERICCA Trial Hausenloy et al N Engl J Med . 2015;373:1408–1417. A multi-center trial of remote ischemic preconditioning for heart surgery Meybohm et al N Engl J Med. 2015;373:1397–1407. Ever since its discovery more than 2 decades ago, remote ischemic preconditioning (RIPC) has generated tremendous interest among scientists and clinicians alike. However, two recent large, well-conducted, randomized controlled trials (RCTs) have failed to identify any significant benefit of RIPC during cardiac surgery. A reconciliatory yet objective review of cumulative evidence with regard to cardiac surgery reveals that RIPC in preclinical studies reduced infarct size after experimental myocardial infarction (MI), which is different from cardiac surgery; improved release of biomarkers, but not hard clinical end points, in proof-of-concept clinical trials with discordant results; and failed to produce significant improvement in outcomes in meta-analyses. This difficult journey of RIPC across the valley of death underscores the importance of scientific rigor and exercise of caution in interpreting data at every step of the way until efficacy of a purported therapy is proven conclusively in large RCTs . RIPC is a phenomenon, whereby brief episodes of ischemia in a distant vascular bed protect other organs in the body from subsequent ischemic injury. The concept that a noninvasive and simple procedure can protect organs during elective ischemic episodes has continued to generate tremendous interest among clinicians and scientists. Promising results from numerous basic studies led to many smaller clinical trials and meta-analyses, and then to two large, well-conducted RCTs. The recent results from Effect of Remote Ischaemic Preconditioning on Clinical Outcomes in CABG Surgery (ERICCA) and RIPHeart, however, have failed to identify any significant benefit of RIPC on hard clinical end points or surrogate markers of organ protection. …

Mechanical function of the left atrium is improved with epicardial ligation of the left atrial appendage: Insights from the LAFIT-LARIAT Registry

BACKGROUND Left atrial (LA) strain (ε) and ε rate (SR) analysis by 2-dimensional speckle tracking echocardiography is a novel method for functional assessment of the LA. OBJECTIVE The purpose of this study was to determine the impact of left atrial appendage (LAA) exclusion by Lariat epicardial ligation on mechanical function of the LA by performing ε and SR analysis before and after the procedure. METHODS A total of 66 patients who underwent successful LAA exclusion were included in the study. Of these 66 patients, 32 had adequate paired data for ε and SR analysis. SR during ventricular systole (LA-SRs) represents LA reservoir function, and SR during early ventricular diastole (LA-SRe) represents LA conduit function. ε and SR were determined from apical 4- and 2-chamber views using the electrocardiographic QRS as a reference point. LA volume index as surrogate for LA remodeling was measured from apical views. RESULTS Mean patient age was 70 ± 9.2 years. LAA ligation resulted in improved reservoir function (LA-SRs: pre 0.72, confidence interval [CI] 0.63-0.83 vs post 0.81, CI 0.73-0.98; P = .043) and conduit function (LA-SRe: pre 0.74, CI 0.67-0.99 vs post 0.89, CI 0.82-1.07; P = .025). LA volume index improved significantly with the Lariat (pre 35.4, CI 29.4-37.2 vs post 29.2, CI 28.2-35.9; P <.023). CONCLUSION LAA exclusion seems to improve mechanical function of the LA and results in reverse LA remodeling.

Meta-Analysis of Preclinical Data Reveals Efficacy of Cardiac Stem Cell Therapy for Heart Repair

Cell therapy has rapidly emerged as a potential option for cardiac repair in patients with ischemic heart disease. Since the turn of the century, several forms of cell therapy have been evaluated in clinical trials, including skeletal myoblasts, bone marrow mononuclear cells, mesenchymal stem cells, and cardiac stem cells (CSCs). Cell therapy, in its various forms, has generally been efficacious, providing modest improvements in cardiac structure and function in patients with acute myocardial infarction (MI), as well as chronic ischemic heart disease.1 Although bone marrow cells are relatively easy to harvest and deliver, these are not natural residents of cardiac tissue, and their ability to regenerate lost myocardium remains controversial. In the absence of an obvious choice, the search for newer cellular substrates has continued. Article, see p 1223 In 2003, Beltrami et al2 described the existence of c-kit+ cells in the heart, which were reported to be self-replicating, clonogenic, and multipotent, giving rise to cardiomyocytes, smooth muscle cells, and new blood vessels in ischemic rat hearts. Subsequent demonstration of heart repair with intravascular delivery of c-kit+ CSCs paved the way for clinical translation using intracoronary delivery.3 Intense research in this area quickly resulted in the discovery of several additional types of cardiac progenitors, including cardiosphere-derived cells (CDCs), Sca-1+ cells, cardiac side population cells, Isl1+ cells, and epicardial progenitors, among others. Of these, c-kit+ CSCs and CDCs have already been tested in randomized controlled trials in humans. Intracoronary injection of culture-expanded autologous c-kit+ CSCs into hearts of ischemic cardiomyopathy patients improved left ventricular ejection fraction (LVEF) and reduced infarct size in the Stem Cell Infusion in Patients With Ischemic cardiomyopathy (SCIPIO) trial.4 Injection of autologous CDCs into the infarct-related artery reduced scar mass and increased regional contractility with a nonsignificant …

Adjunctive ablation strategies improve the efficacy of pulmonary vein isolation in non-paroxysmal atrial fibrillation: a systematic review and meta-analysis

ABSTRACT Background: Pulmonary vein (PV) isolation (PVI) has suboptimal outcomes in patients with non-paroxysmal atrial fibrillation (AF). Adjunctive strategies employed to ablate non-PV triggers have shown favorable outcomes. Aims: To delineate the incremental benefit of adjunctive ablation in patients with non-paroxysmal AF through a meta-analysis. Methods and results: Database searches through August 2016 identified five non-randomized and seven randomized controlled trials (enrolling 1694 patients). The adjunctive strategies employed for non-PV ablation included focal impulse and rotor modulation; empirical linear lines, ablation of complex fractionated atrial electrograms and ganglionated plexi. The risk ratio (RR) for AF recurrence, calculated with random effects meta-analysis showed a 36% reduction of AF recurrence at a median follow up of 12 months (RR: 0.64, 95% Confidence interval: 0.48 to 0.85; p = 0.003). The benefits persisted during longer follow up when assessed in subgroup analysis. Conclusions: Addition of adjunctive ablation to PVI improves outcomes.

Bone Marrow Cell Therapy for Ischemic Heart Disease and the Role of Cardiac Imaging in Evaluation of Outcomes

Cell therapy for cardiac repair has gained vigorous momentum over the past two decades. Several different types of cells, including skeletal myoblasts, cardiac stem cells, and bone marrow cells (BMCs) have been used in patients with myocardial infarction and cardiomyopathy. A large number of clinical trials of BMC therapy that each enrolled a small number of patients have already been completed. Although results from these trials utilizing diverse cell types injected via different routes in greatly variable numbers have been disparate, findings from the majority of meta-analyses indicate that BMC therapy is beneficial. These results show a modest yet significant improvement in cardiac structural and functional parameters in BMC-treated patients compared with controls. Importantly, subgroup analysis of pooled data shows generally concordant findings with regard to changes in LV structure and function measured by left ventriculogram, echocardiography, SPECT and MRI. However, the selection of imaging technique(s) for cell therapy trials often depends on not only accuracy of data, but also logistics and patient characteristics. Furthermore, besides information gathered by imaging, the effects of cell therapy are also reflected in patient outcomes. Cumulative evidence from meta-analyses also indicates that BMC therapy is associated with improvement in patient survival and other important clinical end-points. The outcomes from ongoing large randomized controlled trials are eagerly awaited at this time for conclusive answers in an emerging and highly promising field.