Cardiovascular magnetic resonance patterns of biopsy proven cardiac involvement in systemic sclerosis

Systemic sclerosis (SSc) is a rare chronic systemic autoimmune disease associated with different autoantibodies, the most common are anti-topoisomerase I (Anti-Scl-70) and anti-centromere antibodies (ACA). SSc is associated with high morbidity and mortality [1]. The pathogenesis of SSc is not entirely understood but microvascular changes are suspected to be the main cause of connective tissue infiltration and fibrosis [2]. Besides cutaneous manifestations, visceral involvement especially of bowel, lung, heart and kidney is more common and occurs earlier in patients with diffuse cutaneous subset of SSc (dcSSc) than in patients with limited cutaneous SSc (lcSSc) [3, 4]. In general, the prognosis in patients with myocardial involvement is poor [2].

In these patients with cardiac involvement, non-segmental perfusion defects can be observed in myocardial stress perfusion cardiovascular magnetic resonance (CMR), suggesting resemblances in the pathogenesis of SSc associated Raynaud’s phenomenon and transient myocardial ischemia [5]. Cardiac Raynaud’s phenomenon may be one reason for subsequent myocardial fibrosis, in addition to non-specific hypertrophy.

Several CMR studies have pointed out characteristic findings in patients with SSc. These are: Pericardial effusion [6], left ventricular (LV) and right ventricular (RV) diastolic and systolic dysfunction, LV hypertrophy, perfusion defects and myocardial late gadolinium enhancement (LGE) [5, 7‐10].

Standard treatment of SSc includes cyclophosphamide, which can be cardiotoxic [11]. In our patient group with severe scleroderma, CMR was part of a routine diagnostic work up in the course of preparation and risk stratification for autologous stem cell transplantation and escalation of potentially cardiotoxic therapy. Myocardial histopathological fibrosis and inflammation in SSc is by trend associated with cardiac events [12].

Aim of this study was to systematically determine morphological and functional CMR imaging patterns in systemic sclerosis in patients with histopathologically confirmed myocardial involvement in SSc.

In the present study we systematically evaluated CMR findings in a rare subgroup of SSc patients with histopathologically confirmed myocardial involvement.

In CMR, pathologic findings were documented in all SSc patients, confirming a high occurrence of abnormal volumetric data as compared to normal healthy collectives (95%CI). Diastolic dysfunction is known to develop early in the course of myocardial involvement in SSc even before the appearance of clinical symptoms [24]. The pericardial effusion found in the majority of our patients is known to be common in SSc [25], and might contribute to the development of diastolic dysfunction [26]. Pericardial effusion is also common in pulmonary arterial hypertension [25], reflecting the complexity of cardiopulmonary involvement in SSc. Notably, a number of patients only had a slight or minimal pericardial effusion, that will commonly be classified as unspecific. Regional or global enhancement by LGE imaging indicating myocardial fibrosis can be regarded as morphologic correlate for restricted diastolic and systolic function as well as for myocardial electrical conduction disorders, potentially resulting in ventricular dyssynchrony. RV dilatation occurred independently from pulmonary hypertension in a relevant number of patients, a phenomenon that has already been described previously [9]. In this context, RV dilatation may indicate RV involvement as a primary symptom in contrast to secondary dilatation.

In visual reading and semi-quantitative evaluation, we found typical non-coronary distribution of full intensity LGE as described before: a linear enhancement [7]; as well as patchy pattern at the insertion points of the right ventricle—which is also typically found in hypertrophy and pulmonary artery hypertension, the latter being frequently co-existent due to severe lung involvement in SSc patients [27]. In the semi-quantitative evaluation, grayscale intermediate intensity LGE was most frequent. We performed semi-quantitative T₁ evaluation with an ordinal scale by means of the inversion time localizer. Pathologic nulling patterns of inversion time localizer were common in our patient group, indicating severe diffuse myocardial fibrosis. Diffuse myocardial fibrosis frequently evades visual detection and is significantly underestimated in LGE quantification, for nulling of the myocardium suppresses general enhancement by shifting the threshold [28]. As a result, diffusely involved myocardium may appear normal. In semi-quantitative LGE evaluation, the region of interest for remote myocardium may be placed in regions with less but still pathologic contrast enhancement, visually not identified as such. Although diffuse general fibrosis can be detected and quantified using T₁-mapping, the values remain unspecific for diffuse fibrosis [29]. We did not find a ‘runaway’ TI with initially short TI and large incremental steps during image acquisition, which is known to be typical for amyloidosis [30]. In consequence, non-invasive assessment of the extent of myocardial fibrosis in SSc remains challenging and the implication of imaging findings for prognosis and further treatment remains uncertain. Fibrosis in biopsy may only correlate with T₁- mapping for absolute quantification of fibrosis. None of our parameters is likely to correlate with fibrosis in biopsy: LGE does shift threshold of healthy towards pathologic when nulling myocardium, and functional parameters are subject to situational adaption. Extent of cardiac involvement in SSc is not necessarily dependent on other objectively verifiable parameters and subject to subclinical periods, primary or secondary involvement and influenced by cardiotoxic therapy [2, 12].

CMR is accepted as one of the non-invasive modalities to investigate SSc involvement of the heart [31]. Yet, to determine the degree of cardiac involvement seems to be difficult even for experienced readers. To date, criteria for the CMR diagnosis of myocardial involvement in SSc are not defined. CMR was performed and evaluated before EMB in all patients, so that no influence on imaging and initial blinded reading can be stated.

As systolic dysfunction is a rare finding in SSc, the severity of the involvement tends to be underestimated [32]. Based on the inversion time localizer principle, T₁-mapping should be a promising method to further investigate diffuse myocardial fibrosis in SSc involvement [29]. T1-mapping does not require healthy remote myocardium to detect diffuse fibrosis. Extracellular volume determination in T1-mapping has recently shown the potential to correlate with myocardial fibrosis [33].

Our results might contribute to improve the non-invasive diagnosis of cardiac involvement in SSc, using CMR to identify and estimate cardiac involvement. Discrete CMR imaging patterns could be found concurrently, also in severe SSc myocardial involvement. In our retrospective evaluation, myocardial involvement in SSc was systematically underdiagnosed in the initial clinical report blinded to the subsequent histopathologic work-up with true positive diagnoses in only 30 % of our SSc cohort. The main reason may be underestimation of subtle morphologic and functional findings in SSc involvement, as this is a rare cardiac diagnosis. To date, mainly CMR findings in the maximum degree of occurrence have been published, potentially leading to a trend to underestimate subtle, yet SSc-typical, findings. Most CMR findings appear to be unspecific and can be found in a variety of diseases. However, the combination of certain findings as described in our work seems to be characteristic for cardiac SSc involvement. For the lack of correlation, CMR cannot replace EMB. EMB itself is rarely performed in a clinical setting. Application of the proposed criteria may improve assessment of clinically relevant SSc involvement. Although CMR findings in patients with cardiac involvement in SSc can easily go underdiagnosed and classified as unspecific, the combination of several CMR findings is frequent and therefore allows the diagnosis of cardiac involvement in patients with SSc by CMR: Besides distinct LGE patterns, most important findings are involvement of both ventricles, pathologic LV/RV contractility, dyssynchrony or restriction. Reading of inversion time localizer for diffuse LGE and can be easily implemented without additional technical requirements.

This approach might be useful for risk stratification when considering therapeutic options, and may eventually reduce morbidity and mortality in a patient group at risk for major adverse cardiac events. Currently two studies are recruiting SSc patients eligible for autologous stem cell transplantation, one in Chicago, IL, USA and one in Tübingen, Germany (ClinicalTrials.gov NCT01445821; NCT01895244) [34]. These studies aim to reduce cardiac toxicity of the therapy regimen with effective use of stem cell transplantation [11].

CMR seems to be a valuable tool to identify and assess the extent of cardiac involvement and therefore might be useful for risk stratification and making a decision upon therapeutic strategies. Myocardial involvement in systemic sclerosis can be assumed if pathologic findings in three categories are found: 1) pericardial effusion; 2) ventricular kinesic pattern (LV and RV hypokinesia, dyskinesia, dyssynchrony, and diastolic restriction); 3) reduced LV-EF or RV-EF; 4) positive LGE or pathologic inversion time localizer; 5) right ventricular dilatation.