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CMR in non-ischaemic cardiomyopathies – what is new?

Professor Plein who is Professor of Cardiology as well as a British Heart Foundation Senior Clinical Research Fellow and Honorary Consultant       Cardiologist, has also served on the EACVI Scientific documents committee since 2014 for an initial 2 year term and has contributed to several position papers on cardiovascular imaging. Most of the recent scientific documents include recommendations for the use of CMR, reflecting the growing role of CMR in clinical practice in Europe.

His research is focused on developing MRI methods for the assessment of ischaemic heart disease and heart failure, in particular methods for myocardial perfusion and coronary MRI. In clinical applications, these and other methods are being applied to patients with acute and stable coronary symptoms and various aetiologies of heart failure.

Cardiac Magnetic Resonance (CMR) is a highly versatile imaging modality that can provide accurate and quantitative anatomical and functional   information in a range of cardiac and vascular conditions, including in particular cardiomyopathy. Its high     tissue contrast and spatial resolution are further attributes of the modality as well as its safety. Cardiac Magnetic Resonance does not expose patients or medical staff to ionising radiation and CMR contrast agents have a better risk profile than iodine-based X-ray contrast agents.

The main past drawbacks of CMR – being claustrophobia and implantable devices - are being addressed with the introduction of wide bore CMR scanners and MR-conditional devices. Over the past two decades, CMR has become a routine diagnostic test in several European countries such as the United Kingdom and Germany. In some parts of Europe, access to CMR remains patchy,     often as a result of national or local governance and reimbursement policies.

Guidelines recommend CMR

Several current European and international practice guidelines include recommendations for Cardiac Magnetic Resonance in the management of patients with cardiac, pericardial and vascular disease. In patients with heart failure and cardiomyopathy, guidelines suggest CMR to accurately assess chamber size and function and late gadolinium enhanced (LGE) CMR to distinguish ischemic from non-ischemic cardiomyopathy.

While in ischemic cardiomyopathy, LGE CMR may show myocardial     infarction, in non-ischemic dilated cardiomyopathy, it can detect mid wall fibrosis - a finding that is independently associated with adverse clinical outcome over and above left ventricular ejection fraction as was demonstrated in a publication in JAMA by Gulati et al. (‘Association of fibrosis with mortality and sudden cardiac death in patients with non-ischemic dilated cardiomyopathy’. JAMA. 2013;309:896-9080).

HCMR study well underway

The presence of fibrosis on LGE CMR has also been associated with worse outcome in hypertrophic cardiomyopathy (HCM), an observation that has motivated the large multi-center HCMR study (Novel Markers of Prognosis in Hypertrophic Cardiomyopathy, Identifier: NCT01915615). The study is testing the hypothesis that HCM patients with a higher rate of adverse events can be identified by novel CMR findings and aims to develop a predictive model of cardiovascular outcomes in HCM.

The study is organized by the University of Oxford, UK and the University of Virginia, US. By October 2015, over 1,000 of the targeted 2,750 patients with clinically diagnosed hypertrophic cardiomyopathy studies at baseline who will be observed for up to 5 years after index cardiac magnetic resonance imaging and blood draw for genetics and biomarkers, had been recruited in 40 centers across Europe and the USA. Demographic data, clinical risk factors, as well as novel markers from CMR, genotyping, and serum biomarkers of collagen turnover and myocardial injury will be collected and patients will be enrolled over a 2-year period and followed for 3-5 years (mean of 4 years).

Rationale for the HCMR study

The rationale for the HCMR study can be found in the fact that           presently used risk predictors in HCM for the clinical outcomes of sudden cardiac death (SCD) and heart failure (HF) are still insufficient and limit clinical trials and institution of novel therapies in this disease.

This large scale, prospective clinical registry will systematically answer the important question whether, through addition of a combination of advanced CMR phenotyping, ge-netic and biomarker analysis, risk stratification in HCM could be substantially improved over presently used clinical risk predictors. Emerging novel blood, genetic, and CMR markers offer the paradigm-shifting promise of reliably identifying those at risk. In addition, this will be the largest genotyped population of HCM available to correlate with comprehensive CMR and biomarker evaluation. This will allow unique opportunities to evaluate genotype-phenotype correlations and compare specific genetic subsets in a manner that has not been possible in the past. This study will also establish a predictive model that can be used to assess risk given a patient’s combination of risk factors. This will help to select patients for future clinical trials to prevent SCD and HF. In addition, it will identify surrogate endpoints to monitor treatment response in HCM. In this way, the evidence base will be established in HCM to enable clinical trial design to reduce morbidity and mortality in HCM in a cost-effective manner.

Predictive model of cardiovascular outcomes in HCM

The specific aim of this study is thus – as briefly mentioned before - to develop a predictive model of cardio-vascular outcomes in hypertrophic cardiomyopathy by using exploratory data mining methods to identify demographic, clinical, and novel CMR, genetic and biomarker variables associated with the outcomes and to develop a score from the predictive model that can be used to assess risk given a patient’s combination of risk factors, thus establishing the evidence base to enable clinical trial design to reduce morbidity and mortality in HCM in a cost-effective manner.

The primary endpoint of this ­prospective study is the composite of cardiac death (SCD and HF death), aborted SCD including appropriate ICD firing, and need for heart transplantation. Secondary endpoints   include all-cause mortality, ventricular tachyarrhythmias, hospitalization for heart failure, atrial fibrillation, and stroke.

The study will be powered to identify risk markers in a Cox model (imaging, serum, and genetic beyond standard clinical risk factors) with a hazard ratio of 1.5 or greater for the primary endpoint, which will be cardiac death (including SCD and HF death), aborted SCD (appropriate discharge of an implantable cardioverter-defibrillator), and need for heart transplantation. Secondary endpoints include all-cause mortality, ventricular tachyarrhythmias, hospitalization for heart failure, atrial     fibrillation, and stroke. This study will enable establishment of a predictive model that will help to identify         patients at risk as well as patients for future clinical trials to prevent SCD and HF. In addition, it will identify surrogate endpoints to monitor treatment response in HCM.

T1 mapping promising

Increasingly, T1 mapping by CMR is used to characterize tissue quantitatively. Evidence is beginning to accumulate that T1 mapping has incremental value over LGE CMR in non-ischemic heart disease and ongoing larger clinical studies, including HCMR, will assess its role and impact on outcomes. For clinicians and patients, this may offer the       opportunity to further improve risk stratification of patients with non-   ischemic cardiomyopathy. The way forward for Cardiac Magnetic Resonance is to conduct further large outcome studies to more clearly define the role of CMR in ischemic and non-ischemic heart disease and to promote the expansion of CMR across Europe so that patients and clinicians can benefit equally of this well-established imaging modality.