Cardiac Troponin I DK183 (TnIDK183) is the clinically best characterised mutation of all familial hypertrophic cardio-myopathy (FHC)-associated mutations. To clarify the variable clinical manifestation of the disease in TnIDK183 patients, we generated a corresponding transgenic mouse model. Multiple lines were obtained with varying expression levels. Non-transgenic siblings and transgenic mice expressing Flag-tagged wild type mcTnI showed no abnormalities (controls). TnIDK184 mice grew up normally except for some mice of the highest expression lines which died suddenly. Surprisingly, investigations of in vivo heart function by MRI displayed no left ventricular

(LV) hypertrophy. Instead, both the right and LV masses are markedly reduced with unaltered LV wall thickness. This results in smaller hearts with reduced stroke volume and cardiac output but increased ejection fraction. The severity of the dysfunction seems to be age and dose dependent. EM studies revealed areas of myofibrillar disarray with abnormal short sarcomeres, contractory bands, and swollen mitochondria. Force measurements on single myofibrils showed increased Ca²⁺-sensitivity and higher maximal active and passive force development indicating a hypercontractile state. Despite the absence of classical LV hypertrophy, our mouse model provides a tool to study several aspects of the functional progress of this disease.