The recently introduced cardiovascular-kidney-metabolic (CKM) syndrome captures the close interplay between metabolic risk factors, chronic kidney disease, and cardiovascular disease, but insufficiently reflects the important additional role of the liver. Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disease worldwide, is strongly associated with cardiovascular events, kidney disease progression, and all-cause mortality, yet remains frequently under-recognized in routine clinical practice. We propose the concept of a cardiovascular-kidney-liver-metabolic syndrome (CKLMS) and present a multidisciplinary, primary care-centered framework for its assessment and management. Based on expert consensus and current evidence, the framework integrates cardiovascular, renal, hepatic, and metabolic risk stratification using accessible, validated tools feasible in primary care, including blood pressure and lipid profiling, assessment of kidney function and albuminuria, non-invasive liver fibrosis testing, and systematic screening for diabetes and obesity. Management emphasizes early lifestyle intervention, use of pharmacological therapies with multi-organ benefit, and clearly defined referral pathways to specialist care. Primary care professionals are positioned as coordinators of longitudinal, patient-centered, multidisciplinary management. Early, integrated identification and treatment of CKLMS in primary care represents a pragmatic and effective strategy to prevent disease progression, reduce cardiovascular and kidney events, and improve long-term outcomes.
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide, (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as an effective therapy for obesity and type 2 diabetes mellitus (T2DM). Its dual-incretin mechanism may offer enhanced metabolic benefits compared with selective GLP-1 receptor agonists such as semaglutide. A structured narrative review of clinical trials, real-world observational studies, and contextual cardiovascular outcome analyses was conducted. Literature was sourced from ClinicalTrials.gov and relevant scientific databases to compare tirzepatide and semaglutide across weight, glycemic, cardiometabolic, and safety outcomes. Across completed head-to-head randomized trials, tirzepatide consistently achieved greater reductions in body weight, and HbA1c than semaglutide in individuals with obesity or T2DM. Semaglutide, however, has the most mature evidence for cardiovascular risk reduction, as demonstrated in the SUSTAIN-6, PIONEER-6, and SELECT trials. The SURPASS-CVOT trial established cardiovascular non-inferiority for tirzepatide compared with dulaglutide, alongside improvements in cardiometabolic risk factors. Real-world studies reported heterogeneous cardiovascular outcomes. Tirzepatide demonstrates superior metabolic efficacy in direct comparative trials, whereas semaglutide currently has the strongest evidence for cardiovascular benefit. Treatment selection should be individualized based on clinical priorities and patient characteristics.
Environmental risk factors-air pollution, noise, heat, chemical contamination, and light pollution-are increasingly recognized as key contributors to cardiovascular disease but remain underrepresented in clinical guidelines and public health strategies. This comprehensive review, developed under the auspices of the European Society of Cardiology (ESC), synthesizes current evidence on the cardiovascular consequences of environmental exposures. Building on prior ESC recommendations on air pollution, the consensus statement extends the focus to include climate change, urban heat islands, chemical pollutants, noise, and light pollution, highlighting their shared pathophysiological mechanisms: oxidative stress, inflammation, endothelial dysfunction, and circadian disruption. Epidemiological and experimental studies confirm that these exposures exacerbate the incidence of coronary artery disease, stroke, heart failure, arrhythmias, and hypertension-even at levels below existing regulatory thresholds. It is proposed the exposome framework as a conceptual tool to understand the cumulative lifetime impact of environmental hazards on cardiovascular health. Special attention is given to vulnerable populations, including children, the elderly, socioeconomically disadvantaged groups, and patients with pre-existing cardiovascular disease. The document outlines urgent research needs, such as the need for high-resolution exposure data, exploration of gene-environment interactions and molecular pathways, and the development of real-world and mechanistic studies assessing interventions. Mitigation strategies are discussed across individual, clinical, and policy levels, with a call for heart-healthy urban design, stricter emissions legislation, and equitable access to clean environments. Cardiologists are uniquely positioned to advocate for environmental cardiovascular health, bridging the gap between science, clinical care, and policy. This statement aims to accelerate that translation by raising awareness and promoting action across disciplines.
Ethyl maltol is a ubiquitous synthetic flavor enhancer. Despite its widespread use in foods, beverages, and electronic cigarettes, and its potential for environmental dispersion, its long-term cardiovascular safety remains unevaluated. Here, we employed an integrative strategy commencing with network toxicology and machine learning to identify pivotal molecular targets. The interaction between ethyl maltol and the key target was scrutinized via molecular docking and dynamics simulations. Cardiovascular toxicity was subsequently validated through in vivo and in vitro experiments, incorporating transcriptomic and single-cell RNA sequencing analyses. HMOX1 was identified as the central target. Molecular simulations confirmed stable binding between ethyl maltol and HMOX1. In mice, ethyl maltol exposure (5, 10, 20 mg/kg) induced anemia, platelet activation, reduced hindlimb perfusion, and impaired endothelium-dependent vasodilation, concomitant with upregulated vascular adhesion molecules. In human endothelial cells, ethyl maltol (10, 20, 40 μM) suppressed cell viability and triggered HMOX1 expression, NLRP3 inflammasome activation, and NF-κB signaling. Mechanistically, ethyl maltol appears to subvert the typically protective HMOX1 response into a driver of chronic vascular inflammation and adhesion. This study unveils a previously unrecognized cardiovascular risk associated with ethyl maltol, mediated through HMOX1-driven inflammatory dysregulation. It establishes a translatable paradigm for the safety assessment of prevalent food additives and environmental contaminants.
Environmental pollutants per- and polyfluoroalkyl substances (PFAS) are ubiquitous across populations worldwide and may contribute to the global burden of cardiovascular disease (CVD) by directly impacting the cardiovascular system or through CVD risk factors. This cross-sectional study investigates associations between 17 different PFAS and PFAS mixtures with established CVD risk factors-overweight/obesity, dyslipidemia, and hypertension-as well as risk of liver fibrosis (fibrosis index FIB-4) in a population sample of 3508 Norwegian adults (49.7% women; mean age 61.0 years, SD 10.2) from the sixth survey of the Tromsø Study (2007/2008). High PFAS serum concentrations were observed in this Arctic population, with eight PFAS (PFHxS, PFHpS, PFHpA, PFOS, PFOA, PFNA, PFDA, PFUnDA) detected in ≥70% of participants. All investigated PFAS were associated with one or more CVD risk factors. PFHpS and PFNA were associated with overweight/obesity in both sexes; ∑17PFAS, PFHxS, and PFOS in men only. ∑17PFAS, PFOS, PFOA, PFNA, PFDA, and PFUnDA were associated with dyslipidemia in both sexes; PFHpS in men only. In women, ∑17PFAS, PFHxS, PFHpS, PFHpA, PFOS, PFOA, and PFNA were associated with hypertension. In men, neither individual PFAS nor ∑17PFAS were associated with hypertension; however, the principal component score comprising PFHpA and PFOA was associated with hypertension. ∑17PFAS, PFHxS, PFHpS, PFOS, PFOA, PFNA, and PFUnDA were associated with increased liver fibrosis risk in both sexes; PFHpA and PFDA in men only. The associations of PFAS with adverse risk profiles highlight the potential harmful effects of PFAS and warrant further investigations in prospective and toxicology studies.
The potential therapeutic applications of glucagon-like peptide-1 (GLP-1) have led to the development of GLP-1 receptor agonists (GLP-1RAs), which replicate GLP-1's effects. The primary use of GLP-1RAs is the management of type 2 diabetes (T2DM) by stimulation of insulin secretion. In addition to its metabolic functions, GLP-1 exhibits significant anti-inflammatory effects through various molecular pathways, utilizing both direct and indirect mechanisms. Experimental studies have revealed that GLP-1RAs modulate multiple inflammatory pathways, including cytokine production, oxidative stress, glucotoxicity, lipotoxicity, and immune cell recruitment across multiple organs. They interact with their receptors on immune cells, thereby reducing the production of inflammatory cytokines and decreasing the infiltration of immune cells into tissues. There is considerable overlap among the pathways activated by GLP-1R in cardiovascular tissue, which can lead to anti-apoptotic, antioxidative, and anti-inflammatory effects. Clinical studies have confirmed the anti-inflammatory effects of GLP-1RAs in conditions such as acute myocardial infarction, left ventricular dysfunction, coronary artery disease, and ST-segment elevation myocardial infarction. Notably, GLP-1RAs are included in the European Society of Cardiology guidelines for managing cardiovascular disease in patients with T2DM.
Cardiovascular diseases (CVDs) continue to be the world's leading cause of death, driven by intricate processes such as inflammation, endothelial dysfunction, oxidative stress, and apoptosis. MicroRNAs (miRNAs), small non-coding RNAs that influence mRNA translation, have become recognized as key regulators of these harmful mechanisms in conditions like heart attack, heart failure, and atherosclerosis. Because they remain stable in the bloodstream, miRNAs hold promise as convenient, minimally invasive biomarkers for early CVD detection, assessing risk, and forecasting outcomes. On the treatment side, targeting miRNAs offers a way to correct disrupted molecular pathways with precision, though moving this approach into clinical use presents hurdles such as refining delivery methods, avoiding unintended effects, and achieving specificity for certain tissues. Current studies emphasize progress in understanding how miRNAs contribute to CVD development and their emerging potential in personalized care. Yet, translating these findings into routine practice will require overcoming technical challenges and establishing consistent standards. This evolving area holds great potential to transform cardiovascular medicine through precise diagnostics and targeted therapies, potentially addressing current shortcomings in treatment effectiveness.
This pilot study evaluated the feasibility and learner acceptance of a blended learning model integrating Flipped Classroom (FC) and Think-Pair-Share (TPS) strategies in a cardiovascular pharmacology course for pharmacy students. A single-group, post-intervention evaluation was conducted with 62 undergraduate pharmacy students. The intervention featured: pre-class self-study with real prescriptions, interactive lectures, structured TPS activities, and gamified incentives. Evaluation focused on Kirkpatrick's Level 1 (Reaction), using a satisfaction survey to assess student perceptions. Student satisfaction was notably high. Most students perceived real prescriptions as highly effective for engagement (93.5%) and learning (90.3%). Peer discussions (74.2%), pre-class preparation (93.5%), and the instructor's explanations (93.6%) were also rated as highly effective. The majority (87.1%) preferred group exams and perceived the method as improving future consultation skills (90.3%). The FC/TPS model, augmented with authentic materials, demonstrated high feasibility and was exceptionally well received by students. These positive perceptions support its implementation in similar contexts and justify further research with controlled designs to measure its impact on objective learning outcomes.
Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants increasingly associated with cardiovascular outcomes. While mechanistic studies have reported oxidative stress, developmental toxicity, and gene expression alterations in cardiac models, it remains unclear how these findings integrate with structural cardiomyopathy frameworks. A bibliometric analysis was conducted using 469 publications retrieved from Scopus, PubMed, and Web of Science (1992-2025) using PFAS and cardiac-related search terms. Knowledge structure was evaluated using co-occurrence network analysis (VOSviewer), thematic mapping (Biblioshiny), overlay visualization, and citation timeline analysis (CiteSpace). Keyword co-occurrence analysis identified two dominant thematic domains: (1) mechanistic and developmental cardiotoxicity (e.g., oxidative stress, gene expression, zebrafish), and (2) clinical cerebrovascular outcomes centered on patent foramen ovale and stroke. Thematic mapping positioned PFAS exposure descriptors as central but broadly defined themes, whereas structural cardiomyopathy constructs did not form cohesive or central clusters. Overlay analysis demonstrated temporal expansion toward molecular toxicology after 2018, without parallel growth in myocardial remodeling descriptors. Citation burst analysis revealed stable thematic progression rather than rapid cardiomyopathy-centered acceleration. PFAS-associated cardiac research demonstrates progressive growth but remains structurally segmented. Mechanistic toxicology and clinical cardiovascular outcome studies operate largely in parallel, with limited integration into adult structural cardiomyopathy frameworks. These findings suggest the need for greater incorporation of myocardial phenotyping and remodeling endpoints in PFAS cardiac toxicology research.
Phenethylamine (PEA) and its analogues are frequently present in pre-workout and weight loss food supplements and share structural similarity with amphetamine and the endogenous catecholamines (nor)adrenaline and dopamine, suggesting potential sympathomimetic activity. Multiple adverse cardiovascular events have been associated with the use of food supplements containing these ingredients, while knowledge of the underlying pharmacology and toxicology of such food supplements and their ingredients remains limited. Therefore, the aim of the current study was to investigate the acute cardiovascular effects of a selection of PEAs in conscious rats. Heart rate (HR), arterial pressure (AP) and body temperature were continuously, and wirelessly, monitored using pressure telemetry in Wistar-Kyoto rats that were intravenously exposed to cumulative doses of PEA and seven commonly used analogues: BMPEA, halostachine, higenamine, isopropyloctopamine, p-octopamine, p-synephrine and p-tyramine. All PEAs, except PEA itself and BMPEA, significantly altered AP with maximal absolute increases between 65 and 103 mmHg. Maximal absolute increases in HR induced by higenamine and isopropyloctopamine were found to be 110 and 123 beats per minute, respectively. The PEA analogues BMPEA, p-octopamine, halostachine and p-synephrine, instantly lead to reduced body temperatures, ranging from minus 0.5 to minus 1.5°C. This study demonstrates that several PEAs, exert pronounced and rapid effects on AP, HR and body temperature in rats. The magnitudes of these effects were similar to or even higher than the cardiovascular changes induced by adrenaline, suggesting that combining these substances with physical exercise may amplify sympathetic load and pose a serious health risk, particularly for individuals with underlying cardiovascular vulnerabilities.
Activated charcoal is widely used in the medical management of acute intoxications, yet its gross appearance at autopsy is poorly described and may represent a diagnostic pitfall. We report a case highlighting this issue. An elderly man with a history of cardiovascular disease, diabetes mellitus, and prostate cancer was found unresponsive in his closed residential garage after making suicidal statements. Open bottles of amlodipine and glimepiride were found on his person. He was hospitalized, where routine toxicology screening was negative, and he died in the intensive care unit less than 24 h after admission. At autopsy, the stomach contained an abundant amount of dense, black, odorless, thick material adherent to the gastric mucosa which wiped off after gentle cleaning. After removal, the underlying mucosa was intact, without hemorrhage or ulceration. Review of medical records indicated that activated charcoal had been administered during hospitalization due to concern for intentional medication ingestion. Subsequent expanded toxicology testing demonstrated a markedly elevated amlodipine concentration, consistent with acute toxicity. The cause of death was certified as amlodipine toxicity, and the manner of death as suicide. This case illustrates the characteristic gross appearance of activated charcoal in the stomach and discusses its potential to mimic other causes of black gastric contents, including gastrointestinal hemorrhage, caustic ingestion, Wischnewsky spots, hydrocarbons, black esophagus, and iron deposition. Awareness of this finding and careful correlation of gross autopsy findings with medical history and toxicologic results are essential to avoid misinterpretation and diagnostic error in forensic practice.
The optimal blood pressure (BP) targets for patients with type 2 diabetes (T2D) remain debated among international guidelines. This retrospective cohort analysis evaluated the associations of specific systolic and diastolic BP (SBP and DBP) categories with long-term mortality in patients with T2D. We analyzed 2,198 adults with T2D from the National Health and Nutrition Examination Survey (NHANES) 1999-2018. Participants were stratified by baseline SBP (<130, 130-140, ≥140 mmHg) and DBP (<80, 80-89, ≥90 mmHg). Multivariable Cox proportional hazards models were constructed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, cardiovascular, cerebrovascular, and diabetes-related mortality, adjusting for comprehensive baseline covariates. Over a median follow-up of 97.0 months, an SBP ≥140 mmHg was significantly associated with elevated risks for all-cause (HR = 1.66, 95% CI: 1.28-2.16), cardiovascular (HR = 1.53, 95% CI: 1.10-2.13), cerebrovascular (HR = 3.98, 95% CI: 1.71-9.27), and diabetes-related mortality (HR = 1.84, 95% CI: 1.06-3.16) compared to an SBP <130 mmHg. Conversely, a DBP of 80-89 mmHg was associated with significantly lower all-cause (HR = 0.67, 95% CI: 0.46-0.98) and cardiovascular mortality (HR = 0.57, 95% CI: 0.35-0.93) than a DBP <80 mmHg, indicating a distinct J-curve phenomenon. In this observational study, baseline SBP <140 mmHg and DBP 80-89 mmHg were associated with favorable survival outcomes in patients with T2D. These findings suggest that individualized blood pressure management warrants further investigation, taking into account the limitations of observational data and single baseline measurements.
Cardiovascular diseases cause about 20.5 million deaths, making them one of the primary causes of death worldwide. Hypertension and hyperlipidaemia are major modifiable risk factors for cardiovascular diseases, and current medications pose significant side effects and often fail to prevent long-term complications, highlighting the need for alternative therapies. This study evaluates the therapeutic potential of BN2 ((Z)-N-(4-(4-chlorophenyl)-6-(4-fluorophenyl)pyrimidin-2-yl)-1-(furan-2-yl)methanimine) against sodium fluoride (NaF)-induced cardiometabolic injury. In zebrafish models exposed to NaF, reactive oxygen species (ROS) and the antioxidant enzyme activities (SOD, CAT, GST, GPx) were measured. Cholesterol and triglyceride accumulation were observed and quantified using HPLC. Cardiac function was evaluated by measuring heart rate, pericardial oedema, erythrocyte damage and scoring heart tissue section histopathologically. At the molecular level, gene expression of important hypertensive and hyperlipidaemic markers (agtr1a, nppa, postnb, fn1a and col11a1b) was measured by RT-qPCR analysis. BN2 reduced ROS levels, enhanced antioxidant enzyme activities (SOD, CAT, GST, GPx) and decreased lipid accumulation. It ameliorated NaF-induced bradycardia, reduced pericardial oedema, normalized erythrocyte function and lowered cardiac tissue damage. In molecular terms, BN2 down-regulated the expression of agtr1a, nppa, fn1a, postnb and col11a1b and up-regulated mstnb and bcl2a. BN2 efficacy was similar to captopril throughout all evaluated parameters. Our results demonstrate that, in zebrafish models, BN2 effectively modulates oxidative stress, cardiac damage, lipid accumulation and inflammation, establishing it as a promising therapeutic candidate for preventing cardiovascular diseases.
Despite optimal lipid-lowering treatment, numerous older adults with atherosclerotic cardiovascular disease continue to experience progression driven by inflammation, referred to as residual inflammatory risk. Cellular senescence and the senescence-associated secretory phenotype (SASP) significantly contribute to vascular inflammaging; however, pharmacological interventions in aging populations are still inadequately investigated. This review synthesizes evidence regarding the role of SASP in atherosclerosis and critically evaluates senotherapeutic strategies, emphasizing mechanisms, preclinical efficacy, and translational potential. Senescent endothelial cells, vascular smooth muscle cells, and foam cells aggregate in plaques, secreting pro-inflammatory cytokines (IL-1α, IL-6, MCP-1) and matrix metalloproteinases that enhance plaque susceptibility. Two complementary pharmacological strategies have emerged. Senolytics (dasatinib combined with quercetin, fisetin, and lanatoside C) specifically eradicate senescent cells by inhibiting anti-apoptotic pathways (BCL-2, PI3K/AKT, and HSP90). Senomorphics (rapamycin, metformin, JAK/STAT inhibitors, NF-κB inhibitors) attenuate SASP expression through modulation of mTOR, NF-κB, and JAK/STAT pathways. Preclinical studies indicate that senolytics diminish the burden of senescent cells, reduce plaque area, and limit necrotic core expansion, while simultaneously improving plaque stability. Senomorphics provide comparable advantages with profiles appropriate for prolonged utilization. Targeting SASP constitutes a rational strategy to alleviate residual inflammatory risk. Nonetheless, significant knowledge deficiencies persist concerning patient selection, dosing protocols, drug-drug interactions with cardiovascular treatments, and long-term safety. Translation necessitates stringent clinical trials in geriatric cardiovascular patients. This review offers an extensive pharmacological framework for senotherapeutics in atherosclerosis.
Environmental exposure to heavy metals and endocrine-disrupting chemicals (EDCs) activates the NLRP3 inflammasome, driving chronic inflammation that worsens or may underlie cardiovascular disease, neurodegeneration, and accelerated aging. This review examines the molecular mechanisms by which lead, cadmium, mercury, arsenic, bisphenol A, phthalates, and dioxins modulate NLRP3 signaling. Lead and cadmium activate NLRP3 through mitochondrial dysfunction and oxidative stress, whereas mercury and arsenic suppress inflammasome assembly by preventing apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization. EDCs engage receptor-mediated pathways: aryl hydrocarbon receptor (AhR) activation directly represses NLRP3 transcription, yet bisphenol A and phthalates override this suppression through NF-κB activation. Developmental timing critically determines outcomes such as prenatal exposures epigenetically programing persistent NLRP3 dysregulation. Sex hormones have been shown to modulate distinct inflammatory landscapes: estrogen suppresses NLRP3 via ERβ-dependent mechanisms, while testosterone amplifies inflammasome-dependent pathology. The skin serves as a primary interface for environmental chemical exposure and cutaneous NLRP3 activation. NLRP3-deficient mice exhibit 34% increased lifespan, and pharmacological inhibition with MCC950 extends lifespan in progeria models. The CANTOS trial demonstrated that targeting inflammation through IL-1β neutralization confers cardiovascular benefits in high-risk humans. These findings position NLRP3 as a central integrator through which the chemical exposome accelerates inflammaging and identify inflammasome inhibition as a therapeutic strategy for environmental disease prevention.
Exposure to cadmium, a trace metallic element, is a major health concern. Cadmium is associated with a higher risk and predisposition to cardiovascular disease. Identifying molecular targets involved in such an effect is complexified by in utero embryonic and fetal development. To overcome those difficulties, we used the established vertebrate heart model of Xenopus laevis to analyze the neural cell adhesion molecules NCAM and FGF receptors involved in early cardiac development under cadmium treatment. Cadmium exposure is performed from fertilization until the completion of mature heart development at the end of stage 45. Additional molecular modifications occurring within the heart are detected in the expressing signaling system of Xenopus oocytes. Exposure to cadmium results in the absence of heart ventricular myocardial trabeculae and disrupts the regulation of NCAM adhesion molecules and FGF receptor signaling in Xenopus. An increase in polysialylation (PSA) of NCAM is observed, accompanied by the deregulation in the expression of Golgi effectors Rab11 GTPase and Golph3. The sialyltransferases ST8Sia2 and ST8Sia4 are not increased at the transcriptional level but are accumulated in the Golgi apparatus. The highly sialylated NCAM interacts with the FGF receptor, prevents the formation of a complex with Integrin, FAK is O-GlcNAcylated, and the receptor translocation to the nucleus is impaired. Furthermore, the polysialylated-NCAM/FGF receptor signaling recruits higher amounts of Shp2 and leads to Erk2 hyperphosphorylation. Additionally, blocking FAK with a specific antibody in the normal polysialylated-NCAM/FGF receptor signaling causes the deregulated molecular phenotype. These results represent a significant advancement for future studies in environmental toxicology and cardiac developmental dysfunctions resulting from cadmium exposure.
Coronary artery disease (CAD) remains a major global health burden with limited precision for early risk assessment and stratification. This study aims to investigate circulating Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) potentially associated with the presence and severity of CAD as a non-invasive biomarker. This cross-sectional study included 179 participants undergoing coronary angiography comprising 84 with angiographically confirmed CAD and 95 without CAD. Coronary lesion severity was assessed using the Gensini score and categorized as non-CAD, non-complex CAD, or complex CAD. Circulating MALAT1 expression was quantified by qPCR. Correlation analyses, hierarchical logistic regression, ordinal logistic regression, and ROC analyses were applied to evaluate the diagnostic performance between MALAT1, CAD risk, and CAD severity. MALAT1 expression was significantly higher in CAD participants than those without CAD, and greatest among participants with complex CAD. MALAT1 positively correlated with BMI, LDL, non-HDL, and triglycerides, while negatively correlated with LVEF, CI, CO, RV diameter, and HDL. In multivariable models, MALAT1 independently associated with CAD alongside age, sex, BMI, CI, hypertension, concomitant cardiovascular disease, and medication therapy. MALAT1 showed high specificity but moderate sensitivity for identifying CAD , and improved diagnostic performance when combining with agePredictive accuracy was strongest in participant aged ≥60 years. After multivariable adjustment, MALAT1 remained independently associated with CAD severity, particularly for complex CAD. Circulating MALAT1 is independently associated with both CAD risk and coronary lesion severity. Its enhanced predictive performance in older individuals suggests promising value as a non-invasive biomarker for refined cardiovascular risk stratification.
Cardiovascular-kidney-metabolic (CKM) syndrome represents a continuum of interrelated adiposity, insulin resistance, cardiovascular disease, kidney dysfunction, and metabolic disturbances that evolve across the lifespan. Emerging evidence demonstrates that both biological sex and sociocultural gender significantly shape CKM risk, progression, and clinical expression. CKM syndrome pathogenesis reflects complex multisystem interactions involving adipose tissue dysfunction, neurohormonal activation, inflammatory signaling, and vascular impairment, all of which exhibit important sex-specific patterns. This review examines CKM syndrome from a sex- and gender-informed perspective, highlighting how endogenous and exogenous sex hormones, reproductive transitions, pregnancy-related complications, and dietary exposures shape the long-term CKM syndrome risk. Particular attention is given to the roles of estrogen and testosterone in modulating adipose biology, vascular function, and metabolic regulation. Polycystic ovary syndrome is discussed as a model of androgen excess and multisystem metabolic vulnerability that accelerates CKM features. Finally, we address brain vulnerability within CKM syndrome, emphasizing shared inflammatory, vascular, and neuroendocrine mechanisms linking metabolic dysfunction to cognitive decline and neuropsychiatric disorders. Recognizing these interconnected and sex-specific influences is critical for advancing precision prevention and treatment strategies across the CKM syndrome spectrum.
Acute intermittent porphyria (AIP), a rare disorder of heme biosynthesis, may manifest with neurovisceral crises affecting autonomic regulation. This study aimed to assess blood pressure (BP) pattern and hypertension prevalence in AIP patients. This prospective case-control study included patients with overt AIP (at least one attack) and a control group, matched by age, sex and body mass index (BMI). All participants underwent detailed clinical assessment, biochemical and cardiovascular phenotyping with 24-hour BP monitoring and echocardiography in the tertiary centers. The study comprised 90 patients with AIP, of whom 42 (47%) were assessed also during attacks, and 90 controls (mean age 39±11 years, 79% female). Hypertension was more prevalent in AIP patients (58%) compared to controls (31%, P < 0.001). Additionally, AIP patients showed higher mean systolic BP (SBP, 123.7 ± 13.1 vs. 116.9 ± 10.8 mmHg, P < 0.001) and diastolic BP (DBP, 77.7 ± 9.5 vs. 73.2 ± 7.1 mmHg, P < 0.001). Nocturnal hypertension, a non-dipping BP pattern and left ventricular hypertrophy were more frequently observed in the AIP group. Age, BMI and history of paresis were independently associated with hypertension in AIP patients. During AIP attacks, BP was significantly higher than during remission (SBP 135.4 ± 18.4 vs. 121.9 ± 12.8 mmHg, P < 0.001; DBP 84.6 ± 13.8 vs. 76.5 ± 10.1 mmHg, P < 0.001). The differences correlated with changes in the plasma concentrations of normetanephrine. AIP is associated with a higher prevalence of hypertension, an unfavourable nocturnal BP profile and cardiac structural changes. BP rises significantly during AIP attacks, which is likely mediated by catecholaminergic surges. This underscores the need for cardiovascular monitoring in AIP patients. gov, Number NCT05882136.
Caffeine is widely consumed and generally considered safe at customary doses. How-ever, high-dose preparations available online pose a risk of severe and potentially fatal intoxication. Although uncommon, lethal caffeine poisoning is associated with profound cardiovascular and neurological toxicity. A rare case of intentional acute caffeine intoxication with fatal outcome is presented. A 25-year-old woman ingested an estimated 60 tablets containing 200 mg of caffeine each, purchased online. She was admitted to hospital shortly after ingestion of the caffeine tablets with palpitations, agitation, dizziness, and repeated vomiting. On examination, she presented with arterial hypotension (90/60 mmHg) and marked sinus tachycardia (150 beats/min), accompanied by psychomotor agitation. Her blood caffeine concentration measured by means of high-performance liquid chromatography (HPLC) was 177 µg/mL. The patient's condition rapidly deteriorated, with the development of convulsive syndrome progressing to coma, extreme ventricular tachycardia, exotoxic shock, and toxic cardiomyopathy. Despite intensive care management, including mechanical ventilation and advanced cardiopulmonary resuscitation, the patient died several hours after admission. In conclusion, this case underscores the life-threatening potential of acute high-dose caffeine ingestion and highlights the risk associated with unrestricted access to concentrated caffeine products. Early recognition and aggressive management are crucial, yet may be insufficient in cases of massive overdose.