Search Results (466)

Although evaluating coronary flow velocity reserve (CFVR) via stress echocardiography (SE) has been available for over three decades, its integration into routine clinical practice remains underutilized globally despite substantial technical and conceptual advances. A diminished CFVR serves as a potent predictor of major adverse cardiovascular events (MACE) and all-cause mortality across a broad spectrum of cardiovascular diseases. Its prognostic value is particularly robust in epicardial coronary artery disease, heart failure, coronary microvascular dysfunction, nonischemic cardiomyopathies, metabolic disorders (e.g., diabetes mellitus and obesity), hypertrophic cardiomyopathy, systemic autoimmune diseases, and cardiac allograft vasculopathy. This comprehensive narrative review details the technical methodology for interrogating resting and stress-induced coronary flow velocity (CFV) under physical and pharmacological protocols. Furthermore, it highlights the clinical applicability of CFVR by synthesizing single-center observational insights with evidence from large-scale multicenter registries, advocating for its broader adoption into diagnostic workflows to refine risk stratification and guide therapeutic management. Full article

Background/Objectives: Diabetic cardiomyopathy (DCM) is a major cardiovascular complication of diabetes mellitus characterized by progressive myocardial remodeling driven by oxidative stress, inflammation, and fibrosis. The interleukin-33 (IL-33)/soluble suppression of tumorigenicity 2 (sST2) signaling axis has recently emerged as an important regulator of cardiac remodeling and a potential therapeutic target in DCM. N-acetylcysteine (NAC) and glycine exhibit complementary antioxidant and anti-inflammatory properties; however, their combined effects on circulating IL-33 and sST2 levels and myocardial structural remodeling in experimental diabetes remain insufficiently investigated. This study evaluated the effects of NAC and glycine, administered alone or in combination, on oxidative stress, inflammatory biomarkers, cardiac morphology, and serum sST2 levels in streptozotocin-induced diabetic rats. Methods: Thirty-four adult Wistar rats were randomly assigned to five groups: healthy controls, untreated diabetic animals, diabetic animals treated with NAC (100 mg/kg/day), glycine (250 mg/kg/day), or combined NAC and glycine for 12 weeks. Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg). Serum concentrations of sST2, IL-33, malondialdehyde (MDA), and superoxide dismutase (SOD) activity were determined. Cardiac remodeling was evaluated by stereological and histopathological analyses. Results: Experimental diabetes significantly increased serum sST2, IL-33, and MDA concentrations and induced marked myocardial remodeling characterized by expansion of the interstitial and perivascular compartments, increased connective tissue deposition, and reduced cardiomyocyte volume density. Both NAC and glycine significantly attenuated these biochemical and structural abnormalities compared with untreated diabetic animals. Treatment effects varied across outcomes. The combined NAC and glycine regimen was associated with particularly pronounced reductions in sST2 and IL-33 and with preservation of myocardial architecture, whereas the magnitude of improvement in oxidative stress markers differed between treatment groups. Conclusions: NAC and glycine, administered either alone or in combination, attenuated several biochemical and structural alterations associated with streptozotocin-induced diabetes. The magnitude of these effects varied across the assessed outcomes, with the combined regimen showing particularly favorable effects on circulating sST2 and IL-33 levels and myocardial structural remodeling, while some oxidative stress parameters showed greater improvement with NAC monotherapy. These outcome-dependent effects highlight the potential complementary actions of NAC and glycine without implying uniform superiority of the combined regimen. Overall, these findings provide an experimental basis for further investigation of NAC- and glycine-based therapeutic approaches for diabetes-associated myocardial remodeling. Full article

Background/Objectives: Diabetic cardiomyopathy is an under-recognized complication of type 1 diabetes mellitus (T1DM), often co-existing with diabetic nephropathy. This study investigates whether patients with T1DM and end-stage renal disease (ESRD) undergoing simultaneous pancreas–kidney transplantation (SPKT) show echocardiographic signs of cardiomyopathy prior to surgery and explores whether cardiac changes are more attributable to diabetes itself or to chronic kidney disease. Methods: We retrospectively analyzed preoperative echocardiographic data of 16 SPKT patients with T1DM and ESRD, using 2D speckle tracking for strain assessment. Data were compared to individually matched control groups: (1) ESRD patients without diabetes (n = 20) and (2) healthy controls (n = 48). Left and right ventricular/atrial function and structure were analyzed, including 2D speckle-tracking analysis. A mixed-effects model adjusted for age, sex, coronary artery disease, and hypertension. Results: SPKT patients exhibited significant structural changes in the left heart, including increased left ventricular mass and left atrial volume index, alongside reduced global longitudinal strain (GLS), global radial strain (GRS), and global circumferential strain (GCS) compared to healthy controls. GRS and GCS were significantly lower in the SPKT group than in the ESRD group without diabetes. Left atrial strain and strain rates were reduced in both disease groups. Right ventricular and atrial strain parameters did not significantly differ between groups. Mixed model analysis confirmed significant strain differences in the left ventricle even after adjusting for confounders. Conclusions: T1DM patients with end-stage nephropathy awaiting SPKT show echocardiographic abnormalities compatible with subclinical myocardial dysfunction, with predominant involvement of the left heart. Compared to non-diabetic ESRD patients, the diabetic cohort exhibited greater impairment in left ventricular strain parameters, supporting a pathophysiologic role of diabetes independent of kidney disease. Speckle-tracking analysis demonstrated potential utility for detecting early signs of myocardial dysfunction in this high-risk population. Full article

Diabetes mellitus (DM) is a progressive metabolic disorder in which mitochondrial dysfunction is increasingly recognized as a central contributor to metabolic deterioration and diabetic complications. However, whether dysregulated mitochondrial dynamics represents a primary pathogenic driver, an adaptive response, or a consequence of metabolic stress remains incompletely understood. This review summarizes current advances in the molecular mechanisms governing mitochondrial fission, fusion, and mitophagy, with particular emphasis on their coordinated roles in mitochondrial quality control rather than isolated morphological changes. We discuss how disrupted mitochondrial dynamics contributes to pancreatic β-cell dysfunction, insulin resistance, diabetic nephropathy (DN), diabetic cardiomyopathy (DCM), diabetic retinopathy (DR), and diabetic osteoporosis (DOP) through context-dependent regulation of oxidative stress, bioenergetics, inflammation, and endoplasmic reticulum–mitochondria crosstalk. Furthermore, we critically evaluate emerging therapeutic strategies, including metformin, sodium–glucose cotransporter 2 inhibitors, mitochondrial fission inhibitors, and mitochondria-targeted antioxidants, highlighting both their therapeutic potential and current translational challenges. We propose that restoring the physiological equilibrium among mitochondrial fission, fusion, and mitophagy, rather than unidirectionally inhibiting a single pathway, represents a more promising strategy for preventing and treating diabetes and its complications. Full article

Background: Diabetic cardiomyopathy (DCM) is a serious cardiovascular complication specific to diabetes mellitus, with rising global prevalence. Ferroptosis, an iron-dependent form of regulated cell death driven by lethal lipid peroxidation, has been implicated in the pathogenesis of DCM. However, the key regulatory genes remain poorly characterized. This study aimed to identify and validate ferroptosis-related signature genes in DCM. Methods: Three murine transcriptomic datasets (GSE123975, GSE155377, and GSE210611) were retrieved from GEO and merged after batch correction. Differentially expressed genes were intersected with weighted gene co-expression network analysis disease-associated module genes and FerrDb ferroptosis annotations to define the ferroptosis-related differentially expressed gene candidate pool. LASSO regression and random forest selection then prioritized hub genes, defined operationally as candidates consistently prioritized by both machine-learning algorithms rather than by network-topological centrality. Classification performance was evaluated by ROC analysis and validated in two independent cohorts (GSE161931 and GSE274500). mMCPcounter estimated immune and stromal infiltration. ScRNA-seq (GSE290095) and spatial transcriptomic (GSE290094) profiling characterized cellular distribution, predicted cardiomyocyte network perturbations and tissue-level expression patterns. High-fat diet/streptozotocin (HFD/STZ)-induced DCM rat models provided experimental validation. Results: Acot1 and Txnip were identified as hub genes, with strong discriminatory performance in the discovery cohort (AUC = 1.000 and 0.988; in-sample estimates, n = 26) and independent external validation (AUC = 0.951 and 0.988). Immune profiling linked both genes inversely with vessel scores, and Txnip was also linked with eosinophils. Single-cell analysis localized Acot1 enrichment to cardiomyocytes and endothelial cells, while Txnip was broadly expressed across multiple cell types, with elevated levels in DCM. In silico knockout analysis predicted distinct cardiomyocyte network perturbation profiles for Acot1 and Txnip, and spatial transcriptomics revealed modest but disease-specific spatial associations between hub gene expression and ferroptosis driver scores (Acot1: rho = 0.123; Txnip: rho = 0.154). Both genes were significantly upregulated at mRNA and protein levels in HFD/STZ-induced DCM rats, with concurrent GPX4 depletion, ACSL4 accumulation, and FTH1 reduction consistent with ferroptosis activation. Conclusions: This study identifies Acot1 and Txnip as ferroptosis-related molecular signatures in DCM and provides multistep prioritization and validation spanning bulk transcriptomics, single-cell and spatial transcriptomics, and in vivo experimental verification, offering potential targets for ferroptosis-targeted therapeutic intervention. Full article

Diabetes mellitus results from insulin resistance, progressive pancreatic β-cell dysfunction, dysregulated hepatic and adipose metabolism, oxidative stress, and inflammation. Plant-derived compounds can modulate several of these processes, yet pharmacological breadth does not necessarily produce a reproducible therapy. This critical narrative review links phytochemical identity and product composition to intestinal carbohydrate digestion, insulin secretion, hepatic glucose production, GLUT4 trafficking, AMPK and PPARγ signaling, the incretin–DPP-4 axis, renal glucose handling, and diabetic organ injury. Alkaloids, flavonoids, phenolic acids, tannins, saponins, and polysaccharides are considered alongside evidence concerning nephropathy, neuropathy, ocular disease, hepatopathy, and cardiomyopathy. Controlled human studies provide product-specific signals, particularly for chemically defined berberine preparations and mulberry alkaloids, whereas most other interventions remain supported by small, short, or chemically undercharacterized trials. The strongest candidates are those for which defined chemistry, plausible exposure, mechanism, and controlled clinical findings converge. Progress requires authenticated raw material, validated analytical fingerprints, pharmacokinetic and toxicological characterization, herb–drug interaction testing, and trials using the same standardized product. These interventions should remain supervised adjuncts or drug-discovery leads rather than substitutes for established diabetes treatment. Full article

Background: Left ventricular thrombus (LVT) is a serious complication associated with cardiomyopathy and impaired left ventricular (LV) systolic function. Patients with a resolved LVT remain at risk for recurrence and subsequent thromboembolism. However, the factors influencing the recurrence of LVT are not yet fully understood. The aim of this study was to identify the risk factors and clinical outcomes related to LVT recurrence and to improve follow-up strategies and treatment options. Methods and results: We retrospectively investigated patients confirmed to have a resolved LVT by transthoracic echocardiography from January 2018 to April 2021 at Zhongshan Hospital Fudan University. All patients received anticoagulant therapy for more than 6 months and underwent at least two follow-up transthoracic echocardiograms. No statistically significant differences were observed in baseline characteristics between the LVT recurrence and non-recurrence groups, including gender, age, diabetes, hyperlipidemia, renal function, previous stroke history, other underlying medical conditions, ejection fraction, or left ventricular diameter. Patients in the recurrence group exhibited a higher prevalence of previous myocardial infarction and percutaneous coronary intervention compared to the non-recurrence group (84.6% vs. 61.1%, p = 0.03; 76.9% vs. 52.8%, p = 0.03). Additionally, patients in the recurrence group tended to have more ventricular aneurysms (50.0% vs. 22.2%, p = 0.008) and larger previous thrombus sizes (27.7 ± 12.6 vs. 21.4 ± 9.1 mm, p = 0.008) compared to those in the non-recurrence group. Multivariate logistic regression analysis indicated that the longitudinal diameter of the LVT was an independent risk factor for LVT recurrence (OR 1.058, 95% CI 1.003–1.115, p = 0.04). ROC curve analysis revealed an area under the curve of 0.647 for the longitudinal diameter of the LVT, with an optimal cut-off value of 23.5 mm, a sensitivity of 62%, and a specificity of 64%. After a follow-up duration of 3.0 ± 2.5 years, the incidence of non-fatal myocardial infarction and major adverse cardiovascular events (MACEs) in the recurrence group was significantly higher than that in the non-recurrence group [non-fatal myocardial infarction: 3 (11.5%) vs. 1 (1.4%), p = 0.02; MACE: 7 (26.9%) vs. 7 (9.7%), p = 0.01]. No statistically significant differences were found in bleeding events, systemic embolism, or all-cause death between the two groups. Conclusions: Our study indicates that a history of myocardial infarction, the presence of ventricular aneurysm, and a larger thrombus diameter are significant factors influencing LVT recurrence. Furthermore, the longitudinal diameter of the thrombus is identified as an independent risk factor for recurrence following resolution. The threshold for LVT diameter requiring extended anticoagulation and the required duration of anticoagulation need to be confirmed in future studies. Full article

Diabetic cardiomyopathy (DCM) is characterized by myocardial remodeling that may already be evident during prediabetes, yet the molecular alterations accompanying these early changes remain poorly understood. The present study examined mouse models of Nucleoside diphosphate kinase B (NDPK-B)-deficient prediabetes and streptozotocin-induced diabetes using O-GlcNAc-associated proteomic profiling to define stage-specific molecular alterations during the progression from prediabetic to diabetic cardiomyopathy. Both models exhibited increased left ventricular extracellular matrix deposition and impaired diastolic function, together with activation of the hexosamine biosynthesis pathway. Profiling of O-GlcNAc-associated proteins uncovered extensive remodeling of the mitochondrial proteome already at the prediabetic stage, with respiratory complex I among the most prominently altered targets, alongside changes in substrate metabolism and inflammatory signaling. In overt DCM, the putative O-GlcNAc proteomic profile was associated with a shift toward wider lipid-dependent metabolic reprogramming and remodeling of mitochondrial proteins. These findings identify early remodeling of the mitochondrial O-GlcNAc-associated proteome as a molecular signature of prediabetic cardiomyopathy and highlight respiratory complex I proteins as candidate targets for future mechanistic investigations. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a global epidemic strongly associated with an increased risk of heart failure, independent of coronary artery disease or hypertension. This condition, historically termed diabetic cardiomyopathy (DCM) and recently redefined as “diabetic myocardial disorder,” remains frequently underdiagnosed in its subclinical stages. The objective of this non-systematic review is to synthesize current evidence on the pathophysiological mechanisms, diagnostic advancements, and evolving therapeutic strategies for diabetic myocardial involvement. Methods: A comprehensive review of contemporary literature was conducted, focusing on recent consensus statements from the ESC and AHA, large-scale epidemiological data (IDF/WHO), and pivotal clinical trials (EMPA-REG, DAPA-HF, and LEADER). We analyzed the role of multimodal imaging—specifically speckle-tracking echocardiography (STE) and multiparametric cardiac magnetic resonance (CMR)—and circulating biomarkers in early phenotyping. Results: Pathophysiological drivers include lipotoxicity, oxidative stress, and AGE-mediated fibrosis. Advanced imaging techniques, such as global longitudinal strain (GLS) and CMR T1-mapping/ECV quantification, demonstrate superior sensitivity over LVEF in detecting early subendocardial dysfunction and diffuse fibrosis. Furthermore, NT-proBNP serves as a robust prognostic marker for the HFpEF-like trajectory typical of diabetes. Clinically, the therapeutic landscape has shifted with SGLT2 inhibitors and GLP-1 receptor agonists, which provide significant cardioprotection and reduction in heart failure hospitalizations through mechanisms beyond glycemic control. Conclusions: Diabetic myocardial disorder represents a complex continuum within the cardiometabolic spectrum. Early detection through multimodal imaging and biomarkers is essential for risk stratification. Integrating novel glucose-lowering therapies with proven cardiovascular benefits is now mandatory to alter the natural history of the disease and prevent progression to overt heart failure. Full article

Diabetic cardiomyopathy (DCM) is a cardiac condition characterized by various structural and functional abnormalities that are associated with diabetes mellitus. Its development involves multiple factors, among which endothelial dysfunction plays a significant role. To fully describe the relationship between DCM and endothelial dysfunction, we conducted a literature search across several databases, including PubMed, Web of Science, and EMBASE. Our review of DCM research focused on understanding its mechanisms, exploring the methods used to diagnose it, and potential treatment options. Although researchers have made significant progress in DCM diagnosis and treatment in recent years, considerable challenges persist as well. Artificial intelligence (AI)-based multimodal approaches may provide new opportunities for cardiovascular risk stratification and early DCM screening, but DCM-specific models still require external validation before clinical implementation. Regarding treatment options, emerging evidence suggests potential benefits of medications that enhance mitochondrial function and antioxidant properties, as well as anti-inflammatory therapies and lifestyle modifications. Future research should focus on combining different relevant data types, such as genetic and molecular information, to improve the AI tools utilized in medical environments. This study aims to identify novel markers for diagnosing DCM and to devise tailored treatment approaches. These advancements have the potential to improve the prognosis of DCM patients and enhance the identification and management of this condition. Full article

Cardiovascular diseases remain the leading cause of mortality worldwide and are closely associated with obesity and metabolic dysfunction. Adipose tissue is now recognized as a heterogeneous endocrine and immunometabolic organ that actively communicates with the cardiovascular system through adipokines, inflammatory mediators, metabolites, and extracellular vesicles. Under physiological conditions, adipose–cardiac crosstalk contributes to metabolic and cardiovascular homeostasis, whereas adipose tissue dysfunction promotes inflammation, fibrosis, endothelial injury, and cardiac remodeling. This review summarizes the heterogeneity of adipose depots and their secretomes, discusses the molecular mechanisms underlying adipose–cardiac communication, and highlights their contributions to atherosclerosis, heart failure, hypertension, diabetic cardiomyopathy, and atrial fibrillation. We further discuss emerging biomarkers, therapeutic strategies, and precision medicine approaches targeting the adipose–cardiac axis. Understanding depot-specific signaling networks may facilitate the development of novel diagnostic and therapeutic interventions for cardiometabolic diseases. Full article

Background and Objectives: Coronary artery disease may be difficult to detect by resting echocardiography when left ventricular ejection fraction is preserved and regional wall motion abnormalities are absent. This study aimed to assess whether resting Tissue Doppler Imaging-derived mitral annular velocities can help identify CAD in patients with suspected angina pectoris. Materials and Methods: We conducted a cross-sectional observational study of 92 patients hospitalized with suspected angina pectoris who underwent elective coronary angiography at the Institute of Cardiovascular Diseases in Timișoara (January 2025–February 2026). Patients with conditions known to affect TDI-derived parameters were excluded, including previous acute coronary syndrome or myocardial revascularization, significant valvular disease, cardiomyopathies, relevant arrhythmias or conduction abnormalities, permanent pacing, reduced ejection fraction, and pericardial disease. Laboratory and echocardiographic data were collected. ROC curve analysis, univariable logistic regression and multivariable logistic regression were performed to evaluate the diagnostic performance of TDI-derived parameters and their independent association with coronary artery disease. Results: Patients with CAD had significantly lower average E′ values (7.4 ± 1.9 vs. 8.9 ± 1.8 cm/s, p < 0.001) and average S′ values [7.0 (IQR 6.0–7.5) vs. 9.0 (IQR 8.1–10.0) cm/s, p < 0.001], together with higher E/E′ ratios [9.33 (IQR 8.23–11.15) vs. 7.87 (IQR 5.93–9.51), p = 0.002]. Average S′ showed the highest discriminative ability for coronary artery disease, with an AUC of 0.899 (95% CI: 0.819–0.952, p < 0.0001). The optimal Youden-derived cut-off was ≤7.5 cm/s, yielding 77.42% sensitivity and 93.33% specificity. After adjustment for age, male sex, body mass index, diabetes, smoking status, hypertension and LVEF, dichotomized S′ remained an independent predictor of coronary artery disease (OR = 45.49, 95% CI: 8.03–257.68, p < 0.0001), with an adjusted model AUC of 0.92 and 88.04% correct classification. Conclusions: TDI, particularly S′ velocity, may be a useful resting echocardiographic parameter for identifying CAD in selected patients with preserved LVEF and no resting regional wall motion abnormalities. Rather than serving as a universal diagnostic marker, S′ should be considered a complementary, easily obtainable parameter that may improve non-invasive assessment in this specific clinical setting. Full article

Sodium–glucose co-transporter 2 (SGLT2) inhibitors confer cardioprotection in patients with and without diabetes; however, whether SGLT2 is expressed in cardiac tissue and how these drugs act locally in the heart remains unclear. We investigated SGLT2 expression and the effects of empagliflozin in human iPSC-derived cardiac cells exposed to diabetogenic conditions. SGLT2 expression and the effects of empagliflozin were assessed in iPSC-derived cardiomyocytes, endothelial cells, and cardiac fibroblasts under acute diabetogenic conditions using protein expression and metabolic activity assays, and in a multicellular 3D cardiac microtissue model using metabolic activity and contraction analyses. SGLT2 was detected in all three iPSC-derived cardiac cell types with nuclear and perinuclear localisation; no membrane-bound expression was observed. Endothelial cell SGLT2 expression was elevated under diabetogenic conditions. Diabetogenic stress reduced metabolic activity in both cardiomyocytes and endothelial cells; empagliflozin partially rescued endothelial cell metabolic activity but had no effect in cardiomyocytes. Empagliflozin reversed diabetogenic stress-induced cardiac fibroblast activation. 3D cardiac microtissues under diabetogenic conditions exhibited prolonged relaxation time, reduced beat rate variability, and reduced metabolic activity. Empagliflozin maintained metabolic activity at levels comparable to those of the control but did not rescue relaxation time or beat rate variability. The responsiveness of non-myocytes (endothelial cells and cardiac fibroblasts) to empagliflozin, in the absence of any effect on cardiomyocytes, suggests that non-myocyte-mediated mechanisms may contribute to the clinically observed cardioprotection of SGLT2 inhibitors. Full article

Background: Diabetic cardiomyopathy (DCM) is characterized by myocardial inflammation, apoptosis, and fibrosis that contribute to ventricular remodeling and dysfunction. We investigated the effects of 5-methoxytryptophan (5-MTP) on histopathological and molecular markers of myocardial remodeling in a rat model of DCM. Methods: Forty-eight Sprague–Dawley rats with DCM induced by a high-fat high-fructose diet and low-dose streptozotocin (25 mg/kg) were randomized to control or 5-MTP treatment (25, 50, or 100 mg/kg) and evaluated after 8, 16, and 32 days. Histopathological assessment using hematoxylin–eosin and Masson’s trichrome staining, along with immunohistochemical analysis of inflammatory, apoptotic, and fibrotic markers, was performed. Results: Myocardial inflammatory histopathological scores did not differ significantly among groups. Myocardial fibrosis assessed by Masson’s trichrome staining was significantly reduced at day 16 (p = 0.020), with all 5-MTP doses demonstrating lower fibrosis scores than DCM controls. Collagen I expression did not differ significantly. Caspase-3 expression was significantly reduced in all treatment groups at day 16 (p = 0.029), with persistent reduction at day 32 only in the 100 mg/kg group (p = 0.004). Early molecular modulation was observed through reduced TGF-β expression at day 8 in the 25 mg/kg and 50 mg/kg groups, followed by reduced SMAD3 expression at day 16 in the 25 mg/kg and 100 mg/kg groups. At day 16, AKT expression increased in the 25 mg/kg group, while cytoplasmic NF-κB expression decreased in the 25 mg/kg and 100 mg/kg groups. Conclusion: 5-MTP demonstrated time-dependent changes in molecular and histopathological markers associated with myocardial remodeling in experimental DCM. Full article

Epicardial adipose tissue (EAT) is a distinct form of visceral adipose tissue that lies within the pericardium and directly adjacent to the myocardium. Individuals with type 2 diabetes mellitus (T2DM) exhibit excessive and metabolically active EAT, which contributes to the development of early diabetic myocardial disease, formerly referred to as diabetic cardiomyopathy. Recent studies have demonstrated that excess EAT is characterized by a proinflammatory profile that may adversely affect the underlying myocardium, leading to impaired diastolic and systolic function. In this review, we discuss the role of excessive EAT as a source of proinflammatory and profibrotic cytokines that influence adjacent ventricular and atrial myocardium through local tissue crosstalk. In addition to metabolic alterations, enlarged EAT induces hemodynamic changes that result in pericardial constraint and enhanced ventricular interdependence, both of which are hallmarks of diabetic pericardial disease. We further analyze the interplay among T2DM, inflammation, obesity, and increased EAT on the one hand, and myocardial dysfunction characterized by myocardial stiffness, elevated filling pressures, and diastolic and systolic dysfunction on the other. We emphasize that the distinct immunometabolic activity of perivascular adipose tissue may lead to a paradigm shift in the understanding of coronary artery disease, moving from a predominantly endoluminal to an exoluminal perspective. A wide range of dietary, lifestyle, and pharmacological interventions are available within this emerging diabeto-cardiometabolic continuum, each with a potential role; however, the timing of intervention is crucial. This review also explores the potential effects of antidiabetic and other pharmacological agents that modulate EAT thickness, volume, and/or activity, and discusses directions for future mechanistic and clinical research. Full article