A, Izu LT, Balke CW. Hypertensioninduced remodeling of cardiac excitation-contraction coupling in ventricular myocytes occurs prior to hypertrophy development. Am J Physiol Heart Circ Physiol 293: H3301-H3310, 2007. First published September 14, 2007; doi:10.1152/ajpheart.00259.2007.-Hypertension is a major risk factor for developing cardiac hypertrophy and heart failure. Previous studies show that hypertrophied and failing hearts display alterations in excitation-contraction (E-C) coupling. However, it is unclear whether remodeling of the E-C coupling system occurs before or after heart disease development. We hypothesized that hypertension might cause changes in the E-C coupling system that, in turn, induce hypertrophy. Here we tested this hypothesis by utilizing the progressive development of hypertensive heart disease in the spontaneously hypertensive rat (SHR) to identify a window period when SHR had just developed hypertension but had not yet developed hypertrophy. We found the following major changes in cardiac E-C coupling during this window period. 1) Using echocardiography and hemodynamics measurements, we found a decrease of left ventricular ejection fraction and cardiac output after the onset of hypertension. 2) Studies in isolated ventricular myocytes showed that myocardial contraction was also enhanced at the same time.3) The action potential became prolonged. 4) The E-C coupling gain was increased.5) The systolic Ca 2ϩ transient was augmented. These data show that profound changes in E-C coupling already occur at the onset of hypertension and precede hypertrophy development. Prolonged action potential and increased E-C coupling gain synergistically increase the Ca 2ϩ transient. Functionally, augmented Ca 2ϩ transient causes enhancement of myocardial contraction that can partially compensate for the greater workload to maintain cardiac output. The increased Ca 2ϩ signaling cascade as a molecular mechanism linking hypertension to cardiac hypertrophy development is also discussed. heart failure; action potential; L-type Ca 2ϩ channel; ryanodine receptor SYSTEMIC HYPERTENSION is a major risk factor for cardiac hypertrophy and heart failure. The severe impact of hypertensive heart disease (HHD) is underscored by the fact that ϳ30% of the US adult population have hypertension (17) and 60% of these develop cardiac hypertrophy (13, 36). However, the cellular and molecular mechanisms linking hypertension to heart diseases remain unclear. Extensive evidence has demonstrated that cardiac hypertrophy is associated with remodeling of the excitation-contraction (E-C) coupling system and enhanced myocardial contraction (11,22,33), and heart failure is marked by diminished contractility (2, 3, 6, 18). An important yet unanswered question is whether changes in E-C coupling are directly linked to hypertension or are merely markers of later-stage hypertrophy. We hypothesized that hypertension might directly cause remodeling of the cardiac E-C coupling system.Previous studies using hearts that had already developed s...

Sleep is a critical process that is well-conserved across mammalian species, and perhaps most animals, yet its functions and underlying mechanisms remain poorly understood. Identification of genes and pathways that can influence sleep may shed new light on these functions. Genomic screens enable the detection of previously unsuspected molecular processes that influence sleep.In this study, we report results from a large-scale phenotyping study of sleep-wake parameters for a population of single-gene knockout mice. Sleep-wake parameters were measured using a high throughput, non-invasive piezoelectric system called PiezoSleep. Knockout mice generated on a C57BL6/N (B6N) background were monitored for sleep and wake parameters for five days. By analyzing data from over 6000 mice representing 343 single gene knockout lines, we identified 122 genes influencing traits like sleep duration and bout length that have not been previously implicated in sleep, including those that affect sleep only during a specific circadian phase.PiezoSleep also allows assessment of breath rates during sleep and this was integrated as a supplemental tool in identifying aberrant physiology in these knockout lines. Sex differences were evident in both normal and altered sleep behavior. Through a combination of genetic and phenotypic associations, and known QTLs for sleep, we propose a set of candidate genes playing specific roles in sleep. The high "hit rate" demonstrates that many genes can alter normal sleep behaviors through a variety of mechanisms. Further investigation of these genes may provide insight into the pathways regulating sleep, functional aspects of sleep, or indirect potentially pathological processes that alter normal sleep.

Electrical stability in the heart depends on two important factors; restitution of action potential duration (APD) and memory. Repolarization currents play an important role in determining APD and also affect memory. We determined the effects of blocking the rapid component of the delayed rectifier (I(Kr)) on a quantifiable measure of memory, i.e. hysteresis in restitution of APD, in swine. Transmembrane potentials were recorded from right ventricular endocardial tissues. Two pacing protocols with explicit control of diastolic interval (DI) were used to change DIs in a sequential and sinusoidal pattern to quantify hysteresis in restitution of APD. E-4031 (5 µM/L) was used to block I(Kr). Measures of memory and restitution were quantified by calculating hysteresis loop thickness, area, overall tilt, and maximum and minimum delays between DIs and APDs. Blocking I(Kr) with E-4031 increased the baseline APD, loop thickness, area, and tilt (p<0.05). However, loop thickness did not increase beyond what could be predicted by the increase in baseline APD after block of I(Kr). The substantial change in APD after blocking I(Kr) suggests that this current plays a major role in repolarization in the swine. Loop thickness is a measure of memory, an increase in which is predicted by theory to reduce instability in activation. In our study, the substantial increase in loop thickness could be accounted for by an equally substantial increase in APD and therefore does not necessarily indicate increased memory after blocking I(Kr). Our results also suggest that factors based on restitution and memory need to be considered in the context of operating point, i.e. baseline APD, when they are used to explore mechanisms that affect electrical stability in the heart.

Age-related differences in lumbar contribution to the trunk motion in the sagittal plane were investigated. Sixty individuals between 20-70 years old in five gender-balanced age groups performed forward bending and backward return with slow and fast paces. Individuals older than 50 years old, irrespective of the gender or pace, had smaller lumbar contribution than those younger than this age. The lumbar contribution to trunk motion was also smaller in female participants than male participants, and under fast pace than under the slow pace. Age-related differences in lumbar contributions suggest the synergy between the active and passive lower back tissues is different between those above and under 50 years old, differences that are likely to affect the lower back mechanics. Therefore, detailed modelling should be conducted in future to find the age-related differences in the lower back mechanics for tasks involving large trunk motion. Practitioner Summary: Lumbar contribution to the sagittal trunk motion was observed to be smaller in individuals above 50 years old than those below this age. This could be an indication of a likely change in the synergy between the active and passive lower back tissues, which may disturb the lower back mechanics.

Introduction Medical societies and cardiac implantable electronic devices (CIED) manufacturers recommend avoiding close or direct contact between the body of transvenous leads and ablation catheters used to treat cardiac arrhythmias. These recommendations are made despite the lack of clinical studies. However, the target myocardium for successful ablation can be contiguous to CIED leads. Methods and Results We examine in vitro the effects of direct application of radiofrequency (RF) and cryo-ablation energy on the integrity and functionality of CIED leads (excluding the pacing electrodes and defibrillation coils). A saline bath was created to mimic the body milieu. CIED leads, including all commercially available lead insulation materials, were connected to a CIED pulse generator and placed in direct contact with ablation catheter in the tissue bath. RF and cryo-ablation energy were delivered under various conditions, including maximal ablation power, temperature and impedance via the RF generator. CIED lead functionality, reflective of conductor integrity, was evaluated through lead impedance monitoring during ablation. CIED leads were then visually inspected, and examined with optic and electron microscopy as per protocol. A total of 42 leads were studied. All leads showed absence of insulation damage at the site of ablation visually and with microscopy. Lead functionality was also preserved in all leads. Conclusion Catheter ablation in contact with CIED leads using radiofrequency or cryo-ablation in vitro did not affect lead body integrity and function despite aggressive ablation settings. It may be reasonable to perform ablation in contact with the body of CIED leads when clinically necessary.