Long-term survival and life expectancy following an acute heart failure hospitalization in Australia and New Zealand

Aims: Contemporary long-term survival following a heart failure (HF) hospitalization is uncertain. We evaluated survival up to 10 years after a HF hospitalization using national data from Australia and New Zealand, identified predictors of survival, and estimated the attributable loss in life expectancy. Methods and results: Patients hospitalized with a primary diagnosis of HF from 2008–2017 were identified and all-cause mortality assessed by linking with Death Registries. Flexible parametric survival models were used to estimate survival, predictors of survival and loss in life expectancy. A total of 283 048 patients with HF were included (mean age 78.2 ± 12.3 years, 50.8% male). Of these, 48.3% (48.1–48.5) were surviving by 3 years, 34.1% (33.9–34.3) by 5 years and 17.1% (16.8–17.4) by 10 years (median survival 2.8 years). Survival declined with age with 53.4% of patients aged 18–54 years and 6.2% aged ≥85 years alive by 10 years (adjusted hazard ratio [aHR] for mortality 4.84, 95% confidence interval [CI] 4.65–5.04 for ≥85 years vs. 18–54 years) and was worse in male patients (aHR 1.14, 95% CI 1.13–1.15). Prior HF (aHR 1.20, 95% CI 1.18–1.22), valvular and rheumatic heart disease (aHR 1.11, 95% CI 1.10–1.13) and vascular disease (aHR 1.07, 95% CI 1.04–1.09) were cardiovascular comorbidities most strongly associated with long-term death. Non-cardiovascular comorbidities and geriatric syndromes were common and associated with higher mortality. Compared with the general population, HF was associated with a loss of 7.3 years in life expectancy (or 56.6% of the expected life expectancy) and reached 20.5 years for those aged 18–54 years. Conclusion: Less than one in five patients hospitalized for HF were surviving by 10 years with patients experiencing almost 60% loss in life expectancy compared with the general population, highlighting the considerable persisting societal burden of HF. Concerted multidisciplinary efforts are needed to improve post-hospitalization outcomes of HF

Steatosis drives monocyte-derived macrophage accumulation in human metabolic dysfunction-associated fatty liver disease

BACKGROUND & AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MAFLD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. METHODS: Liver tissue from 21 participants was collected at time of bariatric surgery and analysed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n = 3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. RESULTS: We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14 CONCLUSIONS: The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans. MdMs appear to participate in lipid uptake during early stages of MALFD. IMPACT AND IMPLICATIONS: Metabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD

Sudden cardiac death due to deficiency of the mitochondrial inorganic pyrophosphatase PPA2

We have used whole exome sequencing to identify biallelic missense mutations in the nuclearencoded mitochondrial inorganic pyrophosphatase (PPA2) in ten individuals from four unrelated pedigrees that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis and cardiac arrhythmia and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutated PPA2 containing mitochondria from fibroblasts showed the activity of inorganic pyrophosphatase significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations, and suggest that PPA2 is a new cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized

Novel Management of Heart Failure

This thesis explores novel therapies in both acute decompensated heart failure and chronic heart failure. Heart failure (HF) continues to be a major medical problem worldwide. In this complex condition, haemodynamic and neurohormonal imbalances occur simultaneously. The presentation of HF is heterogeneous and prognosis, despite therapeutic advances remains poor. Opportunities to intervene arise in each stage of HF with unique targets according to the stage of disease. Despite proven therapies, including angiotensin converting enzyme inhibitors/ angiotensin receptor blockade, beta blockers and mineralocorticoid receptor antagonists, the five year mortality remains above 50% therefore the search for new and improved therapies remains necessary. Chapter 1: A literature review which discusses the epidemiology, pathophysiology and available treatments for HF and their limitations. In this literature review, an overview of the urocortin peptides is also provided. Urocortin-2, has potential as a therapeutic agent and is the key element involved in two studies discussed in this thesis. Chapter 2: Describes key methodologies incorporated in the three studies. Chapter 3: Reports the results of a study on the effects of urocortin-2 as an adjunct to conventional therapy in 53 patients hospitalised with acute decompensated HF. In this double-blind placebo-controlled randomised trial, urocortin-2 produced favourable haemodynamic effects in the acute decompensated setting without major adverse effects. Urocortin-2 warrants further investigation to explore its full potential on renal and hormonal effects as a therapeutic agent in acute decompensated heart failure. Chapter 4: Explores the effect of urocortin-2 on muscle sympathetic nerve activity (SNA) in eight healthy volunteers and four patients with stable HF. The results do not support the hypothesis that urocortin-2 inhibits muscle SNA in man as opposed to inhibition of cardiac SNA in conscious sheep. The response does not differ between healthy volunteers and HF patients. Chapter 5: Explores left atrial pressure and left atrial waveform effects of varying cardiac resynchronisation therapy (CRT) settings in eight patients with stable HF. Optimal CRT settings corresponded to lower left atrial pressure and more favourable waveform characteristics. The study demonstrated that it was feasible to use this implantable left atrial pressure sensor to guide CRT optimisation. Chapter 6: Summarises the key findings learned from the studies presented in Chapter 3-5. Areas of interests learned from these studies and proposed research direction are discussed. Chapter 7: References quoted in this thesis

Novel Management of Heart Failure

This thesis explores novel therapies in both acute decompensated heart failure and chronic heart failure. Heart failure (HF) continues to be a major medical problem worldwide. In this complex condition, haemodynamic and neurohormonal imbalances occur simultaneously. The presentation of HF is heterogeneous and prognosis, despite therapeutic advances remains poor. Opportunities to intervene arise in each stage of HF with unique targets according to the stage of disease. Despite proven therapies, including angiotensin converting enzyme inhibitors/ angiotensin receptor blockade, beta blockers and mineralocorticoid receptor antagonists, the five year mortality remains above 50% therefore the search for new and improved therapies remains necessary. Chapter 1: A literature review which discusses the epidemiology, pathophysiology and available treatments for HF and their limitations. In this literature review, an overview of the urocortin peptides is also provided. Urocortin-2, has potential as a therapeutic agent and is the key element involved in two studies discussed in this thesis. Chapter 2: Describes key methodologies incorporated in the three studies. Chapter 3: Reports the results of a study on the effects of urocortin-2 as an adjunct to conventional therapy in 53 patients hospitalised with acute decompensated HF. In this double-blind placebo-controlled randomised trial, urocortin-2 produced favourable haemodynamic effects in the acute decompensated setting without major adverse effects. Urocortin-2 warrants further investigation to explore its full potential on renal and hormonal effects as a therapeutic agent in acute decompensated heart failure. Chapter 4: Explores the effect of urocortin-2 on muscle sympathetic nerve activity (SNA) in eight healthy volunteers and four patients with stable HF. The results do not support the hypothesis that urocortin-2 inhibits muscle SNA in man as opposed to inhibition of cardiac SNA in conscious sheep. The response does not differ between healthy volunteers and HF patients. Chapter 5: Explores left atrial pressure and left atrial waveform effects of varying cardiac resynchronisation therapy (CRT) settings in eight patients with stable HF. Optimal CRT settings corresponded to lower left atrial pressure and more favourable waveform characteristics. The study demonstrated that it was feasible to use this implantable left atrial pressure sensor to guide CRT optimisation. Chapter 6: Summarises the key findings learned from the studies presented in Chapter 3-5. Areas of interests learned from these studies and proposed research direction are discussed. Chapter 7: References quoted in this thesis

Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline

Abstract Omecamtiv mecarbil (OM) is a novel medicine for systolic heart failure, targeting myosin to enhance cardiomyocyte performance. To assist translation to clinical practice we investigated OMs effect on explanted human failing hearts, specifically; contractile dynamics, interaction with the β1–adrenoceptor (AR) agonist (−)‐noradrenaline and spontaneous contractions. Left and right ventricular trabeculae from 13 explanted failing hearts, and trabeculae from 58 right atrial appendages of non‐failing hearts, were incubated with or without a single concentration of OM for 120 min. Time to peak force (TPF) and 50% relaxation (t50%) were recorded. In other experiments, trabeculae were observed for spontaneous contractions and cumulative concentration‐effect curves were established to (−)‐noradrenaline at β1‐ARs in the absence or presence of OM. OM prolonged TPF and t50% in ventricular trabeculae (600 nM, 2 µM, p < .001). OM had no significant inotropic effect but reduced time dependent deterioration in contractile strength compared to control (p < .001). OM did not affect the generation of spontaneous contractions. The potency of (−)‐noradrenaline (pEC50 6.05 ± 0.10), for inotropic effect, was unchanged in the presence of OM 600 nM or 2 µM. Co‐incubation with (−)‐noradrenaline reduced TPF and t50%, reversing the negative diastolic effects of OM. OM, at both 600 nM and 2 µM, preserved contractile force in left ventricular trabeculae, but imparted negative diastolic effects in trabeculae from human failing heart. (−)‐Noradrenaline reversed the negative diastolic effects, co‐administration may limit the titration of inotropes by reducing the threshold for ischemic side effects

Correction to: The potential prognostic utility of\ua0salivary galectin-3 concentrations in\ua0heart failure (Clinical Research in Cardiology, (2019), 10.1007/s00392-019-01557-0)

The original version of this article unfortunately contained a mistake. The correct version of the Funding are given below:

The potential prognostic utility of salivary galectin-3 concentrations in heart failure

Background: Patients with HF are at a higher risk of rehospitalisation and, as such, significant costs to our healthcare system. A non-invasive method to collect body fluids and measure Gal-3 could improve the current management of HF. In this study, we investigated the potential prognostic utility of salivary Galectin-3 (Gal-3) in patients with heart failure (HF). Methods: We collected saliva samples from patients with HF (n = 105) either at hospital discharge or during routine clinical visits. Gal-3 concentrations in saliva samples were measured by ELISA. The Kaplan–Meier survival curve analysis and Cox proportional regression model were used to determine the potential prognostic utility of salivary Gal-3 concentrations. Results: The primary end point was either cardiovascular death or hospitalisation. Salivary Gal-3 concentrations were significantly higher (p 172.58 ng/mL had a significantly (p 172.58 ng/mL demonstrated a higher cumulative risk of the primary outcome compared to those with lower Gal-3 levels, even after adjusting for other variables. Confirming our findings in a larger multi-centre clinical trial in the future would enable salivary Gal-3 measurements to form part of routine management for patients with HF. Graphical abstract: [Figure not available: see fulltext.].</p

Heart transplantation from brain dead donors:A systematic review of animal models

Despite advances in mechanical circulatory devices and pharmacologic therapies, heart transplantation (HTx) is the definitive and most effective therapy for an important proportion of qualifying patients with end-stage heart failure. However, the demand for donor hearts significantly outweighs the supply. Hearts are sourced from donors following brain death, which exposes donor hearts to substantial pathophysiological perturbations that can influence heart transplant success and recipient survival. Although significant advances in recipient selection, donor and HTx recipient management, immunosuppression, and pretransplant mechanical circulatory support have been achieved, primary graft dysfunction after cardiac transplantation continues to be an important cause of morbidity and mortality. Animal models, when appropriate, can guide/inform medical practice, and fill gaps in knowledge that are unattainable in clinical settings. Consequently, we performed a systematic review of existing animal models that incorporate donor brain death and subsequent HTx and assessed studies for scientific rigor and clinical relevance. Following literature screening via the U.S National Library of Medicine bibliographic database (MEDLINE) and Embase, 29 studies were assessed. Analysis of included studies identified marked heterogeneity in animal models of donor brain death coupled to HTx, with few research groups worldwide identified as utilizing these models. General reporting of important determinants of heart transplant success was mixed, and assessment of posttransplant cardiac function was limited to an invasive technique (pressure-volume analysis), which is limitedly applied in clinical settings. This review highlights translational challenges between available animal models and clinical heart transplant settings that are potentially hindering advancement of this field of investigation.</p