Reza Ardehali

Systematic Review: The Comparative Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Graft Surgery

Context The relative benefits and harms of coronary artery bypass graft surgery (CABG) versus percutaneous coronary intervention (PCI) are sometimes unclear. Contribution This systematic review of 23 randomized trials found that survival at 10 years was similar for CABG and PCI, even among diabetic patients. Procedural strokes and angina relief were more common after CABG (risk difference, 0.6% and about 5% to 8%, respectively), whereas repeated revascularization procedures were more common after PCI (risk difference, 24% at 1 year). Caution Only 1 small trial used drug-eluting stents. Few patients with extensive coronary disease or poor ventricular function were enrolled. The Editors Coronary artery bypass graft (CABG) surgery and catheter-based percutaneous coronary intervention (PCI), with or without coronary stents, are alternative approaches to mechanical coronary revascularization. These 2 coronary revascularization techniques are among the most common major medical procedures performed in North America and Europe: In 2005, 261000 CABG procedures and 645000 PCI procedures were performed in the United States alone (1). However, the comparative effectiveness of CABG and PCI remains poorly understood for patients in whom both procedures are technically feasible and coronary revascularization is clinically indicated. In patients with left main or triple-vessel coronary artery disease with reduced left ventricular function, CABG is generally preferred because randomized, controlled trials (RCTs) have shown that it improves survival compared with medical therapy (2, 3). In patients with most forms of single-vessel disease, PCI is generally the preferred form of coronary revascularization (4), in light of its lower clinical risk and the evidence that PCI reduces angina and myocardial ischemia in this subset of patients (5). Most RCTs comparing CABG and PCI have been conducted in populations with coronary artery disease between these extremes, namely patients with single-vessel, proximal left anterior descending disease; most forms of double-vessel disease; or less extensive forms of triple-vessel disease. We sought to evaluate the evidence from RCTs on the comparative effectiveness of PCI and CABG. We included trials using balloon angioplasty or coronary stents because quantitative reviews have shown no differences in mortality or myocardial infarction between these PCI techniques (6, 7). We also included trials using standard or minimally invasive CABG or both procedures (8, 9). We sought to document differences between PCI and CABG in survival, cardiovascular complications (such as stroke and myocardial infarction), and freedom from angina. Finally, we reviewed selected observational studies to assess the generalizability of the RCTs. Methods Data Sources We searched the MEDLINE, EMBASE, and Cochrane databases for studies published between January 1966 and August 2006 by using such terms as angioplasty, coronary, and coronary artery bypass surgery, as reported in detail elsewhere (10). We also sought additional studies by reviewing the reference lists of included articles, conference abstracts, and the bibliographies of expert advisors. We did not limit the searches to the English language. Study Selection We sought RCTs that compared health outcomes of PCI and CABG. We excluded trials that compared PCI alone or CABG alone with medical therapy, those that compared 2 forms of PCI, and those that compared 2 forms of CABG. The outcomes of interest were survival, myocardial infarction, stroke, angina, and use of additional revascularization procedures. Two investigators independently reviewed titles, abstracts, and the full text as needed to determine whether studies met inclusion criteria. Conflicts between reviewers were resolved through re-review and discussion. We did not include results published solely in abstract form. Data Extraction and Quality Assessment Two authors independently abstracted data on study design; setting; population characteristics (sex, age, race/ethnicity, comorbid conditions, and coronary anatomy); eligibility and exclusion criteria; procedures performed; numbers of patients screened, eligible, enrolled, and lost to follow-up; method of outcome assessment; and results for each outcome. We assessed the quality of included trials by using predefined criteria and graded their quality as A, B, or C by using methods described in detail elsewhere (10). In brief, a grade of A indicates a high-quality trial that clearly described the population, setting, interventions, and comparison groups; randomly allocated patients to alternative treatments; had low dropout rates; and reported intention-to-treat analysis of outcomes. A grade of B indicates a randomized trial with incomplete information about methods that might mask important limitations. A grade of C indicates that the trial had evident flaws, such as improper randomization, that could introduce significant bias. Data Synthesis and Analysis We used random-effects models to compute weighted mean rates and SEs for each outcome. We computed summary risk differences and odds ratios between PCI and CABG and the 95% CI for each outcome of interest at annual intervals. Because the results did not differ materially when risk differences and odds ratios (10) were used and the low rate of several outcomes (for example, procedural mortality) made the risk difference a more stable outcome metric (11, 12), we report here only the risk differences. We assessed heterogeneity of effects by using chi-square and I 2 statistics (13). When effects were heterogeneous (I 2 > 50%), we explored the effects of individual studies on summary effects by removing each study individually. We assessed the possibility of publication bias by visual inspection of funnel plots and calculated the number of missing studies required to change a statistically significant summary effect to not statistically significant (11). We performed analyses by using Comprehensive Meta-Analysis software, version 2.0 (Biostat, Englewood, New Jersey). Inclusion of Observational Studies We also searched for observational data to evaluate the generalizability of the RCT results, as reported in detail elsewhere (10). In brief, we included observational studies from clinical or administrative databases that included at least 1000 recipients of each revascularization procedure and provided sufficient information about the patient populations (such as demographic characteristics, preprocedure coronary anatomy, and comorbid conditions) and procedures performed (such as balloon angioplasty vs. bare-metal stents vs. drug-eluting stents). Role of the Funding Source This project was supported by the Agency for Healthcare Research and Quality. Representatives of the funding agency reviewed and commented on the study protocol and drafts of the manuscript, but the authors had final responsibility for the design, conduct, analysis, and reporting of the study. Results We identified 1695 potentially relevant articles, of which 204 merited full-text review (Appendix Figure). A total of 113 articles reporting on 23 unique RCTs met inclusion criteria (Table 1 [14126]). These trials enrolled a total of 9963 patients, of whom 5019 were randomly assigned to PCI and 4944 to CABG. Most trials were conducted in Europe, the United Kingdom, or both locations; only 3 trials were performed in the United States. The early studies (patient entry from 1987 to 1993) used balloon angioplasty as the PCI technique, and the later studies (patient entry from 1994 to 2002) used stents as the PCI technique. Only 1 small trial of PCI versus CABG used drug-eluting stents (116). Nine trials limited entry to patients with single-vessel disease of the proximal left anterior descending artery, whereas the remaining 14 trials enrolled patients with multivessel disease, either predominantly (3 trials) or exclusively (11 trials). Appendix Figure. Study flow diagram. CABG= coronary artery bypass grafting; CAD= coronary artery disease; PCI= percutaneous coronary intervention; RCT= randomized, controlled trial. Table 1. Overview of Randomized, Controlled Trials The quality of 21 trials was graded as A, and 1 trial (117) was graded as B. One trial (116) was graded as C because randomization may not have been properly executed (details are available elsewhere [10]). We performed sensitivity analyses by removing these studies from the analysis, and our summary results did not change statistically significantly. The average age of the trial participants was 61 years, 27% were women, and most were of European ancestry. Roughly 20% had diabetes, half had hypertension, and half had hyperlipidemia. Whereas approximately 40% of patients had a previous myocardial infarction, few had heart failure or poor left ventricular function. Among studies that enrolled patients with multivessel coronary disease, most had double-vessel rather than triple-vessel disease. Revascularization procedures were performed by using standard methods for the time the trial was conducted (Table 1). Among patients with multivessel disease, more grafts were placed during CABG than vessels were dilated during PCI. Among patients assigned to PCI, stents were commonly used in the recent studies, but in the earlier trials, balloon angioplasty was standard. Among patients assigned to CABG, arterial grafting with the left internal mammary artery was frequently done, especially in more recent trials. Some studies used minimally invasive, direct coronary artery bypass and off-pump operations to perform CABG in patients with single-vessel left anterior descending disease (Table 1). Short-Term and Procedural Outcomes Survival (within 30 days of the procedure) was high for both procedures: 98.9% for PCI and 98.2% for CABG. When data from all trials were combined, the survival difference between PCI and CABG was small and not statistically significant (0.2% [95% CI, 0.3% to 0.6%]) (Figure 1

An antibody against SSEA-5 glycan on human pluripotent stem cells enables removal of teratoma-forming cells

An important risk in the clinical application of human pluripotent stem cells (hPSCs), including human embryonic and induced pluripotent stem cells (hESCs and hiPSCs), is teratoma formation by residual undifferentiated cells. We raised a monoclonal antibody against hESCs, designated anti–stage-specific embryonic antigen (SSEA)-5, which binds a previously unidentified antigen highly and specifically expressed on hPSCs—the H type-1 glycan. Separation based on SSEA-5 expression through fluorescence-activated cell sorting (FACS) greatly reduced teratoma-formation potential of heterogeneously differentiated cultures. To ensure complete removal of teratoma-forming cells, we identified additional pluripotency surface markers (PSMs) exhibiting a large dynamic expression range during differentiation: CD9, CD30, CD50, CD90 and CD200. Immunohistochemistry studies of human fetal tissues and bioinformatics analysis of a microarray database revealed that concurrent expression of these markers is both common and specific to hPSCs. Immunodepletion with antibodies against SSEA-5 and two additional PSMs completely removed teratoma-formation potential from incompletely differentiated hESC cultures.

Endogenous Wnt signalling in human embryonic stem cells generates an equilibrium of distinct lineage-specified progenitors

The pluripotent nature of human embryonic stem cells (hESCs) makes them convenient for deriving therapeutically relevant cells. Here we show using Wnt reporter hESC lines that the cells are heterogeneous with respect to endogenous Wnt signalling activity. Moreover, the level of Wnt signalling activity in individual cells correlates with differences in clonogenic potential and lineage-specific differentiation propensity. The addition of Wnt protein or, conversely, a small-molecule Wnt inhibitor (IWP2) reduces heterogeneity, allowing stable expansion of Wnthigh or Wntlow hESC populations, respectively. On differentiation, the Wnthigh hESCs predominantly form endodermal and cardiac cells, whereas the Wntlow hESCs generate primarily neuroectodermal cells. Thus, heterogeneity with respect to endogenous Wnt signalling underlies much of the inefficiency in directing hESCs towards specific cell types. The relatively uniform differentiation potential of the Wnthigh and Wntlow hESCs leads to faster and more efficient derivation of targeted cell types from these populations.

Developmental Heterogeneity of Cardiac Fibroblasts Does Not Predict Pathological Proliferation and Activation

Rationale: Fibrosis is mediated partly by extracellular matrix–depositing fibroblasts in the heart. Although these mesenchymal cells are reported to have multiple embryonic origins, the functional consequence of this heterogeneity is unknown. Objective: We sought to validate a panel of surface markers to prospectively identify cardiac fibroblasts. We elucidated the developmental origins of cardiac fibroblasts and characterized their corresponding phenotypes. We also determined proliferation rates of each developmental subset of fibroblasts after pressure overload injury. Methods and Results: We showed that Thy1+CD45−CD31−CD11b−Ter119− cells constitute the majority of cardiac fibroblasts. We characterized these cells using flow cytometry, epifluorescence and confocal microscopy, and transcriptional profiling (using reverse transcription polymerase chain reaction and RNA-seq). We used lineage tracing, transplantation studies, and parabiosis to show that most adult cardiac fibroblasts derive from the epicardium, a minority arises from endothelial cells, and a small fraction from Pax3-expressing cells. We did not detect generation of cardiac fibroblasts by bone marrow or circulating cells. Interestingly, proliferation rates of fibroblast subsets on injury were identical, and the relative abundance of each lineage remained the same after injury. The anatomic distribution of fibroblast lineages also remained unchanged after pressure overload. Furthermore, RNA-seq analysis demonstrated that Tie2-derived and Tbx18-derived fibroblasts within each operation group exhibit similar gene expression profiles. Conclusions: The cellular expansion of cardiac fibroblasts after transaortic constriction surgery was not restricted to any single developmental subset. The parallel proliferation and activation of a heterogeneous population of fibroblasts on pressure overload could suggest that common signaling mechanisms stimulate their pathological response.

Aspirin and Clopidogrel Resistance

Despite aspirins and clopidogrels proven benefit in reducing cardiovascular (CV) events, recurrent CV events still occur in patients receiving antiplatelet therapy. Many of these patients are resistant or only partially responsive to the antiplatelet effects of aspirin and clopidogrel, as determined by standard platelet assays. However, current clinical guidelines do not support routine screening for aspirin or clopidogrel resistance, in part because determination of the most appropriate screening test has not been established. This review attempts to (1) describe the phenomena of clinical aspirin and clopidogrel resistance (ie, treatment failure), (2) discuss the complexity of defining and identifying aspirin and clopidogrel resistance, (3) identify factors that may be responsible for aspirin and clopidogrel resistance, (4) outline several standard platelet function assays and their limitations, and (5) describe potential new antiplatelet therapies that may benefit aspirin- or clopidogrel-resistant patients.

Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice

Significance The nature of postnatal cardiomyogenesis in mammals remains in dispute. Here, we provide cell-level evidence for the birth of cardiomyocytes in newborn and adult mice. Our clonal analysis, based on the mosaic analysis with double markers mouse model, shows that cardiomyocytes are the parent cell of origin of cardiomyocytes that are generated postnatally. Our findings confirm that limited, symmetric division of cardiomyocytes is a rare phenomenon in the mouse heart after birth. The mammalian heart has long been considered a postmitotic organ, implying that the total number of cardiomyocytes is set at birth. Analysis of cell division in the mammalian heart is complicated by cardiomyocyte binucleation shortly after birth, which makes it challenging to interpret traditional assays of cell turnover [Laflamme MA, Murray CE (2011) Nature 473(7347):326–335; Bergmann O, et al. (2009) Science 324(5923):98–102]. An elegant multi-isotope imaging-mass spectrometry technique recently calculated the low, discrete rate of cardiomyocyte generation in mice [Senyo SE, et al. (2013) Nature 493(7432):433–436], yet our cellular-level understanding of postnatal cardiomyogenesis remains limited. Herein, we provide a new line of evidence for the differentiated α-myosin heavy chain-expressing cardiomyocyte as the cell of origin of postnatal cardiomyogenesis using the “mosaic analysis with double markers” mouse model. We show limited, life-long, symmetric division of cardiomyocytes as a rare event that is evident in utero but significantly diminishes after the first month of life in mice; daughter cardiomyocytes divide very seldom, which this study is the first to demonstrate, to our knowledge. Furthermore, ligation of the left anterior descending coronary artery, which causes a myocardial infarction in the mosaic analysis with double-marker mice, did not increase the rate of cardiomyocyte division above the basal level for up to 4 wk after the injury. The clonal analysis described here provides direct evidence of postnatal mammalian cardiomyogenesis.

Isolation of primitive endoderm, mesoderm, vascular endothelial and trophoblast progenitors from human pluripotent stem cells

To identify early populations of committed progenitors derived from human embryonic stem cells (hESCs), we screened self-renewing, BMP4-treated and retinoic acid–treated cultures with >400 antibodies recognizing cell-surface antigens. Sorting of >30 subpopulations followed by transcriptional analysis of developmental genes identified four distinct candidate progenitor groups. Subsets detected in self-renewing cultures, including CXCR4+ cells, expressed primitive endoderm genes. Expression of Cxcr4 in primitive endoderm was confirmed in visceral endoderm of mouse embryos. BMP4-induced progenitors exhibited gene signatures of mesoderm, trophoblast and vascular endothelium, suggesting correspondence to gastrulation-stage primitive streak, chorion and allantois precursors, respectively. Functional studies in vitro and in vivo confirmed that ROR2+ cells produce mesoderm progeny, APA+ cells generate syncytiotrophoblasts and CD87+ cells give rise to vasculature. The same progenitor classes emerged during the differentiation of human induced pluripotent stem cells (hiPSCs). These markers and progenitors provide tools for purifying human tissue-regenerating progenitors and for studying the commitment of pluripotent stem cells to lineage progenitors.

Isolated Disease of the Proximal Left Anterior Descending Artery: Comparing the Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Surgery

OBJECTIVES This study sought to systematically compare the effectiveness of percutaneous coronary intervention and coronary artery bypass surgery in patients with single-vessel disease of the proximal left anterior descending (LAD) coronary artery. BACKGROUND It is uncertain whether percutaneous coronary interventions (PCI) or coronary artery bypass grafting (CABG) surgery provides better clinical outcomes among patients with single-vessel disease of the proximal LAD. METHODS We searched relevant databases (MEDLINE, EMBASE, and Cochrane from 1966 to 2006) to identify randomized controlled trials that compared outcomes for patients with single-vessel proximal LAD assigned to either PCI or CABG. RESULTS We identified 9 randomized controlled trials that enrolled a total of 1,210 patients (633 received PCI and 577 received CABG). There were no differences in survival at 30 days, 1 year, or 5 years, nor were there differences in the rates of procedural strokes or myocardial infarctions, whereas the rate of repeat revascularization was significantly less after CABG than after PCI (at 1 year: 7.3% vs. 19.5%; at 5 years: 7.3% vs. 33.5%). Angina relief was significantly greater after CABG than after PCI (at 1 year: 95.5% vs. 84.6%; at 5 years: 84.2% vs. 75.6%). Patients undergoing CABG spent 3.2 more days in the hospital than those receiving PCI (95% confidence interval: 2.3 to 4.1 days, p < 0.0001), required more transfusions, and were more likely to have arrhythmias immediately post-procedure. CONCLUSIONS In patients with single-vessel, proximal LAD disease, survival was similar in CABG-assigned and PCI-assigned patients; CABG was significantly more effective in relieving angina and led to fewer repeat revascularizations.

Statin Use in Patients With Extremely Low Low-Density Lipoprotein Levels Is Associated With Improved Survival

Background— Aggressive lipid management has recently become the standard of care for patients with coronary heart disease. The safety and effectiveness of statin usage for patients with extremely low low-density lipoprotein (LDL) levels are less clear, however. The aim of this study was to investigate the safety and clinical outcomes of statin treatment in patients with LDL cholesterol levels below 60 mg/dL. Methods and Results— A total of 6107 consecutive patients with LDL levels less than 60 mg/dL were identified from a tertiary care medical center or affiliated community clinic. Statin therapy was defined as a prescription during the 150 days after the low LDL value was obtained. The propensity to be treated with a statin was used to adjust the association of statin therapy and survival. A total of 4295 patients (70%) had at least 1 prescription for any medication during the 150-day observation period after the low LDL value. Their mean age was 65 years, 43% had prior ischemic heart disease, and 47% had diabetes mellitus. Statins were prescribed in 2564 patients (60%) after the low LDL value was observed. During a mean follow-up of 2.0±1.4 years after the observation period, there were 510 deaths. After controlling for the propensity to receive a statin, statin therapy was associated with improved survival (hazard ratio [HR], 0.65; 95% CI, 0.53 to 0.80). This lower mortality was also observed for subgroups of patients already taking statins at baseline (HR, 0.58; 95% CI, 0.38 to 0.88), those with extremely low LDL levels (<40 mg/dL, n=623; HR, 0.51; 95% CI, 0.33 to 0.79), and those without a history of ischemic heart disease (n=2438; HR, 0.58; 95% CI, 0.42 to 0.80). Statin use was not associated with an increase in malignancy, transaminase elevation, or rhabdomyolysis. Conclusions— Statin therapy in the setting of a very low LDL level appears to be safe and is associated with improved survival.

Overexpression of BCL2 enhances survival of human embryonic stem cells during stress and obviates the requirement for serum factors

The promise of pluripotent stem cells as a research and therapeutic tool is partly undermined by the technical challenges of generating and maintaining these cells in culture. Human embryonic stem cells (hESCs) are exquisitely sensitive to culture conditions, and require constant signaling by growth factors and cell–cell and cell–matrix interactions to prevent apoptosis, senescence, and differentiation. Previous work from our laboratory demonstrated that overexpression of the prosurvival gene BCL2 in mouse embryonic stem cells overrode the requirement of serum factors and feeder cells to maintain mESCs in culture. To determine whether this prosurvival gene could similarly protect hESCs, we generated hESC lines that constitutively or inducibly express BCL2. We find that BCL2 overexpression significantly decreases dissociation-induced apoptosis, resulting in enhanced colony formation from sorted single cells, and enhanced embryoid body formation. In addition, BCL2-hESCs exhibit normal growth in the absence of serum, but require basic fibroblast growth factor to remain undifferentiated. Furthermore, they maintain their pluripotency markers, form teratomas in vivo, and differentiate into all three germ layers. Our data suggest that the BCL2 signaling pathway plays an important role in inhibiting hESC apoptosis, such that its overexpression in hESCs offers both a survival benefit in conditions of stress by resisting apoptosis and obviates the requirement for serum or a feeder layer for maintenance.