Treatment Of Atherosclerotic Vascular Disease Research Articles

FLOW PATTERNS OF CAROTID ATHEROSCLEROTIC PLAQUES USING A NEW US TECHNOLOGY: VECTORIAL DOPPLER (V FLOW ®)

Cardiovascular disease caused by atherosclerosis is the first cause of mortality and disability around the world. To understand the pathophysiology of the atherosclerotic plaques and specially their hemodynamics, the changes with their evolution or with the therapeutic interventions are essential to develop effective diagnostic and therapeutic interventions to stop the cardiovascular pandemics. Ultrasound is a cheap, simple and accessible methodology that experienced in the last three decades an astounding development in terms of technology and diagnostic precision. In the field of doppler ultrasound, Power doppler and color doppler enabled a detailed evaluation of cardiac valves, arteries and veins that conducted to impressive diagnostic precision and to enable advances in therapeutic interventions. Recently a new doppler technology based on processing in blocks the ultrasound information and transduce it into a vector representation of the displacement of blood flow in the space, named VFLOW®, conducted to a new field of investigation of complex flow patterns, by means of the instantaneous measurement of speed, flow gradients, wall shear stress and vessel wall stiffness. We conducted an investigation of different hemodynamic patterns according to plaque structure and vascular regional hemodynamics. Two main groups of plaques have been described, the soft ones (“expanding”) and the stiff or hard ones (“non expanding”). The first type has been associated with acute cardiovascular complications and increased cardiovascular risk and just the opposite, chronic lesions in stable disease to the later. We analyze in this paper the characterization of both types of plaques, their hemodynamic patterns and in particular, for the first time, the behavior of the wall shear stress at different sectors of the plaques which may be linked to their development and/or complications. This technology deserves further development face to future applications in the diagnosis and treatment of atherosclerotic vascular disease.

Curaxin CBL0137 inhibits endothelial inflammation and atherogenesis via suppression of the Src-YAP signalling axis.

Atherosclerotic vascular disease is the leading cause of mortality and morbidity worldwide. Our previous study uncovered that endothelium-specific knockdown of YAP suppresses atherogenesis, suggesting that YAP is a promising therapeutic target against atherosclerotic vascular disease. We established a drug screening platform, which aimed to identify new YAP inhibitors for anti-atherosclerotic treatment. Drug screening was performed by a luciferase reporter gene assay. RNA sequencing was performed to acquire the transcriptomic profile of CBL0137-treated endothelial cells. We assessed and validated the inhibitory effect of CBL0137 on YAP activity and inflammatory response in HUVECs and HAECs. We evaluated the vasoprotective effect of CBL0137 in vivo against plaque formation in ApoE-/- mice, using both disturbed flow-induced and chronic western diet-induced atherosclerotic models. We identified CBL0137 as a novel YAP inhibitor from an FDA drug library. CBL0137 inhibited YAP activity by restraining its phosphorylation at Y357. CBL0137 inhibited YAP activity to repress endothelial inflammation. Mechanistically, CBL0137 suppressed YAP phosphorylation at Y357 via the tyrosine-protein kinase Src. Furthermore, administration of CBL0137 ameliorated endothelial inflammation and the atherogenesis induced by disturbed flow and consumption of an atherogenic diet in ApoE-/- mice. To our knowledge, this is the first study to identify CBL0137 as a novel YAP inhibitor. We have demonstrated that pharmacologically targeting YAP by CBL0137 inhibits atherogenesis. The present results suggest that CBL0137 holds promise as a new drug for the treatment of atherosclerotic vascular disease.

Modified Lipoproteins Induce Arterial Wall Inflammation During Atherogenesis.

Circulating apolipoprotein B-containing lipoproteins, notably the low-density lipoproteins, enter the inner layer of the arterial wall, the intima, where a fraction of them is retained and modified by proteases, lipases, and oxidizing agents and enzymes. The modified lipoproteins and various modification products, such as fatty acids, ceramides, lysophospholipids, and oxidized lipids induce inflammatory reactions in the macrophages and the covering endothelial cells, initiating an increased leukocyte diapedesis. Lipolysis of the lipoproteins also induces the formation of cholesterol crystals with strong proinflammatory properties. Modified and aggregated lipoproteins, cholesterol crystals, and lipoproteins isolated from human atherosclerotic lesions, all can activate macrophages and thereby induce the secretion of proinflammatory cytokines, chemokines, and enzymes. The extent of lipoprotein retention, modification, and aggregation have been shown to depend largely on differences in the composition of the circulating lipoprotein particles. These properties can be modified by pharmacological means, and thereby provide opportunities for clinical interventions regarding the prevention and treatment of atherosclerotic vascular diseases.

Macrophage-targeted nanomedicine for the diagnosis and treatment of atherosclerosis.

Nanotechnology could improve our understanding of the pathophysiology of atherosclerosis and contribute to the development of novel diagnostic and therapeutic strategies to further reduce the risk of cardiovascular disease. Macrophages have key roles in atherosclerosis progression and, therefore, macrophage-associated pathological processes are important targets for both diagnostic imaging and novel therapies for atherosclerosis. In this Review, we highlight efforts in the past two decades to develop imaging techniques and to therapeutically manipulate macrophages in atherosclerotic plaques with the use of rationally designed nanoparticles. We review the latest progress in nanoparticle-based imaging modalities that can specifically target macrophages. Using novel molecular imaging technology, these modalities enable the identification of advanced atherosclerotic plaques and the assessment of the therapeutic efficacy of medical interventions. Additionally, we provide novel perspectives on how macrophage-targeting nanoparticles can deliver a broad range of therapeutic payloads to atherosclerotic lesions. These nanoparticles can suppress pro-atherogenic macrophage processes, leading to improved resolution of inflammation and stabilization of plaques. Finally, we propose future opportunities for novel diagnostic and therapeutic strategies and provide solutions to challenges in this area for the purpose of accelerating the clinical translation of nanomedicine for the treatment of atherosclerotic vascular disease.

MODERN OPPORTUNITIES OF ATHEROSCLEROSIS PHARMACOTHERAPY: NEW DIRECTIONS

Despite the successful achievements in modern applied medicine and the application of hypolipidemic drugs into clinical practice for the past 50 years, the issue of prevention and treatment of atherosclerotic vascular disease (AVD) remains unsolved. Implementation of the theory of immunopathogenesis of atherosclerosis that was experimentally proved by modern studies allows the specialists to expand the possibilities of pharmacotherapy and pharmacoprevention for AVD. Thus, the aim of the present study was to analyze new directions in the development of anti-atherosclerotic drugs (AAD) with a pathogenetic activity that suppressed chronic autoimmune inflammation in the areas of atherosclerotic damage of vessels. In the course of the study, the search and analysis of the publications in the databases Web of Science, PubMed, and RSCI (Russian Science Citation Index) for the period of 2016-2018 were performed. According to the performed analysis, the most perspective molecular targets for AAD are pro-inflammatory and anti-inflammatory cytokines that develop a disbalance in patients with AVD. Thus, the drugs that are based on monoclonal antibodies to the tumor necrosis factor α (TNFα), and pro-inflammatory interleukins (1β, 17А), used for the treatment of rheumatoid arthritis and psoriasis, can be used for the treatment of AVD. Recombinant interleukins 6, 13, 19, and substances that suppress the expression of interferon regulatory factors will also exert an antiatherogenic effect. The studies on the modeling of the pathogenesis of AVD in inbred animals showed that other molecular targets for AAD could be enzymes involved in the lipid and immune cells metabolism. They include inositol requiring enzyme 1, proprotein convertase subtilisin/Kexin type 9, and the enzymes of paraoxonase family. Besides, the review includes the discussion of the successful application of drugs based on monoclonal antibodies to TNFα (infliximab), IL-17A (secukinumab) and IL-1β (canakinumab), as well as the drugs with antienzymatic activity (evolocumab and darapladib), in clinical practice for the treatment of AVD. The modern knowledge on molecular mechanisms of immunopathogenesis can give grounds for the development of drugs for pathogenetic pharmacotherapy and pharmacoprevention for the complications of AVD. The most effective solution would be the indication of drugs that affect the disbalance of cytokines and metabolic processes in the immune cells.

Exercise and Peripheral Arteriosclerosis.

Adaptation of a healthy lifestyle including adequate daily physical activity is shown to reduce 80% of cardiovascular mortality and 40% of cancer-related deaths. A large body of evidence exists proving that this relationship is dose dependent, and even half of the recommended normal physical activity yields significant risk reduction. There has been no medical therapy that would provide such high percentages of reduction in mortality to date. The World Health Organization, therefore, has started an initiative to implement exercise into daily life as a primary prevention measure. Herein, we will focus on the effects of exercise on the vasculature, mainly the peripheral vasculature, in the context of atherosclerotic disease. Exercise has a fundamental role in the pathogenesis, diagnosis, and treatment of atherosclerotic vascular disease. It exerts a protective effect against the development of atherosclerosis irrespective of other cardiovascular risk factors. Additionally, exercise induces changes in vascular hemodynamics helping us to elucidate the presence of obscure vascular involvement. Once again, exercise is the main treatment modality in peripheral arterial disease with accumulating evidence to reduce symptoms and improve both exercise capacity and cardiovascular symptoms.

A Review based on Biodegradable and Bioabsorbable Stents for Coronary Artery Disease

In the treatment of atherosclerotic vascular disease, angioplasty is widely used and has made a significant progress in the recent years. Drug-eluting stents are effective as well as raising the concerns associated like restenosis. In order to solve the problem of In-stent Restenosis; biodegradable stents are modified in such a way to superfluous permanent stent. Targeted drug delivery has more powerful impact as compared to metallic stents with thin coating of drug. Numerous research groups have investigated biodegradable materials like corrosive metals, polycarbonates, polyesters & bacterial-derived polymers for developing stents. A biodegradable stent is assumed to be ideal if it can be accurately installed under the fluoroscopic regulation and detect the target lesion with a trivial endovascular torment. Likewise, the advantages of bio-absorbable polymeric stents are not correlated with late stent thrombosis and leave no stent behind, they are completely suitable for Magnetic Resonance Imaging (MRI) and Multi-Slice Computer Tomography (MSCT) imaging. This survey covers the distinctive stent line-ups and bio-absorbable stents and their potentials.

Evaluation of Combination of Low Dose Atorvastatin plus Ezetimibe and Aspirin in the Treatment of Atherosclerotic Vascular Disease

Objective: To evaluate the effect of combination of low dose of atorvastatin plus ezetimibe and aspirin in the treatment of Atherosclerotic Vascular Disease (AVD) with special emphasis on rhabdomyolysis. Experimental Design: Thirty male rats were allocated to five groups as normal control, disease control, and test groups I, II, III. All groups except normal control group received high fat diet for 10 weeks and treatment was initiated in test groups after the completion of 4th week, after rise in lipid levels and bodyweight of the rats when compared with normal control rats was noted. Normal control and disease control group animals received vehicle and test groups were treated with ezetimibe, 0.986mg/kg (Clinical dose 10 mg) and aspirin, 7.708mg/kg (Clinical dose 75 mg) along with differential doses of atorvastatin per orally. Test groups I, II, III received atorvastatin dose of 1.027mg/kg, 0.770mg/kg, 0.513mg/kg p.o. respectively which were equal to clinical doses of 10mg, 7.5mg and 5 mg of atorvastatin respectively. Body weight, lipid profile and grip strength were evaluated biweekly and histopathology of aorta was carried out at the end of the study. Results: The results of study reveal that test group II had significantly decreased the increased body weight, lipid levels, accumulation of lipids on the walls of aorta and incidence of rhabdomyolysis. Conclusion: The study demonstrates that atorvastatin at clinical dose of 7.5 mg have shown a decrease in the incidence rhabdomyolysis without loss of hypolipidemic activity when given along with clinical doses of ezetimibe and aspirin in the management of AVD. Key words: Atherosclerotic Vascular Disease, Atorvastatin, High Fat Diet Model, Rhabdomyolysis, Statins.

Abstract 559: Exploiting Macrophage Autophagy-Lysosomal Biogenesis With the Natural Sugar Trehalose as a Therapy for Atherosclerosis

The autophagy-lysosome system is a catabolic cellular mechanism that degrades dysfunctional proteins and organelles. In atherosclerosis, there is mounting evidence that this process is rendered dysfunctional particularly in plaque macrophages and is an important trigger for plaque progression. In an effort to characterize practical inducers of macrophage degradative capacity, we now describe the unique vascular benefits of a natural sugar called trehalose, a recognized autophagy inducer with a currently unknown mechanism of action. Trehalose-treated macrophages display enhanced autophagy via a process that involves lysosomal stress and resultant activation of TFEB, the master transcriptional regulator of autophagy-lysosomal biogenesis. We find an important downstream effect of trehalose to be the induction of p62-dependent selective autophagy of cytotoxic polyubiquitinated protein aggregates and dampening of IL-1β/inflammasome function. We confirm the relevance of these in vitro observations in several pro-atherogenic (ApoE-/-) mouse models. Administration of trehalose during eight weeks of Western diet feeding potently induces autophagy and TFEB in plaque macrophages with concomitant reductions in polyubiquitinated protein aggregate burden along with significantly reduced plaque size and complexity. Importantly, these findings are completely abrogated in mice deficient in macrophage autophagy (ATG5-/-) or the selective autophagy chaperone (p62-/-). Further detailed pharmacokinetic evaluation of trehalose shows that physiologically relevant concentrations are indeed achievable in mice. Taken together, our data support the serious consideration of this safe and natural sugar as a potent inducer of macrophage degradative capacity in the treatment of atherosclerotic vascular disease.

A Review on Biodegradable and Bioabsorbable Stents for Coronary Artery Disease

In the recent years Angioplasty has made a significant progress and is being widely used in the treatment of atherosclerotic vascular disease. Drug-eluting stents are not only effective but are also raising the concerns associated like restenosis. Biodegradable stents are being developed as an alternative to permanent stents which may be a potential alternative in solving the problem of in-stent restenosis. When compared to metallic stents with a thin coated drug, a fully degradable stent may be more potential in targeted drug delivery. Biodegradable materials like polycarbonates, polyesters, corrodible metals and bacterial-derived polymers have been investigated by various research groups in designing stents. A biodegradable stent is considered to be perfect if it could be reliably deploy under the fluoroscopic guidance and locate the target lesion with an insignificant endovascular trauma. In addition the byproducts developed during the degradation should be nontoxic, lead to the minimal inflammation at the target site and should disappear in a minimal period of time without a noteworthy displacement from the deployment site. Even though stents made of biodegradable materials were launched into the market with initial clinical data, more advanced research is necessary to solve the various issues associated with these stents.

The role of the lymphatic system in cholesterol transport.

Reverse cholesterol transport (RCT) is the pathway for removal of peripheral tissue cholesterol and involves transport of cholesterol back to liver for excretion, starting from cellular cholesterol efflux facilitated by lipid-free apolipoprotein A1 (ApoA1) or other lipidated high-density lipoprotein (HDL) particles within the interstitial space. Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream. There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels. Hence, it is important to better understand the processes governing ApoA1 and HDL influx into peripheral tissues from the bloodstream, modification and facilitation of cellular cholesterol removal within the interstitial space, and transport through the lymphatic vasculature. New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease.

Beyond statins: new lipid lowering strategies to reduce cardiovascular risk.

Statins are the first-line therapy in LDL-Cholesterol (LDL-C) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease. Yet, a significant proportion of patients remain at high risk. Recently, a number of new therapies have been developed to further lower LDL-C. These agents may provide clinical benefit on top of statin therapy in patients with high residual risk, severe hypercholesterolemia or as an alternative for patients who are intolerant to statins. We review four novel approaches based on the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein-B100 (apoB), Cholesteryl ester transport protein (CETP) and microsomal triglyceride transfer protein (MTP). ApoB and MTP inhibitors (Mipomersen and Lomitapide) are indicated only for homozygous familial hypercholesterolemia patients. The results of ongoing trials with CETP and PCSK9 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease.

OP30 Therapeutic approach in endothelial dysfunction by a novel implantable endogenous hydrogen sulfide loaded electrospun fibrous membranes

Recently, it has been reported that Hydrogen sulfide (H 2 S) plays an anti-atherosclerotic role both in vitro and in vivo . Its deficiency leads to early development and progression of atherosclerosis especially. This study was designed to investigate S-propargyl-cysteine (SPRC), an H 2 S modulator, as well as its effect on the progression of endothelial-protective effect in oxidized Low-Density Lipoprotein (oxLDL) induced apoptosis in Human umbilical vein endothelial cells (HUVECs) and underlying mechanisms. Implantable biodegradable SPRC-loaded poly (l-lactide) (PLA) fibrous membranes were successfully fabricated using co-electrospinning technology to control drug release and improve drug utilization. Polymeric drug delivery systems are capable of improving therapeutic efficacy, reducing toxicity, and enhancing patient compliance due to their controlled delivery of drugs. Electrospinning is a remarkably simple and powerful technique used to generate polymeric fibers at a sub-micrometer scale (ranging from approximately 50 nm to several μm). Biodegradable electrospun poly (l-lactide) (PLA, FDA) was demonstrated their potential as effective carriers for drug delivery. Implantable biodegradable SPRC-loaded poly (l-lactide) (PLA) fibrous membranes were successfully fabricated using co-electrospinning technology to control drug release and improve drug utilization. The in vivo releasing time of SPRC lasted for 72 h, and the drug concentration released in HUVECs could be controlled by varying the drug content of the electrospun fibers. 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and 5,5′,6,6′-Tetrachloro-1,1′,3,3′- tetraethyl-imidacarbocyanine iodide (JC-1) assays indicated that SPRC/PLA electrospun fibrous membranes significantly inhibited the HUVECs apoptosis. In addition, Marginal changes in the lipid parameters were found in the SPRC/PLA electrospun fibrous membranes-treated HUVECs, with advanced glycation end products (AGES), triglyceride (TG) and high-density lipid cholesterol (HDL-C) elevation reduction at the 6% dose. These findings suggested that SPRC/PLA electrospun membrane is a very promising new treatment for early and long-term treatment of atherosclerotic vascular disease.

Pharmacotherapies for lipid modification: beyond the statins

The widespread clinical use of statins has contributed to significant reductions in the rate of cardiovascular morbidity and mortality over the past 3 decades, and statins are considered first-line therapy for the prevention and treatment of atherosclerotic vascular disease. Nevertheless, various other lipid-lowering agents can provide clinical benefit by supplementing or augmenting statin therapy in patients with severe hypercholesterolaemia or mixed dyslipidaemia, or by providing an alternative for patients who are intolerant to statins. Bile acid resins and niacin were prescribed for lipid modification for years before the introduction of the statins, and new data continue to emerge regarding their use in different patient groups and for specific conditions. Ezetimibe can be appropriate for patients whose primary lipid abnormality is an elevated LDL-cholesterol level, whereas the fibrates seem to be most beneficial in patients with low levels of HDL cholesterol and elevated triglycerides. At the end of 2012 and the beginning of 2013, the first microsomal triglyceride transfer protein inhibitor, lomitapide, and the first antisense therapy to target apolipoprotein B, mipomersen, were approved for the treatment of individuals with extremely elevated LDL-cholesterol levels caused by homozygous familial hypercholesterolaemia. Although two agents in the experimental class of cholesteryl ester transfer protein inhibitors have failed to show a benefit in clinical trials, newer drugs in this class could provide an additional strategy to address residual cardiovascular risk in patients treated with statins.

Effects of Chimeric Decoy Oligodeoxynucleotide in the Regulation of Transcription Factors NF‐κB and Sp1 in an Animal Model of Atherosclerosis

Atherosclerosis is a multifactorial and progressive disease in which the inflammatory reaction and inflammation-related factors play important roles at all stages. Modulation of NF-κB and Sp1 expression may be important targets for the prevention and treatment of atherosclerotic vascular disease. To develop a novel therapeutic approach in atherosclerosis, we examined the simultaneous suppression of the transcription factors NF-κB and Sp1 which regulate inflammation. We employed chimeric decoy oligodeoxynucleotide (ODN) containing the consensus of NF-κB and Sp1-binding sites to suppress these transcription factors simultaneously and to test chimeric decoy for anti-atherogenic effects in an atherogenic diet-induced atherosclerotic mouse model with inflammatory stimulation. C57BL/6 mice were fed with an atherogenic diet (15% fat, 1.25% cholesterol and 0.5% cholic acid) for 12 weeks to induce atherosclerosis; lipopolysaccharide (LPS, 2 mg/kg) was intraperitoneally injected in the first week of study to simulate underlying infectious burden during development of atherosclerosis. Decoy ODNs were injected into tail vein at 2, 4, 6, 8, 10 and 12 weeks after only three LPS injections in mice fed the atherogenic diet. Chimeric decoy ODN alleviated atherosclerotic changes and reduced serum cholesterol and inflammatory cytokines. In accordance with these results, the expressions of atherosclerotic markers were inhibited by chimeric decoy ODN. Chimeric decoy ODN modulates multiple pathogenic aspects of an atherogenic diet-induced atherosclerosis with inflammatory stimulation: hypercholesterolaemia and inflammation. Therefore, this study demonstrates the efficacy of chimeric decoy ODN on atherosclerosis with immunological complication.

Hemodynamic Simulation of Intra-stent Blood Flow

The stent has been a major breakthrough for the treatment of atherosclerotic vascular disease. The permanent vascular implant of a stent, however, changes the blood flow hemodynamics and may consequently affect the restenosis process. Computational Fluid Dynamics (CFD) has been widely used to analyze the hemodynamic behavior and wall shear stress (WSS) distribution in stented arteries. The objective of this study is to present a thorough comparison among various CFD models to investigate the effects of rheological properties and pulsatile flow on hemodynamic simulation of the intra-stent blood flow. Several CFD models were developed with various modeling setups – axisymmetric parallel ring vs. 3-D stented artery model, Newtonian vs. non-Newtonian flow, and steady-state vs. pulsatile flow. Simulated results show that the minimum WSS occurs at the recirculation zones located at the downstream or backside of each stent struts. The rheological effect on WWS is minor in the axisymmetric parallel ring model; however, it becomes slightly significant in the 3-D stented artery model, with Newtonian flow being a more conservative assumption. For given pulsatile waveforms, the steady-state and pulsatile flow resulted in fairly similar trends in the WSS distribution. Therefore, it is reasonable to simulate the intra-stent blood flow as a steady-state Newtonian flow, which could be beneficial in more complex simulations and drastically reduce the computational time. These findings will provide great insights for future stent design optimization to reduce restenosis.

Apolipoprotein A‐1 Deficiency in Older Adults with Spontaneous Cerebral Lobar Hemorrhage

An 80-year-old woman was admitted to the Stroke Unit at Sant'Andrea Hospital (La Spezia, Italy) for spontaneous right cerebellar hemorrhage (Figure 1A); she complained of cognitive impairment and had a cerebellar hemorrhage 1 year before. Angio-computed tomography (CT) of the intracranial vessels did not show any vascular malformations. Her apolipoprotein A-1 (apoA-1) plasma level was 92 mg/dL (normal range 105–205 mg/dL) and her high-density lipoprotein cholesterol (HDL-C) was 29 mg/dL. An 82-year-old woman with diabetes mellitus and hypertension, treated with metformin and ramipril, presented a spontaneous hemorrhage in the right temporal and occipital lobes (Figure 1B). She was admitted to the Neurosurgery Unit, where she underwent digital subtraction angiography of intracranial vessels, which was normal. Her apoA-1 plasma concentration was 91 mg/dL, and her HDL-C was 70 mg/dL. An 86-year-old woman with hypertension and severe cognitive deficits, receiving treatment with furosemide, was admitted to the emergency department for a sudden-onset left hemiparesis; CT scan showed intraparenchymal right frontal hemorrhage (Figure 1C). Angio-CT of the intracranial vessels was normal. Her apoA-I plasma level was 79 mg/dL, and her HDL-C was 29 mg/dL. ApoA-1 is a 28-KDa protein synthesized by the liver and small intestine. It plays a critical role in the formation, metabolism, and catabolism of HDL-C, a plasma lipoprotein whose levels are highly linked to protection against the development of cardiovascular disease.1 As expected, gene deletion of apoA-1 results in extremely low levels of HDL-C in mice, which are significantly more likely to develop atherosclerosis. Hepatic overexpression of apoA-1 significantly raises HDL-C levels and inhibits the progression of and even regresses atherosclerosis in mice. Thus, upregulation of endogenous apoA-I expression is widely considered to be one of the most promising approaches in HDL-C-related therapies.2 Mutated apoA-1 causes rare forms of late-onset familial amyloidosis that are inherited in an autosomal-dominant manner and are characterized by asymptomatic cholestatic hepatopathy and nephropathy, the latter presenting with slowly progressive renal failure without proteinuria due to selective tubular involvement. In a subset of individuals, a progressive cardiomyopathy leading to heart failure may be observed. Skin, peripheral nerves, and the larynx are also frequently involved.3 None of the women described above had clinical or laboratory signs of systemic amyloidosis. The accumulation of amyloid in the walls of small and medium-sized cerebral arteries causes cerebral amyloid angiopathy (CAA). In most cases, the accumulated amyloid is composed of the amyloid-beta peptide, the same found in the plaques of individuals with Alzheimer's disease (AD). Amyloid deposition in cerebral blood vessels can have several clinical consequences. First, it can remain asymptomatic, as suggested by the neuropathological observation that, during normal aging, approximately 50% of individuals aged 80 and older have CAA. Second, it can weaken the vessel wall, causing vessel rupture and intracerebral hemorrhage. Finally, it can obliterate the vessel lumen, leading to ischemia.4 CAA-related hemorrhage is a major cause of spontaneous cerebral lobar hemorrhages in older adults with normal or high blood pressure.5 A recent study demonstrated that apoA-1 significantly decreased amyloid-beta toxicity against brain vascular smooth cells in transgenic mice. It concluded that lack of apoA-1 aggravates memory deficits along with significantly greater CAA.6 In another study, an oral apoA-1 mimetic peptide was administered in a mouse model of AD and showed improvement of cognitive function and reduction of amyloid burden.7 We hypothesized that low plasma concentrations of apoA-1 would favor amyloid angiopathy and the consequent lobar hemorrhages in older adults. We report three patients with spontaneous and lobar hemorrhages low plasma levels of apoA-1. This sample is too small to draw any conclusion, but if this finding is confirmed in a larger sample, plasma levels of apoA-1 could become a useful diagnostic test in older adults with amyloid angiopathy at risk of hemorrhagic strokes. In addition, oral administration of apoA-1 mimetic peptides could be studied not only in the treatment of atherosclerotic vascular diseases, but also in preventing amyloid deposition in cerebral blood vessels. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Massimiliano Godani: Study concept and design. Cesare Capellini: Acquisition, analysis and interpretation of CT data. Massimo Del Sette: Supervision of the manuscript. Sponsor's Role: None.

Endothelial arginase II and atherosclerosis

Atherosclerotic vascular disease is the leading cause of morbidity and mortality in developed countries. While it is a complex condition resulting from numerous genetic and environmental factors, it is well recognized that oxidized low-density lipoprotein produces pro-atherogenic effects in endothelial cells (ECs) by inducing the expression of adhesion molecules, stimulating EC apoptosis, inducing superoxide anion formation and impairing protective endothelial nitric oxide (NO) formation. Emerging evidence suggests that the enzyme arginase reciprocally regulates NO synthase and NO production by competing for the common substrate L-arginine. As oxidized LDL (OxLDL) results in arginase activation/upregulation, it appears to be an important contributor to endothelial dysfunction by a mechanism that involves substrate limitation for endothelial NO synthase (eNOS) and NO synthesis. Additionally, arginase enhances production of reactive oxygen species by eNOS. Arginase inhibition in hypercholesterolemic (ApoE-/-) mice or arginase II deletion (ArgII-/-) mice restores endothelial vasorelaxant function, reduces vascular stiffness and markedly reduces atherosclerotic plaque burden. Furthermore, arginase activation contributes to vascular changes including polyamine-dependent vascular smooth muscle cell proliferation and collagen synthesis. Collectively, arginase may play a key role in the prevention and treatment of atherosclerotic vascular disease.

Emerging Molecular Targets for Intravascular Imaging of High-Risk Plaques

Accumulating evidence links catastrophic cardiovascular events to the inflammatory, angiogenic, and apoptotic biological profiles underlying high-risk atherosclerotic plaques. While biological detail is opaque to traditional anatomical imaging readouts, emerging molecular imaging approaches are now yielding significant clinical insights into the biological diagnosis, characterization, and treatment of atherosclerotic vascular disease. Yet, while clinical molecular imaging approaches are available for larger arterial beds such as the carotid arteries or aorta, molecular imaging pathways for human coronary arterial plaques are lacking. Excitingly, the recent advent of intravascular near-infrared fluorescence technology now offers new potential for in vivo molecular imaging of key molecular and cellular targets in coronary-sized vasculature. Here we provide a framework for coronary artery–targeted molecular imaging using intravascular imaging technology, and present key molecular imaging targets relevant to the detection of high-risk, vulnerable coronary plaques.

Histamine H1 Receptor Promotes Atherosclerotic Lesion Formation by Increasing Vascular Permeability for Low-Density Lipoproteins

Enhanced endothelial permeability leading to intimal accumulation of low-density lipoproteins (LDL) stimulates the formation of atherosclerotic lesions. Histamine is known to increase vascular permeability. Whether this affects the formation of atherosclerotic lesions, however, remains elusive. Apolipoprotein E-null (ApoE(-/-)) mice treated with a histamine H1 receptor but not an H2 receptor antagonist developed 40% fewer atherosclerotic lesions in the aorta than placebo-treated controls. Similarly, genetic deletion of the H1 but not the H2 receptor resulted in a 60% reduction of lesions compared with ApoE(-/-) controls. The H1 receptor enhanced LDL permeability and lipid accumulation in the aorta, whereas plasma lipoprotein levels remained unaltered. In contrast, the H1 receptor did not affect proliferation and migration of vascular smooth muscle cells. Bone marrow transplantation confirmed that the formation of atherosclerotic lesions depended on the H1 receptor in vascular cells, whereas its presence in bone marrow-derived cells was irrelevant for plaque development. Mice expressing the H1 receptor exhibited higher levels of the chemokine (C-C motif) ligand 5 and higher numbers of macrophages and T-helper lymphocytes in plaques, higher numbers of circulating lymphocytes, and larger spleens. These data indicate that H1 but not H2 receptor activation drives the formation of atherosclerotic lesions through an increased vascular permeability for LDL, which is associated with an enhanced secondary aortic and systemic inflammation. These data open novel perspectives for the prevention and treatment of atherosclerotic vascular disease.