Sudden cardiac death (SCD) is a common mode of death in heart failure (HF) and results
from prolonged action potential duration (APD) and ventricular arrhythmias. During the
pathogenesis and progression of HF, a myriad number of signaling pathways are altered,
including microRNAs. microRNAs are small noncoding RNAs that fine-tune gene expression
by translational repression or transcript destabilization. Interestingly, microRNAs are
dysregulated during HF, suggesting a potential involvement in the development and
progression of the disease. Here, miR-19 was identified as an important regulator of heart
function. Zebrafish lacking miR-19 developed severe bradycardia and reduced cardiac
contractility. While mammals express two isoforms of miR-19, the zebrafish genome encodes
for four members (19a-d). The reduction of miR-19b specifically was found to be sufficient to
reduce heart rate by 30 % and to induce heart failure. Patch-clamp experiments from whole
hearts showed that miR-19b deficient zebrafish exhibit significantly prolonged ventricular
APD caused by impaired repolarization. Additionally these fish show increased sensitivity to
an AV-Block, which is a characteristic feature of long QT-Syndrome in zebrafish. qRT-PCR
revealed that miR-19b directly and indirectly regulates the expression of cardiac ion channels
and thereby modulates APD and shape. This study describes miR-19b as an essential
regulator of electrical activity of the heart and identifies it as a potential candidate gene
causative for human long QT syndrome