Reverse re-modelling chronic heart failure by reinstating heart rate variability.

Heart rate variability (HRV) is a crucial indicator of cardiovascular health. Low HRV is correlated with disease severity and mortality in heart failure. Heart rate increases and decreases with each breath in normal physiology termed respiratory sinus arrhythmia (RSA). RSA is highly evolutionarily conserved, most prominent in the young and athletic and is lost in cardiovascular disease. Despite this, current pacemakers either pace the heart in a metronomic fashion or sense activity in the sinus node. If RSA has been lost in cardiovascular disease current pacemakers cannot restore it. We hypothesized that restoration of RSA in heart failure would improve cardiac function. Restoration of RSA in heart failure was assessed in an ovine model of heart failure with reduced ejection fraction. Conscious 24 h recordings were made from three groups, RSA paced (n = 6), monotonically paced (n = 6) and heart failure time control (n = 5). Real-time blood pressure, cardiac output, heart rate and diaphragmatic EMG were recorded in all animals. Respiratory modulated pacing was generated by a proprietary device (Ceryx Medical) to pace the heart with real-time respiratory modulation. RSA pacing substantially increased cardiac output by 1.4 L/min (20%) compared to contemporary (monotonic) pacing. This increase in cardiac output led to a significant decrease in apnoeas associated with heart failure, reversed cardiomyocyte hypertrophy, and restored the T-tubule structure that is essential for force generation. Re-instating RSA in heart failure improves cardiac function through mechanisms of reverse re-modelling; the improvement observed is far greater than that seen with current contemporary therapies. These findings support the concept of re-instating RSA as a regime for patients who require a pacemaker.

Confocal Scanning Microscopy in Assessment of Cardiac Allograft Rejection--A Pilot Study.

Cardiac allograft rejection is typically diagnosed on the basis of hematoxylin and eosin (H&E) histology of endomyocardial biopsies. This diagnosis is made based on the degree of immune cell infiltrate and associated myocyte damage. However, considerable variability in rejection grading between pathologists can occur. Confocal microscopy provides high contrast and high resolution imaging that has the potential to provide detailed views of pathological features of allograft rejection. In this pilot study we sought to determine if confocal microscopy could be used to detect features of cardiac rejection. This was achieved by collection of additional sample at 30 biopsy procedures from 15 heart transplant patients. Routine pathological grading of H&E histology identified 5 gradings of 0R, 21 gradings of 1R, and 3 gradings of 2R. From these gradings, 3 samples for 0R, 9 samples for 1R, and 3 samples for 2R were imaged by confocal microscopy. This was achieved by fluorescently labeling sections with DAPI, wheat germ agglutinin, and phalloidin, to visualize the cell nuclei, cell border and extracellular matrix, and muscle cell actin, respectively. Labeling with these fluorescent markers was of high contrast. However, we did note variability in DAPI and phalloidin labeling of tissue sections. Confocal imaging of these labels revealed the following features at high resolution: perivascular and/or interstitial infiltrate, myocyte damage, and Quilty lesions. In particular increased detail of damaged myocytes reveals distortion in myofilament organization that could be exploited to distinguish between 1R and 2R grades. In conclusion, confocal microscopy provided high contrast and resolution imaging of cardiac biopsies that could be explored further to aid assessment of cardiac allograft rejection.

A copper(II)-selective chelator ameliorates diabetes-evoked renal fibrosis and albuminuria, and suppresses pathogenic TGF-beta activation in the kidneys of rats used as a model of diabetes.

AIMS/HYPOTHESIS: The selective Cu(II) chelator triethylenetetramine (TETA) extracts systemic Cu(II) into the urine of diabetic humans and rats as a model of diabetes, and in the process also normalises hallmarks of diabetic heart disease. However, the role of Cu and its response to TETA in animals with diabetic nephropathy were previously unknown. Here, we report the effects of TETA treatment on Cu and other essential elements, as well as on indices of renal injury and known pathogenic molecular processes, in kidneys from a rat model of diabetes. METHODS: Rats at 8 weeks after streptozotocin-induction of diabetes were treated with oral TETA (34 mg/day in drinking water) for a further 8 weeks and then compared with untreated diabetic control animals. RESULTS: Renal tissue Cu was substantively elevated by diabetes and normalised by TETA, which also suppressed whole-kidney and glomerular hypertrophy without lowering blood glucose. The urinary albumin: creatinine ratio was significantly elevated in the rat model of diabetes but lowered by TETA. Total collagen was also elevated in diabetic kidneys and significantly improved by TETA. Furthermore, renal cortex levels of TGF-beta1, MAD homologue (SMAD) 4, phosphorylated SMAD2, fibronectin-1, collagen-III, collagen-IV, plasminogen activator inhibitor-1 and semicarbazide-sensitive amine oxidase all tended to be elevated in diabetes and normalised by TETA. CONCLUSIONS/INTERPRETATION: Dysregulation of renal Cu homeostasis may be a key event eliciting development of diabetic nephropathy. Selective Cu(II) chelation can protect against pathogenic mechanisms that lead to or cause diabetic nephropathy and might be clinically useful in the treatment of early-stage diabetic kidney disease.

Effect of changes in action potential spike configuration, junctional sarcoplasmic reticulum micro-architecture and altered t-tubule structure in human heart failure.

Using a Monte-Carlo model of L-type Ca2+ channel (DHPR) gating, we have examined the effect of changes in the early time course of the action potential as seen in human heart failure on excitation contraction coupling. The time course of DHPR Ca2+ influx was coupled into a simple model of sarcoplasmic reticulum Ca2+ release. Our model shows that the loss of the initial spike in human heart failure should reduce the synchrony of Ca2+ spark production and lead to the appearance of late Ca2+ sparks and greater non-uniformity of intracellular Ca2+. Within the junctional space of the cardiac dyad, a small increase in the mean distance of a DHPR from a RyR results in a marked decrease in the ability of the DHPR-mediated increase in local [Ca2+] concentration to activate RyRs. This suggests that the efficiency of EC coupling may be reduced if changes in micro-architecture develop and such effects have been noted in experimental models of heart failure. High resolution imaging of t-tubules in tachycardia-induced heart failure show deranged t-tubule structure. While in normal human hearts t-tubules run mainly in a radial direction, t-tubules in the heart failure samples were oriented more toward the long axis of the cell. In addition, t-tubules may become dilated and bifurcated. Our data suggest that changes in the micro-architecture of the cell and membrane structures associated with excitation-contraction coupling, combined with changes in early action potential configuration can reduce the efficiency by which Ca2+ influx via DHPRs can activate SR calcium release and cardiac contraction. While the underlying cause of these effects is unclear, our data suggest that geometric factors can play an important role in the pathophysilogy of the human heart in failure.