Paul M. Grossman

Sustained release of multiple growth factors from injectable polymeric system as a novel therapeutic approach towards angiogenesis.

PurposeThe aim was to investigate that a bio-degradable alginate and poly lactide-co-glycolide (PLG) system capable of delivering growth factors sequentially would be superior to single growth factor delivery in promoting neovascularization and improving perfusion.MethodsThree groups of apoE null mice underwent unilateral hindlimb ischemia surgery and received ischemic limb intramuscular injections of alginate (Blank), alginate containing VEGF165 (VEGF), or alginate containing VEGF165 combined with PLG microspheres containing PDGF-BB (VEGF/PDGF). Vascularity in the ischemic hindlimb was assessed by morphologic and immunohistochemical end-points, while changes in blood flow were assessed by Laser Doppler Perfusion Index. Muscle VEGF and PDGF content was assessed at multiple time points.ResultsIn the VEGF/PDGF group, local tissue VEGF and PDGF levels peaked at week 2 and 4, respectively, with detectable PDGF levels at week 6. At week 6, mean vessel mean diameter was significantly greater in the VEGF/PDGF group compared to the VEGF or Blank groups with evidence of well-formed smooth muscle-lined arterioles.ConclusionsSequential delivery of VEGF and PDGF using an injectable, biodegradable platform resulted in stable and sustained improvements in perfusion. This sustained, control-released, injectable alginate polymer system is a promising approach for multiple growth factor delivery in clinical application.

Routine stent implantation vs. percutaneous transluminal angioplasty in femoropopliteal artery disease: a meta-analysis of randomized controlled trials

AIMSnWe performed a meta-analysis of randomized controlled trials comparing routine stenting (ST) with percutaneous transluminal angioplasty (PTA) for symptomatic superficial femoral-popliteal artery (SFPA) disease.nnnMETHODS AND RESULTSnTen trials were pooled randomizing patients to ST (n = 724 limbs) or PTA with provisional stenting (n = 718 limbs) with a follow-up period of 9-24 months. The mean lesion length was similar in the two groups (45.8 mm in the ST group and 43.3 mm in the PTA group). We calculated the summary risk ratios (RRs) for immediate technical failure, restenosis, and target vessel revascularization (TVR) using random-effects models. The immediate technical failure was higher in the PTA group than in the ST group [17.1 vs. 5.9%, respectively, RR = 0.28, 95% confidence interval (CI) = 0.15-0.54, P < 0.001], with 10.3% of the PTA patients undergoing stenting because of suboptimal result. There was a trend for lower restenosis in the ST group (37.6% in ST vs. 45.3% in PTA, RR = 0.85, 95% CI = 0.69-1.06, P = 0.146), but no difference in the need for TVR (20% in ST vs. 20.2% in PTA, RR = 0.98, 95% CI = 0.78-1.23, P = 0.89). In an analysis restricted to nitinol stents, there was a trend towards reduction in TVR (RR = 0.79, 95% CI = 0.59-1.06, P = 0.12).nnnCONCLUSIONnDespite the higher immediate success, routine stenting was not associated with a significant reduction in the rate of restenosis or TVR. Our data do not support use of routine stenting as the primary endovascular treatment for short SFPA lesions.

The association of sex with outcomes among patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction in the contemporary era: Insights from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2)

BACKGROUNDnhistorically, women with ST elevation myocardial infarction (STEMI) have had a higher mortality compared with men. It is unclear if these differences persist among patients undergoing contemporary primary percutaneous coronary intervention (PCI) with focus on early reperfusion.nnnMETHODSnwe assessed the impact of sex on the outcome of 8,771 patients with acute STEMI who underwent primary PCI from 2003 to 2008 at 32 hospitals participating in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium PCI registry. A propensity-matched analysis was performed to adjust for differences in baseline characteristics and comorbidities between men and women.nnnRESULTSntwenty-nine percent of the cohort was female. Compared with men, women were older and had more comorbidity. Female sex was associated with a higher unadjusted in-hospital mortality (6.02% vs 3.45%, odds ratio [OR] 1.79, 95% CI 1.45-2.22, P < .0001) and higher risk of contrast-induced nephropathy (OR 1.75, P < .0001), vascular complications (OR 2.13, P < .0001), and postprocedure transfusion (OR 2.84, P < .0001). The gap in sex-specific mortality narrowed over time. In a propensity-matched analysis, female sex was associated with a higher rate of transfusion (OR 1.88, 95% CI 1.57-2.24, P < .0001) and vascular complications (OR 1.65, 95% CI 1.26-2.14, P < .0002); but there was no difference in mortality (OR 1.30, 95% CI 0.98-1.72, P = .07).nnnCONCLUSIONSnwomen make up approximately one third of patients undergoing primary PCI for STEMI. Female sex is associated with an apparent hazard of increased mortality among patients undergoing primary PCI for STEMI, but this difference is likely explained by older age and worse baseline comorbidities among women.

A Comparison of Abciximab and Small-Molecule Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Primary Percutaneous Coronary Intervention A Meta-Analysis of Contemporary Randomized Controlled Trials

Background—Current guidelines recommend abciximab as the preferred agent for patients undergoing primary percutaneous coronary intervention, yet small-molecule glycoprotein IIb/IIIa inhibitors are more commonly used in clinical practice. The objective of our meta-analysis was to evaluate for differences in clinical outcome between small-molecule glycoprotein IIb/IIIa inhibitors and abciximab in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Methods and Results—Five randomized trials (n=2138 patients) comparing tirofiban or eptifibatide with abciximab as an adjunctive therapy to primary percutaneous coronary intervention were included in this meta-analysis. Summary odds ratios (ORs) for 30-day death, reinfarction, and major bleeding were calculated using random- and fixed-effect models. There were no differences in 30-day mortality (1.9% for small molecule versus 2.3% for abciximab; OR, 0.84; 95% CI, 0.46 to 1.55; P=0.58), reinfarction (1.3% versus 1.2%; OR, 1.22; 95% CI, 0.51 to 2.91; P=0.69), or major bleeding (1.7% versus 1.3%; OR, 1.21; 95% CI, 0.58 to 2.49; P=0.61) between the 2 adjunctive strategies. Similarly, there was no significant difference in the incidence of death (3.9% versus 5%; OR, 0.77; 95% CI, 0.41 to 1.46; P=0.43) or reinfarction on follow-up at 8 months between small-molecule glycoprotein IIb/IIIa inhibitors and abciximab. Conclusion—In patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction, no difference in outcome could be identified in patients treated with small-molecule glycoprotein IIb/IIIa inhibitor or abciximab.

Design of the Del-1 for therapeutic angiogenesis trial (DELTA-1), a phase II multicenter, double-blind, placebo-controlled trial of VLTS-589 in subjects with intermittent claudication secondary to peripheral arterial disease.

The objective of this phase II investigation is to assess the safety and efficacy of a plasmid mediated approach to induce angiogenesis/arteriogenesis with the angiomatrix protein Del-1 (developmentally regulated endothelial locus 1), in subjects with intermittent claudication (IC) secondary to peripheral arterial disease (PAD). VLTS-589 is an investigational nonviral therapeutic comprising a plasmid-expressing Del-1 formulated with poloxamer 188 (facilitating agent). One hundred subjects with bilateral PAD and IC will be randomized after careful screening to bilateral intramuscular delivery of VLTS-589 or placebo. A total of 84 mg of plasmid or placebo will be delivered as 42 intramuscular injections (2 ml per injection, 21 injections or 42 ml in each extremity of either plasmid or placebo) in both lower extremities. The subjects in the study will be followed at regular intervals for a year after study drug administration (days 30, 90, 180, and 365) with the primary endpoint being the safety and tolerability of VLTS-589 and change in peak walking time (PWT) at day 90. The secondary endpoints include percent and absolute change in resting ankle brachial Index, claudication onset time, and quality of life measured at various time points. DELTA-1 represents the largest plasmid-based gene transfer trial designed to test the efficacy of a Del-1 as a therapeutic approach in patients with IC caused by PAD. The novel aspects of the protocol include the usage of a Del-1 plasmid-polaxamer formulation to enhance gene transfer at doses that are an order of magnitude different than other comparable trials in a unique bilateral intramuscular dosing pattern to maximize transfection/clinical efficacy and general applicability to patients with PAD.

Variation in Outcomes after Percutaneous Coronary Intervention in the United States and Predictors of Periprocedural Mortality

The objective of this study was to characterize variation in mortality rates across hospitals performing percutaneous coronary intervention (PCI) in the United States. For this purpose, data (n = 735,022) from the Nationwide Inpatient Sample from 1996 to 2001 were analyzed. The primary outcome for the analysis was postprocedural in-hospital mortality. Mortality rates were calculated by race, gender, geographic region, comorbid status and hospital volume. There were significant variations in mortality across gender groups, comorbid status, regions and by hospital volume status. Independent predictors of mortality in this large cohort were older age, female gender, lower income and lower hospital volume. The data suggests targets for quality improvement initiatives for patients undergoing PCI particularly in the elderly, females, lower income patients and low volume hospitals. Even in the contemporary era of adjunctive pharmacological therapies and ubiquitous use of stents, hospital volume remains a significant independent predictor of in-hospital mortality.

Annulus Instead of LVOT Diameter Improves Agreement Between Echocardiography Effective Orifice Area and Invasive Aortic Valve Area

Calculating effective orifice area (EOA) in aortic stenosis (AS) relies on geometric assumptions regarding the left ventricular outflow tract (LVOT). There is no consensus on the optimal site for LVOT measurementxa0on transthoracic echocardiography (TTE), with guidelines permitting flexibility [(1)][

Contemporary outcomes with percutaneous vascular interventions for peripheral critical limb ischemia in those with and without poly-vascular disease.

Given the very ill nature of patients with critical limb ischemia (CLI), the use of percutaneous vascular interventions (PVIs) for limb salvage may or may not be efficacious; in particular, for those with polyvascular arterial disease. Herein, we reviewed large, multi-institutional outcomes of PVI in polyvascular and peripheral arterial disease (PAD) patients with CLI. An 18-hospital consortium collected prospective data on patients undergoing endovascular interventions for PAD with 6-month follow-up from January 2008 to December 2011. The patient cohort included 4459 patients with CLI; of those, 3141 patients had polyvascular (coronary artery disease, cerebrovascular disease and PAD) disease, whereas 1318 patients suffered from only PAD. All patients were elderly and with significant comorbidities. The mean ankle–brachial index (ABI) was 0.44 and was not different between those with and without polyvascular disease. Polyvascular patients had more femoropopliteal and infra-inguinal interventions and less aortoiliac interventions than PAD patients. Pre- and post-procedural cardioprotective medication use was less in the PAD patients as compared with polyvascular patients. Vascular complications requiring surgery were higher in PAD patients whereas other access complications were similar between groups. At 6-month follow-up, death was more common in the polyvascular group (6.7% vs 4.1%, p<0.001) as was repeat PVI, but no difference was found in the amputation rate. Considering the group as a whole at the 6-month follow-up, predictors of amputation/death included age (HR=1.01; 95% CI=1.002–1.02), anemia (HR=2.6; 95% CI=2.1–3.2), diabetes mellitus (HR=1.6; 95% CI=1.3–1.9), congestive heart failure (HR=1.6; 95% CI=1.4–1.9), and end-stage renal failure (HR=1.9; 95% CI=1.5–2.3), while female sex was protective (HR=0.7; 95% CI=0.6–0.8). In conclusion, from examination of this large, multicenter, multi-specialist practice registry, patients with polyvascular disease had higher 6-month mortality than PAD patients, but this was not a factor in 6-month limb amputation outcomes. This study also underscores that PAD patients still lag in cardioprotective medication use as compared with polyvascular patients.

Mortality Predictors in Patients Referred for but Not Undergoing Transcatheter Aortic Valve Replacement

Although transcatheter aortic valve replacement (TAVR) has expanded the proportion of patients with aortic stenosis (AS) who are candidates for valve replacement, some patients remain untreated, and their outcomes are not clear. We evaluated 172 consecutive patients with severe symptomatic AS referred for TAVR who declined (n = 55) or were not candidates for (n = 117) intervention. We examined clinical and echocardiographic variables associated with mortality. There were 77 deaths, and mean follow-up was 17.9 ± 10.9 months for survivors. Mortality rate at 1 and 2 years was 39.2% and 52.6%, respectively. There was a significant difference in mortality rate between patients who declined the procedure and those who were not candidates (p = 0.001), with 1-year mortality rates of 20.6% and 48.4%, respectively. On multivariate analysis, 4 variables were independently associated with all-cause mortality: New York Heart Association Class IV heart failure (hazard ratio [HR] 2.6, 95% confidence interval [CI] 1.6 to 4.2, p <0.001), glomerular filtration rate <48 ml/min (HR 2.1, 95% CI 1.3 to 3.4, p = 0.002), albumin <3.9 g/dl (HR 1.9, 95% CI 1.2 to 3.1, p = 0.007), and ejection fraction <50% (HR 1.9, 95% CI 1.4 to 3.0, p = 0.01). In this new era with expanded treatment options, patients with severe symptomatic AS who remain untreated after referral for TAVR experience a mortality rate of 39% at 1 year. The presence of advanced heart failure, renal dysfunction, low albumin, and/or left ventricular dysfunction identifies patients at higher risk of mortality.

Coronary artery perforations after contemporary percutaneous coronary interventions: Evaluation of incidence, risk factors, outcomes, and predictors of mortality.

We sought to evaluate the incidence, risk factors, in‐hospital, and long‐term outcomes and predictors of mortality of coronary artery perforations (CAP) in the contemporary percutaneous coronary intervention (PCI) era.