Publications

Increased signaling by G(i)-coupled receptors has been implicated in dilated cardiomyopathy. To investigate the mechanisms, we used transgenic mice that develop dilated cardiomyopathy after conditional expression of a cardiac-targeted G(i)-coupled receptor (Ro1). Activation of G(i) signaling by the Ro1 agonist spiradoline caused decreased cellular cAMP levels and bradycardia in Langendorff-perfused hearts. However, acute termination of Ro1 signaling with the antagonist nor-binaltorphimine did not reverse the Ro1-induced contractile dysfunction, indicating that Ro1 cardiomyopathy was not due to acute effects of receptor signaling. Early after initiation of Ro1 expression, there was a 40% reduction in the abundance of the sarcoplasmic reticulum Ca(2+)-ATPase (P < 0.05); thereafter, there was progressive impairment of both Ca(2+) handling and force development assessed with ventricular trabeculae. Six weeks after initiation of Ro1 expression, systolic Ca(2+) concentration was reduced to 0.61 +/- 0.08 vs. 0.91 +/- 0.07 microM for control (n = 6-8; P < 0.05), diastolic Ca(2+) concentration was elevated to 0.41 +/- 0.07 vs. 0.23 +/- 0.06 microM for control (n = 6-8; P < 0.01), and the decline phase of the Ca(2+) transient (time from peak to 50% decline) was slowed to 0.25 +/- 0.02 s vs. 0.13 +/- 0.02 s for control (n = 6-8; P < 0.01). Early after initiation of Ro1 expression, there was a ninefold elevation of matrix metalloproteinase-2 (P < 0.01), which is known to cause myofilament injury. Consistent with this, 6 wk after initiation of Ro1 expression, Ca(2+)-saturated myofilament force in skinned trabeculae was reduced to 21 +/- 2 vs. 38 +/- 0.1 mN/mm(2) for controls (n = 3; P < 0.01). Furthermore, electron micrographs revealed extensive myofilament damage. These findings may have implications for some forms of human heart failure in which increased activity of G(i)-coupled receptors leads to impaired Ca(2+) handling and myofilament injury, contributing to impaired ventricular pump function and heart failure.

BACKGROUND

Previous studies suggest that markers of inflammation are elevated in patients with atrial fibrillation (AF). However, because inflammation has been implicated in contributing to risk of both AF and coronary artery disease (CAD), which are often present in the same populations, it is important to control for confounding by the presence of CAD. We therefore examined several biomarkers of inflammation and ultimately genotyped IL-6 polymorphisms in patients with AF in a cohort of subjects with known CAD.

METHODS

We performed a cross-sectional analysis of 971 participants in the Heart and Soul Study, 46 of whom had AF. Interleukin-6, C-reactive protein, tumor necrosis factor-alpha, CD-40 ligand, monocyte chemoattractant protein-1, and fibrinogen levels were measured.

RESULTS

In both unadjusted and adjusted analyses, IL-6 was the only biomarker significantly associated with AF (median IL-6 3.76 and 2.52 pg/mL in those with and without AF, respectively, P = .0005; adjusted odds ratio 1.77, P = .032). The IL-6-174CC genotype was significantly associated with the presence of AF in the adjusted analysis (odds ratio 2.34, P = .04) and with higher IL-6 levels (P = .002).

CONCLUSIONS

In this cohort of subjects with CAD, AF was significantly associated with elevated IL-6 levels and the IL-6-174CC genotype. No associations were found with other biomarkers, including C-reactive protein. This suggests that IL-6 is a uniquely important mediator in the pathophysiology of AF.

Human immunodeficiency virus (HIV) immunopathogenesis in children remains poorly understood. We assessed T cell immune activation in antiretroviral therapy-naive children in Uganda (n=154). Increased CD4+ and CD8+ T cell activation strongly correlated with decreased CD4+ T cell percentage. Interestingly, no correlation between plasma HIV RNA level and T cell activation was observed after controlling for CD4+ T cell count. In addition, the presence of Gag-specific CD4+ T helper responses was associated with increased HIV-specific CD8+ T cells. Understanding the balance between immune activation and T cell immunity in HIV-infected children may provide further insights into the mechanisms leading to effective immune control.