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At least 19 recordsLinked to original sources
PubMed2025

How to Study Gene Expression and Gain of Function of Hoxb1 in Mouse Heart Development.

Anterior Hox genes are required for genetic identity and anterior posterior patterning of the second heart field (SHF), which contributes to the formation of the embryonic heart in vertebrates. Defective contribution of SHF cells to the arterial or venous pole of the heart is often associated with severe congenital heart defects. The mouse Cre-lox system allows the activation of expression of any gene of interest in restricted tissues. We developed a gain of function approach that relies on the use of a CAG transgene to ectopically activate Hoxb1 expression in SHF cardiac progenitor cells through specific Cre activation. Therefore, we generated a floxed transgenic mouse line, CAG-Hoxb1-eGFP, which upon recombination by Cre recombinase conditionally induces robust Hoxb1 and eGFP expression. When induced within the anterior SHF lineage, we detected heart defects in mouse embryos such as right ventricular hypoplasia. Here, we describe the strategy for generating and genetically crossing this transgenic mouse line. We also provide detailed protocols for whole-mount embryo and paraffin section in situ RNAscope hybridization and X-gal staining allowing investigation of SHF contribution during heart development.

Animals↗
PubMed2025

Charting Postnatal Heart Development Using In Vivo Single-Cell Functional Genomics.

The transition at birth, marked by increased circulatory demands and rapid growth, necessitates extensive remodeling of the heart's structure, function, and metabolism. This transformation requires precise spatial and temporal coordination among diverse cardiac cell types; central to this process is cardiomyocyte maturation, yet the regulatory mechanisms driving these changes remain poorly understood. Here, we present a temporal and spatial atlas of postnatal hearts by integrating single-nucleus transcriptomics with image-based spatial transcriptomics, which uncovers the dynamic regulatory networks of cardiomyocyte maturation. To functionally interrogate candidate regulators in vivo , we developed Probe-based Indel-detectable Perturb-seq (PIP-seq), a high-throughput platform that uses probe-based chemistry to directly capture sgRNA expression, perturbation status, and transcriptomic profiles at single-nucleus resolution. Applying PIP-seq to postnatal cardiac development identified 21 novel regulators of cardiomyocyte maturation, highlighting critical nodal points in this process. Our study establishes a high-resolution framework for dissecting postnatal heart development, underscoring the integrative and highly ordered roles of microenvironment and intercellular communication in cardiomyocyte maturation. Importantly, PIP-seq enables systematic, high-throughput exploration of gene function and networks underlying complex biological processes in their native in vivo context.

Journal Article↗
PubMed2026

CD109 exhibits a dynamic expression pattern in coronary endothelium and endocardial-derived valve mesenchyme during heart development with preserved morphogenesis following endothelial-specific deletion.

BACKGROUND: CD109 encodes a GPI-linked glycoprotein that acts as a signaling modulator in the TGF-β pathway. CD109 has emerged in several genome-wide association studies as linked to coronary artery disease, myocardial infarction, and angina pectoris. Heterozygous loss-of-function mutations in CD109 have also been reported in patients with congenital heart defects, suggesting potential developmental relevance, though CD109 has never been investigated in the context of cardiovascular development. We previously identified Cd109 upregulation in murine atrioventricular valves undergoing myxomatous degeneration following a reduction of epicardial-derived cells. Here, we characterize Cd109 expression in the murine cardiovascular system and assess its function during development using in vitro and in vivo approaches. RESULTS: We found that Cd109 is strongly expressed in the endothelium of the coronary vasculature and in endocardial-derived subpopulations in the atrioventricular valves. This expression persists through key stages in cardiovascular development. Western blotting and immunostaining confirm endothelial expression in heart and lung tissues. siRNA-mediated knockdown of CD109 in primary human endothelial cells led to dysregulation of vascular development pathways and decreased tube formation capacity. We generated endothelial-specific Cd109 knockout mice, eliminating Cd109 expression from heart and lung tissues without overt consequences for atrioventricular valve or coronary vascular morphogenesis during heart development. CONCLUSION: CD109 exhibits a highly dynamic spatiotemporal expression pattern during cardiovascular development, with enriched expression in coronary endothelial cells and endocardial-derived subpopulations in the valves. Despite this striking developmental expression pattern, previously reported human genetic associations with cardiovascular diseases, and endothelial-associated phenotypes following siRNA-mediated CD109 knockdown in a primary human endothelial cell line, endothelial/endocardial-lineage deletion of Cd109 did not produce overt abnormalities in atrioventricular valve or coronary vascular morphogenesis during embryonic development. Collectively, these findings identify CD109 as a useful marker of coronary endothelial and endocardial-derived valve cell populations and suggest that CD109 may function in a context-dependent or modulatory manner rather than as an essential regulator of cardiovascular morphogenesis under normal developmental conditions.

CD109↗
PubMed1977

Effect of triac on the developing heart.

Triac (diethanolamine salt of triiodothyroacetic acid) was administered by intramuscular injection to 12 pregnant female rats. These were divided into a control group and three other groups, each receiving different doses of triac. The effect of triac on the hearts of their offspring was studied morphologically. Histological examination showed evidence of only mild hypertrophy, but ultrastructurally, disarray of myocardial fibrils and other changes similar to those observed in patients with hypertrophic cardiomyopathy were found in the litter of the group receiving the highest dose. It is suggested that thyroid function should be studied in patients with obscure cardiac disease.

Animals↗
PubMed2026

Hypoxia-activated scleraxis a mediates epicardial progenitor differentiation into a unique cardiac perivascular cell type.

The epicardium provides progenitor cells and paracrine signals essential for heart development and regeneration, yet the mechanisms regulating epicardial cell fate remain poorly understood. Here, we identify the transcription factor Scleraxis a (scxa) as a key regulator of epicardial progenitor differentiation in zebrafish. Single-cell transcriptomics, genetic lineage tracing, and cardiac injury models reveal transient scxa expression in activated epicardial progenitor cells (aEPCs) during developmental coronary angiogenesis and heart regeneration. scxa+ epicardial cells predominantly differentiate into a previously uncharacterized col18a1a+ perivascular population, termed epicardial-derived perivascular mesenchymal cells (Epi-PMCs), which is distinct from pericytes, vascular smooth muscle cells, and mammalian adventitial fibroblasts. Epi-PMCs closely associate with coronary vessels and may contribute to vascular stabilization and remodeling, potentially through collagen XVIII. Loss of scxa increases coronary vessel density. Hypoxia and Hif signaling induce scxa expression, identifying a hypoxia-responsive mechanism that promotes epicardial differentiation toward a vascular-supportive fate during heart development and regeneration.

Animals↗
PubMed2025

Exploring genetic mapping and co-expression patterns to illuminate significance of Tbx20 in cardiac biology.

The transcription factor Tbx20 is integral to heart development and plays a significant role in various cardiac diseases. Despite its established importance, the regulatory mechanisms and functional significance of Tbx20 remain incompletely understood. To elucidate these mechanisms, we initially conducted eQTL mapping to identify genetic loci associated with Tbx20 expression in heart tissue from BXD mice. Co-expression and enrichment analyses revealed pathways linked to Tbx20, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and FoxO signaling. Additionally, protein-protein interaction studies identified essential cardiac proteins, such as Myl2 and Myl7, along with upstream regulators like Mef2c. To validate our bioinformatic findings, we performed quantitative reverse transcription polymerase chain reaction (qRT-PCR) to assess the relative mRNA expression levels of TBX20 and Mef2c in the heart tissues of BXD mice compared to their parental strains (B6 and D2). Our results demonstrated significant up-regulation of both TBX20 and Mef2c in the BXD group relative to the parental strains. Conversely, both genes were down-regulated in B6, D2, Control, and Treatment groups when compared to BXD mice. These findings confirm the predicted regulatory roles of TBX20 and Mef2c in cardiac development as suggested by our initial analyses.This study not only reinforces the critical role of Tbx20 in cardiac gene regulation but also highlights its potential as a therapeutic target for cardiovascular disorders. Further investigations into Tbx20 and its interactions will enhance our understanding of heart biology and contribute to the development of targeted therapies for heart diseases.

Animals↗
PubMed2026

Empagliflozin and functional aerobic capacity in individuals with increased risk of heart failure: The Empire Prevent Cardiac trial.

BACKGROUND: Higher maximal oxygen consumption (VO₂ max) is associated with lower risk of developing heart failure (HF). Empagliflozin improves VO2 max in HF with reduced ejection fraction, but the effect on VO2 max in individuals at risk of HF remain unknown. OBJECTIVE: This study aimed to evaluate the effect of 180 days treatment with empagliflozin compared to placebo on VO2 max, daily physical activity level, and quality of life (QoL) in individuals with overweight or obesity and risk of HF. METHOD: This investigator-initiated, double-blinded, randomized, placebo-controlled, multicenter trial included elderly individuals with body mass index >28 kg/m2 and at least one additional risk factor for HF, including hypertension, ischemic heart disease, stroke, or chronic kidney disease. Individuals with HF or type 2 diabetes mellitus were excluded. The primary endpoint was the mean difference in change of VO2 max. The secondary outcome was objectively measured physical activity level. QoL was an explorative outcome. RESULTS: Among 191 randomized individuals (94 empagliflozin, 97 placebo), 89% had hypertension and 66% ischemic heart disease. At baseline, 69% were male, median age was 68 years, median body mass index 31.9 kg/m², mean left ventricular ejection fraction 65 ± 9%, and mean VO₂ max 18.1 ± 4.3 mL/min/kg. Empagliflozin did not change VO2 max with an estimated treatment difference of -0.2 mL/min/kg (97.5% confidence interval -1.2 to 0.8), adjusted P = 1.00. No significant treatment differences were observed for neither daily physical activity nor QoL. CONCLUSIONS: Empagliflozin did not affect VO2 max, physical activity level, or QoL in elderly individuals with overweight or obesity and risk of HF.

Humans↗
PubMed2026

Prediction of incident heart failure in established atherosclerotic cardiovascular disease: the SMART2-HF model.

BACKGROUND AND AIMS: Patients with established atherosclerotic cardiovascular disease (ASCVD) are at high risk of developing heart failure (HF). However, incident HF is not part of the risk assessment of current guideline-recommended models. The aim of this study was to develop and externally validate the SMART2-HF model for prediction of incident HF in patients with ASCVD. METHODS: SMART2-HF was developed in 7698 individuals with established ASCVD (coronary, cerebrovascular, or peripheral artery disease, or abdominal aortic aneurysm) but without prior HF from the UCC-SMART cohort. Cox proportional hazards models including sex-predictor interactions and with age as the time scale were derived to estimate the 10-year and lifetime risk of incident HF (hospitalization for HF or HF-related death), accounting for competing non-HF mortality. Predictors, limited to routinely available clinical characteristics, were aligned with the SMART2 risk model for recurrent cardiovascular (CV) risk in the same population. External validation was performed in 240 741 patients with ASCVD from six data sources: the Clinical Practice Research Datalink, the HUNT3 study, the SWEDEHEART Registry, the ASCVD-Particles cohort, the Estonian Biobank and the international REACH Registry. RESULTS: During a median follow-up of 11.2 years (interquartile range 6.1-16.4 years), 1031 incident HF events (13%) occurred in the UCC-SMART cohort. In the external validation data sources, a total of 24 885 incident HF events (10%) occurred. The pooled C-statistic was .696 (95% confidence interval .674-.717), with consistent performance in subgroups by sex and type of ASCVD. Predicted risks matched observed incidence in external validation. CONCLUSIONS: The SMART2-HF model enables the prediction of incident HF in patients with ASCVD. Aligned with the guideline-recommended SMART2 model for recurrent CV risk, SMART2-HF can be used as a complementary tool in this population.

Humans↗
PubMed2025

Single-Cell Splicing Isoform Atlas of the Adult Human Heart and Heart Failure.

BACKGROUND: Alternative splicing plays crucial roles in normal heart development and cardiac disease by influencing protein-coding sequences, functional domains, and molecular networks. However, a detailed characterization of the human heart isoform landscape remains incomplete. METHODS: Leveraging long-read single-nucleus RNA sequencing and computational analysis, we dissected full-length isoform heterogeneities, expression patterns, and usage shifts across cell types, cell states, and cardiac conditions of the adult left ventricle. We applied in silico approaches to assess the functional relevance of identified isoforms; validated isoform compositions of representative cardiac genes using reverse transcription quantitative polymerase chain reaction and targeted amplicon sequencing; and developed a web server for interactive navigation of our results. RESULTS: The data revealed that isoform heterogeneity is widespread in the cardiac cellular system, serving as a posttranscriptional buffer mechanism that calibrates the molecule reservoirs in human hearts. In healthy left ventricles, ≈30% of cell type-specific genes were polyform, using multiple isoforms tailored to cell type-specific programs. Among ubiquitously expressed genes, >300 showed differential isoform usage with cell type specificity in normal hearts. Comparisons of cardiomyocytes across conditions uncovered 379 genes with marked isoform usage shifts, most of which are predicted to change protein coding outcomes through direct changes in protein coding sequences and switches between intron retention and non-protein-coding biotypes. In contrast, cell state-specific programs tend to operate on monoform genes associated with changes among cell states. In addition, our data revealed heart failure-associated differential isoform usage events in stromal and immune cell types in the cardiac microenvironment. CONCLUSIONS: We present a comprehensive atlas of splicing isoforms in the normal adult heart and heart failure through long-read single-nucleus RNA sequencing and computational analyses. The results suggest crucial roles of isoforms in buffering core cellular programs and contributing to disease-associated cell states. The full-length details of these cell-specific isoforms serve as an important reference for downstream translational and mechanistic studies and are available on our online data portal at https://github.com/gaolabtools/heart-isoform-atlas.

Humans↗
PubMed1975

Combination of delta9-tetrahydrocannabinol with oxymorphone or pentobarbital: Effects on ventilatory control and cardiovascular dynamics.

Marijuana is widely used, yet few data concerning its actions combined with other drugs exist. Psychologic, respiratory and cardiovascular effects of delta9-tetrahydrocannabinol (THC), the active component of marijuana, combined with oxymorphone (OXM) or with pentobarbital (PBL), were studies in 15 healthy volunteers. Oxymorphone, 1.0 mg/70 kg, iv, caused sedation and ventilatory depression (minute ventilation: 24.9 plus or minus 11.9 SD to 14.1 plus or minus 4.9 1/min with PETCO2 held at 50 torr) in eight volunteers. TCH (27, 40, 60, 90, and 134 mug/kg, iv) increased sedation and further decreased ventilation with each TCH dose to 6.6 plus or minus 3.7 1/min after 134 mug/kg. The combination of OXM and THC decreased the CO2-ventilation slope from 2.23 to 0.88 1/min/torr. When THC, 134 mug/kg, was added to OXM, which alone caused no significant cardiovascular change, cardiac index (4.1 plus or minus 1.3 to 5.0 plus or minus 2.2 1/min/m-2) and heart rate (66 plus or minus 12 to 107 plus or minus 31 beats/min) significantly increased and total peripheral resistance (1,030 plus or minus 260 to 660 plus or minus 200 dynes-sec/cm-5) decreased. Heart rates exceeded 150 beats/min in two subjects after 27 and 134 mug/kg THC. Pentobarbital alone, 100 mg/70 kg, iv, caused no significant ventilatory or cardiovascular change. THC, after PBL pretreatment, induced hallucinations and anxiety in five of seven volunteers; four failed to complete all five doses of THC becuase of the severe psychologic effects. The combination of PBL and 40 to 134 mug/kg THC did not affect ventilation significantly. After PBL pretreatment, THC significantly increased heart rate (76 plus or minus 17 to 130 plus or minus 32 beats/min). Cardiac index also increased (3.8 plus or minus 0.8 to 5.6 plus or minus 1.9 1/min/m-2) and total peripheral resistance decreased (1,070 plus or minus 240 to 720 plus or minus 300 dynes-sec/cm-5). Three subjects developed heart rates esceeding 150 beats/min after 27, 27, and 90 mug/kg THC; in all three, heart rates fell from maximal value with a further dose of THC.

Adult↗
PubMed2025

New Genetic Loci Implicated in Cardiac Morphology and Function Using Three-Dimensional Population Phenotyping.

BACKGROUND: Cardiac remodeling occurs in the mature heart and is a cascade of adaptations in response to stress, which are primed in early life. A key question remains as to the processes that regulate the geometry and motion of the heart and how it adapts to stress. METHODS: We performed spatially resolved phenotyping using machine learning-based analysis of cardiac magnetic resonance imaging in 47 549 UK Biobank participants. We analyzed 16 left ventricular spatial phenotypes, including regional myocardial wall thickness and systolic strain in both circumferential and radial directions. In up to 40 058 participants, genetic associations across the allele frequency spectrum were assessed using genome-wide association studies with imputed genotype participants, and exome-wide association studies and gene-based burden tests using whole-exome sequencing data. We integrated transcriptomic data from the GTEx project and used pathway enrichment analyses to further interpret the biological relevance of identified loci. To investigate causal relationships, we conducted Mendelian randomization analyses to evaluate the effects of blood pressure on regional cardiac traits and the effects of these traits on cardiomyopathy risk. RESULTS: We found 42 loci associated with cardiac structure and contractility, many of which reveal patterns of spatial organization in the heart. Whole-exome sequencing revealed 3 additional variants not captured by the genome-wide association study, including a missense variant in CSRP3 (minor allele frequency 0.5%). The majority of newly discovered loci are found in cardiomyopathy-associated genes, suggesting that they regulate spatially distinct patterns of remodeling in the left ventricle in an adult population. Our causal analysis also found regional modulation of blood pressure on cardiac wall thickness and strain. CONCLUSIONS: These findings provide a comprehensive description of the pathways that orchestrate heart development and cardiac remodeling. These data highlight the role that cardiomyopathy-associated genes have on the regulation of spatial adaptations in those without known disease.

Humans↗
PubMed2025

Transcription factor 4 maintains endothelial cell identity by inhibiting endothelial to mesenchymal transition.

Endothelial to mesenchymal transition (EndoMT) is essential for embryonic heart development and contributes to many pathological processes. It is unclear how the balance between endothelial cell (EC) identity and EndoMT mediators is regulated to drive this transition. This study identifies transcription factor 4 (TCF4; also known as ITF2) as a critical EC identity gene. TCF4 knockdown impairs EC phenotype and function, and induces a transition towards a mesenchymal-like state. This discovery suggests that TCF4 safeguards EC identity against EndoMT. Mechanistically, TCF4 directly binds to the promoter of multiple key genes in the transforming growth factor-β (TGFβ) signaling pathway, thereby repressing their expression. TCF4 expression is consistently down-regulated in three EndoMT models. TCF4 down-regulation diminishes its inhibitory effect on the TGFβ signaling pathway, leading to pathway activation and subsequently enhancing EndoMT. This, in turn, further suppresses TCF4 expression. Consequently, the TCF4-TGFβ feedback loop is formed to intensify the EndoMT process. We demonstrate that introducing exogenous TCF4 disrupts this TCF4-TGFβ feedback loop of EndoMT, rescuing the EC phenotype and function under TGFβ stimulation, as well as ECs from human patients with heart failure. Our results reveal a key role for TCF4 in safeguarding EC identity and preventing EndoMT, suggesting a therapeutic potential of targeting TCF4 for EndoMT-related cardiovascular diseases.

Humans↗
PubMed1976

Detection of cyclic sleep phenomena using instantaneous heart rate.

The development of the Heart Beat Domain and the Fourier transform of the Heart Beat Domain (which we call the Beatquency Domain) has provided new and useful tools for the quantitative analysis of sleep level patterns. This method of analysis has produced remarkable intersubject as well as intra-subject consistency and the only physiologic parameter required in the analysis is beat-by-beat heart rate. This analytical tool was designed to aid in the detection of sleep cycles, or more specifically, the rhythmic transitions from REM+ (awake Stages 1 and REM combined) to NREM (Stage 2, 3 and 4 combined) over a normal night of sleep. Employing this method on minute-by minute sleep recordings from 9 normal sleep subjects, 2 complete nights each, we were able to distinguish between the REM+ and NREM stages with an average accuracy of approximately 80%. Considering that beat-by-beat heart rate was our only criteria, we felt that the algorithm performed with significant success.

Heart Rate↗
PubMed1976

[Use of beta-stimulators in chronic ischemic heart disease with complete atrioventricular block complicated by congestive circulatory insufficiency].

In 23 patients with full atrioventricular block and congestive heart failure developing against the background of chronic ischaemic heart disease Isuprel was injected intravenously at a speed of 1 to 3 muG/min. A positive chronotropic effect of the drug was observed and attributed to the dose employed. Isuprel produced a positive dynamics in the structure of the cardiac cycle in the treated patients. A course of such therapy resulted in a reduction, or even disappearance of the circulatory insufficiency signs in the majority of patients, but sinus rhythm could not be restored in either of them. The noted side effects were typical of beta-stimulators. Two patients developed anginal pains in the zone of the heart when the drug was given intravenously.

Adrenergic beta-Agonists↗
PubMed1975

Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease.

The body cholesterol pool increases with decreasing plasma-high-density-lipoprotein (H.D.L.) but is unrelated to the plasma concentrations of total cholesterol and other lipoproteins. This finding supports existing evidence that H.D.L. facilitates the uptake of cholesterol from peripheral tissues and its transport to the liver for catabolism and excretion. Plasma-H.D.L., is reduced in several conditions associated with an increased risk of future ischaemic heart-disease (I.H.D.), namely hypercholesterolaemia, hypertriglyceridaimia, male sex, obesity, and diabetes mellitus, while subjects with existing clinical I.H.D. have lower levels of H.D.L. than healthy subjects within the same community. It is proposed that a reduction of plasma-H.D.L. concentration may accelerate the development of atherosclerosis, and hence I.H.D., by impairing the clearance of cholesterol from the arterial wall.

Arteries↗