PubMed Health⌕ Search

Biomedical subjects

Martina Brueckner

Publications and source records attributed to Martina Brueckner.

10 recordsLinked to original sources
PubMed2026

Multiomics approaches to cardiovascular disease: technological innovations and clinical translation.

Cardiovascular diseases (CVDs) remain the leading cause of global morbidity and mortality, reflecting a persistent gap between clinical phenotyping and the molecular mechanisms that govern disease initiation, progression, and interindividual variability. Recent advances in emerging technologies have fundamentally reshaped cardiovascular physiology by enabling high-resolution, cross-layer profiling of the heart and vasculature across genomic, epigenomic, transcriptomic, proteomic, metabolomic, lipidomic, glycomic, and fluxomic layers, increasingly at single-cell and spatial resolution. These approaches reveal CVD as a coordinated, multilayered process driven by dynamic interactions among cell types, regulatory programs, and metabolic states, rather than isolated gene-level defects. In this review, we synthesize how emerging multiomic, computational, and functional genomic technologies are redefining the study of cardiovascular disease across molecular, cellular, and tissue levels. We highlight recent innovations in single-cell and spatial atlases, long-read sequencing, proteomics and metabolomics, integrative data modeling, and functional omics approaches, including genome-scale perturbation screens and single-cell perturbation frameworks. These platforms enable mechanistic dissection of regulatory circuits, distinguish primary disease drivers from secondary adaptations, and directly assess therapeutic reversibility, advancing the field beyond associative biomarker discovery toward mechanism-guided target prioritization. We further discuss key methodological and translational challenges accompanying high-dimensional cardiovascular data, including preanalytical variability, control selection, temporal misalignment across molecular layers, population diversity, and reference bias. By integrating technological innovation with computational rigor and functional validation, this review frames emerging omics-enabled strategies as a unified, physiologically grounded framework for translating molecular insight into clinically meaningful cardiovascular phenotypes and advancing precision cardiovascular medicine.

Humans↗
PubMed2026

Prothrombin G20210A and Factor V Leiden Variants Are Not Associated With Thrombotic Events in Congenital Heart Disease: An Observational Trial.

BACKGROUND: Thrombotic events, including acute ischemic stroke, are more common in individuals with congenital heart disease (CHD). Whether common thrombophilia variants contribute to thrombotic risk in this population remains unclear. We evaluated whether prothrombin G20210A (F2 c.97G>A) and factor V Leiden (F5 c.1601G>A; p.Arg534Gln) are associated with thrombotic events in CHD. METHODS: Participants in the Pediatric Cardiac Genomics Consortium with exome sequencing and electronic medical record data were identified. Individuals were stratified by prothrombin G20210A and factor V Leiden genotypes, ventricular physiology, and antithrombotic therapy. The primary outcome was the presence of International Classification of Diseases (ICD) or Phecodes (phenotype codes) for thrombotic events. RESULTS: Among 4008 participants (median age, 11.4 [interquartile range, 5.1-17.9] years; 44.4% boys), thrombotic events occurred in 737 (18%), including 93 (13%) with acute ischemic stroke. Compared with the Genome Aggregation Database, the CHD cohort had a lower prevalence of heterozygous prothrombin G20210A and factor V Leiden variants. Variant prevalence did not differ between participants with and without thrombotic events. Single-ventricle CHD was associated with higher thrombosis frequency than biventricular CHD (35% versus 16%, P≤0.0001), without differences in variant prevalence. CONCLUSIONS: In this multicenter CHD cohort, prothrombin G20210A and factor V Leiden were not significantly associated with thrombotic outcomes, supporting recommendations against routine screening. Given low variant prevalence, the study was powered to exclude only large associations. Reduced variant frequency suggests survivorship bias beginning in fetal life. Larger integrated clinical-genomic studies are needed to refine thrombotic risk stratification in CHD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03347214.

Humans↗
PubMed2006

The emerging complexity of the vertebrate cilium: new functional roles for an ancient organelle.

Cilia and flagella are found on the surface of a strikingly diverse range of cell types. These intriguing organelles, with their unique and highly adapted protein transport machinery, have been studied extensively in the context of cellular locomotion, sexual reproduction, or fluid propulsion. However, recent studies are beginning to show that in vertebrates particularly, cilia have been recruited to perform additional developmental and homeostatic roles. Here, we review advances in deciphering the functional components of cilia, and we explore emerging trends that implicate ciliary proteins in signal transduction and morphogenetic pathways.

Animals↗
PubMed2005

TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome.

Holt-Oram syndrome (HOS) is an autosomal dominant heart-hand syndrome characterized by congenital heart disease (CHD) and upper limb deformity, and caused by mutations in the TBX5 gene. To date, the sensitivity of TBX5 genetic testing for HOS has been unclear. We now report mutational analyses of a nongenetically selected population of 54 unrelated individuals who were consecutively referred to our center with a clinical diagnosis of HOS. TBX5 mutational analyses were performed in all individuals, and clinical histories and findings were reviewed for each patient without reference to the genotypes. Twenty-six percent of the complete cohort was shown to have mutations of the TBX5 gene. However, among those subjects for whom clinical review demonstrated that their presentations met strict diagnostic criteria for HOS, TBX5 mutations were identified in 74%. No mutations were identified in those subjects who did not meet these criteria. Thus, these studies validate our clinical diagnostic criteria for HOS including an absolute requirement for preaxial radial ray upper limb malformation. Accordingly, TBX5 genotyping has high sensitivity and specificity for HOS if stringent diagnostic criteria are used in assigning the clinical diagnosis.

Abnormalities, Multiple↗
PubMed2005

Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused.

The hedgehog (Hh) pathway is conserved from Drosophila to humans and plays a key role in embryonic development. In addition, activation of the pathway in somatic cells contributes to cancer development in several tissues. Suppressor of fused is a negative regulator of Hh signaling. Targeted disruption of the murine suppressor of fused gene (Sufu) led to a phenotype that included neural tube defects and lethality at mid-gestation (9.0-10.5 dpc). This phenotype resembled that caused by loss of patched (Ptch1), another negative regulator of the Hh pathway. Consistent with this finding, Ptch1 and Sufu mutants displayed excess Hh signaling and resultant altered dorsoventral patterning of the neural tube. Sufu mutants also had abnormal cardiac looping, indicating a defect in the determination of left-right asymmetry. Marked expansion of nodal expression in 7.5 dpc embryos and variable degrees of node dysmorphology in 7.75 dpc embryos suggested that the pathogenesis of the cardiac developmental abnormalities was related to node development. Other mutants of the Hh pathway, such as Shh, Smo and Shh/Ihh compound mutants, also have laterality defects. In contrast to Ptch1 heterozygous mice, Sufu heterozygotes had no developmental defects and no apparent tumor predisposition. The resemblance of Sufu homozygotes to Ptch1 homozygotes is consistent with mouse Sufu being a conserved negative modulator of Hh signaling.

Animals↗
PubMed2004

A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels.

The homeobox gene Hhex has recently been shown to be essential for normal liver, thyroid and forebrain development. Hhex(-/-) mice die by mid-gestation (E14.5) and the cause of their early demise remains unclear. Because Hhex is expressed in the developing blood islands at E7.0 in the endothelium of the developing vasculature and heart at E9.0-9.5, and in the ventral foregut endoderm at E8.5-9.0, it has been postulated to play a critical role in heart and vascular development. We show here, for the first time, that a null mutation of Hhex results in striking abnormalities of cardiac and vascular development which include: (1) defective vasculogenesis, (2) hypoplasia of the right ventricle, (3) overabundant endocardial cushions accompanied by ventricular septal defects, outflow tract abnormalities and atrio-ventricular (AV) valve dysplasia and (4) aberrant development of the compact myocardium. The dramatic enlargement of the endocardial cushions in the absence of Hhex is due to decreased apoptosis and dysregulated epithelial-mesenchymal transformation (EMT). Interestingly, vascular endothelial growth factor A (Vegfa) levels in the hearts of Hhex(-/-) mice were elevated as much as three-fold between E9.5 and E11.5, and treatment of cultured Hhex(-/-) AV explants with truncated soluble Vegfa receptor 1, sFlt-1, an inhibitor of Vegf signaling, completely abolished the excessive epithelial-mesenchymal transformation seen in the absence of Hhex. Therefore, Hhex expression in the ventral foregut endoderm and/or the endothelium is necessary for normal cardiovascular development in vivo, and one function of Hhex is to repress Vegfa levels during development.

Animals↗
PubMed2003

Two populations of node monocilia initiate left-right asymmetry in the mouse.

The vertebrate body plan has conserved handed left-right (LR) asymmetry that is manifested in the heart, lungs, and gut. Leftward flow of extracellular fluid at the node (nodal flow) is critical for normal LR axis determination in the mouse. Nodal flow is generated by motile node cell monocilia and requires the axonemal dynein, left-right dynein (lrd). In the absence of lrd, LR determination becomes random. The cation channel polycystin-2 is also required to establish LR asymmetry. We show that lrd localizes to a centrally located subset of node monocilia, while polycystin-2 is found in all node monocilia. Asymmetric calcium signaling appears at the left margin of the node coincident with nodal flow. These observations suggest that LR asymmetry is established by an entirely ciliary mechanism: motile, lrd-containing monocilia generate nodal flow, and nonmotile polycystin-2 containing cilia sense nodal flow initiating an asymmetric calcium signal at the left border of the node.

Animals↗
PubMed2003

Cilia are at the heart of vertebrate left-right asymmetry.

Handed asymmetry of the shape and position of the internal organs is found in all vertebrates, and is essential for normal cardiac development. Recent genetic and embryological experiments in mouse embryos have demonstrated that left-right asymmetry is established by directional flow of extraembryonic fluid surrounding the node, which is driven by motile monocilia.

Animals↗
PubMed2002

Conserved function for embryonic nodal cilia.

How left right handedness originates in the body plan of the developing vertebrate embryo is a subject of considerable debate. In mice, a left right bias is thought to arise from a directional extracellular flow (nodal flow) that is generated by dynein-dependent rotation of monocilia on the ventral surface of the embryonic node. Here we show that the existence of node monocilia and the expression of a dynein gene that is implicated in ciliary function are conserved across a wide range of vertebrate classes, indicating that a similar ciliary mechanism may underlie the establishment of handedness in all vertebrates.

Animals↗