Medicine and Pharmacology

Abstract: Background: Familial hypercholesterolaemia (FH) is a prevalent monogenic disorder where genetic diagnosis enables risk re-stratification and management for entire families, serving as a paradigm for personalized medicine. Data on FH in South-East Asia are limited, and family cascade screening has not previously been documented in Vietnam. Objectives: To identify the prevalence of pathogenic variants in FH-associated genes and evaluate the feasibility of cascade screening in a Vietnamese cohort. Materials and methods: We conducted a prospective single-centre cohort study involving 500 consecutive patients with premature coronary artery disease (CAD) at a Vietnamese tertiary centre between March 2023 and September 2025. Patients underwent next-generation sequencing of LDLR, APOB, and PCSK9 genes, with variants classified according to American College of Medical Genetics and Genomics criteria. First-degree relatives of patients who tested positive for a variant were offered genetic counselling and cascade sequencing. Results: A pathogenic or likely pathogenic variant was identified in 18 of 500 patients (3.6%; 95% CI 2.1–5.4%), primarily within the LDLR gene. Variant carriers were younger, exhibited significantly higher LDL-cholesterol levels, and presented with more extensive coronary disease compared to non-carriers (all p < 0.001). Cascade screening completed in 13 families identified the family-specific variant in 46 of 105 first-degree relatives (43.8%; 95% CI 34.7–53.4%), many of whom were young and asymptomatic. Conclusions: Precise genetic diagnosis in a small number of index patients facilitated the identification of a large group of high-risk relatives who would otherwise have remained undiagnosed. This approach underscores the potential of personalized medicine in managing inherited cardiovascular disorders in Vietnam.

Abstract: Doxorubicin (DOX) is a potent chemotherapeutic agent widely used in the clinical treatment of various malignancies. However, its therapeutic application is significantly constrained by dose-dependent cardiotoxicity, with accelerated cardiac aging emerging as a particularly challenging issue. This presents a critical limitation to its clinical use, emphasizing the urgent need for targeted cardioprotective strategies to mitigate DOX-induced cardiotoxicity. Cellular senescence, marked by permanent cell cycle arrest, plays a key role in the development of DOX-induced cardiac aging. DOX has been shown to induce cellular stress and senescence in multiple cardiac cell types, leading to impaired cardiac function. Understanding the molecular pathways and mechanisms through which DOX triggers cardiac aging is essential for the development of effective interventions to address its cardiotoxic side effects. In this review, we discuss the molecular mechanisms underlying DOX-induced senescence in different cardiac cell types and summarize the current progress in anti-aging therapeutic strategies aimed at alleviating DOX-related cardiac complications.

Abstract: Background:The impressive progress of research in the cardiovascular sciences in the last several decades has contributed to the development of highly advanced therapeutic tools for the management of chronic heart failure (CHF). In spite of whole array of pharmacologic and invasive treatment methods, the mortality rate in CHF is still high. The growing evidence indicates the significant influence of central nervous system (CNS), cognitive functions and thermoregulation on aerobic capacity, symptoms and prognostication in CHF. The goal of our review is to present the recent advancements in the experimental and clinical research on the brain-heart interactions in CHF. Methods: A narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar. Results: There is a close link between CNS functions ( cognitive functions, thermoregulation), symptoms and prognostications in CHF, which may contribute to the development of brand-new therapeutic tools and schemes in the nearest future. Conclusions: Brain processing has enormous impact on the course of CHF. The in-depth understanding of CNS mechanisms controlling physical fitness in CHF may contribute to the implementation of brand-new treatment methods and creation of interdisciplinary medical teams targeting various parts and functions of CNS involved in the pathophysiology of the disease.

Abstract: Background: Minimally invasive cardiac valve surgery (MIVS) is established as a safe alternative to conventional sternotomy, yet the technical complexity of annular suturing remains a significant barrier to procedural efficiency. Automated annular suturing devices (RAM®) have been introduced to mechanize and standardize suture placement specifically during valve replacements. This study evaluates the clinical feasibility, safety, and device usability of automated suturing during its institutional introductory phase. Methods: We retrospectively reviewed 43 consecutive patients undergoing MIVS supported by the RAM® system between 2021 and 2025. The cohort was stratified into RAM-supported Mitral Valve Replacements (RAM-MVR, n=26) and Aortic Valve Replacements (RAM-AVR, n=17). Technical parameters, device configurations, and perioperative outcomes were descriptively analyzed and contextualized within our mature institutional percutaneous MIVS benchmark platform (n=182). Results: Automated annular suturing achieved 100% technical feasibility with zero mechanical malfunctions or suture-line failures. In the RAM-MVR group, the median aortic cross-clamp and cardiopulmonary bypass (CPB) times were 73.0 minutes (IQR 64.0–91.0) and 114.5 minutes (IQR 94.8–129.5), respectively. RAM-AVR cases demonstrated a median cross-clamp time of 58.0 minutes (IQR 50.0–63.0). Conclusion: Automated annular suturing represents a robust and predictable technology that integrates seamlessly into a mature percutaneous MIVS environment. The system provides reliable standardization of valve anchoring across varying positions, yielding stable procedural times and excellent hemodynamic performance without introducing device-specific morbidity.

Abstract: Background/Objectives: New-onset atrial fibrillation is a common complication of acute myocardial infarction and is associated with increased mortality, heart failure, and recurrent cardiovascular events. Prediction models for the occurrence of atrial fibrillation may facilitate early risk stratification, improve patient monitoring, and support personalized therapeutic decision-making in clinical practice. Methods: A prospective study included 150 patients with acute myocardial infarction admitted within 24 hours of symptom onset. Clinical, laboratory, electrocardiographic, and echocardiographic data were collected, and a machine learning model was developed to predict new-onset atrial fibrillation. Model performance was evaluated using ROC-AUC, while SHAP analysis was applied to identify and quantify the contribution of individual predictors. Results: The machine learning model demonstrated excellent predictive performance, achieving an accuracy of 97.0%, ROC-AUC of 0.991, and precision–recall AUC of 0.991 in the independent test set. SHapley Additive Explanations (SHAP) and permutation importance analyses identified the E/e′ ratio, left ventricular mass index, left ventricular ejection fraction, left atrial volume index, oxidative stress markers (malondialdehyde and superoxide dismutase), NT-proBNP, and complete revascularization as the most influential predictors of new-onset atrial fibrillation after acute myocardial infarction. Conclusions: Machine learning combined with SHAP-based explainability showed high potential for predicting new-onset atrial fibrillation after acute myocardial infarction. This approach may improve individualized risk assessment and clinical decision-making, pending validation in larger multicenter cohorts.

Abstract: Atherosclerosis is a multiphase disease, yet contemporary cardiovascular risk stratification relies predominantly on calculators that estimate event probability within a limited pathophysiological window. Framingham, SCORE2, GLOBORISK and PREVENT capture lipid burden, metabolic parameters, and renal function but do not organize the full chronological sequence of atherogenesis, do not assign measurable biomarkers to each stage, and do not integrate vascular aging — a biological process that modulates every phase of the cascade. We propose CASCADE (Chronological Atherosclerosis Staging: Connecting Aging, Disease, and Environment), a conceptual framework that applies disease staging to atherosclerosis by organizing it into seven pathophysiological phases with assigned biomarkers and incorporating vascular aging as a transversal dimension. The framework is developed through narrative synthesis of mechanistic, epidemiological, and clinical trial evidence across cardiovascular, metabolic, and aging research, integrating current international guidelines, landmark intervention trials, and emerging evidence on biological aging, endothelial biology, and environmental determinants of cardiovascular risk. CASCADE proposes seven phases preceded by an upstream environmental and behavioral layer (F0) that constitutes the substrate of cumulative exposure rather than a biological phase of the individual: adaptive metabolic response driven by insulin resistance (F1), vascular response and arterial stiffening (F2), endothelial injury and barrier dysfunction (F3), atherogenic lipoprotein retention indexed by apolipoprotein B (F4), plaque vulnerability and biological heterogeneity in which lipoprotein(a) becomes informative (F5), subclinical atherosclerosis (F6), and clinical cardiovascular disease (F7). Each phase is mapped to a proposed dominant biomarker and a reversibility zone (reversible, transition, or irreversible). Vascular aging — characterized by arterial stiffness, cellular senescence, epigenetic drift, and clonal hematopoiesis — traverses all phases as a modifiable dimension, with specific biological clocks applicable at each stage. The framework complements existing risk calculators by providing chronological context for the upstream phases (F0–F3), where conventional tools offer limited guidance and the potential for disease modification is greatest. CASCADE is proposed as a hypothesis-generating organizational framework, not a validated scoring system. It invites prospective evaluation of whether individuals traverse identifiable, modifiable phases of atherosclerotic disease — and whether integrating vascular aging measurement at each stage improves risk assessment and therapeutic decision-making.

Abstract: Review objectives: This scoping review aims to map the extent and nature of digital, biomarker, and multi-omics evidence on stress and cardiometabolic health trajectories among women in Sub-Saharan Africa, with particular attention to hypertension, glycemic and diabetes-related outcomes, adiposity and obesity, dyslipidemia, metabolic syndrome, pregnancy-related cardiometabolic conditions, and cardiovascular sequelae. In addition, the review will consider patterns of vulnerability and potential indicators of cardiometabolic resilience, defined broadly as the capacity to maintain or regain health despite exposure to stressors, where these are explicitly examined or can be inferred from study findings. Cardiometabolic markers are being captured alongside real-time physiological and behavioral data through digital tools and wearable technologies, providing opportunities for early detection, continuous monitoring, and risk stratification of cardiometabolic disorders (CMDs). The review will further assess the degree of integration across these domains, while identifying key research gaps and emerging methodological trends. Methods: The review will follow the Joanna Briggs Institute methodology for scoping reviews and will be reported in accordance with the PRISMA extension for Scoping Reviews. A comprehensive search will be conducted across electronic databases, including MEDLINE (PubMed), Embase, Scopus, Web of Science Core Collection, CINAHL, PsycINFO, Global Index Medicus, the Cochrane Library, and IEEE Xplore, as well as grey literature sources such as Google Scholar, World Health Organization Institutional Repository for Information Sharing, and the World Bank Open Knowledge Repository using pre-specified Boolean operators and keywords. Studies published in English from January 2015 to the date involving women aged 18 years and above in Sub-Saharan Africa that examine stress in relation to cardiometabolic outcomes using digital, biomarker, and/or multi-omics approaches will be included. Findings will be synthesized descriptively, with evidence stratified by cardiometabolic domain where feasible, including blood pressure and hypertension, glycemic and diabetes-related outcomes, adiposity and obesity, lipid-related outcomes, pregnancy-related cardiometabolic conditions, and broader cardiovascular outcomes.

Abstract: In contemporary cardiac surgery, preservation of cognitive function has become the principal criterion of success; however, postoperative cognitive dysfunction (POCD), documented in 30–80% of patients, negates the benefits of the operation. Traditional risk factors explain only part of the genesis of this deficit. A key link is clonal haematopoiesis of indeterminate potential (CHIP): somatic mutations in haematopoietic stem cells lead to expansion of mutant immunocytes with hyperproduction of IL-1β and IL-6. Under cardiopulmonary bypass conditions, CHIP potentiates the systemic cytokine response, initiating neuroinflammation — from blood–brain barrier disruption to microglial activation and neuronal death. The prevalence of CHIP reaches 10–20% in the general population over 70 years of age and 44% among cardiac surgery patients; an allelic burden ≥2% is associated with a 2- to 3-fold increased risk of stroke and persistent POCD. This review proposes a new paradigm, viewing CHIP-associated inflammation as a systemic driver of neurological risk. Molecular mechanisms, clinical epidemiology and prospects for targeted therapy (IL-1β, IL-6 and JAK2 inhibitors) and cellular correction of the bone marrow niche are discussed. The strategic conclusion is that controlling CHIP opens a new front in the battle to preserve patients' intellect after cardiac surgical interventions.

Abstract: Background/Objectives: Oxidative stress is a major contributor to the pathogenesis of cardiovascular diseases including hypertension, ischemic cardiomyopathy, heart failure. MicroRNAs (miRNAs) have been extensively investigated in various contexts, and some of them have been identified to play a role in cardiovascular disease. This review focuses on miR-103 and miR-155, two miRNAs implicated in the modulation of oxidative stress and cardiovascular remodeling. Methods: The following queries were used in PubMed since inception until May 2026: (("miR-155" OR "microRNA-155" OR miR155) AND ("oxidative stress" OR ROS OR "reactive oxygen species") AND ("cardiovascular disease" OR cardiovascular OR cardiac OR heart OR vascular)); (("miR-103" OR "microRNA-103" OR miR103) AND ("oxidative stress" OR ROS OR "reactive oxygen species") AND ("cardiovascular disease" OR cardiovascular OR cardiac OR heart OR vascular)). Results: A total of 7 citations for miR-103 and 79 citations for miR-155 were identified. Reviews and papers about diseases other than those on cardiac/vascular involvement were excluded. miR-155 emerges as a potential regulator of inflammatory-redox signaling, whereas miR-103 appears more closely linked to cell fate and metabolic pathways. In both cases, available evidence supports a context-dependent role that challenges simplistic classification as pro- or anti-oxidant miRNAs. Conclusions: Available evidence suggests that both miR-103 and miR-155 are important regulators of oxidative stress-related pathways in cardiovascular disease. Nevertheless, the context-dependent effects observed across different cardiovascular disorders raise concerns regarding the safety of systemic miRNA modulation-based therapeutical strategies. Future studies should clarify the determinants of this context-dependent behavior and identify the specific conditions under which these miRNAs exert protective or harmful effects, which might pave the way for the development of miRNA-based therapeutic strategies targeting oxidative stress and cardiovascular remodeling.

Abstract: Cardiotoxic complications are influenced by demographic and genetic factors that contribute to myocardial structural and electrophysiological abnormalities. This study aimed to assess the impact of age, sex, and genetic polymorphisms on the development of cardiotoxic complications. A total of 89 patients aged 18–78 years underwent electrocardiography, echocardiography, and molecular genetic testing for polymorphisms in GPX4, SOD2, COL1A1, CAT, EDN1, and COMT. Left ventricular hypertrophy (LVH) was detected in 58.4% of patients, reduced left ventricular ejection fraction (LVEF &lt;50%) in 23.6%, arrhythmias in 46.1%, and ischemic changes in 28.1%. Increasing age was associated with LVH, reduced LVEF, and ischemic myocardial changes (p&lt;0.05). Sex-specific differences showed a higher prevalence of rhythm disturbances in women and ischemic changes in men. Individual genetic polymorphisms were associated with specific cardiac phenotypes, while combined genetic risk (≥2 unfavourable alleles) was significantly associated with higher rates of LVH, arrhythmias, and impaired myocardial contractility. The findings support a polygenic model of cardiotoxicity and highlight the relevance of integrating demographic and genetic factors to enable personalised cardiovascular risk stratification and early prevention of cardiac complications.

Abstract:

Background: Cardiopulmonary exercise testing (CPET) is widely used for prognostic assessment and risk stratification in patients with heart failure (HF). However, its feasibility and clinical utility in patients with advanced HF requiring intravenous inotropic support remain unclear. Methods: This observational study included hospitalized patients with HF who received intravenous inotropic therapy and underwent CPET during index hospitalization. The primary outcome was a composite of HF rehospitalization or cardiovascular death. Results: A total of 528 patients hospitalized for HF required intravenous inotropic therapy; 50 patients were included. CPET was safely completed in all patients without exercise-related adverse events. The median peak VO₂ was 12.5 mL/kg/min, and the median VE/VCO₂ slope was 38.3. During a median follow-up of 762 days, 12 primary events occurred. In univariable analysis, the VE/VCO₂ slope, O₂ pulse, and maximal workload were significantly associated with the primary outcome, whereas peak VO₂ was not. A VE/VCO₂ slope >38.2 was associated with a significantly higher 3-year event rate compared with a slope ≤38.2 (40% vs. 8%, p = 0.021). Conclusions: CPET is feasible and safe in selected patients with advanced HF requiring inotropic support, and the VE/VCO₂ slope provides important prognostic information even in this high-risk population.

Abstract: Large intracoronary thrombus burden during percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) remains technically challenging when conventional manual aspiration is ineffective or dedicated thrombectomy systems are unavailable, unsuitable, or undeliverable. Routine aspiration thrombectomy is not guide-line-supported, but selective bail-out thrombus-removal strategies remain relevant in refractory thrombus-rich PCI. This contemporary review of the literature on this unmet need, supplemented by six "real-world" single-center clinical examples, describes off-label guide-extension catheter (GEC)-assisted thrombus aspiration and places it within the contemporary thrombectomy landscape, including manual aspiration catheters, sustained mechanical aspiration platforms, and stent-retriever-based systems. The heterogeneous examples, predominantly involving the right coronary artery, illustrate procedural mechanics, patient selection, technical pitfalls, and risk mitigation, however, they do not provide efficacy or safety evidence. GEC-assisted aspiration may be useful when bulky proximal thrombus cannot be captured by smaller catheters or when a GEC can be po-sitioned coaxially near the thrombus face under uninterrupted negative pressure. Therefore, the technique remains operator-dependent, off-label, and anatomically con-strained. It should be regarded as a contingency maneuver rather than an alternative to purpose-built systems with more formal device-specific evaluation. Prospective registries and comparative studies are required before efficacy, safety, or relative value of this approach can be established.

Abstract: Artificial intelligence (AI) and machine learning (ML) are increasingly being evaluated as decision-support tools for forecasting postoperative complications after cardiothoracic surgery. This narrative review synthesises peer-reviewed clinical, biomedical informatics, and digital-health literature across acute kidney injury (AKI), postoperative atrial fibrillation (POAF), pulmonary complications, neurological outcomes, mortality, wound monitoring, wearable surveillance, and post-discharge monitoring. Rather than treating reported AUC values as interchangeable evidence of algorithmic superiority, this review emphasises that model performance depends on at least three interacting factors: algorithmic architecture, data richness, and validation strategy. Conventional tools such as EuroSCORE II and Society of Thoracic Surgeons (STS) models remain clinically useful because they are familiar, transparent, and externally established; however, many rely on static perioperative snapshots and are less suited to continuously updated intraoperative and postoperative data streams. Contemporary ML models, including gradient-boosting approaches, support-vector methods, convolutional neural networks, and wearable-based algorithms, may improve discrimination in selected settings, particularly when dynamic laboratory trajectories, physiological time-series, imaging data, or remote-monitoring signals are available. However, current evidence remains limited by single-centre development, heterogeneous endpoints, inconsistent calibration reporting, limited decision-curve analysis, low positive predictive values in surveillance applications, and sparse prospective implementation. Future work should prioritise multicentre external validation, calibration, clinical utility analysis, standards-based electronic medical record interoperability, and implementation pathways that preserve clinician oversight.

Abstract: Background and Objectives: Oral low-dose minoxidil has achieved widespread clinical adoption for androgenetic alopecia (AGA), yet its subclinical cardiovascular structural effects at dermatological doses remain uncharacterized. We aimed to evaluate the effects of dutasteride and three different doses of oral minoxidil (1, 2.5, and 5 mg/day) on carotid intima-media thickness (CIMT) and CIMT-derived vascular age in healthy young men. Methods: A prospective, randomized, four-group pharmacological study enrolling 44 healthy young male subjects assigned to dutasteride 0.5 mg/day (n = 12), oral minoxidil 1 mg/day (n = 8), 2.5 mg/day (n = 12), or 5 mg/day (n = 12). High-resolution carotid ultrasonography was performed at baseline and at the end of follow-up. Primary outcomes included bilateral CIMT, maximum CIMT, and CIMT-derived vascular age. Within-group changes were assessed with the Wilcoxon signed-rank test; between-group comparisons used the Kruskal-Wallis test with post hoc Mann-Whitney U testing. Results: Thirty-one participants completed the study. Groups were well balanced at baseline (all p &gt; 0.05). The minoxidil 5 mg group exhibited statistically significant within-group increases in right CIMT (471 ± 78 vs. 555 ± 87 µm; p &lt; 0.05), maximum CIMT (509 ± 79 vs. 575 ± 76 µm; p &lt; 0.05), and CIMT-derived vascular age (35.9 ± 15.2 vs. 48.2 ± 14.9 years; p &lt; 0.05). The right CIMT delta of the minoxidil 5 mg group (Δ = +79 ± 57 µm) was significantly greater than that of the dutasteride group (Δ = −21 ± 79 µm; p = 0.032). A clear dose-dependent gradient was observed across minoxidil groups for right CIMT and maximum CIMT deltas. Dutasteride showed a consistent, non-significant trend toward CIMT reduction across all parameters. Conclusions: Oral minoxidil at 5 mg/day is associated with adverse carotid arterial wall remodeling and accelerated vascular aging in healthy young men, with a dose-dependent pattern suggesting a pharmacodynamic threshold between 1 and 2.5 mg/day. Dutasteride showed a favorable vascular profile.

Abstract: Aortitis—inflammation of the aortic wall—presents at the interface of vasculitis, infection, structural aortic disease, and cardiovascular risk. It may occur in giant cell arteritis (GCA), Takayasu arteritis, IgG4-related disease, drug-induced injury, infection, or as an isolated finding after aortic surgery. Modern imaging detects aortic inflammation more frequently, but the main challenge is classification rather than detection: determining whether disease is infectious or immune-mediated, active or dominated by fixed structural damage, systemic or isolated, and whether the dominant threat is aneurysm, dissection, undertreated infection, or avoidable immunosuppression. This review considers aortitis as a high-risk vascular syndrome requiring aetiology-first classification rather than descriptive labelling. Before escalating immunosuppression, infection must be actively excluded and inflammatory activity distinguished from fixed vascular damage. Treatment should be individualised according to phenotype, age, vascular territory, comorbidity, and toxicity risk, with surveillance continuing even after symptoms and inflammatory markers improve. Optimal care depends on multidisciplinary assessment integrating rheumatology, infectious diseases, vascular surgery, radiology, and cardiology expertise. Progress will require standardised imaging definitions, registries linking inflammatory control with structural vascular outcomes, and validation of artificial intelligence (AI) tools before clinical adoption.

Abstract: Percutaneous coronary intervention (PCI) treats focal coronary obstruction by compressing plaque, injuring the vessel wall and placing a metallic or bioresorbable scaffold. Most treated segments heal, but a small minority enter a prolonged, excessive or unstable repair state that contributes to in-stent restenosis (ISR), in-stent neoatherosclerosis and stent thrombosis (ST). Human evidence is strongest for delayed healing, uncovered struts, macrophage-rich neoatherosclerosis and hypersensitivity-associated late thrombosis, whereas routine immune biomarker-guided care remains unsupported. The narrowed lumen is only the visible endpoint; beneath it sits vascular repair shaped by de-vice-material exposure, local haemodynamics and host immunity. Endothelial denuda-tion and platelet activation initiate fibrin deposition, complement signalling and dam-age-associated molecular-pattern (DAMP) release. Neutrophils, monocytes and macro-phages dominate early, followed by lymphocytes and vascular smooth muscle cells that remodel the repair compartment. Drug-eluting stents (DES) have markedly reduced early neointimal hyperplasia, yet selected late failures still involve delayed endothelial recovery, chronic peristrut inflammation, hypersensitivity and neoatherosclerotic transformation. Immune biology is useful at the bedside only when interpreted with procedural context, device design and patient phenotype. Imaging-defined endpoints and paired immune phenotyping are therefore needed to guide treatment by mechanism instead of angiography or isolated biomarkers.

Abstract: Cardiac disease is a leading cause of morbidity and early death across several lysosomal storage disorders (LSDs); however, the cardiomyopathies of Fabry, Pompe, and Danon disease are still largely treated as separate, substrate-specific disorders. We argue that they are better understood as variations on a single theme: the breakdown of the autophagy–lysosome system within cardiomyocytes. In the healthy heart, this system clears damaged proteins and organelles and is regulated by mTORC1 and the master regulator TFEB. Once lysosomal degradation or autophagosome–lysosome fusion fails, undegraded substrates and defective mitochondria accumulate, driving hypertrophy, interstitial fibrosis, and conduction disease. Danon disease, resulting from the loss of LAMP2, is the clearest example of a primary defect in autophagic flux, whereas the glycogen storage of Pompe disease and the globotriaosylceramide accumulation of Fabry disease impair flux through different upstream mechanisms that converge on the same downstream injury. The same framework extends to other storage disorders with cardiac involvement, such as mucopolysaccharidosis (MPS). We trace this shared pathobiology from molecule to bedside, examine biomarkers that reflect lysosomal and autophagic dysfunction rather than storage alone, and re-examine treatment in that light: why enzyme replacement therapy corrects substrate accumulation but leaves much of the autophagic and mitochondrial damage unresolved, and why gene therapy—particularly AAV9-LAMP2B for Danon disease—together with autophagy- and TFEB-directed strategies may help close that gap. Viewing these disorders through a single mechanistic lens reshapes how we monitor them and where future therapies should be directed.

Abstract: Exercise induced pulmonary hypertension (EIPH) represents an abnormal pulmonary vascular response to increased blood flow during exercise, best characterized by a disproportionate rise in pulmonary arterial pressure relative to cardiac output. The shift from fixed pressure thresholds to flow-adjusted metrics, particularly the mPAP–cardiac output slope, reflects a more physiologically sound approach and is now incorporated in the 2022 guidelines of the European Society of Cardiology / European Respiratory Society as well as the World Symposium of PH.EIPH is a hemodynamic phenotype, not a standalone disease. Accumulating evidence demonstrates that EIPH has important diagnostic and prognostic implications. It is associated with reduced exercise capacity, increased risk of adverse cardiovascular outcomes, and reduced survival, even in patients with normal resting hemodynamics. Exercise hemodynamic abnormalities may also identify early or latent pulmonary vascular disease and early left heart dysfunction, particularly in at-risk populations such as systemic sclerosis, HFpEF, and genetic predisposition. In this review, we provide the current definition of EIPH as well as an overview of the prognostic implications and management of exercise induced PH in cardiac and pulmonary diseases.

Abstract: During acute coronary occlusion, ischemia is a major determinant of the cell response to subsequent reperfusion and is the major precursor of the typical “ischemia-reperfusion injury” (IRI). Therefore, elucidating the full IRI process primarily relies on a good understanding of ischemia-induced alterations. Ischemic arrhythmias frequently arise during the acute phase of a myocardial infarction (MI) and originate in the terminal arborizations of the cardiac conduction system. These ventricular arrhythmias are triggered by abnormal Ca2+-dependent depolarisations (DADs) of Purkinje cells (Pcells) due to increased spontaneous Ca2+ release by the sarcoplasmic reticulum (SR). This early alteration of the conduction tissue is also likely to provide a substrate for IRI-related arrhythmogenicity. Recent evidence associates the ischemic phase of the MI with a significant increase in SERCA2 pump expression in Pcells, suggesting that enhanced SR-Ca2+ release results from an augmentation of Ca²⁺ sequestration by the SR in those cells. We examined this hypothesis by assessing the impact of ischemia on the dynamics of SR Ca²⁺ uptake in live Pcells by high-resolution confocal microscopy in a classical canine model of LAD coronary ligation. Pcells from five normal hearts were compared with cells from five hearts 48 Hrs after coronary occlusion. Purkinje-specific Ca2+ events, namely peripheral Ca²⁺ wavelets (Wlets) and central cell-wide waves (CWWs), were analysed to assess the regional SR Ca²⁺ transport of Pcells. A total of 83 normal and 126 MI Wlets, along with 10 normal and 30 MI CWWs, were analysed to compare the peripheral and central SR-Ca2+-transports of Pcells between normal and ischemic hearts. 48 hours following the onset of ischemia, individual SR Ca²⁺ release sites exhibited a 60% increase in Ca²⁺ spark firing rate. However, the site density remained unchanged, indicating an acceleration of intra-SR Ca²⁺ cycling rather than direct alteration of the SR Ca²⁺ release channels. While central CWWs remained unchanged, a 37% acceleration of resting Ca²⁺ restoration was readily visible in peripheral Wlets, consistent with enhanced SR Ca²⁺ uptake at the cell periphery. Computational modelling reproduced these findings when Ca2+ uptake rate was numerically increased by 35%, confirming that augmented SERCA activity is sufficient to explain the pro-arrhythmic SR-Ca2+ release of Pcells after MI. Our findings confirm that the augmentation of Ca2+ pump density in the periphery of Pcells is associated with an increase in the SR-Ca2+ uptake, explaining the arrhythmogenicity of Purkinje fibres in ischemic heart. This ischemia-mediated pro-arrhythmic remodelling of intracellular Ca2+ handling in the conduction system is also likely to contribute to triggered activity during subsequent reperfusion.

Abstract: Background: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. Mitochondrial dysfunction is increasingly recognized as a central contributor to the pathogenesis of heart failure, ischemic heart disease, cardiomyopathy and vascular disorders. Mitochondrial quality control (MQC), comprising mitophagy, mitochondrial biogenesis, and mitochondrial dynamics, is essential for maintaining cardiac energy homeostasis and cellular integrity. This systematic review evaluates the molecular mechanisms and therapeutic potential of MQC in cardiovascular disease. Methods: A systematic literature search was conducted according to PRISMA 2020 guidelines using PubMed, Embase, Web of Science, and Scopus. Experimental, translational, and clinical studies investigating MQC pathways in cardiovascular disease were included. Evidence relating to mitophagy, mitochondrial biogenesis and therapeutic modulation was extracted and synthesized. Results: Disruption of MQC was consistently associated with impaired mitochondrial turnover, oxidative stress, bioenergetic failure, inflammation and adverse cardiac remodeling. Key mitophagy regulators, including PINK1, Parkin, BNIP3 and FUNDC1, demonstrated cardioprotective effects, while suppression of mitochondrial biogenesis pathways involving PGC-1α, NRF1, NRF2 and TFAM contributed to disease progression. Emerging therapies, including SGLT2 inhibitors, AMPK activators, NAD+-enhancing agents and mitochondrial-targeted antioxidants, showed potential to restore mitochondrial homeostasis and improve cardiac function. Conclusion: MQC represents a critical determinant of cardiovascular health. Therapeutic strategies targeting mitophagy and mitochondrial biogenesis may offer promising approaches for preventing mitochondrial dysfunction, limiting cardiac injury and improving outcomes in cardiovascular disease.