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Background The cardiac remodelling process in advanced heart failure due to pressure overload has not been clearly defined but likely involves mechanisms of cardiac fibrosis and cardiomyocyte hypertrophy. The aim of this study was to examine pressure overload (PO)-induced cardiac remodelling processes and their reversibility after unloading in both humans with heart failure and a mouse model of PO induced by aortic constriction. Methods & Results Speckle tracking echocardiography showed PO-induced cardiac dysfunction in mice was reversible after removal of aortic constriction to unload. Masson's Trichrome staining suggested that PO-induced myocardial fibrosis was reversible, however detailed analysis of 3-dimensional collagen architecture by scanning electron microscopy demonstrated that matrix remodelling was not completely normalised as a disorganised network of thin collagen fibres was evident. Analysis of human left ventricular biopsy samples from HF patients revealed increased presence of large collagen fibres which were greatly reduced in paired samples from the same individuals after unloading by left ventricular assist device implantation. Again, an extensive network of small collagen fibres was still clearly seen to closely surround cardiomyocytes after unloading. Other features of PO-induced remodelling including increased myofibroblast content, cardiomyocyte disarray and hypertrophy were largely reversed upon unloading in both humans and mouse model. Previous work in humans demonstrated that receptors for adiponectin, an important mediator of cardiac fibrosis and hypertrophy, decreased in heart failure patients and returned to normal after unloading. Here we provide novel data showing a similar trend for adiponectin receptor adaptor protein APPL1, but not APPL2 isoform. Conclusions LV unloading diminishes PO-induced cardiac remodelling and improves function. These findings add new insights into the cardiac remodelling process, and provide novel targets for future pharmacologic therapies. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The objective of the study is to determine cardiac autonomic control in patients undergoing assessment for and/or LVAD therapy. Methods: Heart rate variability (HRV) was measured in 17 explanted LVAD, 17 implanted LVAD and 23 NYHA III–IV classified chronic heart failure (CHF) patients and ten healthy matched controls under three conditions: supine free breathing, standing and supine controlled breathing. Five measures of HRV were assessed: mean R–R interval (mR–R), high frequency (HF) and low frequency (LF) spectral power, LF in normalised units (LFnu), and LF to HF (LF:HF) ratio. Results: Repeat measures ANOVA showed significant (p<0.05) differences in HRV between all three conditions within groups. Lower values were observed in CHF for LF(in log natural units) compared with explanted patients (−1.4 [95% CI −2.6 to −0.7], p=0.04) and controls (−2.1 [−3.5 to −0.7], p=0.001) and for LF:HF compared with implanted patients under paced breathing conditions (z =−2.7, p=0.007) and controls in standing (z =−2.9, p=0.004) and paced breathing conditions (z =−2.3, p=0.02). However, no significant differences were seen between explanted, implanted and control groups under any condition. Conclusions: Patients implanted with an LVAD and explanted from a LVAD following myocardial recovery demonstrate a more normal dynamic response to autonomic stimuli and have a lower HRV risk profile compared to CHF patients. [Copyright &y& Elsevier]

Abstract: Background: Sleep disordered breathing (SDB) is highly prevalent in patients with chronic heart failure (CHF) and is associated with adverse effects on cardiac geometry and function. Continuous positive airway pressure (CPAP) has been proved an effective treatment modality for obstructive sleep apnoea (OSA), whereas adaptive servoventilation (ASV) is more effective in patients with central sleep apnoea (CSA). The impact of selection of therapy and effective apnoea alleviation on cardiac performance and reverse left ventricular remodelling (r-LVR) has not yet been evaluated. Methods: Eighty five patients with stable CHF were screened for SDB and underwent polysomnography and treatment according to the type of SDB. Clinical evaluation and a comprehensive echocardiographic study was performed before initiation of therapy and after six months of effective treatment (ventilator use >5h/day with AHI <5events/h). Results: Seventeen compliant patients under effective treatment were included in the analysis (8 OSA under Autoset CPAP and 9 CSA under ASV). In both groups, a significant improvement in all measured, conventional and TDI LV systolic indexes was recorded, including LVEF (32%±6% vs. 27%±6%, p<0.001). A decrease in LV end-systolic volume (189±94ml vs. 211±88ml, p=0.015, difference >10%) was indicative of r-LVR. Furthermore, RV systolic parameters were also increased (TAPSE, p<0.001; systolic TDI wave from lateral tricuspid annular aspect, p=0.001), whereas right heart dimensions and areas were diminished, indicating better pulmonary haemodynamics. Moreover, a significant improvement in patients' clinical status, as evaluated by New York Heart Association Class was also documented at the end of six months follow-up. Conclusions: Effective alleviation of SDB in CHF patients is associated with significant improvements in LV and RV systolic function and r-LVR. Longitudinal studies are needed to evaluate effects on morbidity and mortality. [Copyright &y& Elsevier]

Abstract: Background: Cardiac resynchronization therapy (CRT) promotes left ventricular (LV) reverse remodelling and affects myocardial collagen turnover in heart failure (HF) patients. Osteopontin (OPN) is a matrix glycoprotein required for the activation of fibroblasts upon TGF-β1 stimulation. In humans, plasma OPN and OPN-expressing lymphocytes correlate with the severity of HF. We sought to evaluate whether plasma OPN and TGF-β1 reflect LV reverse remodelling following CRT. Methods: Eighteen patients (12 men, mean age 65±11years) undergoing CRT were studied. Patients underwent baseline clinical and echocardiographic evaluation, and assessment of plasma OPN and TGF-β1. The evaluation was repeated 8.5±4months after device implantation. Eight healthy age- and sex-matched subjects served as controls. Results: In HF patients, baseline plasma OPN and TGF-β1 were higher as compared to control subjects (OPN: 99±48 vs 59±22ng/ml; p<0.05; TGF-β1: 15.9±8.0 vs 9.3±5.6ng/ml; p<0.05). At follow-up, 12 patients responded to CRT and showed LV reverse remodelling, whereas 6 did not. Plasma OPN decreased in CRT responders (108±47 vs 84±37ng/ml; p=0.03) and increased in non-responders (79±58 vs 115±63ng/ml; p<0.01). TGF-β1 showed a trend towards reduction in responders (17.5±8.7 vs 10.2±8.9ng/ml; p=0.08) and was unchanged in non-responders. A significant correlation (r=−0.56; p=0.01) was found between relative changes of LVESV and plasma OPN. Conclusions: CRT-induced LV reverse remodelling is reflected by changes in plasma OPN. Circulating OPN may represent a marker of LV dilation/impairment and an indicator of the response to HF therapies promoting LV reverse remodelling. [Copyright &y& Elsevier]