Ischemic heart disease remains the most significant cause of morbidity and mortality worldwide. Although conventional therapies such as β-blockers, angiotensin inhibitors, statins, and percutaneous coronary intervention have reduced mortality in industrialized nations, progress has plateaued, and global ischemic burden continues to rise. Recent advances in molecular biology have enabled mechanistic interrogation of canonical cardioprotective signaling pathways at a resolution not previously achievable. Parallel advances in exercise biology and mesenchymal stem cell-derived exosomes (MSC-EXO) research suggest an opportunity for synergistic cardioprotection. Exercise operates as a complex molecular stimulus that can activate redox-sensitive kinases, autophagy regulators, and metabolic stimulus that extends beyond its classic descriptive cell-autonomous kinase activation and metabolic remodeling within the cardiomyocyte itself. Exercise is now recognized as a multi-organ secretome-generating stimulus that mobilizes circulating extracellular vesicles, exerkines, and microRNA-loaded exosomes as systemic paracrine mediators capable of signaling across tissue boundaries. This reframing establishes exercise biology and MSC-EXO research as fields operating through a shared biological currency called vesicle-mediated intercellular communication. State-of-the-art investigations have sought to decode this “exercise secretome” and develop tools to modulate these chemical cascades. Multiple experimental studies report that MSC-EXO function as biologically active paracrine vectors that deliver regulatory microRNAs and proteins to recipient cells and promote angiogenesis, suppress apoptosis, and support mitochondrial function. This mechanistic review assesses the effectiveness of interventions on canonical pathways such as ERK and AKT/mTOR on isoproterenol (ISO)-induced myocardial ischemia models to the heart based on recent animal and human studies. Supporting literature on stem cell biology, exosome delivery strategies, and translational barriers is discussed to construct an integrated mechanistic framework that demonstrates how this therapy reinforces and sustains reparative signaling in an ISO-induced ischemic environment. Exercise biology and MSC-EXO research represent a synergistic therapeutic strategy with the potential to advance regenerative cardioprotection in ischemic cardiomyopathy, wherein, exercise-induced kinase sensitization and metabolic preconditioning establish a permissive intracellular environment, and targeted exosome delivery amplifies the same ERK, PI3K-Akt, and mTOR survival networks to sustain reparative signaling beyond what either intervention achieves independently.

We read with great interest the meta-analysis by Parsi et al showing the strong therapeutic effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in heart failure. Because the expression of sodium-glucose cotransporter-2 in cardiomyocytes is minimal, the exact pathways for their direct cardioprotective actions are not fully defined. In this correspondence, we summarize emerging evidence and advance an integrated view that places Ca2+/calmodulin-dependent protein kinase II (CaMKII) as a central molecular target. CaMKII is a key factor in heart failure progression. By phosphorylating a host of key substrates such as ryanodine receptor 2, L-type calcium channels and voltage-gated sodium channel voltage-gated sodium channel type V 1.5, it facilitates ionic imbalance, predisposition to arrhythmia, and structural remodeling. We highlight the way SGLT2i may exercise their benefits through coordinated suppression of CaMKII activity via enhanced ionic homeostasis, decreased oxidative injury and suppressed inflammatory signaling. This mechanistic framework offers a unified explanation for the reported clinical and experimental improvements associated with SGLT2i, such as improved electrical stability, improved systolic and diastolic function, and reduction of pathological cardiac remodeling.

BACKGROUND Wire-based pressure pullback gradient (PPG) is the reference method for differentiating focal from diffuse coronary artery disease (CAD). However, it requires invasive instrumentation and hyperaemia. The quantitative flow ratio (QFR)-derived PPG [QFR virtual pullback (QVP) index] is a non-invasive alternative. AIM To evaluate the correlation between QVP index and PPG, and to explore the diagnostic performance of QVP index for identifying focal CAD. METHODS We retrospectively studied 74 patients (86 vessels) who underwent coronary angiography, fractional flow reserve (FFR), wire-based PPG, angio-based QFR and QVP index between December 2021 and October 2023. The primary analysis focused on FFR-significant lesions (FFR ≤ 0.75, n = 31), as these are clinically relevant for guiding percutaneous coronary intervention. QVP index was calculated from the maximal QFR drop over 20 mm and the length of the epicardial segment with the greatest reduction. Focal disease was defined by PPG > 0.73. RESULTS QFR was strongly correlated with FFR (r = 0.84, P < 0.001). In FFR significant vessels (FFR ≤ 0.75, n = 31), QVP index showed a moderate correlation with PPG (r = 0.45, P = 0.01). QVP index demonstrated excellent intra-observer and inter-observer variability with intraclass correlation coefficients of 0.918 (P < 0.001) and 0.932 (P < 0.001), respectively. QVP index predicted focal disease (defined as PPG > 0.73) with area under the curve of 0.73 (P = 0.02). A retrospectively derived threshold of QVP index > 0.53 yielded 90% sensitivity and 53% specificity (P = 0.04), though this cut-off was derived from the same dataset and should be regarded as hypothesis-generating. CONCLUSION QVP index correlates with PPG in FFR-significant lesions and may help to identify focal CAD patterns. However, these findings are hypothesis-generating and derived from a small, retrospective, single-centre cohort without external validation. Prospective multicentre studies are needed to validate cut-offs and determine whether QVP index provides incremental clinical value beyond existing physiological and imaging tools.

BACKGROUND Obesity-related heart failure in patients is often associated with a high symptom burden. However, no treatments have been proven to specifically target obesity-related heart failure with preserved ejection fraction (HFpEF). AIM To evaluate the efficacy of semaglutide in patients with obesity and HFpEF. METHODS Per the PRISMA guidelines, studies reporting clinical outcomes of semaglutide in patients with obesity and HFpEF were included. The outcomes included percentage weight change and adjudicated heart failure events. Both random and common effects models were used for the data analysis. The random intercept logistic regression model was used to compute the proportions, and the Peto method was used to compute the odds ratios (OR). A P ≤ 0.05 was considered significant. RESULTS In total, three studies with 1463 patients with obesity and HFpEF were included in the study. The mean age of the patients was 68.8 ± 3.47 years. 50.7% of the patients were females. Patients who received semaglutide had statistically higher odds of achieving 10% (OR = 6.35; 95%CI: 1.54-26.21; P < 0.00001) and 15% (OR = 9.44; 95%CI: 2.91-30.60; P < 0.0001) weight reductions compared to those who received placebo. Additionally, patients who received semaglutide had lower odds of adjudicated heart failure event (OR = 0.29; 95%CI: 0.14-0.58; P = 0.0005) when compared to patients on placebo. CONCLUSION Our study demonstrates that semaglutide is significantly effective in reducing weight and potentially lowering the risk of heart failure events. This suggests that semaglutide could be a promising therapeutic option for managing obesity-related HFpEF.

BACKGROUNDThe use of apixaban in chronic hemodialysis (HD) patients for non-valvular atrial fibrillation (NVAF) is still controversial regarding benefit of stroke protection vs risk of bleeding. Rotational thromboelastometry (ROTEM) is a point of care method that evaluates clot formation in whole blood and has been used as an evaluation tool for bleeding risk assessment in non-HD apixaban users.AIMTo determine whether bleeding risk can be predicted using ROTEM activated with tissue factor (EXTEM) in HD patients receiving apixaban for NVAF.METHODSNineteen HD patients with NVAF treated with apixaban for at least 8 days were enrolled. Four dosing regimens were recorded as prescribed by their physician, from 2.5 mg once daily on a non-dialysis day to 5 mg twice daily. Standard coagulation tests, along with ROTEM and apixaban drug levels (using liquid anti-Xa assay) were performed once on a non-dialysis day before and two hours after apixaban morning pill administration. Patients were subsequently monitored for thrombotic/bleeding events and all-cause mortality.RESULTSOver a median follow-up period of 36 months, six patients experienced a bleeding event (group A) and 13 remained free of bleeding (group B). Six deaths were recorded: Three due to major bleeding, one from thrombotic stroke, and two unrelated to coagulopathy. EXTEM clotting time (CT)-post was the only parameter that significantly differed between group A and group B (P = 0.013). Each 1-second increase in CT-post was linked to an 8% higher likelihood of a bleeding event (odds ratio = 1.08, 95% confidence interval: 1.0-1.17; P = 0.048). A significant progressive increase was observed with the drug’s trough and peak levels (P < 0.05) across the four dosing regimens but no significant relationship was found between CT and apixaban dose groups.CONCLUSIONEarly detection of bleeding risk in HD patients with NVAF on Apixaban maybe be effectively achieved through frequent monitoring using ROTEM EXTEM post CT, thereby helping to reduce associated morbidity.

BACKGROUNDLeft ventricular noncompaction (LVNC) is a genetic cardiomyopathy. It is characterized by intensely developed trabeculae in the ventricles with deep intertrabecular lacunae. LVNC manifests as arrhythmias and heart failure with a predisposition for thrombus formation.AIMTo study predictors of arrhythmic, thromboembolic events and adverse outcomes (death/transplantation) in adult patients with LVNC.METHODSAdult patients with LVNC were included (n = 125; mean follow-up: 14 months). Electrocardiography, echocardiography, and 24-hour electrocardiography monitoring were performed. Other procedures were conducted for some patients including: Coronary angiography; cardiac magnetic resonance imaging; cardiac computed tomography; genetic testing; myocardial pathological examination; and anti-cardiac antibody level estimation. Primary endpoints were death, heart transplantation, combined endpoint (death + transplantation), and sudden cardiac death. Secondary endpoints were intracardiac thrombosis, embolic events, myocardial infarction, sustained ventricular tachycardia (VT), and implantable cardioverter-defibrillator intervention.RESULTSLVNC manifestations included non-sustained VT, thrombosis/embolism, sustained VT, and sudden cardiac death. Non-sustained VT was associated with the New York Heart Association (NYHA) chronic heart failure (CHF) class, poor R-wave progression, superimposed myocarditis, and higher mortality. Thrombosis/embolism was associated with NYHA CHF class ≥ 3, right ventricular end-diastolic diameter ≥ 3 cm, right atrium volume ≥ 67 mL, left ventricle end-diastolic diameter ≥ 6.3 cm, and velocity time integral ≤ 11.2 cm. Sustained VT was associated with premature ventricular contractions (PVCs), low QRS voltage, and atrioventricular block. PVCs > 500/day were predictive of defibrillator intervention. Fatal outcomes were associated with E wave/A wave ratio > 1.9, left ventricle ejection fraction < 35%, NYHA CHF class ≥ 3, VT, and myocarditis.CONCLUSIONFrequent PVCs, non-sustained VT, low QRS voltage, and signs of systolic dysfunction on echocardiogram are predictors of life-threatening events in patients with LVNC.

Physical exercise is a cornerstone of cardiac rehabilitation, with resistance training increasingly recognized as essential due to the "muscular hypothesis" in cardiac-related frailty. However, many patients are unable to achieve the required training intensities to gain the associated benefits, highlighting the need for alternative approaches. Blood flow restriction (BFR) training has recently emerged as a promising strategy for this population. This qualitative mini-review explores the acute effects and long-term adaptations of BFR training in patients undergoing cardiac rehabilitation, aiming to provide insights into its potential as a viable and effective intervention in health-related outcomes.

Percutaneous coronary intervention (PCI) for coronary and peripheral stenoses has advanced rapidly over the past three decades, driven by a series of innovative techniques since the introduction of the first balloon angioplasty. Significant progress in stent technology, beginning with bare-metal stents and followed by drug-eluting stents, has expanded the scope for successful revascularisation in complex lesions. However, challenges such as late stent thrombosis and in-stent restenosis (ISR) persist. Thus, further improvement in PCI techniques and devices is essential to achieve better patient outcomes. In recent years, drug-coated balloons (DCBs) have emerged as a promising alternative designed to overcome the limitations associated with drug-eluting stents, including the risks of late stent thrombosis, ISR, and the need for prolonged dual antiplatelet therapy. Several DCBs have been evaluated for both coronary and peripheral lesions, showing encouraging results in preclinical and clinical studies. DCBs have demonstrated efficacy in the treatment of ISR and have shown potential in other clinical scenarios, such as small-vessel disease and diffuse lesions. In this review, we present the underlying technology, mechanisms of action, key preclinical findings, emerging clinical indications, recent trial outcomes, and future perspectives of DCBs as they continue to define their role in PCI.

Kataveni et al’s meta-analysis offers an important contemporary synthesis of randomized evidence comparing fractional flow reserve-guided percutaneous coronary intervention and coronary artery bypass grafting (CABG) in multivessel coronary artery disease (CAD). The pooled analysis found no significant difference in all-cause mortality or stroke, yet CABG was superior in reducing myocardial infarction, major adverse cardiac events, and repeat revascularization. These results confirm CABG’s durability even in the era of physiological lesion assessment and second-generation drug-eluting stents. From a traditional Chinese medicine (TCM) perspective, multivessel CAD corresponds to syndromes such as “heart vessel obstruction” and “Qi and blood stagnation”, in which local blockage is compounded by systemic imbalance. While revascularization addresses the structural impediment to blood flow, TCM approaches, including herbal medicine, acupuncture, and lifestyle therapy, aim to improve microcirculation, reduce inflammation, and support recovery, potentially mitigating recurrent ischemic events. This commentary argues that future research should integrate optimal revascularization strategies with rigorously evaluated TCM interventions to address both the anatomical and systemic dimensions of CAD and improve long-term patient outcomes.

Voltage substrate mapping is a promising tool for the treatment of atrial fibrillation (AF). It is helpful to detect atrial fibrosis, which includes areas with low bipolar voltage, heterogeneous conduction properties, and shortened effective refractory period. The voltage amplitude is typically defined as the maximal peak-to-peak level within a specified time window of interest. Contemporary electroanatomic mapping platforms now enable many thousands of data points to be mapped, so that a geometric model of the atrial endocardium is constructable over a short period of time. This mapping procedure is often done with bipolar electrodes to cancel the far-field signal. The recording site coordinates are projected onto an atrial shell, with interpolation of the voltage data across the shell surface. The amplitude of the recorded bipolar electrogram depicted on the three-dimensional shell provides detailed information for substrate mapping. Wherever there are areas of low peak-to-peak voltage, it is thought to mark the presence of abnormal tissue properties and conduction. However, uncontrolled variables and environmental factors affecting voltage level include the oncoming electrical activation wavefront direction, the catheter incidence angle, the force applied to the catheter, and the region-variable shape and structure of atrial tissue. Techniques and settings to acquire atrial voltage data for AF analysis have not been standardized. Methods to characterize atrial electrograms are also presently limited. These factors affect quality and reproducibility of the mapping results. Herein, voltage substrate mapping and its variables pertaining to AF and radiofrequency ablation are described and discussed, with suggestions for future work efforts.