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BACKGROUND:Inflammation is associated with cardiac remodeling and heart failure, but how it is initiated in response to nonischemic interventions in the absence of cell death is not known. We tested the hypothesis that activation of Ca2+/calmodulin-dependent protein kinase II δ (CaMKIIδ) in cardiomyocytes (CMs) in response to pressure overload elicits inflammatory responses leading to adverse remodeling. METHODS:Mice in which CaMKIIδ was selectively deleted from CMs (cardiac-specific knockout [CKO]) and floxed control mice were subjected to transverse aortic constriction (TAC). The effects of CM-specific CaMKIIδ deletion on inflammatory gene expression, inflammasome activation, macrophage accumulation, and fibrosis were assessed by quantitative polymerase chain reaction, histochemistry, and ventricular remodeling by echocardiography. RESULTS:TAC induced increases in cardiac mRNA levels for proinflammatory chemokines and cytokines in ≤3 days, and these responses were significantly blunted when CM CaMKIIδ was deleted. Apoptotic and necrotic cell death were absent at this time. CMs isolated from TAC hearts mirrored these robust increases in gene expression, which were markedly attenuated in CKO. Priming and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome, assessed by measuring interleukin-1β and NOD-like receptor pyrin domain-containing protein 3 mRNA levels, caspase-1 activity, and interleukin-18 cleavage, were increased at day 3 after TAC in control hearts and in CMs isolated from these hearts. These responses were dependent on CaMKIIδ and associated with activation of Nuclear Factor-kappa B and reactive oxygen species. Accumulation of macrophages observed at days 7 to 14 after TAC was diminished in CKO and, by blocking Monocyte Chemotactic Protein-1 signaling, deletion of CM Monocyte Chemotactic Protein-1 or inhibition of inflammasome activation. Fibrosis was also attenuated by these interventions and in the CKO heart. Ventricular dilation and contractile dysfunction observed at day 42 after TAC were diminished in the CKO. Inhibition of CaMKII, Nuclear Factor-kappa B, inflammasome, or Monocyte Chemotactic Protein-1 signaling in the first 1 or 2 weeks after TAC decreased remodeling, but inhibition of CaMKII after 2 weeks did not. CONCLUSIONS:Activation of CaMKIIδ in response to pressure overload triggers inflammatory gene expression and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome in CMs. These responses provide signals for macrophage recruitment, fibrosis, and myocardial dysfunction in the heart. Our work suggests the importance of targeting early inflammatory responses induced by CM CaMKIIδ signaling to prevent progression to heart failure.

Context Concern is increasing in both the medical community and among the general public about the possible transmission of hepatitis C virus (HCV) from infected health care workers to their patients. Until now, no reliable estimates for the risk of such transmission exist. Objective To estimate the probability of HCV transmission from a surgeon to a susceptible patient during invasive procedures. Design A model consisting of 4 probabilities was used: (A) the probability that the surgeon is infected with HCV, (B) the probability that the surgeon might contract percutaneous injuries, (C) the probability that an HCV-contaminated instrument will recontact the wound, and (D) the probability of HCV transmission after exposure. Values for the calculations were taken from published studies. Results When the surgeon's HCV status is unknown, the risk of HCV transmission during a single operation is 0.00018% ± 0.00002% (mean ± SD). If the surgeon is HCV RNA positive, this risk equals 0.014% ± 0.002%. The likelihoods of transmission in at least 1 of 5000 invasive procedures performed by a surgeon during 10 years are 0.9% ± 0.1% (HCV status unknown) and 50.3% ± 4.8% (HCV RNA positive), respectively. Conclusions The calculated risks for HCV transmission from a surgeon to a susceptible patient during a single invasive procedure are comparable to the chance of acquiring HCV by receiving a blood transfusion. These figures could provide a basis for further discussions on this controversial subject and might also be relevant for future recommendations on the management of HCV-infected health care workers.

The indicator-dilution principle has been employed to study coronary blood flow and the venous drainage into the coronary sinus ( CS) in the dog. Nine open-chest dogs were prepared to allow separate perfusion and flow measurement of the right and left coronary arteries ( RCAand LCA) as well as simultaneous sampling at two sites in the CS. By injecting indicator at various sites in the arterial tree, it has been demonstrated that the posterior circumflex artery drains chiefly to the CS near the CS ostium; the left anterior descending drains chiefly to the area of the CS far upstream from the CS ostium, and the RCA does not drain to the CS. These drainage data have been used to help determine the adequacy of mixing of dye and blood, and to measure LCA flow. Adequate mixing of dye and blood was frequently achieved by the criteria established, but LCA flow was accurately measured with only a minority of injections. It is likely that pecularities of the anatomy of the coronary vascular bed account for the discrepancies.