PURPOSE:The role of the natriuretic peptides in radiation heart injury (RHI) has not been thoroughly examined. Pharmacologic modulation of the natriuretic peptide system with sacubitril/valsartan (sac/val) has led to improvements in heart failure therapy, and preliminary data suggest that RHI is associated with decreased atrial natriuretic peptide (ANP). In this study, we assessed sac/val as a radioprotector in a partial-heart irradiation mouse model and explored preliminary trends in patients receiving thoracic irradiation. METHODS AND MATERIALS:Female 8-10-week-old C57BL/6J mice were randomly assigned to receive sham irradiation, with or without sac/val, or irradiation with or without sac/val. The superior two-thirds of the heart was exposed to 20 Gy of x-rays using a small animal radiation research platform. Cardiac function was assessed at 10-week intervals over 30 weeks by transthoracic echocardiography and electrocardiography. Plasma levels of ANP were analyzed at 30 weeks. Small retrospective clinical series were undertaken in patients undergoing thoracic radiation therapy, to assess ANP dynamics and sac/val safety. RESULTS:At 30 weeks, irradiated mice that received sac/val exhibited a marked improvement in structural remodeling, systolic longitudinal strain, diastolic function, and electrophysiological parameters, compared with irradiated animals that did not receive sac/val. Functional sparing with sac/val was detectable as early as 10 weeks postirradiation by global longitudinal strain. Animals and patients tolerated the combination of sac/val with radiation without additional adverse effects. NT-proANP levels generally decreased among patients during thoracic radiation therapy and posttreatment NT-proANP changes were dose dependent. There was no effect on tolerability or efficacy of (chemo)radiation for patients on sac/val concurrently for heart failure. CONCLUSIONS:Sac/val attenuated structural and functional aspects of RHI and was well tolerated in animals when given with radiation. Clinical data suggest that ANP changes dynamically during radiation therapy and that sac/val is safe to take concurrently. Further investigation of sac/val as a cardiac radioprotector is warranted.

Coronary microvascular dysfunction (CMD) is an established pathological driver of heart failure, with endothelial cell (EC) dysfunction representing a central determinant of its development and progression. EC impairment disrupts normal coronary microvascular tone and perfusion, and promotes myocardial inflammation, fibrosis, and cardiomyocyte stress, as characteristic features of the diabetic heart. CMD is often clinically silent and undiagnosed, whilst conventional therapies targeting cardiometabolic risk factors are largely ineffective towards restoring microvascular integrity. Emerging evidence implicates epigenetic dysregulation, including DNA and RNA methylation, as a critical mechanism underlying maladaptive EC signalling. These key modifications encode microvascular memory, sustaining endothelial dysfunction even after risk factors are optimally controlled; DNA methylation stabilises pathogenic transcription whilst RNA methylation regulates transcript stability and translation to support continued disruption of EC homeostasis. Indeed, preclinical studies demonstrate that pharmacological DNA methylation inhibitors and RNA methylation modulators can restore healthy EC function, reflected by reduced inflammation and preserved microvascular integrity, positioning such epigenetic pathways as central determinants of CMD with clear mechanistic relevance and therapeutic potential. Selective methylation targeting therefore offers exciting translational promise to reprogram dysfunctional ECs in diabetic patients, reversing CMD and preventing development and progression of associated heart failure. This timely review summarises current knowledge of EC epigenetic regulation, focusing on methylation modifications, and explores how emerging mechanistic insights may be leveraged to advance therapeutic targeting of CMD in the diabetic heart as foundation for development of innovative clinical management strategies.

A patient-linked in-vitro model system to investigate the interplay of cardiac and vascular cells offers opportunities to understand pathogenesis. Here we establish that novel 3D structure of iPSC-derived vascularised cardiac organoids (VCO), originated from donors with type 2 diabetes mellitus (T2DM) demonstrate pronounced mechanistic, cellular and mitochondrial dysfunction when compared to non-diabetic counterparts. Integrated RNA sequencing, functional assays, and RT-PCR analyses identified novel molecular signatures indicative of mitochondrial dysfunction and impaired mitophagy. Notably, these analyses demonstrated a significant upregulation of TINF2, a telomeric protein and key components of the shelterin complex. To our knowledge, the involvement of TINF2 has not previously been reported in cardiac or vascular-specific cell types, nor altered in T2DM. Transgenic targeting of TINF2 successfully reversed the associated targets of T2DM-related mitochondrial dysfunction and crucially re-established mitophagy and a normalised pattern of transcription factor expressions within cardiac- and vascular specific cells. Our findings reveal the vital role of the TINF2 protein in T2DM-associated mitochondrial dysfunction in a glucose-independent study and the potential for re-targeting mitophagy for the treatment of T2DM.

Background: Diabetes mellitus is associated with low-grade inflammation, resulting in susceptibility to infections and related complications. Histone deacetylase 11 (HDAC11) regulates host immune responses upon infections including fungal and gram-negative bacterial infections. Here, we hypothesise that bacterial infection may influence epigenetic regulation via HDAC11, resulting in the exacerbation of the inflammation responses. Methods: Induced pluripotent stem cells (iPSCs) from non-diabetic (ND) and diabetic (DB) donors were differentiated into endothelial cells (ECs). The iPSCs-derived ECs (iPS-ECs) were infected with Escherichia coli (E. coli) to mimic sepsis. Bulk RNA sequencing was performed to validate the gene expression in transcriptomic level. qRT-PCR, ELISA, and western blot were conducted to assess gene expression levels. Immunocytochemistry (ICC) staining was used to visualise the protein expression, and functional tests were performed to assess the iPS-ECs' response to infection. Results: This study revealed that HDAC11 expression is significantly elevated in iPS-ECs derived from DB donors when infected with E. coli. HDAC11 upregulation was associated with increased production of pro-inflammatory cytokines and vascular dysfunction. Administration of a HDAC11 inhibitor effectively suppressed pro-inflammatory cytokine expression and restored endothelial function. Mechanistic analyses demonstrated that interaction of HDAC11 with the signal transducer and activator of transcription 3 (STAT3) sustained the inflammatory response in iPS-ECs derived from DB donors. Conclusion: Our findings highlight the role of HDAC11 to mediate inflammation-driven vascular impairment in diabetes, suggesting HDAC11 is a promising therapeutic target to mitigate endothelial dysfunction and inflammation, improving endothelial health in people with diabetes.

Diabetic vascular complications remain a major cause of morbidity and mortality, yet the molecular mechanisms underlying endothelial dysfunction in diabetes remain incompletely understood. Endothelial dysfunction is a key contributor to vascular pathology, and patient-derived induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) provide a human platform to investigate disease-associated endothelial phenotypes under controlled conditions. Here, we identify the RNA-binding protein Quaking-7 (QKI-7) as a key regulatory factor associated with endothelial dysfunction in patient-derived iPSC-ECs. Using cells derived from diabetic and non-diabetic donors maintained under standard culture conditions, we demonstrate that elevated QKI-7 expression is associated with reduced expression of endothelial homeostatic genes (COL4A2, JUN, TMEM184A, and PPP1R15A) and impaired angiogenic capacity, including reduced tube formation. Importantly, these findings were further validated in three-dimensional blood vessel organoid models, supporting the relevance of QKI-7-associated endothelial phenotypes in a more physiologically complex vascular system. Connectivity mapping identified FDA-approved compounds, including simvastatin, halcinonide, and retinoic acid, as potential modulators of QKI-7-associated pathways. Functional validation in iPSC-ECs demonstrated that these compounds reduce QKI-7 expression and improve endothelial functional readouts. Together, these findings identify QKI-7 as a regulatory node associated with endothelial dysfunction in patient-derived iPSC-ECs and highlight the utility of human iPSC-based vascular models for identifying candidate therapeutic strategies. While these models capture endothelial phenotypes associated with diabetic donor origin, further studies in more complex in vivo systems will be required to establish causal relevance to vascular disease.

Ischaemic heart disease (IHD) is a chronic condition that can cause pathological cardiac remodelling and heart failure (HF). In this study, we sought to determine how cardiac fibroblasts were altered post-experimental myocardial infarction (MI). Female C57BL6 mice underwent experimental MI by permanent left coronary artery ligation. Cardiac fibroblasts were isolated from extracted heart tissue of experimental MI mice and subsequently treated with the pro-fibrotic cytokine, TGF-β, for 24 h and analysed using high throughput LC-MS/MS analysis. Findings were validated using mass spectrometry data generated from human left ventricular tissue analysis, which were collected from patients with ischaemic cardiomyopathy (ISCM) and age/sex-matched patients without clinical HF (NF). Proteomic analysis revealed significant protein expression changes in mouse cardiac fibroblasts after MI. These changes were most pronounced at 1 month post-MI, compared to earlier time points (3 days and 1 week). TGF-β treatment profoundly affected fibroblast cells extracted from MI mice, indicating a heightened sensitivity to pro-fibrotic factors after myocardial injury. Extracellular matrix (ECM) proteins significantly altered in MI fibroblasts following TGF-β treatment were significantly associated with cardiac remodelling. Notably, Lox was significantly changed in both isolated fibroblasts treated with TGF-β from experiment MI mice and human ISCM. Isolated cardiac fibroblasts from MI mice are more susceptible to developing pathogenic traits following TGF-β treatment than isolated fibroblasts from normal heart tissue. ECM proteins associated with these enhanced fibroblast activities and functions are evident. These altered proteins may play a functional role in MI-associated cardiac dysfunction.

Progenitor endothelial colony forming cells (ECFCs) are critical for vascular homeostasis and hold therapeutic potential for ischaemic cardiovascular disease (CVD). As angiogenic capacity and efficacy within diseased tissues is particularly impacted in diabetic patients, who show high incidence of ischaemic CVD, targeting of critical ECFC pathways in this setting represents an innovative focus towards enhancing intrinsic vasoreparative function. We previously reported that NADPH oxidase 4 (NOX4)-derived reactive oxygen species promote cord blood-derived ECFC (CB-ECFC) pro-angiogenic response, whilst NOX4 overexpression (OE) enhances revascularisation capacity. Here, we aimed to investigate specific influence of NOX4-dependent signalling on CB-ECFC angiogenic dysfunction observed upon exposure to both experimental and clinical diabetes to define whether NOX4 may represent a viable therapeutic target in this context. CB-ECFCs were cultured in high glucose (D-glucose, 25 mmol/L) or control media (5 mmol/L) ± phorbol 12-myristate 13- acetate (PMA, 500 nmol/L) for 72 h with assessment of migratory/tubulogenic capacity and NOX4 mRNA expression (qRT-PCR). Detailed analysis of angiogenic function and signalling (Western blot, RNA sequencing) was performed in CB-ECFCs isolated from donors with gestational diabetes prior to NOX4 plasmid OE to define rescue potential and key mechanistic pathways (network analysis, proteome profiling). Statistical significance was determined using one-way ANOVA with Bonferroni post-host testing or paired/unpaired Student’s t-test, as appropriate. PMA-stimulated CB-ECFC migration and tube-forming capacity observed in control cells was suppressed in experimental diabetes in parallel with reduced NOX4 expression and rescued by plasmid NOX4OE. As direct evidence of clinical relevance, CB-ECFCs from gestational diabetic donors showed reduced angiogenic potential associated with attenuated NOX4, eNOS activity and downregulation of key vasoreparative signalling. Furthermore, NOX4OE rescued angiogenic function in chronically diabetic CB-ECFCs via modulation of downstream signalling involving both direct and indirect enhancement of pro-angiogenic protein expression (endoglin/SERPINE1/E2F1) linked to reduced p53 phosphorylation. Taken together, these data indicate for the first time that reduced NOX4 expression plays a pivotal role in CB-ECFC angiogenic dysfunction linked with diabetes whilst highlighting NOX4-dependent signalling as a potential target to protect and augment their intrinsic vasoreparative capacity towards addressing current translational barriers.

Diabetic cardiomyopathy (DbCM) is a progressive disease and common complication of metabolic diabetes. It is characterised by onset of cardiac structural and functional impairments and can lead to direct development of clinical heart failure (HF) or predispose to hypertensive/ischaemic stress. DbCM is a complex disease which involves several metabolic and pathogenic factors. We characterised an established high-fat diet/streptozotocin (HFD/STZ)-induced DbCM model incorporating typical features of human disease to determine its suitability for preclinical evaluation of novel therapeutics prior to advancement to human trials. Male C57BL/6J mice were randomised to HFD and single-dose STZ (100 mg/kg) or control diet (CD) and vehicle. HFD/STZ mice developed type 2 diabetes mellitus (T2DM), reflected by high fasting blood glucose and HbA1c levels, reduced β-cell function, and increased insulin resistance without systolic blood pressure alteration. Furthermore, HFD/STZ mice displayed progressive diastolic dysfunction, evidenced by decreased MV E/A ratio, together with elevated chronic left ventricular (LV) filling pressure parameters, measured by left atrial (LA) area and LA volume, compared to controls, in parallel with LV hypertrophy and fibrosis. Monocyte trafficking into diabetic hearts was identified by single-nuclei RNA sequencing analysis, which revealed an interferon-α response in DbCM mice, whilst plasma proteomics confirmed the involvement of inflammatory processes with elevated plasma C-reactive protein in DbCM progression. Taken together, our HFD/STZ-induced DbCM model exhibits a unique DbCM pre-clinical phenotype reflecting a "triple-hit" of human DbCM features comprising (1) T2DM with insulin resistance, (2) progressive diastolic dysfunction and LV remodelling, and (3) metabolic inflammation. This improved HFD/STZ-induced DbCM model supports clinically relevant research on DbCM progression from early stages to cardiac dysfunction and remodelling as the basis for translational investigation.

Diabetic cardiomyopathy (DbCM) is recognised as a key mediator and determinant of heart failure (HF), particularly HF with preserved ejection fraction (HFpEF). Improved understanding of mechanisms underlying transition from early-stage DbCM to HFpEF will inform innovative evidence-based treatment approaches, which are urgently required to alleviate increasing disease burden. This study aimed to determine whether inhibition of neprilysin activity by Sacubitril/Valsartan in both experimental and clinical DbCM attenuates adverse remodelling through promotion of cardioprotective signalling. Sacubitril/Valsartan effectively reduced plasma neprilysin activity in both diabetic patients with pre-clinical HFpEF from the PARABLE trial (baseline (Val n = 25; Sac/Val n = 35) and 3 months after treatment (Val n = 21/25; Sac/Val n = 33/35)) and DbCM (high-fat diet and streptozotocin) mice. Plasma neprilysin activity at baseline was correlated with worsening cardiac performance at 18 months indicated by left atrial stiffness index in patients (n = 44/60), whilst diastolic dysfunction and pathological remodelling in DbCM mice were improved by Sacubitril/Valsartan, but not Valsartan. snRNA-sequencing showed that progressive experimental DbCM is characterised by chronic low-grade inflammation, reflected by increased infiltration of pro-inflammatory monocytes (Ccr2+ Ly6chi) and reduction in MHC-II macrophages, which was prevented by Sacubitril/Valsartan. Informatics analysis implicated IRF7 as a central mediator of Sacubitril/Valsartan-induced immunomodulation in DbCM, whilst treatment of M2-like pro-repair macrophages with the neprilysin inhibitor, LBQ657 and Valsartan suppressed glucose-induced IRF7 expression and paracrine activation of cardiac fibroblast differentiation in vitro. Immune cells are significantly involved in DbCM progression, impacting myocardial homeostasis and HF progression. Neprilysin inhibition by Sacubitril/Valsartan improved adverse cardiac remodelling in experimental DbCM through direct regulation of inflammation, highlighting immunomodulation as a novel mechanism underlying established its cardioprotective actions.

Background and purpose: Radiation induced cardiotoxicity (RICT) is as an important sequela of radiotherapy to the thorax for patients. In this study, we aim to investigate the dose and fractionation response of RICT. We propose global longitudinal strain (GLS) as an early indicator of RICT and investigate myocardial deformation following irradiation. Methods: RICT was investigated in female C57BL/6J mice in which the base of the heart was irradiated under image-guidance using a small animal radiation research platform (SARRP). Mice were randomly assigned to a treatment group: single-fraction dose of 16 Gy or 20 Gy, 3 consecutive fractions of 8.66 Gy, or sham irradiation; biological effective doses (BED) used were 101.3 Gy, 153.3 Gy and 101.3 Gy respectively. Longitudinal transthoracic echocardiography (TTE) was performed from baseline up to 50 weeks post-irradiation to detect structural and functional effects. Results: Irradiation of the heart base leads to BED-dependent changes in systolic and diastolic function 50 weeks post-irradiation. GLS showed significant decreases in a BED-dependent manner for all irradiated animals, as early as 10 weeks after irradiation. Early changes in GLS indicate late changes in cardiac function. BED-independent increases were observed in the left ventricle (LV) mass and volume and myocardial fibrosis. Conclusions: Functional features of RICT displayed a BED dependence in this study. GLS showed an early change at 10 weeks post-irradiation. Cardiac remodelling was observed as increases in mass and volume of the LV, further supporting our hypothesis that dose to the base of the heart drives the global heart toxicity.

Purpose: Despite technological advances in radiotherapy (RT), cardiotoxicity remains a common complication in patients with lung, oesophageal and breast cancers. Statin therapy has been shown to have pleiotropic properties beyond its lipid-lowering effects. Previous murine models have shown statin therapy can reduce short-term functional effects of whole-heart irradiation. In this study, we assessed the efficacy of atorvastatin in protecting against the late effects of radiation exposure on systolic function, cardiac conduction, and atrial natriuretic peptide (ANP) following a clinically relevant partial-heart radiation exposure. Materials and Methods: Female, 12-week old, C57BL/6j mice received an image-guided 16 Gy X-ray field to the base of the heart using a small animal radiotherapy research platform (SARRP), with or without atorvastatin from 1 week prior to irradiation until the end of the experiment. The animals were followed for 50 weeks with longitudinal transthoracic echocardiography (TTE) and electrocardiography (ECG) every 10 weeks, and plasma ANP every 20 weeks. Results: At 30-50 weeks, mild left ventricular systolic function impairment observed in the RT control group was less apparent in animals receiving atorvastatin. ECG analysis demonstrated prolongation of components of cardiac conduction related to the heart base at 10 and 30 weeks in the RT control group but not in animals treated with atorvastatin. In contrast to systolic function, conduction disturbances resolved at later time-points with radiation alone. ANP reductions were lower in irradiated animals receiving atorvastatin at 30 and 50 weeks. Conclusions: Atorvastatin prevents left ventricular systolic dysfunction, and the perturbation of cardiac conduction following partial heart irradiation. If confirmed in clinical studies, these data would support the use of statin therapy for cardioprotection during thoracic radiotherapy.

AbstractAimsDynamic alterations in cardiac DNA methylation have been implicated in the development of heart failure (HF) with evidence of ischaemic heart disease (IHD); however, there is limited research into cell specific, DNA methylation sensitive genes that are affected by dysregulated DNA methylation patterns. In this study, we aimed to identify DNA methylation sensitive genes in the ischaemic heart and elucidate their role in cardiac fibrosis.MethodsA multi‐omics integrative analysis was carried out on RNA sequencing and methylation sequencing on HF with IHD (n = 9) versus non‐failing (n = 9) left ventricular tissue, which identified Integrin beta‐like 1 (ITGBL1) as a gene of interest. Expression of Itgbl1 was assessed in three animal models of HF; an ischaemia‐reperfusion pig model, a myocardial infarction mouse model and an angiotensin‐II infused mouse model. Single nuclei RNA sequencing was carried out on heart tissue from angiotensin‐II infused mice to establish the expression profile of Itgbl1 across cardiac cell populations. Subsequent in vitro analyses were conducted to elucidate a role for ITGBL1 in human cardiac fibroblasts. DNA pyrosequencing was applied to assess ITGBL1 CpG methylation status in genomic DNA from human cardiac tissue and stimulated cardiac fibroblasts.ResultsITGBL1 was >2‐fold up‐regulated (FDR adj P = 0.03) and >10‐fold hypomethylated (FDR adj P = 0.01) in human HF with IHD left ventricular tissue compared with non‐failing controls. Expression of Itgbl1 was up‐regulated in three isolated animal models of HF and showed conserved correlation between increased Itgbl1 and diastolic dysfunction. Single nuclei RNA sequencing highlighted that Itgbl1 is primarily expressed in cardiac fibroblasts, while functional studies elucidated a role for ITGBL1 in cardiac fibroblast migration, evident in 50% reduced 24 h fibroblast wound closure occurring subsequent to siRNA‐targeted ITGBL1 knockdown. Lastly, evidence provided from DNA pyrosequencing supports the theory that differential expression of ITGBL1 is caused by DNA hypomethylation.ConclusionsITGBL1 is a gene that is mainly expressed in fibroblasts, plays an important role in cardiac fibroblast migration, and whose expression is significantly increased in the failing heart. The mechanism by which increased ITGBL1 occurs is through DNA hypomethylation.

Background Obesity and metabolic syndrome, including Type 2 Diabetes Mellitus (T2DM), are increasingly linked to neurological factors, influenced by lifestyle. Electrical Vestibular Nerve Stimulation (VeNS) has shown potential in improving metabolic factors in T2DM. However, no large-scale Randomized Controlled Trials (RCTs) have been conducted to assess VeNS's impact on T2DM management. Methods This double-blinded, sham-controlled RCT will compare the effects of active VeNS against sham VeNS over a 24-week period, with assessments at baseline, mid-intervention (12 weeks), and conclusion (24 weeks). The aim is to recruit 300 participants, aged 22–70 years (18–70 years in non-US sites) and diagnosed with T2DM for at least 90 days, who will be randomized into active (VeNs device) or control (sham device) groups in a 1:1 ratio. Participants will self-administer active VeNS or sham stimulation aiming for 1 hour daily (7 hours per week) over the 24 weeks. The primary objective is to evaluate changes in HbA1c (%) from baseline to week 24. Secondary objectives include assessing responder rates for HbA1c targets set by ADA and AACE, HbA1c reduction of at least 0.5%, changes in body weight, Body Mass Index (BMI), Waist-to-Hip Ratio (WHR), body composition, lipid profiles, pulse rate, blood pressure, fasting glucose, SMBG readings, medication adjustments, healthcare usage, and quality of life metrics (ADDQoL, EQ-5D-5L, DTSQ). Treatment tolerability will also be evaluated Discussion This study protocol presents an innovative approach to managing Type 2 Diabetes Mellitus (T2DM) by combining Electrical Vestibular Nerve Stimulation (VeNS) with a lifestyle modification program. The implications for clinical practice in T2DM management could be significant. The combination of VeNS with lifestyle modifications may offer a novel, non-pharmacological treatment avenue, potentially improving patient outcomes and reducing reliance on traditional medication regimes. Trial registration: ClinicalTrials.gov: NCT04595968. Registered 22 October 2020, https://clinicaltrials.gov/study/NCT04595968

AbstractIntroductionSeveral landmark randomized‐controlled trials (RCTs) have demonstrated the efficacy of sodium‐glucose co‐transport 2 (SGLT2) inhibitors in reducing all‐cause mortality, cardiovascular (CV) mortality and heart failure (HF) hospitalizations. Much interest surrounds their mechanism of action and whether they have direct effects on reverse cardiac remodelling. Therefore, we conducted a meta‐analysis of placebo controlled RCTs evaluating the impact of SGLT2 inhibition on imaging derived markers of reverse cardiac remodelling in patients with HF.MethodsWe performed a systematic review and meta‐analysis in accordance with the Preferred Reporting Items for Systematic Review and Meta‐Analysis (PRISMA) Statement and Cochrane Collaboration. Data interrogation of each major database including PubMed, EMBASE, MEDLINE and Cochrane Library was performed.RCTs evaluating HF patients >18 years comparing SGLT2 inhibitor versus placebo‐control were included. Outcome measures included left ventricular end‐diastolic volume and volume index (LVEDV/LVEDVi), left ventricular end‐systolic volume and volume index (LVSDV/LVSDVi), left ventricular ejection fraction (LVEF), left ventricular mass index (LVMi), left atrial volume index (LAVi) and left ventricular global longitudinal strain (LV GLS). Studies with an HF with preserved ejection fraction population were excluded from analysis of parameters, which would be significantly affected by baseline LVEF, such as volumes and LVEF. The mean difference and standard error were extracted from each study and a random effects model used pool the mean difference and standard error across studies. A pre‐specified sub‐group analysis was performed to stratify results according to imaging modality used (cardiac magnetic resonance imaging and echocardiography). This study is registered on PROSPERO: CRD42023482722.ResultsSeven randomized, placebo‐controlled trials in patients with HF comprising a total population of 657 patients were included. Overall LVEF of included studies ranged from 29 ± 8.0% to 55.5 ± 4.2%. In studies included in analysis of HFrEF parameters, baseline LVEF ranged from 29 ± 8% to 45.5 ± 12%. Pooled data demonstrated SGLT2 inhibition, compared with placebo control, resulted in significant improvements in mean difference of LVEDV [−11.62 ml (95% confidence interval, CI −17.90 to −5.25; z = 3.67, P = 0.0004)], LVEDVi [−6.08 ml (95% CI −9.96 to −2.20; z = 3.07; P = 0.002)], LVESV [−12.47 ml (95% CI −19.12 to −5.82; z = 3.68; P = 0.0002)], LVESVi [−6.02 ml (95% CI −10.34 to −1.70; z = 2.73; P = 0.006)], LVM [−9.77 g (95% CI −17.65 to −1.89; z = 2.43; P = 0.02)], LVMi (−3.52 g [95% CI −7.04 to 0.01; z = 1.96; P = 0.05)] and LVEF [+2.54 mL (95% CI 1.10 to 3.98; z = 3.62; P = 0.0005)]. No significant difference in GLS (n = 327) [+0.42% (95%CI −0.19 to 1.02; P = 0.18)] or LAVi [−3.25 ml (95% CI −8.20 to 1.69; z = 1.29; P = 0.20)] was noted.ConclusionThis meta‐analysis provides additional data and insight into the effects of SGLT2 inhibition on reverse cardiac remodelling in patients with HF. Compared with placebo control, we found that treatment with a SGLT2 inhibitor produced significant improvements in several markers of reverse cardiac remodelling.