University of Groningen
Myocardial Magnetic Resonance Imaging in the characterization of Chronic Coronary
Syndromes
van Dijk, Randy
DOI:
10.33612/diss.147542794
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2020
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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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10
This thesis focused on the application of various CMR imaging techniques in the characterization of chronic coronary syndromes along the whole ischemic cascade with a special focus on improving diagnostic accuracy and protocol efficiency. MRI offers a wide range of possible clinical applications to assess cardiac disease. The multi-parametric possibilities of CMR to not only study cardiac function but, amongst other things, also cardiac structure, perfusion and fibrosis make it an excellent modality for clinical assessment of patients with CCS. It is essential to optimize the accuracy and efficiency of the individual CMR protocol components to assure optimal use of the technique. In the assessment of CAD two key influencing factors for the accuracy of the diagnostic test are: stress adequacy for perfusion and optimal GE for scar imaging.
Subclinical alterations
In Part I chapter 2 cardiac structure and function in smokers and non-smokers were
compared. Active tobacco smoking had a significant adverse effect on both LV and RV end-systolic volume, ejection fraction and LV peak global strain. These results show that smoking causes subclinical alterations in cardiac structure and function. These results are in line with previous studies focusing on the influence of cardiac risk factors on cardiac structure and function [1]. The toxic metabolites of tobacco smoking possibly cause (subclinical) epicardial coronary artery disease or coronary micro vascular diseases which ultimately result in subclinical alterations in cardiac structure and function.
Stress adequacy
CMR myocardial perfusion was the focus of part II. In chapter 3 the available data
on the effects of caffeine on myocardial perfusion measurements was summarized in a systematic review. Several studies indicate a significant effect of caffeine on myocardial perfusion measurements across different imaging modalities (SPECT, PET, ICA and CMR) [2]. The studies focusing on PET, ICA and CMR all showed an effect of caffeine on myocardial perfusion measurements when adenosine was the stressor agent of choice. It appears that caffeine ingestion negatively affects the response to adenosine, resulting in a lower hyperemic response.
Achieving adequate myocardial hyperemia is essential for the assessment of myocardial ischemia. In clinical practice the hemodynamic responses of the patient during stressor agent administration such as a drop in blood pressure or increase in heart rate is used as a check for achieving adequate hyperemia. However, these hemodynamic parameters only have limited correlation with the myocardial perfusion response [3]. Caffeine, a
Chapter 10
well-known addictive substance with widespread territories of consumption, threatens to influence the diagnostic performance of myocardial perfusion measurements by antagonizing the cardiac vasodilatory effects of the most frequently used stressor agents. False negative CMR perfusion results due to causes such as recent caffeine consumption should be prevented at all cost to assure adequate patient stratification in patients with suspected CCS. In chapter 4 of this thesis several potential indicators
of stress adequacy were assessed. Our results show that the visual Splenic Switch Off sign (SSO) and splenic T1-mapping failed to predict recent caffeine intake. These results are in line with a recent publication showing no difference in both the presence of the SSO as well as splenic perfusion ratio (SPR) irrespective of recent caffeine intake [4]. Our results showed that myocardial T1-reactivity was significantly lower in patients with recent caffeine intake as compared to patients without recent caffeine intake. Myocardial T1-reactivity was used as the most promising biomarker for stress-adequacy in chapter 5. In this chapter the effects of recent caffeine intake on either
adenosine or regadenoson induced hyperemia was studied. Our results show that recent caffeine intake significantly influences the myocardial T1-reactivity in patients undergoing adenosine perfusion CMR, whereas the T1-reactivity in patients undergoing regadenoson perfusion CMR appears to be unaffected by recent caffeine intake. A recent publication by Seitz et al. addresses the ongoing discussion about the effect of caffeine on myocardial perfusion measurements [4]. The authors performed adenosine perfusion CMR and measured semi-quantitative perfusion. They report a significant inter-patient difference between caffeine naïve and repeated CMR perfusion after caffeine ingestion. The result was mainly driven by a reduced Myocardial Perfusion Reserve Index (MPRI) in remote myocardium. MPRI in ischemic segments was not significantly different between caffeine naïve and repeated CMR after caffeine ingestion. Current clinical decision making with CMR perfusion analysis is still predominantly based on visual analysis. For the visual analysis adequate contrast differences between ischemic and remote myocardium is essential. Attenuation of remote myocardial perfusion by caffeine decreases this contrast difference and increases the risk of false negative CMR interpretations. Data on the relationship between caffeine ingestion and the response to regadenoson are scarce. Zhao et al. reported that peak increase of myocardial blood flow was not influenced by caffeine in conscious dogs. They did report on a dose-dependent reduction in duration of vasodilation by regadenoson due to caffeine administration in dogs [5]. Tejani et al. reported discrepant findings by reporting a significant decrease in the amount of ischemic segments after caffeine ingestion before regadenoson SPECT [6]. An explanation for these discrepant findings might lie in the nature of the SPECT analysis, which is primarily based on qualitative analysis of contrast differences. Caffeine
General discussion and summary
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ingestion might attenuate the vasodilator effect in remote myocardium and cause a decrease in contrast difference between diseased and normal myocardium, resulting in a downscaling of the examination to less extensive. With native T1-mapping changes in MBV can be assessed. This analysis is probably more sensitive and provides a better insight in the mechanism as compared to qualitative visual analysis.
To maintain the high diagnostic accuracy of CMR perfusion in the evaluation of patients with CCS it is crucial to extensively instruct patients to withhold from caffeine ingestion a minimal of 24 hours before the CMR examination. In case of suspected recent caffeine intake rescheduling of the procedure or switching to regadenoson as the preferred vasodilator agent should be considered. T1-reactivity can be calculated relatively simple by placing a single ROI in a mid-ventricular infero-septal segment and could be used as a quality check for adequate hyperemia in case of normal visual interpretation of perfusion images or suspicion of recent ingestion of substances containing caffeine. Reported normal ranges for T1-reactivity at 1.5T range from 2.6% using MOLLI to 6.2% using a shortened MOLLI (shMOLLI) sequence [7].
Myocardial perfusion
The meta-analysis in chapter 6 evaluated the diagnostic accuracy of semi-quantitative
and quantitative CMR perfusion analysis in patients with suspected CCS. CMR first pass perfusion has high diagnostic accuracy for the assessment of CAD [8]. However, the visual analysis of CMR first pass perfusion is error prone due to, amongst other things, the subjective nature and lack of consensus on definition of perfusion deficits. Semi-quantitative and quantitative analysis have the potential to improve the diagnostic performance of CMR first pass perfusion by providing a more objective measure of myocardial perfusion. In our meta-analysis the semi-quantitiative upslope and more complex quantitative deconvolution models showed comparable diagnostic accuracy in our meta-analysis. Most semiquantitative and quantitative CMR perfusion analysis are still quite labour intensive, time consuming and error prone due to reliability on correct contour placement. However, more sophisticated acquisition and post processing techniques have been designed that allow for the generation of quantitative flow maps that show potential for clinical implementation and provide a more standardizable analysis of CMR perfusion [9-12]. However, calculation of true quantitative myocardial blood flow using CMR perfusion is extremly difficult due to, amongst other things, the non-linear relationship between Gadolinium concentration and Signal intensity. At higher concentrations the intensity curves will become saturated. The high concentration of Gadolinium in the blood pool will mainly cause oversaturation of the AIF due to high
Chapter 10
T2* decay. The oversaturated AIF is subsequently used to correct the TAC curve and will cause a systematic overestimating of MBF. Attempts to correct for this phenomenon focus on acquisition techniques such as dual sequence and dual bolus CMR perfusion. The dual bolus technique attempts to correct for the oversaturation by acquiring images for the AIF after the administration of a low dose contrast bolus followed by a separate acquisition after a standard dose for the TAC curves. An important limitation of this technique is the temporal separation between the AIF and TAC acquisitions as it does not take into account the hemodynamic changes in between the acquisitions. The dual sequence technique combines a low resolution AIF acquisition with a high resolution TAC acquisition. The low resolution AIF curve is less sensitive for T2* decay and oversaturation reducing the underestimation of MBF. These quantitative flow maps show potential to reduce the subjectivity in CMR perfusion analysis and could be more sensitive to subtle changes in perfusion as compared to visual perfusion analysis. The values for myocardial perfusion still depend significantly on a list of assumptions and the deconvolution model of choice. These deconvolution models make assumptions of varying complexity to model true myocardial perfusion. The lack of validation and standardization of these quantitative perfusion techniques limits current possibilities for clinical implication.
Tissue characterization
In Chapter 7 the potential of native T1-mapping to provide a contrast free assessment
of myocardial perfusion and fibrosis was explored using a MOLLI based native T1-mapping technique. The main aim of this study was to assess native T1 characteristic in specific regions of interest with relative hypo perfusion or LGE indicative of infarction and compare these to normal myocardium. Our results show that T1-reactivity is significantly lower in both ischemic and infarcted myocardium when compared to normal myocardium. Furthermore, native T1-values in infarcted myocardium were significantly higher in infarcted as compared to normal and ischemic myocardium. Our findings were consistent with previous research by Liu et al. focusing on shMOLLI based native T1-mapping validating the concept of native stress T1-mapping on a different scanner and with a different T1-mapping sequence [13,14]. In ischemic regions the myocardium is probably already at maximal vasodilation without any additional capacity to increase vasodilation under stressor agents. The concept of stress T1-mapping was further assessed recently by Bohnen et al. This study focused on regadenoson perfusion CMR and performed both ROI specific and segmental analysis of the native T1-maps [15]. They were able to provide additional confirmation of the concept of stress T1-mapping after regadenoson perfusion CMR by showing distinct differences in native T1 patterns
General discussion and summary
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between normal, ischemic and infarcted myocardium by using focal ROIs that were copied from perfusion images to T1 maps as reference technique. Using this approach, the real incremental value to current clinical practice is lacking because contrast media administration is still necessary for the first pass perfusion and LGE images. For a truly contrast free assessment of myocardial perfusion defects and fibrosis stress T1-mapping should be able to indicate segmental differences. By assessing the performance of segmental T1-mapping, Bohnen et al. highlighted an important limitation of the technique. The diagnostic performance of blinded segmental T1-mapping analysis was far inferior (AUC 0.68) as compared to the perfusion and LGE guided ROI method (AUC 0.85). This indicated that when applying the 16 segment AHA segmentation model stress T1-mapping performs poorly probably due to the heterogeneity of tissue within one segment (mixture of normal, ischemic and/or scar) resulting in averaging of the values within the segment. Normal, ischemic and infarcted myocardium show different native T1-mapping patterns. However, the technique is insufficiently developed for use in clinical practice as a true Gadolinium free segmental analysis of myocardial perfusion defects and fibrosis in patients with CCS. Future research should focus on the improvement of these limitations.
In chapter 8 a new post contrast T1-map based method for myocardial scar tissue
assessment in patients with suspected CCS was compared to conventional single shot LGE. In line with previous studies synthetic LGE images had a high accuracy as compared to conventional single show LGE [16, 17]. The synthetic images can be used to decrease the subjective selection of TI time and improve image quality. In our study 5 short axis (SA) slices were acquired with the T1-mapping technique. Acquiring more SA slices would significantly increase both acquisition time and the amount of breath holds. A high proportion of patients would have probably had trouble with maintaining proper breath holds with significant negative effects on image quality. In clinical practice a minimum of 10-14 short axis slices are usually required with optional additional long axis views or stacks to assure optimal spatial coverage. Achieving the same spatial coverage at acceptable acquisition time is challenging with the synthetic technique at the moment, strongly limiting the potential clinical use of the technique. However, synthetic LGE images still have an important possible application in clinical practice. The images could be used to decrease subjectivity and increase LGE image quality in a hybrid approach. The use of synthetic T1-map based scouts in combination with a fast single shot LGE technique showed promising results in a study by Gassenmeier et al. Compared to the conventional TI-scout, the use of a synthetic T1-map based scout improved both qualitative and quantitative image quality of the single shot LGE images [18].
Chapter 10
Future perspectives
The proportion of patients with obstructive Coronary Artery Disease during invasive coronary angiography is low (around 40% of patients) even when liberal criteria (diameter stenosis
>
50%) are used [19]. This implies that the clinical consequences of revascularization are even lower. Apparently, the real-life selection of patients referred for ICA continues to be suboptimal and a more informative non-invasive diagnostic algorithm is required to be applied to the real-life referrals for ICA. Several noninvasive imaging techniques show potential in the evaluation of CAD and are recommended in intermediate risk patients [20, 21]. A combination of high quality Computed Tomography Angiography (CTA) and multi-parametric information on myocardial function, perfusion and fibrosis with Cardiac Magnetic Resonance (CMR) perfusion might be a pragmatic approach to guide real-life referrals for ICA. This future perspective is the main focus of the ongoing REPLACE-IT trial of which the design paper is included in this thesis.Conclusion
This thesis focused on CMR image techniques in the characterization of coronary syndromes. CMR show great potential for clinical application in CCS from the subclinical to clinical stage. Several key components of the accuracy and efficiency of the diagnostic tests should be safeguarded. Caffeine ingestion prior to adenosine perfusion CMR should be avoided. T1-reactivity can aid by providing a biomarker of stress adequacy. Regadenoson is a valid substitute for adenosine in case of suspected recent caffeine ingestion. Synthetic T1-map based images can aid by improving optimal GE for LGE imaging.
General discussion and summary
185
References
1. Petersen SE, Sanghvi MM, Aung N, Cooper JA, Paiva JM, Zemrak F, Fung K, Lukaschuk E, Lee AM, Carapella V, Kim YJ, Piechnik SK, Neubauer S. The impact of cardiovascular risk factors on cardiac structure and function: Insights from the UK Biobank imaging enhancement study. PloS One 2017 Oct 3;12(10):e0185114
2. van Dijk R, Ties D, Kuijpers D, van der Harst P, Oudkerk M. Effects of Caffeine on Myocardial Blood Flow: A Systematic Review. Nutrients. 2018 Aug 13;10(8)
3. Mishra RK, Dorbala S, Logsetty G, Hassan A, Heinonen T, Schelbert HR, et al. Quantitative relation between hemodynamic changes during intravenous adenosine infusion and the magnitude of coronary hyperemia: Implications for myocardial perfusion imaging. J Am Coll Cardiol 2005;45(4):553–8
4. Seitz A, Kaesemann P, Chatzitofi M, Löbig S, Tauscher G, Bekeredjian R, Sechtem U, Mahrholdt H, Greulich S. Impact of caffeine on myocardial perfusion reserve assessed by semiquantitative adenosine stress perfusion cardiovascular magnetic resonance. Journal of Cardiovascular Magnetic Resonance 2019 24;21(1):33
5. Zhao G, Messina E, Xu X, Ochoa M, Sun HL, Leung K, Shryock J, Belardinelli L, Hintze TH. 6. Caffeine attenuates the duration of coronary vasodilation and changes in hemodynamics
induced by regadenoson (CVT-3146), a novel adenosine A2A receptor agonist. J Cardiovasc Pharmacol 2007 49(6):369-75
7. Tejani FH, Thompson RC, Kristy R, Bukofzer S. Effect of caffeine on SPECT myocardial perfusion imaging during regadenoson pharmacologic stress: a prospective, randomized, multicenter study. Int J Cardiovasc Imaging. 2014 Jun;30(5):979-89
8. Piechnik SK, Neubauer S, Ferreira VM. State-of-the-art review: stress T1 mapping-technical considerations, pitfalls and emerging clinical applications. MAGMA. 2018 31(1):131-141 9. Takx RA, Blomberg BA, El Aidi H, Habets J, de Jong PA, Nagel E, Hoffmann U, Leiner T.
Diagnostic accuracy of stress myocardial perfusion imaging compared to invasive coronary angiography with fractional flow reserve meta-analysis. Circ Cardiovasc Im 2015
10. Kellman P, Hansen MS, Nielles-Vallespin S, Nickander J, Themudo R, Ugander M, Xue H. Myocardial perfusion cardiovascular magnetic resonance: optimized dual sequence and reconstruction for quantification. J Cardiovasc Magn Reson. 2017 19(1):43
11. Henrik Engblom, Hui Xue, Shahnaz Akil, Marcus Carlsson, Cecilia Hindorf, Jenny Oddstig, Fredrik Hedeer, Michael S. Hansen, Anthony H. Aletras, Peter Kellman, and Håkan Arheden. Fully quantitative cardiovascular magnetic resonance myocardial perfusion ready for clinical use: a comparison between cardiovascular magnetic resonance imaging and positron emission tomography. J Cardiovasc Magn Reson. 2017; 19: 78.
12. Ishida M, Schuster A, Morton G, Chiribiri A, Hussain S, Paul M, Merkle N, Steen H, Lossnitzer D, Schnackenburg B, Alfakih K, Plein S, Nagel E. Development of a universal dual-bolus injection scheme for the quantitative assessment of myocardial perfusion cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2011 13:28
13. Sánchez-González J, Fernandez-Jiménez R, Nothnagel ND, López-Martín G, Fuster V, Ibañez B. Optimization of dual-saturation single bolus acquisition for quantitative cardiac perfusion and myocardial blood flow maps. J Cardiovasc Magn Reson. 2015 17:21
14. Liu A, Wijesurendra RS, Francis JM, Robson MD, Neubauer S, Piechnik SK, Ferreira VM.
Chapter 10
Adenosine Stress and Rest T1 Mapping Can Differentiate Between Ischemic, Infarcted, Remote, and Normal Myocardium Without the Need for Gadolinium Contrast Agents. JACC Cardiovasc Imaging. 2016 Jan;9(1):27-36
15. Liu A, Wijesurendra RS, Liu JM, Greiser A, Jerosch-Herold M, Forfar JC, Channon KM, Piechnik SK, Neubauer S, Kharbanda RK, Ferreira VM. Gadolinium-Free Cardiac MR Stress T1-Mapping to Distinguish Epicardial From Microvascular Coronary Disease. J Am Coll Cardiol. 2018 Mar 6;71(9):957-968
16. Bohnen S, Prüßner L, Vettorazzi E, Radunski UK, Tahir E, Schneider J, Cavus E, Avanesov M, Stehning C, Adam G, Blankenberg S, Lund GK, Muellerleile K. Stress T1-mapping cardiovascular magnetic resonance imaging and inducible myocardial ischemia. Clin Res Cardiol. 2019 108(8):909-920
17. Varga-Szemes A, van der Geest RJ, Spottiswoode BS, Muscogiuri G, De Cecco CN, Suranyi P, Rehwald WG, Schoepf JU. Quantification of myocardial late gadolinium enhancement using synthetic inversion recovery imaging. J Cardiovasc Magn Reson 2015; 17(Suppl 1): O8. 18. Varga-Szemes A, van der Geest RJ, Schoepf UJ, Spottiswoode BS, De Cecco CN, Muscogiuri
G, Wichmann JL, Mangold S, Fuller SR, Maurovich-Horvat P, Merkely B, Litwin SE, Vliegenthart R, Suranyi P. Effect of inversion time on the precision of myocardial late gadolinium enhancement quantification evaluated with synthetic inversion recovery MR imaging. Eur Radiol 2017 Aug;27(8):3235-3243
19. Gassenmaier S, van der Geest RJ, Schoepf UJ, Suranyi P, Rehwald WG, De Cecco CN, Mastrodicasa D, Albrecht MH, De Santis D, Lesslie VW, Ruzsics B, Varga-Szemes A. Quantitative inversion time prescription for myocardial late gadolinium enhancement using T1-mapping-based synthetic inversion recovery imaging: reducing subjectivity in the estimation of inversion time. Int J Cardiovasc Imaging 2018 34(6):921-929
20. Patel MR, Peterson ED, Dai D, Brennan JM, Redberg RF, Anderson HV, Brindis RG, Douglas PS. Low diagnostic yield of elective coronary angiography. N Engl J Med 2010
21. Mordi IR, Badar AA, Irving RJ, Weir-McCall JR, Houston JG, Lang CC. Efficacy of noninvasive cardiac imaging tests in diagnosis and management of stable coronary artery disease. Vasc Health Risk Manag 2017
22. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, Prescott E, Storey RF, Deaton C, Cuisset T, Agewall S, Dickstein K, Edvardsen T, Escaned J, Gersh BJ, Svitil P, Gilard M, Hasdai D, Hatala R, Mahfoud F, Masip J, Muneretto C, Valgimigli M, Achenbach S, Bax JJ, ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC). Europ Heart J 2019
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11
This thesis focused on the potential of cardiac Magnetic Resonance Imaging in the characterization of CCS. CCS are still the main cause of morbidity and mortality worldwide. The diagnosis of the different stages of CCS has important clinical consequences. CMR can provide information on myocardial tissue along the whole spectrum of CCS, ranging from subtle (sub-)clinical alteration to ischemia and infarction.
Subclinical alterations
Tobacco smoking is an important established modifiable cardiac risk factor. However, data on the effects of tobacco smoking on cardiac structure and function is scarce. In
chapter 2 we compared cardiac structure and function in smokers and non-smokers.
Tobacco smoking has a significant adverse effect on both LV and RV end-systolic volume, ejection fraction and LV peak global strain. These results show that CMR is a sensitive tool that can detect subclinical alterations in cardiac structure and function caused by smoking.
Myocardial perfusion
In part II we report on the potential of CMR for assessment of myocardial perfusion
in patients with suspected CCS. In chapter 3 we reviewed the available literature on
the possible influence of caffeine on myocardial perfusion measurements. Caffeine intake had a significant negative effect on both dipyridamole and adenosine induced hyperemia, across different perfusion modalities/measurements. The negative impact of caffeine ingestion on the hyperemic effect causes an increased risk of false negative scan interpretations. In patients with suspected CCS it is essential to prevent misclassification due to false negative scan results as these misclassifications will cause possible undertreatment of patients. Caffeine intake should be discouraged in the 12-24 hours before the examination. However, the widespread and strong cultural integration of caffeine consumption makes the adherence to this recommendation difficult. In
Chapter 4 and 5 we focused on patients at high risk of false negative perfusion results
due to self-reported recent caffeine intake before clinically scheduled CMR perfusion in patients with suspected CCS. In chapter 4 we investigated several potential indicators
of stress adequacy. Our results show that the visual Splenic Switch Off sign (SSO) and splenic T1-mapping failed to predict recent caffeine intake. Myocardial T1-reactivity was significantly lower in patients with recent caffeine intake as compared to patients without recent caffeine intake. The myocardial T1-reactivity was used as a biomarker for stress-adequacy in chapter 5. In this chapter we assessed the effects of recent caffeine
intake on either adenosine or regadenoson induced hyperemia. Our results show that recent caffeine intake significantly influences the myocardial T1-reactivity in patients
Chapter 11
undergoing adenosine perfusion CMR, whereas the T1-reactivity in patients undergoing regadenoson perfusion CMR appears to be unaffected by recent caffeine intake. Caffeine ingestion prior to vasodilator perfusion CMR should be discouraged. In case of suspected recent caffeine ingestion, patients scheduled for adenosine perfusion CMR should be re-scheduled or the clinician should switch to regadenoson as the vasodilator agent of choice to prevent misclassification due to false negative scan results in patients with suspected CCS.
The meta-analysis in chapter 6 evaluated the diagnostic accuracy of semi-quantitative
and quantitative CMR perfusion analysis in patients with suspected CCS. CMR first pass perfusion has high diagnostic accuracy for the assessment of CAD [8]. However, the visual analysis of CMR first pass perfusion is error prone due to, amongst other things, the subjective nature and lack of consensus on definition of perfusion deficits. Semi-quantitative and Semi-quantitative CMR perfusion analysis are still quite labour-intensive, time consuming and error prone due to reliability on correct contour placement and show no incremental diagnostic accuracy on top of visual analysis. The lack of validation and standardization of these semi-quantitative perfusion techniques limits current clinical implication.
Tissue characterization
Part III of this thesis focused on the potential of CMR for tissue characterization with
native T1-mapping and Late Gadolinium Enhancement in patients with suspected CCS. In Chapter 7 we focused on the potential of differentiating normal, ischemic and
infarcted myocardium using native T1-mapping. Our results show that T1-reactivity is significantly lower in both ischemic and infarcted myocardium when compared to normal myocardium. Furthermore, native T1-values in infarcted myocardium were significantly higher in infarcted as compared to normal and ischemic myocardium. In
Chapter 8 we compared a new post contrast T1-map based method for myocardial scar
tissue assessment to conventional single shot Late Gadolinium Enhancement imaging (LGE). We report that early synthetic post contrast T1-map based LGE images can accurately depict myocardial fibrosis when compared to conventional single shot LGE.
Future perspectives
In part IV of this thesis we present the rationale and design of the REPLACE-IT trial.
This trial will focus on the value of non-invasive imaging with CCTA and CMR for the assessment of patients with suspected CCS. The trial will investigate the role of non-invasive imaging techniques to guide clinical decision making.
English summary
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12
Dit proefschrift gaat over de toepassing van cardiale MRI beeldvorming bij de karakterisatie van chronische coronair syndromen (CCS). CCS zijn nog steeds de belangrijkste oorzaak van morbiditeit en mortaliteit wereldwijd. De diagnose van de verschillende stadia van CCS heeft belangrijke diagnostische en prognostische waarde. Cardiale MRI heeft binnen dit kader een grote potentiele toegevoegde waarde omdat de beeldvormende techniek in staat is om nauwkeurige informatie te geven over de conditie van het hart variërend van subtiele subklinische veranderingen tot de aan- of afwezigheid van ischemie en/of infarcering. Om de beeldvormende techniek een goede kans te geven zijn een aantal zaken echter belangrijk: standardisatie van klinische protocollen, het voorkomen van vals negatieve testuitslagen en tijd efficiëntie. In dit proefschrift worden een aantal wetenschappelijke publicaties samengevat die ingaan op de rol cardiale MRI in de karakterisatie van CCS met een speciale focus op het robuust maken van de klinische protocollen.
Subklinische veranderingen
Het roken van tabaksproducten is een belangrijke bekende risicofactor voor hart- en vaatziekten. Er is echter weinig informatie beschikbaar over de onafhankelijke effecten van tabaksrook op het hartspierweefsel en de hartfunctie. In hoofdstuk 2 is gekeken naar
de verschillen in de opbouw en functie van de hartspier in een geselecteerde populatie van rokers en niet-rokers zonder de aanwezigheid van andere veel voorkomende cardiale risicofactoren. In de populatie rokers was er sprake van een significant hoger linker- en rechterventrikel volume, lagere ejectie fractie en toegenomen linkerventrikel globale strain. Deze resultaten laten zien dat roken subklinische veranderingen in het hartspierfweefsel veroorzaakt. Dit onderzoek onderstreept het onafhankelijke effect van roken op het hartspierweefsel. Het onderzoek laat ook zien dat cardiale MRI een gevoelige techniek is die in staat is om subklinische veranderingen op te sporen.
Myocard perfusie
Deel II van dit proefschrift gaat over de toepassing van cardiale MRI voor
myocardperfusie onderzoek bij patiënten met verdenking op CCS. Hoofdstuk 3 is een
systematische review waar de recente literatuur over de mogelijke invloed van cafeïne op myocard perfusie is samengevat. Verspreid over alle diagnostische perfusie modaliteiten (SPECT, PET, CT, MRI, ICA) had cafeïne een significant negatief effect op hyperemie geïnduceerd door dipyridamole of adenosine. Dit negatieve effect vergroot de kans op vals-negatieve testuitslagen. Het is van essentieel belang om misclassificatie door vals negatieve testuitslagen te voorkomen omdat misclassificatie kan leiden tot mogelijk
Chapter 12
onderbehandeling van patiënten. Cafeïne inname moet streng afgeraden worden in de 12-24 uur voorafgaand aan het onderzoek. In de praktijk is dit echter lastig door de wijdverspreide en sterke culturele integratie van cafeïne consumptie. In hoofdstuk 4 en 5 is er gekeken naar patiënten met een verhoogd risico op een vals-negatieve testuitslag
door zelf-gerapporteerde recente caffeine inname voorafgaand aan een reeds geplande klinische cardiale MRI bij patiënten met verdenking op CCS. In hoofdstuk 4 lag de focus
op verschillende potentiële indactoren van adequate stress tijdens cardiale MRI met vaatverwijdende medicatie. Onze resultaten laten zien dat de Splenic Switch Off sign (SSO) en T1-mapping van de milt beide niet in staat waren om patiënten met recente caffeine inname te identificeren. Myocardiale T1-mapping was echter wel significant lager in patiënten met recente caffeine inname vergeleken met patiënten zonder recente caffeine inname. De myocardiale T1-reactiviteit is vervolgens gebruikt als een biomarker voor adequaatheid van stress in hoofdstuk 5. In dit hoofdstuk hebben we de effecten
van recente caffeine inname op adenosine en regadenoson bestudeerd. Adenosine en regadenoson zijn beide vaatverwijdende medicamenten die worden gebruikt om tijdens perfusie onderzoek inspanning van het hart na te bootsen. Adenosine is op het moment nog het middel van eerste keuze doordat het een stuk goedkoper is. Uit de resultaten bleek dat recente caffeine inname een significant effect had op de myocardiale T1-reactiviteit bij patiënten die adenosine perfusie onderzoek ondergingen. Dit effect was echter afwezig bij de patiënten in de groep die regadenoson perfusie MRI heeft ondergaan.
Caffeine inname voorafgaand aan perfusieonderzoek met adenosine moet worden afgeraden. Wanneer er klinisch een verdenking is op recente inname van caffeine zal het herplannen van de patiënt of het gebruik van regadenoson moeten worden overwogen. Dit is belangrijk om het risico op valsnegatieve testuitslagen en onderbehandeling te verlagen.
De diagnostische waarde van semi-quantitatieve en quantitatieve perfusie MRI analyse in patiënten met verdenking op CCS is samengevat in de meta-analyse van hoofdstuk 6. Cardiale MRI perfusie heeft een hoge diagnostische nauwkeurigheid voor de
beoordeling van significant coronairlijden. De visuele beoordeling is echter foutgevoelig door de subjectieve manier van beoordelen en het gebrek aan standaardisatie van de definitie van een perfusie defect. De semi-kwantitatieve en kwantitatieve perfusie analyses zijn nog steeds vrij tijd- en arbeidsintensief en foutgevoel door afhankelijkheid van de beoordeling op de plaatsing van de juiste contouren door de beoordelaar. De diagnostische waarde van (semi-)kwantitatieve perfusie analyse technieken was dan ook vergelijkbaar met die van de visuele beoordeling. De implementatie van deze (semi-)
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kwantitatieve perfusie analyse technieken is beperkt door het gebrek aan validatie en standardisatie.
Hartspierweefsel karakterisatie
Deel III van dit proefschrift gaat over de mogelijkheden van natieve T1-mapping en
Late aankleuring (LGE) om met cardiale MRI het hartspierweefsel in patiënten met de verdenking op CCS te karakteriseren. De mogelijkheid om met natieve T1-mapping een onderscheid te maken tussen normaal, ischemisch en geïnfarceerd myocardweefsel is onderzocht in hoofdstuk 7. De resultaten laten zien dat in ischemisch en geïnfarceerd
myocardweefsel de T1-reactiviteit significant lager is dan in normaal hartspierweefsel. Daarnaast zijn de natieve T1-waarden in geïnfarceerd hartspierweefsel hoger in vergelijking met normaal of ischemisch hartspierweefsel. Deze resultaten geven aan dat natieve T1-mapping ingezet kan worden om een onderscheid te maken tussen gebieden van het hart met normale, verminderde of afwezige bloedtoevoer door ischemie of infarcering.
In hoofdstuk 8 is een vergelijking gemaakt tussen een nieuwe post contrast
T1-map gebaseerde methode voor de beoordeling van litteken op de hartspier en de conventionele LGE beeldvorming. De resultaten laten zien dat vroege (2-3 min post contrast) synthetische T1-map LGE beeldvorming accuraat myocardiale fibrose kan afbeelden in vergelijking met de gouden standaard van conventionele LGE beeldvorming (10-15 min post-contrast).
Toekomstperspectief
In deel IV introduceren we de rationale en het design van de REPLACE-IT trial. In
deze trial zal worden gekeken naar de waarde van non-invasieve beeldvorming middels CCTA en MRI voor de beoordeling van patiënten met verdenking op CCS. De trial zal informatie geven over de toepassing van non-invasieve beeldvorming voor het sturen van klinische besluitvorming ten aanzien van coronaire interventies. Het primaire doel van de trial is het terugdringen van de hoeveelheid onnodige hartkatheterisaties.
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Dankwoord/
Acknowledgments
Dankwoord
In dit dankwoord wil ik iedereen bedanken die wetenschappelijk of vriendschappelijk heeft bijgedragen aan het tot stand komen van dit proefschrift.
Promotoren Geachte professor van der Harst, beste Pim. Toen ik in 2016 een open
sollicitatie stuurde naar het UMCG voor een ANIOS positie bij de cardiologie was ik verrast toen u me terug belde met de vraag of ik geïnteresseerd was in een PhD positie bij de ischemie groep. Een PhD positie precies op het raakvlak van mijn interesse gebieden: cardiologie en beeldvorming. Al snel wist u me te enthousiasmeren en besloot ik om de uitdaging aan te gaan. Mijn oprechte dank voor de begeleiding door de jaren heen. U bracht me in contact met professor Oudkerk en het Center for Medical Imaging. Professor Oudkerk, graag bedank ik u voor de kritische blik en de kansen die u mij heeft gegeven om mij op wetenschappelijk vlak te ontwikkelen.
Copromotor De totstandkoming van dit proefschrift zou onmogelijk zijn geweest
zonder de hulp en steun van dr. Kuijpers, radioloog in het Haaglanden Medisch Centrum Bronovo, Den Haag. Dirkjan, jouw eindeloze enthousiasme voor cardiale beeldvorming, in het bijzonder cardiale MRI, hebben mij enorm geïnspireerd en hebben er voor gezorgd dat ik mijn promotietraject als bijzonder leerzaam en enerverend heb ervaren. Enorm bedankt voor de fijne samenwerking.
Research coördinator Onder de vleugels van Stella Noach, de research coördinator
van de afdeling, werd ik door het moeras van wetenschappelijk onderzoek gedragen. Lieve Stella, zonder jou had ik denk ik al na een aantal maanden de handdoek in de ring gegooid… Het bureaucratische slagveld rondom wetenschappelijk onderzoek wist regelmatig het bloed onder mijn nagels vandaan te halen. Jouw optimisme, behulpzaamheid en menselijkheid hielden mij met beide benen op de grond en we hebben ons er moedig samen door heen geslagen. Het wordt ondertussen wel een keer tijd dat je bij ons langs komt in Apeldoorn voor een welverdiend “bedankt voor alles diner”.
Coauteurs Alle andere coauteurs wil ik graag bedanken voor hun waardevolle input,
feedback en prettige samenwerking. Naast de inhoudelijk betrokken collega’s, wil ik ook graag alle andere (oud-)collega’s van het CMI en de afdeling cardiologie bedanken.
G2 triade gebouw Merel, Marleen, Gertjan, Wout, Marly, Monique, Stella en de rest
van G2. Bedankt voor de fijne samenwerking en alle gezellige borrels, congresdiners en feestjes! Daarnaast ook een welverdiend dankwoord aan Rick Mencke (de PhD koning) voor zijn kritische blik, luisterend oor en alle gezelligheid tijdens mijn promotietraject.
Chapter 13
Ischemie groep Daan, Marie-Sophie, Tom, Carlijn, Hilde, Abdullah, Jan-Walter en
de rest van de ischemie groep van de cardiologie. Onwijs bedankt voor de gezellige momenten en de verhelderende discussies.
Ook wil ik graag alle MRI en CT laboranten van het UMCG en het Haaglanden Medisch
Centrum Bronovo bedanken voor de fijne samenwerking.
Ten slotte een special woord van dank voor al mijn familie en vrienden.
Familie Lieve papa en mama, bedankt voor jullie liefde, steun en warmte. Ik kan me
geen betere ouders toewensen! Doordat jullie me altijd vrij hebben gelaten om mijn hart te volgen ben ik precies op de goede plek terecht gekomen. Ook de rest van mijn familie wil ik graag bedanken voor alle goede zorgen en gezelligheid.
De helden die hebben gezorgd voor de nodige afleiding van de serieuze kant van het
PhD-leven wil ik ook enorm bedanken. De pipa-wolters fanclub en de andere twee
van de drie musketiers. Femke, Linda, Demi, Cora, Carina, Luuk en Leander: “vaak ben
je te bang” en “born to be alive”. Soms kon het niet gekker en ik hoop dat het nog veel vaker zo gezellig (en gek) gaat zijn als altijd.
Om af te sluiten met de meest belangrijke persoon in mijn leven… Jermo. Met gemak
kan ik een heel proefschrift vullen met positieve dingen over jou. Sinds ik jou ontmoet heb is mijn leven enorm veranderd. Ik geniet elke dag weer van het feit dat we samen zijn en van jouw positieve karaktereigenschappen. Om er voor de vorm een paar te noemen: jouw positieve levensinstelling, warme karakter, gezonde relativeringsvermogen, humor, intelligentie en handigheid. Je hebt me enorm geholpen op zowel emotioneel als inhoudelijk vlak bij het tot stand komen van dit proefschrift en daarvoor ben ik je eeuwig dankbaar.
Dankwoord
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van Dijk R MD, Kuijpers D MD PhD, Kaandorp T.A.M MD PhD , van Dijkman P.R.M MD, Vliegenthart R MD PhD, van der Harst P MD PhD, Oudkerk M MD PhD. Effects of Caffeine intake prior to stress Cardiac Magnetic Resonance Perfusion Imaging on Regadenoson- versus Adenosine-induced hyperemia as measured by T1 mapping. Published: International Journal of Cardiovascular Imaging May 2017
van Dijk R MD, Dirkjan Kuijpers MD PhD, Theodore A.M. Kaandorp MD PhD, Paul R.M. van Dijkman MD PhD, Rozemarijn Vliegenthart MD PhD, Pim van der Harst MD PhD, Matthijs Oudkerk MD PhD. Accurate Late Gadolinium Enhancement prediction by Early T1 based quantitative Synthetic mapping. Published: European Radiology August 2017
van Dijk* R MD, van Assen* M MSc, R. Vliegenthart MD PhD, de Bock GH PhD, van der Harst P MD PhD, Oudkerk M MD PhD. Diagnostic performance of semi-quantitative and quantitative stress MR perfusion analysis: A meta-analysis. Published: Journal of Cardiovascular Magnetic Resonance November 2017
Dirkjan Kuijpers MD PhD, Randy van Dijk MD, Marly van Assen, , T.A.M. Kaandorp MD PhD, Paul R.M. van Dijkman MD PhD, Rozemarijn Vliegenthart MD PhD, Pim van der Harst MD PhD, Matthijs Oudkerk MD PhD. Disagreement between splenic switch-off and myocardial T1-mapping after caffeine intake. Published: International Journal of Cardiovascular Imaging November 2017
M. van Assen MSc, R. van Dijk MD, D. Kuijpers MD PhD, R. Vliegenthart MD PhD, M. Oudkerk MD PhD. Delta T1 as an imaging biomarker in myocardial tissue characterization. Published: International Journal of Cardiovascular Imaging February 2018
van Dijk R MD, Ties D MD, Kuijpers D MD PhD, van der Harst P MD PhD, Oudkerk M MD PhD, Effects of Caffeine on Myocardial Blood Flow: A Systematic Review. Published: Nutrients August 2018
Ties D, BSc, van Dijk R, MD, Pundziute G, MD, PhD, Lipsic E, MD, PhD, Vonck T.E., Heuvel, A.F.M., MD, PhD, Vliegenthart R, MD, PhD, Oudkerk M, MD, PhD, Van Der Harst P, MD, PhD. Computational Quantitative Flow Ratio to assess severity of coronary artery stenosis. Published: International Journal of Cardiology May 2018
Chapter 14
Tobias Härle, MD, Mareike Luz, Sven Meyer, MD, PhD, Felix Vahldiek, Pim van der Harst, MD, PhD,MD, van Dijk R, MD, Ties D, MSc, Javier Escaned, MD, PhD, Justin Davies, MD, PhD, Albrecht Elsässer, MD. Influence of hydrostatic pressure on intracoronary indices of stenosis severity in vivo. Published: Clinical Research Cardiology November 2017
Tom Hendriks M.D., Randy van Dijk M.D., Najod Alsabaan Bsc, Pim van der Harst M.D. PhD. Active tobacco smoking impairs cardiac systolic function. Published: Scientific Reports May 2020
Runlei Ma, Daan Ties, Marly van Assen, Gert Jan Pelgrim, Grigory Sidorenkov, Peter M A van Ooijen, Pim van der Harst, Randy van Dijk, Rozemarijn Vliegenthart. Towards reference values of pericoronary adipose tissue attenuation: impact of coronary artery and tube voltage in coronary computed tomography angiography. Published: European Radiology Jul 2020
List of publications
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Chapter 15
Randy van Dijk was born on July 11th, 1991 in Groningen, The Netherlands. After
completing high school at Röllingcollege Belcampo in 2009, he started his study in Medicine at the Rijksuniversiteit Groningen (RUG). During his study he acquired a special interest in cardiology and cardiovascular imaging. After graduating from medical school in 2015 he started as a PhD student at the cardiology department of the University Medical Center Groningen (UMCG) under supervision of prof dr. P. van der Harst and prof dr. M. Oudkerk. His research was focused on Magnetic Resonance Imaging and Computed Tomography Imaging of cardiovascular disease, of which some of the results are presented in this thesis. Currently, he started as an intern at the Cardiology department of the Gelre Hospital in Apeldoorn.
Curriculum Vitae
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