Impact of Heterogeneity of Human Peripheral Blood Monocyte Subsets on Myocardial Salvage in Patients With Primary Acute Myocardial Infarction

ObjectivesWe examined whether distinct monocyte subsets contribute in specific ways to myocardial salvage in patients with acute myocardial infarction (AMI).BackgroundRecent studies have shown that monocytes in human peripheral blood are heterogeneous.MethodsWe studied 36 patients with primary AMI. Peripheral blood sampling was performed 1, 2, 3, 4, 5, 8, and 12 days after AMI onset. Two monocyte subsets (CD14+CD16−and CD14+CD16+) were measured by flow cytometry. The extent of myocardial salvage 7 days after AMI was evaluated by cardiovascular magnetic resonance imaging as the difference between myocardium at risk (T2-weighted hyperintense lesion) and myocardial necrosis (delayed gadolinium enhancement). Cardiovascular magnetic resonance imaging was also performed 6 months after AMI.ResultsCirculating CD14+CD16−and CD14+CD16+monocytes increased in AMI patients, peaking on days 3 and 5 after onset, respectively. Importantly, the peak levels of CD14+CD16−monocytes, but not those of CD14+CD16+monocytes, were significantly negatively associated with the extent of myocardial salvage. We also found that the peak levels of CD14+CD16−monocytes, but not those of CD14+CD16+monocytes, were negatively correlated with recovery of left ventricular ejection fraction 6 months after infarction.ConclusionsThe peak levels of CD14+CD16−monocytes affect both the extent of myocardial salvage and the recovery of left ventricular function after AMI, indicating that the manipulation of monocyte heterogeneity could be a novel therapeutic target for salvaging ischemic damage

Genetic modulation of the SERCA activity does not affect the Ca²⁺ leak from the cardiac sarcoplasmic reticulum

The Ca(2+) content in the sarcoplasmic reticulum (SR) determines the amount of Ca(2+) released, thereby regulating the magnitude of Ca(2+) transient and contraction in cardiac muscle. The Ca(2+) content in the SR is known to be regulated by two factors: the activity of the Ca(2+) pump (SERCA) and Ca(2+) leak through the ryanodine receptor (RyR). However, the direct relationship between the SERCA activity and Ca(2+) leak has not been fully investigated in the heart. In the present study, we evaluated the role of the SERCA activity in Ca(2+) leak from the SR using a novel saponin-skinned method combined with transgenic mouse models in which the SERCA activity was genetically modulated. In the SERCA overexpression mice, the Ca(2+) uptake in the SR was significantly increased and the Ca(2+) transient was markedly increased. However, Ca(2+) leak from the SR did not change significantly. In mice with overexpression of a negative regulator of SERCA, sarcolipin, the Ca(2+) uptake by the SR was significantly decreased and the Ca(2+) transient was markedly decreased. Again, Ca(2+) leak from the SR did not change significantly. In conclusion, the selective modulation of the SERCA activity modulates Ca(2+) uptake, although it does not change Ca(2+) leak from the SR