Jack L. Martin

Human Epicardial Adipose Tissue Is a Source of Inflammatory Mediators

Background—Inflammatory mediators that originate in vascular and extravascular tissues promote coronary lesion formation. Adipose tissue may function as an endocrine organ that contributes to an inflammatory burden in patients at risk of cardiovascular complications. In this study, we sought to compare expression of inflammatory mediators in epicardial and subcutaneous adipose stores in patients with critical CAD. Methods and Results—Paired samples of epicardial and subcutaneous adipose tissues were harvested at the outset of elective CABG surgery (n=42; age 65±10 years). Local expression of chemokine (monocyte chemotactic protein [MCP]-1) and inflammatory cytokines (interleukin [IL]-1&bgr;, IL-6, and tumor necrosis factor [TNF]-&agr;) was analyzed by TaqMan real-time reverse transcription–polymerase chain reaction (mRNA) and by ELISA (protein release over 3 hours). Significantly higher levels of IL-1&bgr;, IL-6, MCP-1, and TNF-&agr; mRNA and protein were observed in epicardial adipose stores. Proinflammatory properties of epicardial adipose tissue were noted irrespective of clinical variables (diabetes, body mass index, and chronic use of statins or ACE inhibitors/angiotensin II receptor blockers) or plasma concentrations of circulating biomarkers. In a subset of samples (n=11), global gene expression was explored by DNA microarray hybridization and confirmed the presence of a broad inflammatory reaction in epicardial adipose tissue in patients with coronary artery disease. The above findings were paralleled by the presence of inflammatory cell infiltrates in epicardial adipose stores. Conclusions—Epicardial adipose tissue is a source of several inflammatory mediators in high-risk cardiac patients. Plasma inflammatory biomarkers may not adequately reflect local tissue inflammation. Current therapies do not appear to eliminate local inflammatory signals in epicardial adipose tissue.

Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle.

The maximal exercise capacity of patients with chronic heart failure is frequently reduced. To investigate whether this exercise intolerance is caused by inadequate nutritive flow to skeletal muscle, we compared cardiac outputs, leg blood flow, and leg metabolism during maximal bicycle exercise in seven patients with normal maximal oxygen uptake (VO2) (greater than 20 ml/min/kg; group A), eight patients with heart failure and moderately reduced maximal VO2 (15 to 18 ml/min/kg; group B), and eight patients with heart failure and markedly reduced maximal VO2 (less than 14 ml/min/kg; group C). As the severity of exercise intolerance increased from group A to group C there was a progressive decline in cardiac output and leg blood flow at any given workload accompanied by a progressive decline in maximal cardiac output (liters/min) (A, 12.4 +/- 1.0; B, 8.7 +/- 0.9; C, 5.5 +/- 0.7), maximal leg flow (liters/min) (A, 4.0 +/- 0.3; B, 2.6 +/- 0.4; C, 1.4 +/- 0.2), and maximal leg VO2 (ml/min) (A, 564 +/- 49; B, 403 +/- 41; C, 213 +/- 35 ml/min). All patients terminated exercise because of severe leg fatigue. At termination of exercise, all three groups exhibited similar marked levels of leg O2 extraction (%) (A, 80 +/- 2; B, 83 +/- 3; C, 89 +/- 1) and high femoral-arterial lactate gradients (mg/dl) (A, 15.4 +/- 2.6; B, 18.3 +/- 3.5; C, 19.2 +/- 3.6), suggesting that exercise was limited when a critical level of muscle underperfusion was reached. These data suggest that the reduced maximal exercise capacity of patients with chronic heart failure is primarily due to impaired nutritive flow to skeletal muscle and resultant muscular fatigue.

Diabetes-Induced Oxidative Stress and Low-Grade Inflammation in Porcine Coronary Arteries

Background—Multiple pathways contribute to accelerated coronary atherosclerosis in diabetics, including increased oxidative stress and inflammatory burden. Accordingly, the mechanisms of abnormal formation of reactive oxygen species and the changes in inflammatory gene expression were examined in diabetic coronary arteries. Methods and Results—In pigs with streptozotocin-induced diabetes, superoxide formation was augmented in coronary media and adventitia because of increased NAD(P)H oxidase activity (3 months) accompanied by upregulated expression of its cytosolic subunit, p22phox. Diabetes-induced oxidative stress resulted in the inflammatory response in the adventitia (increased expression of interleukin-6, tumor necrosis factor-&agr;, monocyte chemotactic protein-1, vascular cell adhesion molecule-1 [VCAM-1]) and in the media (VCAM-1). To examine the mechanisms of these changes, studies with isolated coronary fibroblasts were undertaken. Advanced glycation end products (AGEs), rather than glucose itself, upregulated expression of interleukin-6, VCAM-1, and monocyte chemotactic protein-1 mRNAs. These results were paralleled by increased interleukin-6 secretion (P <0.01) and augmented leukocyte adhesion to AGE-stimulated coronary cells (P <0.001). AGEs increased expression of phosphorylated forms of mitogen-activated protein kinases in coronary cells (ERK1/2 and JNK) and resulted in redox-sensitive expression of inflammatory genes that was inhibited by several inhibitors of oxidative pathways [NAD(P)H oxidase inhibitors, N-acetylcysteine, and pyrrolidine dithiocarbamate]. Conclusions—Diabetes increased NAD(P)H oxidase activity and oxidative stress, producing inflammatory responses in porcine coronary media and adventitia. AGEs activated ERK1/2 and JNK signaling pathways and induced the expression of several inflammatory genes in coronary cells in a redox-sensitive manner. These results suggest the involvement of AGEs in the development of accelerated coronary atherosclerosis in diabetes.

Phase 2 Reentry as a Trigger to Initiate Ventricular Fibrillation During Early Acute Myocardial Ischemia

Background—Phase 2 reentry caused by heterogeneous loss of the transient outward potassium current (Ito)–mediated epicardial action potential (AP) dome can produce a closely coupled R-on-T extrasystole leading to ventricular fibrillation (VF) under conditions of ST-segment elevation unrelated to ischemia. The present study examined the role of phase 2 reentry in the initiation of VF during early myocardial ischemia. Methods and Results—Regional myocardial ischemia was produced in an isolated, arterially perfused canine right ventricular wedge preparation. Transmembrane APs from 2 epicardial sites at each side of the ischemic border were simultaneously recorded together with measurements of extracellular potassium concentration ([K+]o) and a transmural ECG. Loss of the Ito-mediated epicardial AP dome in the ischemic zone but not in the perfused tissue resulted in phase 2 reentry and associated R-on-T extrasystoles capable of initiating VF in 7 of 15 preparations during the first 3 to 9 minutes of myocardial ischemia, with marked ST-segment elevation and [K+]o accumulation. The Ito and phase 1 magnitude of epicardium contributed importantly to the onset of VF. Phase 1 magnitude and Ito density at +30 mV in the group with phase 2 reentry–related R-on-T extrasystoles were 32.2±1.3 mV and 30.3±0.5 pA/pF (n=7), respectively, significantly greater than those (24.0±1.8 mV and 23.2±1.0 pA/pF) in the group without the extrasystoles (n=8, P<0.01). Conclusions—Acute regional myocardial ischemia results in markedly heterogeneous loss of Ito-mediated epicardial AP domes across the ischemic border, leading to phase 2 reentry. Phase 2 reentry can in turn produce an R-on-T extrasystole capable of initiating VF.

Effect of hydralazine on perfusion and metabolism in the leg during upright bicycle exercise in patients with heart failure.

The aerobic exercise capacity of patients with chronic heart failure is frequently impaired because of inadequate O2 transport to working skeletal muscle. To determine whether hydralazine improves O2 transport to working muscle, we examined the effect of intravenous hydralazine on blood flow (measured by thermodilution) and metabolism in the leg during maximal upright bicycle exercise in 10 patients with chronic heart failure. Hydralazine increased maximal exercise cardiac output (5.6 +/- 0.7 to 6.7 +/- 0.6 l/min; p less than .01) and decreased systemic O2 extraction (79 +/- 3% to 65 +/- 2%; p less than .01) but did not alter maximal O2 uptake (787 +/- 105 vs 779 +/- 82 ml/min). Leg blood flow at maximal exercise increased from 1.6 +/- 0.2 to 2.1 +/- 0.4 l/min (p less than .03); the proportion of cardiac output delivered to the leg remained unchanged (59 +/- 3% vs 57 +/- 9%). This increase in flow was associated with a decrease in O2 extraction in the leg (84 +/- 2% to 79 +/- 2%; p less than .01) and no change in peak femoral venous lactate (59.1 +/- 7.4 vs 54.1 +/- 5.3 mg/dl), suggesting that there is functional or anatomic shunting of the augmented limb flow rather than delivery to metabolizing muscle. These data suggest that hydralazine augments flow to the exercising limb in patients with heart failure but that this augmented flow does not increase oxygen availability within working muscle.

Reliable anticoagulation with enoxaparin in patients undergoing percutaneous coronary intervention: The pharmacokinetics of enoxaparin in PCI (PEPCI) study.

The objective of this study was to evaluate the pharmacokinetic response to intravenous (IV) enoxaparin given 8–12 hr after subcutaneous (SC) dosing in patients undergoing percutaneous coronary intervention (PCI). Fifty‐five patients received SC enoxaparin (1 mg/kg every 12 hr) followed by an IV bolus (0.3 mg/kg) 8–12 hr after the last SC dose, at the start of PCI or during catheterization. Anti‐Xa levels were within the target range in 98% of patients 2–8 hr after the last SC dose, in 96% of patients following the IV bolus, and in 91% of patients for a further 2 hr. Subcutaneous enoxaparin (1 mg/kg every 12 hr) provides sufficient anti‐Xa levels for PCI 2–8 hr after the last dose. An additional 0.3 mg/kg enoxaparin dose given IV 8–12 hr after the last SC dose reliably maintains anti‐Xa levels within the target for at least 2 additional hr. Catheter Cardiovasc Interv 2004;61:163–170.

A randomized trial comparing compression, perclose proglide™ and Angio‐Seal VIP™ for arterial closure following percutaneous coronary intervention: The cap trial

Objective: This prospective randomized trial compared the Angio‐Seal VIP™ with Perclose Proglide™ and to manual compression with respect to time to hemostasis and ambulation, patient satisfaction, and vascular complications following percutaneous coronary intervention (PCI). Background: The use of arterial closure devices for the reduction of vascular complications following PCI remains controversial. There have been no head to head trials comparing these most commonly used arterial closure devices following PCI. Methods: Two hundred patients undergoing PCI were randomized to manual compression, Perclose Proglide™ or Angio‐Seal VIP™. Ambulation was allowed 3 hr after Perclose Proglide™ or Angio‐Seal VIP™ and 6 hr after compression. Results: There were 10 failures to deploy Perclose Proglide™ and none for Angio‐Seal™ (P < 0.01). Time to hemostasis was significantly shorter with Angio‐Seal VIP™ compared with Perclose Proglide™ (5.3 vs. 46.8 min, P < 0.01). Time to ambulation was shorter with Angio‐Seal VIP™ than with Perclose Proglide™ (261 vs. 334 min, P < 0.05) and the time to ambulation, as expected, was longest with compression (943 min, P < 0.01 vs. Angio‐Seal VIP™ and Perclose Proglide™). Delay in ambulation was higher with Perclose Proglide™ than with Angio‐Seal VIP™ (18 vs. 9, P < 0.01). There was no significant difference in major vascular complications between groups. Compared with compression, patient discomfort was significantly improved with Angio‐Seal™ (1.5 vs. 2.0, P < 0.01), but not with Perclose Proglide™. Conclusion: The Angio‐Seal VIP™ device has a high rate of deployment success, which is significantly better than that of Perclose Proglide™. Angio‐Seal VIP™ allows for earlier hemostasis and ambulation compared with both compression and Perclose Proglide™ and is associated with greater patient satisfaction compared with compression.

Local Delivery of Enoxaparin to Decrease Restenosis After Stenting: Results of Initial Multicenter Trial Polish-American Local Lovenox NIR Assessment Study (The POLONIA Study)

Background—Enoxaparin inhibits smooth muscle cell proliferation in experimental models. Intimal hyperplasia has been found to be the principal cause of restenosis after coronary stent implantation. We sought to determine whether the intramural delivery of enoxaparin before stenting of de novo lesions decreases restenosis. Methods and Results—One hundred patients who were undergoing stenting were randomly assigned to either local administration of enoxaparin during predilation with reduced systemic heparinization or stenting with standard, systemic heparinization. All patients were treated with the same type of stent (NIR). The primary study end point was late luminal loss. The secondary end points were major adverse cardiac events, target lesion revascularization, and angiographic restenosis at 6 months. Angiographic follow-up at 6 months was completed in all except 1 patient. Late luminal loss was reduced to 0.76±0.42 mm in the local enoxaparin delivery group versus 1.07±0.49 mm in the systemic heparinization group (P <0.001). Restenosis, using a binary definition, occurred in 10% of patients in the enoxaparin group and in 24% of patients in the systemic heparinization group (P <0.05). Target lesion revascularization rates occurred in 8% of the enoxaparin group and 22% of the systemic heparinization group (P <0.05). There were no deaths and no emergent CABGs were performed. The only subacute stent closure and non–Q-wave infarction occurred in a patient assigned to the systemic heparinization group. Conclusions—This is the first prospective randomized trial in which the local delivery of a drug, enoxaparin, resulted in significant reduction in late luminal loss and restenosis after stent implantation in de novo coronary lesions.

Myocardial energetics and clinical response to the cardiotonic agent MDL 17043 in advanced heart failure

Cardiotonic agents may prove useful in the long-term treatment of chronic heart failure provided myocardial efficiency is enhanced and clinical status is improved. Accordingly, the short-term hemodynamic and clinical response to the phosphodiesterase inhibitor, MDL 17043, was evaluated. Intravenous increments of 0.05 mg/kg (maximal total 3 mg/kg) were given to a peak cardiac output response in 13 patients with New York Heart Association functional class IV heart failure secondary to ischemic or myopathic disease. Significant (p less than 0.05) responses at peak effect (1.7 mg/kg) included an increase in cardiac output (3.5 to 4.6 liters/min) and heart rate (86 to 90 beats/min) and a decrease in pulmonary capillary wedge (25 to 17 mm Hg), mean arterial (85 to 78 mm Hg) and right atrial (10 to 7 mm Hg) pressures. Coronary sinus flow (measured in nine patients) increased (122 to 144 ml/min, p less than 0.01) as did myocardial oxygen uptake (14.1 to 15.1 ml/min, p less than 0.01), whereas myocardial extraction of oxygen (78 to 72%, p less than 0.01) and lactate (24 to 9%, p less than 0.01) decreased with three patients producing lactate at the time of their peak cardiac output response. Nine of the 12 patients given long-term oral therapy improved at least one functional class at 2 weeks. This improvement was sustained at 20 weeks in five patients. Thus, MDL 17043 acutely improves the function of the failing heart. However, the decrease in oxygen extraction occurring with increased myocardial oxygen uptake suggests that intracoronary shunting may occur along with an increase in oxygen demand and contribute to myocardial anaerobiosis in some patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Extent and distribution of in-stent intimal hyperplasia and edge effect in a non-radiation stent population.

Intimal hyperplasia within the body of the stent is the primary mechanism for in-stent restenosis; however, stent edge restenosis has been described after brachytherapy. Our current understanding about the magnitude of in vivo intimal hyperplasia and edge restenosis is limited to data obtained primarily from select, symptomatic patients requiring repeat angiography. The purpose of this study was to determine the extent and distribution of intimal hyperplasia both within the stent and along the stent edge in relatively nonselect, asymptomatic patients scheduled for 6-month intravascular ultrasound (IVUS) as part of a multicenter trial: Heparin Infusion Prior to Stenting. Planar IVUS measurements 1 mm apart were obtained throughout the stent and over a length of 10 mm proximal and distal to the stent at index and follow-up. Of the 179 patients enrolled, 140 returned for repeat angiography and IVUS at 6.4 +/- 1.9 months and had IVUS images adequate for analysis. Patients had 1.2 +/- 0.6 Palmaz-Schatz stents per vessel. There was a wide individual variation of intimal hyperplasia distribution within the stent and no mean predilection for any location. At 6 months, intimal hyperplasia occupied 29.3 +/- 16.2% of the stent volume on average. Lumen loss within 2 mm of the stent edge was due primarily to intimal proliferation. Beyond 2 mm, negative remodeling contributed more to lumen loss. Gender, age, vessel location, index plaque burden, hypercholesterolemia, diabetes, and tobacco did not predict luminal narrowing at the stent edges, but diabetes, unstable angina at presentation, and lesion length were predictive of in-stent intimal hyperplasia. In a non-radiation stent population, 29% of the stent volume is filled with intimal hyperplasia at 6 months. Lumen loss at the stent edge is due primarily to intimal proliferation.