Late onset sporadic dilated cardiomyopathy caused by a cardiac troponin T mutation

Abstract

Mutations in TNNT2, encoding cardiac troponin T, commonly shows early onset, aggressive dilated cardiomyopathy (DCM). This observation may influence the decision of whether to undertake clinical genetic testing for TNNT2 in later onset DCM. Further, the trigger for late onset DCM remains enigmatic. A 70-year-old woman, previously healthy with a left ventricular ejection fraction of 50%-55% at age 69, presented with DCM of unknown cause and a 4-month history progressive heart failure requiring cardiac transplantation. Clinical genetic testing revealed a novel TNNT2 R139H mutation but no relevant variants in 18 other DCM genes. Her explanted heart showed partial fatty replacement in the right ventricle. Sequencing for five arrhythmogenic right ventricular dysplasia genes was negative. Functional studies in porcine cardiac skinned fibers reconstituted with the mutant R139H troponin T protein showed decreased Ca(2+) sensitivity at pH 7, characteristic of DCM. Because fatty infiltration may acidify the myocellular environment, maximal force development examined at pH 6.5 was diminished, suggesting a possible environmental trigger. We conclude that the TNNT2 R139H mutation was likely to be disease causing. Further, later age of onset may not be relevant to exclude genetic testing for TNNT2 mutations.

Figure 1

Explanted heart. A transverse section of explanted heart at about the proximal third between the atrioventricular groove and apex shows moderate amount of epicardial fat and marked fatty infiltration of the right ventricular wall. There is dilatation of the right ventricular cavity, slight dilatation of the left ventricular cavity, and the left ventricular wall has a normal uniform thickness without myocardial lesions.

Figure 2

Photomicrograph of the right ventricular wall. The extensive fatty infiltration of the myocardium and absence of fibrosis is shown in this trichrome stained section.

Figure 3

Pedigree. Squares represent males; circles represent females. The presence (+) of a troponin T mutation is indicated for those from whom DNA was available. Filled symbols indicate IDC. Gray symbols indicate another form of cardiovascular abnormality or diagnosis. See text for detailed clinical descriptions.

Figure 4

Normalized pCa‐force relationship in skinned cardiac muscle fibers. The Ca²⁺ dependence of force development was measured in each preparation after whole troponin (Tn) displacement and reconstitution at pH 7.0 and pH 6.5. The maximal force recovery was also evaluated and no significant difference was observed at pH 7.0 between fibers containing wild‐type human cardiac troponin T (HCTnT‐WT) and HCTnT‐R139H (57.4 ± 1.8 vs. 58.9 ± 4.7), respectively. However, a difference in maximal force recovery was observed at pH 6.5 between HCTnT‐WT and HCTnT‐R139H (53.9 ± 2.6 vs. 43.8 ± 2.7), respectively. Data in each experiment are the average of 5 experiments and expressed as mean ± S.E. *=p < 0.05 compared to the HCTnT‐WT.