Steven E. Pfau

Modulation of circulating cellular adhesion molecules in postmenopausal women with coronary artery disease

OBJECTIVES The present study examined the association of estrogen (E2) and the inflammatory response of endothelium in coronary artery disease (CAD) by measuring circulating cellular adhesion molecules (cCAMs) in subjects with atherosclerosis. BACKGROUND Atherosclerotic plaque demonstrates features similar to inflammation. Endothelial cell activation by inflammatory cytokines induces expression of cellular adhesion molecules (CAMs), thereby perhaps augmenting leukocyte adhesion and recruitment and subsequent development of atherosclerosis. The incidence of CAD is lower in women; this may be due to the cardioprotective effects of E2. METHODS Consecutive eligible subjects with CAD admitted for cardiac catheterization were studied. The groups evaluated were men, postmenopausal women receiving E2 replacement therapy (ERT), postmenopausal women not receiving ERT and premenopausal women. Control groups included men and women without CAD. Preprocedural blood samples were drawn from all groups. Measurements of cCAMs, E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 were performed by enzyme-linked immunoabsorbant assay. E2 levels were assessed by radioimmunoassay. RESULTS We observed a statistically significant increase in all cCAMs in men with CAD and postmenopausal women with CAD not receiving ERT compared with postmenopausal women with CAD receiving ERT. Premenopausal women with CAD and postmenopausal women with CAD receiving ERT had a significant increase in VCAM-1 alone compared with the female control group. CONCLUSIONS A possible mechanism by which E2 exerts one of its cardioprotective effects is by limiting the inflammatory response to injury by modulating the expression of CAMs from the endothelium.

Myocardial blood-flow response during mental stress in patients with coronary artery disease

Positron emission tomography was used to quantify changes in myocardial blood flow during mental stress in patients with and without coronary artery disease. Blunted augmentation of myocardial blood flow during mental stress was observed in regions without significant epicardial stenosis.

Effect of Non–Insulin-Dependent Diabetes Mellitus on Myocardial Insulin Responsiveness in Patients With Ischemic Heart Disease

BackgroundPatients with non–insulin-dependent diabetes mellitus (NIDDM) exhibit poor clinical outcomes from myocardial ischemia. This may reflect an impairment in their cardiac insulin-response system. Methods and ResultsWe used AV balance and intracoronary infusion techniques to compare the intrinsic cardiac responsiveness to insulin in 26 coronary disease patients with (n=13) and without (n=13) NIDDM. During fasting, NIDDM hearts demonstrated lower fractional extraction of glucose from arterial plasma than controls (1.0±0.5% versus 2.1±0.5%, P <0.05) despite higher circulating insulin levels (26±5 versus 13±4 &mgr;U · mL, P <0.05). This was compensated for by higher circulating glucose levels, so that net cardiac glucose uptake in the 2 groups was equivalent (5.2±1.1 versus 5.3±1.1 &mgr;mol · min). Intracoronary insulin infusion produced an ≈3-fold increase in fractional extraction and net uptake of glucose across the heart in both groups (to 3.7±0.4% and 18.3±3.5 &mgr;mol · min in NIDDM and to 5.4±0.7% and 17.7±4.3 &mgr;mol · min in controls) accompanied by an ≈30% increase in net lactate uptake, suggesting preserved insulin action on both glucose uptake and glucose oxidation in the NIDDM heart. In nondiabetics, insulin consistently increased coronary blood flow, but this effect was absent in NIDDM. ConclusionsIn contrast to their peripheral tissues and coronary vasculature, the myocardium of patients with NIDDM expresses a competent insulin-response system with respect to glucose metabolism. This suggests that insulin resistance is mediated at the level of individual organs and that different mechanisms are involved in muscle and vascular tissue.

Effect of plasma insulin level on myocardial blood flow and its mechanism of action

Considerable evidence suggests that coronary endothelium regulates myocardial blood flow and metabolism by elaborating vasoactive substances. The physiologic signals mediating this process are uncertain. To test the hypothesis that the process is influenced by physiologic variation in local insulin concentration, we examined the effect of direct intracoronary insulin infusion on myocardial blood flow and oxidative substrate metabolism in 10 patients with coronary heart disease. Ten men (aged 51 to 68 years) who were fasting received a 60-minute intracoronary infusion of insulin at a rate (10 mU/min) sufficient to raise coronary venous plasma insulin from 12+/-4 to 133+/-17 mU/ml without increasing the systemic insulin level. Local coronary hyperinsulinemia increased coronary sinus blood flow in every subject, from 50+/-4 to 61+/-6 ml/min (p<0.01). Insulin also increased myocardial uptake of glucose (from 6+/-1 to 17+/-6 mmol/min) and lactate (from 8+/-2 to 12+/-5 mmol/min), resulting in approximately 30% increase in total oxidative substrate uptake, but without increasing myocardial oxygen consumption (7.0+/-0.7 vs. 7.1+/-0.8 ml/min). Thus, physiologic elevation in the local plasma insulin concentration increases coronary blood flow in the absence of any increase in myocardial oxygen demand or consumption, suggesting a primary reduction in coronary tone, while simultaneously restraining the oxidation of imported substrates. These observations are consistent with insulin-mediated elaboration of vasoactive and/or paracrine factors within the coronary circulation.

Electromechanical mapping for detecting myocardial viability and ischemia in patients with severe ischemic cardiomyopathy.

This study was designed to evaluate several electromechanical mapping parameters for assessment of myocardial viability and inducible ischemia as defined by dipyridamole single-photon emission computed tomographic (SPECT) imaging at rest in patients with severe ischemic cardiomyopathy. Unipolar voltage, normalized unipolar voltage, bipolar voltage, and fragmentation were compared with tracer uptake at rest and reversibility on stress or rest quantitative technetium-99m sestamibi SPECT imaging in 32 patients with severe ischemic cardiomyopathy (left ventricular ejection fraction 0.24 +/- 0.08). In dysfunctional myocardial segments, logistic regression showed unipolar voltage, normalized unipolar voltage, and bipolar voltage to be predictive of viable myocardium (> or = 60% tracer uptake at rest) and was significantly higher in viable than in nonviable segments (p <0.01). A unipolar voltage of > or = 7.1 mV was the best predictor of viable myocardium. In dysfunctional viable segments, unipolar voltage was significantly higher in reversible than in fixed segments (p <0.001), and a unipolar voltage of > or = 8.5 mV had optimal power for identifying reversibility on dipyridamole SPECT imaging. We conclude that in patients with severe ischemic cardiomyopathy, unipolar voltage can identify viable from nonviable myocardium and reversible from fixed viable defects as defined by dipyridamole technetium-99m sestamibi SPECT imaging.

Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack

Background: Insulin resistance is highly prevalent among patients with atherosclerosis and is associated with an increased risk for myocardial infarction (MI) and stroke. The IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone decreased the composite risk for fatal or nonfatal stroke and MI in patients with insulin resistance without diabetes mellitus, after a recent ischemic stroke or transient ischemic attack. The type and severity of cardiac events in this population and the impact of pioglitazone on these events have not been described. Methods: We performed a secondary analysis of the effects of pioglitazone, in comparison with placebo, on acute coronary syndromes (MI and unstable angina) among IRIS participants. All potential acute coronary syndrome episodes were adjudicated in a blinded fashion by an independent clinical events committee. Results: The study cohort was composed of 3876 IRIS participants, mean age 63 years, 65% male, 89% white race, and 12% with a history of coronary artery disease. Over a median follow-up of 4.8 years, there were 225 acute coronary syndrome events, including 141 MIs and 84 episodes of unstable angina. The MIs included 28 (19%) with ST-segment elevation. The majority of MIs were type 1 (94, 65%), followed by type 2 (45, 32%). Serum troponin was 10× to 100× upper limit of normal in 49 (35%) and >100× upper limit of normal in 39 (28%). Pioglitazone reduced the risk of acute coronary syndrome (hazard ratio, 0.71; 95% confidence interval, 0.54–0.94; P=0.02). Pioglitazone also reduced the risk of type 1 MI (hazard ratio, 0.62; 95% confidence interval, 0.40–0.96; log-rank P=0.03), but not type 2 MI (hazard ratio, 1.05; 95% confidence interval, 0.58–1.91; P=0.87). Similarly, pioglitazone reduced the risk of large MIs with serum troponin >100× upper limit of normal (hazard ratio, 0.44; 95% confidence interval, 0.22–0.87; P=0.02), but not smaller MIs. Conclusions: Among patients with insulin resistance without diabetes mellitus, pioglitazone reduced the risk for acute coronary syndromes after a recent cerebrovascular event. Pioglitazone appeared to have its most prominent effect in preventing spontaneous type 1 MIs. Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT00091949.

Dose distributions in bifurcated coronary vessels treated with catheter-based photon and beta emitters in intravascular brachytherapy

The dose distributions in the bifurcated vessels treated with intravascular brachytherapyline sources are complicated and depend on the bifurcation geometry consisting of a main and a branch vessel at different angles. To investigate the dosimetric effects at the bifurcation, calculations were performed on branching vessels of various bifurcation angles ranging from 20 degrees to 90 degrees. Two catheter based delivery systems were considered in the calculations using a 40 mm long radioactive sources of 192Ir or 90Sr/Y. It was assumed that the bifurcated vessel was treated in twoseparate source insertions, once for the main vessel and later for the branch vessel. Calculations were performed for different values of source gap from 0 to 9 mm, at the junction of main and branch vessels. Our results indicate that main vessel always receives a higher dose (up to 200%) when the branch vessel is also treated. Hot spots at portions of the main vessel near the junction cannot be totally avoided without severely underdosing the branch vessel. For bifurcation angle greater than 45 degrees, a 4 mm source gap can almost ensure that overdosing of the main vessel does not exceed 60% and underdosing of the branch vessel does not exceed 10% for 192Ir. However, for 90Sr/Y, the same is not possible unless the bifurcation angle is larger than 70 degrees. Dose heterogeneity using 90Sr/Y is more sensitive to the value of source gap than 192Ir because 90Sr/Y source provides a sharper dose-fall-off than 192Ir. For both photon and beta emitters, there is no acceptable solution for bifurcation angles less than 30 degrees, where the activity of the line source has a uniform distributions. Appropriate choice of gap at the junction can only help to reduce either overdosing of the main vessel or underdosing of the branch vessel, but not both.

Cardiac Outcomes After Ischemic Stroke or TIA: Effects of Pioglitazone in Patients with Insulin Resistance Without Diabetes

Background: Insulin resistance is highly prevalent among patients with atherosclerosis and is associated with an increased risk for myocardial infarction (MI) and stroke. The IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone decreased the composite risk for fatal or nonfatal stroke and MI in patients with insulin resistance without diabetes mellitus, after a recent ischemic stroke or transient ischemic attack. The type and severity of cardiac events in this population and the impact of pioglitazone on these events have not been described. Methods: We performed a secondary analysis of the effects of pioglitazone, in comparison with placebo, on acute coronary syndromes (MI and unstable angina) among IRIS participants. All potential acute coronary syndrome episodes were adjudicated in a blinded fashion by an independent clinical events committee. Results: The study cohort was composed of 3876 IRIS participants, mean age 63 years, 65% male, 89% white race, and 12% with a history of coronary artery disease. Over a median follow-up of 4.8 years, there were 225 acute coronary syndrome events, including 141 MIs and 84 episodes of unstable angina. The MIs included 28 (19%) with ST-segment elevation. The majority of MIs were type 1 (94, 65%), followed by type 2 (45, 32%). Serum troponin was 10× to 100× upper limit of normal in 49 (35%) and >100× upper limit of normal in 39 (28%). Pioglitazone reduced the risk of acute coronary syndrome (hazard ratio, 0.71; 95% confidence interval, 0.54–0.94; P=0.02). Pioglitazone also reduced the risk of type 1 MI (hazard ratio, 0.62; 95% confidence interval, 0.40–0.96; log-rank P=0.03), but not type 2 MI (hazard ratio, 1.05; 95% confidence interval, 0.58–1.91; P=0.87). Similarly, pioglitazone reduced the risk of large MIs with serum troponin >100× upper limit of normal (hazard ratio, 0.44; 95% confidence interval, 0.22–0.87; P=0.02), but not smaller MIs. Conclusions: Among patients with insulin resistance without diabetes mellitus, pioglitazone reduced the risk for acute coronary syndromes after a recent cerebrovascular event. Pioglitazone appeared to have its most prominent effect in preventing spontaneous type 1 MIs. Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT00091949.

Brachytherapy for in-stent restenosis in general interventional practice: a single institution's experience using four radiation devices.

BACKGROUND The effectiveness of brachytherapy for the treatment of in-stent restenosis (ISR) has been established in a number of large randomized controlled trials. Efficacy of this therapy in general population is less well established. METHODS AND MATERIALS We report our experience of 207 patients, 236 coronary lesions, treated with brachytherapy between November 2000 and November 2002. All commercially available brachytherapy devices, as well as one investigational device, were utilized. This cohort was followed over 9 months and clinical outcomes were obtained with subsequent analysis of patient and lesion-specific characteristics. RESULTS Average treatment age was 62.5 years; 73% were male and the most frequent presentation was unstable angina (74%). All patients had successful delivery of radiation, with no in-hospital deaths. Novoste BetaCath device was used for 163 (65%) lesions, Cordis Checkmate for 56 (24%) lesions, Interventional Therapies device in 13 (8%) lesions, and Guidant Galileo in 4 lesions (3%). At a mean follow-up of 9.1 months, 78.7% were free of major adverse cardiac event (MACE). Twenty-one patients required repeat PTCA (10.1%), 19 had CABG (9.2%), 3 had MI (1.4%), and there was 1 death (0.5%). Unadjusted MACE rates for each device were 21% for Novoste, 28% for Checkmate, 8% for Interventional Therapies, and 50% for Galileo. Lesion length, minimal lumen diameter, renal failure, diabetes, and smoking did not predict treatment failure; only age was inversely correlated with MACE (P=.002). CONCLUSION When applied across a spectrum of patients, lesions, and devices, brachytherapy retains its effectiveness with outcomes similar to those reported in randomized clinical trials.

Initiation of cardiac allograft rejection

Although cardiac transplantation has become a viable therapeutic option for end-stage heart disease, long-term success is limited by rejection and medical complications of immunosuppression. Earliest events in rejection revolve around T-lymphocyte recognition of foreign antigen through a panel of specialized cell surface proteins. This is followed by a cascade of signaling events, transcription of multiple genes, and cytokine production. The central importance of these events, collectively known as T-cell activation, to the rejection process is underscored by the clinical utility of cyclosporine, which prevents T-cell activation. The specific site of action of cyclosporine within the T cell has recently been elucidated at the molecular level, revealing important details of T-cell biology. Once the immune response has been initiated, localization of inflammatory cells to the graft requires alteration in the functional state of the vascular endothelium, which can then express adhesive ligands for immune effector cells. Recent evidence suggests that host natural killer lymphocytes may play a role in this process. Understanding the molecular details of these and other early events in rejection will facilitate the development of more specific and effective immunosuppressive therapies.