Tillmann Cyrus

Anti-angiogenic perfluorocarbon nanoparticles for diagnosis and treatment of atherosclerosis.

Complementary developments in nanotechnology, genomics, proteomics, molecular biology and imaging offer the potential for early, accurate diagnosis. Molecularly-targeted diagnostic imaging agents will allow noninvasive phenotypic characterization of pathologies and, therefore, tailored treatment close to the onset. For atherosclerosis, this includes anti-angiogenic therapy with specifically-targeted drug delivery systems to arrest the development of plaques before they impinge upon the lumen. Additionally, monitoring the application and effects of this targeted therapy in a serial fashion will be important. This review covers the specific application of alpha(nu)beta(3)-targeted anti-angiogenic perfluorocarbon nanoparticles in (1) the detection of molecular markers for atherosclerosis, (2) the immediate verification of drug delivery with image-based prediction of therapy outcomes, and (3) the serial, noninvasive observation of therapeutic efficacy.

Use of mechanical assist during high-risk PCI and STEMI with cardiogenic shock.

Infarct size may be reduced by left ventricular unloading after ST‐segment elevation MI (STEMI) in addition to reperfusion therapy. Likewise, high‐risk percutaneous coronary intervention (PCI) may benefit from periprocedural support especially in patients with low cardiac output at baseline or when periprocedural hemodynamic deterioration is anticipated. Traditionally, intraaortic balloon‐pumps have been used in acute MI with cardiogenic shock. As this modality has limited hemodynamic benefits, new developments have focused on active hemodynamic assist devices. These devices actively unload the left ventricle increasing cardiac output by 2.5–5 L/min and are increasingly easier to implant and monitor. Thus, interventional cardiologists will be able to offer a safer more effective alternative to an increasing patient population with complex cardiac conditions and high‐risk PCI.

Magnetic resonance nanoparticles for cardiovascular molecular imaging and therapy

Molecular vascular imaging represents a novel tool that promises to change the current medical paradigm of ‘see and treat’ to a ‘detect and prevent’ strategy. Nanoparticle agents, such as superparamagnetic nanoparticles and perfluorocarbon nanoparticle emulsions, have been developed for noninvasive imaging, particularly for magnetic resonance imaging. Designed to target specific epitopes in tissues, these agents are beginning to enter clinical trials for cardiovascular applications. The delivery of local therapy with these nanoparticles, using mechanisms such as contact-facilitated drug delivery, is in the advanced stages of preclinical research. Ultimately, combined diagnostic and therapeutic nanoparticle formulations may allow patients to be characterized noninvasively and segmented to receive custom-tailored therapy. This review focuses on recent developments of nanoparticle technologies with an emphasis on cardiovascular applications of magnetic resonance imaging.

MR three-dimensional molecular imaging of intramural biomarkers with targeted nanoparticles.

In this study, porcine carotid arteries were subjected to balloon overstretch injury followed by local delivery of paramagnetic nanoparticles targeted to alphavbeta3-integrin expressed by smooth muscle cells or collagen III within the extracellular matrix. Carotid T1-weighted angiography and vascular imaging was performed at 1.5T. While MR angiograms were indistinguishable between control and targeted vessel segments, alphavbeta3-integrin-and collagen Ill-targeted nanoparticles spatially delineated patterns and volumes of stretch injury. In conclusion, MR molecular imaging with alphavbeta3-integrin or collagen Ill-targeted nanoparticles enables the non-invasive, three-dimensional characterization of arterial pathology unanticipated from routine angiography.

Nanomedicine Opportunities in Cardiology

Abstract:u2002 Despite myriad advances, cardiovascular‐related diseases continue to remain our greatest health problem. In more than half of patients with atherosclerotic disease, their first presentation to medical attention becomes their last. Patients often survive their first cardiac event through acute revascularization and placement of drug‐eluting stents (DES), but only select coronary lesions are amenable to DES placement, resulting in the use of bare metal or no stent, both of which lack the benefit of antirestenotic therapy. In other patients, transient ischemic attacks (TIAs) and stroke constitute the initial presentation of disease. In these patients, the diagnostic and therapeutic options are woefully inadequate. Nanomedicine offers options to each of these challenges. Antiangiogenic paramagnetic nanoparticles may be used to serially assess the severity of atherosclerotic disease in asymptomatic, high‐risk patients by detecting the development of plaque neovasculature, which reflects the underlying lesion activity and vulnerability to rupture. The nanoparticles can locally deliver antiangiogenic therapy, which may acutely retard plaque progression, allowing aggressive statin therapy to become effective. Moreover, these agents may be useful as a quantitative marker to guide atherosclerotic management in an asymptomatic patient. In those cases proceeding to the catheterization laboratory for revascularization, nanoparticles incorporating antirestenotic drugs can be delivered directly into the wall of lesions not amenable to DES placement. Targeted nanoparticles could help ensure that antirestenotic drugs are available for all lesions. Moreover, displacement of antiproliferative agents from the intimal surface into the vascular wall is likely to improve rehealing of the endothelium, improving postprocedural management of these patients.

Molecular Imaging by Cardiovascular MR

Do molecularly-targeted contrast agents have what it takes to usher in a paradigm shift as to how we will image cardiovascular disease in the near future? Moreover, are non-invasive vulnerable plaque detection and preemptive treatments with these novel nanoparticulate agents within reach for clinical applications? In this article, we attempt to make a compelling case for how the advent of molecularly-targeted nanoparticle technology may change the way we detect atherosclerotic lesions, determine their clinical significance and even provide non-invasive treatments. Focusing on imaging with cardiovascular MR, an overview of the latest developments in this rapidly evolving field of so-called intelligent contrast agents that are able to interrogate the vascular wall and various complementary advanced imaging technologies are presented.

Expression of thromboxane synthase, prostacyclin synthase and thromboxane receptor in atherosclerotic lesions: Correlation with plaque composition

OBJECTIVESnProstaglandins, such as thromboxane A(2) (TxA(2)) and prostacyclin (PGI(2)), are bioactive lipid mediators that are implicated in the pathogenesis of atherosclerosis. In the current study, we tested the hypothesis that thromboxane synthase (TXAS), prostacyclin synthase (PGIS) and thromboxane receptor (TP) are expressed within the atherosclerotic lesion.nnnMETHODSnAtherosclerotic aorta segments were obtained from low-density lipoprotein receptor deficient (LDL r-KO) mice on a high fat diet. Expression levels of TXAS, PGIS and TP were evaluated by real-time quantitative reverse transcription PCR, and immunohistochemistry; TxA(2) and PGI(2) biosynthesis was also assayed.nnnRESULTSnAfter 8 weeks on the fat diet, aortic arches from LDL r-KO mice showed a significant increase in PGIS, TXAS, TP mRNA, TxA(2) and PGI(2) levels, when compared with controls. By contrast, after 16 weeks on the high fat diet PGIS and PGI(2) were significantly reduced, whereas TXAS and TP message and protein and TxA(2) levels were further and significantly increased in the atherosclerotic tissues when compared with the 8-week group. These changes correlated with the cellular composition of the atherosclerotic lesions.nnnCONCLUSIONSnTXAS, PGIS and TP are all present within the atherosclerotic lesion areas, their levels change during progression of atherogenesis and contribute to TxA(2) and PGI(2) formation.

Coronary CT angiography (CCTA) and advances in CT plaque imaging

The goal of this review is to highlight current advances in the non-invasive detection of clinically significant atherosclerotic disease including the so-called vulnerable plaque with computed tomography. Atherosclerotic disease encompasses stages of plaque progression, stabilization, and even regression. Traditionally, the focus of diagnostic imaging has been the detection of lumen-occluding atheroma. However, advances in our understanding of the pathophysiology of atherosclerotic plaque have shown that, in certain stages of plaque progression, plaque is “vulnerable” and able to cause acute coronary syndromes despite “non-significant” vascular occlusion at baseline. This provides a rationale to improve our non-invasive imaging technology. Presented here are improvements in soft-tissue resolution with technical advancements as well as contrast-enhancement and lately even nanotechnology-based technology which are geared to detect the clinically elusive vulnerable plaque and provide an opportunity for preventative therapy.