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Cardiovascular Magnetic Resonance to Guide and Monitor the Myocardial Response to Treatment

2019; Lippincott Williams & Wilkins; Volume: 12; Issue: 12 Linguagem: Inglês

10.1161/circimaging.119.010045

1942-0080

Brian P. Halliday, Dudley J. Pennell,

Cardiac electrophysiology and arrhythmias

HomeCirculation: Cardiovascular ImagingVol. 12, No. 12Cardiovascular Magnetic Resonance to Guide and Monitor the Myocardial Response to Treatment Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCardiovascular Magnetic Resonance to Guide and Monitor the Myocardial Response to Treatment Brian P. Halliday, MBChB, PhD, MRCP and Dudley J. Pennell, MD, FRCP, FMedSci Brian P. HallidayBrian P. Halliday National Heart and Lung Institute, Imperial College London and Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital. London, United Kingdom (B.P.H. and D.J.P.). and Dudley J. PennellDudley J. Pennell Dudley J. Pennell, MD, Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, SW3 6NP, London, United Kingdom. Email E-mail Address: [email protected] National Heart and Lung Institute, Imperial College London and Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital. London, United Kingdom (B.P.H. and D.J.P.). National Heart Lung Institute, Imperial College, London, United Kingdom (D.J.P.). Originally published12 Dec 2019https://doi.org/10.1161/CIRCIMAGING.119.010045Circulation: Cardiovascular Imaging. 2019;12:e010045This article is a commentary on the followingMyocardial Storage, Inflammation, and Cardiac Phenotype in Fabry Disease After One Year of Enzyme Replacement TherapySee Article by Nordin et alCardiovascular magnetic resonance (CMR) is moving from delivering diagnosis and prognosis to guiding therapy with the aim of improving outcome. A number of existing and developing examples illustrate this transition. One well-known use of CMR which impacts on contemporary patient treatment is T2* imaging to quantify myocardial iron in patients receiving regular blood transfusion, as typified by thalassemia major patients. For decades before the introduction of T2* CMR, heart failure and associated arrhythmias had been the predominant cause of death among patients with thalassemia major.1 In the United Kingdom, the number of deaths from iron overload among these patients increased rapidly between 1960 and 1990.2 This was likely contributed to by the under-detection of myocardial iron overload linked to the absence of a noninvasive diagnostic test and the subsequent underuse of iron chelators. After the introduction of T2* imaging to quantify myocardial iron load in United Kingdom in the late 1990s, resulting in the use of iron chelator therapy tailored to the heart iron concentration, the cardiac mortality fell by 71% in 2000 to 2003.2 The identification of a validated threshold for severe cardiac loading (T2* 40%.11,12 This is particularly important in DCM following the results of the DANISH trial (The Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality), which failed to show a reduction in mortality with implantable cardioverter defibrillators in patients with DCM.13 Another recent trial in DCM, TRED-HF (withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy), demonstrated the use of CMR end points to track adverse remodeling after attempted treatment withdrawal in patients with recovered function, taking advantage of the superior inter-study reproducibility of this modality.14 In hypertrophic cardiomyopathy, LGE CMR is likewise considered important in risk stratification of patients for implantable cardioverter defibrillators, as fibrosis has been associated with higher risk.15 The results of the HCMR registry (Hypertrophic Cardiomyopathy Registry) and updated guidelines are awaited.Other promising areas include the use of T2 mapping to guide treatment in inflammatory cardiomyopathies.16,17 Cardiac involvement is increasingly recognized among patients with extracardiac sarcoidosis, and active disease is typically treated with immunosuppression. Endomyocardial biopsy is associated with the risk of complications and sampling error, while positron emission tomography/computed tomography involves ionizing radiation. Parametric mapping is noninvasive and free of ionizing radiation and, therefore, has the potential to be used for serial testing and guide the use of immunosuppression. Prospective studies investigating the diagnostic sensitivity and specificity for active sarcoidosis are required. Myocarditis is also an increasingly recognized and life-threatening complication of ICI (immune checkpoint inhibitors), occurring in 1% to 2% of cases.16 These agents are extremely effective at treating particular forms of cancer and indications for their use are expanding. In the largest series to date, the incidence of major adverse cardiovascular events in patients with ICI-associated myocarditis was 46% over a median follow-up of 102 days.16 Prompt recognition of this complication is, therefore, required to guide the expedient introduction of high-dose steroid therapy. CMR with LGE imaging and parametric mapping is the predominant modality used to diagnosis this condition.In this edition of the Journal, further evidence of the development of CMR for treatment guidance is presented by Nordin et al,18 who present data to suggest that serial CMR assessment of the myocardial changes associated with Fabry disease may be a feasible way to track the type and magnitude of response to therapy. The authors are to be commended for conducting a multicenter study in this rare but important disease. As with cardiac amyloidosis, disease response has traditionally been measured using serial measurement of left ventricular mass with echocardiography. This, however, is poorly reproducible and does not characterize the changes that are occurring at a tissue level. CMR not only offers the ability to measure left ventricular mass more precisely but also track intracellular sphingolipid accumulation using T1 mapping and myocardial inflammation and scar using a combination of T2 mapping and LGE imaging.The data support the notion that myocardial involvement in Fabry disease is slowly progressive, both in early stage disease if untreated and the later stages of the disease. In the early stages, increasing myocardial mass secondary to intracellular storage appears to predominate. Later in the disease inflammation and deteriorating myocardial function occur with rising T2 values and troponin. The observation that myocardial mass and native T1 did not increase in patients with advanced disease on enzyme replacement therapy may be related to the small numbers, or a reflection that enzyme replacement therapy is able to slow sphingolipid storage but cannot prevent the toxic myocardial effects of that which has already accumulated.Perhaps most interesting was the observation that there was an increase in native T1 and a trend towards a reduction in left ventricular mass among patients with early myocardial involvement who were established on enzyme replacement therapy. These changes were most evident in patients with modest left ventricular hypertrophy. While we must bear in mind the small number of patients on which these observations were made, these fit with previous research demonstrating reduction of mass and clearance of sphingolipid from myocardial endothelial cells in a randomized trial of recombinant α-galactosidase A.19 It also fits with the notion that there may be a sweet-spot for starting enzyme replacement therapy, likely early in the disease course. The benefits of prolonged therapy must, however, be balanced against the costs, the frequent attendance for twice-weekly intravenous infusions and the risk of developing inhibitory antibodies.Novel oral therapies which stabilize mutant forms of α-galactosidase and reduce substrate may overcome some of these problems.20,21 Heterogeneity in response to different types of therapy appears likely. As well as being used as an end point in clinical trials, CMR represents a feasible, reproducible, and accurate noninvasive option to track the myocardial responses to these therapies and guide choice of regimen. It is also possible that therapies targeting the toxic, inflammatory effects of sphingolipid accumulation will emerge in addition to agents which reduce storage. The characterization of the tissue changes may become even more important in guiding treatment in this setting.Overall, these data provide the springboard for additional investigation. As the investigators acknowledge, further work in larger populations with longer follow-up is required to ensure replication of the findings and also compare the myocardial effects of different therapies. Perhaps most importantly, a disease threshold is required to guide institution of therapy that ensures improvement in outcome and balances the benefits against the risks and costs of long-term treatment. We must bear in mind that while current trials have shown that available therapies improve biomarkers of disease severity, data on their effect on long-term outcomes are lacking. Finally, any treatment threshold taking into account native T1 or T2 times will need to be vendor, center, and field-strength specific given the recognized variation in normal ranges. The investigators in this study scanned phantoms at interval times throughout the study to ensure that serial changes in T1/T2 times reflected disease changes rather than measurement instability over time. Adopting such rigorous protocols in local clinical centers will be important to ensure stability over time if these are to be used to guide therapy and monitor myocardial treatment response.In conclusion, while the use of T2* in patients at risk of myocardial iron overload remains the exemplar of how CMR guides therapy, the increasing volume of data across several disease processes, including Fabry disease, suggests that native T1, T2, ECV mapping, and LGE can follow this lead with the ultimate aim of guiding therapy and improving the outcomes and quality of life of our patients (Figure).Download figureDownload PowerPointFigure. The use of cardiovascular magnetic resonance (CMR) to guide the management of patients with cardiovascular disease. The CMR techniques and the treatments they may be used to guide for patients with ischemic heart disease (late gadolinium enhancement [LGE]), dilated cardiomyopathy (DCM), myocardial iron overload (T2*), Fabry disease (native T1/T2), cardiac amyloidosis (ECV/T2), and inflammatory cardiomyopathy (T2). ECV indicates extracellular volume.DisclosuresDr Pennell receives research support from Siemens, ApoPharma, and La Jolla and is a consultant to ApoPharma. The other author reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Dudley J. Pennell, MD, Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, SW3 6NP, London, United Kingdom. Email dj.[email protected]nhs.ukReferences1. Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia Register.Lancet. 2000; 355:2051–2052. doi: 10.1016/S0140-6736(00)02357-6CrossrefMedlineGoogle Scholar2. 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