Cardiomyocyte Regeneration in Human Myocarditis.

BACKGROUND

Newly generated cardiomyocytes (NGCs) concur with the recovery of human myocarditis occurring spontaneously in around 50% of cases. However, NGCs decline with age, and their modality of myocardial homing and integration are still unclear.

METHODS

We retrospectively assessed NGCs in 213 consecutive patients with endomyocardial biopsy denoting acute myocarditis, with normal coronaries and valves. Tissue samples were processed for histology (H&E), immunohistochemistry for the evaluation of inflammatory infiltrates, immunostaining for alpha-sarcomeric-actin, junctional connexin-43, Ki-67, and phosphorylated STAT3 (p-STAT3), and Western blot (WB) for HMGB1. Frozen samples were analyzed using polymerase chain reaction (PCR) for cardiotropic viruses. Controls included 20 normal surgical biopsies.

RESULTS

NGCs were defined as small myocytes (diameter < 10 µm) with nuclear positivity to Ki-67 and p-STAT3 and positive immunostaining for cytoplasmic α-sarcomeric actin and connexin-43. Their number/mm in relation to age and pathway of integration was evaluated. NGCs crossed the membrane and grew integrated within the empty necrotic myocytes. NGC mean diameter was 6.6 ± 3.34 vs. 22.5 ± 3.11 µm adult cells; their number, in comparison to LVEF, was 86.3 ± 10.3/mm in patients between 18 and 40 years, 50.4 ± 13.8/mm in those between 41 and 60, and 15.1 ± 5.7/mm in those between 61 and 80. Control NGCs' mean diameter was 0.2 ± 0.2 mm. PCR was positive for viral genomes in 16% of cases; NGCs were not statistically different in viral and non-viral myocarditis. WB analysis revealed a higher expression of HMGB1 in myocarditis compared to myocardial controls.

CONCLUSIONS

NGCs are constantly recognizable in acute human myocarditis. Their number declines with age. Their integration within necrotic myocytes allows for the preservation of the cardiac structure and function.