Search Results (1,083)

Purpose: Hypertension in women is a dynamic, hormone sensitive condition shaped by cumulative physiological changes across the life course. This review summarises current evidence relating vascular ageing, hormonal regulation, metabolic dysfunction, and reproductive history to blood pressure regulation in women. Materials and Methods: A narrative review of the literature was conducted using PubMed, Scopus and Google Scholar. Clinical, epidemiological, and mechanistic studies were synthesised to evaluate factors influencing hypertension in women. Reports in which menopausal status was not defined, or previous reproductive milestones were not documented, were excluded or interpreted with caution. Results: Evidence suggests that menopause, vascular ageing, metabolic dysfunction, androgen to oestrogen balance, and reproductive history interact to influence endothelial function, neurohormonal regulation, renal sodium handling, and vascular resistance. Ageing-related mechanisms, including cellular senescence, chronic low-grade inflammation, and genetic susceptibility, may contribute to increased cardiovascular risk. Hypertensive disorders of pregnancy identify women who are at higher risk of developing cardiovascular disease later in life and provide an opportunity for earlier risk assessment and prevention. Emerging therapies, including GLP-1 receptor agonists and SGLT2 inhibitors, may offer additional options for improving cardiovascular risk management, although their role in sex-specific prevention remains an evolving area of research. Conclusions: Hypertension in women is best understood within a life-course framework. Incorporating reproductive history, menopausal status, metabolic health, and emerging risk markers may improve cardiovascular risk assessment and support earlier intervention. Full article

Oxidative stress contributes to heart failure (HF) progression by mechanisms that go beyond hemodynamic overload, including mitochondrial dysfunction, endothelial injury, inflammation, and fibrotic remodeling. This review evaluates the relationship between redox imbalance, Galectin-3 (Gal-3), fibrosis, and imaging findings in HF. Reactive oxygen species (ROS) generated by mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and xanthine oxidase may disturb calcium handling, impair mitochondrial function, activate fibroblasts, and promote ferroptosis. Biomarkers of oxidative injury and antioxidant reserve, including malondialdehyde (MDA), 8-hydroxy-2′-deoxyguanosine (8-OHdG), and circulating thiols, provide information complementary to natriuretic peptides. Experimental evidence supports a context-dependent role of Gal-3 in fibro-inflammatory remodeling, whereas circulating Gal-3 should be regarded as a complementary biomarker rather than as a direct measure of myocardial fibrosis. Echocardiography assesses functional remodeling through diastolic indices, myocardial deformation, and right ventricular–pulmonary arterial (RV–PA) coupling, while cardiac magnetic resonance characterizes focal scar and diffuse interstitial remodeling using late gadolinium enhancement, native T1 mapping, and extracellular volume fraction. Therapeutic strategies are increasingly shifting from nonspecific antioxidant supplementation toward targeting ROS sources and downstream pathways, with SGLT2 inhibitors emerging as clinically relevant agents with indirect redox-modulating effects. Integrated redox, fibro-inflammatory, hemodynamic, and imaging phenotyping may refine risk stratification, although prospective validation is required before routine implementation. Full article

Background: Hyperuricemia has long been linked to the progression of chronic kidney disease (CKD), although the role of serum uric acid (sUA) reduction in kidney preservation remains uncertain. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower sUA levels and exert renoprotective effects, but it is unclear whether these findings are mechanistically related. Methods: Adult patients with type 2 diabetes mellitus and hyperuricemia were included from a retrospective cohort. Patients treated with empagliflozin (n = 70) or dapagliflozin (n = 78) were pooled into a single group and compared with an allopurinol-treated group (n = 66). Exploratory mediation-informed analysis models assessed associations between treatment, changes in sUA (ΔsUA), and changes in estimated glomerular filtration rate (ΔeGFR) at 12 and 36 months. Dose–response and nonlinear associations between ΔsUA and ΔeGFR were additionally examined. Results: At 12 months, SGLT2 inhibitor treatment was associated with greater ΔsUA compared with allopurinol (B = 22.62, p = 0.040); its direct association with ΔeGFR remained significant after adjustment for ΔsUA (B = −6.14, p < 0.001). At 36 months, the association of treatment with ΔsUA was no longer significant, whereas association with ΔeGFR persisted (B = −11.8, p < 0.001). No dose–response or nonlinear relationship was identified between ΔsUA and ΔeGFR, while treatment remained an independent predictor of ΔeGFR at both time points. Conclusions: Reductions in sUA do not appear to mediate the renoprotective effects of SGLT2 inhibitors. The preservation of kidney function associated with SGLT2 inhibitor therapy is likely driven by mechanisms independent of sUA lowering. Full article

Background/Objectives: optimization of the therapeutic efficacy of antidiabetic agents is still a great challenge in the management of type 2 diabetes mellitus (T2DM), and attention is becoming more and more focused on the use of adjunctive agents that help target the drug action beyond the classic glycemic target. This study examined the effect of co-administration of an Artemisia herba-alba Asso (Asteraceae) aqueous extract on the glucose-lowering effect of dapagliflozin, a sodium–glucose cotransporter-2 (SGLT2) inhibitor. Methods: qualitative phytochemical screening and total phenolic and total flavonoid content were used to characterize the aqueous preparation. Male Wistar albino rats were divided into eight groups (10 rats each): four healthy and four diabetic rats induced with streptozotocin (STZ). Vehicle control, oral administration of an aqueous A. herba-alba preparation (0.39 g/kg twice daily), dapagliflozin (0.143 mg/kg/day), or a combination of both was given for 30 days. At baseline and days 7, 14, 21, and 30, glycated hemoglobin (HbA1c) was measured by nephelometry. Parallel fasting blood glucose (FBG) was monitored. Results: the diabetic animals treated with the combination regimen showed the greatest and most sustained decrease in HbA1c (from 4.42 ± 0.40% at baseline to 3.44 ± 0.17% at day 30; p < 0.001) and the greatest decrease in FBG (from 186.0 to 122.2 mg/dL). A. herba-alba monotherapy had little effect on HbA1c and had minimal effect on FBG (214.9 to 217.6 mg/dL); dapagliflozin monotherapy had a modest effect on HbA1c. The untreated diabetic controls (n = 10) showed a progressive increase in HbA1c from 4.45 ± 0.60% at 72 h post-induction to 11.90 ± 0.99% by day 30 (p < 0.001), consistent with delayed hemoglobin glycation relative to the rise in blood glucose. The repeated-measures ANOVA showed a highly significant interaction between time and treatment (p < 0.001). Conclusions: this study showed that the phytochemically defined aqueous A. herba-alba preparation is a beneficial adjunct to SGLT2 inhibitor therapy, an effect not observed with either treatment alone. Full article

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus, and a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide. It is characterized by proteinuria, mesangial expansion, glomerulosclerosis and progressive loss of renal function. Current therapeutic strategies of DN, including renin–angiotensin–aldosterone system (RAAS) blockade, glucagon-like peptide-1 receptor agonists, non-steroidal mineralocorticoid receptor, and sodium-glucose cotransporter-2 (SGLT2) inhibitors, only slow the progression of the disease rather than reversing the pathology. Therefore, there is a growing interest in identifying alternative or complementary therapeutic agents, particularly those derived from natural products with multi-targeted activities. Psoralea corylifolia Linn (PCL) is a medicinal herb commonly used in traditional Asian medicine. It has known pharmacological properties on oxidative stress, inflammation, fibrosis and metabolic disorders. Accumulating recent studies indicated that PCL and its bioactive compounds, such as psoralen, bakuchiol, and corylin, mitigate pathological conditions in various diseases. Here, the current review will provide our current knowledge of major identified and characterized PCL focusing on their biological activity and function, particularly in DN. 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

Accumulating data indicate a role for the dysregulation of the cell cycle, autophagy and apoptosis in diabetic kidney disease. We aimed to evaluate the mediators of the PI3K/Akt and MAPK/ERK signaling pathways in the kidney of db/db mice, a model of type 2 diabetes, treated by the SGLT2 inhibitor empagliflozin, the DPP4 inhibitor linagliptin, and metformin. Eight-week-old male db/db mice were randomly assigned to treatment by these agents or vehicle for 8 weeks. Age-matched db/+ mice acted as controls. AMPKα1 and PI3Kp110β were evaluated in the renal cortex and medulla by Western Blot. Phosphorylated forms of principal molecules involved in the PI3K/Akt and MAPK/ERK pathways were assessed by multiplex analysis. Db/db mice had decreased PI3Kp110β, increased phospho-PTEN, HSP27 and MEK1 in the renal cortex and medulla, BAD in the renal cortex and decreased phospho-rpS6 in the renal medulla. Empagliflozin prevented the changes in the levels of cortical PI3Kp110β, phospho-MEK1, and medullar phospho-PTEN. Linagliptin restored PI3Kp110β levels. Both agents further decreased medullar phospho-rpS6. Metformin upregulated cortical AMPKα1, medullar PI3Kp110β, phospho-GSK-3α/β and MEK1, and increased phospho-HSP27 in the renal cortex and medulla. The data may provide further explanation of the mechanism underlying the development of diabetic kidney disease, as well as the renal protective effect of anti-diabetic agents. Full article

Obesity and type 2 diabetes mellitus (T2DM) represent pandemic metabolic illnesses hallmarked by defective pancreatic β-cell function and blunted insulin release. As a conserved small GTPase (guanosine triphosphatase), ADP-ribosylation factor 6 (ARF6) governs fundamental cellular events encompassing vesicle trafficking, cytoskeleton remodeling and lipid metabolic turnover. Emerging data confirm that ARF6 acts as a master rheostat of glucose-stimulated insulin secretion (GSIS) in β-cells through downstream cell division control protein 42/Ras-related C3 botulinum toxin substrate 1 (Cdc42/Rac1) cascades. Pathogenic ARF6 hyperactivation triggers a cascade of β-cell lesions: mitochondrial impairment, autophagic suppression and exacerbated inflammatory signaling, accelerating the progression of obesity and T2DM. First-line therapeutics ranging from GLP-1 (Glucagon-like peptide-1) receptor agonists and metformin to SGLT2 (Sodium-Glucose Cotransporter 2) inhibitors partially restore metabolic homeostasis by rectifying aberrant ARF6-dependent signaling axes. This review comprehensively delineates ARF6’s canonical cellular roles, mechanistic bridges connecting ARF6 to β-cell failure and metabolic deterioration, and functional crosstalk between ARF6 and established anti-metabolic pharmacotherapies. We further address unresolved research gaps and prospective translational avenues, offering actionable perspectives to advance ARF6 as a tractable therapeutic target for obesity and T2DM management. Full article

Background/Objectives: Patients receiving a cardiac implantable electronic device (CIED) for conduction disease may remain at substantial long-term risk despite preserved systolic function at implantation. The prognostic association of sodium–glucose cotransporter-2 (SGLT2) inhibitor use in this population is uncertain. We therefore examined the relationship between early documented SGLT2 inhibitor use and subsequent all-cause mortality in patients with preserved left ventricular ejection fraction (LVEF) undergoing CIED implantation for conduction disease. Methods: In this retrospective single-center cohort study, we screened consecutive adults who underwent CIED implantation for conduction disease between January 2018 and June 2024. Patients with LVEF ≥ 50% and complete clinical, laboratory, electrocardiographic, and echocardiographic data were included. SGLT2 inhibitor exposure was defined as documented initiation or active use within 3 months after implantation. The primary endpoint was all-cause mortality. Associations were evaluated using multivariable Cox proportional-hazards regression and Kaplan–Meier analyses. Results: Among 2176 screened patients, 540 fulfilled the eligibility criteria, of whom 206 (38.1%) had documented SGLT2 inhibitor exposure. During a median observation period of 64.2 months (range, 7–90 months), 185 deaths occurred. SGLT2 inhibitor exposure was associated with a lower adjusted hazard of death (HR, 0.48; 95% CI, 0.38–0.69; p < 0.001). Survival also differed between exposure groups in the overall cohort (log-rank p = 0.006) and in patients without either heart failure or diabetes mellitus (log-rank p = 0.020). Conclusions: In patients with preserved LVEF undergoing CIED implantation for conduction disease, documented SGLT2 inhibitor use was independently associated with lower all-cause mortality. These observational findings are hypothesis-generating and warrant confirmation in prospective studies. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) has been evaluated through a glucocentric model centered on hyperglycemia, glycated haemoglobin (HbA1c) targets, and complications. However, obesity-associated T2DM reflects a broader metabolic ecosystem in which glycemic control interacts with adiposity, inflammation, muscle function, renal stability, and treatment mechanisms. Therapeutic response may be better captured through patient-level responder phenotypes than through mean changes in isolated outcomes. We aimed to determine, in adults with obesity-associated T2DM maintained on stable 12-month metformin-based regimens, the distribution of concordant versus discordant glycemic–adiposity response phenotypes and the frequency of high multidimensional response, and to describe how these phenotypes were distributed across treatment classes. Methods: This secondary patient-level analysis used a real-world cohort from a Bucharest tertiary diabetes center. Of 291 screened adults, 166 completed 12-month follow-up without treatment change. Regimens included metformin alone or combined with sulfonylurea, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or insulin. Responses were defined as HbA1c reduction ≥ 0.5 percentage points, fat mass reduction ≥ 5%, hs-CRP reduction ≥ 20%, and handgrip strength decline ≤ 1 kg. Primary phenotypes and a 0–4 multidimensional score were derived. Results: Mean age was 59.7 ± 13.0 years, BMI 36.3 ± 4.4 kg/m², and baseline HbA1c 8.9 ± 1.0%. Glycemic–adiposity, glycemic-only, adiposity-only, and low/non-response phenotypes occurred in 49 (29.5%), 88 (53.0%), 9 (5.4%), and 20 (12.0%) patients, respectively. A high multidimensional response occurred in 78 (47.0%), and complete response in 25 (15.1%). GLP-1 receptor agonists showed the most consistent concordant glycemic–adiposity response, whereas insulin was predominantly glycemic-only. Conclusions: In obesity-associated T2DM, therapeutic response was heterogeneous and frequently discordant across metabolic domains. Patient-level responder phenotyping may complement conventional HbA1c-centered evaluation by identifying response quality across glycemic, adiposity, inflammatory, and functional dimensions. This approach may support more individualized diagnostic interpretation and treatment optimization in real-world diabetes care. Full article

Background/Objectives: Metabolic syndrome (MetS), defined by abdominal obesity, dysglycemia, dyslipidemia, hypertension, and insulin resistance, markedly increases the risk of type 2 diabetes mellitus and cardiovascular disease. Affecting an estimated 25–30% of the global adult population, MetS represents a major and growing public health challenge. A growing body of evidence supports a significant bidirectional relationship between MetS and oral health, particularly periodontitis. The present study aimed to synthesize current evidence on the pathophysiological mechanisms, epidemiological associations, interventional outcomes, and clinical implications of the bidirectional relationship between metabolic syndrome (MetS) and periodontitis. Methods: A narrative review following the SANRA framework was performed. PubMed, Scopus, and Web of Science were searched for articles published in January 2021–March 2026 using MeSH and free-text terms including “metabolic syndrome”, “periodontal disease”, “insulin resistance”, and “oral microbiota”. Eligible studies included original research and systematic reviews in English with full-text availability; animal and in vitro studies were included if directly informative of mechanistic pathways. Results: A total of 64 references were selected for inclusion. Shared mechanisms include chronic systemic inflammation, insulin resistance, oxidative stress, adipokine imbalance, endothelial dysfunction, and oral–gut microbiome dysbiosis. Cross-sectional and longitudinal studies show that MetS components are independently associated with higher prevalence and severity of periodontitis; meta-analyses report pooled odds ratios of 1.7–1.9 compared with metabolically healthy controls. Non-surgical periodontal therapy produces modest but significant reductions in glycated hemoglobin (HbA1c) and systemic inflammatory markers. Sodium–glucose cotransporter-2 (SGLT2) inhibitors may alter oral microbiota composition and cause mucosal changes, while glucagon-like peptide-1 (GLP-1) receptor agonists may increase caries risk through gastrointestinal side effects and xerostomia; both drug classes warrant proactive dental monitoring. Conclusions: The bidirectional relationship between MetS and oral health supports integrated screening and interdisciplinary management. Routine periodontal assessment should be integrated into the metabolic risk management pathway, and dental professionals should screen patients with severe periodontitis for metabolic risk factors. The oral microbiome emerges as a promising target for future mechanistic research and therapeutic intervention. Recognition of oral health as an integral component of metabolic health may improve risk stratification, prevention, and long-term patient outcomes. Large-scale randomized controlled trials with standardized endpoints are needed to establish causal directionality and optimize combined therapeutic strategies. Full article

Dapagliflozin (DAPA), a selective sodium–glucose cotransporter 2 inhibitor, is widely used in the management of type 2 diabetes mellitus, with additional indications in heart failure and chronic kidney disease. The growing analytical demand for DAPA determination in pharmaceutical formulations, fixed-dose combinations, and biological matrices has stimulated the development of diverse analytical methods. This review provides a comprehensive evaluation of reported techniques for DAPA quantification in different matrices. Approaches discussed include chromatographic methods (TLC, RP-HPLC, UHPLC, LC-MS/MS), electromigration techniques (CE), and spectroscopic methods (UV–Vis, spectrofluorimetry). Emphasis is placed on key performance characteristics such as selectivity, sensitivity, linearity, robustness, and applicability to stability studies and bioanalysis. Recent trends, including the application of Quality by Design, green analytical chemistry principles, and advanced hyphenated techniques, are also addressed. While RP-HPLC remains widely used for routine quality control due to its robustness and accessibility, LC-MS/MS is generally regarded as the method of choice for trace-level bioanalysis owing to its superior sensitivity and selectivity. CE and spectroscopic techniques offer cost-effective and environmentally friendly alternatives, though with certain limitations. This review highlights current methodological gaps and outlines future directions for developing more sensitive and sustainable analytical strategies. Full article

Background/Objectives: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) raise hemoglobin in patients with heart failure (HF). We characterized the prevalence, dynamics, predictors and prognostic implications of three hemoglobin states (anemia, normal, and erythrocytosis) at baseline and during the first year on SGLT2i therapy. Methods: Prospective single-center registry of 1244 HF patients with a baseline hemoglobin who initiated dapagliflozin or empagliflozin (March 2022–October 2025). Hemoglobin was categorized at baseline, 6 and 12 months using WHO sex-specific thresholds. We analyzed inter-category transitions, predictors of each hemoglobin category at each timepoint, time-to-event outcomes (all-cause death, MACE, thrombosis) in landmark analyses, and the correlation of hemoglobin change with concurrent changes in left ventricular ejection fraction and NT-proBNP. Results: At baseline, 23.6% had anemia, 71.1% were normal, and 5.3% had erythrocytosis. The prevalence of erythrocytosis remained low throughout, with a modest, transient rise to 8.0% at 6 months before returning toward baseline (5.9% at 12 months), even though the underlying composition of patients was highly dynamic. Among baseline-normal patients, downward transition to anemia (7.8% at 6 months, 9.2% at 12 months) occurred at rates equal to or greater than upward transition to erythrocytosis (7.7% and 6.0%, respectively). The prevalence of anemia decreased significantly between baseline and the follow-up timepoints. Across timepoints, the patient’s own baseline hemoglobin was the dominant independent predictor of both subsequent erythrocytosis and subsequent anemia. Other independent predictors of erythrocytosis were higher adherence to SGLT2i, male sex, current smoking, COPD or asthma, higher heart rate and lower serum albumin. Other independent predictors of anemia were non-adherence to or discontinuation of SGLT2i, peripheral arterial disease, advanced age, diabetes, lower eGFR, higher NT-proBNP and lower serum albumin. Increases in hemoglobin from baseline were associated with greater concurrent reductions in NT-proBNP at 6 and 12 months but were not associated with changes in LVEF at either timepoint. Anemia was independently associated with all-cause death at the baseline and 6-month landmarks (adjusted HRs are 2.23 and 2.45, respectively; time-varying HR is 2.55), with a consistent but non-significant point estimate at 12 months (aHR of 1.90), and with significant 6-month MACE estimate (aHR of 3.07). Erythrocytosis was not associated with mortality, MACE or thrombosis at any timepoint, although the small number of patients and thrombotic events limits interpretation. Dapagliflozin and empagliflozin were associated with indistinguishable hemoglobin trajectories. Conclusions: On SGLT2i therapy, anemia carries the dominant prognostic signal and identifies a high-risk subgroup; erythrocytosis is uncommon, transient and showed no detectable association with adverse outcomes, though thrombotic events were too few for firm safety conclusions. Routine monitoring of hemoglobin for anemia is of higher clinical importance compared to erythrocytosis; these single-center findings require external validation. Full article

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening condition characterized by elevated pulmonary vascular resistance eventually causing right ventricular failure and premature death. Despite advances in targeted therapies, morbidity and mortality levels remain high, highlighting the need for additional treatment strategies that address the disease’s multifactorial pathophysiology. Attention has recently centred on two pharmacological groups with proven roles in other cardiovascular settings: sodium–glucose cotransporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists (MRAs). SGLT2 inhibitors have demonstrated robust clinical benefits in heart failure (HF), type 2 diabetes mellitus (T2DM), and chronic kidney disease (CKD), extending survival and reducing hospitalizations. Although their primary actions involve renal glucose and sodium handling, accumulating evidence suggests they may also exert favourable effects on the pulmonary vasculature, endothelial function, and right ventricular performance. In parallel, elevated aldosterone levels have been implicated in vascular remodelling, inflammation, and fibrosis in PAH, suggesting a potential therapeutic role for MRAs. However, the strength and clinical significance of these associations remain under investigation. The aim of this review is to synthesize and critically appraise the current evidence regarding the potential role of SGLT2 inhibitors and MRAs in the treatment of pulmonary arterial hypertension, exploring their mechanistic rationale, preclinical findings, and available clinical data to determine whether these agents may offer additional therapeutic benefit in PAH management. Full article

Heart failure with preserved ejection fraction (HFpEF) is an increasingly common form of heart failure (HF) that is best understood as a systemic, multiorgan syndrome rather than a disease of left-ventricular filling alone. This review has three specific aims: first, to synthesize genetic and molecular pathways that are most relevant to non-ischemic HFpEF; second, to distinguish HFpEF-enriched mechanisms from evidence extrapolated from ischemic cardiomyopathy or HFrEF; and third, to consider translational implications for populations with high consanguinity, including the Kingdom of Saudi Arabia. The available evidence indicates that chronic inflammatory signaling involving CCL2, CCL5, TLR3, PTGS2/COX-2, IL-6/JAK/STAT3, NF-kB, and NLRP3 acts upstream of endothelial dysfunction, nitric-oxide/cGMP/PKG impairment, mitochondrial reactive oxygen species generation, and fibroblast activation. Extracellular-matrix regulators including ASPN, COL1A1, and MMP2 then amplify collagen deposition and myocardial stiffness, whereas mitochondrial genes and proteins such as ATP5C1 contribute to impaired oxidative phosphorylation, reduced ATP reserve, defective fatty-acid oxidation, and blunted mitophagy. Protein-quality-control pathways involving HSP90AA1, CCT2/CCT5, PSMA3, and stress-responsive STAT3 further link metabolic stress to proteotoxic injury. Epigenetic mechanisms, including DNA methylation and microRNAs such as miR-155, miR-1297, and miR-4649-3p, add a regulatory layer that may improve risk stratification but remains insufficiently validated for routine clinical use. In high-consanguinity settings, recessive cardiomyopathy variants can cluster in families and contribute to earlier NIHF presentations; however, population-level HFpEF-specific variant frequencies remain limited, and findings from HFrEF or dilated cardiomyopathy should be interpreted as candidate pathway evidence rather than definitive HFpEF markers. Translationally, SGLT2 inhibitors, mineralocorticoid-receptor antagonism, biomarker panels, and structured genetic evaluation provide the most clinically actionable bridge from molecular mechanisms to precision HFpEF care. Full article