Myocardial Magnetic Resonance Imaging in the characterization of Chronic Coronary
Syndromes
van Dijk, Randy
DOI:
10.33612/diss.147542794
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Publication date:
2020
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
van Dijk, R. (2020). Myocardial Magnetic Resonance Imaging in the characterization of Chronic Coronary
Syndromes. University of Groningen. https://doi.org/10.33612/diss.147542794
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General introduction
Cardiac disease remains the leading cause of mortality worldwide with an estimated 18 million deaths in 2016 and an expected increase to nearly 24 million by 2030 [1, 2]. Coronary Artery Disease (CAD) is a major contributor to the cardiovascular related mortality rate [3]. The recently updated European Society of Cardiology (ESC) guidelines (2019) on the diagnosis and treatment of CAD distinguish two main disease entities based on clinical presentation: Acute Coronary syndromes and Chronic Coronary syndromes (CCS) [4]. The natural history of CCS follows a cascade from subclinical alterations to established significant epicardial coronary disease and is irrevocably related to the risk of Major Adverse Cardiac Events (MACE) which increases gradually over time as the disease progresses.
Invasive Coronary angiography
In clinical practice, the current reference standard for diagnosing relevant CAD is Invasive Coronary Angiography (ICA) combined with Functional measurements such as Fractional Flow Reserve (FFR) and instantaneous wave Free Ratio (iFR) when appropriate [5]. However, in an elective setting the proportion of ICA procedures showing obstructive CAD is relatively low at 40-60% [6]. Furthermore, ICA suffers from the inherent risks of invasive procedures ranging from subtle access hematomas to arteriovenous fistulas, coronary dissections, embolisms, myocardial infarctions, stroke or even death [7] with the more serious complications occurring in 0.05-1% of all ICA procedures [8].
Non-invasive imaging
Non-invasive imaging techniques such as Single Photon Emitting Computed Tomography (SPECT), Positron Emitting Tomography (PET), Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) show potential to be used as tools for the rule-in and rule-out of CAD. The tomography-based techniques all share the disadvantage of inherent exposure to radiation. However, MRI can provide valuable information in every step of the CCS cascade on cardiac structure, function, perfusion and fibrosis at high accuracy [9] without exposing the patient to radiation. Even subtle (subclinical) alterations in cardiac function can be assessed with techniques such as strain analysis [10]. Accurate information on cardiac function, perfusion and fibrosis can be acquired using cine, first pass perfusion and Late Gadolinium Enhancement (LGE) imaging, respectively and these acquisitions can be easily combined in one examination. In the clinical setting of ischemic cardiomyopathy, myocardial perfusion
and viability evaluation using first pass perfusion and LGE imaging techniques both show high diagnostic and prognostic impact [9, 13, 14]. In patients with CCS, CMR shows the potential to aid in patient stratification for further invasive treatment.
Stress adequacy
CMR can be used to assess the functional consequences of CCS by evaluating myocardial perfusion during vasodilator induced hyperemia. One of the major components leading to successful and accurate stress first-pass perfusion imaging is achieving adequate hyperemia. For CMR perfusion hyperemia is mostly induced pharmaceutically. Adequate stress is essential to unmask regions of the myocardium with relative hypo-perfusion as an indicator of obstructive CCS The most widely used stressor agents to achieve hyperemia and mimic cardiac stress are adenosine and regadenoson. Both cause coronary hyperemia by binding to the cardiac adenosine A2A-receptor [15, 16]. Whereas adenosine is a short acting and nonspecific adenosine receptor agonist (with a chance of bronchospasm as a side effects due to binding to the adenosine A2B-receptor) [15], regadenoson is a longer acting specific A2A-receptor agonist. The advantage of regadenoson is the fact that enables potent hyperemia while it lacks the side-effects of adenosine such as bronchospasms. This makes regadenoson the preferred vasodilator agent in patient with a history of pulmonary hypersensitivity (Chronic Obstructive Pulmonary Disease (COPD) or asthma) [17, 18]. Caffeine is a well-known adenosine receptor antagonist and a possible cause of false negative CMR perfusion results in patients with suspected obstructive CCS [19]. Patients undergoing vasodilator stress examinations are usually instructed to withhold consumption of caffeine containing beverages and foods for 12-24 hours before the examination. However, due to the profound and widespread cultural integration of caffeine ingestion and the addictive nature of the substance, adherence to these instructions is often doubtful, resulting in false negative examinations. This clinical dilemma has sparked the search for objective markers for stress adequacy to reduce the risk of false negative perfusion results due to insufficient stress and by this avoid misclassification and undertreatment of patients with obstructive CCS. The distinct magnetic properties of different tissue components and contrast agents with magnetic properties (usually Gadolinium based) provide potential for CMR to be used for tissue characterization [11, 12, 20]. Cardiac dedicated ECG triggered T1-maps provide pixel wise quantitative information on T1-values of the myocardium [21, 22]. The basis for T1-mapping is the variation in longitudinal magnetization due to differences in tissue composition. Myocardial diseases such as myocardial edema, extracellular matrix expansion and myocardial fibrosis or necrosis show an increase in native T1-values compared to healthy myocardium [12]. The T1-maps
maps can be used for identification and differentiation of a wide range of myocardial diseases that result in changes in the myocardium affecting T1 values, as mentioned before, including hypertrophic/dilated cardiomyopathy, myocarditis and amyloidosis [23-25]. Native T1-mapping also enables the quantitative assessment of changes in myocardial water content from rest to stress during perfusion CMR. This sensitivity to changes in myocardial water contact shows potential for application in the assessment of stress adequacy and ischemia assessment for the clinical evaluation of patients with possible obstructive CCS. The use of native T1-maps for differentiation between normal, perfusion defects and fibrosis in ischemic cardiomyopathy might allow for a fast and contrast agent free assessment of cardiac ischemia.
Late gadolinium Enhancement
In infarcted regions the micro vascular structure and cardiomyocytes will be partly replaced by fibrotic tissue [27]. When a Gadolinium based contrast agent is administered it will slowly seep into the interstitial space of damaged myocardium due to micro vascular leakage. The contrast agent will remain there for a prolonged time due to binding to large proteins and the absence of the micro vascular bed. Both the wash in and wash out of the contrast agent will be slower in infarcted myocardium as compared to both normal and ischemic myocardial tissue. The presence of endocardial or transmural enhancement due to accumulated contrast 10-15 minutes after contrast administration is indicative of myocardial infarction (MI). This Late Gadolinium Enhancement (LGE) will usually show a logical pattern following a coronary territory. Cardiac viability assessment using LGE has prognostic implications in patients with CCS and can be used to guide treatment decisions.
For the assessment of conventional LGE images it is essential that the myocardial signal is adequately nulled [28, 29]. This is needed to assure maximal contrast between healthy myocardial tissue and fibrotic tissue. The most widely used LGE series are dependent on nulling the myocardium by acquiring a single slice inversion time scout (TI-scout) before acquiring the LGE short axis stack and long axis images. This TI-scout provides a sample of the contrast between healthy and infarcted myocardium at varying TI-times. Based on the TI-scout, the TI is selected on which the myocardium appears the most black. This TI is used to subsequently acquire the LGE images. Selecting the appropriate TI for LGE is subjective and highly dependent on user experience making the method prone to errors resulting in an increased risk of either false negative or false positive interpretations. Recently, a new Gadolinium enhancement technique developed to reduce motion artifacts by more efficiently registering individual T1-map
measurements acquired with Modified Look Locker Inversion Recovery (MOLLI) images was introduced in which synthetic phase sensitive inversion recovery (IR) images were generated based on post-Gadolinium T1 mapping pixel values [30-32]. This MOLLI based technique not only allows for fast T1 mapping of the myocardium, but also generate synthetic IR images which can be calculated retrospectively at any inversion time (TI) producing images containing excellent delayed enhancement contrast [33]. Current guidelines recommend a waiting period of 8-12 minutes after the last bolus of contrast agent before acquiring the LGE images to assure an adequate balance between the wash in and washout. This waiting period makes current CMR protocols tedious and is one of the limiting factors for the broad application of the technique in common clinical practice. The hyperemic effects of vasodilator agents might allow a shortening of the waiting period before acquiring LGE images and by this shorten total acquisition time. To summarize, CMR has the potential to provide a wealth of information on cardiac structure, function, tissue characterization and perfusion which are relevant to assess the presence and severity of CCS. The current clinical protocols show room for improvement through better objectification of stress adequacy, decreasing total acquisition time and/ or need for Gadolinium administration.
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Outline of thesis
This thesis focuses on the potential of Cardiac Magnetic Resonance Imaging in the characterization of CCS. The clinical application of several relatively new CMR acquisition techniques and analysis methods for the assessment of CCS at different phases of the disease process will be explored such as strain analysis, native T1-mapping and synthetic LGE.
Part I of this thesis focuses on the functional analysis of subclinical alterations in
myocardial tissue with cine imaging and strain analysis. In chapter 2 a nested case control
study is presented which focused on the impact of the classical modifiable cardiac risk factor smoking on cardiac structure and function in patients free from established CCS. In part II the potential of CMR for the assessment of perfusion defects in the setting
of suspected stable CAD was explored. In chapter 3 a systematic review of the available
data on the effects of recent caffeine intake on myocardial perfusion measurements across different non-invasive imaging modalities is presented. In chapter 4 and 5 the potential
of native T1-mapping (myocardial and splenic) and the visual Splenic Switch Off sign (SSO) for the assessment of stress adequacy in patients suspected of obstructive CCS and at high risk of false negative perfusion results because of recent caffeine intake was explored. In chapter 4 suggested CMR based indicators of stress adequacy were studied
for their ability to distinguish between patients with and without recent caffeine intake. The most promising biomarker for stress adequacy (myocardial T1-reactivity) was used to explore the differences between the effects of recent coffee intake on either adenosine or regadenoson induced hyperemia in chapter 5. A meta-analysis on the diagnostic accuracy
of both semi-quantitative and quantitative first pass CMR perfusion analysis is presented in chapter 6.
Part III of this thesis will focus on the potential of CMR for tissue characterization with native
T1-mapping and Gadolinium Enhancement in patients with suspected CCS. In chapter 7
the use of native T1-mapping for cardiac tissue characterization by discriminating between normal, ischemic and infarcted myocardium is explored. In chapter 8 a new synthetic
early post-contrast T1-map based technique to assess cardiac fibrosis was compared to conventional TI-scout based single shot LGE.
The research presented in this thesis has laid the foundation for the final part of this thesis.
Part IV chapter 9 focuses on the rationale and design of the REPLACE-IT trial. In this
prospective trial the application of CMR and Coronary CT angiography (CCTA) in the evaluation and management of patients with suspected CAD will be studied.
