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Risk Factors for Cardiovascular Events in Japanese Patients Treated with Fluvastatin from the Long-Term Event Monitoring (LEM) Study
Ryuichi Morishita, Hiroshige Itakuraa, Noriaki Nakaya, Masayuki Yoshida, Masato Odawara,  Atsuhiro Ichihara and Kyoichi Mizuno
[Abstract] [Purchase Inquiry Form] [PMID: 21824105 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00171]


Telomere/Telomerase System: A New Target of Statins Pleiotropic Effect?
Fabiola Olivieri, Ilaria Mazzanti, Angela Marie Abbatecola, Rina Recchioni, Fiorella Marcheselli, Antonio Domenico Procopio and Roberto Antonicelli
[Abstract] [Purchase Inquiry Form] [PMID: 22022767 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00175]


Statin-Induced Myotoxicity: Pharmacokinetic Differences among Statins and the Risk of Rhabdomyolysis, with Particular Reference to Pitavastatin
Alberico L. Catapano
[Abstract] [Purchase Inquiry Form] [PMID: 22022768 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00176]


The Effects of Newer Beta-Adrenoceptor Antagonists on Vascular Function in Cardiovascular Disease  
Markus Wehland, Jirka Grosse, Ulf Simonsen, Manfred Infanger, Johann Bauer and Daniela Grimm
[Abstract] [Purchase Article] [PMID: 22022769 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00177]


Aldosterone, Mineralocorticoid Receptor and the Metabolic Syndrome: Role of the Mineralocorticoid Receptor Antagonists
Vanessa Ronconi, Federica Turchi, Gloria Appolloni, Valentina di Tizio, Marco Boscaro and Gilberta Giacchetti
[Abstract] [Purchase Inquiry Form] [PMID: 22022770 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00178]


Blood Pressure Control and Antihypertensive Treatment
Guido Grassi, Gino Seravalle and Giuseppe Mancia
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00179]


Antiplatelet Therapy for Secondary Prevention in Stroke – Making the Right Choice
Geoffrey Ling
[Abstract] [Purchase Inquiry Form] [PMID: 22022772 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00180]


Pharmacotherapy for the Metabolic Syndrome
Arthur L.M. Swislocki, David Siegel and Ishwarlal Jialal
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00181]


Dealing with the Substance Abuse Epidemic and Infective Endocarditis: Clinical, Immunologic and Pathogenetic Aspects
Ioannis Starakis, George Panos and Elias Mazokopakis
[Abstract] [Purchase Inquiry Form] [PMID: 22022774 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00182]


Thrombotic Thrombocytopenic Purpura and Anti-Thrombotic Therapy Targeted to Von Willebrand Factor
Zhou Zhou and Jing-Fei Dong
[Abstract] [Purchase Inquiry Form] [PMID: 22022775 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00183]


Vascular Pathology from Smoking: Look at the Microcirculation
Aurelio Leone and Linda Landini
[Abstract] [Purchase Inquiry Form] [PMID: 22022776 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00184]


Editorial: Current Topics on the Epidemiology, Pathogenesis, and Treatment of Diabetes Mellitus and its Complications
Moses S. Elisaf
[PMID: 22022776 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00195]


Aliskiren in Patients with Diabetes: A Systematic Review
Evangelos C. Rizos, Aris P. Agouridis and Moses S. Elisaf
[Abstract] [Purchase Inquiry Form] [PMID: 22239623 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00196]


Genetic Risk Factors for Type 2 Diabetes: Insights from the Emerging Genomic Evidence
Evangelia E. Ntzani and Fotini K. Kavvoura
[Abstract] [Purchase Inquiry Form] [PMID: 22239624 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00197]


Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: Pathogenesis and Treatment Options
Konstantinos Tziomalos, Vassilios G. Athyros and Asterios Karagiannis
[Abstract] [Purchase Inquiry Form] [PMID: 22239625 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00198]


Pros and Cons of Aggressive Blood Pressure Lowering in Patients with Type 2 Diabetes
Rigas G. Kalaitzidis and George L. Bakris
[Abstract] [Purchase Inquiry Form] [PMID: 22239626 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00199]


Recent Developments on Coronary Microvasculopathy after Heart Transplantation: A New Target in the Therapy of Cardiac Allograft Vasculopathy
Francesco Tona, Martina P. Marra, Marny Fedrigo, Giulia Famoso, Roberto Bellu, Gaetano Thiene, Gino Gerosa, Annalisa Angelini and Sabino Iliceto
[Abstract] [Purchase Inquiry Form] [PMID: 22239627 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00200]


Editorial: The Evolution of Cell Therapy towards Enhancing Vascular Regeneration in the Clinic
Erik J. Suuronen
[PMID: 22239628 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00201]


Insulin- and Growth Factor-Resistance Impairs Vascular Regeneration in Diabetes Mellitus
Richard M. Cubbon, Noman Ali, Anshu Sengupta and Mark T. Kearney
[Abstract] [Purchase Inquiry Form] [PMID: 22239629 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00202]


Cell-Based Therapy to Promote Angiogenesis in the Brain Following Ischemic Damage
Masahiro Uemura, Yukiko Kasahara, Kazuyuki Nagatsuka and Akihiko Taguchi
[Abstract] [Purchase Inquiry Form] [PMID: 22239630 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00203]


Genetically Modified Endothelial Progenitor Cells in the Therapy of Cardiovascular Disease and Pulmonary Hypertension
Jessie R. Lavoie and Duncan J. Stewart
[Abstract] [Purchase Inquiry Form] [PMID: 22239631 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00204]


Regenerative Therapies for Improving Myocardial Perfusion in Patients with Cardiovascular Disease: Failure to Meet Expectations but Optimism for the Future
Frank W. Sellke, Antonio D. Lassaletta, Michael P. Robich, Louis M. Chu and Marc Ruel
[Abstract] [Purchase Inquiry Form] [PMID: 22239632 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00205]


Strategies for Enhancing Progenitor Cell Mobilization and Function in Diabetes
Mattia Albiero and Gian P. Fadini
[Abstract] [Purchase Inquiry Form] [PMID: 22239633 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00206]


Clinically Relevant Extracellular-Matrix Scaffolds for Cell Transplantation and Vascular Repair
Rashmi Tiwari-Pandey, Hadi Toeg, Frank W. Sellke and Marc Ruel
[Abstract] [Purchase Inquiry Form] [PMID: 22239634 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00207]


Biofunctional Materials for Directing Vascular Development
Jennifer E. Saik, Melissa K. McHale and Jennifer L. West
[Abstract] [Purchase Inquiry Form] [PMID: 22239635 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00208]


Using Extracellular Matrix-Derived Peptides to Alter the Microenvironment for Myocardial Repair
Shirley S. Mihardja and Randall J. Lee
[Abstract] [Purchase Inquiry Form] [PMID: 22239636 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00209]


Tissue Engineering a Small Diameter Vessel Substitute: Engineering Constructs with Select Biomaterials and Cells
Joann E. McBane, Soroor Sharifpoor, Rosalind S. Labow, Marc Ruel, Erik J. Suuronen and J. Paul Santerre
[Abstract] [Purchase Inquiry Form] [PMID: 22239637 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00210]


Imaging Stem Cell Therapy for the Treatment of Peripheral Arterial Disease
Julia D. Ransohoff and Joseph C. Wu
[Abstract] [Purchase Inquiry Form] [PMID: 22239638 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00211]


Statins and Portal Hypertension: A New Pharmacological Challenge
Gonzalo Ramírez, Jimmy Briceño and Armando Rojas
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00212]


Cytochrome P450 1B1 and 2C9 Genotypes and Risk of Ischemic Vascular Disease, Cancer, and Chronic Obstructive Pulmonary Disease
Diljit Kaur-Knudsen, Stig E. Bojesen and Børge G. Nordestgaard
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00213]


Perioperative/Periprocedural Effects of Statin Treatment for Patients Undergoing Vascular Surgery or Endovascular Procedures: An Update
Kosmas I. Paraskevas, Frank J. Veith, Christos D. Liapis and Dimitri P. Mikhailidis
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00214]


Antiplatelet Therapy in Patients with Diabetes Mellitus
Erik L. Grove and Soren Gregersen
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00215]


Editorial: Should Chronic Kidney Disease be Considered as a Coronary Heart Disease Equivalent?
Vasilios G. Athyros, Niki Katsiki, Asterios Karagiannis and Dimitri P. Mikhailidis
[BSP/CVP/E-Pub/00216]


Interrupting the Natural History of Diabetes Mellitus: Lifestyle, Pharmacological and Surgical Strategies Targeting Disease Progression
Kaivan Khavandi, Jack Brownirgg, Mohammed Hankir, Harpreet Sood, Naveed Younis, Joy Worth, Adam Greenstein, Handrean Soran, Anthony Wierzbicki and David J. Goldsmith
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00217]


Association of platelet activation with vascular cognitive impairment: implications in dementia development?
Konstantinos Stellos, Niki Katsiki, Prokopia Tatsidou, Boris Bigalke and Christoph Laske
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00218]


Acute Coronary Syndromes in Patients with Chronic Kidney Disease
Beata Skóra, Anna Gluba, Maciej Banach, Piotr Rozentryt, Lech Poloński and Jacek Rysz
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00219]


Rationale of Statin Therapy in Septic Patients
Mariusz Piechota, Marcin Barylski, Simon Hannam, Magdalena Piechota-Urbańska and Maciej Banach
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00220]


Milk Fat Globule Epidermal Growth Factor VIII Signaling in Arterial Wall Remodeling
Mingyi Wang, Hejia H. Wang and Edward G. Lakatta
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00221]


Angiogenesis and Hypertension: The Dual Role of Anti-Hypertensive and Anti-Angiogenic Therapies
Patrizia Ferroni, David Della-Morte, Raffaele Palmirotta, Tatjana Rundek and Fiorella Guadagni, Mario Roselli
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00222]


Molecular Link between Intravascular Hemolysis and Vascular Occlusion in Sickle Cell Disease
Zhou Zhou, Donald L. Yee and Prasenjit Guchhait
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00223]


Sex Differences in Biomarkers for Predicting Cardiovascular and Coronary Events
Erjon Agushi, Raffaele Bugiardini and Borejda Xhyheri
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00224]


The Effects of Incretins on Energy Homeostasis: Physiology and Implications for the Treatment of Type 2 Diabetes Mellitus and Obesity
Spyridon Karras, Dimitrios G. Goulis, Gesthimani Mintziori, Niki Katsiki and Themistoklis Tzotzas
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00225]


Current Evidence for Antithrombotic Therapy after Peripheral Vascular Interventions
Sibu P. Saha, Thomas F. Whayne, Jr and Debabrata Mukherjee
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00226]


Editorial: Inflammation, Coagulation, Vascular Permeability and Thrombosis
Massimo Cugno
[BSP/CVP/E-Pub/00227]


Interactions between Inflammation and Coagulation in Autoimmune and Immune-Mediated Skin Diseases
Angelo V. Marzano, Alberto Tedeschi, Ilaria Polloni, Carlo Crosti and Massimo Cugno
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00228]


Involvement of Coagulation and Hemostasis in Inflammatory Bowel Diseases
Antoni Stadnicki
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00229]


Hypereosinophilic Syndrome, Churg-Strauss Syndrome and Parasitic Diseases: Possible Links between Eosinophilia and Thrombosis
Alberto Maino, Raffaella Rossio, Massimo Cugno, Angelo V. Marzano and Alberto Tedeschi
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00230]


Potential Effect of Anti-Inflammatory Treatment on Reducing the Cardiovascular Risk in Rheumatoid Arthritis
Cecilia Chighizola, Tommaso Schioppo, Francesca Ingegnoli and Pier Luigi Meroni
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00231]


Inflammation and Coagulation in Urticaria and Angioedema
Massimo Cugno, Riccardo Asero, Alberto Tedeschi, Riccardo Lazzari and Angelo V. Marzano
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00232]


Crosstalk between Inflammation and Coagulation: The Lessons of Sepsis
Tom van der Poll and Marcel Levi
[Abstract] [Purchase Inquiry Form] [BSP/CVP/E-Pub/00233]



Abstracts



Risk Factors for Cardiovascular Events in Japanese Patients Treated with Fluvastatin from the Long-Term Event Monitoring (LEM) Study
Ryuichi Morishita, Hiroshige Itakuraa, Noriaki Nakaya, Masayuki Yoshida, Masato Odawara,  Atsuhiro Ichihara and Kyoichi Mizuno
[Purchase Inquiry Form] [PMID: 21824105 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00171]

Objective: Long-term event monitoring (LEM) study was designed to evaluate the long-term lipid-lowering efficacy and safety of fluvastatin in Japanese patients with hypercholesterolemia. From LEM study, the present study focused on the impact of risk factors such as diabetes after statin treatment on event prevention.

Methods: In LEM study, patients (n=21,139) who started fluvastatin between 2000/4/1 and 2002/3/31 in Japan were prospectively registered and followed up for 3 years (secondary prevention cohort) or 5 years (primary prevention cohort).

Results: Of the patients registered, 19,084 were included in this sub-analysis. In the secondary prevention, complication of cardiac disease demonstrated 8.27- and 2.89-fold higher incidence in cardiac events and cerebral events, respectively as compared to primary prevention (P<0.001). Complication of cerebrovascular disease also demonstrated a 2.22- and 5.29-fold higher incidence in cardiac events and cerebral events (P<0.01 and P<0.001, respectively). Presence of DM in patients without complication significantly increased the incidence in both cardiac events (2.37) and cerebral events (2.15) as compared to non-DM patients for primary prevention (P<0.001 and P<0.01, respectively). For the secondary prevention, DM Patients with complication of cardiac disease showed a significantly higher incidence in both cardiac events (1.59) and cerebral events (3.79) as compared to non-DM patients (P<0.05 and P<0.01, respectively). In contrast, DM Patients with complication of cerebrovascular disease showed a significantly higher incidence in cerebral events (2.58, P<0.05), but not cardiac events, as compared to non-DM patients. Similarly, presence of hypertension significantly increased the incidence in both cardiac (1.64) and cerebral events (1.81) for primary prevention (P<0.01 and P<0.05, respectively). For the secondary prevention, hypertension in patients with complication of cardiac or cerebrovascular disease did not affect incidence in both cardiac and cerebral events. In the patients without complication, high triglycerides and low HDL cholesterol, but not LDL cholesterol, increased cerebral events, while only LDL cholesterol significantly increased cardiac events. For the secondary prevention, high triglycerides or low HDL cholesterol, but not LDL cholesterol, significantly increased the relative risk of cardiac events in the patients with complication of cardiac disease.

Conclusion: LEM study, a large-scale prospective study of long-term fluvastatin treatment for hypercholesterolemia in Japanese patients, demonstrated high impact of complications such as DM and hypertension as well as high triglycerides or low HDL cholesterol on cardiac and cerebral events. After long-term statin treatment, the control of other factors rather than LDL cholesterol might be important to avoid cardiac and cerebral events.
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Telomere/Telomerase System: A New Target of Statins Pleiotropic Effect?
Fabiola Olivieri, Ilaria Mazzanti, Angela Marie Abbatecola, Rina Recchioni, Fiorella Marcheselli, Antonio Domenico Procopio and Roberto Antonicelli
[Purchase Inquiry Form] [PMID: 22022767 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00171]
[BSP/CVP/E-Pub/00175]

Statins are well established drugs for primary and secondary prevention of coronary artery disease (CAD). Despite the well-known ability of statins to lower cholesterol, it is now clear that clinical benefits are also substantially higher than expected and several clinical trials, like JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial) have indicated that such clinical effects are independent of cholesterol reduction. These cholesterol-independent actions have been named “pleiotropic effects” and include: anti-oxidation and anti-inflammatory effects, modulation of immune activation, stabilization of atherosclerotic plaque, decreased platelet activation, inhibition of cardiac hypertrophy, reduction of cytokine-mediated vascular smooth muscle cell (VSMC) proliferation and improvement of endothelial function. Recently, additional pleiotropic effects of statins on “cellular senescence” have been seen in different cell types, including endothelial progenitor cells (EPC), endothelial cells (EC), VSMC and chondrocytes. At the molecular level, the effect of statins on cellular senescence could be mediated by their interaction with the telomere/telomerase system. Recent evidence suggests that the anti-aging effects of statins are linked to their ability to inhibit telomere shortening by reducing either directly and indirectly oxidative telomeric DNA damage, as well as by a telomere capping proteins dependent mechanism. In this review, we discuss the pleiotropic effects of statins, focusing on the telomere/telomerase system. We will also present our current findings regarding leukocyte telomere length in very old people with myocardial infarction on statin therapy.
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Statin-Induced Myotoxicity: Pharmacokinetic Differences among Statins and the Risk of Rhabdomyolysis, with Particular Reference to Pitavastatin
Alberico L. Catapano
[Purchase Inquiry Form] [PMID: 22022768 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00176]

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most widely prescribed therapeutic class of drugs worldwide, with established clinical benefits both in terms of improving serum lipid profiles and reducing cardiovascular events and mortality. Although statins have a favorable risk-to-benefit ratio, they have the potential to cause adverse events which can result in muscular inflammation (myositis), muscle breakdown (rhabdomyolysis) and, ultimately, kidney failure. While the incidence of rhabdomyolysis is approximately 3.4 cases per 100,000 person-years with standard-dose statin therapy, the risk of developing the condition increases substantially at higher therapeutic doses. This effect may be exacerbated by prescribing statins in combination with certain other medications because drug–drug interactions increase statin exposure by interacting with enzymes that would normally be involved in their metabolism and clearance. Co-administration of drugs that inhibit the cytochrome P450 (CYP) enzymes responsible for metabolizing statins, or that interact with the organic anion-transporting polypeptides (OATPs) responsible for statin uptake into hepatocytes, substantially increases the risk of developing myotoxicity. Such effects vary among statins according to their metabolic profile. For example, pitavastatin, a novel statin approved for the treatment of hypercholesterolemia and combined (mixed) dyslipidemia, is not catabolized by CYP3A4, unlike other lipophilic statins, and may be less dependent on the OATP1B1 transporter for its uptake into hepatocytes before clearance. Such differences in drug–drug interaction profiles among available statins offer the possibility of reducing the risk of myotoxicity among high-risk patients.
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The Effects of Newer Beta-Adrenoceptor Antagonists on Vascular Function in Cardiovascular Disease  
Markus Wehland, Jirka Grosse, Ulf Simonsen, Manfred Infanger, Johann Bauer and Daniela Grimm
[Purchase Article] [PMID: 22022769 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00177]

This review provides a systematic overview of the influence of the third generation beta-adrenoceptor antagonists on vascular and/or endothelial function at a cellular level as well as of the advantages of their application in hypertension, heart failure and coronary artery disease. Drugs antagonizing the beta-adrenoceptors have been in use for the treatment of hypertension for decades. In systolic heart failure and post-myocardial infarction, beta-adrenoceptor antagonists were proven to be effective in decreasing the number of deaths and improving morbidity. However, beta-adrenoceptor antagonists are a heterogeneous drug group, consisting of agents with different selectivity for adrenoceptors and/or additional effects in heart and peripheral circulation. Beta-adrenoceptor antagonists comprise a multitude of different agents, which may have additional properties exceeding the pure receptor blockade. These features may provide additional benefit in the treatment of hypertension. The third generation drug nebivolol exerts a nitric oxide-mediated vasodilating activity which has positive effects on intima and media thickness and arterial rigidity, a major risk factor in cardiovascular disease. Moreover, anti-proliferative, anti-inflammatory, and anti-oxidative properties have been detected for carvedilol and nebivolol, contributing to their additional value in treatment of hypertension and heart failure.
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Aldosterone, Mineralocorticoid Receptor and the Metabolic Syndrome: Role of the Mineralocorticoid Receptor Antagonists
Vanessa Ronconi, Federica Turchi, Gloria Appolloni, Valentina di Tizio, Marco Boscaro and Gilberta Giacchetti
[Purchase Inquiry Form] [PMID: 22022770 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00178]

Several lines of evidence suggest a detrimental effect of aldosterone excess on the development of metabolic alterations. Glucose metabolism derangements due to aldosterone action are frequently observed not only in patients with primary aldosteronism but also in patients with obesity. A contribution to the hyperaldosteronism observed in obese subjects can be attributed, at least in part, to the action of still unidentified adipocyte-derived factor. Aldosterone, through genomic and non-genomic actions contributes to induce several abnormalities: pancreatic fibrosis, impaired beta cell function, as well as reduced skeletal muscle and adipose tissue insulin sensitivity. Oxidative stress, systemic inflammation, together with these metabolic alterations may explain the appearance of the cardiometabolic syndrome and the progression of cardiovascular and renal diseases, in the presence of inappropriate aldosterone levels. The biological actions of aldosterone are mediated by mineralocorticoid receptor (MR), although MR can be activated through an aldosterone-independent fashion. Besides salt-water homeostasis, MR activation promotes inflammation, endothelial dysfunction, cardiovascular remodelling and affects adipose tissue differentiation and function. Clinical and experimental studies have shown that MR blockade is able to suppress inflammation, to improve endothelium-dependent vasorelaxation, but most interestingly, to improve pancreatic insulin release as well as insulin-mediated glucose utilization. These actions indicate MR antagonists as a useful therapeutic tool able not only to reduce cardiovascular risk and renal damage, but also to improve metabolic sequaelae.
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Blood Pressure Control and Antihypertensive Treatment
Guido Grassi, Gino Seravalle and Giuseppe Mancia
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00179]

Several lines of evidence show that blood pressure (BP) control in treated hypertensive patients is largely unsatisfactory and that this depends on a variety of factors, such as the poor patient’s compliance, insufficient use of combination drug treatment as well as true difficulties in achieving well controlled BP. This review article will be focused on the main features of BP control by discussing the data obtained in clinical trials as well as the results available in clinical practice. The paper will also discuss the possible factors responsible for these findings as well as the favourable outcome on cardiovascular risk profile of an effective control of elevated BP. The possible approaches for controlling elevated BP values will be highlighted.
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Antiplatelet Therapy for Secondary Prevention in Stroke – Making the Right Choice
Geoffrey Ling
[Purchase Inquiry Form] [PMID: 22022772 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00180]

In 2004, approximately 9 million people worldwide experienced a stroke, with the majority being ischemic in nature. While the prognosis for recovery can be good, long-term survival and functional outcome can be improved. Stroke survivors are at an increased risk for recurrent stroke and other ischemic vascular events and face significant cross-risk for atherothrombotic conditions affecting the coronary and peripheral vascular beds. As such, the secondary prevention of ischemic events in patients with stroke has focused on the treatment of atherosclerosis as a whole, with antiplatelet therapy playing a key role. There is some controversy regarding optimal antiplatelet therapy following stroke. The appropriate use of specific agents, the impact of stroke type and proper dosing, and other questions stem from an incomplete understanding of the issues, variability in clinical trial data, diversity in patient demographics, and differences in antiplatelet regimens. This review evaluates the clinical evidence for antiplatelet therapy in patients that have suffered an ischemic stroke, with an emphasis on balancing the benefits of a particular antiplatelet regimen with its attendant risk profile. The critical assessment of emerging trial data and its impact on existing treatment guidelines may aid in choosing the most appropriate antiplatelet regimen for comprehensive secondary prevention following stroke.
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Pharmacotherapy for the Metabolic Syndrome
Arthur L.M. Swislocki, David Siegel and Ishwarlal Jialal
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00181]

The Metabolic Syndrome (MetS) confers a greater risk for both diabetes and cardiovascular diseases. Both insulin resistance and low grade inflammation appear to be pivotal in the pathogenesis of this disorder. The cornerstone of treatment presently is therapeutic lifestyle change with the emphasis on weight loss by diet and exercise. It appears that the evidence base will support statins as first line therapy for the dyslipidemia. Also, there is a limited role for both bile acid sequestrants and fibrates in certain subgroup of patients. It would appear that the Angiotensin converting enzyme inhibitors (ACEs) and angiotensin II receptor blockers (ARBs) are the preferred therapy for hypertension but invariably combination therapy with additional drugs is required keeping in mind that certain drugs can exacerbate the dyslipidemia and or glycemia of MetS. Whilst metformin appears to be the drug of choice for the dysglycemia, thiazolidinediones (TZDs) like pioglitazone can also be beneficial but recent concern about bladder cancer has resulted in its discontinuation in certain countries in Europe. Metformin therapy has been shown to prevent new onset MetS. Modulating the incretin axis can prove very fruitful. A drug targeting all 3 disorders would be ideal but to date does not exist.
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Dealing with the Substance Abuse Epidemic and Infective Endocarditis: Clinical, Immunologic and Pathogenetic Aspects
Ioannis Starakis, George Panos and Elias Mazokopakis
[Purchase Inquiry Form] [PMID: 22022774 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00182]

Although infective endocarditis (IE) is not the most frequent infection seen in intravenous (IV) drug abusers (IVDAs), health care providers should always regard it as a possible diagnosis in this population. Many researchers have tried to elucidate the clinical, epidemiologic, immunologic and pathogenetic aspects of this entity. Right-sided endocarditis accounts for almost 10% of all IE episodes and has been most commonly interrelated with IV use of illicit substances. On the other hand, recent reports have proposed that left-sided valve participation is seen more often now than in the past. While, our progress in medicine, new diagnostic criteria and especially modern imaging techniques have broadened our ability to recognize IE, there are still some gray areas regarding right-sided IE. Our aim is to comprehensively review the clinical features and complications and also the possible pathogenetic and immunologic mechanisms implicated in IE patients who are injecting illicit substances.
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Thrombotic Thrombocytopenic Purpura and Anti-Thrombotic Therapy Targeted to Von Willebrand Factor
Zhou Zhou and Jing-Fei Dong
[Purchase Inquiry Form] [PMID: 22022775 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00183]

Resting endothelial cells lining the inner surface of blood vessels have anti-thrombotic and anti-inflammatory actions, critical for maintaining normal vascular homeostasis. Upon localized or systemic stimulation, endothelial cells are activated to secrete bioactive molecules; among them is von Willebrand factor (VWF). Freshly secreted VWF is enriched in ultra-large (UL) forms that are anchored to endothelial cells to form long string-like structures, to which platelets tether and aggregate. This prothrombotic event is normally prevented by proteolytic cleavage of ULVWF multimers by ADAMTS-13 at a single peptide bond of Tyr¹⁶⁰⁵-Met¹⁶⁰⁶ in the A2 domain. The cleavage reduces the size and adhesion activity of (UL)VWF multimers. Lacking this cleaving activity due to mutations in the ADAMTS13 gene or autoantibodies to the metalloprotease is associated with systemic microvascular thrombosis found in patients with thrombotic thrombocytopenic purpura (TTP). Recombinant ADAMTS-13 can therefore be a therapeutic agent to reduce prothrombotic activity of ULVWF multimers. Alternatively, blocking an interaction between ULVWF and its platelet receptor could achieve the same therapeutic goal. This review discusses potentials of using recombinant ADAMTS-13 and VWF-blocking agents as therapeutics for TTP and other acquired ADAMTS-13 deficiencies.
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Vascular Pathology from Smoking: Look at the Microcirculation
Aurelio Leone and Linda Landini
[Purchase Inquiry Form] [PMID: 22022776 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00184]

Both conduit and resistance arterial vessels may show vascular morphological and functional alterations due to cigarette smoking. Pathological lesions involve the arterial wall or intravascular lumen with, primarily, narrowing and thrombo-embolic events as an effect of endothelial and blood cell changes related to smoking. Functional disorders are the result of a wide spectrum of biochemical, physiological and metabolic factors. While conduit vessel alterations have been widely investigated, little is known about the changes induced by smoking on the microcirculation. It would seem that the endothelium, platelet aggregation and adhesiveness, nervous system and metabolic changes play a role in damaging resistance arteries and, then, the microcirculation. The result of these effects is changes in blood flow and perfusion particularly to the heart, brain and kidney.  Alterations of the microcirculation can cause severe and widespread damage because, in addition to the complications of the atherosclerotic lesion which characterizes large arteries, there is a failure of body organs linked to the degree of microvascular damage. Moreover, it seems that 2 major compounds of cigarette smoke are capable of determining vascular damage; initially, nicotine acts preferably on large arteries and carbon monoxide on small arteries, although both compounds damage the vascular system.
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Aliskiren in Patients with Diabetes: A Systematic Review
Evangelos C. Rizos, Aris P. Agouridis and Moses S. Elisaf
[Purchase Inquiry Form] [PMID: 22239623 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00196]

Objective:Diabetic patients are at risk of macro- and micro-vascular complications, including diabetic nephropathy, and have difficulties in achieving blood pressure (BP) goals. Aliskiren, a direct renin inhibitor, inhibits the first step of the renin angiotensin aldosterone system. We aimed to systematically address the relevant evidence on the effects of aliskiren in diabetic individuals.
Methods: We considered randomized controlled trials (RCTs) evaluating aliskiren in diabetic patients. Information was recorded independently by 2 investigators. We were limited to trials published in English.

Results: PubMed search retrieved 16 items. After excluding 12, we ended with 4 eligible studies with 1488 participants. Mean baseline BP levels were 143/82 mmHg and median follow up was 2 months. Aliskiren was compared against angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) or aliskiren plus ACE inhibitor/ARB in 2 studies and against placebo in the other 2. The most frequent indication for aliskiren therapy was diabetes plus hypertension and albuminuria. Aliskiren seems to be effective in reducing BP levels, albuminuria in diabetics, either as monotherapy (compared with placebo), or in addition to ACE inhibitors/ARB (compared with monotherapy), without any major safety considerations.

Conclusions: There are promising results on the effect of aliskiren in diabetic patients, but the available evidence is limited so far. This is a poorly investigated field with few RCTs and new studies focusing on “hard” outcomes are needed.
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Genetic Risk Factors for Type 2 Diabetes: Insights from the Emerging Genomic Evidence
Evangelia E. Ntzani and Fotini K. Kavvoura
[Purchase Inquiry Form] [PMID: 22239624 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00197]

Type-2 diabetes is a complex disease modified by a number of environmental and genetic factors that contribute at varying degrees to the final phenotype and possibly interact with each other. Deciphering the genetic background of the disease serves multiple goals ranging from expanding our knowledge on the disease pathogenesis and identifying future targets for drug development to successfully personalize clinical disease prediction and prognosis. In the present review, we aimed to systematically appraise the current evidence on genome-wide association studies (GWAS) on type-2 diabetes, identify the gene targets that have been assessed to-date, and discuss issues that stem from the rapid growth of this literature. Our search identified more than 60 recently identified loci implicated with type-2 diabetes and related traits assessed in populations of European and Asian ancestry. A considerable number of the proposed genes seem to be related to beta-cell development and function, but there are several genes identified as “diabetes-genes” whose underlying pathway linked to diabetes remains poorly understood.  Despite the increasing numbers of identified genetic markers, a large proportion of the observed type-2 diabetes heritability remains unexplained; larger GWAS on enhanced genotyping platforms, refined ascertainment of the characteristics of the populations under study and additional information from whole-genome sequencing will contribute to a  more comprehensive view of the genetic architecture of the disease. This information is also anticipated to improve the predictive ability of multiple-loci genetic risk scores that will eventually be able to identify disease susceptibility over and above the traditional non-genetic risk factors.
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Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: Pathogenesis and Treatment Options
Konstantinos Tziomalos, Vassilios G. Athyros and Asterios Karagiannis
[Purchase Inquiry Form] [PMID: 22239625 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00198]

Non-alcoholic fatty liver disease (NAFLD) is a common disorder and its prevalence is expected to increase due to the rising incidence of type 2 diabetes mellitus (T2DM) and obesity. NAFLD is associated with increased mortality rates and cardiovascular disease is the leading cause of death in these patients. The pathogenesis of NAFLD is not completely elucidated but insulin resistance and oxidative stress appear to play a major role. NAFLD is more prevalent and more severe in patients with T2DM. A multitude of pharmacological agents have been evaluated in NAFLD but most studies were small, short-term and yielded unsatisfactory results in terms of efficacy. Patients with T2DM and NAFLD appear to be even less responsive to the evaluated agents. Thus, the optimal management strategy for NAFLD remains unclear. On the other hand, preliminary data suggest that lifestyle intervention can reduce the incidence of NAFLD in overweight or obese patients with T2DM. Accordingly, prevention of obesity and T2DM is of paramount importance for the reduction of the prevalence of NAFLD and of its associated cardiovascular and liver-related complications.
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Pros and Cons of Aggressive Blood Pressure Lowering in Patients with Type 2 Diabetes
Rigas G. Kalaitzidis and George L. Bakris
[Purchase Inquiry Form] [PMID: 22239626 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00199]

The goal of treating hypertension in patients with diabetes is reduction of macrovascular and microvascular complications. Most current guidelines recommend more aggressive treatment goals with blood pressure (BP) targets of <130/80mmHg. Retrospective data analyses suggest an association between a lower BP and slower declines in chronic kidney disease (CKD) as well as greater cardiovascular (CV) risk reduction in patients with Type 2 diabetes. Such recommendations, however, are not supported by appropriately powered prospective outcome trials. Indeed, several important questions regarding aggressive lowering of BP levels are still unanswered. Major limitations of most existing clinical trials of BP lowering in diabetes is the failure to either target or achieve mean systolic BP values below 130mmHg.  Data from more recent randomized trials that evaluated different levels of BP do not support a BP below 130/80 mmHg as providing further CV risk reduction and  compared to levels below 140/90 mmHg. One consistent benefit of a lower BP level, however, is on reduction of cerebrovascular events. There is reasonable evidence that a lower BP level does further slow progression of advanced proteinuric kidney disease such that a BP goal <130/80 mmHg is defensible. This review examines the data for and against aggressive BP lowering in patients with diabetes.
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Recent Developments on Coronary Microvasculopathy after Heart Transplantation: A New Target in the Therapy of Cardiac Allograft Vasculopathy
Francesco Tona, Martina P. Marra, Marny Fedrigo, Giulia Famoso, Roberto Bellu, Gaetano Thiene, Gino Gerosa, Annalisa Angelini and Sabino Iliceto
[Purchase Inquiry Form] [PMID: 22239627 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00200]

Heart transplantation (HTx) is the treatment of choice for patients with refractory end-stage heart diseases. Although the procedure is considered effective in extending and improving quality of life, the onset of cardiac allograft vasculopathy (CAV) continues to limit the long-term success of HTx. Emerging data indicate that the endothelium plays a significant role in the onset, progression and complication of this multifactorial disease, with both immunologic and non-immunologic risk factors contributing to its development. Improving our understanding of the integral role of the coronary microcirculation in CAV is of crucial clinical interest since it could provide further insights into the related pathophysiological mechanisms and possible new strategies for CAV prevention and therapy. Assessment of coronary microvasculopathy has been shown to be of predictive value after HTx. Predominant allograft microvascular dysfunction is detectable in 15-20% of patients after HTx. Very recently, stenotic microvasculopathy (detected in biopsy samples) has been characterized as a prognostic factor for long-term survival after HTx. The ability to detect and distinguish changes in epicardial and microvascular function may aid in identifying modifiable factors that lead to CAV. Improved immunosuppressive drugs, including mycophenolate mofetil and proliferation signal inhibitors, as well as statins (in part via immunomodulation), may have a beneficial effect on coronary microcirculation after HTx, although there is still a need to confirm the impact of vasodilators in improving the prognosis of HTx patients. We review the role of coronary microvasculopathy in HTx, its prevention and new potential pharmacological interventions.
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Insulin- and Growth Factor-Resistance Impairs Vascular Regeneration in Diabetes Mellitus
Richard M. Cubbon, Noman Ali, Anshu Sengupta and Mark T. Kearney
[Purchase Inquiry Form] [PMID: 22239629 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00201]

Diabetes and pre-diabetes are major contributors to cardiovascular mortality and morbidity. Insulin resistance is a key pathophysiological determinant of the metabolic and vascular abnormalities noted in these disorders. Ineffective vascular repair is likely to be an important contributor to the development of endothelial dysfunction, and subsequently atherosclerosis, in patients with diabetes. Beyond the systemic effects of the insulin resistant phenotype, including factors such as dysglycaemia and inflammation, cellular insulin resistance is emerging as an important factor in diabetic vascular disease. Disordered signal transduction via the PI3-kinase/Akt and MAP-kinase cascades is a hallmark of cellular insulin resistance, and such changes have been linked with both endothelial dysfunction and impaired angiogenesis. In this review we highlight the importance of insulin resistance to vascular repair and regeneration, discuss important cross-talk between the intracellular signalling of insulin and key pro-angiogenic molecules, and link these concepts to common patterns of vascular disease.
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Cell-Based Therapy to Promote Angiogenesis in the Brain Following Ischemic Damage
Masahiro Uemura, Yukiko Kasahara, Kazuyuki Nagatsuka and Akihiko Taguchi
[Purchase Inquiry Form] [PMID: 22239630 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00202]

Cell-based therapies are a novel approach for regeneration of microvasculature. We have shown that administration of CD34-positive cells, the rich cell fraction of endothelial progenitor cells, after stroke induces angiogenesis that results in enhanced endogenous neurogenesis and functional recovery in a murine model. Moreover, injury-induced neurogenesis occurs in the human brain following a stroke during the acute to sub-acute period. Based on these observations, clinical trials of cell therapies that aim to regenerate micro-circulation in the brain following a stroke are ongoing worldwide. This review summarizes the current basic research findings about the link between angiogenesis and neurogenesis in the post-stroke brain and introduces the ongoing clinical trials of cell-based therapies for patients that have suffered a stroke.
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Genetically Modified Endothelial Progenitor Cells in the Therapy of Cardiovascular Disease and Pulmonary Hypertension
Jessie R. Lavoie and Duncan J. Stewart
[Purchase Inquiry Form] [PMID: 22239631 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00203]

Since their initial discovery, endothelial progenitor cells (EPCs) have held tremendous promise for cell therapy for a variety of cardiovascular diseases including pulmonary hypertension. The clinical experience to date suggests that circulating or bone marrow mononuclear cells and EPCs can induce neovascularization, and enhance cardiac repair after myocardial function, as well as improvements in the hemodynamic and functional status of patients with idiopathic pulmonary arterial hypertension. Although these results are promising, the overall magnitude of the clinical benefits seen in these trials appear to be rather modest. Indeed, strong experimental evidence points towards a reduction in mobilization and impairment in function of EPCs in preclinical models and patients with cardiac disease or with cardiovascular risk factors such as advanced age, type I and II diabetes, hypercholesterolemia, coronary artery disease, as well as other conditions such as pulmonary hypertension. Genetic engineering of EPCs ex vivo, prior to transplantation, is a promising cell-enhancement strategy for restoring the angiogenic potential of autologous, patient-derived cells. This review provides an update of the experimental studies that have used gene-modified EPC therapy to treat ischemic cardiovascular disease and pulmonary hypertension.
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Regenerative Therapies for Improving Myocardial Perfusion in Patients with Cardiovascular Disease: Failure to Meet Expectations but Optimism for the Future
Frank W. Sellke, Antonio D. Lassaletta, Michael P. Robich, Louis M. Chu and Marc Ruel
[Purchase Inquiry Form] [PMID: 22239632 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00204]

Cardiovascular disease continues to be a major cause of death in the Western world and has been extending into areas previously seemingly immune to its effects. Catheter-based interventions and coronary artery bypass surgery have markedly improved cardiovascular health, but a number of patients with coronary artery disease cannot undergo repeated interventions or they receive an incomplete revascularization with standard revascularization methods, which has been associated with a poor clinical outcome. Despite early demonstration of improvement in myocardial perfusion and function with growth factor, gene therapy or cellular therapies, clinical studies have found little if any real benefit. The discordance between positive pre-clinical studies and essentially negative clinical trials may in part be explained by a number of factors including abnormal vascular signaling, oxidative stress, a hostile local myocardial environment and technical issues related to the administration of these therapies. Patients with end-stage coronary disease are vastly different from the young, healthy animals that are generally used for pre-clinical testing. The presence of diabetes, hypercholesterolemia, and other conditions associated with endothelial dysfunction and coronary disease and altered vascular signaling can significantly limit the effectiveness of growth factors on the development of collateral vessels. This paper summarizes the results of regenerative therapies for the treatment of coronary disease and discusses the reasons why growth factor protein, gene therapies and cellular therapies have not been overall successful to date.
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Strategies for Enhancing Progenitor Cell Mobilization and Function in Diabetes
Mattia Albiero and Gian P. Fadini
[Purchase Inquiry Form] [PMID: 22239633 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00205]

Bone marrow (BM) holds a pool of stem and progenitor cells whose role is not limited to hematopoiesis. Indeed, growing evidences showed that BM-derived progenitors could contribute to various extents to cardiovascular homeostasis. Notably, diabetic patients experience an intrinsic defect of the progenitor pool, whereas some recent works point directly to an intrinsic defect of the BM, resulting in defective mobilization and impaired functions of progenitors. These defects could have important pathophysiological roles in the development of diabetic complications. An integrated approach, which enhances mobilization of progenitors and improves their functions, could represent a novel method to improve cardiovascular repair by endogenous progenitors. Furthermore, potential clinical trials of cell therapy would gain benefit from stratagems that enhance the number and functions of progenitors prior to transplantation. In this review we discuss the strategies to stimulate the mobilization of progenitors in diabetes and the protocols to improve their functions.
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Clinically Relevant Extracellular-Matrix Scaffolds for Cell Transplantation and Vascular Repair
Rashmi Tiwari-Pandey, Hadi Toeg, Frank W. Sellke and Marc Ruel
[Purchase Inquiry Form] [PMID: 22239634 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00206]

Due to the very limited ability of cardiac tissue to self-regenerate, the replacement of damaged cardiomyocytes and the repair of damaged extracellular matrix (ECM) are highly sought-after therapeutic strategies. Cell transplantation in ECM scaffolds has been shown to improve retention, phenotype, and function in vascular and muscle repair. In addition to cellular patches that involve the use of biomaterial scaffolds in combination with cells, acellular patches may have a role in intrinsically recruiting cells to damaged areas. This review focuses on the clinically relevant ECM scaffolds, their interactions with cells to stimulate functions such as adhesion, migration, proliferation, and differentiation, and their intrinsic role in ECM remodeling leading to vascular and possibly myocardial repair.
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Biofunctional Materials for Directing Vascular Development
Jennifer E. Saik, Melissa K. McHale and Jennifer L. West
[Purchase Inquiry Form] [PMID: 22239635 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00207]

Engineered tissue constructs are inherently limited by their lack of microvascularization. Evidence suggests that combining a scaffold material with cells and their cell-secreted signals instigates tubule formation, and various strategies can be employed to tailor the vascular response. This review focuses on rationally designed materials capable of supporting functional neovessel formation and stabilization. Biomaterial scaffolds and their use as growth factor delivery systems are discussed, as well as other functional enhancement strategies to direct cellular responses for effective formation of a mature vascular network.
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Using Extracellular Matrix-Derived Peptides to Alter the Microenvironment for Myocardial Repair
Shirley S. Mihardja and Randall J. Lee
[Purchase Inquiry Form] [PMID: 22239636 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00208]

Myocardial repair remains a major challenge for both cellular and tissue engineering approaches.  Several studies have been conducted looking at utilizing extracellular matrix-based therapies to promote repair after a myocardial infarction.  In this review, strategies for treating myocardial infarctions using extracellular matrix-derived peptides are discussed.  Using an ischemia/reperfusion myocardial infarction rodent model, we showed that extracellular-matrix-derived peptides were able to induce angiogenesis and alter the negative remodeling seen after a myocardial infarction.  This therapy opens up a potentially new non-invasive strategy for repairing damaged cardiac tissue.
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Tissue Engineering a Small Diameter Vessel Substitute: Engineering Constructs with Select Biomaterials and Cells
Joann E. McBane, Soroor Sharifpoor, Rosalind S. Labow, Marc Ruel, Erik J. Suuronen and J. Paul Santerre
[Purchase Inquiry Form] [PMID: 22239637 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00209]

Cardiovascular disease (CVD) is a leading cause of death and hospitalization worldwide.  The need for small caliber vessels (<6mm) to treat CVD patients has grown; however the availability of autologous vessels in cardiac and peripheral bypass candidates is limited.  The search for an alternative vessel source is widespread with both natural and synthetic tissue engineered materials being investigated as scaffolds.  Despite decades of exhaustive studies with decellularized extracellular matrices (ECM) and synthetic graft materials, the field remains in search of a commercially viable biomaterial construct substitute.  While the previous materials have been assessed by evaluating their compatibility with fibroblasts, smooth muscle cells and endothelial cells, current materials are being conceived based on their interactions with stem cells, progenitor cells and monocytes, as the latter may hold the key to repair and regeneration.  The graft’s ability to recruit and maintain these cells has become a major research focus.  The successful tissue engineering of a small caliber vessel graft requires the use of optimal material chemistry and biological function to promote cell recruitment into the graft while maintaining each functional phenotype during vessel tissue maturation.  The discussion of these significant research challenges constitutes the focus of this review.
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Imaging Stem Cell Therapy for the Treatment of Peripheral Arterial Disease
Julia D. Ransohoff and Joseph C. Wu
[Purchase Inquiry Form] [PMID: 22239638 PubMed - indexed for MEDLINE] [BSP/CVP/E-Pub/00210]

Arteriosclerotic cardiovascular diseases are among the leading causes of morbidity and mortality worldwide. Therapeutic angiogenesis aims to treat ischemic myocardial and peripheral tissues by delivery of recombinant proteins, genes, or cells to promote neoangiogenesis. Concerns regarding the safety, side effects, and efficacy of protein and gene transfer studies have led to the development of cell-based therapies as alternative approaches to induce vascular regeneration and to improve function of damaged tissue. Cell-based therapies may be improved by the application of imaging technologies that allow investigators to track the location, engraftment, and survival of the administered cell population. The past decade of investigations has produced promising clinical data regarding cell therapy, but design of trials and evaluation of treatments stand to be improved by emerging insight from imaging studies. Here, we provide an overview of pre-clinical and clinical experience using cell-based therapies to promote vascular regeneration in the treatment of peripheral arterial disease. We also review four major imaging modalities and underscore the importance of in vivo analysis of cell fate for a full understanding of functional outcomes.
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Statins and Portal Hypertension: A New Pharmacological Challenge
Gonzalo Ramírez, Jimmy Briceño and Armando Rojas
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00212]

Portal hypertension is a hemodynamic abnormality that involves a high risk of disability as well as a reduced life expectancy in patients with cirrhosis. Progress in the knowledge of pathophysiology of portal hypertension has opened a new perspective for different pharmacological approaches. In this context, the pleiotropic actions of statins on endothelial cell function have emerged as new options to reduce portal pressure levels by targeting multiple molecular pathways involved in hepatic vascular homeostasis. We highlight how statins may target some molecular pathways involved in the pathophysiology of portal hypertension and how these drugs may correct impaired hepatic vascular tone.
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Cytochrome P450 1B1 and 2C9 Genotypes and Risk of Ischemic Vascular Disease, Cancer, and Chronic Obstructive Pulmonary Disease
Diljit Kaur-Knudsen, Stig E. Bojesen and Børge G. Nordestgaard
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00213]

The aim of this review is to summarize present knowledge of genetic variation in cytochrome P450 1B1 (CYP1B1) and 2C9 (CYP2C9) genes and risk of tobacco-related cancer, female cancer, chronic obstructive pulmonary disease and ischemic vascular disease. The CYP1B1 and CYP2C9 enzymes metabolize polycyclic aromatic hydrocarbons found in tobacco smoke and thereby generate disease-causing metabolites suggested to be important in tobacco-related diseases. Furthermore, CYP1B1 also metabolizes estrogen while CYP2C9 metabolizes arachidonic acid, both creating metabolites potentially important in risk of female cancer or ischemic vascular disease. Genetic variation in genes coding for CYP1B1 and CYP2C9 enzymes have shown altered enzyme activity affecting levels of metabolites and thus potentially risk of disease. So far, however, findings have been inconsistent. Recently, large studies on the association between genetic variation in CYP1B1 and CYP2C9 and risk of disease with considerable statistical power rebutted the hypotheses that these genetic variants affect risk of tobacco-related cancer, female cancer, chronic obstructive pulmonary disease and ischemic vascular disease.
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Perioperative/Periprocedural Effects of Statin Treatment for Patients Undergoing Vascular Surgery or Endovascular Procedures: An Update
Kosmas I. Paraskevas, Frank J. Veith, Christos D. Liapis and Dimitri P. Mikhailidis
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00214]

Introduction/Aim: We reviewed the literature for studies evaluating the effects of statins on vascular patients undergoing open surgical or endovascular procedures.

Methods: MEDLINE was searched using the search terms “statins and vascular surgery”, “statins and endovascular procedures”, “statins and perioperative effects” and “statins and postoperative complications”.

Results: Preoperative statin use is associated with lower perioperative/periprocedural death, myocardial infarction and stroke rates. Statins may also reduce postoperative complications as well as hospitalization rates and costs. Statins reduce the incidence of postoperative/postprocedural renal insufficiency and help the earlier recovery of complete kidney function in vascular patients. A loading dose of statins prior to a procedure may be associated with improved cardiovascular outcomes.

Conclusions: Statins are associated with several beneficial actions in patients undergoing open surgical or endovascular procedures. Nevertheless, statin use in vascular patients still remains underutilized and suboptimal. Ideally, statins should be initiated a minimum of 2 weeks before the procedure. Extended-release formulas may be preferable perioperatively to cover the first 1-2 days after the procedure when oral intake may not be feasible. Statins should be administered to all vascular disease patients, whether they are managed conservatively or are undergoing open surgical or endovascular procedures.
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Antiplatelet Therapy in Patients with Diabetes Mellitus
Erik L. Grove and Soren Gregersen
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00215]

Platelets are key players in arterial thrombosis, and oral antiplatelet therapy is a cornerstone in the treatment and prevention of cardiovascular events. However, although currently approved antiplatelet drugs have proved successful in reducing cardiovascular events, platelet-dependent thrombosis remains an important cause of morbidity and mortality in patients with coronary artery disease. It is well-known that patients with diabetes mellitus (DM) have an increased risk of cardiovascular events and, therefore, understanding the mechanism of action and safety profile of antiplatelet drugs in this high-risk population is of particular interest. There is considerable inter-individual variation in the efficacy of established antiplatelet drugs, and high on-treatment platelet reactivity is associated with an increased risk of cardiovascular events, thus prompting the search for novel drugs against platelet-dependent thrombosis. New antiplatelet treatment strategies include drugs with more efficient and reversible platelet inhibition. This review discusses selective inhibitors of the platelet cyclooxygenase enzyme, thienopyridine and non-thienopyridine inhibitors of the platelet adenosine diphosphate (ADP) receptor, phosphodiesterase inhibitors, and protease-activated receptor (PAR) antagonists. An overview of currently available antiplatelet drugs is provided, focusing on benefits and limitations in patients with DM. Furthermore, the rationale for new oral antiplatelet drugs under development is discussed with particular focus on the potential role of these drugs to improve cardiovascular outcomes in patients with DM.
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Editorial: Should Chronic Kidney Disease be Considered as a Coronary Heart Disease Equivalent?
Vasilios G. Athyros, Niki Katsiki, Asterios Karagiannis and Dimitri P. Mikhailidis
[BSP/CVP/E-Pub/00216]

Current evidence suggests that chronic kidney disease (CKD) is associated with an excess risk for cardiovascular disease (CVD) events. In patients with stage 3 CKD (estimated glomerular filtration rate-eGFR 30-59 ml/min/1.73m²) lifestyle measures and appropriate drugs may reduce CVD risk and stabilize (or even reverse) renal function deterioration. Furthermore, CKD is included in recent international guidelines as a population at high CVD risk. The aim should be to effectively reduce CVD risk as well as progression of CKD.
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Interrupting the Natural History of Diabetes Mellitus: Lifestyle, Pharmacological and Surgical Strategies Targeting Disease Progression
Kaivan Khavandi, Jack Brownirgg, Mohammed Hankir, Harpreet Sood, Naveed Younis, Joy Worth, Adam Greenstein, Handrean Soran, Anthony Wierzbicki and David J. Goldsmith
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00217]

In recent decades, we have seen a surge in the incidence of diabetes in industrialized nations; a threat which has now extended to the developing world. Type 2 diabetes is associated with significant microvascular and macrovascular disease, with considerable impact on morbidity and mortality. Recent evidence has cast uncertainty on the benefits of very tight glycaemic goals in these individuals. The natural history of disease follows an insidious course from disordered glucose metabolism in a pre-diabetic state, often with metabolic syndrome and obesity, before proceeding to diabetes mellitus. In the research setting, lifestyle, pharmacological and surgical intervention targeted against obesity and glycaemia has shown that metabolic disturbances can be halted and indeed regressed if introduced at an early stage of disease. In addition to traditional anti-diabetic medications such as the glinides, sulphonylureas and the glitazones, novel therapies manipulating the endocannabinoid system, neurotransmitters, intestinal absorption and gut hormones have shown dual benefit in weight loss and glycaemic control normalisation. Whilst these treatments will not and should not replace lifestyle change, they will act as invaluable adjuncts for weight loss and aid in normalising the metabolic profile of individuals at risk of diabetes. Utilizing novel therapies to prevent diabetes should be the focus of future research, with the aim of preventing the challenging microvascular and macrovascular complications, and ultimately cardiovascular death.
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Association of platelet activation with vascular cognitive impairment: implications in dementia development?
Konstantinos Stellos, Niki Katsiki, Prokopia Tatsidou, Boris Bigalke and Christoph Laske
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00218]

Cardiovascular risk factors are associated with coronary artery disease (CAD) and with cognitive dysfunction. However, the precise pathogenic mechanisms responsible for this association remain elusive. In the present study, CAD patients with cognitive impairment showed significantly higher platelet activation compared with CAD patients without cognitive impairment. In addition, we identified platelet activity to be a significant independent predictor for the severity of cognitive impairment in these patients. We discuss the link between platelet hyperactivity and dementia (including Alzheimer`s disease) based on the literature and our findings. We also discuss the potential mechanisms involved. This link may become a therapeutic option.
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Acute Coronary Syndromes in Patients with Chronic Kidney Disease
Beata Skóra, Anna Gluba, Maciej Banach, Piotr Rozentryt, Lech Poloński and Jacek Rysz
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00219]

Chronic kidney disease (CKD) is associated with high cardiovascular morbidity and mortality. The available data suggest that efforts to reduce mortality in the CKD population should be focused on treatment and prevention of, among others, coronary artery disease and congestive heart failure. Accelerated atherosclerosis present in CKD patients also leads to a decline in renal function. Definite data concerning the treatment of heart failure in CKD patients are lacking, because patients with significant renal impairment have mostly been excluded from randomized studies. Nevertheless, it seems that CKD patients should receive similar cardiovascular treatment to that used in patients with normal kidney function, but the doses of drugs ought to be titrated to achieve an optimal effect while avoiding adverse events. Several studies have also shown that despite the high risk, in patients with acute coronary syndrome (ACS), revascularization procedures in patients with CKD appear to be advantageous in the long run and are therefore justified. However, large clinical trials are needed to confirm the benefits and to identify possible disadvantages associated with various methods of treatment.
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Rationale of Statin Therapy in Septic Patients
Mariusz Piechota, Marcin Barylski, Simon Hannam, Magdalena Piechota-Urbańska and Maciej Banach
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00220]

Statins are well-established and effective drugs in the treatment of hyperlipidemias. However the effects of statins extend beyond lipid-lowering. The pleiotropic effects of statins have been shown to modify inflammatory cell signaling of the immune response to infection. Statins have emerged as potential immunomodulatory and antioxidant agents that might impact on sepsis outcomes. It was postulated that statins may be candidates for the treatment of sepsis. Recent animal and human data suggest that statin therapy might be beneficial in patients before the onset of sepsis or in its initial period, but should be used with care when patients are diagnosed with severe sepsis or septic shock. Some analyses also provide evidence for statins as an adjuvant therapy in sepsis. Because of the divergent results of studies, the potential benefit needs to be validated in randomized, controlled trials. In this review, we describe current evidence on the use of statins in the prevention and treatment of sepsis.
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Milk Fat Globule Epidermal Growth Factor VIII Signaling in Arterial Wall Remodeling
Mingyi Wang, Hejia H. Wang and Edward G. Lakatta
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00221]

Arterial inflammation and remodeling, important sequellae of advancing age, are linked to the pathogenesis of age-associated arterial diseases e.g. hypertension, atherosclerosis, and metabolic disorders. Recently, high-throughput proteomic screening has identified milk fat globule epidermal growth factor VIII (MFG-E8) as a novel local biomarker for aging arterial walls. Additional studies have shown that MFG-E8 is also an element of the arterial inflammatory signaling network. The transcription, translation, and signaling levels of MFG-E8 are increased in aged, atherosclerotic, hypertensive, and diabetic arterial walls in vivo as well as activated vascular smooth muscle cells (VSMC) and a subset of macrophages in vitro. In VSMC, MFG-E8 increases proliferation and invasion as well as the secretion of inflammatory molecules. In endothelial cells (EC), MFG-E8 not only facilitates apoptosis and procoagulation, but also mediates the interactions between EC and VSMC. In addition, MFG-E8 has been found to be an essential component of the endothelial-derived microparticles that relay biosignals and modulate arterial wall phenotypes.  This review mainly focuses upon the landscape of MFG-E8 expression and signaling in adverse arterial remodeling. Recent discoveries have suggested that MFG-E8 associated interventions are novel approaches for the retardation of the enhanced rates of VSMC proliferation and EC apoptosis that accompany arterial wall inflammation and remodeling during aging and age-associated arterial disease.
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Angiogenesis and Hypertension: The Dual Role of Anti-Hypertensive and Anti-Angiogenic Therapies
Patrizia Ferroni, David Della-Morte, Raffaele Palmirotta, Tatjana Rundek and Fiorella Guadagni, Mario Roselli
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00222]

Essential hypertension may be a consequence of structural and functional alterations of the microvascular network growth resulting partly from abnormal regulation of vascular endothelial growth factor (VEGF), one of the most potent known angiogenic factors. As data from clinical trials on anti-VEGF drugs are becoming available, it is increasingly recognized that VEGF, in addition to being a proliferation and migration factor, is also a maintenance and protection factor for endothelial cells, whose altered regulation may cause a disturbance of vascular homeostasis. Elevated VEGF levels in hypertensive patients were shown to correlate with cardiovascular risk, early microvascular and target organ damage; accordingly treatment of hypertension significantly reduced VEGF levels. Recently and in agreement with the theory that impaired angiogenesis can contribute to increased peripheral resistance and raised blood pressure (BP), an involvement of VEGF gene promoter polymorphisms in the pathophysiology of hypertension has been hypothesized.  In the last decade, anti-VEGF drugs have been used in clinical practice, especially in the oncology field. This review will summarize the present understanding of the contribution of VEGF to neoangiogenesis in hypertension and its possible role as a marker of vascular damage. Given the well established effects that antihypertensive drugs exert on the vasculature beyond BP lowering (pleiotropic effects), we will also discuss the effects of antihypertensive treatment on circulating VEGF levels. The biological mechanism and clinical impact of hypertensive complications during anti-angiogenic treatments will also be reviewed.
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Molecular Link between Intravascular Hemolysis and Vascular Occlusion in Sickle Cell Disease
Zhou Zhou, Donald L. Yee and Prasenjit Guchhait
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00223]

Intravascular hemolysis is a major component of anemia in sickle cell disease (SCD).  Plasma extracellular hemoglobin (ECHb) liberated by intravascular hemolysis has deleterious effects on the vasculature. ECHb scavenges nitric oxide (NO) and promotes the pathogenesis of several clinical events including pulmonary hypertension, priapism and non-hemorrhagic strokes. ECHb reduces the bioavailability of NO which down-regulates platelet activation, leading to platelet aggregation and vascular clot formation. Recently we have identified an additional mechanism whereby increased hemolysis can lead to a prothrombotic state in SCD by increasing the activity of von Willebrand factor (VWF), a multimeric plasma glycoprotein secreted by the endothelium. Our studies show that ECHb binds to the A2-domain on VWF at the proteolytic site of the metalloprotease, ADAMTS13, and blocks VWF cleavage in vitro. Elevated ECHb is associated with high levels of ultralarge and hyperactive VWF multimers in SCD patients’ plasma. A sub-population of VWF multimers, bound to ECHb is hyperactive, and exists in greater quantity in SCD patients’ plasma compared to normal controls. These results suggest a possible role for plasma ECHb in the accumulation of hyperactive VWF multimers in vivo that may mediate thrombotic and vasoocclusive complications in SCD patients.
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Sex Differences in Biomarkers for Predicting Cardiovascular and Coronary Events
Erjon Agushi, Raffaele Bugiardini and Borejda Xhyheri
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00224]

Introduction: Primary and secondary prevention of cardiovascular Disease (CVD) are major concerns and priorities. The best tools that we actually have to prevent CVD are the biomarkers. Numerous studies have shown that the presentation of cardiac disease in women is quite different from the presentation in men. Thus, one question arises “Are there any differences in biomarkers as well?” The answer to this question could open new avenues for a tailored management of cardiac diseases.

Method And Results: We searched the PubMed and Medline databases for articles comparing differences between the 2 genders in terms of biomarker expression. Keywords used included “Cardiovascular biomarkers sex differences”. We reviewed the role of different biomarkers in the 2 genders in relation to cardiac events.

Conclusions: Differences of expressions in biomarker levels were found between the 2 genders. Further investigation should be promoted.
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The Effects of Incretins on Energy Homeostasis: Physiology and Implications for the Treatment of Type 2 Diabetes Mellitus and Obesity
Spyridon Karras, Dimitrios G. Goulis, Gesthimani Mintziori, Niki Katsiki and Themistoklis Tzotzas
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00225]

Energy homeostasis in mammalians is a teleological process regulated by the interplay between caloric intake and energy expenditure. Incretins are a significant component of the complex homeostatic network regulating the metabolic state in humans. This narrative review will focus on the basic concepts regarding incretin physiology and their regulatory feedback mechanisms affecting energy homeostasis. In this context, glucagon-like peptide 1 (GLP-1) promotes satiety and weight loss through centrally and peripherally mediated pathways. On the other hand, gastric inhibitory peptide (GIP) is implicated in energy storage by its actions on adipose tissue. Understanding this biological model requires a holistic approach, since it is dually manifested by promoting weight reduction, in the case of GLP-1, or favoring lipid accumulation, in the case of GIP. The complete spectrum of incretin actions related to energy homeostasis is yet to be fully elucidated. Currently, new drugs based on incretin physiology are available for treatment of type 2 diabetes mellitus, whereas the implication of similar drugs in the treatment of obesity is under investigation. These agents exert several beneficial effects that minimize cardiovascular risk.
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Current Evidence for Antithrombotic Therapy after Peripheral Vascular Interventions
Sibu P. Saha, Thomas F. Whayne, Jr and Debabrata Mukherjee
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00226]

There is occurring a progressive increase in peripheral arterial disease (PAD) in the United States and around the World.  This is undoubtedly associated with deterioration in health status and an increase in cardiovascular risk factors. There are multiple old and new antithrombotic and anticoagulation medications that have been used for the treatment of PAD. Several are considered in this review. The purpose of antithrombotics in surgery is the prevention of thrombosis of surgical bypass grafts in order to help maintain their patency. Multiple different medication approaches can be made in association with surgery.  Just as in the case of peripheral vascular surgery, thrombosis also plagues the long-term maintenance of patency following peripheral vascular interventions (PVIs). Platelets play a key role in the initiation and propagation of thrombus formation following these PVIs and the use of antithrombotic medication helps reduce the likelihood of intravascular thrombus formation and adverse ischemic events during and after the procedure. Currently used antithrombotic agents after percutaneous peripheral revascularization include aspirin, clopidogrel, cilostazol and warfarin. Available medications remain in a state of flux and new oral direct thrombin and Factor Xa inhibitors may also find a place as clinical evidence-based medicine accumulates.
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Editorial: Inflammation, Coagulation, Vascular Permeability and Thrombosis
Massimo Cugno
[BSP/CVP/E-Pub/00227]

Ample evidence exists on the close link among the immune response, inflammation and coagulation [1, 2]. Proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) induce the expression of tissue factor (TF) the main initiator of blood coagulation [2]. TF activates the coagulation cascade generating thrombin which leads to the formation of fibrin clot from fibrinogen. At the cellular level, the coagulant mediators act on protease-activated receptors (PARs) inducing the expression of proinflammatory cytokines [3]. In turn, the two systems - coagulation and inflammation - activate each other, thus increasing the response. This self-refuelling loop may be amplified by the dysfunction of the major natural anticoagulant pathways (i.e. antithrombin, protein C system, and tissue factor pathway inhibitor) occurring in several inflammatory conditions [4]. Inflammation affects the coagulation system as observed in sepsis [5], rheumatoid arthritis [6, 7], autoimmune skin diseases [8, 9], inflammatory bowel diseases [10], and hypereosinophilic syndromes [11] which show an increased risk of thrombosis. Moreover, inflammatory mediators, acting synergistically with coagulation factors, may contribute to increase vascular permeability in conditions like urticaria and other cutaneous disorders [12, 13]. In this issue we will focus on several aspects of the complex interplay between inflammation and coagulation in different human diseases: sepsis (Chapter 1), rhematoid arthritis (Chapter 2), autoimmune and immune-mediated skin diseases (Chapter 3), urticaria and angioedema (Chapter 4), inflammatory bowel diseases (Chapter 5), and hypereosinophilic conditions (Chapter 6). The final aim is to identify new targets for therapies that can modify the dysregulation of coagulation and inflammation pathways, acting both locally, by preventing tissue damage and vascular hyperpermeability, and systemically, by reducing thrombotic risk.
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Interactions between Inflammation and Coagulation in Autoimmune and Immune-Mediated Skin Diseases
Angelo V. Marzano, Alberto Tedeschi, Ilaria Polloni, Carlo Crosti and Massimo Cugno
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00228]

Inflammation and coagulation systems are simultaneously activated in autoimmune and immune-mediated skin disorders, and the cross-talk that amplifies and maintains their activation seems to have both local and systemic implications. This interplay occurs in bullous pemphigoid (BP), the prototype autoimmune blistering disease in which eosinophil recruitment and thrombin generation locally contribute to the formation of bullae and inflammatory tissue damage. Moreover, the systemic activation of coagulation may explain the increased thrombotic risk observed in BP patients. Atopic dermatitis (AD), a chronically relapsing immune-mediated inflammatory skin disease, also involves the local and systemic activation of coagulation, which means that a prothrombotic state could theoretically develop, although the incidence of thrombosis is not increased in AD patients probably because of their young age. In psoriasis, a erythematous-squamous inflammatory immune-mediated skin disorder, the activation of coagulation seems to be mainly systemic and related to systemic inflammation, thus potentially contributing to the disease-related increase in cardiovascular risk in this disease. The activation of coagulation has also been suggested an additional pathomechanism in dermatitis herpetiformis (DH), a chronic-relapsing autoimmune skin disease associated with gluten sensitivity and celiac disease, but its precise role has not yet been defined. Taken together, these data provide the rationale for controlled clinical trials aimed at evaluating the usefulness of anticoagulant treatment in autoimmune skin disorders to counteract the local and systemic effects of coagulation activation.
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Involvement of Coagulation and Hemostasis in Inflammatory Bowel Diseases
Antoni Stadnicki
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00229]

Inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis (UC) are idiopathic, intestinal and systemic inflammatory disorders which are immunologically mediated with the activation of plasma proteolytic cascades. The activation of coagulation in IBD is related to the activity and colonic extension of the disease, but may still be persistent in a quiescent stage. Factor XIII seems to be as much a coagulation factor as a connective tissue factor which may contribute to intestinal healing. Fibrinolytic capacity is reduced in systemic circulation of IBD patients. Platelets activation is a feature of IBD which contributes to a pathogenic inflammatory sequel. There is evidence that coagulation activation may in turn mediate and amplify inflammatory cascades in IBD, especially via activating PARs related pathways. The etiology of thromboembolism in IBD seems to be multifactorial but is largely attributable to the coagulation activation and platelet aggregation during systemic inflammation. Thromboembolic (TE) complications in both Crohn’s disease and UC appear to have at least 3 – 4 fold increased risk of developing compared to control patients. Currently, no single TE laboratory marker has a predictive value, but a recently developed endogenous thrombin potential test may have a potentially predicative value in IBD.  At present, no interaction between IBD and inherited factors of thrombophilia has been found. An efficacy of heparin treatment in UC is still controversial, although heparin is safe in UC flare. Prophylactic anticoagulation against TE is currently not fully defined, however, high – risk patients should be considered for using a moderate dose of heparin.
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Hypereosinophilic Syndrome, Churg-Strauss Syndrome and Parasitic Diseases: Possible Links between Eosinophilia and Thrombosis
Alberto Maino, Raffaella Rossio, Massimo Cugno, Angelo V. Marzano and Alberto Tedeschi
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00230]

Throughout the past decade, a possible role of eosinophils in blood coagulation and thrombosis has been suggested. We conducted a Pubmed (MEDLINE) search of case and series referring to any kind of thrombotic events described in three conditions characterised by persistent blood eosinophilia i.e. the hypereosinophilic syndrome (HES), the Churg Strauss syndrome (CSS), and parasitic infestations from 1966 to date. One hundred and ninety-two articles were found regarding thrombotic events in HES and CSS, and 209 cases of thrombosis were extracted. One hundred and seventy-seven articles dealing with parasitic diseases and thrombosis were found, but only 15 manuscripts reporting thrombosis of unknown origin in 22 patients were selected. In HES, arterial thromboses were more frequent than in CSS (p=0.006), representing almost half of the cases (45%), while venous and mixed artero-venous thrombosis were respectively 28% and 27%. In contrast, in CSS there was a predominance of venous thrombosis (56%, p=0.006), with arterial thrombosis representing 38% of total thrombotic events, and mixed thrombosis being the least frequent (4%). The higher incidence of arterial thrombosis in HES patients can be explained by the common cardiac involvement (64% of patients). In the 22 patients with parasitoses and thrombosis, 15 had arterial thrombosis (68%) and 7 had venous thrombosis (32 %). Literature analysis shows that there are numerous reports of thrombotic events in patients with eosinophil-related disorders supporting a role for eosinophils in thrombosis. This observation raises the problem of prevention and treatment of thromboembolism particularly in HES and CSS patients.
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Potential Effect of Anti-Inflammatory Treatment on Reducing the Cardiovascular Risk in Rheumatoid Arthritis
Cecilia Chighizola, Tommaso Schioppo, Francesca Ingegnoli and Pier Luigi Meroni
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00231]

Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis with an increased mortality burden, largely attributable to cardiovascular disease. There is extensive evidence that patients with RA experience accelerated atherosclerosis, which is considered as the main responsible of this increased cardiovascular burden. Nowadays atherosclerosis is regarded as an inflammatory condition: hence, the cumulative inflammatory burden of RA, with the abundant synthesis of proinflammatory cytokines, contributes directly to the early formation of the atheromatic plaque. It is therefore reasonable to postulate that, by alleviating inflammation, drugs commonly used in RA treatment may ameliorate the cardiovascular profile of these patients. Here we provide an extensive review of the literature, focusing on the effects of the available anti-rheumatic agents on cardiovascular mortality and morbidity among RA sufferers.
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Inflammation and Coagulation in Urticaria and Angioedema
Massimo Cugno, Riccardo Asero, Alberto Tedeschi, Riccardo Lazzari and Angelo V. Marzano
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00232]

Urticaria is a skin disease characterised by short-lived surface swellings of the dermis (wheals) frequently accompanied by itching. It is classified as acute or chronic depending on whether the wheal recurrence occurs for less or more than six weeks. Acute urticaria is often due to a hypersensitivity reaction, whereas about 50% of the cases of chronic urticaria are regarded as autoimmune. Urticaria may occur alone or in association with a deeper swelling (angioedema) involving the subcutaneous and/or submucosal tissues, and last from hours to a few days. Angioedema can also develop alone, and may be idiopathic or be caused by allergies, inherited or acquired deficiencies of C1-inhibitor protein, or adverse drug reactions. An interplay between inflammation and coagulation has been proposed as a pathomechanism in urticaria and urticaria-associated angioedema (in which histamine and thrombin are involved), as well as in angioedema due to C1-inhibitor deficiency, which involves various biological systems. An increase in the plasma markers of thrombin generation, fibrinolysis and inflammation has been documented during exacerbations of urticaria and angioedema, with the marker levels decreasing to normal during remission. However, the hypercoagulable state in chronic urticaria and angioedema has not been reported to be associated with any increased risk of thrombosis, although there have been a number of reports of cardiovascular events occurring during episodes of acute urticaria. These observations have provided the rationale for the clinical evaluation of anticoagulant and antifibrinolytic drugs, the efficacy of which has sometimes been demonstrated.
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Crosstalk between Inflammation and Coagulation: The Lessons of Sepsis
Tom van der Poll and Marcel Levi
[Purchase Inquiry Form] [BSP/CVP/E-Pub/00233]

Sepsis results in the concurrent activation of inflammatory and procoagulant pathways.  Bacterial products and proinflammatory cytokines trigger the coagulation system primarily via induction of tissue factor. During sepsis, activation of coagulation is accompanied by impaired function of major anticoagulant mechanisms, including antithrombin, the protein C system and fibrinolysis. Protease activated receptors (PARs) form the molecular connection between coagulation and inflammation, and especially PAR1 seems to play an eminent role in sepsis pathogenesis. Activated protein C (APC) can cleave PAR1 when associated with either the endothelial protein C receptor (EPCR) or CD11b/CD18, resulting in broad cytoprotective effects mediated by sphingosine 1 phosphate (S1P) receptor 1 (S1P1). In contrast, activation of PAR1 by high dose thrombin results in barrier disruptive effects in endothelial cells via an S1P3 dependent mechanism. Recombinant APC protects against mortality in experimental endotoxemia and sepsis by effects that can be mediated by either EPCR - PAR1 dependent (endothelial cells, dendritic cells) or CD11b/CD18 – PAR1 dependent (macrophages) mechanisms. These protective APC effects do not rely on the anticoagulant properties of this protein. APC mutants that lack anticoagulant properties but retain the capacity to activate PAR1 are promising new drugs for sepsis treatment.
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