Tbx5-dependent pathway regulating diastolic function in congenital heart disease.

[holt-oram syndrome]

At the end of every heartbeat , cardiac myocytes must relax to allow filling of the heart . Impaired relaxation is a significant factor in heart failure , but all pathways regulating the cardiac relaxation apparatus are not known . Haploinsufficiency of the T -box transcription factor Tbx 5 in mouse and man causes congenital heart defects (CHDs ) as part of Holt-Oram syndrome (HOS ). Here , we show that haploinsufficiency of Tbx 5 in mouse results in cell-autonomous defects in ventricular relaxation . Tbx 5 dosage modulates expression of the sarco (endo )plasmic reticulum Ca (2 +)-ATPase isoform 2 a encoded by Atp 2 a 2 and Tbx 5 haploinsufficiency in ventricular myocytes results in impaired Ca (2 +) uptake dynamics and Ca (2 +) transient prolongation . We also demonstrate that Tbx 5 can activate the Atp 2 a 2 promoter . Furthermore , we find that patients with HOS have significant diastolic filling abnormalities . These results reveal a direct genetic pathway that regulates cardiac diastolic function , implying that patients with structural CHDs may have clinically important underlying anomalies in heart function that merit treatment .