Understanding Of Heart Failure Research Articles

Management of Chronic Heart Failure in Dialysis Patients: A Challenging but Rewarding Path.

Chronic heart failure (CHF) is a common complication and cause of death in dialysis patients. Although several clinical guidelines and expert consensus on heart failure (HF) in the general population have been issued in China and abroad, due to abnormal renal function or even no residual renal function (RRF) in dialysis patients, the high number of chronic complications, as well as the specificity, variability, and limitations of hemodialysis (HD) and peritoneal dialysis (PD) treatments, there are significant differences between dialysis patients and the general population in terms of the treatment and management of HF. The current studies are not relevant to all dialysis-combined HF populations, and there is an urgent need for high-quality studies on managing HF in dialysis patients to guide and standardize treatment. After reviewing the existing guidelines and literature, we focused on the staging and diagnosis of HF, management of risk factors, pharmacotherapy, and dialysis treatment in patients on dialysis. Based on evidence-based medicine and clinical trial data, this report reflects new perspectives and future trends in the diagnosis and treatment of HF in dialysis patients, which will further enhance the clinicians' understanding of HF in dialysis patients.

Sex-specific cardiovascular protein levels and their link with clinical outcome in heart failure.

This study aims to provide insight into sex-specific cardiovascular protein profiles and their associations with adverse outcomes, which may contribute to a better understanding of heart failure (HF) pathophysiology and the optimal use of circulating proteins for prognostication in women and men. In 250 stable patients with HF with reduced ejection fraction (HFrEF), we performed trimonthly blood sampling (median follow-up: 26 [17-30] months). We selected all baseline samples and two samples closest to the primary endpoint (PEP; composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or one sample closest to censoring and applied the Olink Cardiovascular III panel. We used linear regression to study sex-based differences in baseline levels and joint models to study differences in the prognostic value of serially measured proteins. In 66 women and 184 men (mean age of 66 and 67years, respectively), 21% and 28% reached the PEP, respectively. Mean baseline levels of fatty acid-binding protein 4, secretoglobin family 3A member 2, paraoxonase 3, and trefoil factor 3 were higher in women (Pinteraction : 0.001, 0.007, 0.018, and 0.049, respectively), while matrix metalloproteinase-3, interleukin 1 receptor-like 1, and myoglobin were higher in men (Pinteraction : <0.001, 0.001, and 0.049, respectively), independent of clinical characteristics. No significant differences between sexes were observed in the longitudinal associations of proteins with the PEP. Only peptidoglycan recognition protein 1 showed a suggestive interaction with sex for the primary outcome (Pinteraction =0.028), without multiple testing correction, and was more strongly associated with adverse outcome in women {hazard ratio [HR] 3.03 [95% confidence interval (CI), 1.42 to 6.68], P=0.008} compared with men [HR 1.18 (95% CI, 0.84 to 1.66), P=0.347]. Although multiple cardiovascular-related proteins show sex differences at baseline, temporal associations with the adverse outcome do not differ between women and men with HFrEF.

Correlation between energy loss index and B-type natriuretic peptide: a vector flow mapping study.

Vector Flow Mapping (VFM) and Energy Loss (EL) evaluation are emerging echocardiographic techniques that offer detailed insights into cardiac function. This study aimed to explore the relationship between EL parameters and B-type natriuretic peptide (BNP) levels, a well-established marker of heart failure severity. Our study prospectively enrolled 62 patients experiencing shortness of breath and suspected heart failure, who underwent echocardiography and had BNP levels measured between January 2018 and August 2020. Patients were stratified based on BNP levels, and their clinical and echocardiographic characteristics were evaluated. Univariate and multivariate regression analyses were performed to assess the correlation between BNP levels and various echocardiographic variables, including VFM parameters. Patients were stratified into two groups based on their BNP levels: BNP < 200pg/ml (n = 53) and BNP ≥ 200pg/ml (n = 9). Patients with BNP ≥ 200pg/ml presented significantly different clinical and echocardiographic characteristics, such as older age, larger left ventricular mass and volume indices, higher pulmonary artery systolic pressure, higher E/e' ratio, and larger EL parameters. Multivariate regression analysis demonstrated the E/e' ratio and ELA (EL during Atrial contraction phase/A wave ratio as significant determinants of logBNP. Receiver operating characteristic curve analysis showed ELA/A > 36.0J/m2 as a significant predictor of high BNP with 89% sensitivity and 85% specificity. ELA/A demonstrated an incremental diagnostic value over elevated left atrial pressure for predicting high BNP (C statistic = 0.98 vs 0.74, P = 0.006). This study provides novel insights into the potential utility of EL parameters as auxiliary indicators of cardiac load, thereby enhancing our understanding of heart failure.

Heart Failure Burden in Oman as a Mid-East Exemplar Versus Global Perspectives: An Integrative Review.

Heart failure (HF), a clinical syndrome caused by a structural and functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and pulmonary congestion. This study intends to investigate the state of heart failure (HF) in Oman and assess it in comparison of global trends. Ten published literatures from the past 20 years were included after a thorough search of databases (Arab World Research Source, EBSCOhost, Medline, and Google Scholar). These studies were reviewed considering the global literature. We have observed an increase in HF cases especially in older adults, over the past two decades in Oman. Acute coronary syndrome and non-compliance with medication are two factors that contribute to acute HF, according to recent research. Ischemic heart disease is the leading cause of HF in the Omani population. The mortality rate for HF patients in Oman was reported to be 25% after a one-year follow-up. The younger population that is diagnosed with HF in Oman is significantly worse than in other nations, according to these data, which are consistent with global trends. The lack of published studies and data sets hampered our understanding of heart failure (HF); yet prevalence of HF is rising and is anticipated to surge with the rise in diabetes mellitus and hypertension and other related cardiovascular precursors. Therefore, HF requires more investigation. In terms of worldwide trends, HF in Oman appears to be even worse; additional information is required to grasp the full picture on HF.

Abstract P1021: Estimating Cardiac Cell Composition In Gtex With Single-nucleus Reference Profiles.

Heart failure (HF) is a heterogeneous condition defined by an inability of the heart to meet the circulatory needs of the body. HF is the result of a maladaptive response to chronic stressors during which the heart undergoes structural and cellular remodeling. For example, cardiomyocytes undergo apoptosis after chronic overstimulation while fibroblasts proliferate to fill gaps left by the loss of larger cells. Although changes to the cellular makeup of the heart are known to mediate HF pathology, estimates of basal cardiac cellular composition vary widely. Moreover, despite our understanding of HF as a complex condition that is influenced by environmental and genetic factors, most studies on heart composition only examine small groups of individuals or inbred models. Recent efforts have used single-nucleus RNAseq (snRNAseq) to tally nuclear proportions as a proxy for cellular proportions. However, cellular dissociation biases for certain cell types and skews the resulting estimates. Furthermore, snRNAseq studies are expensive, making them infeasible and underpowered for population-scale analyses. To avoid these issues, we developed a method to estimate cellular composition of bulk RNAseq using cell-type-specific references defined in snRNAseq. While most deconvolution tools are designed for single-cell RNAseq inputs, our method considers the technical and biological differences of snRNAseq. It also allows for the inclusion of additional reference datasets, utilizes simulated controls, and leverages an existing deconvolution tool, MuSiC. We apply our method to the Genome-Tissue-Expression project (GTEx), a multi-tissue database with bulk RNAseq from hundreds of subjects and snRNAseq from a small subset of those subjects. We estimated left ventricular cellular composition in 386 individuals, revealing considerable heterogeneity. We found significant correlations between subject phenotypes and discrete cell populations. This analysis demonstrates our ability to leverage existing, public datasets to accurately map the understudied variability of cardiac cell type variation across human populations. We now look to incorporate genomic datasets to find genetic markers that link composition estimates to population-level variation.

Needs of patients with multi-morbidity and heart failure for the development of a mHealth to improve their self-management: A qualitative analysis.

To provide practical information regarding needs, preferences of content and format of an app to assist the self-management in patients with multi-morbidity and heart failure (HF). The three-phase study was conducted in Spain. Six integrative reviews, a qualitative methodology based on Van Manen's hermeneutic phenomenology through semi-structured interviews and user stories were used. Data collection continued until data saturation was reached. All data were transcribed verbatim and analysed using a framework approach. Thematic analysis technique following the methods of Braun and Clarke was used for emerging themes. Integrative reviews conducted included practical recommendations to include in the content and format of the App and helped create the interview guide. Interviews revealed 15 subthemes that captured the meaning of narratives offering contextual insights into the development of the App. The main effective mechanisms of multicomponent interventions for patients with HF must contain (a) components that increase the patient's understanding of HF, (b) self-care, (c) self-efficacy and participation of the family/informal caregiver, (4) psychosocial well-being and (5) professional support and use of technology. User stories revealed that patients prioritized improvements in direct contact with health services in case of emergency (90%), nutritional information (70%), type of exercises in order to improve their physical condition (75%) and information about food and drug interaction (60%). The importance of motivation messages (60%) was highlighted by transversal way. The three-phase process integrating theoretical basis, evidence from integrative reviews and research findings from target users has been considered a guide for future app development.

Heart Failure in Patients with Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited cardiomyopathy characterized as fibro-fatty replacement, and a common cause for sudden cardiac death in young athletes. Development of heart failure (HF) has been an under-recognized complication of ACM for a long time. The current clinical management guidelines for HF in ACM progression have nowadays been updated. Thus, a comprehensive review for this great achievement in our understanding of HF in ACM is necessary. In this review, we aim to describe the research progress on epidemiology, clinical characteristics, risk stratification and therapeutics of HF in ACM.

An Enhanced Random Forests Approach to Predict Heart Failure From Small Imbalanced Gene Expression Data.

Myocardial infarctions and heart failure are the cause of more than 17 million deaths annually worldwide. ST-segment elevation myocardial infarctions (STEMI) require timely treatment, because delays of minutes have serious clinical impacts. Machine learning can provide alternative ways to predict heart failure and identify genes involved in heart failure. For these scopes, we applied a Random Forests classifier enhanced with feature elimination to microarray gene expression of 111 patients diagnosed with STEMI, and measured the classification performance through standard metrics such as the Matthews correlation coefficient (MCC) and area under the receiver operating characteristic curve (ROC AUC). Afterwards, we used the same approach to rank all genes by importance, and to detect the genes more strongly associated with heart failure. We validated this ranking by literature review and gene set enrichment analysis. Our classifier employed to predict heart failure achieved MCC = +0.87 and ROC AUC = 0.918, and our analysis identified KLHL22, WDR11, OR4Q3, GPATCH3, and FAH as top five protein-coding genes related to heart failure. Our results confirm the effectiveness of machine learning feature elimination in predicting heart failure from gene expression, and the top genes found by our approach will be able to help biologists and cardiologists further our understanding of heart failure.

Abstract 16673: Empowering Heart Failure Patients Through Technology and Focused Education

Introduction: Heart Failure (HF) patient engagement after hospital discharge is key to preventing readmission and compliance. According to Medicare Hospital Compare the average rate of unplanned readmission is 21.6% Objective: The Rise Above Heart Failure™(RAHF) pilot program was created to identify strategies to reduce the burden of common HF complications and ultimately reduce hospitalization. The pilot included targeted quality improvement strategies, provider engagement, and a redesigned patient journey. Methods: Three North Texas pilot sites received quality improvement consultation and measured their progress towards improved guideline-directed care by tracking the impact to the 1,347 patients discharged with heart failure in Get With The Guidelines®-Heart Failure (GWTG-HF). The RAHF Pilot Program focused on engaging key stakeholders who working in partnership with AHA staff, developed a new patient journey for patients in the pilot. Results: The percent of HF patients who received 60 minutes of heart failure education by a qualified heart failure educator was analyzed and yielded the following results: the program hospitals saw an average adherence of 51.0% in Q2 and 53.9% adherence in Q4 (%Δ =5.8%). Additionally, the pilot program’s average of 50.47% during Q2-Q4 was more than 10% greater than the national average during the same time period. In the outpatient setting, HF PATH app users completed both a pre and post knowledge assessment between Oct 2019 - March 2020. A perfect score on the assessment is 19. The average pre-score for these participants is 16.33, while the average post-score for these participants is 17. Conclusions: Midterm results indicate that the program is successfully increasing HF patient education to increase patient awareness and understanding of HF, as represented by higher adherence to the 60 Minutes of Heart Failure Education measure and positive trends in the HF Path app knowledge assessment scores.

Heart Failure: Novel and Emerging Therapies

Heart failure (HF) is increasing in prevalence and continues to have poor prognosis despite using up-to-date guideline-directed medical treatment and device intervention. There is a dire need for new therapies that can improve patient outcomes. New recently tested medical and interventional therapies have proven effective in reducing the morbidity, mortality and improving the quality of life for patients with HF and these therapies are discussed in details in this review. Ongoing large scale clinical trials are underway to determine the efficacy and safety of novel therapies of HF. Development of these medical and interventional therapies are improving our understanding of HF and paving the way to better clinical outcomes.

Heart to breathe: partial ablation of rostral ventrolateral medulla catecholaminergic neurons mediates disordered breathing in volume overload heart failure rats

Heart to breathe: partial ablation of rostral ventrolateral medulla catecholaminergic neurons mediates disordered breathing in volume overload heart failure rats

Naive Expectations to Resignation: A Comparison of Life Descriptions of Newly Diagnosed Versus Chronic Persons Living With Stage D HF.

Purpose:This study examined life descriptions of persons with stage D heart failure (HF) comparing those newly diagnosed to those with chronic HF.Methods:A secondary analysis of interviews from 75 participants followed in a longitudinal study of persons with stage D HF was thematically analyzed. There were 24 participants who were recently diagnosed with stage D HF (less than 2 years) and 51 participants with HF longer than 2 years.Results:Both groups shared life descriptions along a continuum, where recently diagnosed participants described naive expectations with hope for improvement, while the chronic group appeared resigned to their fate and the reality of the limitations of living with HF. Four themes illustrated differences between the groups: outlook on life, activity adjustments, understanding of HF, and mood.Conclusions:Although persons with stage D HF share the same life descriptions, they have differing perspectives of life with HF. Findings from this study can help health-care providers tailor interventions based on the length of time from diagnosis.

Whole exome analyses to examine the impact of rare variants on left ventricular traits in African American participants from the HyperGEN and GENOA studies.

Left ventricular (LV) hypertrophy, highest in prevalence among African Americans, is an established risk factor heart failure. Several genome wide association studies have identified common variants associated with LV-related quantitative-traits in African Americans. To date, however, the effect of rare variants on these traits has not been extensively studied, especially in minority groups. We therefore investigated the association between rare variants and LV traits among 1,934 African Americans using exome chip data from the Hypertension Genetic Epidemiology Network (HyperGEN) study, with replication in 1,090 African American from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We used single-variant analyses and gene-based tests to investigate the association between 86,927 variants and six structural and functional LV traits including LV mass, LV internal dimension-diastole, relative wall thickness, left atrial dimension (LAD), fractional shortening (FS), and the ratio of LV early-to-late transmitral velocity (E/A ratio). Only rare variants (MAF <1% and <5%) were considered in gene-based analyses. In gene-based analyses, we found a statistically significant association between potassium voltage-gated channel subfamily H member 4 (KCNH4) and E/A ratio (P=8.7*10-8 using a burden test). Endonuclease G (ENDOG) was associated with LAD using the Madsen Browning weighted burden (MB) test (P=1.4*10-7). Neither gene result was replicated in GENOA, but the direction of effect of single variants in common was comparable. G protein-coupled receptor 55 (GPR55) was marginally associated with LAD in HyperGEN (P=3.2*10-5 using the MB test) and E/A ratio in GENOA, but with opposing directions of association for variants in common (P=0.03 for the MB test). No single variant was statistically significantly associated with any trait after correcting for multiple testing. The findings in this study highlight the potential cumulative contributions of rare variants to LV traits which, if validated, could improve our understanding of heart failure in African Americans.

Accuracy of Self-Reported Heart Failure. The Atherosclerosis Risk in Communities (ARIC) Study

ObjectiveThe aim of this work was to estimate agreement of self-reported heart failure (HF) with physician-diagnosed HF and compare the prevalence of HF according to method of ascertainment. Methods and ResultsARIC cohort members (60–83 years of age) were asked annually whether a physician indicated that they have HF. For those self-reporting HF, physicians were asked to confirm their patients' HF status. Physician-diagnosed HF included surveillance of hospitalized HF and hospitalized and outpatient HF identified in administrative claims databases. We estimated sensitivity, specificity, positive predicted value, kappa, prevalence and bias–adjusted kappa (PABAK), and prevalence. Compared with physician-diagnosed HF, sensitivity of self-report was low (28%–38%) and specificity was high (96%–97%). Agreement was poor (kappa 0.32–0.39) and increased when adjusted for prevalence and bias (PABAK 0.73–0.83). Prevalence of HF measured by self-report (9.0%), ARIC-classified hospitalizations (11.2%), and administrative hospitalization claims (12.7%) were similar. When outpatient HF claims were included, prevalence of HF increased to 18.6%. ConclusionsFor accurate estimates HF burden, self-reports of HF are best confirmed by means of appropriate diagnostic tests or medical records. Our results highlight the need for improved awareness and understanding of HF by patients, because accurate patient awareness of the diagnosis may enhance management of this common condition.

P1446Common genetic background of left ventricular global longitudinal strain and diastolic function: new insights into the understanding of heart failure with preserved ejection fraction?

P1446Common genetic background of left ventricular global longitudinal strain and diastolic function: new insights into the understanding of heart failure with preserved ejection fraction?

Lung ultrasound as a translational approach for non-invasive assessment of heart failure with reduced or preserved ejection fraction in mice.

Heart failure (HF) has become an epidemic and constitutes a major medical, social, and economic problem worldwide. Despite advances in medical treatment, HF prognosis remains poor. The development of efficient therapies is hampered by the lack of appropriate animal models in which HF can be reliably determined, particularly in mice. The development of HF in mice is often assumed based on the presence of cardiac dysfunction, but HF itself is seldom proved. Lung ultrasound (LUS) has become a helpful tool for lung congestion assessment in patients at all stages of HF. We aimed to apply this non-invasive imaging tool to evaluate HF in mouse models of both systolic and diastolic dysfunction. We used LUS to study HF in a mouse model of systolic dysfunction, dilated cardiomyopathy, and in a mouse model of diastolic dysfunction, diabetic cardiomyopathy. LUS proved to be a reliable and reproducible tool to detect pulmonary congestion in mice. The combination of LUS and echocardiography allowed discriminating those mice that develop HF from those that do not, even in the presence of evident cardiac dysfunction. The study showed that LUS can be used to identify the onset of HF decompensation and to evaluate the efficacy of therapies for this syndrome. This novel approach in mouse models of cardiac disease enables for the first time to adequately diagnose HF non-invasively in mice with preserved or reduced ejection fraction, and will pave the way to a better understanding of HF and to the development of new therapeutic approaches.

New Classification for Heart Failure with Mildly Reduced Ejection Fraction: Greater clarity or more confusion?

The latest European Society of Cardiology (ESC) guidelines for the diagnosis and management of heart failure include a new patient group for those with heart failure with mildly reduced ejection fraction (HFmrEF). By defining this group of patients as a separate entity, the ESC hope to encourage more research focusing on patients with HFmrEF. Previously, patients with this condition were caught between two classifications-heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. Hopefully, the inclusion of new terminology will not increase confusion, but rather aid our understanding of heart failure, a complex clinical syndrome.

The fate of sulfate in chronic heart failure.

New leads to advance our understanding of heart failure (HF) pathophysiology are urgently needed. Previous studies have linked urinary sulfate excretion to a favorable cardiovascular risk profile. Sulfate is not only the end product of hydrogen sulfide metabolism but is also directly involved in various (patho)physiological processes, provoking scientific interest in its renal handling. This study investigates sulfate clearance in chronic HF (CHF) patients and healthy individuals and considers its relationship with disease outcome. Parameters related to renal sulfate handling were determined in and compared between 96 previously characterized CHF patients and sex-matched healthy individuals. Among patients, sulfate clearance was analyzed for associations with clinical and outcome parameters. In CHF patients, plasma sulfate concentrations are significantly higher, whereas 24-h urinary excretion, fractional excretion, and clearance of sulfate are significantly lower, compared with healthy individuals. Among patients, sulfate clearance is independently associated with diuretics use, creatinine clearance and 24-h urinary sodium excretion. Sulfate clearance is associated with favorable disease outcome [hazard ratio per SD increase 0.38 (95% confidence interval 0.23-0.63), P < 0.001]. Although significance was lost after adjustment for creatinine clearance, the decrease of sulfate clearance in patients is independent of this parameter, indicating that sulfate clearance is not merely a reflection of renal function. This exploratory study reveals aberrant sulfate clearance as a potential contributor to CHF pathophysiology, with reduced levels in patients and a positive association with favorable disease outcome. Further research is needed to unravel the nature of its involvement and to determine its potential as a biomarker and target for therapy.NEW & NOTEWORTHY Sulfate clearance is decreased in chronic heart failure patients compared with healthy individuals. Among patients, sulfate clearance is positively associated with favorable disease outcome, i.e., a decreased rehospitalization rate and increased patient survival. Hence, decreased sulfate clearance may be involved in the pathophysiology of heart failure.

Heart failure: an historical perspective

The story of heart failure (HF) traces a path from the oldest records of human healing practices several millennia ago, winding through various changing models of physiology, sickness and health. It passes through today’s landscape of neurohormonal modulation, device therapy, and assist devices, towards a future of therapies, some in development today, some as-yet unimagined, based on pathophysiological insights yet to come. This review attempts to follow the path and notes the traces left by earlier travellers, as well as the therapeutic improvements made possible by the developments in our understanding of HF that followed from their successes and failures. As we focus on pathophysiology, transplantation and mechanical assist devices will be treated more cursorily. Likewise, as this is a history of the development of modern (sometimes ‘Western’ although more properly ‘global’ or ‘scientific’) medicine, alternative therapies are not discussed in this paper.

16 Hospitalisation with acute heart failure: the patient’s view: results from a qualitative study of the acute heart failure pathway

Unplanned ED visits and admissions are expensive for healthcare systems and often stressful for the patient and family. To improve the use of healthcare resources and the patient experience of care the Global Heart Failure Awareness Programme (HFA of the ESC) emphasises increasing public awareness of the common symptoms of heart failure (HF) and empowering and supporting those with HF to actively engage in their care. This study explored the experiences of patients and GPs. Patients were recruited following an unplanned HF admission to Hospital. The established HF Unit provides monitoring, optimises therapies and provides patient education for 3 months post discharge. We also interviewed General Practitioners (GPs). Data were collected by semi-structured interview and analysed using an inductive, thematic process involving constant comparison. Twenty-four patients were recruited: Mean age of 81 years: 12 (50%) > 80 years: 10 (41%) > 85 years: Male 15 (63%), 9 (37%) de-novo HF, 17 (71%) had more than 3 co-morbidities and 8 (33%) > 3 non-cardiovascular co-morbidities. 11 (46%) lived alone. 6/15 patients with an existing diagnosis of HF had >3 admissions in the past 12 months. Seven GPs took part in the study. Key themes Understanding of HF Patients had a limited understanding of HF. They interpreted their symptoms as related to co-morbid conditions or age: breathlessness due to lung disease: fatigue due to older age. These symptoms did not fit with patient’s views of HF (palpitations or chest pain) or their view of the type of person who developed HF (sedentary lifestyle). This understanding appeared derived from a general knowledge of heart disease portrayed in the media. Continuity of care Patients described a close relationship with their GP that developed from regular monitoring related to comorbidities, on-going medication review, geographical proximity and ease of access. They viewed the GP as a ‘trusted’ source of knowledge. The majority turned to the GP when they sought resolution for symptoms. Following hospital discharge the HFU scheduled face-to-face and telephone follow-up. Patients appreciated the regular contact and were reassured by their monitoring. Fragmentation of care GP’s described barriers to obtaining diagnostic tests. This left them unable to give patients a formal diagnosis or start conversations about HF. Patients described limited access to the HFU for support or information. Some experienced frustration as they attempted to navigate between systems: HFU, GP and ED. Patients in this study were elderly. They had multiple co-morbidities that led to a reliance on the GP. Their limited knowledge of HF resulted in them identifying HF symptoms as related to co-morbid conditions. Fragmentation of care between primary and secondary care were barriers to prompt treatment and to provision of on-going information and supportive resources. These factors contributed to unplanned hospital admission and provided a negative experience of care. These results are now being tested in a larger population and different healthcare organisation.