Hansjörg Habisch

Malondialdehyde (MDA) is a widely used biomarker of lipid peroxidation, yet its relationships with lipoprotein subclasses remain poorly explored, particularly in metabolic syndrome (MS). We investigated associations of free MDA measured by the TBARS assay (MDA-TBARS) and total MDA quantified by high-performance liquid chromatography (MDA-HPLC) with NMR spectroscopy-measured lipoprotein subclasses in 65 healthy volunteers (HV) and 65 patients with MS. MDA-HPLC concentrations were higher than MDA-TBARS, and the two measures were strongly correlated. Free MDA levels were significantly elevated in MS, whereas total MDA did not differ between groups. In HV, MDA-TBARS showed positive relationships with VLDL and IDL, as well as triglyceride enrichment of LDL, IDL, and HDL, and a negative relationship with levels and cholesterol content of small, dense HDL, as well as cholesterol and phospholipid content of LDL subclasses. MDA-HPLC only showed a positive association with VLDL levels in HV. In contrast, no significant associations between MDA and lipoproteins were observed in MS. Multivariable analyses confirmed that lipoprotein profiles were able to discriminate between low and high MDA levels in HV, but not in patients with MS. In conclusion, interactions between oxidative stress and lipoproteins are strongly context dependent, being preserved in health but disrupted in MS, with free MDA emerging as a more informative marker of lipoprotein-associated lipid peroxidation.

Methane is a unique archaeal metabolite that links gut microbial ecology to host physiology. Although intestinal methane production varies by several orders of magnitude between individuals and has been associated with gastrointestinal transit and disease states, the ecological and functional determinants underlying this variation remain poorly understood. Here, we integrate breath methane phenotyping with shotgun metagenomics, metatranscriptomics, comparative genomics, cultivation and stable-isotope tracing in 80 deeply characterized individuals to determine the species-level and functional basis of human gut methanogenesis. Breath methane levels strongly reflected archaeal abundance but could not fully explain methane emission; species-resolved profiling revealed that methane emission represents distinct archaeome states rather than differences in methanogen quantity alone. High methane emitters were dominated by Methanobrevibacter smithii and M. intestini, whereas low emitters harbored a previously uncharacterized Methanobrevibacter lineage (M. sp900766745), for which we propose the name Candidatus Methanobrevibacter hominipaucus sp. nov. Comparative genomics revealed that M. sp900766745 represents a metabolically streamlined lineage lacking several methyl-compound utilization pathways and displaying reduced substrate acquisition capacity. Communities of low-emission individuals exhibited reduced microbial transcriptional activity and accumulated incompletely processed dietary metabolites, indicating lower fermentative turnover and altered hydrogen flux.

Excess salt is a major contributor to hypertension and hypertensive kidney injury, yet the early molecular events linking salt exposure to kidney damage remain incompletely understood. The Dahl salt-sensitive rat is a well-established model of salt-induced hypertension, but early metabolic and transcriptional remodeling in the kidney has not been fully characterized. We investigated early kidney alterations in 35 Dahl salt-sensitive rats fed a high-sodium (HSD) or low-sodium diet (LSD). A subgroup of HSD-fed rats received the ACE inhibitor imidapril at a subdepressor dose (1 mg/kg/day) to examine blood pressure-independent effects. Kidney tissue from 12-week-old animals was analyzed using histology, electron microscopy, transcriptomics, metabolomics, and angiotensin peptide profiling. HSD-fed rats developed hypertension by week 9 and showed kidney remodeling by week 12, including metabolic and transcriptional alterations suggestive of disrupted tricarboxylic acid cycle activity and impaired oxidative phosphorylation in the absence of overt fibrosis. Intra-kidney angiotensin I, II, and angiotensin 1–7 levels were reduced under HSD. Subdepressor ACE inhibition did not significantly alter blood pressure, kidney injury, angiotensin peptide levels, or the transcriptional and metabolic alterations observed in HSD-fed animals. These findings indicate that high salt intake induces early metabolic and extracellular matrix remodeling that is not modified by subdepressor ACE inhibition.

Rationale: Pulmonary hypertension is defined by pulmonary hemodynamics, but diagnostic and prognostic biomarkers remain limited. Nuclear magnetic resonance (NMR) spectroscopy provides detailed insights, particularly in the lipid metabolism. Objectives: To explore circulating NMR-derived metabolites and lipoprotein-related parameters for their association with pulmonary hemodynamics and to analyse their prognostic properties in pulmonary arterial hypertension (PAH). Methods: Retrospective analysis of a PAH cohort with complete diagnostic workup including right heart catheterization and baseline serum samples, from the prospective GRaz Pulmonary Hypertension-Metabolism (GRAPH-M) registry. Measurements: NMR-derived metabolites and lipoprotein-related parameters were analyzed for their association with clinically relevant parameters of PAH. We defined PHIHDL, a score derived from high-density lipoprotein (HDL) related measures based on their strong association with pulmonary hemodynamics, and evaluated its prognostic value. Results: We included 100 patients with PAH treated at the PH clinic of LKH University Hospital, Medical University of Graz, between 2011 and 2021. Age was 61±15 years, female/male ratio 2.5, BMI 26±7 kg/m ² , mPAP 41±16 mmHg, PAWP 8.8±3.2 mmHg, PVR 8.0±4.9 WU, and median survival was 8.0 years. During follow-up, 46 patients died. We identified a cluster of 12 HDL-related measures that showed significant inverse association to pulmonary hemodynamics and derived PHIHDL from the reversed scaled average of these particles. PHIHDL was associated with all-cause mortality after adjustment for age and sex (HR 2.96, 95% CI 1.52-5.70), independent of the clinical risk scores COMPERA 2.0 and REVEAL Lite 2. Conclusion: PHIHDL, a pulmonary hemodynamics-based metabolomic score, provides independent prognostic information beyond established risk scores in PAH.

Context and Objective Mild autonomous cortisol secretion (MACS) is associated with increased mortality, mainly because of cardiovascular disease. Here we investigated the effects of cortisol-lowering medical treatment on blood pressure regulation, cardiac fat depots, heart function and morphology, and other cardiovascular risk factors. Design, Setting and Intervention In this secondary analysis of our prospective, open-label, single-center study at the Medical University of Vienna, we investigated 15 patients with MACS (12 females; age 59 [53–64] years) before and after 12 weeks of treatment with evening doses of metyrapone (500 mg at 6 p.m. and 250 mg at 10 p.m.). Outcome measures and Methods Cardiac fat stores, morphology and myocardial function were evaluated using cardiac magnetic resonance imaging and spectroscopy. Orthostatic blood pressure regulation was measured by standardized protocols. Lipidomics, renin-angiotensin-aldosterone-system activity and branched-chain amino acid (BCAA) concentrations were assessed. Results Mean supine systolic (137[121-139] vs 122[115-129] mmHg; p=0.041) and diastolic (89[80-93] vs 75[71-86] mmHg; p=0.045) blood pressure decreased after treatment in patients without changes in concomitant antihypertensive medication. Epicardial fat was lower at follow up compared to baseline (1032.70[894.23-1482.90] vs 929.37[736.12-1317.15]mm²; p=0.022). No changes in paracardial- and intramyocardial fat, as well as in cardiac function and morphology were observed. The aldosterone-to-angiotensin II ratio was lower at follow up (1.56[0.87–2.82] vs 1.21[0.98–1.92]; p=0.042) and alterations in lipid profiles, but not in BCAA levels were identified. Conclusions Treatment with evening doses of metyrapone improved blood pressure and reduced epicardial adipose tissue.

Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by abnormal proliferation and differentiation of blasts. PRMT5, a methyltransferase that catalyzes symmetric dimethylation of arginine (SDMA) residues, has been implicated in cancer stem cell homeostasis and shown to be a potential therapeutic target in AML. However, given the toxicity of complete PRMT5 inhibition, there is a need to identify effective synergistic therapies. Through a targeted screen of compounds that inhibit key nodes of PRMT5-regulated pathways, we identified a synthetic lethality between inhibition of PRMT5 and LSD1, a lysine demethylase known to affect AML blast differentiation. The two inhibitors broadly reshape the transcriptome of targeted cells and synergize to promote AML differentiation and eventually growth inhibition and apoptosis, in a p53-dependent manner. To leverage this synthetic lethal interaction, we generated new dual compounds to inhibit both enzymes and recapitulated the effects of the drug combination. Our results uncover an unexpected convergence of PRMT5- and LSD1-regulated targets, paving the way for new therapeutic opportunities.

The human gut is colonized by trillions of microbes that influence the health of their human host. Whereas many bacterial species have now been linked to a variety of different diseases, the involvement of Archaea, an evolutionarily distinct group of microbes, in human disease remains elusive. By analyzing 19 independent clinical studies, we demonstrate that associations between Archaea and human diseases are widespread yet highly heterogeneous, with a pronounced and consistent enrichment of Methanobrevibacter smithii in colorectal cancer (CRC) patients. Metabolic modelling and in vitro co-culture identified distinct mutualistic interactions of M. smithii with CRC-causing bacteria such as Fusobacterium nucleatum , including metabolic enhancement. Metabolomics further reveal archaeal-derived compounds with tumor-modulating properties. Together, our results provide mechanistic insights into how the human gut archaeome may participate in CRC-associated microbial networks through metabolic cooperation with bacteria.

Background: New biomarkers are needed to improve risk prediction in patients with acute heart failure. We aimed to identify serum lipids with prognostic value and clinical utility in patients hospitalized due to acute heart failure. Methods: Targeted mass spectrometry–based lipidomics was performed on serum samples from 315 (discovery) and 139 (validation) patients prospectively enrolled in 2 observational acute heart failure studies. Prognostic lipids were identified by consolidating orthogonal partial least squares discriminant analysis, least absolute shrinkage and selection operator regression, and random forest (Boruta) results into a single ranking using TopKSignal. Results: In the discovery cohort, lysophosphatidylethanolamine 20:4, lysophosphatidylcholine 20:4, lysophosphatidylcholine 14:0, and lysophosphatidylethanolamine 18:1 were most strongly associated with in‐hospital mortality. Serum concentrations were significantly lower in nonsurvivors, and these inverse associations remained significant after adjustment in both cohorts, except for lysophosphatidylethanolamine 18:1 after adjustment for OPTIMIZE‐HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure) in the validation cohort. These lipids demonstrated moderate discriminative performance (area under the curve, 0.72–0.76 in the discovery and 0.71–0.77 in the validation cohort) and provided additional prognostic value beyond ADHERE (Acute Decompensated Heart Failure National Registry), GWTG‐HF (Get With The Guidelines Heart Failure), and OPTIMIZE‐HF (Δarea under the curve, 0.04–0.17) scores. Decision curve analyses showed improved net clinical benefit for mortality prediction across threshold probabilities of 12% to 35% in the discovery and 15% to 28% in the validation cohort. Conclusions: Low serum levels of lysophosphatidylethanolamine 20:4, lysophosphatidylcholine 20:4, lysophosphatidylcholine 14:0, and lysophosphatidylethanolamine 18:1 were independently associated with in‐hospital mortality in acute heart failure. These findings suggest that specific lysophospholipids may serve as novel prognostic biomarkers, warranting validation in larger studies to confirm their clinical applicability.

Chronic obstructive pulmonary disease (COPD) is a severe progressive lung disease, often caused by prolonged exposure to cigarette smoke and environmental factors. Preclinical COPD research predominately relies on chronic smoke or elastase animal models, each with their own advantages and limitations, such as limited pathophysiological insights or long treatment times. Here we describe a novel and time-efficient mouse model of COPD based on bacterial LPS and the reactive aldehyde acrolein (Acro). Mice were treated once per week for 4 weeks with a combination of both LPS and Acro. Histological, inflammatory, and metabolomic alterations were analyzed by histological quantification, multicolor flow cytometry, and nuclear magnetic resonance. Acro/LPS treatment induced moderate airspace enlargement and bronchial remodeling. These structural changes were associated with a distinct inflammatory profile marked by an increase in macrophages and T-helper cells, as well as increased cytokines, including CXCL11, IL-17a, and TNF-α. Strong inflammation, consisting of T-helper and B cells, was detected in the perivascular and peribronchial spaces and increased macrophages in the alveolar regions. In addition, intervention with the steroid dexamethasone induced a strong reduction in T cells and macrophages and partially ameliorated histological alterations. Furthermore, we could detect alterations in the metabolome of serum and tissue, including an increase in COPD-associated metabolites like trimethylamine N-oxide, as well as a misbalance in energy-related metabolites and several amino acids. In summary, we can describe a practical, representative, and time-efficient mouse model of COPD, with the potential to study the immunological and pathophysiological development of the disease.