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01 januari 2023, Item does not contain fulltext, 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.

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Contains fulltext : 196255.pdf (publisher's version ) (Open Access), In nonhigh risk patients with hypertrophic cardiomyopathy (HC), the presence of extensive late gadolinium enhancement (LGEext) at cardiovascular magnetic resonance (CMR) imaging has been proposed as a risk modifier in the decision process for implantable cardioverter defibrillator implantation. With a pretest risk of about 10%, a strategy that alters the likelihood of LGEext could markedly affect efficacious CMR imaging. Our aim was to study the potential of clinical variables and biomarkers to predict LGEext. In 98 HC patients without any clear indication for implantable cardioverter defibrillator implantation, we determined the discriminative values of a set of clinical variables and a panel of biomarkers (hs-cTnT, NTproBNP, GDF-15, and Gal-3, CICP) for LGEext, that is, LGE >/=15% of the left ventricular mass. LGEext was present in 10% (10/98) of patients. The clinical prediction model contained a history of nonsustained ventricular tachycardia, maximal wall thickness and reduced systolic function (c-statistic: 0.868, p <0.001). Of all biomarkers, only hs-cTnT was associated with LGEext, in addition to the improved clinical model of diagnostic accuracy (p=0.04). A biomarker-only strategy allowed the exclusion of LGEext in half of the cohort, in case of a hs-cTnT concentration less than the optimal cutoff (Youden index; 8 ng/L-sensitivity 100%, specificity 54%). In conclusion, in this nonhigh risk HC cohort, the pretest likelihood of LGEext can be altered using clinical variables and the addition of hs-cTnT. The promising findings with the use of hs-cTnT only call for new initiatives to study its impact on efficacious CMR imaging in a larger HC population, either with or without additional use of clinical variables.

Contains fulltext : 200148.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, BACKGROUND: The incidence of cardiovascular events is higher in patients with primary aldosteronism than in patients with essential hypertension (EHT), despite similar blood pressure levels. This suggests detrimental cardiovascular effects of aldosterone. Amongst others, it has been suggested that galectin-3 (Gal-3) is a key mediator in aldosterone-induced myocardial fibrosis. OBJECTIVE: We studied whether patients with primary aldosteronism have higher plasma Gal-3 concentrations than patients with EHT and evaluated its reversibility after adrenalectomy. METHODS: In a retrospective cohort from our tertiary referral centre, we measured plasma Gal-3 concentrations in 78 patients with primary aldosteronism, 39 cured primary aldosteronism patients after adrenalectomy and 56 patients with EHT. Paired samples were available in 11 patients (preadrenalectomy and postadrenalectomy). We compared plasma Gal-3 levels by univariate analysis of covariance with correction for cardiovascular risk factors, plasma creatinine concentration, plasma potassium levels and alcohol intake. RESULTS: Adjusted plasma Gal-3 concentrations in patients with primary aldosteronism, patients after adrenalectomy and patients with EHT were 11.39 +/- 0.60, 11.64 +/- 0.81 and 11.41 +/- 0.73 ng/ml, respectively (mean +/- SD; P = 0.95). In 11 patients of whom paired samples were available, mean Gal-3 concentrations increased from 10.03 +/- 1.67 ng/ml preadrenalectomy to 14.36 +/- 2.07 ng/ml postadrenalectomy (P < 0.01). CONCLUSION: In patients with primary aldosteronism, plasma Gal-3 concentrations are not elevated when compared with patients with EHT, and levels do not decrease after adrenalectomy. These results are in contrast to previous studies and do not support a pathophysiological role of plasma Gal-3 in the increased cardiovascular risk in patients with primary aldosteronism.

Contains fulltext : 182343.pdf (publisher's version ) (Closed access), In response to heart failure (HF), the heart reacts by repressing adult genes and expressing fetal genes, thereby returning to a more fetal-like gene profile. To identify genes involved in this process, we carried out transcriptional analysis on murine hearts at different stages of development and on hearts from adult mice with HF. Our screen identified Oplah, encoding for 5-oxoprolinase, a member of the gamma-glutamyl cycle that functions by scavenging 5-oxoproline. OPLAH depletion occurred as a result of cardiac injury, leading to elevated 5-oxoproline and oxidative stress, whereas OPLAH overexpression improved cardiac function after ischemic injury. In HF patients, we observed elevated plasma 5-oxoproline, which was associated with a worse clinical outcome. Understanding and modulating fetal-like genes in the failing heart may lead to potential diagnostic, prognostic, and therapeutic options in HF.

Item does not contain fulltext, AIMS: A kinase interacting protein 1 (AKIP1) stimulates physiological growth in cultured cardiomyocytes and attenuates ischaemia/reperfusion (I/R) injury in ex vivo perfused hearts. We aimed to determine whether AKIP1 modulates the cardiac response to acute and chronic cardiac stresses in vivo. METHODS AND RESULTS: Transgenic mice with cardiac-specific overexpression of AKIP1 (AKIP1-TG) were created. AKIP1-TG mice and their wild-type (WT) littermates displayed similar cardiac structure and function. Likewise, cardiac remodelling in response to transverse aortic constriction or permanent coronary artery ligation was identical in AKIP1-TG and WT littermates, as evidenced by serial cardiac magnetic resonance imaging and pressure-volume loop analysis. Histological indices of remodelling, including cardiomyocyte cross-sectional diameter, capillary density, and left ventricular fibrosis were also similar in AKIP1-TG mice and WT littermates. When subjected to 45 min of ischaemia followed by 24 h of reperfusion, AKIP1-TG mice displayed a significant two-fold reduction in myocardial infarct size and reductions in cardiac apoptosis. In contrast to previous reports, AKIP1 did not co-immunoprecipitate with or regulate the activity of the signalling molecules NF-kappaB, protein kinase A, or AKT. AKIP1 was, however, enriched in cardiac mitochondria and co-immunoprecipitated with a key component of the mitochondrial permeability transition (MPT) pore, ATP synthase. Finally, mitochondria isolated from AKIP1-TG hearts displayed markedly reduced calcium-induced swelling, indicative of reduced MPT pore formation. CONCLUSIONS: In contrast to in vitro studies, AKIP1 overexpression does not influence cardiac remodelling in response to chronic cardiac stress. AKIP1 does, however, reduce myocardial I/R injury through stabilization of the MPT pore. These findings suggest that AKIP1 deserves further investigation as a putative treatment target for cardioprotection from I/R injury during acut

Contains fulltext : 154705.pdf (publisher's version ) (Open Access), Pathological cardiac hypertrophy is characterized by a shift in metabolic substrate utilization from fatty acids to glucose, but the molecular events underlying the metabolic remodeling remain poorly understood. Here, we investigated the role of liver X receptors (LXRs), which are key regulators of glucose and lipid metabolism, in cardiac hypertrophic pathogenesis. Using a transgenic approach in mice, we show that overexpression of LXRalpha acts to protect the heart against hypertrophy, fibrosis, and dysfunction. Gene expression profiling studies revealed that genes regulating metabolic pathways were differentially expressed in hearts with elevated LXRalpha. Functionally, LXRalpha overexpression in isolated cardiomyocytes and murine hearts markedly enhanced the capacity for myocardial glucose uptake following hypertrophic stress. Conversely, this adaptive response was diminished in LXRalpha-deficient mice. Transcriptional changes induced by LXRalpha overexpression promoted energy-independent utilization of glucose via the hexosamine biosynthesis pathway, resulting in O-GlcNAc modification of GATA4 and Mef2c and the induction of cytoprotective natriuretic peptide expression. Our results identify LXRalpha as a key cardiac transcriptional regulator that helps orchestrate an adaptive metabolic response to chronic cardiac stress, and suggest that modulating LXRalpha may provide a unique opportunity for intervening in myocyte metabolism.

Contains fulltext : 127542.pdf (publisher's version ) (Open Access), The (pro)renin-renin receptor, (P)RR has been claimed to be a novel element of the renin-angiotensin system (RAS). The function of (P)RR has been widely studied in renal and vascular pathology but the cardio-specific function of (P)RR has not been studied in detail. We therefore generated a transgenic mouse (Tg) with cardio-restricted (P)RR overexpression driven by the alpha-MHC promotor. The mRNA expression of (P)RR was approximately 170-fold higher (P<0.001) and protein expression approximately 5-fold higher (P<0.001) in hearts of Tg mice as compared to non-transgenic (wild type, Wt) littermates. This level of overexpression was not associated with spontaneous cardiac morphological or functional abnormalities in Tg mice. To assess whether (P)RR could play a role in cardiac hypertrophy, we infused ISO for 28 days, but this caused an equal degree of cardiac hypertrophy and fibrosis in Wt and Tg mice. In addition, ischemia-reperfusion injury was performed in Langendorff perfused isolated mouse hearts. We did not observe differences in parameters of cardiac function or damage between Wt and Tg mouse hearts under these conditions. Finally, we explored whether the hypoxia sensing response would be modulated by (P)RR using HeLa cells with and without (P)RR overexpression. We did not establish any effect of (P)RR on expression of genes associated with the hypoxic response. These results demonstrate that cardio-specific overexpression of (P)RR does not provoke phenotypical differences in the heart, and does not affect the hearts' response to stress and injury. It is concluded that increased myocardial (P)RR expression is unlikely to have a major role in pathological cardiac remodeling.

It is hard to find an appropriate definition of ‘play’ in animals that encompasses all its forms and varieties. Consequently, the adaptive function of play is a highly debated subject. Here, we review earlier proposed hypotheses about the functionality of play. Specifically, we describe hypotheses for a less common form of play: adult-adult social play. In addition, a case study on social play in adult bonobos (Pan paniscus) is provided. We use recordings of social play in European zoos (Apenheul, Frankfurt, Stuttgart and Wuppertal) to test predictions drafted from earlier proposed hypotheses. These entail that adult social play is used to assess and manipulate uncertain social relationships. Our preliminary results seem to confirm that the certainty of inter-individual relations play an important role in the adaptive function of (adult) social play.

Item does not contain fulltext, PURPOSE OF REVIEW: In patients with type 2 diabetes mellitus, treatment with metformin is associated with a lower cardiovascular morbidity and mortality, compared with alternative glucose-lowering drugs. It has been suggested that metformin might exert direct protective effects on the heart. RECENT FINDINGS: This review appraises recent experimental animal studies on the effect of metformin on myocardial ischaemia-reperfusion injury and remodeling. In murine models of myocardial infarction, the administration of metformin potently limits infarct size. Activation of adenosine monophosphate-activated protein kinase, increased formation of adenosine, and the prevention of opening of the mitochondrial permeability transition pore at reperfusion all contribute to this cardioprotective effect. In addition, metformin therapy attenuates postinfarction cardiac remodeling. There is evidence that activation of adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase, and a reduced collagen expression are crucial for this effect. SUMMARY: The finding that metformin limits myocardial infarct size and remodeling in animal models of myocardial infarction suggests that patients suffering from myocardial ischaemia could benefit from treatment with metformin, even when these patients do not have diabetes. Currently, several clinical trials are being performed to test this hypothesis.

Contains fulltext : 97633.pdf (publisher's version ) (Closed access), The transient receptor potential channel C6 (TRPC6) is a slit diaphragm-associated protein in podocytes involved in regulating glomerular filter function. Gain-of-function mutations in TRPC6 cause hereditary focal segmental glomerulosclerosis (FSGS), and several human acquired proteinuric diseases show increased glomerular TRPC6 expression. Angiotensin II (AngII) is a key contributor to glomerular disease and may regulate TRPC6 expression in nonrenal cells. We demonstrate that AngII regulates TRPC6 mRNA and protein levels in cultured podocytes and that AngII infusion enhances glomerular TRPC6 expression in vivo. In animal models for human FSGS (doxorubicin nephropathy) and increased renin-angiotensin system activity (Ren2 transgenic rats), glomerular TRPC6 expression was increased in an AngII-dependent manner. TRPC6 expression correlated with glomerular damage markers and glomerulosclerosis. We show that the regulation of TRPC6 expression by AngII and doxorubicin requires TRPC6-mediated Ca(2+) influx and the activation of the Ca(2+)-dependent protein phosphatase calcineurin and its substrate nuclear factor of activated T cells (NFAT). Accordingly, calcineurin inhibition by cyclosporine decreased TRPC6 expression and reduced proteinuria in doxorubicin nephropathy, whereas podocyte-specific inducible expression of a constitutively active NFAT mutant increased TRPC6 expression and induced severe proteinuria. Our findings demonstrate that the deleterious effects of AngII on podocytes and its pathogenic role in glomerular disease involve enhanced TRPC6 expression via a calcineurin/NFAT positive feedback signaling pathway.

Contains fulltext : 47840.pdf (publisher's version ) (Closed access), INTRODUCTION: Current guidelines of chronic heart failure (CHF) do not recommend the use of oral anticoagulants (OAC) or antiplatelet therapy (APT). We performed a post-hoc analysis to evaluate the effect of the use of anti-thrombotic therapy with APT and OAC. PATIENTS AND METHODS: We examined 427 patients with advanced CHF, and assessed the effects of the use of APT or OAC at baseline on mortality. We employed a Cox-proportional hazard model to value the effects of APT or OAC use. RESULTS: After a mean follow-up of 3.4 years (range 2.0-5.4), 214 patients died (51%). Forty-one (41) percent (95%CI: 29-53%) of the patients on APT died, and 52% (47-57%) of the patients not on APT (P=0.07). Forty-eight (48) percent (42-54%) of the patients on OAC died, and 55% (46-63%) of the patients not on OAC (P=0.20). This effect of OAC was seen both in patients in sinus rhythm and in atrial fibrillation. After adjusting for important prognostic variables, such as age, LVEF, renal function, and NYHA class, both the use of APT (hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.40-0.97; P=0.04) and the use of OAC (HR 0.60, 95%-CI 0.43-0.83; P<0.01) were related to an improved prognosis. CONCLUSION: This post-hoc analysis suggests that in CHF patients the use of APT or OAC is associated with a higher survival.

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