Heart failure-induced microbial dysbiosis contributes to colonic tumour formation in mice.

AIMS: Heart failure (HF) and cancer are the leading causes of death worldwide. Epidemiological studies revealed that HF patients are prone to develop cancer. Preclinical studies provided some insights into this connection, but the exact mechanisms remain elusive. In colorectal cancer (CRC), gut microbial dysbiosis is linked to cancer progression and recent studies have shown that HF patients display microbial dysbiosis. This current study focussed on the effects of HF-induced microbial dysbiosis on colonic tumour formation. METHODS AND RESULTS: C57BL/6J mice were subjected to myocardial infarction (MI), with sham surgery as control. After six weeks faeces were collected, processed for 16 s rRNA sequencing, and pooled for faecal microbiota transplantation. CRC tumour growth was provoked in germ-free mice by treating them with Azoxymethane/Dextran sodium sulphate. The CRC mice were transplanted with faeces from MI or sham mice. MI-induced HF resulted in microbial dysbiosis, characterized by a decreased α-diversity and microbial alterations on the genus level, several of which have been associated with CRC. We then performed faecal microbiota transplantation with faeces from HF mice in CRC mice, which resulted in a higher endoscopic disease score and an increase in the number of tumours in CRC mice. CONCLUSION: We demonstrated that MI-induced HF contributes to colonic tumour formation by altering the gut microbiota composition, providing a mechanistic explanation for the observed association between HF and increased risk for cancer. Targeting the microbiome may present as a tool to mitigate HF-associated co-morbidities, especially cancer.

Improving goal striving and resilience in older adults through a personalized metacognitive self-help intervention: a protocol paper.

BACKGROUND: Successful aging is often linked to individual's ability to demonstrate resilience: the maintenance or quick recovery of functional ability, well-being, and quality of life despite losses or adversity. A crucial element of resilience is behavioral adaptability, which refers to the adaptive changes in behavior in accordance with internal or external demands. Age-related degradation of executive functions can, however, lead to volition problems that compromise flexible adjustment of behavior. In contrast, the reliance on habitual control has been shown to remain relatively intact in later life and may therefore provide an expedient route to goal attainment among older adults. In the current study, we examine whether a metacognitive self-help intervention (MCSI), aimed at facilitating goal striving through the gradual automatization of efficient routines, could effectively support behavioral adaptability in favor of resilience among older adults with and without (sub-clinical) mental health problems. METHODS: This metacognitive strategy draws on principles from health and social psychology, as well as clinical psychology, and incorporates elements of established behavioral change and activation techniques from both fields. Additionally, the intervention will be tailored to personal needs and challenges, recognizing the significant diversity that exist among aging individuals. DISCUSSION: Despite some challenges that may limit the generalizability of the results, our MCSI program offers a promising means to empower older adults with tools and strategies to take control of their goals and challenges. This can promote autonomy and independent functioning, and thereby contribute to adaptability and resilience in later life. TRIAL REGISTRATION: Pre-registered, partly retrospectively. This study was pre-registered before the major part of the data was collected, created, and realized. Only a small part of the data of some participants (comprising the baseline and other pre-intervention measures), and the full dataset of the first few participants, was collected prior to registration, but it was not accessed yet. See: https://osf.io/5b9xz.

Health literate-sensitive shared decision-making in maternity care: needs for support among maternity care professionals in the Netherlands.

BACKGROUND: Shared decision-making (SDM) in maternity care is challenging when clients have insufficient health literacy (HL) skills. This study gained insight in how professionals apply HL-sensitive SDM in Dutch maternity care and their needs for support therein. METHODS: Maternity care professionals (n = 30) completed a survey on SDM and the role of HL. Midwives (n = 13) were observed during simulated conversations discussing pain relief options and interviewed afterwards. The client-actors were instructed to portrait specific inadequate HL skills. Observation items focused on adapting communication to HL, and SDM (OPTION-5). RESULTS: In the survey, professionals indicated experiencing most challenges when estimating clients' information comprehension. Observations showed that most midwives created choice awareness and informed clients about options, whereas exploring preferences and actual decision-making together with clients were observed less frequently. Their perceived HL-related obstacles and needs for support related to clients' information comprehension. In the interviews, midwives reported putting much effort into explaining available options in maternity care, but also that decisions about pain relief are often postponed until the moment of labour. CONCLUSION: Professionals' self-reported needs focus on clients' information comprehension. However, observations indicate that it is not the stage of informing, but rather value clarification and actual decision-making that need improvement in HL-sensitive SDM.

Corrigendum: The interplay between quality of life and resilience factors in later life: a network analysis.

[This corrects the article DOI: 10.3389/fpsyg.2021.752564.].

Fibrotic Marker Galectin-3 Identifies Males at Risk of Developing Cancer and Heart Failure.

Background: Cancer and heart failure (HF) are the leading causes of death in the Western world. Shared mechanisms such as fibrosis may underlie either disease entity, furthermore it is unknown whether this relationship is sex-specific. Objectives: We sought to investigate how fibrosis-related biomarker galectin-3 (gal-3) aids in identifying individuals at risk for new-onset cancer and HF, and how this differs between sexes. Methods: Gal-3 was measured at baseline and at 4-year follow-up in 5,786 patients of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study. The total follow-up period was 11.5 years. An increase of ≥50% in gal-3 levels between measurements was considered relevant. We performed sex-stratified log-rank tests and Cox regression analyses overall and by sex to evaluate the association of gal-3 over time with both new-onset cancer and new-onset HF. Results: Of the 5,786 healthy participants (50% males), 399 (59% males) developed new-onset cancer, and 192 (65% males) developed new-onset HF. In males, an increase in gal-3 was significantly associated with new-onset cancer (both combined and certain cancer-specific subtypes), after adjusting for age, body mass index, hypertension, smoking status, estimated glomerular filtration rate, diabetes mellitus, triglycerides, coronary artery disease, and C-reactive protein (HR: 1.89; 95% CI: 1.32-2.71; P < 0.001). Similar analyses demonstrated an association with new-onset HF in males (HR: 1.77; 95% CI: 1.07-2.95; P = 0.028). In females, changes in gal-3 over time were neither associated with new-onset cancer nor new-onset HF. Conclusions: Gal-3, a marker of fibrosis, is associated with new-onset cancer and new-onset HF in males, but not in females.

Age differences in routine formation: the role of automatization, motivation, and executive functions.

Medication adherence can be vital for one's health, especially in older adults. However, previous research has demonstrated that medication adherence is negatively affected by age-related cognitive decline. In the current study we investigated whether older adults are able to compensate for this decline by relying more on the formation of efficient, automatized routines. To this end, we directly compared daily (placebo) medication adherence in a healthy sample of 68 younger (18-29 years) and 63 older adults (65-86 years) over a period of 4 weeks. We show that despite an age-related decline in cognitive functions (i.e., poorer working memory, prospective memory, task switching, and goal-directed control), older adults adhered better to a daily pill intake routine than younger adults did and, in line with our hypothesis about increased routine formation, reported higher subjective automaticity of pill intake. Across age groups, automatization of pill intake was related to intake regularity and conscientiousness, but not to individual differences in habit tendency as measured in the lab nor to explicit strategic planning. Crucially, the age-related increase in pill intake adherence was mediated by experienced automatization as well as motivation. These findings demonstrate that intact habitual processes and high motivation aid older adults in successfully forming daily routines.

Divergent effects of myostatin inhibition on cardiac and skeletal muscles in a mouse model of pressure overload.

The transforming growth factor-ß (TGF-ß) superfamily member, myostatin, is a negative regulator of muscle growth and may contribute to adverse cardiac remodeling. Whether suppressing myostatin could benefit pressure-overloaded heart remains unclear. We investigated the effects of pharmacological inhibition of myostatin on cardiac fibrosis and hypertrophy in a mouse model of pressure overload induced by transverse aortic constriction (TAC). Two weeks after the surgery, TAC and sham mice were randomly divided into groups receiving mRK35, a monoclonal anti-myostatin antibody, or vehicle (PBS) for 8 wk. Significant progressive cardiac hypertrophy was observed in TAC mice, as reflected by the increased wall thickness, ventricular weight, and cross-sectional area of cardiomyocytes. In the groups treated with mRK35, compared with sham mice, cardiac fibrosis was increased in TAC mice, accompanied with elevated mRNA expression of fibrotic genes. However, among the TAC mice, mRK35 did not reduce cardiac hypertrophy or fibrosis. Body weight, lean mass, and wet weights of tibialis anterior and gastrocnemius muscle bundle were increased by mRK35. When compared with the TAC-PBS group, the TAC mice treated with mRK35 demonstrated greater forelimb grip strength and a larger mean size of gastrocnemius fibers. Our data suggest that mRK35 does not attenuate cardiac hypertrophy and fibrosis in a TAC mouse model but has positive effects on muscle mass and muscle strength. Anti-myostatin treatment may have therapeutic value against muscle wasting in cardiac vascular disease.NEW & NOTEWORTHY Recent research has highlighted the importance of inhibiting TGF-ß signaling in mitigating cardiac dysfunction and remodeling. As myostatin belongs to the TGF-ß family, we evaluated the impact of myostatin inhibition using mRK35 in TAC-operated mice. Our data demonstrate that mRK35 significantly increased body weight, muscle mass, and muscle strength but did not attenuate cardiac hypertrophy or fibrosis. Pharmacological inhibition of myostatin may provide therapeutic benefits for the management of muscle wasting in cardiovascular diseases.

Association of Initial and Longitudinal Changes in C-reactive Protein With the Risk of Cardiovascular Disease, Cancer, and Mortality.

OBJECTIVE: To evaluate the value of serial C-reactive protein (CRP) measurements in predicting the risk of cardiovascular disease (CVD), cancer, and mortality. METHODS: The analysis was performed using data from two prospective, population-based observational cohorts: the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study and the Framingham Heart Study (FHS). A total of 9253 participants had CRP measurements available at two examinations (PREVEND: 1997-1998 and 2001-2002; FHS Offspring cohort: 1995-1998 and 1998-2001). All CRP measurements were natural log-transformed before analyses. Cardiovascular disease included fatal and nonfatal cardiovascular, cerebrovascular and peripheral vascular events, and heart failure. Cancer included all malignancies except nonmelanoma skin cancers. RESULTS: The mean age of the study population at baseline was 52.4±12.1 years and 51.2% (n=4733) were women. Advanced age, female sex, smoking, body mass index, and total cholesterol were associated with greater increases in CRP levels over time (Pall<.001 in the multivariable model). Baseline CRP, as well as increase in CRP over time (ΔCRP), were associated with incident CVD (hazard ratio [HR]: 1.29 per 1-SD increase; 95% confidence interval [CI]: 1.29 to 1.47, and HR per 1-SD increase: 1.19; 95% CI: 1.09 to 1.29 respectively). Similar findings were observed for incident cancer (baseline CRP, HR: 1.17; 95% CI: 1.09 to 1.26; ΔCRP, HR: 1.08; 95% CI: 1.01 to 1.15) and mortality (baseline CRP, HR: 1.29; 95% CI: 1.21 to 1.37; ΔCRP, HR: 1.10; 95% CI: 1.05 to 1.16). CONCLUSION: Initial as well as subsequent increases in CRP levels predict future CVD, cancer, and mortality in the general population.

Can the Brain Strategically Go on Automatic Pilot? The Effect of If-Then Planning on Behavioral Flexibility.

People often have good intentions but fail to adhere to them. Implementation intentions, a form of strategic planning, can help people to close this intention-behavior gap. Their effectiveness has been proposed to depend on the mental formation of a stimulus-response association between a trigger and target behavior, thereby creating an "instant habit." If implementation intentions do indeed lead to reliance on habitual control, then this may come at the cost of reduced behavioral flexibility. Furthermore, we would expect a shift from recruitment of corticostriatal brain regions implicated in goal-directed control toward habit regions. To test these ideas, we performed a fMRI study in which participants received instrumental training supported by either implementation or goal intentions, followed by an outcome revaluation to test reliance on habitual versus goal-directed control. We found that implementation intentions led to increased efficiency early in training, as reflected by higher accuracy, faster RTs, and decreased anterior caudate engagement. However, implementation intentions did not reduce behavioral flexibility when goals changed during the test phase, nor did it affect the underlying corticostriatal pathways. In addition, this study showed that "slips of action" toward devalued outcomes are associated with reduced activity in brain regions implicated in goal-directed control (ventromedial prefrontal cortex and lateral orbitofrontal cortex) and increased activity of the fronto-parietal salience network (including the insula, dorsal anterior cingulate cortex, and SMA). In conclusion, our behavioral and neuroimaging findings suggest that strategic if-then planning does not lead to a shift from goal-directed toward habitual control.

Individual Differences in Corticostriatal White-matter Tracts Predict Successful Daily-life Routine Formation.

Despite good intentions, people often fail to cross the "intention-behavior gap," especially when goal achievement requires repeated action. To bridge this gap, the formation of automatized routines may be crucial. However, people may differ in the tendency to switch from goal-directed toward habitual control. To shed light on why some people succeed in forming routines while others struggle, the present study related the automatization of a novel, daily routine to individual differences in white-matter connectivity in corticostriatal networks that have been implicated in goal-directed and habitual control. Seventy-seven participants underwent diffusion-weighted imaging and formed the daily routine of taking a (placebo) pill for 3 weeks. Pill intake was measured by electronic pill boxes, and participants filled out a daily online questionnaire on the subjective automaticity of this behavior. Automatization of pill intake was negatively related to striatal (mainly caudate) connectivity with frontal goal-directed and cognitive control regions, namely, ventromedial pFC and anterior cingulate gyrus. Furthermore, daily pill intake was positively related to individual differences in striatal (mainly caudate) connectivity with cognitive control regions, including dorsolateral and anterior pFC. Therefore, strong control networks may be relevant for implementing a new routine but may not benefit its automatization. We also show that habit tendency (assessed with an outcome-devaluation task), conscientiousness, and daily life regularity were positively related to routine automatization. This translational study moves the field of habit research forward by relating self-reported routine automatization to individual differences in performance on an experimental habit measure and to brain connectivity.

Multifactorial Diseases of the Heart, Kidneys, Lungs, and Liver and Incident Cancer: Epidemiology and Shared Mechanisms.

Within the aging population, the frequency of cancer is increasing dramatically. In addition, multiple genetic and environmental factors lead to common multifactorial diseases, including cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, and metabolic-associated fatty liver disease. In recent years, there has been a growing awareness of the connection between cancer and multifactorial diseases, as well as how one can affect the other, resulting in a vicious cycle. Although the exact mechanistic explanations behind this remain to be fully explored, some progress has been made in uncovering the common pathologic mechanisms. In this review, we focus on the nature of the link between cancer and common multifactorial conditions, as well as specific shared mechanisms, some of which may represent either preventive or therapeutic targets. Rather than organ-specific interactions, we herein focus on the shared mechanisms among the multifactorial diseases, which may explain the increased cancer risk. More research on this subject will highlight the significance of developing new drugs that target multiple systems rather than just one disease.

Impaired belief updating and devaluation in adult women with bulimia nervosa.

Recent models of bulimia nervosa (BN) propose that binge-purge episodes ultimately become automatic in response to cues and insensitive to negative outcomes. Here, we examined whether women with BN show alterations in instrumental learning and devaluation sensitivity using traditional and computational modeling analyses of behavioral data. Adult women with BN (n = 30) and group-matched healthy controls (n = 31) completed a task in which they first learned stimulus-response-outcome associations. Then, participants were required to repeatedly adjust their responses in a "baseline test", when different sets of stimuli were explicitly devalued, and in a "slips-of-action test", when outcomes instead of stimuli were devalued. The BN group showed intact behavioral sensitivity to outcome devaluation during the slips-of-action test, but showed difficulty overriding previously learned stimulus-response associations on the baseline test. Results from a Bayesian learner model indicated that this impaired performance could be accounted for by a slower pace of belief updating when a new set of previously learned responses had to be inhibited (p = 0.036). Worse performance and a slower belief update in the baseline test were each associated with more frequent binge eating (p = 0.012) and purging (p = 0.002). Our findings suggest that BN diagnosis and severity are associated with deficits in flexibly updating beliefs to withhold previously learned responses to cues. Additional research is needed to determine whether this impaired ability to adjust behavior is responsible for maintaining automatic and persistent binge eating and purging in response to internal and environmental cues.

Instant habits versus flexible tenacity: Do implementation intentions accelerate habit formation?

Implementation intentions (strategic "if-then" plans) have been shown to support behaviour change. This may be achieved by mentally forming stimulus-response associations, thereby promoting habit formation. Does this deliberate attempt to instal "strategic automaticity" only offer advantages, or does it also come at the cost of reduced flexibility that characterises learnt habits? To investigate this, we tested healthy, young participants on a computerised instrumental learning task. Critically, we introduced implementation intentions ("if I see stimulus X, then I will respond") versus goal intentions ("for outcome Z, I will respond)" during instrumental acquisition, and subsequently assessed behavioural flexibility in an outcome-revaluation test. In Experiment 1, we conducted a between-subjects manipulation of strategic planning, and in Experiment 2, a within-subject manipulation. We hypothesised that implementation intentions would lead to strong stimulus-response associations and consequently impair performance when the signalled outcome value changed and therefore required a different response, while benefitting performance when the outcome value (and required response) remained the same. We found that implementation intentions supported instrumental learning, but impaired test performance overall (most robustly in Experiment 2), irrespective of whether the signalled outcome value had changed. We argue that this general detrimental effect of implementation intentions on test performance is likely a consequence of their negative effect on stimulus-outcome learning. Our findings warrant caution when applying if-then plans to situations where the agent does not already possess perfect knowledge of behavioural contingencies.While implementation intentions may support efficient and fast behavioural execution, this may come at the expense of behavioural flexibility.

Multi-omics analyses identify molecular signatures with prognostic values in different heart failure aetiologies.

BACKGROUND: Heart failure (HF) is the leading cause of morbidity and mortality worldwide, and there is an urgent need for more global studies and data mining approaches to uncover its underlying mechanisms. Multiple omics techniques provide a more holistic molecular perspective to study pathophysiological events involved in the development of HF. METHODS: In this study, we used a label-free whole myocardium multi-omics characterization from three commonly used mouse HF models: transverse aortic constriction (TAC), myocardial infarction (MI), and homozygous Phospholamban-R14del (PLN-R14Δ/Δ). Genes, proteins, and metabolites were analysed for differential expression between each group and a corresponding control group. The core transcriptome and proteome datasets were used for enrichment analysis. For genes that were upregulated at both the RNA and protein levels in all models, clinical validation was performed by means of plasma level determination in patients with HF from the BIOSTAT-CHF cohort. RESULTS: Cell death and tissue repair-related pathways were upregulated in all preclinical models. Fatty acid oxidation, ATP metabolism, and Energy derivation processes were downregulated in all investigated HF aetiologies. Putrescine, a metabolite known for its role in cell survival and apoptosis, demonstrated a 4.9-fold (p < 0.02) increase in PLN-R14Δ/Δ, 2.7-fold (p < 0.005) increase in TAC mice, and 2.2-fold (p < 0.02) increase in MI mice. Four Biomarkers were associated with all-cause mortality (PRELP: Hazard ratio (95% confidence interval) 1.79(1.35, 2.39), p < 0.001; CKAP4: 1.38(1.21, 1.57), p < 0.001; S100A11: 1.37(1.13, 1.65), p = 0.001; Annexin A1 (ANXA1): 1.16(1.04, 1.29) p = 0.01), and three biomarkers were associated with HF-Related Rehospitalization, (PRELP: 1.88(1.4, 2.53), p < 0.001; CSTB: 1.15(1.05, 1.27), p = 0.003; CKAP4: 1.18(1.02, 1.35), P = 0.023). CONCLUSIONS: Cell death and tissue repair pathways were significantly upregulated, and ATP and energy derivation processes were significantly downregulated in all models. Common pathways and biomarkers with potential clinical and prognostic associations merit further investigation to develop optimal management and therapeutic strategies for all HF aetiologies.

Assessing the degree of urbanisation using a single-item self-report measure: a validation study.

The differential impact of rural versus urban residence on mental health remains a controversial topic that requires more in-depth investigations. This calls for a valid and easy measure to assess the degree of urbanisation. The purpose of the present study was to determine the utility of a single-item self-report measure (SIDU) as a tool to classify areas along the rural-urban continuum. The validity of the SIDU was assessed by comparing its scores (1-7) to a commonly used objective surrogate measure of the degree of urbanisation (i.e. surrounding address density, SAD) in two independent older adult samples (A: N = 36, 65+; B: N = 121, 55+). SIDU scores approximated SAD scores, with r = .77 to 0.82, (A), and r = .79 to 0.83 (B). A SIDU threshold score of 6 most accurately distinguished extremely urbanised areas from other areas. Altogether, our findings suggest that SIDU scores could be used as proxy of SAD. Since self-report leaves room for the consideration of additional aspects that confer an urban settlement, this single-item scale may be even more comprehensive, and circumvents the collection and handling of highly sensitive location data when the primary goal is solely to distinguish urbanisation subgroups.

Clonal haematopoiesis of indeterminate potential: associations with heart failure incidence, clinical parameters and biomarkers.

AIM: We aimed to analyse the association of clonal haematopoiesis of indeterminate potential (CHIP) with incident heart failure (HF) in a European population cohort. METHODS AND RESULTS: From the prospective Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort, we included all 374 participants with incident HF and selected 1:1 age- and sex-matched control subjects. Peripheral blood samples of 705 individuals were successfully analysed by error-corrected next generation sequencing for acquired mutations at a variant allele frequency ≥2% in 27 CHIP driver genes. The median age of the study population was 65 years (interquartile range 58-70) and 35.6% were female. CHIP mutations positively correlated with age, smoking, hypertension and cardiovascular biomarkers including N-terminal pro-B-type natriuretic peptide and mid-regional pro-A-type natriuretic peptide, but the frequency of CHIP was comparable in individuals with incident HF and in control participants (18.4% vs. 17.3%; p = 0.69). In multivariable Cox regression models, CHIP was not significantly associated with incident HF (hazard ratio [HR] 1.24, 95% confidence interval [CI] 0.93-1.65; p = 0.144). This association, however, was modified by age (p for CHIP-age interaction = 0.002). Among people younger than 65 years, CHIP mutations were more frequently detected in the case cohort compared to the control cohort (14.2% vs. 5.8%; p = 0.009), and were significantly associated with new-onset HF (HR 2.07, 95% CI 1.30-3.29; p = 0.002). CONCLUSION: Clonal haematopoiesis of indeterminate potential correlates with HF risk factors and biomarkers, and is associated with incident HF in subjects <65 years of age.

Mechanisms shared between cancer, heart failure, and targeted anti-cancer therapies.

Heart failure (HF) and cancer are the leading causes of death worldwide and accumulating evidence demonstrates that HF and cancer affect one another in a bidirectional way. Patients with HF are at increased risk for developing cancer, and HF is associated with accelerated tumour growth. The presence of malignancy may induce systemic metabolic, inflammatory, and microbial alterations resulting in impaired cardiac function. In addition to pathophysiologic mechanisms that are shared between cancer and HF, overlaps also exist between pathways required for normal cardiac physiology and for tumour growth. Therefore, these overlaps may also explain the increased risk for cardiotoxicity and HF as a result of targeted anti-cancer therapies. This review provides an overview of mechanisms involved in the bidirectional connection between HF and cancer, specifically focusing upon current 'hot-topics' in these shared mechanisms. It subsequently describes targeted anti-cancer therapies with cardiotoxic potential as a result of overlap between their anti-cancer targets and pathways required for normal cardiac function.

Mitigating the Harmful Impact of Ageism among Older Individuals: The Buffering Role of Resilience Factors.

Frequent exposure to ageism has significant repercussions on the quality of life and mental well-being/health of older adults. Resilience may play a crucial role in mitigating these effects. The current study aimed to investigate the potential buffering roles of two types of coping variables-behavioral coping and a positive appraisal style-in older adults (N = 2000, aged 55-93). Confirming previous findings, higher levels of perceived negative ageism (PNA) were associated with diminished quality of life and mental well-being, increased depression and loneliness. However, individuals that tend to employ behavioral coping strategies when confronted with challenging/stressful situations showed a weaker relationship between PNA and quality of life, mental well-being, and depression. Embracing a positive appraisal style attenuated the negative impact of PNA on feelings of depression and loneliness. Interestingly, younger older adults appeared to benefit the most from these resilience factors. Despite considerable inter-individual variability, encouraging the utilization of behavioral coping strategies and nurturing a positive appraisal style could serve as effective approaches to mitigate the detrimental effects of PNA.

Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence.

AIMS: Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations. METHODS AND RESULTS: We have measured plasma IGFBP7 concentrations in 2250 subjects with new-onset or worsening heart failure (BIOSTAT-CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT-proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all-cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25-2.46; HR 1.71, 95% CI 1.39-2.11; and HR 1.44, 95% CI 1.23-1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P < 0.001). A biomarker network analysis showed that IGFBP7 levels activate different pathways involved in the regulation of the immune system. Results were externally validated in BIOSTAT-CHF validation cohort. CONCLUSIONS: IGFPB7 presents as an independent and robust prognostic biomarker in patients with HF, with both reduced and preserved ejection fraction. We validate the previously published data showing IGFBP7 has correlations with a number of echocardiographic markers. Lastly, IGFBP7 pathways are involved in different stages of immune system regulation, linking heart failure to senescence pathways.