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Summary Background COVID-19 can lead to multiorgan failure. Dapagliflozin, a SGLT2 inhibitor, has significant protective benefits for the heart and kidney. We aimed to see whether this agent might provide organ protection in patients with COVID-19 by affecting processes dysregulated during acute illness. Methods DARE-19 was a randomised, double-blind, placebo-controlled trial of patients hospitalised with COVID-19 and with at least one cardiometabolic risk factor (ie, hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease). Patients critically ill at screening were excluded. Patients were randomly assigned 1:1 to dapagliflozin (10 mg daily orally) or matched placebo for 30 days. Dual primary outcomes were assessed in the intention-to-treat population: the outcome of prevention (time to new or worsened organ dysfunction or death), and the hierarchial composite outcome of recovery (change in clinical status by day 30). Safety outcomes, in patients who received at least one study medication dose, included serious adverse events, adverse events leading to discontinuation, and adverse events of interest. This study is registered with ClinicalTrials.gov , NCT04350593 . Findings Between April 22, 2020 and Jan 1, 2021, 1250 patients were randomly assigned with 625 in each group. The primary composite outcome of prevention showed organ dysfunction or death occurred in 70 patients (11·2%) in the dapagliflozin group, and 86 (13·8%) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·58–1·10; p=0·17). For the primary outcome of recovery, 547 patients (87·5%) in the dapagliflozin group and 532 (85·1%) in the placebo group showed clinical status improvement, although this was not statistically significant (win ratio 1·09, 95% CI 0·97–1·22; p=0·14). There were 41 deaths (6·6%) in the dapagliflozin group, and 54 (8·6%) in the placebo group (HR 0·77, 95% CI 0·52–1·16). Serious adverse events were reported in 65 (10·6%) of 613 patients treated with dapagliflozin and in 82 (13·3%) of 616 patients given the placebo. Interpretation In patients with cardiometabolic risk factors who were hospitalised with COVID-19, treatment with dapagliflozin did not result in a statistically significant risk reduction in organ dysfunction or death, or improvement in clinical recovery, but was well tolerated. Funding AstraZeneca.

AIMS: Coronavirus disease 2019 (COVID-19) is caused by a novel severe acute respiratory syndrome coronavirus 2. It can lead to multiorgan failure, including respiratory and cardiovascular decompensation, and kidney injury, with significant associated morbidity and mortality, particularly in patients with underlying metabolic, cardiovascular, respiratory or kidney disease. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, has shown significant cardio- and renoprotective benefits in patients with type 2 diabetes (with and without atherosclerotic cardiovascular disease), heart failure and chronic kidney disease, and may provide similar organ protection in high-risk patients with COVID-19. MATERIALS AND METHODS: DARE-19 (NCT04350593) is an investigator-initiated, collaborative, international, multicentre, randomized, double-blind, placebo-controlled study testing the dual hypotheses that dapagliflozin can reduce the incidence of cardiovascular, kidney and/or respiratory complications or all-cause mortality, or improve clinical recovery, in adult patients hospitalized with COVID-19 but not critically ill on admission. Eligible patients will have ≥1 cardiometabolic risk factor for COVID-19 complications. Patients will be randomized 1:1 to dapagliflozin 10 mg or placebo. Primary efficacy endpoints are time to development of new or worsened organ dysfunction during index hospitalization, or all-cause mortality, and the hierarchical composite endpoint of change in clinical status through day 30 of treatment. Safety of dapagliflozin in individuals with COVID-19 will be assessed. CONCLUSIONS: DARE-19 will evaluate whether dapagliflozin can prevent COVID-19-related complications and all-cause mortality, or improve clinical recovery, and assess the safety profile of dapagliflozin in this patient population. Currently, DARE-19 is the first large randomized controlled trial investigating use of sodium-glucose cotransporter 2 inhibitors in patients with COVID-19.

Ceramides are a class of bioactive sphingolipids increasingly recognized in metabolic disease, heart failure (HF), atherosclerosis, and cardiovascular death ([1][1]). Despite accumulating evidence linking ceramides to HF risk, little is known about circulating ceramides and clinical outcomes in HF

Visual Abstract, Highlights • DM is a significant risk factor for major adverse cardiovascular events in patients with HFpEF. • Patients with diabetes with HFpEF have a distinct proteome compared with patients without diabetes with HFpEF. • Proteomics analysis identified higher levels of alpha-1-microglobulin/bikunin precursor protein in patients with diabetes with HFpEF and lower levels of CILP2 and Apo M. • Lower Apo M levels mediate most of the association between diabetes and major adverse cardiovascular events in HFpEF., Summary Diabetes mellitus (DM) is associated with a higher risk of heart failure hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Using SomaScan assays and proteomics analysis of plasma from participants in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial and the Penn Heart Failure Study, this study identified 10 proteins with significantly different expression in patients with HFpEF and DM. Of these, apolipoprotein M was found to mediate 72% (95% CI: 36% to 100%; p

Background: Apo (apolipoprotein) M mediates the physical interaction between high-density lipoprotein (HDL) particles and sphingosine-1-phosphate (S1P). Apo M exerts anti-inflammatory and cardioprotective effects in animal models. Methods: In a subset of PHFS (Penn Heart Failure Study) participants (n=297), we measured apo M by Enzyme-Linked ImmunoSorbent Assay (ELISA). We also measured total S1P by liquid chromatography–mass spectrometry and isolated HDL particles to test the association between apo M and HDL-associated S1P. We confirmed the relationship between apo M and outcomes using modified aptamer-based apo M measurements among 2170 adults in the PHFS and 2 independent cohorts: the Washington University Heart Failure Registry (n=173) and a subset of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial; n=218). Last, we examined the relationship between apo M and ≈5000 other proteins (SomaScan assay) to identify biological pathways associated with apo M in heart failure. Results: In the PHFS, apo M was inversely associated with the risk of death (standardized hazard ratio, 0.56 [95% CI, 0.51–0.61]; P P P P =0.001) in models that adjusted for multiple confounders. This association was present in both heart failure with reduced and preserved ejection fraction and was replicated in the Washington University cohort and a cohort with heart failure with preserved ejection fraction only (TOPCAT). The S1P and apo M content of isolated HDL particles strongly correlated ( R =0.81, P Conclusions: Reduced circulating apo M is independently associated with adverse outcomes across the spectrum of human heart failure. Further research is needed to assess whether the apo M/S1P axis is a suitable therapeutic target in heart failure.

Background Mutations in αB‐crystallin result in proteotoxic cardiomyopathy with desmin mislocalization to protein aggregates. Intermittent fasting (IF) is a novel approach to activate transcription factor EB (TFEB), a master regulator of the autophagy‐lysosomal pathway, in the myocardium. We tested whether TFEB activation can be harnessed to treat advanced proteotoxic cardiomyopathy. Methods and Results Mice overexpressing the R120G mutant of αB‐crystallin in cardiomyocytes (Myh6‐CryABR120G) were subjected to IF or ad‐lib feeding, or transduced with adeno‐associated virus–TFEB or adeno‐associated virus—green fluorescent protein after development of advanced proteotoxic cardiomyopathy. Adeno‐associated virus–short hairpin RNA–mediated knockdown of TFEB and HSPB8 was performed simultaneously with IF. Myh6‐CryABR120G mice demonstrated impaired autophagic flux, reduced lysosome abundance, and mammalian target of rapamycin activation in the myocardium. IF resulted in mammalian target of rapamycin inhibition and nuclear translocation of TFEB with restored lysosome abundance and autophagic flux; and reduced aggregates with normalized desmin localization. IF also attenuated left ventricular dilation and myocardial hypertrophy, increased percentage fractional shortening, and increased survival. Adeno‐associated virus–TFEB transduction was sufficient to rescue cardiomyopathic manifestations, and resulted in reduced aggregates and normalized desmin localization in Myh6‐CryABR120G mice. CryABR120G‐expressing hearts demonstrated increased interaction of desmin with αB‐crystallin and reduced interaction with chaperone protein, HSPB8, compared with wild type, which was reversed by both IF and TFEB transduction. TFEB stimulated autophagic flux to remove protein aggregates and transcriptionally upregulated HSPB8, to restore normal desmin localization in CryABR120G‐expressing cardiomyocytes. Short hairpin RNA–mediated knockdown of TFEB and HSPB8 abrogated IF effects, in vivo. Conclusions IF and TFEB activation are clinically relevant therapeutic strategies to rescue advanced R120G αB‐crystallin mutant‐induced cardiomyopathy by normalizing desmin localization via autophagy‐dependent and autophagy‐independent mechanisms., See Editorial by Mukai et al

Endothelial function may be deranged in heart failure with preserved ejection fraction (HFpEF). Serum NO-derived metabolites (NO m ) might provide a biochemical surrogate of endothelial function in patients with heart failure (HF). We measured serum NO m in 415 participants in the Penn HF Study. Participants with HFpEF (n = 82) and those whose EF had recovered (Recovered-HF, n = 125) were matched 1:1 to heart failure with reduced ejection fraction (HFrEF) participants based on age, gender, race, tobacco use, and eGFR. Serum NO m levels were quantified after chemical reduction coupled with gas-phase chemiluminescence detection. After adjustment for matching covariates and BMI, HFpEF (34.5 μM; interquartile range [IQR] 25.0, 51.5) participants had lower NO m levels than HFrEF (41.0 μM; IQR 28.3, 58.0; ratio of HFpEF:HFrEF 0.82, 95% confidence interval [CI] 0.67 to 0.99; p = 0.04), which further decreased when adjusted for covariates that affect endothelial function (ratio 0.79, 95% CI 0.65 to 0.98; p = 0.03). There were no differences between HFrEF (34.0; IQR 25.3, 49.0) and matched Recovered-HF (36.0 μM; IQR 25.0, 55.0) or HFpEF and Recovered-HF. Age (+21%/10-year increase, p m in HFpEF, whereas age (+11%/10-year increase, p = 0.03), current tobacco use (+67%, p = 0.01), and eGFR (p = 0.01) associated with NO m in Recovered-HF. In conclusion, HFpEF participants have reduced NO m compared with HFrEF in this matched cohort. This might suggest either compromised endothelial function or poor dietary intake. Black race was associated with lower NO m in HFpEF.

Background Cardiac allograft vasculopathy (CAV) is a major cause of mortality after cardiac transplantation. High-density lipoprotein (HDL) cholesterol efflux capacity (CEC) is inversely associated with coronary artery disease. In 2 independent studies, we tested the hypothesis that reduced CEC is associated with mortality and disease progression in CAV. Methods We tested the relationship between CEC and survival in a cohort of patients with CAV ( n = 35). To determine whether reduced CEC is associated with CAV progression, we utilized samples from the Clinical Trials in Organ Transplantation 05 (CTOT05) study to determine the association between CEC and CAV progression and status at 1 year ( n = 81), as assessed by average change in maximal intimal thickness (MIT) on intravascular ultrasound. Results Multivariable Cox proportional hazard models demonstrated that higher levels of CEC were associated with improved survival (hazard ratio 0.26, 95% confidence interval 0.11 to 0.63) per standard deviation CEC, p = 0.002). Patients who developed CAV had reduced CEC at baseline and 1-year post-transplant. We observed a significant association between pre-transplant CEC and the average change in MIT, particularly among patients who developed CAV at 1 year (β = −0.59, p = 0.02, R 2 = 0.35). Conclusion Reduced CEC is associated with disease progression and mortality in CAV patients. These findings suggest the hypothesis that interventions to increase CEC may be useful in cardiac transplant patients for prevention or treatment of CAV.

Background— The failing human heart is characterized by metabolic abnormalities, but these defects remains incompletely understood. In animal models of heart failure there is a switch from a predominance of fatty acid utilization to the more oxygen-sparing carbohydrate metabolism. Recent studies have reported decreases in myocardial lipid content, but the inclusion of diabetic and nondiabetic patients obscures the distinction of adaptations to metabolic derangements from adaptations to heart failure per se. Methods and Results— We performed both unbiased and targeted myocardial lipid surveys using liquid chromatography-mass spectroscopy in nondiabetic, lean, predominantly nonischemic, advanced heart failure patients at the time of heart transplantation or left ventricular assist device implantation. We identified significantly decreased concentrations of the majority of myocardial lipid intermediates, including long-chain acylcarnitines, the primary subset of energetic lipid substrate for mitochondrial fatty acid oxidation. We report for the first time significantly reduced levels of intermediate and anaplerotic acyl-coenzyme A (CoA) species incorporated into the Krebs cycle, whereas the myocardial concentration of acetyl-CoA was significantly increased in end-stage heart failure. In contrast, we observed an increased abundance of ketogenic β-hydroxybutyryl-CoA, in association with increased myocardial utilization of β-hydroxybutyrate. We observed a significant increase in the expression of the gene encoding succinyl-CoA:3-oxoacid-CoA transferase, the rate-limiting enzyme for myocardial oxidation of β-hydroxybutyrate and acetoacetate. Conclusions— These findings indicate increased ketone utilization in the severely failing human heart independent of diabetes mellitus, and they support the role of ketone bodies as an alternative fuel and myocardial ketone oxidation as a key metabolic adaptation in the failing human heart.

Heart transplantation is one of the most definitive therapies for end-stage heart failure. The therapy is unfortunately marred by the devastating complications of cardiac allograft vasculopathy (CAV). Non-invasive screening and assessment for CAV has been greatly limited by both low sensitivity and poor correlation with adverse outcomes. As such, invasive imaging with coronary angiography has emerged as the gold standard for detection of CAV. Although conventional coronary angiography serves well for larger lesions, the modality has been significantly enhanced with adjunct imaging to visualize the intimal hyperplasia that is a hallmark of the disease process. These modalities include intravascular ultrasound (IVUS) and optical coherence tomography (OCT). In the following review, we summarize both the invasive and non-invasive assessments of CAV. We further conclude that the current evidence poorly supports the use of non-invasive testing for early CAV and that a transition should be considered to routine early angiography with adjunctive intravascular imaging.

PURPOSE OF REVIEW: Cholesterol metabolism is increasingly recognized in inflammatory diseases including transplantation. This review discusses the mechanistic underpinnings that tie macrophage cholesterol efflux capacity of high-density lipoprotein to chronic rejection in transplanted patients. RECENT FINDINGS: Animal studies suggest that administration of apolipoprotein A-I, the main protein constituent of high-density lipoprotein, can prevent transplant atherosclerosis. apoA-I administration increases cholesterol efflux capacity of high-density lipoprotein. In patients with cardiac allograft vasculopathy, decreased cholesterol efflux capacity has been associated with poorer survival. In addition, reduced cholesterol efflux capacity in recipients, pre-transplant, has been associated with development of cardiac allograft vasculopathy and renal allograft survival. SUMMARY: These recent findings raise the hypothesis that increasing cholesterol efflux may prevent chronic rejection and improve allograft survival after transplant. Reconstituted high-density lipoprotein significantly increases cholesterol efflux capacity and is currently in clinical development for traditional atherosclerosis. Clinical trials of reconstituted high-density lipoprotein administration in transplantation should be performed.

Background Radiation-treated head and neck cancer (HNC) patients are at high risk for developing radiation vasculopathy, as evidenced by an increased stroke risk. The benefits of screening and assessing the cardiovascular (CV) risk of HNC patients using carotid intima-media thickness (CIMT) ultrasound are not known. Our objective was to determine the prevalence of high CV risk in patients without known CV diseases who received radiation for HNC, determine the percentage of screened patients who had a change in clinical management as a result of an increased CIMT, and to compare this risk-assessment tool to patients' risk classification using the Framingham Risk Score (FRS) and Pooled Cohort Atherosclerotic Cardiovascular Disease (ASCVD) Risk Equation (recommended by American College of Cardiology/American Heart Association Guidelines on the Assessment of Cardiovascular Risk). Hypothesis Risk calculators may not accurately predict risk in this population with a unique risk factor. Carotid IMT may be used to detect radiation vasculopathy in HNC patients. Methods Retrospective medical chart review was conducted on 134 radiation-treated HNC patients. The main outcome measures were CV risk (as determined by CIMT) and clinical management. Also, the FRS and the Pooled Cohort ASCVD Risk Equation were used to compare classification with CIMT. Results Approximately 74% of the cases were at high CV risk using CIMT technique. Approximately half of the HNC patients screened had a change in clinical management characterized by recorded initiation of aspirin and recorded initiation or increase of statin therapies. The FRS and the Pooled Cohort ASCVD Risk Equation failed to detect 40% to 50% of cases found to be at high risk using the CIMT technique. Conclusions Carotid IMT identified a much greater percentage of radiation-treated HNC patients at high CV risk compared with standard CV-risk calculators. By more accurately identifying the patients at high risk, this may lead to more effective prevention, and therefore a reduction in CV events.

Accelerated rejection is uncommon after cardiac transplantation. The mechanism is hypothesized to be mediated by cytotoxic T cells and anti-HLA antibodies resulting from a memory response to the donor allograft in sensitized patients. A role for Natural Killer (NK) cell in cellular rejection has also been suggested. We report a case of fulminant accelerated rejection in a heart transplant recipient, with a history of peripartum cardiomyopathy (PPMC). The patient had no pre-transplant donor specific antibody and flow cytometric T and B cell crossmatches were negative. Autopsy revealed left ventricular subendocardial and intramyocardial hemorrhage with diffuse lymphocytic infiltrates and myocyte damage (Grade 3R rejection). Immunohistochemistry revealed a large proportion (50-70%) of mature CD16+ NK cells with cytotoxic potential in the interstitium and the intra capillary compartments. This case highlights the need for evaluating the potential role of NK cells in accelerated rejection in heart transplant recipients.

Background & Aims The lysosome is an acidic organelle that is important for maintaining cellular and metabolic homeostasis in hepatocytes. Lysosomal dysfunction and chronic inflammation coexist, and both contribute to obesity-associated hepatic insulin resistance. However, in the context of obesity, the interplay between inflammatory signals and hepatic lysosomal function remains largely unknown. Inducible nitric oxide synthase (iNOS) is a hallmark for inflammation, and is activated in obesity. The aim of this study is to understand the molecular link between iNOS-mediated lysosomal nitric oxide (NO) production, hepatic lysosomal function, and autophagy in the context of obesity-associated insulin resistance. Methods The role of iNOS in hepatic autophagy, as related to insulin and glucose homeostasis were studied in mice with diet-induced obesity (DIO). The effects and mechanisms of iNOS-mediated lysosomal NO production on lysosomal function and hepatic autophagy were studied in primary hepatocytes as well as in a mouse model of DIO. Results We demonstrate that obesity promotes iNOS localization to the lysosome and decreases levels of lysosomal arginine, resulting in an accumulation of NO in hepatic lysosomes. This lysosomal NO production is attenuated by treatment with a NO scavenger, while co-overexpression of mTOR and a lysosomal arginine transporter (SLC38A9) enhances lysosomal NO production and suppresses autophagy. In addition, we show that deletion of iNOS ameliorates lysosomal nitrosative stress in the livers of DIO mice, promotes lysosomal biogenesis by activating transcription factor EB (TFEB), and enhances lysosomal function and autophagy. Lastly, deletion of iNOS in mice with DIO improves hepatic insulin sensitivity, which is diminished by suppression of TFEB or autophagy related 7 (Atg7). Conclusions Our studies suggest that lysosomal iNOS-mediated NO signaling disrupts hepatic lysosomal function, contributing to obesity-associated defective hepatic autophagy and insulin resistance., Graphical abstract

This paper addresses the problem of fuzzy controller design for position control of two-wheeled mobile robots subject to unknown kinematic disturbances. Because the conventional T-S fuzzy models are not applicable, the robot is modeled with several subsystems each of which represented by a set of T-S fuzzy rules. With the use of a common quadratic Lyapunov function, LMI based Η∞ switching control synthesis conditions, under arbitrary switching law for such robots are obtained. Moreover, to achieve better closed-loop performance, maximum decay-rate are also considered and LMI conditions are given. Simulation results are also provided to show the effectiveness of the proposed controller.

Cellular automata (CA) are known for their capability in exhibiting interesting emergent behaviour and capacity to generate complex and often aesthetically appealing patterns through the local interaction of rules. Mean information gain has been suggested as a measure of discriminating structurally different two-dimensional (2D) patterns. This paper addresses quantitative evaluation of the complexity of CA generated configurations. In particular, we examine information gain as a spatial complexity measure for discriminating multi-state 2D CA generated configurations. This information-theoretic quantity, also known as conditional entropy, takes into account conditional and joint probabilities of cell states in a 2D plane. The effectiveness of the measure is shown in a series of experiments for multi-state 2D patterns generated by CA. The results of the experiments show that the measure is capable of distinguishing the structural characteristics including symmetries and randomness of 2D CA patterns.

Stable plasma nitric oxide metabolites (NOx), predominantly composed of nitrate, are markers of endogenous nitric oxide (NO) production, NO utilization, and dietary intake and may be indicators of vascular health. We enrolled subjects undergoing a clinically-indicated cardiac MRI. Plasma NOx levels

Introduction: Several studies have implicated energetic deficits in chronic heart failure. Recently, our group has described a state of myocardial substrate deficiency across a broad spectrum of lipid species in non-diabetic end-stage heart failure. We hypothesized that lipid substrate depletion in end-stage heart failure would be associated with dysregulation of short chain acyl-CoA intermediates implicated in important metabolic pathways. Methods: Left ventricular samples were obtained at the time of orthotopic heart transplantation for failing cases with idiopathic dilated cardiomyopathy (DCM) n=16, and brain-dead organ donors without a history of heart failure (NF) n=18. Samples were snap frozen at -80°C for further analysis with liquid chromatography in tandem mass spec LC MS/MS. Stable isotope labeled essential nutrient in cell culture (SILEC) internal standards for acyl-CoAs were generated using 13 C 3 15 N 1 pantotheonate in Hepa1c1c7 cells. Results: In the myocardium of failing as compared to NF, we identified a significant decrease in Succinyl-CoA (Avg 10.5 versus 17.7 pmol/mg, p = 0.004 ), Propionyl-CoA (0.9 versus 1.8 pmol/mg, p=0.004) and a concomitant increase in β-hydroxybutyryl -CoA (BHB-CoA Avg 0.57 versus 0.29 pmol/mg, p =0.008 ). The ratio of myocardial Succinyl-CoA to Acetyl-CoA, a potential marker of tricarboxylic acid cycling, is significantly decreased in end-stage heart failure ( 0.84 versus 1.93, p= 0.005 ). The figure depicts the levels of myocardial acyl-CoA species in the non-diabetic cohort. Conclusion: We have identified important differences in myocardial acyl CoA species—an increase in the ketogenic BHB-CoA and decreased Succinyl-CoA and Propionyl-CoA in end-stage human heart failure. These data, along with the recently identified state of myocardial lipodeficiency, are strongly supporting the concept of a bio-energetic deficit in end-stage heart failure.

Obesity, Sleep Apnea, LV Remodeling and Myocardial Fibrosis Assessed with Cardiac MRI Both obesity and sleep apnea (SA) are predictive of heart failure (HF). Limited data are available regarding the independent effects of SA and obesity on left ventricular (LV) remodeling. We recruited 280

Despite the emergence of sleep apnea (SA) as a significant risk factor for heart failure (HF) mortality, data indicate that SA remains under-diagnosed and under-treated. Less well established, though perhaps more emphasized, is the role of sleep apnea in pulmonary hypertension (PH). SA occurs in approximately 50 % of HF patients, and its consequences include intermittent hypoxemia, arousal, and intra-thoracic pressure swings leading to neurohormonal stimulation, oxidative stress and inflammation. While SA is also considered a cause of PH, severe PH due solely to SA is rare. Combining the results of several studies using Swan-Ganz catheters for diagnosis of PH, approximately 10 % of patients with OSA have PH. Effective treatment of SA in HF is associated with improved survival, while treatment of SA in PH is typically associated with modest hemodynamic improvement.

Radiofrequency epicardial ablation of ventricular tachycardia (VT) is a safe, effective modality for treatment of VT.1 Epicardial VT circuits were originally described in Chagas disease, but the importance of nonendocardial substrates for VT increasingly are recognized in other cardiomyopathies.2 In arrhythmogenic right ventricular cardiomyopathy (ARVC), failure of endocardial VT ablation often is related to epicardial VT origination, with high rates of success seen with epicardial VT ablation.3 While hemopericardium or pericardial inflammation are rare complications of epicardial VT ablation, to our knowledge no case of pericardial constriction and heart failure following epicardial VT ablation has been reported.4 Here we describe a case of pericardial constriction and severe heart failure requiring stripping and “bridge to recovery” right-ventricular assist-device (RVAD) support, which occurred subsequent to recurrent epicardial VT ablations. ### Case Presentation A 46-year-old male who presented with palpitations and episodic syncope underwent cardiac magnetic resonance imaging, which was consistent with ARVC, followed by implantable …

See related article, pp 1041–1049 Congestive heart failure (CHF) is a common end-stage clinical presentation of coronary artery disease or 2 of its major risk factors, hypertension and diabetes mellitus. Because of this, patients with CHF are often prescribed 3-hydroxy-3-methylglutaryl coenzyme-A inhibitors (statins) that not only prevent cardiovascular events such as myocardial infarction, but also reduce the risk of incident heart failure. In concept, statin therapy could benefit patients with CHF by multiple mechanisms, including reduction in further ischemic events, decreased sympathetic activity, or improved endothelial function. However, once heart failure has developed, from either ischemic or nonischemic heart disease, the benefit of statin therapy is more controversial. In the present issue of the Journal, Haack et al1 present a well-executed series of experiments showing that simvastatin treatment significantly improved respiratory variability and arrhythmia observed in a postinfarction rat CHF model. This improvement was associated with amelioration of enhanced peripheral arterial chemosensitivity, a major mechanism mediating periodic breathing and central sleep apnea (CSA) in CHF.2,3 Rats with CHF exhibited increased respiratory variability with reduced tidal volume and augmented ventilatory responses to hypoxia but not hypercapnia. Simvastatin mediated downregulation of the exaggerated hypoxic ventilatory response …

This paper describes a novel implementation of a two-dimensional Cellular Automaton (CA) by introducing a dormant state. An overview of the use of CA’s in the field of Artificial Life reveals that certain crucial aspects of biological realism have been sacrificed in favour of abstraction or have not been considered at all. Conway’s famous “Game of Life” model includes certain fundamental aspects of population dynamics, including the transition from living state to dead state. But even the simplest biological system consists of more stages than the binary state in the Game of Life. The aim of this research is to build an extended CA model of natural biological systems by introducing a dormant state and to investigate the effect of dormancy on simple population dynamics.

The quantitative evaluation of order and complexity conforming with human intuitive perception has been at the core of computational notions of aesthetics. Informational theories of aesthetics have\ud taken advantage of entropy in measuring order and complexity of stimuli in relation to their aesthetic value. However entropy fails to discriminate structurally different patterns in a 2D plane. This paper investigates a computational measure of complexity, which is then compared to a results from a previous experimental study on human aesthetic perception in the visual domain. The model is based on the information gain from specifying the spacial distribution of pixels and their uniformity and nonuniformity in an image. The results of the experiments demonstrate the presence of correlations between a spatial complexity measure and the way in which humans are believed to aesthetically appreciate asymmetry. \ud However the experiments failed to provide a significant correlation\ud between the measure and aesthetic judgements of symmetrical images.