Cardiac MRI for morphology and function

Hermann Eichstädt MD,1 Thomas Störk MD2
1 Department of Cardiology, Charité University Medicine, Berlin, Germany
2 Department of Cardiology, Karl-Olga-Krankenhaus, Stuttgart, Germany

Address for correspondence:
Univ.-Prof. Dr. Hermann Eichstädt
Medizinische Klinik m. S. Kardiologie,
Charité, Campus Virchow-Klinikum, Augustenburger Platz 1
13353 Berlin, Germany
Tel: +49-30-450-553-201
Fax: +49-30-450-553-931
Email: info@prof-hermann-eichstaedt.de


Abstract
Recent advances in technology and sequencing have led to a great expansion in the use of cardiac magnetic resonance imaging (MRI) to include not only the study of cardiac morphology and the imaging of infarcts, but also diagnosis of other coronary artery disease, especially with use of dobutamine stress tests, adenosine perfusion studies, and non-invasive coronary angiography. At present, the method still suffers from the lack of therapeutic interventions in coronary arteries, whereas enormous progress has taken place in imaging of the great arteries. Now, developments in MRI techniques lead to hopes for further consolidation of pathophysiological knowledge and further improvement of diagnostic possibilities.

Myocardial perfusion
Magnetic resonance imaging (MRI) (with contrast medium) is currently used to determine myocardial perfusion and to compare perfusion parameters at rest and during pharmacological stress. Perfusion can be assessed using adenosine and regional wall motion may be analysed using dobutamine. However, neither of these pharmaceuticals is approved for MRI use in Germany.

 Adenosine perfusion studies
In perfusion studies, recording of diastolic images allows the contrast medium to be followed into the myocardium. Today’s measuring speeds permit the storing of up to seven slices per trigger interval. The signal-to-noise ratio is also improved by Steady-State Free Precession (SSFP) sequence compared to the previous EPI-Hybrid sequences. Adenosine acts by stimulating the adenosine A2 receptors in the myocytes of the coronary artery media, increasing adenylylcyclase activity which leads to an increase of cyclic adenosine monophosphate (cAMP), resulting in relaxation of non-atherosclerotic segments of the coronary arteries. Adenosine is usually given at a dose of 140 µg/kg/min as an infusion over 4-6 minutes.

Where there are stenoses, this results in a coronary steal phenomenon after 2 to 3 minutes and leads to a reduction in perfusion which can be visualised with repeated applications of contrast medium (usually 0.05 mmol/kg gadolinium-DTPA). An interval of 10 minutes should be allowed between adenosine imaging and imaging at rest.

Coronary steal effects occur not only with fixed coronary stenoses, but can also appear where there is endothelial dysfunction or even in healthy people who would never develop any impairment of the coronary circulation under other circumstances. Adenosine is immediately (t1/2<10 sec) transported into the myocardial cells by a nucleoside carrier, which is why it can cause a higher grade atrioventricular block in a few cases and occasionally ventricular arrhythmias. Serious reactions can be treated with aminophylline or theophylline (e.g. doses of 50-125 mg).

If there is insufficient coronary dilatation reserve under stress - in healthy individuals, the coronary reserve can increase by a factor of 7 to 9 at the most - one may conclude that there is a load-dependent coronary insufficiency under adenosine. Under healthy conditions, the perfusion reserve index does not fall below a minimum value of 1.5 [1]. Additionally, MRI can also differentiate between myocardial perfusion into the subepicardial and subendocardial layers. Flow reserve can be determined in native coronary vessels and bypasses with some sequence effort about the phase contrast method [2].

Dobutamine stress tests
We adapted the wall motion analysis technique used in radionuclide ventriculography [3,4] and different MRI procedures have been described [5]. For many years, analysis of ventricular function analysis has also been undertaken using stress echocardiography, [6] with increasing attention being paid to measurement of diastolic function [7].

ine-MR in the longitudinal axis. ‘Low dose’ (5 µg/kg/min) and ‘high dose’ (40 µg/kg/min) dobutamine stress in one of our patients after inferior wall infarction. No proof of wall motion disturbances, therefore exclusion of new stress-induced ischaemia
Figure 1. Cine-MR in the longitudinal axis. ‘Low dose’ (5 µg/kg/min) and ‘high dose’ (40 µg/kg/min) dobutamine stress in one of our patients after inferior wall infarction. No proof of wall motion disturbances, therefore exclusion of new stress-induced ischaemia.
The left ventricle can be examined for segmental wall motion disturbances induced by arbutamine or dobutamine using cine sequences, usually with SSFP but also with tagging techniques, [8] possibly with atropine at various doses up to 40 µg/kg, using long- and shortaxis cross-sectional views. Using low-dose dobutamine (5-10 µg/kg/min), hibernating myocardium can be detected if segments with disturbed perfusion do not show any late enhancement. However, until now, these MRI investigations have not necessarily been useful for diagnosis as the techniques have not been standardised.

The MR images provide much more detailed spatial resolution than stress echocardiography, which is still unsatisfactory (Figure 1) [9-11]. Nevertheless, stress echocardiography is used much more frequently, despite having only moderate reliability.

Assessing the viability of the myocardium
Despite the restrictions mentioned above, it has been possible for many years to use MRI to detect larger areas of non-contractile myocardium and also to make assumptions about myocardial fibrosis due to the differences in signal intensity. However, any conclusion about quantification of fibrosis should be viewed very critically.
Transverse representation of an apical anterior infarction scar with late enhancement
Figure 2. Transverse representation of an apical anterior infarction scar with late enhancement.
Myocardial perfusion, which is a fundamental prerequisite for cellular viability, is often measured semiquantitatively as part of routine MR measurements, although it does not necessarily prove the vitality of tissue. This is possible only by quantification of wall motion during load and its increase after pharmacological stimulation, for example with dobutamine, [9] as well as by determination of left ventricular volume [12,13].

The contractile reserve of myocardial segments which had shown hypokinesis at rest may be quantified during pharmacological stress. Areas with only partial scarring from intramural infarction with late enhancement can be examined for their potential for reactivation. The development of necrosis may be measured following surgical or interventional revascularisations (Figure 2) [12,14].

Diagnosis of myocardial infarction
Gadolinium compounds are extracellular contrast media, which preferably mark tissues with increased extracellular spaces caused by interstitial water content as a result of oedema formation and also areas with destruction of cellular membranes, rapid development of fresh granulation tissue and new capillary buds [15]. These changes allow the rapid influx of gadolinium but efflux is protracted because of the absence of efferent capillaries, which we showed in our first histological staining studies of enhanced infarcted areas [16].

Original photos from our first application of Gadolinium 1984/85 in 26 myocardial infarction patients. (a)(b) anteroseptal infarction; (c)(d) anterolateral infarction, before and after 0.1 mmol/kg Gadolinium-DTPA
Figure 3. Original photos from our first application of Gadolinium 1984/85 in 26 myocardial infarction patients. (a)(b) anteroseptal infarction; (c)(d) anterolateral infarction, before and after 0.1 mmol/kg Gadolinium-DTPA [4].
We investigated our first acute patients in the summer of 1984 (Figure 3), whereas the San Francisco group studied experimental infarctions in dogs [17]. This effect, which we were the first working group in the world to describe in 1984, [18] was adapted by Miriam Sperber and Marc Kaiser in 1987 [19]. Subsequently, with reference to our primary work, it was described as “enhanced later echoes” by Gerald Wisenberg 1991, [20] and it was introduced to the American literature by Charles B. Higgins as “delayed greater enhancement” citing our first studies [21]. In the following years, the term ‘late enhancement’ became established and subsequently, with the use of contrast media in cardiac studies, the concept and term ‘contrast enhanced MRI (ceMRI)’ was adopted [22]. Our understanding of the physical effects of contrast media was deepened by the fundamental work of Wolfgang Bauer [23].


Infero-posterior infarction with 'late enhancement'
Figure 4. Infero-posterior infarction with 'late enhancement'.
We have found that the strongest signal increase is measured 10 to 30 min after injection of 0.1 mmol (~0.4 ml)/kg and now the first measurement is made 15 minutes after injection of contrast medium. Since irreparably destroyed myocardium can be visualised by the contrast medium, MRI could potentially be used to demonstrate the location and extent of myocardial scarring before PCI or bypass surgery. However, despite its theoretical value, this method is used just as seldom as scintigraphical methods were used in the past for proof of vitality. Nevertheless, a direct correlation has been proven between the size of the post-infarct late-enhancement area and the reduction in the ejection fraction (Figure 4) [24].

‘Early enhancement’ is seen in healthy and well-perfused myocardium until about 3 minutes after the injection of contrast media, whereas areas with ‘microvascular obstructions’ - similar to small vessel disease - represent multiple and diffuse enhancement spots which can be seen also in later phases of the representation [25].

As a result of the widespread adoption of invasive coronary angiography (more than 715,000 diagnostic investigations took place in Germany in 2004) and the increase in percutaneous coronary interventions (249,000 in Germany in 2004), there seems to be very little requirement for any investigations like ceMRI in the field of coronary angiography.

Other cardiac disease
Use of MRI for other cardiac diagnoses
Following our first descriptions of contrast imaging of infarcted areas, more indications for cardiac MRI, with and without contrast media, were defined, especially for different types of cardiomyopathies [26-8] as well as for myocarditis (Figure 5) [29-31]. However, MRI is not yet established as a reliable diagnostic tool in these indications. We have also used MRI to visualise a large number of heart tumours, with and without contrast media.

Myocarditis is most frequently induced by cardiotropic viruses including coxsackievirus, echovirus and influenzavirus as well as parvovirus and herpesvirus. This leads to focal destruction of cardiac muscle cells, interstitial myocardial fibrosis following vascular exudation as an interstitial oedema, and later to polymorphonuclear and round cell infiltration between the muscle fibres, as well as macrophages surrounding necrotic cardiomyocytes.

At this stage, the conditions are very good for gadolinium enhancement. Following suppression of the myocardium and fatty tissue, the increased proton content can be depicted without contrast medium. In contrast to the homogeneous enhancement observed in myocardial infarctions, the enhancement in myocarditis is predominantly subepicardial, sometimes more streaky and in other cases blotchy. However, validation of these observations remains difficult since in clinical cases of myocarditis, there is usually no reliable reference method for the MRI results. Specific myocardial biopsies represent an exception, which can occasionally be successful and allow active myocarditis to be demonstrated histopathologically [32].

(a) extensive septal scar with ‘late enhancement’ in a case of proven myocarditis; (b)(c) myxosarcoma of the lateral wall of the right atrium [32]. (LV=left ventricle; RV=right ventricle).
Figure 5. (a) extensive septal scar with ‘late enhancement’ in a case of proven myocarditis; (b)(c) myxosarcoma of the lateral wall of the right atrium [32]. (LV=left ventricle; RV=right ventricle).


So-called ‘congenitally corrected transposition’ of the great arteries with ventricular inversion. The aorta arises left anterior (Left Transposition of the Great Arteries, L-TGA) from the morphologically right ventricle with a tricuspid valve which is filled from the left atrium. (AO=aorta; RV=right ventricle; PA=pulmonary artery; LA=left atrium)
Figure 6. So-called ‘congenitally corrected transposition’ of the great arteries with ventricular inversion. The aorta arises left anterior (Left Transposition of the Great Arteries, L-TGA) from the morphologically right ventricle with a tricuspid valve which is filled from the left atrium. (AO=aorta; RV=right ventricle; PA=pulmonary artery; LA=left atrium).


Similar nonischaemic enhancements in the middle myocardial or subepicardial layers with diffuse or streaky distribution may occasionally be observed in dilated cardiomyopathies [33] or amyloidosis [34]. It is still unclear what conclusions can be drawn from such observations. The same applies to right ventricular arrhythmogenic cardiomyopathy [35-7] and to isolated ventricular non-compaction (IVNC) cardiomyopathy [38].

Finally, MRI is extremely valuable for topographic evaluation and classification of complex malformations of the heart and great vessels (Figure 6).

Noninvasive coronary imaging (magnetic resonance coronary angiography - MRCA)

Coronary artery representation RCA with our 3.0 T device (GE Signa 3, T 94) in breath-hold technique using spiral acquisition technology (a) and with the help of a SSFP sequence (b), as well as free breathing with the navigator technique (c, d), showing coronary insertion in the context of an arterial ‘switch’ operation for the correction of a D-TGA (Dextrotransposition of Great Arteries) (AO=aorta; RCA=right coronary artery; SSFP=steady-state free precession; LAD=left anterior descending artery)
Figure 7. Coronary artery representation RCA with our 3.0 T device (GE Signa 3, T 94) in breath-hold technique using spiral acquisition technology (a) and with the help of a SSFP sequence (b), as well as free breathing with the navigator technique (c, d), showing coronary insertion in the context of an arterial ‘switch’ operation for the correction of a D-TGA (Dextrotransposition of Great Arteries) (AO=aorta; RCA=right coronary artery; SSFP=steady-state free precession; LAD=left anterior descending artery).
Cross-sections through the heart, or rarely longitudinal sections, could be represented with the first MRI sequences. The origin of the coronary arteries from the aortic trunk could usually be demonstrated using ECG-triggered spin echo sequences. Nevertheless, decisive progress was only made with fast gradient echo sequences, which allow the satisfactory visualisation of the large epicardial coronary vessels. However, we are still dependent on cooperation from the patient with regard to their breathing technique. With free breathing at a steady breath depth, today’s navigator technology allows precise visualisation of the coronary arteries down to the middle third of their course, [39] but needs a relatively long acquisition time. With the help of the spiral acquisition technique, coronary imaging is also possible with breath-hold technology. Brightblood technology permits representation of the inner volume of the vessels and creates angiography-like pictures [40]. If the pulses are inverted with inversionrecovery technology, black-blood pictures are obtained and the vessel walls can be visualised at sub-millimeter resolution. High-resolution coronary images are now obtained by a sequence with intrinsic high contrast (SSFP) and special navigator technology (affine transformation) with two navigator beams [41].

 Intravascular contrast media in the blood do not diffuse into the interstitial space and make higher contrast possible with the surrounding tissue during free breathing to increase the vessel resolution further for some minutes; [42] the same also applies to bypass grafts [43]. New modifications of contrast media with other ligands, eventually in combination with a higher field strength (3.0 Tesla) will, in the near future, generate information about the consistency of plaques through specific ‘plaque-imaging’, and about vascular occlusion mechanisms (fibrin) (Figure 7).

New perspectives are on the horizon in MRI, including developments in hardware, software and pharmacological adjuncts like contrast media. New hybrid systems will allow a combination of percutanous coronary intervention and molecular MR imaging for regenerative myocardial therapy with localized pharmacological and cellular applications. MR systems with a field strength of 7.0 Tesla will be available for human application, and the adaptations are complete for clinical scanners with 9.5 Tesla for experimental molecular imaging.

The targeting of specific plaque-associated molecules with agents that provide sensitive and specific imaging contrast is already a major goal of molecular imaging. By linking gadolinium to a molecular or cellular targeting vehicle, it is possible to generate MRI contrast a at exact locations of pathological interest. Uptake of superparamagnetic particles of iron oxide, including ultrasmall particles) by macrophages allows the imaging of atherosclerosis. Gadolinium-loaded nanoparticulates with recombinant high-density lipoprotein and gadolinium-containing immuno-micelles are also able to image atherosclerosis. Gadofluorine MR greatly enhances the atherosclerotic aortic wall. Neo-vascularization has been targeted for molecular MRI with an avß3-targeted nanoparticle contrast agent. Key targets for imaging of thrombosis include p-selectin, tissue factor, fibrin, surface markers of activated platelets, and various clotting factors. Firm insights may have great clinical utility in terms of managing patients with coronary artery disease.

Key Learning
  • MRI undoubtedly has a leading role in the diagnosis of complex cardiac morphology
  • Assessment of regional perfusion through provocation of steal phenomena using adenosine and wall motion analysis during stress induced by dobutamine or arbutamine have had well-accepted roles in the evaluation of cardiac function for some years
  • The enhancement of interstitial tissue oedema by contrast media is established and is used in the diagnosis of myocardial infarction
  • Changes in contrast behaviour associated with myocarditis and cardiomyopathies are also under investigation
  • The development of navigator technology and new sequences already allows reasonably reliable representation of the large epicardial coronary vessels

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