Publications

Previous evidence suggests that the dual-specific A kinase-anchoring protein 2 functional polymorphism (AKAP10 (A/G) I646V) influences heart rate (HR) and heart rate variability (HRV) in mice and humans (N=122) with cardiovascular disease. Here, we asked whether this AKAP10 variant predicts HR and HRV in a large sample of healthy humans. Resting HR and short-term time and frequency domain measures of HRV (5 min during paced and unpaced respiration conditions) were assessed in a U.S. community sample (N=1,033) of generally healthy men and women (age 30-54) of European ancestry. Each person was genotyped for the AKAP10 variant. As with previous work, the AKAP10 Val allele predicted greater resting HR (Paced p<.01; Unpaced p<.03) and diminished HRV (Paced ps <.05) suggesting that this variant may modulate the sensitivity of cardiac pacemaker cells to autonomic inputs, possibly conferring risk for arrhythmias and sudden cardiac death.

Enhanced external counterpulsation (EECP) is a noninvasive technique that provides beneficial effects for patients with chronic, symptomatic angina pectoris. However, the direct left ventricular effects of EECP have not been studied invasively. We examined invasive right atrial pressure and left ventricular hemodynamics during EECP. Ten patients referred for diagnostic evaluation underwent left heart catheterization from the radial artery. At baseline and during EECP, left ventricular pressure and volume were measured using a micromanometer pressure-conductance catheter, along with recording of right atrial and central aortic pressures. Hemodynamics were recorded at different lower extremity cuff configuration and cuff inflation pressures. As cuff inflation pressure increased, EECP resulted in a dose-dependent increase in right atrial and aortic diastolic pressure (P < 0.0001). The increase in ventricular preload resulted in increased left ventricular volume. Maximum positive (P = 0.0003) and negative left ventricular dP/dt (P < 0.0001) increased. Left ventricular diastolic pressure decreased. There was a neutral effect on myocardial mechanical efficiency. In conclusion, EECP acutely increased right atrial and central aortic diastolic pressure. The increase in preload attenuated the reduction in left ventricular diastolic pressure resulting from systolic unloading. The increased preload counterbalanced the afterload reduction, resulting in a neutral effect on myocardial efficiency.

Anti-TNF immunotherapy has revolutionized the treatment of some inflammatory diseases, such as RA. However, a major concern is that patients receiving this therapy have an increased risk of fungal and bacterial infection, particularly of reactivating latent tuberculosis (TB). In this issue of the JCI, in an effort to understand how anti-TNF immunotherapy affects host mechanisms required to control TB, Bruns and colleagues examined the effects of the anti-TNF therapeutic infliximab on Mycobacterium tuberculosis-specific human lymphocytes (see the related article beginning on page 1167). The authors report that a granulysin-expressing CD45RA+ subset of effector memory CD8+ T cells that contributes to the killing of intracellular M. tuberculosis is depleted in vivo by infliximab in patients with RA, and that these cells are susceptible to complement-mediated lysis in the presence of infliximab in vitro. The study provides insight into host defense mechanisms that act to control TB infection and how they are affected during anti-TNF immunotherapy for autoimmune disease.