The role of intracoronary imaging in translational research

Abstract: Atherosclerotic cardiovascular disease is a key public health concern worldwide and leading cause of morbidity, mortality and health economic costs. Understanding atherosclerotic plaque microstructure in relation to molecular mechanisms that underpin its initiation and progression is needed to provide the best chance of combating this disease. Evolving vessel wall-based, endovascular coronary imaging modalities, including intravascular ultrasound (IVUS), optical coherence tomography (OCT) and near-infrared spectroscopy (NIRS), used in isolation or as hybrid modalities, have been advanced to allow comprehensive visualization of the pathological substrate of coronary atherosclerosis and accurately measure temporal changes in both the vessel wall and plaque characteristics. This has helped further our appreciation of the natural history of coronary artery disease (CAD) and the risk for major adverse cardiovascular events (MACE), evaluate the responsiveness to conventional and experimental therapeutic interventions, and assist in guiding percutaneous coronary intervention (PCI). Here we review the use of different imaging modalities for these purposes and the lessons they have provided thus far.Nicholas J. Montarello, Adam J. Nelson, Johan Verjans, Stephen J. Nicholls, Peter J. Psalti

Diagnostic and prognostic value of free PAPP-A in coronary artery disease – clinical studies with novel immunoassay

Complications of coronary artery disease are the number one cause of death worldwide, so identification of high-risk individuals is crucial. Pregnancy-associated plasma protein A (PAPP-A) is a candidate cardiac-risk related biomarker, which has been linked to poorer outcome in various cardiovascular patients. Especially, the free form of PAPP-A (fPAPP-A) is linked to cardiovascular events, but thus far no direct assay detecting fPAPP-A has been published. Most available assays measure total PAPP-A and are widely used in prenatal screening where high concentration changes occur. Thus, cardiac-related slight fPAPP-A changes might be undetectable with total PAPP-A assays. Also, PAPP-A is released to circulation after heparin treatment, which is a common anticoagulant used in dissolving thrombus. This might question the ability of PAPP-A to be used as a marker for haparinized patients. I n this thesis, first direct immunoassay targeting fPAPP-A was created and its analytical and clinical performance as cardiac-risk related biomarker was evaluated. The analytical performance of the fPAPP-A assay was evaluated against current guidelines. The risk of death or myocardial infarction in patients admitted to hospital due to chest pain was studied and compared to tPAPP-A and indirect fPAPP-A assays. The developed assay was also used in predicting obstructive CAD in suspected chronic CAD patients. The disease extent and severity was determined with hybrid computed tomography and positron emission tomography myocardial perfusion imaging. Correlation of heparin-induced release of fPAPP-A and atherosclerotic burden was studied in suspected chronic CAD patients. The developed assay sensitively measured fPAPP-A. The risk of death or myocardial infarction correlated with increasing circulating fPAPP-A concentration. Also, fPAPP-A in combination with contemporary cTnI further improved the riskpredictive capability. Accordingly, the fPAPP-A level was elevated in chronic CAD patients who were diagnosed with obstructive CAD. As a biomarker, fPAPP-A outperformed traditional risk factors and other evaluated biomarkers in predicting obstructive CAD. Heparin-induced release of fPAPP-A to circulation was not associated with clinical coronary atherosclerotic characteristristics observed with coronary computed tomography angiography.Suoralla menetelmällä mitattu vapaa PAPP-A diagnostisena ja ennustavana merkkiaineena sepelvaltimotaudissa Sepelvaltimotautiin liittyvät komplikaatiot ovat yleisin kuolinsyy maailmassa, jonka vuoksi korkean riskin potilaiden tunnistaminen ajoissa on tärkeää. Raskauteen liittyvä plasmaproteiini A (PAPP-A) on lupaava merkkiaine, joka on yhdistetty erilaisilla sydänpotilailla heikompaan selviytymiseen ilman sydäntapahtumia. Erityisesti PAPP-A:n vapaa muoto (fPAPP-A) on liitetty sydäntapahtumiin, mutta suoraa määritysmenetelmää fPAPP-A:lle ei ole vielä kehitetty. Useimmat määritykset mittaavat kaikkia PAPP-A:n muotoja ja niitä käytetään raskaudenaikaiseen seulontaan, jolloin pitoisuusmuutokset ovat suuria. Tällaisella määrityksellä mitattuna sydäntapahtumien yhteydessä tapahtuvat pienet fPAPP-A -muutokset saattavat jäädä huomioimatta. PAPP-A:ta vapautuu verenkiertoon myös verihyytymien liuottamiseen käytetyn hepariinilääkityksen vuoksi. Tämä saattaa kyseenalaistaa PAPP-A:n käytön merkkiaineena hepariinilääkityillä potilailla. Väitöskirjatyössä kehitettiin ensimmäinen suora fPAPP-A:ta mittaava immunomääritys. Määrityksen analyyttista toimivuutta evaluoitiin kliinisen kemian ohjeistusten mukaisesti. FPAPP-A:n käyttöä sydänkohtaukseen tai kuolemaan liitettynä merkkiaineena tutkittiin rintakivun vuoksi sairaalaan saapuneilta potilailta ja tuloksia verrattiin epäsuoralla menetelmällä mitattuun fPAPP-A:han sekä kaikkia PAPP-A:n muotoja mittaavaan määritykseen. Lisäksi, fPAPP-A:n yhteyttä ahtauttavaan sepelvaltimotautiin tarkasteltiin epäillyillä vakaaoireisilla sepelvaltimotautipotilailla. Sepelvaltimotaudin vakavuuden ja laajuuden määrittäimiseen käytettiin hybridikuvantamista, jossa hyödynnetään tietokonetomografiaa ja isotooppitutkimusta. Samoilla potilailla tutkittiin myös hepariinin vapauttaman fPAPPA:n yhteyttä sepelvaltimotaudin vaikeusasteeseen. Kehitetty määritys oli herkkä mittaamaan fPAPP-A:ta. Kohonnut fPAPP-A oli yhteydessä suurentuneeseen sydänkohtauksen tai kuoleman riskiin. Yhdistettynä sydänperäisen troponiini I:n kanssa, kyky ennustaa riskä parani entisestään. Lisäksi, ahtauttavaa sepelvaltimotautia sairastavilla potilailla oli kohonnut fPAPP-A - pitoisuus ja fPAPP-A toimi paremmin kuin perinteiset riskitekijät tai muut mitatut merkkiaineet. Hepariinin vuoksi verenkiertoon vapautunut fPAPP-A ei ollut yhteydessä selvaltimotaudin vakavuuteen tai laajuuteen

Intravascular Ultrasound

Intravascular ultrasound (IVUS) is a cardiovascular imaging technology using a specially designed catheter with a miniaturized ultrasound probe for the assessment of vascular anatomy with detailed visualization of arterial layers. Over the past two decades, this technology has developed into an indispensable tool for research and clinical practice in cardiovascular medicine, offering the opportunity to gather diagnostic information about the process of atherosclerosis in vivo, and to directly observe the effects of various interventions on the plaque and arterial wall. This book aims to give a comprehensive overview of this rapidly evolving technique from basic principles and instrumentation to research and clinical applications with future perspectives

The Natural History Investigation of In Vivo Human Coronary Endothelial Function and Atheroma Plaque Progression: Invasive Coronary Imaging Studies

It has been well documented that coronary vasoconstriction, atheroma plaque burden, and ‘vulnerable’ plaque plays a critical role in the pathogenesis of acute coronary syndrome (ACS); yet, the dynamic interaction among these factors in vivo to date have not been evaluated, particularly in the longitudinal study. In this thesis, we described a series of in vivo experiments conducted within the intact epicardial coronary tree from patients who presented with unselected clinical presentation, with the aim to explore the underlying relationship between coronary atheroma burden, plaque composition, and coronary endothelial vasoreactive function. We particularly highlight the potential role of a novel intravascular ultrasound (IVUS) platform which co-register with near infrared spectroscopy (NIRS) in delineating plaque composition. Utilizing this technology allows us to examine the evolution of both grey scale measurement and coronary plaque composition over time. Contrary to currently available imaging platforms for plaque composition, such as virtual histology IVUS or optical coherence tomography (OCT) which is predominantly qualitative, NIRS measurements are automated and quantitative, allowing ready interpretation in the catheterization lab. Of the 2 introductory chapters, chapter 1 explores the developmental history, clinical indication, and research application of IVUS in the past three decades. Chapter 2 reviews the different resistance compartments of the coronary tree and the role of various pharmacological agent in the catheterization lab. This chapter also discusses the role of salbutamol in the evaluation of coronary endothelial function. Chapter 3-5 comprise the result section of this thesis. Chapter 3 describes the effectiveness of OCT in the evaluation of epicardial coronary endothelial function. OCT is known to have superior lateral resolution when compared to other intravascular imaging modalities currently available. In this chapter, we underscore the limitation of OCT, which relies on bolus contrast injection for blood clearance from the field of view, in the invasive coronary endothelial function assessment. A vast number of coronary vasoreactive agents, including salbutamol, are largely dependent on shear stress generated by the microvascular compartment to mediate conduit vessel vasodilation. Injection of contrast bolus at high rate hence may increase the shear stress generated and impact on the reliability of vasomotor response. Chapter 4 outlines the relationship between segmental coronary endothelial dependent and independent function with atheroma plaque volume and associated lipid rich necrotic composition in unselected patients who present with either stable chest pain syndrome or ACS. Utilizing NIRS, we demonstrated that coronary endothelial independent function in response to glyceryl trinitrate (GTN) was strongly associated with atheroma plaque volume irrespective whether the patient presented with stable chest pain or ACS. To a lesser extent, we also found a weak association between plaque containing lipid rich necrotic core with coronary endothelium independent vasodilator function. It was also surprising to note the lack of association between coronary endothelial dependent function with either atheroma volume or composition. Having reviewed previous data in the literature and scrutinised our findings, we concluded that adequate dosing of any vasoreactive agent is crucial to generate the desirable and appropriate vasomotor response. Chapter 5 describes our prospective and serial imaging analysis which aimed to identify the relationship between epicardial coronary vasomotor function and change in atheroma plaque volume and necrotic lipid laden core plaque, over time. Several key insights emerge from this experiment. We identified that epicardial coronary endothelial function seems to influence the progression of plaque volume and its composition in a unique manner. Whilst coronary endothelial dependent function was found to mediate plaque composition progression, the segmental coronary endothelial independent function was more associated with atheroma volume progression. Similar to previous observations, we also found baseline plaque burden and positive remodelling to influence formation of future fibroatheroma. Furthermore, baseline NIRS derived LCBI was independently predictive of both lipid core progression and plaque volume progression. Taken together, these findings underline the role of atheroma structure-vessel function in mediating the mechanism of atheroma plaque progression in intact human epicardial coronary tree and may provide an important prognostic tool in identifying patients who are at risk of developing future coronary event above and beyond the established cardiovascular risk predictive tools.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201

Coronary Angiography

In the intervening 10 years tremendous advances in the field of cardiac computed tomography have occurred. We now can legitimately claim that computed tomography angiography (CTA) of the coronary arteries is available. In the evaluation of patients with suspected coronary artery disease (CAD), many guidelines today consider CTA an alternative to stress testing. The use of CTA in primary prevention patients is more controversial in considering diagnostic test interpretation in populations with a low prevalence to disease. However the nuclear technique most frequently used by cardiologists is myocardial perfusion imaging (MPI). The combination of a nuclear camera with CTA allows for the attainment of coronary anatomic, cardiac function and MPI from one piece of equipment. PET/SPECT cameras can now assess perfusion, function, and metabolism. Assessing cardiac viability is now fairly routine with these enhancements to cardiac imaging. This issue is full of important information that every cardiologist needs to now

The Prevention and Treatment of Atherosclerosis

This special issue of JCM ‘The Prevention and Treatment of Atherosclerosis’ will walk the Readers across novel diagnostic achievements in atherosclerosis and contemporary actions towards optimizing therapy.Everything begins with diagnosis. Accurate diagnostic tools and tests are of utmost importance. Contemporary research on microparticles, non-coding RNAs, proteomic characterization, …, offers detailed molecular characteristics of athero-thrombosis.Prevention is equally important as treatment. The impact of eating habits in prophylaxis of many pathologies, including cardiovascular disease has been documented.Then new pharmacological agents. Managing hypercholesterolemia with PCSK9 inhibitors, shown great potential in efficient lipid lowering to achieve LDL-C treatment goals, as well as reduction in cardiovascular mortality and morbidity.However, therapeutic goals accomplishment requires supervision. Arising number of data support that cardiovascular risk prediction can be improved with imaging modalities displaying atheroma: carotid plaque ultrasonography, coronary calcium score, intravascular ultrasonography, and optical coherent tomography or many others.As atherosclerosis is a progressive disease, it comes the time for more radical management, including endovascular and surgical intervention. There is field for new stent and equipment technologies, new surgical and endovascular techniques, supervision of endovascular procedures with IVUS, OCT, functional flow assessment or cell therapy.From diagnosis to risk stratification, elaborated prevention models, finally to modern and optimized therapeutic intervention

CT coronary angiography: validation and clinical implementation

Coronary heart disease is the most frequent cause of death in the Western society.1 Coronary arteriography, a technique to visualize morphologic characteristics of the coronary arteries, has provided an objective basic standard of diagnosis and fundamentally changed our approach to the patient with suspected coronary artery disease