Arthritis medicines and cardiovascular events--"house of coxibs".
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Adenoma↗
Biomedical subjects
Eric J Topol
Publications and source records attributed to Eric J Topol.
Outcomes of patients with acute coronary syndromes and prior percutaneous coronary intervention: a pooled analysis of three randomized clinical trials.
AIMS: We sought to characterize the outcomes of patients with a prior percutaneous coronary intervention (PCI) who presented with a non-ST-segment elevation acute coronary syndrome (ACS). METHODS AND RESULTS: We analysed the 30 and 180 day outcomes of 3012 patients with prior PCI and 21 154 patients without prior PCI enrolled in three randomized ACS trials (GUSTO IIb, PURSUIT, and PARAGON-B). The median (25th, 75th percentile) interval between the prior PCI and randomization was 647 (123, 1585) days. Patients with prior PCI had significantly more adverse baseline clinical characteristics, left ventricular dysfunction, and multi-vessel coronary artery disease. After adjusting for baseline characteristics and treatment, we found that patients with prior PCI had a significantly lower mortality rate at 30 days [hazard ratio (HR), 0.60; 95% confidence interval (CI), 0.45-0.80; P=0.0006] and 180 days (HR, 0.81; 95% CI, 0.66-0.98; P=0.029). However, no difference was observed in the composite of death or myocardial infarction (MI) at 30 days (HR, 0.95; 95% CI, 0.83-1.08; P=0.42) or 180 days (HR, 1.01; 95% CI, 0.90-1.13; P=0.90). Patients with prior PCI had a higher rate of MI at 180 days (13.3 vs. 12.0%; P=0.045). Prior-PCI patients had lower incidences of in-hospital cardiogenic shock, congestive heart failure (CHF), and atrial fibrillation. CONCLUSION: Patients with prior PCI who present with non-ST-segment elevation ACS have a lower mortality rate than those without prior PCI.
Aged↗
Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial.
CONTEXT: The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain. OBJECTIVE: To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, multicenter, 24-month trial (enrollment April 1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100 mm Hg. A substudy of 274 patients measured atherosclerosis progression by intravascular ultrasound (IVUS). INTERVENTIONS: Patients were randomized to receive amlodipine, 10 mg; enalapril, 20 mg; or placebo. IVUS was performed at baseline and study completion. MAIN OUTCOME MEASURES: The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo. Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo. Events included cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease. The IVUS end point was change in percent atheroma volume. RESULTS: Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (P<.001 for both vs placebo). Cardiovascular events occurred in 151 (23.1%) placebo-treated patients, in 110 (16.6%) amlodipine-treated patients (hazard ratio [HR], 0.69; 95% CI, 0.54-0.88 [P = .003]), and in 136 (20.2%) enalapril-treated patients (HR, 0.85; 95% CI, 0.67-1.07 [P = .16]. Primary end point comparison for enalapril vs amlodipine was not significant (HR, 0.81; 95% CI, 0.63-1.04 [P = .10]). The IVUS substudy showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo (P = .12), with significantly less progression in the subgroup with systolic blood pressures greater than the mean (P = .02). Compared with baseline, IVUS showed progression in the placebo group (P<.001), a trend toward progression in the enalapril group (P = .08), and no progression in the amlodipine group (P = .31). For the amlodipine group, correlation between blood pressure reduction and progression was r = 0.19, P = .07. CONCLUSIONS: Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events. Directionally similar, but smaller and nonsignificant, treatment effects were observed with enalapril. For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.
Adult↗
Economic evaluation of bivalirudin with provisional glycoprotein IIB/IIIA inhibition versus heparin with routine glycoprotein IIB/IIIA inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial.
OBJECTIVES: The purpose of this study was to compare the cost of percutaneous coronary intervention (PCI) using bivalirudin with provisional platelet glycoprotein (GP) IIb/IIIa inhibition with that of heparin + routine GP IIb/IIIa inhibition. BACKGROUND: Although GP IIb/IIIa inhibition has been shown to reduce ischemic complications in a broad range of patients undergoing PCI, many patients currently do not receive such therapy because of concerns about bleeding complications or cost. Recently, bivalirudin with provisional GP IIb/IIIa inhibition has been validated as an alternative to heparin + routine GP IIb/IIIa inhibition for patients undergoing PCI. However, the cost-effectiveness of this novel strategy is unknown. METHODS: In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, 4,651 U.S. patients undergoing non-emergent PCI were randomized to receive bivalirudin with provisional GP IIb/IIIa (n = 2,319) versus heparin + routine GP IIb/IIIa (n = 2,332). Resource utilization data were collected prospectively through 30-day follow-up on all U.S. patients. Medical care costs were estimated using standard methods including bottom-up accounting (for procedural costs), the Medicare fee schedule (for physician services), hospital billing data (for 2,821 of 4,862 admissions), and regression-based approaches for the remaining hospitalizations. RESULTS: Among the bivalirudin group, 7.7% required provisional GP IIb/IIIa. Thirty-day ischemic outcomes including death or myocardial infarction were similar for the bivalirudin and GP IIb/IIIa groups, but bivalirudin resulted in lower rates of major bleeding (2.8% vs. 4.5%, p = 0.002) and minor bleeding (15.1% vs. 28.1%, p < 0.001). Compared with routine GP IIb/IIIa, in-hospital and 30-day costs were reduced by $405 (95% confidence interval [CI] $37 to $773) and $374 (95% CI $61 to $688) per patient with bivalirudin (p < 0.001 for both). Regression modeling demonstrated that, in addition to the costs of the anticoagulants themselves, hospital savings were due primarily to reductions in major bleeding (cost savings = $107/patient), minor bleeding ($52/patient), and thrombocytopenia ($47/patient). CONCLUSIONS: Compared with heparin + routine GP IIb/IIIa inhibition, bivalirudin + provisional GP IIb/IIIa inhibition resulted in similar acute ischemic events and cost savings of $375 to $400/patient depending on the analytic perspective.
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Transcription factor MEF2A mutations in patients with coronary artery disease.
Coronary artery disease (CAD), including its most serious complication myocardial infraction (MI), is the leading cause of death in the US and developed countries. We recently discovered that a seven-amino acid deletion in MEF2A, a transcription factor with a high level of expression in the endothelium of coronary arteries, co-segregates with CAD/MI in one family, and it suppresses transcription activation activity of MEF2A by a dominant-negative mechanism. In this study, we used single-strand conformation polymorphism and DNA sequence analyses to identify mutations in MEF2A in 207 independent CAD/MI patients and 191 controls with normal angiograms. We identified three novel mutations in exon 7 of MEF2A in four of 207 CAD/MI patients (1.93%). No mutations were detected in the 191 controls. The mutations identified here include N263S identified in two independent CAD patients, P279L in one patient and his father with the diagnosis of CAD and G283D in one patient. These mutations are clustered within or close to the major transcriptional activation domain of MEF2A. They significantly reduce the transcriptional activation activity of MEF2A and act by a loss-of-function mechanism. The gene carriers with loss-of-function mutations appear to be associated with less severe CAD. These results suggest that CAD/MI can result from a spectrum of MEF2A transcription dysfunctions ranging from loss-of-function to dominant-negative suppression and that a significant percent of the CAD/MI population (1.93%) may carry mutations in MEF2A, although further definition of the prevalence of MEF2A mutations is warranted.
Adult↗
Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes.
CONTEXT: It is unclear if blood transfusion in anemic patients with acute coronary syndromes is associated with improved survival. OBJECTIVE: To determine the association between blood transfusion and mortality among patients with acute coronary syndromes who develop bleeding, anemia, or both during their hospital course. DESIGN, SETTING, AND PATIENTS: We analyzed 24,112 enrollees in 3 large international trials of patients with acute coronary syndromes (the GUSTO IIb, PURSUIT, and PARAGON B trials). Patients were grouped according to whether they received a blood transfusion during the hospitalization. The association between transfusion and outcome was assessed using Cox proportional hazards modeling that incorporated transfusion as a time-dependent covariate and the propensity to receive blood, and a landmark analysis. MAIN OUTCOME MEASURE: Thirty-day mortality. RESULTS: Of the patients included, 2401 (10.0%) underwent at least 1 blood transfusion during their hospitalization. Patients who underwent transfusion were older and had more comorbid illness at presentation and also had a significantly higher unadjusted rate of 30-day death (8.00% vs 3.08%; P<.001), myocardial infarction (MI) (25.16% vs 8.16%; P<.001), and death/MI (29.24% vs 10.02%; P<.001) compared with patients who did not undergo transfusion. Using Cox proportional hazards modeling that incorporated transfusion as a time-dependent covariate, transfusion was associated with an increased hazard for 30-day death (adjusted hazard ratio [HR], 3.94; 95% confidence interval [CI], 3.26-4.75) and 30-day death/MI (HR, 2.92; 95% CI, 2.55-3.35). In the landmark analysis that included procedures and bleeding events, transfusion was associated with a trend toward increased mortality. The predicted probability of 30-day death was higher with transfusion at nadir hematocrit values above 25%. CONCLUSIONS: Blood transfusion in the setting of acute coronary syndromes is associated with higher mortality, and this relationship persists after adjustment for other predictive factors and timing of events. Given the limitations of post hoc analysis of clinical trials data, a randomized trial of transfusion strategies is warranted to resolve the disparity in results between our study and other observational studies. We suggest caution regarding the routine use of blood transfusion to maintain arbitrary hematocrit levels in stable patients with ischemic heart disease.
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Failing the public health--rofecoxib, Merck, and the FDA.
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Adverse Drug Reaction Reporting Systems↗
ST-segment resolution 60 minutes after combination treatment of abciximab with reteplase or reteplase alone for acute myocardial infarction (30-day mortality results from the resolution of ST-segment after reperfusion therapy substudy).
The combination of abciximab with thrombolytic therapy when treating acute ST-elevation myocardial infarction has been hypothesized to enhance microvascular perfusion. Resolution of ST-segment elevation after thrombolytic therapy is believed to be a marker of myocardial reperfusion and to predict mortality rate. Among 16,588 patients enrolled in the Fifth Global Use of Strategies to Open Occluded Arteries in Acute Myocardial Infarction trial, 1,764 consecutive patients from selected centers had their study electrocardiograms evaluated by a core laboratory for ST-segment deviation resolution 60 minutes after treatment. Patients were categorized into 4 groups: complete resolution (>70%), partial resolution (<70% to 30%), no resolution (<30%), and worsening ST-segment deviation. Patients treated with reteplase or a combination of reteplase plus abciximab had similar rates of complete resolution (32% vs 34%), partial resolution (29% vs 27%), no resolution (15% vs 16%), and worsening ST-segment elevation (23 vs 23%; p = 0.59). The 30-day mortality rates in these 4 groups were 2.1%, 5.2%, 5.5%, and 8.1% (p <0.001). Even after accounting for baseline variables, incomplete ST-segment resolution (<70%) was associated with an increased risk of death within 30 days (adjusted hazard ratio 2.41, 95% confidence interval 1.25 to 4.63, p <0.008). Thus, ST-segment resolution at 60 minutes was no different in patients treated with full-dose reteplase from those treated with a combination of abciximab and reteplase. Patients with >70% ST-segment resolution within 60 minutes had markedly decreased mortality rates, irrespective of treatment.
Abciximab↗
Long-term mortality of patients with acute myocardial infarction in the United States and Canada: comparison of patients enrolled in Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I.
BACKGROUND: In a previous substudy of the GUSTO-I trial, we observed better functional and quality-of-life outcomes among patients in the United States (US patients) compared with patients in Canada. Rates of invasive therapy were significantly higher in the United States and were associated with a small mortality benefit (0.4%, adjusted P=0.02). We sought to determine whether Canadian-US differences in practice patterns in GUSTO-I had an impact on 5-year mortality. METHODS AND RESULTS: Mortality data for 23,105 US and 2898 Canadian patients enrolled in GUSTO-I were obtained from national mortality databases. Median follow-up was 5.46 years in the US and 5.33 years in the Canadian cohort. Five-year mortality rate was 19.6% among US and 21.4% among Canadian patients (P=0.02). After baseline adjustment, enrollment in Canada was associated with a higher hazard of death (1.17; 95% confidence interval, 1.07 to 1.28, P=0.001). Revascularization rates during the index hospitalization in the United States were almost 3 times those in Canada: 30.5% versus 11.4% for angioplasty and 13.1% versus 4.0% for bypass surgery (P<0.01 for both). After accounting for revascularization status as a time-dependent covariate, country was no longer a significant predictor of long-term mortality. These results were confirmed in a propensity-matched analysis. CONCLUSIONS: Our results suggest, for the first time, that the more conservative pattern of care with regard to early revascularization in Canada for ST-segment elevation acute myocardial infarction may have a detrimental effect on long-term survival. Our results have important policy implications for cardiac care in countries and healthcare systems wherein use of invasive procedures is similarly conservative.
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Association of race with complications and prognosis following acute coronary syndromes.
The baseline characteristics, complications, and survival of 489 black and 6,890 non-black patients with acute coronary syndromes were studied. Important racial differences were observed in demographic features, atherosclerosis risk factors, and treatment strategies; however, despite these differences, no independent difference was observed in clinical outcomes according to race. The 1-year mortality rate was 2.9% for black patients and 2.5% for non-black patients (p = 0.93).
Acute Disease↗
Lack of clopidogrel pretreatment effect on the relative efficacy of bivalirudin with provisional glycoprotein IIb/IIIa blockade compared to heparin with routine glycoprotein IIb/IIIa blockade: a REPLACE-2 substudy.
OBJECTIVES: The purpose of this study was to assess if clopidogrel pretreatment affects the relative efficacy of bivalirudin versus heparin with glycoprotein (GP) IIb/IIIa blockade for percutaneous coronary interventions (PCI). BACKGROUND: Although thienopyridine pretreatment may improve clinical outcomes with PCI, it is unknown if bivalirudin's efficacy compared with heparin is dependent upon such pretreatment. METHODS: The Randomized Evaluation in Percutaneous coronary intervention Linking Angiomax to reduced Clinical Events (REPLACE-2) trial was a double-blind, triple-dummy, randomized-controlled trial comparing heparin plus routine GP IIb/IIIa blockade (heparin group) with bivalirudin plus provisional GP IIb/IIIa blockade (bivalirudin group) during PCI. The primary end point was a composite of death, myocardial infarction (MI), urgent revascularization at 30 days, and major in-hospital bleeding. The secondary end point was a 30-day composite of death, MI, and urgent revascularization. Clopidogrel pretreatment was encouraged (300 mg loading, 75 mg/day). RESULTS: Of 6,010 patients enrolled, 5,893 received clopidogrel, with 85.8% in the bivalirudin and 84.6% in the heparin group receiving clopidogrel pretreatment. Bivalirudin (provisional GP IIb/IIIa blockade 7.2%) was noninferior to the heparin group for both primary and secondary end points. Clopidogrel pretreatment did not affect the relative efficacy of bivalirudin versus heparin with GP IIb/IIIa blockade, irrespective of pretreatment duration. Pretreatment was associated with significantly lower primary end point with bivalirudin (8.7% pretreatment vs. 12.9% no pretreatment, p = 0.007), and nonsignificantly with heparin (9.7% vs. 11.7%, respectively, p = 0.20). Multivariable models showed a trend toward lower primary and secondary end points with clopidogrel pretreatment. CONCLUSIONS: Clopidogrel pretreatment at the doses and time administered in this trial did not influence the relative efficacy of bivalirudin versus heparin plus GP IIb/IIIa blockade for PCI. However, pretreatment was associated with a trend towards lower clinical events after PCI.
Aged↗
Comparison of long-term usefulness of clopidogrel therapy after the first percutaneous coronary intervention or coronary artery bypass grafting versus that after the second or repeat intervention.
Patients in the Clopidogrel for the Reduction of Events During Observation trial were subgrouped according to whether they underwent index percutaneous coronary artery revascularization procedures only or this procedure plus subsequent percutaneous or surgical revascularization procedures during 1-year follow-up. The relative risk reduction in ischemic events associated with up-front and long-term clopidogrel compared with placebo was 2-fold greater in patients who required repeat revascularization procedures compared with those who did not (42.4% vs 21.7%).
Aged↗
Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial.
CONTEXT: In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, bivalirudin with provisional glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition was found to be noninferior to heparin plus planned Gp IIb/IIIa blockade in the prevention of acute ischemic end points and was associated with significantly less bleeding by 30 days after percutaneous coronary intervention (PCI). OBJECTIVE: To determine whether the efficacy of bivalirudin remains comparable with that of heparin plus Gp IIb/IIIa blockade over 6 months and 1 year. DESIGN, SETTING, AND PARTICIPANTS: Follow-up study to 1 year of a randomized, double-blind trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002. INTERVENTIONS: Patients were randomly assigned to receive intravenously bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition, or to receive heparin (65 U/kg bolus), with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI. MAIN OUTCOME MEASURES: Incidence of death, myocardial infarction, or repeat revascularization by 6 months and death by 12 months after enrollment. RESULTS: At 6 months, death occurred in 1.4% of patients in the heparin plus Gp IIb/IIIa group and in 1.0% of patients in the bivalirudin group (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.43-1.14; P =.15). Myocardial infarction occurred in 7.4% and 8.2% of patients, respectively (HR, 1.12; 95% CI, 0.93-1.34; P =.24), and repeat revascularization was required in 11.4% and 12.1% of patients, respectively (HR, 1.06; 95% CI, 0.91-1.23; P =.45). By 1 year, death occurred in 2.46% of patients treated with heparin plus Gp IIb/IIIa blockade and in 1.89% of patients treated with bivalirudin (HR, 0.78; 95% CI, 0.55-1.11; P =.16). Nonsignificant trends toward lower 1-year mortality with bivalirudin were present in all patient subgroups analyzed and were of greatest magnitude among high-risk patients. CONCLUSION: Long-term clinical outcome with bivalirudin and provisional Gp IIb/IIIa blockade is comparable with that of heparin plus planned Gp IIb/IIIa inhibition during contemporary PCI.
Abciximab↗
Relationship between activated clotting time and ischemic or hemorrhagic complications: analysis of 4 recent randomized clinical trials of percutaneous coronary intervention.
BACKGROUND: Unfractionated heparin (UFH) is the most widely used antithrombin during percutaneous coronary intervention (PCI). Despite significant pharmacological and mechanical advancements in PCI, uncertainty remains about the optimal activated clotting time (ACT) for prevention of ischemic or hemorrhagic complications. METHODS AND RESULTS: We analyzed the outcome of all UFH-treated patients enrolled in 4 large, contemporary PCI trials with independent adjudication of ischemic and bleeding events. Of 9974 eligible patients, maximum ACT was available in 8369 (84%). The median ACT was 297 seconds (interquartile range 256 to 348 seconds). The incidence of death, myocardial infarction, or revascularization at 48 hours, by ACT quartile, was 6.2%, 6.8%, 6.0%, and 5.7%, respectively (P=0.40 for trend). Covariate-adjusted rate of ischemic complications was not correlated with maximal procedural ACT (continuous value, P=0.29). Higher doses of UFH (>5000 U, or up to 90 U/kg) were independently associated with higher rates of events. The incidence of major or minor bleeding at 48 hours, by ACT quartile, was 2.9%, 3.5%, 3.8%, and 4.0%, respectively (P=0.04 for trend). In a multivariable logistic model with a spline transformation for ACT, there was a linear increase in risk of bleeding as the ACT approached 365 seconds (P=0.01), which leveled off beyond that value. Increasing UFH weight-indexed dose was independently associated with higher bleeding rates (OR 1.04 [1.02 to 1.07] for each 10 U/kg, P=0.001). CONCLUSIONS: In patients undergoing PCI with frequent stent and potent platelet inhibition use, ACT does not correlate with ischemic complications and has a modest association with bleeding complications, driven mainly by minor bleeding. Lower values do not appear to compromise efficacy while increasing safety.
Abciximab↗
Effect of clopidogrel pretreatment on periprocedural rise in C-reactive protein after percutaneous coronary intervention.
This study sought to determine the effect of clopidogrel pretreatment on the increase in C-reactive protein (CRP) after percutaneous coronary intervention. Clopidogrel pretreatment attenuated the periprocedural increase in CRP by 65% and was independently associated with an attenuation in the CRP increase in a multivariate model.
Adult↗
Relation of an elevated white blood cell count after percutaneous coronary intervention to long-term mortality.
Increased inflammatory markers are associated with a poor prognosis after percutaneous coronary intervention. Leukocytes play a key role in inflammation, and an increase in white blood cell (WBC) counts is a nonspecific marker of inflammation. In patients undergoing percutaneous coronary intervention, baseline WBC counts independently predict long-term mortality. In a pooled cohort of patients from the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC), the Evaluation in PTCA to Improve Long-term Outcome with abciximab Glycoprotein IIb/IIIa blockade (EPILOG), and Evaluation of Platelet IIb/IIIa inhibitor for STENTing (EPISTENT) trials, postprocedural WBC counts were also found to be an independent predictor of long-term mortality.
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Double jeopardy of renal insufficiency and anemia in patients undergoing percutaneous coronary interventions.
Anemia and renal insufficiency impart an increased risk of mortality in patients with congestive heart failure. There is a paucity of data on the mortality hazard associated with anemia and renal insufficiency in patients undergoing percutaneous coronary intervention in the setting of contemporary practice. We analyzed the short- and long-term outcomes among patients enrolled in EPIC, EPILOG and EPISTENT trials according to degree of kidney dysfunction (glomerular filtration rate [GFR] <60, 60 to 75, and >75 ml/min/1.73 m2) and by hematocrit (<35, 35 to 39 and 40). GFR was calculated as GFR = 186 x (serum creatinine-1.154) x (age-0.203) x 1.212 (if black) or x 0.742 (if female). There were 20 deaths (3.2%) among 638 patients with a hematocrit of <35, 41 deaths among 2,066 patients (2.0%) with a hematocrit of 35 to 39, and 43 deaths in 3,618 patients (1.2%) with a hematocrit >40 at 6 months (p <0.001). Similarly, a significant increase in mortality was seen with lower GFR [33 of 1,168 (2.9%) at GFR <60, 33 of 1,766 (1.9%) at GFR 60 to 75 and 37 of 3,317 (1.1%) at GFR >75, p <0.001)]. Further, GFR and anemia independently and in combination predicted mortality at 3 years. Thus, renal insufficiency and anemia are significant independent and additive predictors of short- and long-term complications in patients undergoing percutaneous coronary intervention.
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Cellular, but not direct, adenoviral delivery of vascular endothelial growth factor results in improved left ventricular function and neovascularization in dilated ischemic cardiomyopathy.
OBJECTIVES: We sought to compare the effects on angiogenesis and left ventricular (LV) function of adenoviral vascular endothelial growth factor-165 (AdVEGF-165) gene delivery by direct injection of AdVEGF-165 to the transplantation of skeletal myoblasts (SKMB) transfected with AdVEGF-165 in a rat model of ischemic cardiomyopathy. BACKGROUND: Angiogenesis offers the potential for treating ischemic cardiomyopathy. However, the optimal method of delivering angiogenic factors for neovascularization remains undetermined. With the increased clinical interest in cell therapy for the treatment of LV dysfunction, SKMB transplantation may serve as a means of gene transfer. METHODS: Two months after left anterior descending coronary artery ligation, rats received either injection of an adenoviral construct encoding VEGF-165, or 1 million SKMB transfected with AdLuciferase (AdLuc) or AdVEGF-165. Cardiac function was assessed echocardiographically, and neovascularization was assessed histologically four weeks after therapy. RESULTS: Neovascularization was significantly increased by both AdVEGF delivery strategies (100 +/- 7% and 185 +/- 33% increase in vascular density compared with SKMB alone, respectively). However, cell-based delivery, but not direct injection of AdVEGF-165, resulted in increased cardiac function (73.5 +/- 12.6% and 1.5 +/- 8.8% increase in shortening fraction compared with saline control; AdLuc-transfected SKMB: 29.4 +/- 15.0%). The improved function was not due to increased engraftment of VEGF expressing SKMB. Rather, improved function correlated with less apoptosis in the border zone in those animals that received AdVEGF-165 expressing SKMB. CONCLUSION: Our data demonstrate that cell-based delivery of VEGF leads to an improved treatment effect over direct adenoviral injection, and suggest that already developed adenoviral vectors that encode secreted factors could potentially offer greater efficacy in combination with SKMB transplantation.
Adenoviridae↗