Arrhythmogenic cardiomyopathy with left ventricular involvement versus ischemic heart disease: lessons learned from the family study and the reviewed autopsy of a young male

Abstract

Ischemic heart disease (IHD) is the leading cause of sudden cardiac death (SCD) and often non-thrombosed severe coronary stenoses with or without myocardial scars are detected. Left dominant arrhythmogenic cardiomyopathy (LDAC) is a life-threating rare disease which has been more thoroughly studied in the last 10 years. The macroscopic study of an SCD victim was conducted and re-evaluated 9 years later. The cardiological work-up in his first-degree relatives initially comprised an electrocardiogram (ECG) and an echocardiogram. When they were re-evaluted 9 years later, a cardiac magnetic resonance, an ECG-monitoring, an exercise testing and a genetic study were performed and the pedigree was extended accordingly. In 2008, an IHD was suspected in the sports-triggered SCD of a 37-year-old man upon the postmortem (75% stenosis of the left main and circumflex coronary arteries; the subepicardial left ventricular fibrofatty infiltration with mild myocardial degeneration was assumed to be a past myocardial infarction). No cardiomyopathy was identified in any of the two proband’s sisters. Nine years thereafter, distant relatives were diagnosed with LDAC due to a pathogenic desmoplakin mutation. The reanalysis of the two sisters showed ventricular arrhythmias in one of them without structural heart involvement and the reviewed postmortem of the proband was reclassified as LDAC based on the fibrofatty infiltration; both were mutation carriers. The completion of the family study on 19 family members yielded one SCD due to LDAC (the proband), three living patients diagnosed with LDAC (two with a defibrillator), one mutation carrier without structural ventricular involvement, and 14 healthy relatives (who were discharged) with a very good co-segregation of the mutation. Although rare, LDAC exists and sometimes its differential diagnosis with IHD has to be faced. Modifying previous postmortem misdiagnoses can help family screening to further prevent SCDs.

Genetics of Peripartum Cardiomyopathy: Current Knowledge, Future Directions and Clinical Implications

“…Studies of isolated PPCM cases have further implicated TTN in severe PPCM [ 35 ], as well as other disease genes such as KCNH2 , RET and TXNRD2 [ 16 , 36 , 37 ], although the contribution of these genes to PPCM is unclear: the mutations in these cases may merely reflect the co-occurrence of genetic disorders with PPCM. Mutations in FKTN , RBM20 , LMNA and DSP were also linked to PPCM through large cardiomyopathy family studies [ 38 , 39 , 40 , 41 ].…”

Transcriptional regulation profiling reveals disrupted lipid metabolism in failing hearts with a pathogenic phospholamban mutation

“…due to mutations in PKP2, DSG2, DSP, DSC2, JUP, SCN5A, and TNNT2) cardiomyopathies, myotonic dystrophy, obesity, and atrial fibrillation, exhibit fibrofatty infiltration as one of the pathophysiological hallmarks. 11,[13][14][15] However, it is still unclear which cell type(s) or mechanisms are responsible for the adipocyte infiltration by either the activation of the already existing pool of adipocytes or transdifferentiation of (cardiac) cells into adipocytes. 11 Interestingly, next to the extracellular adipocyte infiltration, abnormalities in intracellular cardiomyocyte lipid metabolism have been observed in arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by mutations in PKP2.…”