Critical illness syndromes, such as sepsis and acute respiratory distress syndrome (ARDS), are characterized by substantial clinical heterogeneity and remain major causes of morbidity and mortality worldwide. Increasing evidence suggests that genetic variation contributes to susceptibility, disease severity, and clinical outcomes in critically ill patients. However, the molecular mechanisms linking genetic predisposition to the pathophysiology of sepsis and ARDS remain incompletely understood. In this review, we evaluated genetic associations reported in sepsis and ARDS, including 13 genome-wide studies identifying 19 unique single-nucleotide polymorphisms (SNPs) across 17 distinct genomic loci, as well as 21 meta-analyses of candidate-gene studies identifying 21 SNPs across 16 genes. The identified variants were primarily associated with pathways involved in pathogen recognition, immune and inflammatory signaling, leukocyte recruitment, and endothelial dysfunction. Collectively, these findings support a polygenic basis for susceptibility to critical illness and highlight several biologically relevant pathways that may contribute to sepsis and ARDS pathogenesis. Improved understanding of the functional consequences of these variants may facilitate the identification of potential therapeutic targets and support the development of precision-guided approaches to critical care.

Cannabis has been consumed for centuries, but global regulatory changes over the past three decades have increased the availability and consumption of cannabis. Cannabinoids are touted to have therapeutic potential for many diseases and could be a replacement for opioids for analgesia and sedation. However, cannabinoids can cause substantial adverse cardiovascular events that would mitigate any potential benefit. The endocannabinoid system regulates mood, satiety and memory, and modulates the cardiovascular system. The link between cannabinoids and cardiovascular disease, which used to be limited to evidence from preclinical studies, case reports and case series, is now evident in epidemiological studies. Cannabinoids adversely affect the cardiovascular system, causing myocardial infarction, cerebrovascular accidents, arrhythmia and heart failure. The effects of novel cannabinoids are unknown, and synthetic cannabinoids have the potential to cause even more substantial harm than traditional cannabinoids. Therefore, with the increasing availability and use of cannabis, the acute and chronic effects of this drug are becoming apparent. In this Review, Wu and colleagues discuss the evolution in cannabis regulation, the endocannabinoid system and cannabinoid receptors, the influence of cannabis on cardiovascular risk factors, and the effects of traditional and synthetic cannabinoids on cardiovascular health and disease.

Cardiac fibrosis is a hallmark of cardiovascular and systemic diseases that arises in diverse pathological contexts such as inflammation, metabolic stress, and mechanical overload. Despite its clinical relevance, no FDA-approved therapies directly target cardiac fibrotic remodeling, highlighting persistent challenges in disease organization, model fidelity, and translational strategy. Recent advances in human induced pluripotent stem cell (iPSC)-derived models, engineered heart tissues, and in vivo systems have uncovered new fibrotic drivers, including immune-stroma crosstalk, metabolic reprogramming, and mechanotransduction, that are reshaping therapeutic development. This review synthesizes emerging molecular mechanisms, experimental models, and preclinical and clinical investigations of antifibrotic agents. Distinct from previous reviews, we emphasize cross-contextual alignment to support the development of precision antifibrotic therapy for cardiac fibrosis.

Fibrosis is characterized by excessive extracellular matrix (ECM) deposition, leading to organ stiffness and eventual dysfunction. However, the considerable species differences, lack of counter-screening for toxicity, and the inability to recapitulate the complex microenvironment in 2D cells have led to the failure of promising preclinical drugs in clinical trials. Human induced pluripotent stem cell (iPSC) technology has been increasingly utilized for disease modeling, drug screening, and toxicity testing, enabling precision medicine. To identify novel antifibrotic therapies, I established a multiscale platform that integrates human iPSCs, tissue engineering, and animal models (Figure 1) . First, I developed a protocol to derive cardiac fibroblasts (CFs) from human iPSCs, creating an unlimited cell source to study cardiac fibrosis. This method produces homogenous iPSC-CFs that remain quiescent and sensitive to profibrotic stimuli. For drug screening, I generated ACTA2 reporter iPSC lines to monitor MyoFB activation. To recapitulate the fibrosis-induced contractile dysfunction in vitro , I generated a 3D iPSC-derived engineered heart tissue (EHT) model composed of iPSC-cardiomyocytes (CMs) and iPSC-CFs. Profibrotic stimulation reduced contraction and relaxation velocity, along with increased passive tension, demonstrating that this EHT model faithfully recapitulated the characteristics of cardiac fibrosis in vivo . Leveraging the multiscale platform, I performed a high-throughput screening utilizing a library of ~10,000 compounds on reporter iPSC-CFs, and conducted counter-screenings in iPSC derived CMs and endothelial cells (ECs) to exclude cardiotoxicity. From the bioactive compound library, I identified an adenosine receptor (AR, family A GPCR) antagonist as a potent treatment for cardiac fibrosis. Adenosine promotes fibrosis in multiple organs. Although GPCRs are the largest family of druggable proteins encoded in the human genome, progress in targeting them has been hindered by the lack of tools to reliably measure their signaling modalities. Leveraging state-of-the-art biosensors capable of recording the activity of endogenous GPCRs, I discovered that atypical, Gβγ-dependent GPCR signaling triggered by AR underlies the antifibrotic effects. In summary, the reliable multiscale platform not only AR-triggered Gβγ signaling as a promising target, but also provides a broad approach to discovering safe and effective drugs for fibrosis therapy.

Cigarette smoking is positively and robustly associated with cardiovascular disease (CVD), including hypertension, atherosclerosis, cardiac arrhythmias, stroke, thromboembolism, myocardial infarctions, and heart failure. However, after more than a decade of ENDS presence in the U.S. marketplace, uncertainty persists regarding the long-term health consequences of ENDS use for CVD. New approach methods (NAMs) in the field of toxicology are being developed to enhance rapid prediction of human health hazards. Recent technical advances can now consider impact of biological factors such as sex and race/ethnicity, permitting application of NAMs findings to health equity and environmental justice issues. This has been the case for hazard assessments of drugs and environmental chemicals in areas such as cardiovascular, respiratory, and developmental toxicity. Despite these advances, a shortage of widely accepted methodologies to predict the impact of ENDS use on human health slows the application of regulatory oversight and the protection of public health. Minimizing the time between the emergence of risk (e.g., ENDS use) and the administration of well-founded regulatory policy requires thoughtful consideration of the currently available sources of data, their applicability to the prediction of health outcomes, and whether these available data streams are enough to support an actionable decision. This challenge forms the basis of this white paper on how best to reveal potential toxicities of ENDS use in the human cardiovascular system—a primary target of conventional tobacco smoking. We identify current approaches used to evaluate the impacts of tobacco on cardiovascular health, in particular emerging techniques that replace, reduce, and refine slower and more costly animal models with NAMs platforms that can be applied to tobacco regulatory science. The limitations of these emerging platforms are addressed, and systems biology approaches to close the knowledge gap between traditional models and NAMs are proposed. It is hoped that these suggestions and their adoption within the greater scientific community will result in fresh data streams that will support and enhance the scientific evaluation and subsequent decision-making of tobacco regulatory agencies worldwide. Models for Cardiovascular Toxicity Testing E-cigarettes and nicotine delivery systems can be examined using multiple model systems. In silico models might predict adverse cardiovascular effects that can be screened for using 2-D and 3-D models using induced pluripotent stem cell (iPSC) derived cardiac tissue and “omics” profiling such as single-cell RNA sequencing (scRNA-seq) or high-throughput functional analysis with a multiple electrode array (MEA). Biologic plausibility of detected effects can be corroborated using ex vivo or in vivo models, which may also lead to the discovery of new biomarkers or treatments for CVD.

Environmental pollution causes cardiovascular disease, heart failure, and arrythmias [1–4]. Wildfire emissions are a complex mixture composed of particulate matter (PM), carbon monoxide, methane, nitrous oxide, and polyaromatic hydrocarbons, among others [5], which are linked to arrhythmias [6]. Benzo[a]pyrene is a polyaromatic hydrocarbon and known carcinogen in animal models and is implicated in breast cancer, lung cancer, liver cancer, and skin cancer [7]. Therefore, the further impact of BaP on the cardiovascular system merits further investigation.

Cannabinoids are a class of drugs derived from the Cannabis plant that are widely used for the treatment of various medical conditions and recreational use. Common examples include Δ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), spice, and 2-arachidonoylglycerol (2-AG). With more than 100 cannabinoids identified, their influence on the nervous system, role in pain management, and effects due to illicit use have been extensively studied. However, their effects on peripheral organs, such as the kidneys, require further examination. With dramatic rises in use, production, and legalization, it is essential to understand the impact and mechanistic properties of these drugs as they pertain to renal and cardiovascular physiology. The goal of this review is to summarize prior literature on the expression of cannabinoid receptors and how cannabinoids influence renal function. This review first discusses the interaction of the endocannabinoid system (ECS) and renal physiology and pathophysiology. Following, we briefly discuss the role of the ECS in various kidney diseases and the potential therapeutic applications of drugs targeting the cannabinoid system. Lastly, recent studies have identified several detrimental effects of cannabinoids, not only on the kidney but also in contributing to adverse cardiovascular outcomes. Thus, the negative impact of cannabinoids on renal function and the development of various cardiovascular diseases is also discussed.

The common aldehyde dehydrogenase 2 (ALDH2) alcohol flushing variant known as ALDH2*2 affects ∼8% of the world's population. Even in heterozygous carriers, this missense variant leads to a severe loss of ALDH2 enzymatic activity and has been linked to an increased risk of coronary artery disease (CAD). Endothelial cell (EC) dysfunction plays a determining role in all stages of CAD pathogenesis, including early-onset CAD. However, the contribution of ALDH2*2 to EC dysfunction and its relation to CAD are not fully understood. In a large genome-wide association study (GWAS) from Biobank Japan, ALDH2*2 was found to be one of the strongest single-nucleotide polymorphisms associated with CAD. Clinical assessment of endothelial function showed that human participants carrying ALDH2*2 exhibited impaired vasodilation after light alcohol drinking. Using human induced pluripotent stem cell-derived ECs (iPSC-ECs) and CRISPR-Cas9-corrected ALDH2*2 iPSC-ECs, we modeled ALDH2*2-induced EC dysfunction in vitro, demonstrating an increase in oxidative stress and inflammatory markers and a decrease in nitric oxide (NO) production and tube formation capacity, which was further exacerbated by ethanol exposure. We subsequently found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin mitigated ALDH2*2-associated EC dysfunction. Studies in ALDH2*2 knock-in mice further demonstrated that empagliflozin attenuated ALDH2*2-mediated vascular dysfunction in vivo. Mechanistically, empagliflozin inhibited Na+/H+-exchanger 1 (NHE-1) and activated AKT kinase and endothelial NO synthase (eNOS) pathways to ameliorate ALDH2*2-induced EC dysfunction. Together, our results suggest that ALDH2*2 induces EC dysfunction and that SGLT2i may potentially be used as a preventative measure against CAD for ALDH2*2 carriers.

Cannabis, the most commonly used recreational drug, is illicit in many areas of the world. With increasing decriminalization and legalization, cannabis use is increasing in the United States and other countries. The adverse effects of cannabis are unclear because its status as a Schedule 1 drug in the United States restricts research. Despite a paucity of data, cannabis is commonly perceived as a benign or even beneficial drug. However, recent studies show that cannabis has adverse cardiovascular and pulmonary effects and is linked with malignancy. Moreover, case reports have shown an association between cannabis use and neuropsychiatric disorders. With growing availability, cannabis misuse by minors has led to increasing incidences of overdose and toxicity. Though difficult to detect, cannabis intoxication may be linked to impaired driving and motor vehicle accidents. Overall, cannabis use is on the rise, and adverse effects are becoming apparent in clinical data sets.

Anthracycline-induced cardiotoxicity and potential interventions. (A) The mechanisms of anthracycline toxicity. Anthracycline causes dilated cardiomyopathy that can result in heart failure and arrhythmia. The mechanism of anthracycline-induced cardiotoxicity is dose dependent. Anthracycline-induced cardiotoxicity is related to cardiomyocyte mitochondrial fission, necrosis, and autophagy. (B) Therapies that attenuate the effects of anthracycline on the heart include: afzelin, carvedilol, and GSK2795039 that mitigate the adverse effects of anthracyclines in vitro and in vivo.Unlabelled Image

Purpose of review Exosomes are lipid-bound particles that carry lipids, protein, and nucleic acid and affect cellular function. This review highlights the current knowledge on the crosstalk between exosomes and lipid metabolism and their impact on cardiometabolic disease. Recent findings Recent studies revealed that lipids and lipid metabolizing enzymes are important for exosome biogenesis and internalization and conversely how exosomes affect lipid metabolism, secretion, and degradation. The interplay between exosomes and lipid metabolism affects disease pathophysiology. More importantly, exosomes and lipids might function as biomarkers for diagnosis and prognosis or possibly therapies. Summary Recent advances in our understanding of exosomes and lipid metabolism have implications for our understanding of normal cellular and physiological functions as well as disease pathogenesis. Exosome and lipid metabolism have implications in novel diagnostic tests and treatments of cardiometabolic disease.

Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ 9 -tetrahydrocannabinol (Δ 9 -THC), the psychoactive component of marijuana, binds cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis is an independent risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) were used to model Δ 9 -THC induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference (CRISPRi), and genistein attenuate the effects of Δ 9 -THC. In mice, genistein blocked Δ 9 -THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system (CNS). Genistein is a peripherally restricted CB1 antagonist that attenuates Δ 9 -THC-induced atherosclerosis.

Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ9-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ9-THC. In mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis.

Induced pluripotent stem cells (iPSCs) are a powerful modeling system for medical discovery and translational research. To date, most studies have focused on the potential for iPSCs for regenerative medicine, drug discovery, and disease modeling. However, iPSCs are also a powerful modeling system to investigate the effects of environmental exposure on the cardiovascular system. With the emergence of e-cigarettes, air pollution, marijuana use, opioids, and microplastics as novel cardiovascular risk factors, iPSCs have the potential for elucidating the effects of these toxins on the body using conventional two-dimensional (2D) arrays and more advanced tissue engineering approaches with organoid and other three-dimensional (3D) models. The effects of these environmental factors may be enhanced by genetic polymorphisms that make some individuals more susceptible to the effects of toxins. iPSC disease modeling may reveal important gene-environment interactions that exacerbate cardiovascular disease and predispose some individuals to adverse outcomes. Thus, iPSCs and gene-editing techniques could play a pivotal role in elucidating the mechanisms of gene-environment interactions and understanding individual variability in susceptibility to environmental effects.

Air pollution is a rapidly growing major health concern around the world. Atmospheric particulate matter that has a diameter of less than 2.5 µm (PM2.5) refers to an air pollutant composed of particles and chemical compounds that originate from various sources. While epidemiological studies have established the association between PM2.5 exposure and cardiovascular diseases, the precise cellular and molecular mechanisms by which PM2.5 promotes cardiovascular complications are yet to be fully elucidated. In this review, we summarize the various sources of PM2.5, its components, and the concentrations of ambient PM2.5 in various settings. We discuss the experimental findings to date that evaluate the potential adverse effects of PM2.5 on cardiovascular homeostasis and function, and the possible therapeutic options that may alleviate PM2.5-driven cardiovascular damage.