Background Hypertrophic cardiomyopathy (HCM) is a common genetic disorder caused mainly by mutations in sarcomeric proteins and is characterized by maladaptive myocardial hypertrophy, diastolic heart failure, increased myofilament Ca2+ sensitivity and high susceptibility to sudden death. We tested the following hypothesis: correction of the increased myofilament sensitivity can delay or prevent the development of the HCM phenotype. Methods and Results We used an HCM mouse model with an E180G mutation in α-tropomyosin (Tm180) that demonstrates increased myofilament Ca2+ sensitivity, severe hypertrophy and diastolic dysfunction. To test our hypothesis, we reduced myofilament Ca2+ sensitivity in Tm180 mice by generating a double transgenic (DTG) mouse line. We crossed Tm180 mice with mice expressing a pseudo-phosphorylated cardiac troponin I (cTnI) (S23D and S24D; TnI-PP). TnI-PP mice demonstrated a reduced myofilament Ca2+ sensitivity compared to wild-type mice. The development of pathological hypertrophy did not occur in mice expressing both Tm180 and TnI-PP. Left ventricle performance was improved in DTG compared to their Tm180 littermates, which express wild-type cTnI. Hearts of DTG mice demonstrated no changes in expression of phospholamban (PLN) and Serca2a, increased levels of PLN and TnT phosphorylation, and reduced phosphorylation of TnI compared to Tm180 mice. Moreover, expression of TnI-PP in Tm180 hearts inhibited modifications in the activity of ERK1/2 and GATA-4 in Tm180 hearts. Conclusions Our data strongly indicate that reduction of myofilament sensitivity to Ca2+ and associated correction of abnormal relaxation can delay or prevent development of HCM and should be considered as a therapeutic target for HCM.

Objectives Although mechanical ventilation (MV) is a life-saving intervention in patients suffering from respiratory failure, prolonged MV is often associated with numerous complications including problematic weaning. In contracting skeletal muscle, inadequate O2 supply can limit oxidative phosphorylation resulting in muscular fatigue. However, whether prolonged MV results in decreased diaphragmatic blood and induces an O2 supply-demand imbalance in the diaphragm remains unknown. Design We tested the hypothesis that prolonged controlled MV results in a time-dependent reduction in rat diaphragmatic blood flow and microvascular PO2 and that prolonged MV would diminish the diaphragm’s ability to increase blood flow in response to muscular contractions. Measurements and Main Results Compared to 30 min of MV, 6 hrs of MV resulted in a 75% reduction in diaphragm blood flow (via radiolabeled microspheres), which did not occur in the intercostal muscle or high-oxidative hindlimb muscle (e.g., soleus). There was also a time-dependent decline in diaphragm microvascular PO2 (via phosphorescence quenching). Further, when contrasted to 30 min of MV, 6 hrs of MV significantly compromised the diaphragm’s ability to increase blood flow during electrically-induced contractions which resulted in a ~80% reduction in diaphragm O2 uptake. In contrast, 6 hrs of spontaneous breathing in anesthetized animals did not alter diaphragm blood flow or the ability to augment flow during electrically-induced contractions. Conclusions These new and important findings reveal that prolonged MV results in a time-dependent decrease in the ability of the diaphragm to augment blood flow to match O2 demand in response to contractile activity and could be a key contributing factor to difficult weaning. Although additional experiments are required to confirm, it is tempting to speculate that this ventilator-induced decline in diaphragmatic oxygenation could promote a hypoxia-induced generation of reactive oxygen species in diaphragm muscle fibers and contribute to ventilator-induced diaphragmatic atrophy and contractile dysfunction.

Correction After publication of our paper [1], we discovered that our normalized blood velocity and compliance numbers were 60 times higher than they should have been. The revised Figure 1 and Figure 2, along with Table 1 are shown here with the correct values. Heart rate, blood pressure, and half time to recovery of blood flow and oxygen saturation from the original article are all correct. The statistical analysis and interpretation of the data remain unchanged. We apologize for the error.