James P. Tsikouris

Plasminogen activator inhibitor-1: physiologic role, regulation, and the influence of common pharmacologic agents.

Plasminogen activator inhibitor‐1 (PAI‐1) is the major inhibitor of endogenous thrombolysis, thereby promoting thrombosis. PAI‐1 is also a primary contributor to the development and recurrence of acute myocardial infarction. The renin angiotensin system, hypertriglyceridemia, hyperglycemia and hyperinsulinemia, and estrogen all influence the fibrinolytic system and PAI‐1 in particular. Available data strongly suggest that angiotensin‐converting enzyme (ACE) inhibitors and hormone replacement therapy with estrogen beneficially reduce PAI‐1 production. Metformin, an agent commonly used for non‐insulin‐dependent diabetes mellitus (NIDDM), appears to favorably decrease PAI‐1 production in NIDDM patients but not nondiabetic patients. Among the cholesterollowering statins, clinical literature evaluating pravastatin provides the most compelling data to support this agents favorable effect on PAI‐1. Other available statins either have not displayed an effect on PAI‐1 or do not have clear data to conclusively define their effects on the fibrinolytic system.

Preventing contrast nephropathy: What is the best strategy? A review of the literature

Patients receiving radiocontrast for diagnostic and interventional procedures are at risk for developing contrast nephropathy (CN). In fact, radiocontrast nephropathy is currently the third leading cause of hospital‐acquired renal failure. Understanding that CN has been associated with increased length of hospitalization and mortality, determining the best prevention strategy is of utmost importance. Patients at the greatest risk for developing acute renal failure are patients with diabetes and underlying renal insufficiency. Several therapies have been investigated for the prevention of CN; unfortunately, very few have shown a consistent benefit. Therapies that have been studied include saline hydration, N‐acetylcysteine (NAC), theophylline, calcium channel blockers, diuretics, dopamine, endothelin receptor antagonists, atrial natriuretic peptide, angiotensin‐converting enzyme inhibitors, and prostaglandin E‐1. Using adequate hydration, using low‐osmolar dyes, and minimizing the dose of contrast have all been shown to be effective in reducing CN and are considered the standard of care. While trials with many pharmacologic agents have produced conflicting results, intervention with NAC has also been promising. This article reviews the pathophysiology, risk factors, and therapies that are currently available for the prevention of CN.

Pharmacologic blockade of the renin-angiotensin system: vascular benefits beyond commonly understood pharmacologic actions.

Angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are recognized primarily for their use in hypertension, in heart failure, and after myocardial infarction. New evidence, particularly with ACE inhibitors, has shown their ability to reduce acute coronary events associated with atherosclerosis in patients without a history of the aforementioned cardiac conditions. This is likely due to inhibitory effects on the renin‐angiotensin system—a system that adversely influences fibrinolytic balance, vascular endothelial function, and vascular inflammation, all key components of atherosclerotic progression and adverse coronary outcomes. Results of various studies suggest favorable effects of ACE inhibitors and ARBs on markers of these components, including effects on plasminogen activator inhibitor‐1, endothelin‐1, and nitric oxide by ACE inhibitors, and effects on vascular cell adhesion molecule‐1 and C‐reactive protein by ARBs. Although early evidence suggests that ACE inhibitors may provide a greater beneficial effect on some of these markers compared with ARBs, and that certain ACE inhibitors may provide greater vascular benefits than others, further investigation is required to verify such findings. Overall, understanding the distinct coronary vascular benefits of these agents will emphasize the importance of using them, particularly ACE inhibitors, to improve outcomes in patients with coronary atherosclerotic disease.

Questioning a Class Effect: Does ACE Inhibitor Tissue Penetration Influence the Degree of Fibrinolytic Balance Alteration following an Acute Myocardial Infarction?

There is a common belief in a class effect among angiotensin‐converting enzyme (ACE) inhibitors. This is unsubstantiated for acute myocardial infarction (AMI). Because vascular tissue is a source of the endogenous fibrinolytic markers, and ACE inhibition in vascular tissue favorably influences the fibrinolytic system, the authors hypothesized that a high‐tissue‐penetrating ACE inhibitor would provide a more favorable reduction in plasminogen activator inhibitor‐1 (PAI‐1) and an increase in tissue plasminogen activator (t‐PA) after AMI compared to a low‐tissue‐penetrating ACE inhibitor. In a randomized open‐label trial, patients received the high‐tissue‐penetrating quinapril (n = 15) or low‐tissue‐penetrating enalapril (n = 15) immediately following an AMI. PAI‐1 and t‐PA antigen (ng/mL) were measured at baseline and through 14 days of treatment. There was no difference in baseline PAI‐1 or t‐PA antigen between treatments. PAI‐1 antigen trended toward being lower with quinapril versus enalapril on day 1 (24.44 ± 14.96 vs. 36.94 ± 19.49, respectively, p = 0.059) and was significantly lower on day 3 (17.32 ±9.57 vs. 27.49 ± 9.61, respectively, p = 0.009). Analysis of PAI‐1 antigen over time by two‐factor ANOVA with replication found significantly lower concentrations of PAI‐1 antigen over the entire treatment period with quinapril versus enalapril (p < 0.003). This investigation of ACE inhibitor tissue‐penetrating influence on markers of reinfarction risk suggests there may be a greater early reduction in PAI‐1 with a more highly tissue‐penetrating ACE inhibitor.

Evaluation of angiotensin converting enzyme (ACE)-like activity of acellular hemoglobin.

Despite the tremendous progress in research on hemoglobin (Hb) cellular and molecular responses, the current understanding of Hbs overall intrinsic toxicity is still limited. The complete mechanism of Hb-induced vasoconstriction has not yet been established, particularly the involvement of the renin-angiotensin system (RAS). Some studies emphasized that Hb may augment the vascular responsiveness to angiotensin (Ang)-II. It was also reported that Hb, as well as Ang-II, influences the synthesis of 8-iso prostaglandin F2 alpha, which has an impact on renal flow and possibly RAS. Hb in the presence of H2O2 gains enzymatic activity. Thus, it is possible that Hb directly and/or indirectly can activate RAS. In this study, we monitored the effect of ferrous- and ferryl-Hb, and H2O2 alone, on conversion of Ang-I to its active metabolites. The structural and immunological identity of the resulting products were evaluated by reversed phase C-18 HPLC and ELISA, respectively. Additionally, ACE-like activity of Hbs was measured spectrophotometrically by determining their ability to react with the ACE substrate, the synthetic tripeptide N-[3-(2-furyl)acryloyl]-L-phenylalanylglycylglycine. Results indicate that while ferrous-Hb can serve as a receptor for Ang-I, its ferryl form possesses ACE-like activity, being able to convert, within minutes, Ang-I to Ang-II, Ang-III, Ang-IV, Ang (1-7) and other unresolved fragments. H2O2 itself had a very limited hydrolyzing effect on Ang-I. Based on this study, it can be concluded that ACE-like activity of Hb with rapid formation of active angiotensins may be a contributor to the still unexplained vasoconstrictive response observed immediately after Hb administration.

Review of Catheter Thrombectomy Devices

Acute massive pulmonary embolism (PE) is a frequently fatal event that causes significant compromise of hemodynamic stability. Unfortunately, mortality rates for PE have remained relatively constant despite advances in prophylactic and treatment measures. In addition to embolus size, symptom recognition for diagnosis and emergent treatment are two distinct factors that dictate survival. Treatment generally includes thrombolytic agents; however, not all patients are candidates for aggressive thrombolytic management. Development of catheter thrombectomy devices provides an alternative treatment modality for severe cases when thrombolytics are contraindicated. Catheter thrombectomy devices have undergone major advances over the last decade, but literature support of their success is limited.

Lack of effect on coronary atherosclerotic disease biomarkers with modest dosing of an angiotensin-converting enzyme inhibitor, angiotensin II type-1 receptor blocker, and the combination.

BackgroundAngiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, used alone or in combination, have been shown to improve outcomes in certain populations, primarily when administered in high doses. For stable coronary atherosclerotic disease, however, the relative physiologic effect of these therapies is unclear. Furthermore, because of the notorious subtarget dosing of such agents in clinical practice, we explored the influence of a modest dosing of an angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blockers, and the combination on common biologic markers of coronary atherosclerotic disease. MethodsThis randomized, cross-over study enrolled stable coronary atherosclerotic disease patients (n=20), each receiving three treatments: candesartan 16 mg daily, ramipril 5 mg daily, and candesartan 8 mg plus ramipril 2.5 mg daily. Treatments were administered for 2 weeks with a 2-week washout. Blood samples were collected before and after each treatment. Markers of endothelial function, fibrinolytic balance, and vascular inflammation were measured. ResultsNo significant differences were observed in the pretreatment concentrations of angiotensin-converting enzyme or of any measured biologic marker. Relative to pretreatment levels, candesartan alone was the only therapy to exhibit an action on any measured biomarker – a trend toward increased nitric oxide concentrations (P=0.054). Otherwise, no effects on biologic markers were observed with the treatments. ConclusionThis study of various methods of the renin–angiotensin system inhibition in stable coronary atherosclerotic disease patients demonstrates negligible effects of a modest dosing of ramipril and the combination of ramipril plus candesartan on common biologic markers of coronary atherosclerotic disease. Candesartan at modest doses may favorably influence endothelial function. Overall, however, the results indicate that the commonly practiced subtarget dosing of such treatments provides little, if any, benefit pertaining to key physiologic components of coronary atherosclerotic disease.

Potential In Vitro Interaction Between Tenecteplase and Unfractionated Heparin

Study Objective. To explore the potential of a direct drug interaction between unfractionated heparin (UFH) and tenecteplase that lowers the pharmacologic propensity of UFH to prolong the activated partial thromboplastin time (aPTT).