Non-invasive evaluation of the relationship between electrical and structural cardiac abnormalities in patients with myotonic dystrophy type 1.

BACKGROUND: Cardiac involvement in myotonic dystrophy type 1 (MD1) includes conduction disease, arrhythmias, and left-ventricular (LV) systolic dysfunction leading to an increased sudden cardiac death risk. An understanding of the interplay between electrical and structural myocardial changes could improve the prediction of adverse cardiac events. We aimed to explore the relationship between signs of cardiomyopathy by conventional and advanced cardiovascular magnetic resonance (CMR), and electrical abnormalities in MD1. METHODS: Fifty-seven MD1 patients (43 ± 13 years, 46% male) and 15 matched controls (41 ± 7 years, 53% male) underwent CMR including cine-imaging with feature-tracking strain analysis, late gadolinium enhancement (LGE), and native/post-contrast T1-mapping with extracellular volume calculation. Standard 12-lead and long-term ECG monitoring were performed as screening for rhythm and/or conduction abnormalities. RESULTS: Abnormal ECGs were recorded in 40% of MD1; a pathologic CMR was found in 44%: 21% had an impaired LV-EF and 32% showed non-ischemic LGE. When looking at MD1 patients with available long-term ECG monitoring (n = 39), those with atrial fibrillation (Afib)/flutter(Afl) episodes had lower LV-EF (52 ± 7 vs. 60 ± 5%, p = 0.002), lower global longitudinal strain (- 17 ± 3 vs. - 20 ± 3%, p = 0.034), a trend to lower left atrial emptying fraction (LA-EF) (44 ± 14 vs. 55 ± 8%, p = 0.08), and higher prevalence of LGE (88% vs. 23%, p = 0.001) with an intramural (75% vs. 23%, p = 0.01) and septal (63% vs. 13%, p = 0.009) pattern. In a model including LV-EF (OR 0.8, 95% CI 0.7-1.0, p = NS) and LGE presence (OR 14.8, 95% CI 1.4-159.0, p = 0.026), only LGE was independently associated with the occurrence of Afib/Afl episodes. CONCLUSION: Myocardial abnormalities depicted by non-ischemic LGE-CMR were the only independent predictor for the occurrence of Afib/Afl on ECG monitoring, previously shown to predict adverse cardiac events in MD1.

Identification of Cardiomyopathy-Associated Circulating miRNA Biomarkers in Muscular Dystrophy Female Carriers Using a Complementary Cardiac Imaging and Plasma Profiling Approach.

Background: Different from males with Duchenne/Becker muscular dystrophy (DMD/BMD) in whom overt myopathy is the rule, muscular dystrophy (MD) female carriers are mostly free of skeletal muscle symptoms. However, similar to MD males, these females are also prone to cardiomyopathy. Since circulating microRNAs (miRNAs) have been proposed as diagnostic biomarkers for various cardiovascular diseases, the aim of the current study was to identify specific circulating miRNAs in the plasma of female DMD/BMD carriers that may allow an early and accurate diagnosis of cardiac involvement in these cases. Methods: Twenty-nine female MD carriers and 24 age-matched healthy female controls were prospectively enrolled. All MD carriers and controls underwent comprehensive cardiovascular magnetic resonance (CMR) studies as well as venous blood sampling on the same day. Results: An impaired left ventricular (LV) systolic function was detected in 4 (14%) MD carriers while late gadolinium enhancement (LGE) indicative of myocardial fibrosis was present in 13 female patients (45%)-with an exclusively non-ischemic pattern. Among the circulating miRNAs examined, six were significantly up-regulated in MD carriers compared to female controls: miR-206 (103-fold increase, p < 0.0001), miR-222 (41-fold, p < 0.0001), miR-26a (fourfold, p = 0.029), miR-342 (27-fold, p < 0.0001), miR-378a-3p (minimum 3,600-fold; almost undetectable in controls, p = 0.013), miR-378a-5p (64-fold, p < 0.0001); only two miRNAs were substantially down-regulated in MD carriers: miR-144 (p < 0.0001) and miR-29a (p = 0.002) (both undetectable in carriers). A significant down-regulation of the miR-29c (<0.001-fold, p = 0.006) was observed in MD carriers with abnormal CMR findings (comprising functional and/or structural abnormalities) compared to those with normal CMR examinations. Univariable analyses regarding the presence of abnormal CMR findings resulted in four significant variables: LV end-diastolic volume index (EDVi), LV end-systolic volume index (ESVi), an elevated plasma creatine kinase (CK), and decreased serum miR-29c levels. In subsequent multivariable analysis, the only independent predictor for an abnormal CMR among MD carriers was circulating miR-29c (OR 0.99, 95% CI 0.98-0.99, p = 0.037). Moreover, an elevated CK and/or a downregulated miR-29c level (<0.05 × 10-3) resulted in an improved AUC value of 0.79 (0.62-0.97, p = 0.007) (79, 80 and 80%, sensitivity, specificity and overall accuracy) for the CMR-based diagnosis of cardiomyopathy in MD carriers when compared to using the two parameters individually. Conclusion: In female MD carriers, down-regulation of circulating miR-29c relates to the presence of functional and/or structural cardiac abnormalities (as detected by CMR) and appears to be a promising novel biomarker-in addition to conventional CK plasma levels-for an early diagnosis of cardiomyopathy.

Identification of cardiomyopathy associated circulating miRNA biomarkers in patients with muscular dystrophy using a complementary cardiovascular magnetic resonance and plasma profiling approach.

BACKGROUND: Duchenne and Becker muscular dystrophy (DMD and BMD) are X-chromosomal recessive neuromuscular disorders that are caused by mutations in the dystrophin gene and characterized by cardiac involvement. Circulating microRNAs (miRNAs) have been proposed as diagnostic biomarkers for various cardiovascular diseases. However, circulating miRNAs reflecting the presence and/or disease severity of cardiac involvement in DMD/BMD patients have not been described so far. METHODS: Sixty-three male patients with known MD and 26 age-matched healthy male controls were prospectively enrolled. All MD patients and controls underwent comprehensive cardiovascular magnetic resonance (CMR) studies as well as venous blood sampling on the same day. RESULTS: An impaired left ventricular (LV) systolic function (defined as LV-EF <55 %) was detected in 29 (46 %) and presence of late gadolinium enhancement (LGE) indicative of myocardial fibrosis in 48 (76 %) MD patients with an exclusively non-ischemic pattern. Whereas no significant differences were observed for the 27 selected circulating miRNAs in MD patients with abnormal CMR findings (comprising structural and/or functional impairments) compared to those with completely normal CMR studies, a significant up-regulation of three miRNAs was observed in LGE-positive MD patients compared to LGE-negative ones: miR-222 (1.8-fold, p = 0.035), miR-26a (2.1-fold, p = 0.03) and miR-378a-5p (2.4-fold, p = 0.026). A signature of these three miRNAs (miR-26a, miR-222 and miR-378a-5p) resulted in an area under the curve (AUC) value of 0.74 for the diagnosis of LGE-positive MD patients. In a multivariable model, three independent predictors for LGE presence were identified comprising not only clinical and laboratory markers (LV-EF: OR 0.47, 95 % CI 0.24-0.89, p = 0.021 and elevated hs-Trop: OR 2559, 95 % CI 2.97-22.04*10(5), p = 0.023) but also the circulating miR-222 (OR 938, 95 % CI 938.46, 3.56-24.73*10(4), p = 0.016). CONCLUSIONS: Up-regulation of circulating miRNAs miR-222, miR-26a and miR-378a-5p indicates the presence of myocardial scars in MD patients. Plasma miR-222 appears to be a promising novel biomarker reflecting structural - but not functional - cardiac alterations in MD patients.

Cardiac involvement in female Duchenne and Becker muscular dystrophy carriers in comparison to their first-degree male relatives: a comparative cardiovascular magnetic resonance study.

AIMS: Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders associated with both skeletal myopathy and progressive cardiomyopathy in males. Female DMD/BMD carriers (DMDc/BMDc) are mostly free of skeletal muscle symptoms, but they are also prone to cardiomyopathy. The aim of the current study was to characterize the frequency, pattern, and extent of cardiomyopathy in female DMD/BMD carriers (DMDc/BMDc) in comparison to their first-degree male MD relatives. METHODS AND RESULTS: Thirty-six (age 44 ± 14 years) female MD carriers (20 DMDc and 16 BMDc) constituted the 'MD carrier group' and were prospectively enrolled. All MD carriers underwent a complete CMR study comprising cine- and late gadolinium enhancement (LGE) imaging. In 22 of these women ('female MD carrier comparison group', 7 DMD and 15 BMD), at least one first-degree male relative with a previously established diagnosis of MD underwent the same CMR protocol and was assigned to the 'male MD comparison group' (n = 24, 6 DMD and 18 BMD). In the total MD carrier group, 17 (47%) MD carriers had at least one pathological CMR finding [5 (14%) with a reduced left ventricular ejection fraction (LV-EF) and 16 (44%) with the presence of LGE]. All LGE-positive patients (n = 16) showed non-ischaemic LGE with subepicardial involvement of the LV lateral free wall being the most frequent pattern (13/16, 81%). Compared with BMDc, DMDc demonstrated more frequently a pathological CMR result (65 vs. 19%; P = 0.008)--in spite of being significantly younger (40 ± 11 vs. 50 ± 16 years, P = 0.038). In the male MD comparison group, the same LGE pattern as in female carriers was seen, but with a significantly higher prevalence of cardiac abnormalities compared with their female carrier relatives constituting the female MD comparison group (75 vs. 27%; P = 0.003). CONCLUSION: Cardiac involvement is a frequent finding in female carriers of DMD, but less frequently observed in carriers of BMD. Those DMDc and BMDc with cardiac involvement demonstrate the same myocardial fibrosis pattern as their male counterparts with overt disease.

Characteristic cardiac phenotypes are detected by cardiovascular magnetic resonance in patients with different clinical phenotypes and genotypes of mitochondrial myopathy.

BACKGROUND: Mitochondrial myopathies (MM) are a heterogeneous group of inherited conditions resulting from a primary defect in the mitochondrial respiratory chain with consecutively impaired cellular energy metabolism. Small sized studies using mainly electrocardiography (ECG) and echocardiography have revealed cardiac abnormalities ranging from conduction abnormalities and arrhythmias to hypertrophic or dilated cardiomyopathy in these patients. Recently, characteristic patterns of cardiac involvement were documented by cardiovascular magnetic resonance (CMR) in patients with chronic progressive external ophthalmoplegia (CPEO)/Kearns-Sayre syndrome (KSS) and with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). The present study aimed to characterize the prevalence and pattern of cardiac abnormalities and to test the additional diagnostic value of CMR in this patient population. The hypothesis that different neuromuscular MM syndromes present with different cardiac disease phenotypes was evaluated. METHODS: Sixty-four MM patients (50 ± 15 years, 44% male) and 25 matched controls (52 ± 14 years, 36% male) prospectively underwent cardiac evaluations including CMR (comprising cine- and late-gadolinium-enhancement (LGE) imaging). Based on the neuromuscular phenotype and genotype, the patients were grouped: (a) CPEO/KSS (N = 33); (b) MELAS/-like (N = 11); c) myoclonic epilepsy with ragged-red fibers (MERRF) (N = 3) and d) other non-specific MM forms (N = 17). RESULTS: Among the 64 MM patients, 34 (53%) had at least one abnormal CMR finding: 18 (28%) demonstrated an impaired left ventricular ejection-fraction (LV-EF <60%), 14 (22%) had unexplained LV hypertrophy and 21 (33%) were LGE-positive. Compared to controls, MM patients showed significantly higher maximal wall thickness (10 ± 3 vs. 8 ± 2 mm, p = 0.005) and concentricity (LV mass to end-diastolic volume: 0.84 ± 0.27 vs. 0.67 ± 0.11, p < 0.0001) with frequent presence of non-ischemic LGE (30% vs. 0%, p = 0.001). CPEO/KSS showed a predominantly intramural pattern of LGE mostly confined to the basal LV inferolateral wall (8/10; 80%) in addition to a tendency toward concentric remodelling. MELAS/-like patients showed the highest frequency of cardiac disease (in 10/11 (91%)), a mostly concentric LV hypertrophy (6/9; 67%) with or without LV systolic dysfunction and a predominantly focal, patchy LGE equally distributed among LV segments (8/11; 73%). Patients with MERRF and non-specific MM had no particular findings. Pathological CMR findings indicating cardiac involvement were detected significantly more often than pathological ECG results or elevated cardiac serum biomarkers (34 (53%) vs. 18 (28%) vs. 21 (33%); p = 0.008). CONCLUSION: Cardiac involvement is a frequent finding in MM patients - and particularly present in KSS/CPEO as well as MELAS/-like patients. Despite a high variability in clinical presentation, CPEO/KSS patients typically show an intramural pattern of LGE in the basal inferolateral wall whereas MELAS patients are characterized by overt concentric hypertrophy and a rather unique, focally accentuated and diffusely distributed LGE.

Diagnostic value of CMR in young patients with clinically suspected acute myocarditis is determined by cardiac enzymes.

AIMS: Cardiovascular magnetic resonance (CMR) has become a valuable diagnostic tool for non-invasive diagnosis of acute myocarditis. However, since CMR studies are time- and cost-intensive and its diagnostic accuracy still not perfect, additional parameters are warranted to preselect and identify those individuals in whom a CMR study is likely to add crucial information regarding correct and timely diagnosis of acute myocarditis. The diagnostic value of CMR was evaluated in a population of young patients with clinically suspected acute myocarditis in relation to ECG and serum cardiac enzyme findings. METHODS AND RESULTS: Only young patients aged ≤ 40 years in whom acute myocarditis was highly suspected based on their clinical symptoms, resting ECG findings and/or levels of cardiac enzymes (at presentation) were included to this study. After ruling out obstructive coronary artery disease, a multi-parametric CMR study was performed as part of the diagnostic work-up. The CMR protocol comprised cine sequences, T2-weighted edema imaging and late gadolinium enhancement (LGE) imaging on a 1.5-T MR scanner. 89 patients (28 ± 7 years, 89 % male) were included to this study presenting with symptoms of chest pain (85 %), dyspnea (26 %), fatigue (23 %) and/or palpitations (18 %). Pathological ECG changes were present in 72 patients (81 %). An elevated serum troponin level was measured in 45 patients (51 %). Pathological CMR findings (presence of edema and/or LGE) were detected in 35 patients (39 %). In detail, pathological CMR findings were detected in 36 % of patients with resting ECG changes and in 73 % of patients with troponin rise. In contrast, normal CMR results were obtained in 95 % of patients with negative troponin at presentation, but only in 41 % of patients with normal ECG. On multivariable analysis, a positive serum troponin was the only independent predictor for a pathological CMR finding (OR = 33.26, 95 % CI = 3.04-363.35, p = 0.004). CONCLUSIONS: The clinical use of non-invasive CMR in the work-up of clinically suspected "acute" myocarditis in young patients is only helpful and appropriately indicated in those ones with elevated cardiac enzymes. A pre-selection of such patients for CMR based on serum cardiac enzymes--but not on ECG recordings--may prevent a meaningless overuse of CMR.

Left ventricular systolic function and the pattern of late-gadolinium-enhancement independently and additively predict adverse cardiac events in muscular dystrophy patients.

BACKGROUND: Cardiac involvement is a frequent finding in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies. With this study, we aimed at elucidating the relationship between the phenotypic expression of cardiac involvement and the occurrence of adverse cardiac events in DMD/BMD patients. METHODS: Eighty-eight male DMD/BMD patients (age 29 ± 14 yrs) were prospectively enrolled. All patients underwent cardiovascular magnetic resonance (CMR) comprising cine- and late-gadolinium-enhancement (LGE)-CMR at study entry and were subsequently followed-up for adverse cardiac events. The primary endpoint was defined as all-cause/cardiac death or cardiac transplantation. Secondary endpoints were (1) hospitalization for heart failure and/or (2) occurrence of non-/sustained ventricular tachycardia (VT). RESULTS: During a mean follow-up time of 47 ± 18 months, the primary endpoint was observed in three (3%) and the secondary endpoint in 21 (24%) patients. On multivariable analysis, LV-EF (HR, 95% CI: 0.94, 0.89-0.97, p = 0.001) and the presence of "transmural" LGE (HR, 95% CI: 2.89, 1.09-7.68, p = 0.033) were the only independent predictors for secondary endpoints. A cut-off for LV-EF of 45% was associated with the highest hazard ratio (HR, 95% CI: 11.50, 4.49-29.43, p < 0.0001) in a Cox regression survival analysis. In the group of patients with a LV-EF (>45%), those patients already showing "transmural" LGE had a significantly lower event-free-survival (HR, 95% CI: 13.48, 1.89-96.12, p = 0.009) compared to those without. CONCLUSIONS: An impaired LV systolic function (LV-EF ≤45%) and a "transmural" pattern of myocardial fibrosis independently predict the occurrence of adverse cardiac events in DMD/BMD patients. Even in DMD/BMD patients with relatively preserved LV-EF (>45%), the simple and visually assessable parameter "transmural LGE" is of additive prognostic value.

Myocardial fibrosis imaging based on T1-mapping and extracellular volume fraction (ECV) measurement in muscular dystrophy patients: diagnostic value compared with conventional late gadolinium enhancement (LGE) imaging.

AIM: Cardiac involvement with progressive myocardial fibrosis leading to dilated cardiomyopathy is a major cause of death in muscular dystrophy patients. Extracellular volume fraction (ECV) measurement based on T1-mapping pre- and post-contrast promises the detection of early 'diffuse' myocardial fibrosis that cannot be depicted by conventional contrast-imaging based on late gadolinium enhancement (LGE). With this study, we evaluated the presence of diffuse myocardial fibrosis in regions of 'normal' (LGE-negative) and 'diseased' (LGE-positive) appearing myocardium as well as its relation to the extent of left ventricular (LV) dysfunction and the occurrence of arrhythmias in Becker muscular dystrophy (BMD) patients. METHODS AND RESULTS: Twenty-seven BMD patients (35 ± 12 years) and 17 matched male healthy controls (33 ± 8 years) underwent cardiovascular magnetic resonance (CMR) studies including ECV measurement and LGE-imaging. Ambulatory monitoring of arrhythmic events was performed by means of an external event loop recorder. Twenty BMD patients (74%) demonstrated cardiac involvement as detected by typical inferolateral presence of LGE. Twelve patients (44%) had an impaired LV ejection fraction-all being LGE-positive. Global myocardial ECV was significantly higher in the BMD group (29 ± 6%) compared with the control group (24 ± 2%, P = 0.001). Patients with cardiac involvement demonstrated higher global ECV (31 ± 6%) as well as significantly increased regional ECV not only in LGE-positive segments (34 ± 6%), but also in LGE-negative segments (28 ± 6%) compared with BMD patients without cardiac involvement and to controls, respectively (24 ± 3 and 24 ± 2%, P = 0.005). Global ECV in patients with cardiac involvement substantially correlated to LV ejection fraction (r = -0.629, P = 0.003) and to the number of LGE-positive segments (r = 0.783, P < 0.001). On univariable analysis, global ECV-but not the categorical presence of LGE per se--was significantly associated with arrhythmic events (OR: 1.97, CI: 32.22-1.21, P = 0.032). CONCLUSION: ECV measurement by CMR is a useful tool in assessing the total extent of myocardial fibrosis as well as in depicting subtle diffuse fibrosis in areas of normal appearing myocardium on LGE-images. Thus, myocardial ECV is a potential additional quantitative tool for accurate detection of cardiac involvement and risk stratification in muscular dystrophy patients.

Positive effect of intravenous iron-oxide administration on left ventricular remodelling in patients with acute ST-elevation myocardial infarction - a cardiovascular magnetic resonance (CMR) study.

OBJECTIVES: This study investigated the safety profile and potential "therapeutic" effect of intravenous ultrasmall superparamagnetic iron-oxide (USPIO)-based iron administration regarding infarct healing in patients with ST-elevation myocardial infarction (STEMI). USPIO-administration was recently shown to enable an improved characterization of myocardial infarct pathology in acute STEMI patients. MATERIALS AND METHODS: Seventeen study patients (IRON, 54 ± 9 yrs, 88% male) and 22 matched controls (CONTROL, 57 ± 9 yrs, 77% male) both with primary reperfused STEMI underwent multi-parametric CMR studies in the first week and three months after acute MI. Only IRON patients received a single intravenous bolus of 510 mg elemental iron as ferumoxytol (Feraheme(TM)) within four days following acute MI. RESULTS: Three months later, all patients were alive and there were no adverse cardiac events. Significant improvement in left ventricular (LV) ejection fraction (IRON: 53 ± 10% to 59 ± 9%, p=0.002; CONTROL: 54 ± 6% to 57 ± 10%, p=0.005) as well as shrinkage of infarct size were seen in both groups at follow-up. There was a more pronounced decrease in infarct size in the IRON group (IRON: -10.3 ± 5.4% vs. CONTROL: -7.0 ± 8.4%, p=0.050) in addition to a significant decrease in both endocardial extent and prevalence of transmural infarctions in IRON but not in CONTROL patients. A significant decrease in LV end systolic volume was only seen in the IRON group (71 ± 25 mL to 59 ± 25 mL, p=0.002). CONCLUSIONS: Intravenous iron administration in acute STEMI patients seems to be associated with an improved infarct healing and a beneficial global left ventricular remodelling. These findings together with the good safety profile make USPIO-based iron administration a promising future candidate as a "diagnostic" and "therapeutic" adjunctive solution in acute MI management.

Magnetic resonance of the heart in a muscular dystrophy patient with an MR conditional ICD: assessment of safety, diagnostic value and technical limitations.

Cardiovascular magnetic resonance (CMR) studies in patients with pacemakers or implantable cardioverter/defibrillators (ICD) are increasingly required in daily clinical practice. Therefore, in the last years the manufacturers developed not only MR-conditional pacemakers, but also MR-conditional ICDs. However, the clinical experience regarding the feasibility and limitations of MR studies of the heart in patients with ICDs is still limited. In particular, there are hardly any CMR studies in the same patients performed prior to and post ICD implantation allowing a one-to-one comparison of the obtained CMR images. This is the first presentation of a CMR study in a patient with the world's first and so far only MR-conditional ICD. In our case, a major problem related to the presence of the MR conditional ICD was an image artifact caused by the device's generator which hampered the visualization of the midventricular and apical anterior and antero-lateral segments in all sequences performed. Considering previous studies, right chest implantation of the ICD could probably have helped in this setting and may be preferred in future ICD implantations. Our case report nicely illustrates the real clinical need for specially designed implantable devices that ensure safe and high-quality imaging in patients in whom serial CMR is required.

Imaging of myocardial infarction using ultrasmall superparamagnetic iron oxide nanoparticles: a human study using a multi-parametric cardiovascular magnetic resonance imaging approach.

AIMS: The purpose of this clinical trial was to investigate whether cardiovascular magnetic resonance imaging (CMR) using ferumoxytol (Feraheme™, FH), an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO), allows more detailed characterization of infarct pathology compared with conventional gadolinium-based necrosis/fibrosis imaging in patients with acute myocardial infarction. METHODS AND RESULTS: Fourteen patients who had experienced an acute ST-elevation myocardial infarction were included in this study. Following coronary angiography, a first baseline study (pre-FH) was performed followed by subsequent CMR studies (post-FH) 48 h after intravenous ferumoxytol administration. The CMR studies comprised cine-CMR, T(2)-weighted short tau inversion recovery spin echo imaging, T(2)-mapping, and T(1)-weighted late gadolinium enhancement (LGE) imaging. The median extent of short-axis in-plane LGE was 30% [inter-quartile range (IQR) 26-40%]. The median in-plane extent of T(2)-weighted 'hypoenhancement' in the region of myocardial infarction, which was not present prior to ferumoxytol administration in any patient, was 19% (IQR 14-22%; P < 0.001 compared with the extent of LGE). The median in-plane extent of areas showing signal void in T(2)-mapping images post-FH in the region of myocardial infarction was 16% (IQR 12-18%; P < 0.001 compared with the extent of LGE; P = 0.34 compared with the extent of T(2)-weighted hypoenhancement). A substantial drop in absolute T(2)-values was observed not only in the infarct core and peri-infarct zone, but also in the remote 'healthy' myocardium, although there was only a minor change in the skeletal muscle. Substantial ferumoxytol uptake was detected only in cultured macrophages, but not in peripheral blood monocytes from study patients. CONCLUSION: We could demonstrate in humans that USPIO-based contrast agents enable a more detailed characterization of myocardial infarct pathology mainly by detecting infiltrating macrophages. Considering the multi-functionality of USPIO-based particles and their superior safety profile compared with gadolinium-based compounds, these observations open up new vistas for the clinical application of USPIO.

Magnetic resonance imaging (MRI) of inflamed myocardium using iron oxide nanoparticles in patients with acute myocardial infarction - preliminary results.

OBJECTIVES: Superparamagnetic iron oxide nanoparticle (SPIO)-based molecular imaging agents targeting macrophages have been developed and successfully applied in animal models of myocardial infarction. The purpose of this clinical trial was to investigate whether magnetic resonance imaging (MRI) of macrophages using ferucarbotran (Resovist®) allows improved visualisation of the myocardial (peri-)infarct zone compared to conventional gadolinium-based necrosis/fibrosis imaging in patients with acute myocardial infarction. MATERIAL AND METHODS: The clinical study NIMINI-1 was performed as a prospective, non-randomised, non-blinded, single agent phase III clinical trial (NCT0088644). Twenty patients who had experienced either an acute ST-elevation or non-ST-elevation myocardial infarction (STEMI/NSTEMI) were included to this study. Following coronary angiography, a first baseline cardiovascular magnetic resonance (CMR) study (pre-SPIO) was performed within seven days after onset of cardiac symptoms. A second CMR study (post-SPIO) was performed either 10 min, 4h, 24h or 48h after ferucarbotran administration. The CMR studies comprised cine-CMR, T2-weighted "edema" imaging, T2-weighted cardiac imaging and T1-weighted late-gadolinium-enhancement (LGE) imaging. RESULTS: The median extent of short-axis in-plane LGE was 28% (IQR 19-31%). Following Resovist® administration the median extent of short-axis in-plane T2-weighted hypoenhancement (suggestive of intramyocardial haemorrhage and/or SPIO accumulation) was 0% (IQR 0-9%; p=0.68 compared to pre-SPIO). A significant in-slice increase (>3%) in the extent of T2-weighted "hypoenhancement" (post-SPIO compared to pre-SPIO) was seen in 6/16 patients (38%). However, no patient demonstrated "hypoenhancement" in T2-weighted images following Resovist® administration that exceeded the area of LGE. CONCLUSIONS: T2/T2-weighted MRI aiming at non-invasive myocardial macrophage imaging using the approved dose of ferucarbotran does not allow improved visualisation of the myocardial (peri-) infarct zone compared to conventional gadolinium-based necrosis/fibrosis imaging.

Cardiovascular magnetic resonance imaging (CMR) reveals characteristic pattern of myocardial damage in patients with mitochondrial myopathy.

BACKGROUND: Mitochondrial myopathy comprises various clinical subforms of neuromuscular disorders that are characterised by impaired mitochondrial energy metabolism due to dysfunction of the mitochondrial respiratory chain. No comprehensive and targeted cardiovascular magnetic resonance (CMR) studies have been performed so far in patients with mitochondrial disorders. The present study aimed at characterising cardiac disease manifestations in patients with mitochondrial myopathy and elucidating the in vivo cardiac damage pattern of patients with different subforms of mitochondrial disease by CMR studies. METHODS AND RESULTS: In a prospective study, 37 patients with mitochondrial myopathy underwent comprehensive neurological and cardiac evaluations including physical examination, resting ECG and CMR. The CMR studies comprised cine-CMR, T2-weighted "edema" imaging and T1-weighted late-gadolinium-enhancement (LGE) imaging. Various patterns and degrees of skeletal myopathy were present in the participants of this study, whereas clinical symptoms such as chest pain symptoms (in eight (22%) patients) and various degrees of dyspnea (in 16 (43%) patients) were less frequent. Pathological ECG findings were documented in eight (22%) patients. T2-weighted "edema" imaging was positive in one (3%) patient with MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) only. LGE imaging demonstrated the presence of non-ischemic LGE in 12 (32%) patients: 10 out of 24 (42%) patients with CPEO (chronic progressive external ophthalmoplegia) or KSS (Kearns-Sayre syndrome) and 2 of 3 (67%) patients with MELAS were LGE positive. All 10 LGE-positive patients with CPEO or KSS demonstrated a potentially typical pattern of diffuse intramural LGE in the left-ventricular (LV) inferolateral segments. CONCLUSIONS: Cardiac involvement is a frequent finding in patients with mitochondrial myopathy. A potentially characteristic pattern of diffuse intramural LGE in the LV inferolateral segments was identified in patients suffering from the subforms CPEO or KSS.