Talha A. Farid

Impact of Cell Therapy on Myocardial Perfusion and Cardiovascular Outcomes in Patients With Angina Refractory to Medical Therapy A Systematic Review and Meta-Analysis

RATIONALE The effect of stem/progenitor cells on myocardial perfusion and clinical outcomes in patients with refractory angina remains unclear because studies published to date have been small phase I-II trials. OBJECTIVE We performed a meta-analysis of randomized controlled trials to evaluate the effect of cell-based therapy in patients with refractory angina who were ineligible for coronary revascularization. METHODS AND RESULTS Several data sources were searched from inception to September 2015, which yielded 6 studies. The outcomes pooled were indices of angina (anginal episodes, Canadian Cardiovascular Society angina class, exercise tolerance, and antianginal medications), myocardial perfusion, and clinical end points. We combined the reported clinical outcomes (myocardial infarction, cardiac-related hospitalization, and mortality) into a composite end point (major adverse cardiac events). Mean difference (MD), standardized mean differences, or odds ratio were calculated to assess relevant outcomes. Our analysis shows an improvement in anginal episodes (MD, -7.81; 95% confidence interval [CI], -15.22 to -0.41), use of antianginal medications (standardized MD, -0.59; 95% CI, -1.03 to -0.14), Canadian Cardiovascular Society class (MD, -0.58; 95% CI, -1.00 to -0.16), exercise tolerance (standardized MD, 0.331; 95% CI, 0.08 to 0.55), and myocardial perfusion (standardized MD, -0.49; 95% CI, -0.76 to -0.21) and a decreased risk of major adverse cardiac events (odds ratio, 0.49; 95% CI, 0.25 to 0.98) and arrhythmias (odds ratio, 0.25; 95% CI, 0.06 to 0.98) in cell-treated patients when compared with patients on maximal medical therapy. CONCLUSIONS The present meta-analysis indicates that cell-based therapies are not only safe but also lead to an improvement in indices of angina, relevant clinical outcomes, and myocardial perfusion in patients with refractory angina. These encouraging results suggest that larger, phase III randomized controlled trials are in order to conclusively determine the effect of stem/progenitor cells in refractory angina.

Increased Risk of Adverse Neurocognitive Outcomes With Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors.

Background— There is encouraging evidence of the efficacy of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors; however, their long-term safety remains unclear. We performed a meta-analysis of studies to evaluate the long-term safety of PCSK9 inhibitors. Methods and Results— Our search strategy yielded 11 studies (9 smaller early-phase and 2 larger outcome trials). The outcomes assessed were cumulative serious adverse events, musculoskeletal adverse events, neurocognitive adverse events, and stroke. Odds ratio (OR) was calculated using the Mantel–Haenszel method. Subgroup analysis was done to assess the difference in safety between the smaller early-phase studies and the larger outcome studies. Our meta-analysis suggested no difference in the incidence of serious adverse events (OR, 1.00; 95% confidence interval [CI], 0.88−1.15), musculoskeletal adverse events (OR, 1.01; 95% CI, 0.87−1.13), neurocognitive adverse events (OR, 1.29; 95% CI, 0.64−2.59), or stroke (OR, 1.44; 95% CI, 0.57−3.65) with the use of PCSK9 inhibitors. Subgroup analysis of the 2 large outcome studies did suggest an increased incidence of neurocognitive adverse events (OR, 2.85; 95% CI, 1.34−6.06) with the use of PCSK9 inhibitors. However, the overall incidence of neurocognitive adverse events and stroke was <1%, whereas the cumulative incidence of serious adverse events and musculoskeletal events was >10% in both the groups. Conclusions— Our analysis suggests that PCSK9 inhibitors are not associated with an increased risk of cumulative severe adverse effects, musculoskeletal effects, or stroke. There is a signal toward adverse neurocognitive effects, seen in the outcome studies with a larger sample size and longer follow-up. There should be close monitoring, for the increased risk of neurocognitive events in the ongoing outcome studies and post-marketing surveillance.

Recent Developments in Stem and Progenitor Cell Therapy for Cardiac Repair

Recent Developments in Cardiovascular Research: The goal of “Recent Developments” is to provide a concise but comprehensive overview of new advances in cardiovascular research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings. This will enable readers who are not experts in a particular field to grasp the significance and effect of work performed in other fields. It is our hope and expectation that these “Recent Development” articles will help readers to gain a broader awareness and a deeper understanding of the status of research across the vast landscape of cardiovascular research— The Editors . Making our way through the beginning of the 21st century, we have seen the field of cardiovascular medicine make significant advances in both biomedical research and patient care. Despite these advancements, we continue to face statistics, which force us, time and again, to report heart failure (HF) as a leading cause of death in the United States and in much of the rest of the developed world.1 Indeed, refined pharmacological and surgical approaches have proven effective in management of acute and chronic cardiovascular diseases, but more frequently than not, only palliative measures are available, which serve to merely alleviate the burden of symptoms and delay disease progression to end-stage HF. HF itself is most accurately defined by the heart’s inability to sufficiently deliver blood to the surrounding organs and tissues of the body. Although there are a host of pathologies that can contribute to this condition, myocardial infarction (MI) resulting from atherosclerotic coronary artery disease is the leading event culminating in HF. After infarction, the heart experiences significant myocyte death and tissue necrosis. Damaged cardiac parenchyma is eventually replaced with fibrous scar, which lacks the contractile and conductive properties of normal myocardial …

Identification and Ablation of Dormant Conduction in Atrial Fibrillation Using Adenosine

Background: Ablation is used for treatment of atrial fibrillation (AF) but recurrence is common. Dormant conduction is hypothesized to be responsible for these recurrences, and the role of adenosine in identification and ablation of these pathways is controversial with conflicting results on AF recurrence. Materials and Methods: We conducted a meta‐analysis for studies evaluating AF ablation and adenosine use. Included in the meta‐analysis were human studies that compared ablation using adenosine or adenosine triphosphate (ATP) and reported freedom from AF in patients beyond a minimum follow‐up of 6 months. Results: Our analysis suggests that the use of adenosine leads to a decrease in recurrence of AF compared to the cohort which did not utilize adenosine. Subgroup analysis showed no difference in the recurrence of AF with the modality used for ablation (cryoablation vs. radiofrequency ablation) or with the preparation of adenosine used (ATP vs. adenosine). There was a significant benefit in delayed administration of ATP over early administration. Pooling results of only randomized control trials did not show any significant difference in AF recurrence. Conclusions: Adenosine‐guided identification and ablation of dormant pathways may lead to a decrease in recurrence of AF.

KATP Channel Blockade as a Novel Antiarrhythmic Strategy: Evolving From Tachy to Brady Therapy

A TP-sensitive potassium (KATP) channels have been best characterized in pancreatic tissue where they regulate insulin secretion from b islet cells (1). Since their discovery in cardiac cells (2), they have been shown to play a central role in coupling cellular metabolism with cardiac electrophysiology. The KATP channel is a heterooctamer complex. It consists of tetramers of an inwardly rectifying K channel subunit, the pore-forming subunit, and an outer sulfonylurea receptor subunit, the regulatory subunit. Each of these subunits has different isoforms and differential isoform expression in different organ systems. As a result, their function varies in different tissues, organ systems, and even within a single organ. Under normal physiological conditions, when ATP levels inside cardiomyocytes are replete, KATP channels are closed and do not contribute to action potential configuration. On the contrary, during ischemia (or hypoglycemia) when intracellular ATP levels are depleted, activation of KATP channels results in efflux of potassium to extracellular environment. This can result in shortening of action potential duration (and refractory period) and decreased conduction velocity, creating a substrate for tachy arrhythmias. The roles of KATP channels in cardiac tachy arrhythmogenesis and its modulation to prevent cardiac arrhythmias have been of interest to our laboratory. We have also demonstrated that there is differential expression of KATP channels between epicardium and endocardium in human hearts, contributing to left ventricular transmural dispersion of refractoriness during ischemia that provides a substrate for arrhythmogenesis. Blocking KATP channels using glibenclamide prevents the shortening of action potential (and effective refractor period) caused by ischemia and attenuates the dispersion of refractoriness, contributing to spontaneous termination of ventricular fibrillation (VF) (3). In a biophysically detailed rabbit ventricular computer model, we demonstrated once again that the KATP channel expression heterogeneity led to higher transmural activation rate gradients and sustained VF. The simulated glibenclamide pretreatment could suppress VF by blocking the KATP channels, and an early termination was observed when this drug effect was applied during VF (4). It has been suggested that the expression of KATP channels in heart is not homogeneous. Rather, there is spatial heterogeneity in the expression of KATP channels. Glukhov et al. (5) studied the effect of isoform-specific KATP channel openers in mice and reported that there is differential expression of KATP channel isoforms in mice atria and ventricles that translates into different effects of KATP channel modulation on action potential configuration in these chambers. Additionally, differential expression of KATP channel isoforms has also been demonstrated within the same cardiac chamber in ischemic conditions. Isodoro Taveres et al. (6) demonstrated selectively increased KATP subunit conductance and expression in cardiomyocytes from infarct border zone. Because KATP channels are activated in ischemic conditions, their activation, in the setting of heterogeneous expression, can result in varied effects on action potential duration contributing to spatial heterogeneity of refractory period and arrhythmogenesis. Although there has been some suggestion of KATP channel activation contributing to transient bradyarrhythmias (7), the role of KATP channels, as well as KATP channel modulation, in bradyarrhythmia has not been very well studied. The physiological basis by which KATP

Stent thrombosis with bioabsorbable polymer drug-eluting stents: insights from the Food and Drug Administration database

Background SYNERGY, a bioabsorbable polymer-based, everolimus-eluting stent (BP-DES), recently received regulatory approval in the USA for use in percutaneous coronary interventions. Yet, information on the safety of BP-DES in routine clinical practice is limited. Our aim was to compare the safety of the recently approved BP-DES with current durable polymer drug-eluting stents (DP-DES) by analyzing adverse events, namely, stent thrombosis (ST), reported to the Manufacturer and User Facility Device Experience (MAUDE) database. Materials and methods The MAUDE database requires nationwide mandatory notification for adverse events on devices approved for clinical use. This database was searched for adverse events reported between 1 October 2015 and 25 December 2016, encountered after the placement of either BP-DES or DP-DES. Only those adverse events were included where the exposure period to the stents was comparable after the index procedure. Of all the adverse events reported, the event of interest was ST. Results A total of 951 adverse events were reported. ST occurred in 48/951 of all events, 31/309 and 17/642 when BP-DES or DP-DES were used, respectively (P=0.00001). Of the 31 ST events with BP-DES, 68% (21/31) occurred within less than or equal to 24 h of the index procedure and 52% (16/31) occurred within less than or equal to 2 h. Conclusion Our results raise the possibility of an increased risk of ST, particularly early ST (within 24 h), with the recently approved BP-DES. However, because of the inherent limitations of reporting within the MAUDE database, these data merely highlight a potential need for additional surveillance and randomized trials to assess further the safety of the bioabsorbable platform.

Impact of Cell Therapy on Myocardial Perfusion and Cardiovascular Outcomes in Patients With Angina Refractory to Medical TherapyNovelty and Significance: A Systematic Review and Meta-Analysis

RATIONALE The effect of stem/progenitor cells on myocardial perfusion and clinical outcomes in patients with refractory angina remains unclear because studies published to date have been small phase I-II trials. OBJECTIVE We performed a meta-analysis of randomized controlled trials to evaluate the effect of cell-based therapy in patients with refractory angina who were ineligible for coronary revascularization. METHODS AND RESULTS Several data sources were searched from inception to September 2015, which yielded 6 studies. The outcomes pooled were indices of angina (anginal episodes, Canadian Cardiovascular Society angina class, exercise tolerance, and antianginal medications), myocardial perfusion, and clinical end points. We combined the reported clinical outcomes (myocardial infarction, cardiac-related hospitalization, and mortality) into a composite end point (major adverse cardiac events). Mean difference (MD), standardized mean differences, or odds ratio were calculated to assess relevant outcomes. Our analysis shows an improvement in anginal episodes (MD, -7.81; 95% confidence interval [CI], -15.22 to -0.41), use of antianginal medications (standardized MD, -0.59; 95% CI, -1.03 to -0.14), Canadian Cardiovascular Society class (MD, -0.58; 95% CI, -1.00 to -0.16), exercise tolerance (standardized MD, 0.331; 95% CI, 0.08 to 0.55), and myocardial perfusion (standardized MD, -0.49; 95% CI, -0.76 to -0.21) and a decreased risk of major adverse cardiac events (odds ratio, 0.49; 95% CI, 0.25 to 0.98) and arrhythmias (odds ratio, 0.25; 95% CI, 0.06 to 0.98) in cell-treated patients when compared with patients on maximal medical therapy. CONCLUSIONS The present meta-analysis indicates that cell-based therapies are not only safe but also lead to an improvement in indices of angina, relevant clinical outcomes, and myocardial perfusion in patients with refractory angina. These encouraging results suggest that larger, phase III randomized controlled trials are in order to conclusively determine the effect of stem/progenitor cells in refractory angina.

Impact of Cell Therapy on Myocardial Perfusion and Cardiovascular Outcomes in Patients With Angina Refractory to Medical TherapyNovelty and Significance

RATIONALE The effect of stem/progenitor cells on myocardial perfusion and clinical outcomes in patients with refractory angina remains unclear because studies published to date have been small phase I-II trials. OBJECTIVE We performed a meta-analysis of randomized controlled trials to evaluate the effect of cell-based therapy in patients with refractory angina who were ineligible for coronary revascularization. METHODS AND RESULTS Several data sources were searched from inception to September 2015, which yielded 6 studies. The outcomes pooled were indices of angina (anginal episodes, Canadian Cardiovascular Society angina class, exercise tolerance, and antianginal medications), myocardial perfusion, and clinical end points. We combined the reported clinical outcomes (myocardial infarction, cardiac-related hospitalization, and mortality) into a composite end point (major adverse cardiac events). Mean difference (MD), standardized mean differences, or odds ratio were calculated to assess relevant outcomes. Our analysis shows an improvement in anginal episodes (MD, -7.81; 95% confidence interval [CI], -15.22 to -0.41), use of antianginal medications (standardized MD, -0.59; 95% CI, -1.03 to -0.14), Canadian Cardiovascular Society class (MD, -0.58; 95% CI, -1.00 to -0.16), exercise tolerance (standardized MD, 0.331; 95% CI, 0.08 to 0.55), and myocardial perfusion (standardized MD, -0.49; 95% CI, -0.76 to -0.21) and a decreased risk of major adverse cardiac events (odds ratio, 0.49; 95% CI, 0.25 to 0.98) and arrhythmias (odds ratio, 0.25; 95% CI, 0.06 to 0.98) in cell-treated patients when compared with patients on maximal medical therapy. CONCLUSIONS The present meta-analysis indicates that cell-based therapies are not only safe but also lead to an improvement in indices of angina, relevant clinical outcomes, and myocardial perfusion in patients with refractory angina. These encouraging results suggest that larger, phase III randomized controlled trials are in order to conclusively determine the effect of stem/progenitor cells in refractory angina.

Oxygen Administration Does Not Influence the Prognosis of Acute Myocardial Infarction: A Meta-analysis.

Background: The safety and efficacy of supplemental oxygen in acute myocardial infarction (AMI) remains unclear. Study Question: To evaluate the safety and efficacy of supplemental oxygen in patients who present with AMI. Data Sources: We systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, ISI Web of Science, Scopus, and conference proceedings from inception through January 2016. Study Design: Eligible studies were randomized trials that evaluated the role of oxygen compared with room air in AMI. The clinical outcome measured was 30-day mortality, and odds ratio (OR) was calculated for the measured outcome. The Mantel–Haenszel method was used to pool 30-day mortality in a random-effects model. Sensitivity analysis was carried out to evaluate the effect of revascularization of the culprit artery on the outcome. Results: The pooled analysis suggested no difference in 30-day mortality [OR 1.09; 95% confidence interval (CI), 0.30–4.00; P = 0.89] between oxygen and room air. Metaregression demonstrated that all the between-study variance was because of coronary revascularization (P = 0.01, R2 = 1.0). A subgroup analysis suggested a trend toward increased mortality with oxygen (OR 3.26; 95% CI, 0.94–11.29; P = 0.06) when less than half of the patient population underwent revascularization. On the other hand, there was a nonsignificant numerical decrease in mortality with oxygen (OR 0.41; 95% CI, 0.14–1.19; P = 0.10) in the presence of coronary revascularization. Metaregression confirmed that all the between-study variance was because of coronary revascularization (P = 0.01, R2 = 1.0). Conclusions: In this meta-analysis, we found that the evidence on the safety and efficacy of oxygen was not only weak and inconsistent but also had modest statistical power. The variation in results was mainly because of the presence or absence of revascularization of the culprit artery. Adequately powered studies are needed to further delineate the role of oxygen in patients undergoing coronary revascularization.