Adam Oesterle

Pleiotropic Effects of Statins on the Cardiovascular System

The statins have been used for 30 years to prevent coronary artery disease and stroke. Their primary mechanism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the clearance of LDL-cholesterol. Statins may exert cardiovascular protective effects that are independent of LDL-cholesterol lowering called pleiotropic effects. Because statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small GTP-binding proteins such as Rho and Rac, and their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of proinflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify because the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-cholesterol reduction. This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease.

S100A12 and the S100/Calgranulins

Atherosclerosis is mediated by local and systematic inflammation. The multiligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell–targeted expression of S100A12 demonstrate increased coronary and aortic calcification, as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis-susceptible apolipoprotein E null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 apolipoprotein E null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis, and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis. # Significance {#article-title-96}Atherosclerosis is mediated by local and systematic inflammation. The multiligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell-targeted expression of S100A12 demonstrate increased coronary and aortic calcification, as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis-susceptible apolipoprotein E null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 apolipoprotein E null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis, and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis.

S100A12 and the S100/Calgranulins Emerging Biomarkers for Atherosclerosis and Possibly Therapeutic Targets

Atherosclerosis is mediated by local and systematic inflammation. The multiligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell–targeted expression of S100A12 demonstrate increased coronary and aortic calcification, as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis-susceptible apolipoprotein E null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 apolipoprotein E null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis, and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis. # Significance {#article-title-96}Atherosclerosis is mediated by local and systematic inflammation. The multiligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell-targeted expression of S100A12 demonstrate increased coronary and aortic calcification, as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis-susceptible apolipoprotein E null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 apolipoprotein E null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis, and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis.

Preventing Postoperative Atrial Fibrillation After Noncardiac Surgery: A Meta-analysis

BACKGROUND Although postoperative atrial fibrillation is common after noncardiac surgery, there is a paucity of data regarding prophylaxis. We sought to determine whether pharmacologic prophylaxis reduces the incidence of postoperative atrial fibrillation after noncardiac surgery. METHODS We performed an electronic search of Ovid MEDLINE, the Cochrane central register of controlled trials database, and SCOPUS from inception to September 7, 2016 and included prospective randomized studies in which patients in sinus rhythm underwent noncardiac surgery and examined the incidence of postoperative atrial fibrillation as well as secondary safety outcomes. RESULTS Twenty-one studies including 11,608 patients were included. Types of surgery included vascular surgery (3465 patients), thoracic surgery (2757 patients), general surgery (2292 patients), orthopedic surgery (1756 patients), and other surgery (1338 patients). Beta-blockers (relative risk [RR] 0.32; 95% confidence interval [CI], 0.11-0.87), amiodarone (RR 0.42; 95% CI, 0.26 to 0.67), and statins (RR 0.43; 95% CI, 0.27 to 0.68) reduced postoperative atrial fibrillation compared with placebo or active controls. Calcium channel blockers (RR 0.55; 95% CI, 0.30 to 1.01), digoxin (RR 1.62; 95% CI, 0.95 to 2.76), and magnesium (RR 0.73; 95% CI, 0.23 to 2.33) had no statistically significant effect on postoperative atrial fibrillation incidence. The incidence of adverse events was comparable across agents, except for increased mortality (RR 1.33; 95% CI, 1.03 to 1.37) and bradycardia (RR 2.74; 95% CI, 2.19 to 3.43) in patients receiving beta-blockers. CONCLUSIONS Pharmacologic prophylaxis with amiodarone, beta-blockers, or statins reduces the incidence of postoperative atrial fibrillation after noncardiac surgery. Amiodarone and statins have a relatively low overall risk of short-term adverse events.

Termination of tachycardia with resolution of left bundle branch block: What is the mechanism?

Correctly diagnosing supraventricular tachycardia (SVT) in the electrophysiology (EP) laboratory is often challenging. It may be possible to reach the correct diagnosis by closely examining tachycardia termination. We present an intracardiac electrocardiographic tracing of nonsustained SVT termination that correctly identifies the SVT mechanism.

Late presentation of constrictive pericarditis after limited epicardial ablation for inappropriate sinus tachycardia

The number of radiofrequency catheter ablation (RFA) procedures performed in the epicardial space is increasing. Major acute complications (primarily pericardial bleeding) and delayed complications have been reported in 5% and 2% of cases, respectively. To the best of our knowledge, a single case of constrictive pericarditis after multiple epicardial ablations for ventricular tachycardia has been reported. We describe a late presentation of constrictive pericarditis that occurred after a single percutaneous epicardial procedure with limited ablation for inappropriate sinus tachycardia.

A Subclavian Arteriovenous Fistula Associated with Implantable Cardioverter-Defibrillator Implantation.

Subclavian arteriovenous fistulas (AVFs) should be considered in the differential diagnosis of a patient presenting with worsening CHF symptoms or unilateral edema immediately after device implantation. A palpable thrill may be present or a bruit may be auscultated in the region of the fistula. Ultrasonography has limitations in the subclavian region and definitive diagnosis is only made by angiogram. Percutaneous occlusion of the AVF is preferred as surgical repair is associated with significant morbidity and mortality.

S100A12 and the S100/CalgranulinsSignificance

Atherosclerosis is mediated by local and systematic inflammation. The multiligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell–targeted expression of S100A12 demonstrate increased coronary and aortic calcification, as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis-susceptible apolipoprotein E null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 apolipoprotein E null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis, and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis. # Significance {#article-title-96}Atherosclerosis is mediated by local and systematic inflammation. The multiligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell-targeted expression of S100A12 demonstrate increased coronary and aortic calcification, as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis-susceptible apolipoprotein E null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 apolipoprotein E null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis, and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis.

S100A12 and the S100/CalgranulinsSignificance: Emerging Biomarkers for Atherosclerosis and Possibly Therapeutic Targets

Atherosclerosis is mediated by local and systematic inflammation. The multiligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell–targeted expression of S100A12 demonstrate increased coronary and aortic calcification, as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis-susceptible apolipoprotein E null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 apolipoprotein E null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis, and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis. # Significance {#article-title-96}Atherosclerosis is mediated by local and systematic inflammation. The multiligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell-targeted expression of S100A12 demonstrate increased coronary and aortic calcification, as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis-susceptible apolipoprotein E null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 apolipoprotein E null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis, and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis.