Background Measurement of myocardial iron is key to the clinical management of patients at risk of siderotic cardiomyopathy. The cardiovascular magnetic resonance (CMR) relaxation parameter R2* (assessed clinically via its reciprocal T2*) measured in the ventricular septum is used to assess cardiac iron, but iron calibration and distribution data in humans is limited. Methods and Results Twelve human hearts were studied from transfusion dependent patients following either death (heart failure n=7, stroke n=1) or transplantation for end-stage heart failure (n=4). After CMR R2* measurement, tissue iron concentration was measured in multiple samples of each heart using inductively coupled plasma atomic emission spectroscopy. Iron distribution throughout the heart showed no systematic variation between segments, but epicardial iron concentration was higher than in the endocardium. The mean (±SD) global myocardial iron causing severe heart failure in 10 patients was 5.98 ±2.42mg/g dw (range 3.19–9.50), but in 1 outlier case of heart failure was 25.9mg/g dw. Myocardial ln[R2*] was strongly linearly correlated with ln[Fe] (R2=0.910, p<0.001) leading to [Fe]=45.0•(T2*)−1.22 for the clinical calibration equation with [Fe] in mg/g dw and T2* in ms. Mid-ventricular septal iron concentration and R2* were both highly representative of mean global myocardial iron. Conclusions These data detail the iron distribution throughout the heart in iron overload and provide calibration in humans for CMR R2* against myocardial iron concentration. The iron values are of considerable interest with regard to the level of cardiac iron associated with iron-related death and indicate that the heart is more sensitive to iron loading than the liver. The results also validate the current clinical practice of monitoring cardiac iron in-vivo by CMR of the mid septum.

BackgroundThe right ventricular outflow tract (RVOT) is acknowledged to be responsible for arrhythmogenesis in Brugada syndrome (BrS), but the pathophysiology remains controversial.ObjectivesThis study assessed the substrate underlying BrS at post-mortem and in vivo, and the role for open thoracotomy ablation.MethodsSix whole hearts from male post-mortem cases of unexplained sudden death (mean age 23.2 years) with negative specialist cardiac autopsy and familial BrS were used and matched to 6 homograft control hearts by sex and age (within 3 years) by random risk set sampling. Cardiac autopsy sections from cases and control hearts were stained with picrosirius red for collagen. The RVOT was evaluated in detail, including immunofluorescent stain for connexin-43 (Cx43). Collagen and Cx43 were quantified digitally and compared. An in vivo study was undertaken on 6 consecutive BrS patients (mean age 39.8 years, all men) during epicardial RVOT ablation for arrhythmia via thoracotomy. Abnormal late and fractionated potentials indicative of slowed conduction were identified, and biopsies were taken before ablation.ResultsCollagen was increased in BrS autopsy cases compared with control hearts (odds ratio [OR]: 1.42; p = 0.026). Fibrosis was greatest in the RVOT (OR: 1.98; p = 0.003) and the epicardium (OR: 2.00; p = 0.001). The Cx43 signal was reduced in BrS RVOT (OR: 0.59; p = 0.001). Autopsy and in vivo RVOT samples identified epicardial and interstitial fibrosis. This was collocated with abnormal potentials in vivo that, when ablated, abolished the type 1 Brugada electrocardiogram without ventricular arrhythmia over 24.6 ± 9.7 months.ConclusionsBrS is associated with epicardial surface and interstitial fibrosis and reduced gap junction expression in the RVOT. This collocates to abnormal potentials, and their ablation abolishes the BrS phenotype and life-threatening arrhythmias. BrS is also associated with increased collagen throughout the heart. Abnormal myocardial structure and conduction are therefore responsible for BrS.

SCD in sport is largely due to clinically silent cardiomyopathies or primary electrical disorders (morphologically normal heart). Antecedent symptoms and family history are absent in over 80% of cases, and therefore clinical screening with health questionnaires will fail to identify most athletes with potentially sinister cardiac disorders.