Roger J. Laham

Hospital delays in reperfusion for ST-elevation myocardial infarction: implications when selecting a reperfusion strategy.

Background— It has been suggested that the survival benefit associated with primary percutaneous coronary intervention (PPCI) in ST-segment elevation myocardial infarction may be attenuated if door-to-balloon (DB) time is delayed by >1 hour beyond door-to-needle (DN) times for fibrinolytic therapy. Whereas DB times are rapid in randomized trials, they are often prolonged in routine practice. We hypothesized that in clinical practice, longer DB-DN times would be associated with higher mortality rates and reduced PPCI survival advantage. We also hypothesized that in addition to PPCI delays, patient risk factors would significantly modulate the relative survival advantage of PPCI over fibrinolysis. Methods and Results— DB-DN times were calculated by subtracting median DN time from median DB time at a hospital using data from 192 509 patients at 645 National Registry of Myocardial Infarction hospitals. Hierarchical models that adjusted simultaneously for both patient-level risk factors and hospital-level covariates were used to evaluate the relationship between PCI-related delay, patient risk factors, and in-hospital mortality. Longer DB-DN times were associated with increased mortality (P<0.0001). The DB-DN time at which mortality rates with PPCI were no better than that of fibrinolysis varied considerably depending on patient age, symptom duration, and infarct location. Conclusions— As DB-DN times increase, the mortality advantage of PPCI over fibrinolysis declines, and this advantage varies considerably depending on patient characteristics. As indicated in the American College of Cardiology/American Heart Association guidelines, both the hospital-based PPCI-related delay (DB-DN time) and patient characteristics should be considered when a reperfusion strategy is selected.

Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, double-blind, placebo-controlled trial.

BACKGROUND Angiogenesis is a promising treatment strategy for patients who are not candidates for standard revascularization, because it promotes the growth of new blood vessels in ischemic myocardium. METHODS AND RESULTS We conducted a randomized, double-blind, placebo-controlled study of basic fibroblast growth factor (bFGF; 10 or 100 microg versus placebo) delivered via sustained-release heparin-alginate microcapsules implanted in ischemic and viable but ungraftable myocardial territories in patients undergoing CABG. Twenty-four patients were randomized to 10 microg of bFGF (n=8), 100 microg of bFGF (n=8), or placebo (n=8), in addition to undergoing CABG. There were 2 operative deaths and 3 Q-wave myocardial infarctions. There were no treatment-related adverse events, and there was no rise in serum bFGF levels. Clinical follow-up was available for all patients (16.0+/-6.8 months). Three control patients had recurrent angina, 2 of whom required repeat revascularization. One patient in the 10-microg bFGF group had angina, whereas all patients in the 100-microg bFGF group remained angina-free. Stress nuclear perfusion imaging at baseline and 3 months after CABG showed a trend toward worsening of the defect size in the placebo group (20.7+/-3.7% to 23.8+/-5.7%, P=0.06), no significant change in the 10-microg bFGF group, and significant improvement in the 100-microg bFGF group (19.2+/-5.0% to 9.1+/-5.9%, P=0.01). Magnetic resonance assessment of the target ischemic zone in a subset of patients showed a trend toward a reduction in the target ischemic area in the 100-microg bFGF group (10.7+/-3.9% to 3. 7+/-6.3%, P=0.06). CONCLUSIONS This study of bFGF in patients undergoing CABG demonstrates the safety and feasibility of this mode of therapy in patients with viable myocardium that cannot be adequately revascularized.

Computed tomography angiography and perfusion to assess coronary artery stenosis causing perfusion defects by single photon emission computed tomography: the CORE320 study

AIMS To evaluate the diagnostic power of integrating the results of computed tomography angiography (CTA) and CT myocardial perfusion (CTP) to identify coronary artery disease (CAD) defined as a flow limiting coronary artery stenosis causing a perfusion defect by single photon emission computed tomography (SPECT). METHODS AND RESULTS We conducted a multicentre study to evaluate the accuracy of integrated CTA-CTP for the identification of patients with flow-limiting CAD defined by ≥50% stenosis by invasive coronary angiography (ICA) with a corresponding perfusion deficit on stress single photon emission computed tomography (SPECT/MPI). Sixteen centres enroled 381 patients who underwent combined CTA-CTP and SPECT/MPI prior to conventional coronary angiography. All four image modalities were analysed in blinded independent core laboratories. The prevalence of obstructive CAD defined by combined ICA-SPECT/MPI and ICA alone was 38 and 59%, respectively. The patient-based diagnostic accuracy defined by the area under the receiver operating characteristic curve (AUC) of integrated CTA-CTP for detecting or excluding flow-limiting CAD was 0.87 [95% confidence interval (CI): 0.84-0.91]. In patients without prior myocardial infarction, the AUC was 0.90 (95% CI: 0.87-0.94) and in patients without prior CAD the AUC for combined CTA-CTP was 0.93 (95% CI: 0.89-0.97). For the combination of a CTA stenosis ≥50% stenosis and a CTP perfusion deficit, the sensitivity, specificity, positive predictive, and negative predicative values (95% CI) were 80% (72-86), 74% (68-80), 65% (58-72), and 86% (80-90), respectively. For flow-limiting disease defined by ICA-SPECT/MPI, the accuracy of CTA was significantly increased by the addition of CTP at both the patient and vessel levels. CONCLUSIONS The combination of CTA and perfusion correctly identifies patients with flow limiting CAD defined as ≥50 stenosis by ICA causing a perfusion defect by SPECT/MPI.

Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease : Results of a Phase I open-label dose escalation study

OBJECTIVES Evaluate the safety, tolerability and preliminary efficacy of intracoronary (IC) basic fibroblast growth factor (bFGF, FGF-2). BACKGROUND FGF-2 is a heparin-binding growth factor capable of inducing functionally significant angiogenesis in animal models of myocardial ischemia. METHODS Phase I, open-label dose-escalation study of FGF-2 administered as a single 20-min infusion in patients with ischemic heart disease not amenable to treatment with CABG or PTCA. RESULTS Fifty-two patients enrolled in this study received IC FGF-2 (0.33 to 48 microg/kg). Hypotension was dose-dependent and dose-limiting, with 36 microg/kg being the maximally tolerated dose. Four patients died and four patients had non-Q-wave myocardial infarctions. Laboratory parameters and retinal examinations showed mild and mainly transient changes during the 6-month follow-up. There was an improvement in quality of life as assessed by Seattle Angina Questionnaire and improvement in exercise tolerance as assessed by treadmill exercise testing (510+/-24 s at baseline, 561+/-26 s at day 29 [p = 0.023], 609+/-26 s at day 57 (p < 0.001), and 633+/-24 s at day 180 (p < 0.001), overall p < 0.001). Magnetic resonance (MR) imaging showed increased regional wall thickening (baseline: 34+/-1.7%, day 29: 38.7+/-1.9% [p = 0.006], day 57: 41.4+/-1.9% [p < 0.001], and day 180: 42.0+/-2.3% [p < 0.001], overall p = 0.001) and a reduction in the extent of the ischemic area at all time points compared with baseline. CONCLUSIONS Intracoronary administration of rFGF-2 appears safe and is well tolerated over a 100-fold dose range (0.33 to 0.36 microk/kg). Preliminary evidence of efficacy is tempered by the open-label uncontrolled design of the study.

Therapeutic Angiogenesis With Basic Fibroblast Growth Factor: Technique and Early Results

BACKGROUND Patients not amenable to complete myocardial revascularization by conventional methods present a difficult clinical problem. Here we present the early results and technical considerations of the administration of basic fibroblast growth factor for the induction of collateral growth using heparin-alginate slow-release devices in patients undergoing coronary artery bypass grafting. METHODS Eight patients were enrolled. Patients were candidates if they had at least one graftable obstructed coronary artery and at least one major arterial distribution not amenable to revascularization, a serum creatinine level less than 3 mg/dL, ejection fraction greater than 0.20, and estimated operative mortality of less than 25%. During conventional coronary artery bypass grafting, 10 heparin-alginate devices, each containing either 1 microg or 10 microg of basic fibroblast growth factor, were implanted in the epicardial fat in multiple regions of the unrevascularizable territory and also in the distal distribution of a grafted or patent artery. RESULTS There was no mortality and no evidence of renal, hematologic, or hepatic toxicity during follow-up. Three months after the operation, all patients remain free of angina. Seven patients were examined with stress perfusion scans. Three patients had clear enhancement of perfusion to the unrevascularized myocardium, 1 patient had a new fixed defect, and 3 had minimal overall change but had evidence of new small, fixed perfusion defects. Seven patients had improved or similar myocardial contractile function (ejection fraction at 3-month follow-up = 0.53 +/- 0.22 versus 0.47 +/- 0.14 preoperatively). One patient suffered a perioperative myocardial infarction in the area of basic fibroblast growth factor administration. CONCLUSIONS This preliminary study demonstrates the safety and technical feasibility of therapeutic angiogenesis with basic fibroblast growth factor delivered by heparin-alginate slow-release devices. Further studies examining the safety, clinical efficacy, and long-term results are ongoing.

VEGF administration in chronic myocardial ischemia in pigs

OBJECTIVE Previous investigations have shown the effectiveness of sustained intra- or extravascular administration of vascular endothelial growth factor (VEGF) in chronic myocardial ischemia in improvement of left ventricular function. The present investigations were undertaken in order to evaluate efficacy of a single bolus or local intracoronary delivery. METHODS Yorkshire pigs underwent placement of a left circumflex artery ameroid occluder. Three weeks later the animals were randomized to treatment with VEGF (20 micrograms) accomplished by local intracoronary delivery system (InfusaSleeve, n = 10), intracoronary bolus infusion (n = 7) or by epicardial implantation of an osmotic delivery system (n = 7). An additional group of animals received intracoronary administration of saline and served as a control (n = 9). Three weeks after initiation of therapy, the animals were evaluated with regard to myocardial perfusion and global as well as regional ventricular function. RESULTS All three VEGF treatment groups but not the control animals demonstrated a significant increase in the left-to-left (but not right-to-left) collateral index, myocardial blood flow (pre-therapy LCX vs. LAD (average of all groups): 0.76 +/- 0.35 vs. 0.96 +/- 0.38 ml*min-1*g-1, p = 0.03; post-therapy: LCX vs. LAD: 1.16 +/- 0.39 vs. 1.15 +/- 0.28 ml*min-1*g-1, p = NS) and coronary vasodilatory reserve 3 weeks after growth factor administration. The observed increase in VEGF-induced perfusion correlated with improvement in regional ventricular function in all VEGF-treated groups (pre-therapy vs. post-therapy: i.c. VEGF 20 +/- 5.1 vs. 33 +/- 4.8; local VEGF 16 +/- 2.8 vs. 33.6; pump VEGF 17 +/- 3.8 vs. 34 +/- 4.9 p < 0.05 for all) but not control animals (21 +/- 3.3 vs. 27 +/- 5.8, p = NS). CONCLUSION Single intracoronary delivery (intravascular bolus or local delivery) of VEGF is effective in stimulating physiologically significant angiogenesis in porcine model of chronic myocardial ischemia.

Therapeutic angiogenesis in cardiology using protein formulations.

Therapeutic angiogenesis in cardiovascular disease aims at improving myocardial function by increasing blood flow to ischemic myocardium that is not amenable to traditional forms of revascularization. Preclinical data have provided proof of the concept that angiogenic growth factors such as fibroblast growth factor 2 (FGF-2) and vascular endothelium growth factor (VEGF) may indeed improve myocardial flow and function when administered in ways that ensure prolonged tissue exposure to these short-lived molecules. Although other cytokines have been shown to enhance angiogenesis in vivo, FGF-2 and VEGF have been most widely studied and may serve as prototype proangiogenic drugs. Currently, several delivery techniques that are clinically applicable are being studied with respect to tissue distribution and retention as well as angiogenic efficacy of FGF-2 and VEGF. Although tissue distribution and retention of FGF-2 after intramyocardial injection compares favorably with other routes of administration, efficacy studies are not yet conclusive. At the same time, different protein- and gene-based formulations are being investigated. Arguments for and against protein and gene therapy are presented, showing that protein-based therapy seems to have advantages over gene therapy at the present time, although continuous efforts should be made to increase the tissue exposure time after a single administration of protein. While delivery systems and growth factor formulations are being improved, double-blind, placebo-controlled trials designed with existing animal data in mind, are needed to firmly establish the utility of therapeutic angiogenesis in cardiovascular disease.

Therapeutic Angiogenesis With Recombinant Fibroblast Growth Factor-2 Improves Stress and Rest Myocardial Perfusion Abnormalities in Patients With Severe Symptomatic Chronic Coronary Artery Disease

BackgroundWe report the effects of the administration of recombinant fibroblast growth factor-2 (rFGF-2) protein on myocardial perfusion using single photon emission computed tomography imaging in humans with advanced coronary disease. Methods and ResultsA total of 59 patients with coronary disease that was not amenable to mechanical revascularization underwent intracoronary (n=45) or intravenous (n=14) administration of rFGF-2 in ascending doses. Changes in perfusion were evaluated at baseline and again at 29, 57, and 180 days after rFGF-2 administration. In this uncontrolled study, perfusion scans were analyzed by 2 observers who were blinded to patient identity and test sequence; scans were displayed in random order, with scans from nonstudy patients randomly interspersed to enhance blinding. Combining all dose groups, a reduction occurred in the per-segment reversibility score (reflecting the magnitude of inducible ischemia) from 1.7±0.4 at baseline to 1.1±0.6 at day 29 (P <0.001), 1.2±0.7 at day 57 (P <0.001), and 1.1±0.7 at day 180 (P <0.001). The 37 patients with evidence of resting hypoperfusion had evidence of improved resting perfusion: their per-segment rest perfusion score of 1.5±0.5 at baseline decreased to 1.0±0.8 at day 29 (P <0.001), 1.0±0.8 at day 57 (P =0.003), and 1.1±0.9 at day 180 (P =0.11). ConclusionsThese preliminary data suggest that the administration of rFGF-2 to patients with advanced coronary disease resulted in an attenuation of stress-induced ischemia and an improvement in resting myocardial perfusion; these findings are consistent with a favorable effect of therapeutic angiogenesis.

Gene therapy progress and prospects: therapeutic angiogenesis for limb and myocardial ischemia

After extensive investigation in preclinical studies and recent clinical trials, gene therapy has been established as a potential method to induce therapeutic angiogenesis in ischemic myocardial and limb disease. Advancements in viral and nonviral vector technology including cell-based gene transfer will continue to improve transgene transmission and expression efficiency. An alternative strategy to the use of transgenes encoding angiogenic growth factors is therapy based on transcription factors such as hypoxia-inducible factor-1α (HIF-1α) that regulate the expression of multiple angiogenic genes. Further understanding of the underlying biology of neovascularization is needed to determine the ability of growth factors to induce functionally significant angiogenesis in patients with atherosclerotic disease and associated comorbid conditions including endothelial dysfunction, which may inhibit blood vessel growth. The safety and tolerability of therapeutic angiogenesis by gene transfer has been demonstrated in phase I clinical trials. However, limited evidence of efficacy resulted from early phase II studies of angiogenic gene therapy for ischemic myocardial and limb disease. The utility of therapeutic angiogenesis by gene transfer as a treatment option for ischemic cardiovascular disease will be determined by adequately powered, randomized, placebo-controlled phase II and III clinical trials.

Long-Term (4- to 6-Year) Outcome of Palmaz-Schatz Stenting: Paucity of Late Clinical Stent-Related Problems

OBJECTIVES The purpose of this prospective single-center study was to evaluate the longer-term outcome of Palmaz-Schatz stenting in the treatment of native coronary and saphenous vein bypass graft disease. BACKGROUND The STRESS (Stent Restenosis Study) and BENESTENT (Belgian Netherlands Stent) trials have demonstrated a decrease in both angiographic restenosis and the need for repeat revascularization in the 1st year for vessels treated by stenting rather than balloon angioplasty. Longer-term (1 to 5 years) clinical results of Palmaz-Schatz stenting are not yet well established. Late migration of the stent, metal fatigue, endarteritis and late restenosis have all been proposed as potential late clinical complications of coronary stent implantation. METHODS The study cohort consisted of 175 consecutive patients who underwent elective placement of 194 Palmaz-Schatz stents in 185 vessels. Clinical events (death, myocardial infarction, recurrent angina or any revascularization) were assessed at 6 weeks, 2, 4 and 6 months, 1 year and yearly thereafter. Clinical follow-up was available on all patients at a mean +/- SD of 54 +/- 17 months. RESULTS Angiographic success was achieved in 173 patients (98.9%); angiographic restenosis was observed at 6 months in 26.1% of target sites. The survival rate was 86.7% at 5 years, with a 5-year event-free survival rate decreasing progressively to 50.7%, reflecting primarily repeat revascularization procedures (41.2% at 5 years). However, the rate of repeat revascularization of the treatment site (target site revascularization [TSR]) was 14.4%, 17.7% and 19.8% at 1, 3 and 5 years, respectively, with late (> 1 year) TSR driven by in-stent restenosis in only 3 patients (1.7%). Rates of both 5-year survival (70.5% vs. 93.4%) and event-free survival (21.1% vs. 63.3%) were lower for patients who underwent saphenous vein graft (SVG) stenting than for those with native coronary artery stenting. However, 5-year TSR rates were similar for SVGs (21.9%) and native vessels (19.2%), indicating that the higher incidence of repeat revascularization for SVGs was due to an increase in non-TSR, driven by progressive disease at other sites. CONCLUSIONS The long-term outcome of stenting shows stability of the treated lesion, with only a slight increase in TSR between 2 and 5 years (17.1% to 19.8%). The progressive increase in repeat revascularization over that period (24% to 41%) and most ongoing late events can be attributed to the progression of coronary disease at other sites, rather than to late deterioration of the stent result itself. Such non-TSR events account for the majority of clinical events in the patients who underwent SVG stenting.