Renal Handling of Galectin-3 in the General Population, Chronic Heart Failure, and Hemodialysis

Background-Galectin-3 is a biomarker for prognostication and risk stratification of patients with heart failure (HF). It has been suggested that renal function strongly relates to galectin-3 levels. We aimed to describe galectin-3 renal handling in HF. Methods and Results-In Sprague-Dawley rats, we infused galectin-3 and studied distribution and renal clearance. Furthermore, galectin-3 was measured in urine and plasma of healthy controls, HF patients and hemodialysis patients. To mimic the human situation, we measured galectin-3 before and after the artificial kidney. Infusion in rats resulted in a clear increase in plasma and urine galectin-3. Plasma galectin-3 in HF patients (n=101; mean age 64 years; 93% male) was significantly higher compared to control subjects (n=20; mean age 58 years; 75% male) (16.6 ng/mL versus 9.7 ng/mL, P Conclusions-In this small cross-sectional study, we report that urine levels of galectin-3 are not increased in HF patients, despite substantially increased plasma galectin-3 levels. The impaired renal handling of galectin-3 in patients with HF may explain the described relation between renal function and galectin-3 and may account for the elevated plasma galectin-3 in HF

The erythropoietin receptor expressed in skeletal muscle is essential for mitochondrial biogenesis and physiological exercise

Erythropoietin (EPO) is a haematopoietic hormone that regulates erythropoiesis, but the EPO-receptor (EpoR) is also expressed in non-haematopoietic tissues. Stimulation of the EpoR in cardiac and skeletal muscle provides protection from various forms of pathological stress, but its relevance for normal muscle physiology remains unclear. We aimed to determine the contribution of the tissue-specific EpoR to exercise-induced remodelling of cardiac and skeletal muscle. Baseline phenotyping was performed on left ventricle and m. gastrocnemius of mice that only express the EpoR in haematopoietic tissues (EpoR-tKO). Subsequently, mice were caged in the presence or absence of a running wheel for 4 weeks and exercise performance, cardiac function and histological and molecular markers for physiological adaptation were assessed. While gross morphology of both muscles was normal in EpoR-tKO mice, mitochondrial content in skeletal muscle was decreased by 50%, associated with similar reductions in mitochondrial biogenesis, while mitophagy was unaltered. When subjected to exercise, EpoR-tKO mice ran slower and covered less distance than wild-type (WT) mice (5.5 ± 0.6 vs. 8.0 ± 0.4 km/day, p < 0.01). The impaired exercise performance was paralleled by reductions in myocyte growth and angiogenesis in both muscle types. Our findings indicate that the endogenous EPO-EpoR system controls mitochondrial biogenesis in skeletal muscle. The reductions in mitochondrial content were associated with reduced exercise capacity in response to voluntary exercise, supporting a critical role for the extra-haematopoietic EpoR in exercise performance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00424-021-02577-4

DHRS7c, a novel cardiomyocyte-expressed gene that is down-regulated by adrenergic stimulation and in heart failure

Aims Although cardiac diseases account for the highest mortality and morbidity rates in Western society, there is still a considerable gap in our knowledge of genes that contribute to cardiac (dys) function. Here we screened for gene expression profiles correlated to heart failure. Methods and results By expression profiling we identified a novel gene, termed DHRS7c, which was significantly down-regulated by adrenergic stimulation and in heart failure models. Dhrs7c is a short chain dehydrogenase/reductase (SDR) and is localized to the endo/sarcoplasmic reticulum. Dhrs7c is strongly conserved in vertebrates, and mRNA and protein expression levels were highest in heart and skeletal muscle followed by skin, but were not detectable in other organs. In vitro, both alpha- and beta-adrenergic stimulation repressed Dhrs7c expression in neonatal cardiomyocytes and this could be mimicked by the direct activation of protein kinase C and adenylate cyclase, the respective intracellular targets of these hormones. In contrast, endothelin-1, which also provoked strong hypertrophy development in vitro, did not repress Dhrs7c expression. The latter suggests adrenergic specificity and indicates that down-regulation is not a prerequisite for hypertrophy development. In vivo adrenergic stimulation could also down-regulate Dhrs7c expression. Finally, we confirmed that expression was also down-regulated in two different models of failure and, importantly, also in biopsies from human heart failure patients. Conclusion Our results show that the expression of Dhrs7c, a novel endo/sarcoplasmic reticulum-localized SDR, is inversely correlated with adrenergic stimulation and heart failure development

The vitamin D receptor activator paricalcitol prevents fibrosis and diastolic dysfunction in a murine model of pressure overload

Background: Activation of the vitamin D-vitamin D receptor (VDR) axis has been shown to reduce blood pressure and left ventricular (LV) hypertrophy. Besides cardiac hypertrophy, cardiac fibrosis is a key element of adverse cardiac remodeling. We hypothesized that activation of the VDR by paricalcitol would prevent fibrosis and LV diastolic dysfunction in an established murine model of cardiac remodeling. Methods: Mice were subjected to transverse aortic constriction (TAC) to induce cardiac hypertrophy. Mice were treated with paricalcitol, losartan, or a combination of both for a period of four consecutive weeks. Results: The fixed aortic constriction caused similar increase in blood pressure, both in untreated and paricalcitol- or losartan-treated mice. TAC significantly increased LV weight compared to sham operated animals (10.2 +/- 0.7 vs. 6.9 +/- 0.3 mg/mm, p <0.05). Administration of either paricalcitol (10.5 +/- 0.7), losartan (10.8 +/- 0.4), or a combination of both (9.2 +/- 0.6) did not reduce LV weight. Fibrosis was significantly increased in mice undergoing TAC (5.9 +/- 1.0 vs. sham 2.4 +/- 0.8%, p <0.05). Treatment with losartan and paricalcitol reduced fibrosis (paricalcitol 1.6 +/- 0.3% and losartan 2.9 +/- 0.6%, both p <0.05 vs. TAC). This reduction in fibrosis in paricalcitol treated mice was associated with improved indices of LV contraction and relaxation, e.g. dPdtmax and dPdtmin and lower LV end diastolic pressure, and relaxation constant Tau. Also, treatment with paricalcitol and losartan reduced mRNA expression of ANP, fibronectin, collagen III and TIMP-1. Discussion: Treatment with the selective VDR activator paricalcitol reduces myocardial fibrosis and preserves diastolic LV function due to pressure overload in a mouse model. This is associated with a reduced percentage of fibrosis and a decreased expression of ANP and several other tissue markers. (C) 2012 Elsevier Ltd. All rights reserved

Galectin-3 increase in endurance athletes

Background Galectin-3 is a new and promising biomarker for heart failure and myocardial fibrosis. Although endurance exercise is a crucial element in cardiovascular disease prevention, the relationship between exercise and plasma levels of galectin-3 is still unknown. To date, the relationship between regular exercise and myocardial fibrosis is not fully understood. This study investigates the relationship between endurance exercise and plasma levels of galectin-3. Methods Twenty-one male, healthy non-elite marathon runners were examined before and within 1 hour after a strenuous run of 30km after 4-day training abstinence. Examination included blood samples for galectin-3, echocardiography, and cardiac magnetic resonance imaging (CMR). In addition, to distinguish between cardiac or skeletal muscular origin of galectin-3, 27 C57Bl/6J mice performing voluntary wheel running and 25 sedentary mice were analysed. Results Plasma galectin-3 in endurance athletes increased from baseline to post exercise (12.83.4ng/ml to 19.9 +/- 3.9ng/ml, p Conclusions Plasma galectin-3 is substantially elevated in endurance athletes after running but does not correlate with cardiac function, other biomarkers, or myocardial fibrosis. In mice, we demonstrate that galectin-3 increase during endurance exercise originates primarily from skeletal muscle

Short-term vitamin D3 supplementation lowers plasma renin activity in patients with stable chronic heart failure:An open-label, blinded end point, randomized prospective trial (VitD-CHF trial)

<p>Background Many chronic heart failure (CHF) patients have low vitamin D (VitD) and high plasma renin activity (PRA), which are both associated with poor prognosis. Vitamin D may inhibit renin transcription and lower PRA. We investigated whether vitamin D3 (VitD3) supplementation lowers PRA in CHF patients.</p><p>Methods and Results We conducted a single-center, open-label, blinded end point trial in 101 stable CHF patients with reduced left ventricular ejection fraction. Patients were randomized to 6 weeks of 2,000 IU oral VitD3 daily or control. At baseline, mean age was 64 +/- 10 years, 93% male, left ventricular ejection fraction 35% +/- 8%, and 56% had VitD deficiency. The geometric mean (95% CI) of 25-hydroxyvitamin D3 increased from 48 nmol/L (43-54) at baseline to 80 nmol/L (75-87) after 6 weeks in the VitD3 treatment group and decreased from 47 nmol/L (42-53) to 44 nmol/L (39-49) in the control group (P <.001). The primary outcome PRA decreased from 6.5 ng/mL per hour (3.8-11.2) to 5.2 ng/mL per hour (2.9-9.5) in the VitD3 treatment group and increased from 4.9 ng/mL per hour (2.9-8.5) to 7.3 ng/mL per hour (4.5-11.8) in the control group (P = .002). This was paralleled by a larger decrease in plasma renin concentration in the VitD3 treatment group compared to control (P = .020). No significant changes were observed in secondary outcome parameters, including N-terminal pro-B-type natriuretic peptide natriuretic peptide and fibrosis markers.</p><p>Conclusions Most CHF patients had VitD deficiency and high PRA levels. Six weeks of supplementation with 2,000 IU VitD3 increased 25-hydroxyvitamin D3 levels and decreased PRA and plasma renin concentration.</p>

Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis

BACKGROUND: Galectin-3 has been implicated in the development of organ fibrosis. It is unknown whether it is a relevant therapeutic target in cardiac remodeling and heart failure. METHODS AND RESULTS: Galectin-3 knock-out and wild-type mice were subjected to angiotensin II infusion (2.5 µg/kg for 14 days) or transverse aortic constriction for 28 days to provoke cardiac remodeling. The efficacy of the galectin-3 inhibitor N-acetyllactosamine was evaluated in TGR(mREN2)27 (REN2) rats and in wild-type mice with the aim of reversing established cardiac remodeling after transverse aortic constriction. In wild-type mice, angiotensin II and transverse aortic constriction perturbations caused left-ventricular (LV) hypertrophy, decreased fractional shortening, and increased LV end-diastolic pressure and fibrosis (P<0.05 versus control wild type). Galectin-3 knock-out mice also developed LV hypertrophy but without LV dysfunction and fibrosis (P=NS). In REN2 rats, pharmacological inhibition of galectin-3 attenuated LV dysfunction and fibrosis. To elucidate the beneficial effects of galectin-3 inhibition on myocardial fibrogenesis, cultured fibroblasts were treated with galectin-3 in the absence or presence of galectin-3 inhibitor. Inhibition of galectin-3 was associated with a downregulation in collagen production (collagen I and III), collagen processing, cleavage, cross-linking, and deposition. Similar results were observed in REN2 rats. Inhibition of galectin-3 also attenuated the progression of cardiac remodeling in a long-term transverse aortic constriction mouse model. CONCLUSIONS: Genetic disruption and pharmacological inhibition of galectin-3 attenuates cardiac fibrosis, LV dysfunction, and subsequent heart failure development. Drugs binding to galectin-3 may be potential therapeutic candidates for the prevention or reversal of heart failure with extensive fibrosis

Immediate versus staged complete revascularisation in patients presenting with acute coronary syndrome and multivessel coronary disease (BIOVASC): a prospective, open-label, non-inferiority, randomised trial

BACKGROUND: In patients with acute coronary syndrome and multivessel coronary disease, complete revascularisation by percutaneous coronary intervention (PCI) is associated with improved clinical outcomes. We aimed to investigate whether PCI for non-culprit lesions should be attempted during the index procedure or staged. METHODS: This prospective, open-label, non-inferiority, randomised trial was done at 29 hospitals across Belgium, Italy, the Netherlands, and Spain. We included patients aged 18-85 years presenting with ST-segment elevation myocardial infarction or non-ST-segment elevation acute coronary syndrome and multivessel (ie, two or more coronary arteries with a diameter of 2·5 mm or more and ≥70% stenosis based on visual estimation or positive coronary physiology testing) coronary artery disease with a clearly identifiable culprit lesion. A web-based randomisation module was used to randomly assign patients (1:1), with a random block size of four to eight, stratified by study centre, to undergo immediate complete revascularisation (PCI of the culprit lesion first, followed by other non-culprit lesions deemed to be clinically significant by the operator during the index procedure) or staged complete revascularisation (PCI of only the culprit lesion during the index procedure and PCI of all non-culprit lesions deemed to be clinically significant by the operator within 6 weeks after the index procedure). The primary outcome was the composite of all-cause mortality, myocardial infarction, any unplanned ischaemia-driven revascularisation, or cerebrovascular events at 1 year after the index procedure. Secondary outcomes included all-cause mortality, myocardial infarction, and unplanned ischaemia-driven revascularisation at 1 year after the index procedure. Primary and secondary outcomes were assessed in all randomly assigned patients by intention to treat. Non-inferiority of immediate to staged complete revascularisation was considered to be met if the upper boundary of the 95% CI of the hazard ratio (HR) for the primary outcome did not exceed 1·39. This trial is registered with ClinicalTrials.gov, NCT03621501. FINDINGS: Between June 26, 2018, and Oct 21, 2021, 764 patients (median age 65·7 years [IQR 57·2-72·9] and 598 [78·3%] males) were randomly assigned to the immediate complete revascularisation group and 761 patients (median age 65·3 years [58·6-72·9] and 589 [77·4%] males) were randomly assigned to the staged complete revascularisation group, and were included in the intention-to-treat population. The primary outcome at 1 year occurred in 57 (7·6%) of 764 patients in the immediate complete revascularisation group and in 71 (9·4%) of 761 patients in the staged complete revascularisation group (HR 0·78, 95% CI 0·55-1·11, pnon-inferiority=0·0011). There was no difference in all-cause death between the immediate and staged complete revascularisation groups (14 [1·9%] vs nine [1·2%]; HR 1·56, 95% CI 0·68-3·61, p=0·30). Myocardial infarction occurred in 14 (1·9%) patients in the immediate complete revascularisation group and in 34 (4·5%) patients in the staged complete revascularisation group (HR 0·41, 95% CI 0·22-0·76, p=0·0045). More unplanned ischaemia-driven revascularisations were performed in the staged complete revascularisation group than in the immediate complete revascularisation group (50 [6·7%] patients vs 31 [4·2%] patients; HR 0·61, 95% CI 0·39-0·95, p=0·030). INTERPRETATION: In patients presenting with acute coronary syndrome and multivessel disease, immediate complete revascularisation was non-inferior to staged complete revascularisation for the primary composite outcome and was associated with a reduction in myocardial infarction and unplanned ischaemia-driven revascularisation. FUNDING: Erasmus University Medical Center and Biotronik