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This Focus Issue on ischaemic heart disease, vascular biology and medicine, and brain health contains the ‘The year in cardiovascular medicine 2024: the top 10 papers in ischaemic heart disease’ by EHJ Editors Diana Gorog, Ranil de Silva, and William E. Boden.1 The authors note that ischaemic heart disease remains the leading cause of death globally, according to the World Health Organization. Here, they summarize the top 10 papers in 2024 that they think may help facilitate better classification, detection, risk stratification, and, ultimately, treatment of patients with ischaemic heart disease.
In a Viewpoint article entitled ‘Takotsubo is an acute myocardial ischaemic syndrome’, Robert Sykes, Daniel Ang, and Colin Berry from the University of Glasgow, UK contend that Takotsubo is primarily an acute myocardial ischaemic syndrome rather than primarily acute heart failure, dilated cardiomyopathy, or an acute coronary syndrome.2 The authors summarize the evolving scientific knowledge on the pathophysiology of Takotsubo syndrome, notably on coronary microvascular dysfunction, and make the case for developing mechanistically targeted vasculoprotective therapy for this condition.
There is growing interest in drug-coated balloons (DCB).3–5 In a Fast Track Clinical Research article entitled ‘Individual patient data meta-analysis of paclitaxel-coated balloons vs drug-eluting stents for small-vessel coronary artery disease: the ANDROMEDA study’, Simone Fezzi from the Verona University Hospital in Italy, and colleagues indicate that in randomized clinical trials of patients undergoing percutaneous coronary intervention (PCI) for de novo small-vessel coronary artery disease (SV-CAD), paclitaxel-coated balloon (PCB) angioplasty showed mid-term angiographic or clinical non-inferiority to drug-eluting stent (DES) implantation.6 Nevertheless, these trials have sample size limitations, and the relative safety and efficacy beyond the first year remain uncertain. The ANDROMEDA study was a collaborative, investigator-initiated, individual patient data meta-analysis comparing 3 year clinical outcomes between PCB angioplasty and DES implantation for the treatment of de novo SV-CAD. Multiple electronic databases were searched from May 2010 to June 2024 to identify eligible trials. All the following eligibility criteria were required: (i) random allocations of treatments; (ii) patients with SV-CAD; (iii) treatment with PCB or DES; and (iv) clinical follow-up of at least 36 months. The primary and co-primary endpoints were major adverse cardiac events (MACE), and target lesion failure (TLF), respectively. Individual patient data from three randomized trials, including a total of 1154 patients and 1360 lesions, were combined. At 3 years, PCB was associated with a significantly lower risk of MACE compared with DES (hazard ratio [HR] 0.67), due to a lower risk of myocardial infarction and target vessel revascularization. This benefit persisted after multivariable adjustment (HR 0.75), but did not reach statistical significance in the two-stage analysis (HR 0.67). At the landmark analysis, the risk of MACE between groups was consistent over time. At 3 years, TLF was not significantly different between PCB and DES groups (Figure 1).
The assessment of long-term clinical outcomes of de Novo DCB peRformance: a cOmprehensive, individual patient data Meta-Analysis of ranDomized clinical triAls (ANDROMEDA) study, an individual patient data meta-analysis of three randomized trials (1154 patients and 1360 lesions), comparing 3 year outcomes of PCB angioplasty vs DES implantation for the treatment of SV-CAD. Patients assigned to PCB showed a reduced risk of MACE compared with those assigned to DES. After adding reconstructed time-to-event individual patient data from a fourth trial, the analysis of the co-primary outcome of TLF did not show significant differences between treatment groups. CI, confidence interval; DES, drug-eluting stent; HR, hazard ratio; IPD, individual patient data; MACE, major adverse cardiac event; PLR, P-value of the log-rank test; PCB, paclitaxel-coated balloon; RCT, randomized clinical trial; rIPD, reconstructed time-to-event individual patient data; SV-CAD, small-vessel coronary artery disease; TLF, target lesion failure6
The authors conclude that in patients undergoing PCI for de novo SV-CAD, PCB angioplasty is associated with a reduction in MACE and a non-significant difference in TLF at 3 year follow-up compared with DES implantation. The contribution is accompanied by an Editorial by Christina Lalani, Eric Secemsky, and Robert Yeh from Harvard Medical School in Boston, MA, USA.7 The authors note that despite the theoretical advantages of DCBs over DES for the treatment of CAD, there is still much to learn regarding which patients and which lesions benefit most from DCBs. Regardless, it is becoming clear that the benefits of DCB therapy may not be a class effect—whether for the class of balloons being used or for the types of lesions being treated. It will be important for future studies to evaluate long-term clinical outcomes for specific DCBs compared with the newest generation DES across a variety of lesion types to guide the individualization of care going forward.
Acquired somatic mutations emerged as important drivers of adverse cardiovascular disease outcomes.8–14 Recently, mosaic loss of Y chromosome (LOY) in haematopoietic cells was identified to induce diffuse cardiac fibrosis in male mice. In a Clinical Research article entitled ‘Mosaic loss of Y chromosome and mortality after coronary angiography’, Michael Weyrich from the Goethe University Frankfurt in Germany and colleagues determine the association between LOY and cardiovascular mortality in patients undergoing coronary angiography.15 Loss of Y chromosome was quantified in 1698 male participants of the LURIC study, who underwent coronary angiography, and its association with all-cause and cardiovascular mortality was determined. Furthermore, the interaction between LOY and inherited genetic susceptibility for cardiac fibrosis was assessed. The frequency of LOY steeply increased in male participants of LURIC at the age of 60 years. Loss of Y chromosome >17% was associated with significantly higher all-cause (HR 1.41) and cardiovascular mortality (HR 1.49), which was driven by a higher risk for fatal myocardial infarction (HR 2.65). Loss of Y chromosome >17% was associated with a profibrotic and proinflammatory plasma protein expression profile as characterized by higher plasma levels of osteoprotegerin, matrix metalloproteinase-12, growth differentiation factor 15, heparin-binding EGF-like growth factor, and resistin. Genetic predisposition for lower myocardial fibrosis attenuated the association between LOY and cardiovascular mortality. Genome-wide methylation analyses identified differential methylation in 298 genes. Single-cell RNA sequencing further confirmed differential gene expression of 37 of these genes in LOY in peripheral blood mononuclear cells comprising a set of fibrosis-regulating genes like RPS5. RPS5 silencing in macrophages induced a paracrine induction of collagen expression in cardiac fibroblasts, documenting a functional role in vitro.
The authors conclude that LOY represents an important independent risk factor for cardiovascular mortality in male patients with CAD. Targeting LOY may represent a sex-specific personalized medicine approach. This manuscript is accompanied by an Editorial by Soichi Sano from the National Cerebral and Cardiovascular Center in Osaka, Japan and Kenneth Walsh from the University of Virginia School of Medicine in Charlottesville, VA, USA.16 The authors highlight that LOY in blood represents just one facet of somatic mutations that occur in the haematopoietic system. Any one of these mutations has the potential to significantly alter the function of immune cells and thereby alter the immune response to disease, particularly cardiovascular disease. Furthermore, accumulating evidence has revealed that most tissues and cell types acquire somatic gene mutations and chromosomal alterations with age. Thus, a future challenge lies in deciphering how this ‘somatic mosaicism’ in seemingly normal tissues shapes disease trajectories, and whether monitoring these mosaic changes can ultimately inform preventive strategies and therapeutic interventions.
Current knowledge about upper extremity artery disease (UEAD) is scarce. In a Clinical Research article entitled ‘Hospitalized upper extremity artery disease patients: treatment and long-term outcomes’, Lena Makowski from the University Hospital Muenster in Germany, and colleagues aimed to evaluate the prevalence, treatment patterns, and short- and long-term outcomes of patients suffering from UEAD.17 Retrospective health claims data of patients who were hospitalized with a primary diagnosis of UEAD between 2010 and 2017 were analysed. The data were obtained from 11 legally independent statutory health insurance funds. Risk factors, comorbidities, pharmacotherapy, revascularization procedure, and outcome were evaluated with a particular focus on sex-related disparities (median follow-up time: 5.5 years). Among 2437 UEAD patients (43% female, median age 67 years), 80% were solely atherosclerotic, while 20% had concomitant inflammatory/connective tissue diseases. Cardiovascular risk factors and comorbidities were highly prevalent in both sexes. Coronary, cerebrovascular, and lower extremity artery diseases, and organ failure such as chronic kidney and heart failure, were more frequent in men compared with women. At index hospital stay, women had a higher rate of revascularization than men. The 5 year mortality among the entire population was almost 50%. Furthermore, men had higher rates of upper limb amputation compared with women despite equal secondary preventive pharmacotherapy.
Makowski et al. conclude that UEAD patients, irrespective of the underlying disease type, face a poor prognosis, with an elevated proportion of amputation and mortality. Male sex is linked to increased risk of future cardiovascular and limb events including death. Further investigation is warranted to understand the underlying causes of the sex-related disparities and identify treatment improvements. The contribution is accompanied by an Editorial by Francisco Ujueta and Marie Gerhard-Herman, from the Brigham and Women’s Hospital in Boston, MA, and Aaron Aday from the Vanderbilt University Medical Center in Nashville TN, USA.18 The authors note that the study by Makowski et al. provides a wealth of detail on UEAD and shines a light on the high risk of amputations and mortality among inpatients hospitalized for UEAD. Unfortunately, underdiagnosis and undertreatment with medical therapy such as statins and antiplatelet agents were also noted in this population, mirroring what remains a consistent challenge for patients with lower extremity peripheral artery disease.19–23 Delayed diagnosis and undertreatment probably contribute to the high incidence of amputations and high mortality in patients with UEAD. The authors hope that UEAD follows similar steps to lower extremity atherosclerotic disease, with a growing push for awareness by cardiovascular organizations and a focus in clinical trials to better understand management and patient-centred outcomes.
Vagal parasympathetic dysfunction is strongly associated with impaired exercise tolerance, indicating that co-ordinated autonomic control is essential for optimizing exercise performance. In a Translational Research article entitled ‘Non-invasive vagus nerve stimulation and exercise capacity in healthy volunteers: a randomized trial’, Gareth Ackland from the London School of Medicine and Dentistry in the UK, and colleagues tested the hypothesis that autonomic neuromodulation by non-invasive transcutaneous vagus nerve stimulation (tVNS) can improve exercise capacity in humans.24 This single-centre, randomized, double-blind, sham-controlled, crossover trial in 28 healthy volunteers evaluated the effect of bilateral transcutaneous stimulation of vagal auricular innervation, applied for 30 min daily for 7 days, on measures of cardiorespiratory fitness (peak oxygen consumption [VO2peak]) during progressive exercise to exhaustion. Secondary endpoints included peak work rate, cardiorespiratory measures, and the whole blood inflammatory response to lipopolysaccharide ex vivo. Transcutaneous vagus nerve stimulation applied for 30 min daily over seven consecutive days increased VO2peak by 1.04 mL/kg/min (P = .005), compared with no change after sham stimulation. No carry-over effect was observed following the 2 week washout period. Transcutaneous vagus nerve stimulation increased work rate (P = .006), heart rate (P = .011), and respiratory rate (P < .001) at peak exercise. Analysis of the whole blood transcriptomic response to lipopolysaccharide in serial samples obtained from five participants showed that tVNS reduced the inflammatory response (Figure 2).
Methods, and primary and secondary outcomes for a randomized, double-blind, crossover, sham-controlled trial of non-invasive vagal stimulation in healthy volunteers. tVNS, transcutaneous vagus nerve stimulation; CPET, cardiopulmonary exercise test; RNaseq, RNA sequencing; IL-1β mRNA, interleukin-1 beta mRNA; JAK–STAT, Janus kinase signal transducer and activator of transcription; NF-kappa B, nuclear factor kappa-light-chain-enhancer of activated B cells; TNF, tumour necrosis factor24
The authors conclude that non-invasive vagal stimulation improves measures of cardiorespiratory fitness and attenuates inflammation, offering an inexpensive, safe, and scalable approach to improve exercise capacity.
Members of the CCN matricellular protein family are crucial in various biological processes. In a Translational Science contribution entitled ‘CCN5 suppresses injury-induced vascular restenosis by inhibiting smooth muscle cell proliferation and facilitating endothelial repair via thymosin β4 and Cd9 pathway’, Qi Zhang from the Tongji University School of Medicine in Shanghai, China and colleagues aimed to characterize vascular cell-specific effects of CCN5 on neointimal formation and its role in preventing in-stent restenosis (ISR) after PCI.25 Stent-implanted porcine coronary artery RNA-sequencing and mouse injury-induced femoral artery neointima single-cell RNA sequencing were performed. Plasma CCN5 levels were measured by enzyme-linked immunosorbent assay. Endothelial cell (EC)- and vascular smooth muscle cell (VSMC)-specific CCN5 loss-of-function and gain-of-function mice were generated. Mass spectrometry and co-immunoprecipitation were conducted to identify CCN5-interacting proteins. Additionally, CCN5 recombinant protein (CCN5rp)-coated stents were deployed to evaluate its anti-ISR effects in a porcine model. Plasma CCN5 levels were significantly reduced and correlated closely with the degree of restenosis in ISR patients. CCN5 expression was significantly decreased in VSMCs of stent-implanted porcine coronary segments and injured mouse femoral arteries, especially in synthetic VSMCs. In contrast, elevated CCN5 expression was observed in regenerating ECs of injured vessels. EC and VSMC-specific CCN5 deletion mice exhibited exacerbation of injury-induced neointimal hyperplasia, while CCN5 gain of function alleviated neointimal formation. Mechanistic studies identified thymosin β4 (Tβ4) as a CCN5-interacting protein in ECs, and EC-CCN5 promoted injury repair through the Tβ4 cleavage product Ac-SDKP. Also, CCN5rp promoted EC repair to suppress neointimal hyperplasia via interaction with the Cd9 extracellular domain. Moreover, implantation of a CCN5rp-coated stent significantly increased stent strut coverage with ECs, which suppressed neointimal formation and ultimately alleviated ISR.
Zhang and colleagues conclude that CCN5 exerts a dual protective effect on ISR by inhibiting VSMC proliferation and facilitating EC repair. CCN5rp-coated stents might be promising in the prevention of ISR after PCI. The contribution is accompanied by an Editorial by Simon Brown, Julie Rodor, and Andrew Baker from the University of Edinburgh, UK.26 The authors highlight that ECs and VSMCs cross-talk is important in vascular homeostasis, with efficient re-endothelialization a crucial step in preventing subsequent smooth muscle proliferation. Whilst current stent-coating strategies focus either on promoting re-endothelialization or on limiting smooth muscle proliferation, a strategy that enhances both processes, as proposed by Zhang et al., particularly one which is simplistic in its design through the use of a single recombinant protein, could prove to be effective.
Lacklustre results from recently completed gene therapy clinical trials of vascular endothelial growth factor-A (VEGF-A) delivered by viral vectors have heightened the need to develop alternative delivery strategies. In a Translational Science contribution entitled ‘Extracellular vesicle-mediated VEGF-A mRNA delivery rescues ischaemic injury with low immunogenicity’, Yi You from the Peking University Shenzhen Graduate School in China and colleagues demonstrate the pre-clinical efficacy and safety of extracellular vesicles (EVs) loaded with VEGF-A mRNA for the treatment of ischaemic vascular disease.27 After encapsulation of full-length VEGF-A mRNA into fibroblast-derived EVs via cellular nanoporation (CNP), the collected VEGF-A EVs were delivered into mouse models of ischaemic injury. Target tissue delivery was verified by in situ analysis of protein and gene expression. Functional rescue was confirmed by in vivo imaging and histology. The safety of single and serial delivery was demonstrated using immune-based assays. VEGF-A EVs were generated with high mRNA content using a CNP methodology. VEGF-A EV administration demonstrated expression of exogenous VEGF-A mRNA by in situ RNA hybridization and elevated protein expression by western blot, microscopy, and ELISA. Mice treated with human VEGF-A EVs after femoral or coronary artery ligation exhibited heightened neovascularization in ischaemic tissues with increased arterial perfusion and improvement in left ventricular function, respectively. Serial delivery of VEGF-EVs in injured skin showed improved wound healing with repeat administration. Importantly, as compared with adeno-associated viral and lipid nanoparticle VEGF-A gene therapy modalities, murine VEGF-A EV delivery did not trigger innate or adaptive immune responses at the injection site or systemically.
The authors conclude that VEGF-A EV therapy offers efficient, dose-dependent VEGF-A protein formation with low immunogenicity, resulting in new vessel formation in murine models of ischaemic vascular disease. The contribution is accompanied by an Editorial by Jes-Niels Boeckel from the Universitätsklinikum Leipzig in Germany and Junjie Xiao from Shanghai University in China.28 The authors note that therapy with VEGF-A mRNA-loaded EVs may represent a significant advancement in gene therapy for ischaemic vascular diseases. By addressing the limitations of previous approaches—such as immunogenicity, inefficient gene delivery, rapid RNA degradation, and the inability to administer repeated doses without immune activation—this strategy warrants further clinical evaluation. The transient expression of VEGF-A may reduce risks associated with long-term exposure, and the EV-based approach could be adapted to deliver various other RNA molecules for broader therapeutic applications. Ultimately, this method may help to determine whether VEGF therapy can exert beneficial effects in humans.
The issue is also accompanied by two Discussion Forum contributions. In a manuscript entitled ‘Risk prediction for cardiovascular diseases in Asia-Pacific: to separate subtypes or not, that is a new question’, Songchun Yang from the Central South University in Changsha and Jun Lv from Peking University in China comment on the recent contribution ‘Risk prediction of cardiovascular disease in the Asia-Pacific region: the SCORE2 Asia-Pacific mode’ by Steven Hageman from the University Medical Center Utrecht in the Netherlands, and colleagues.29,30 Hageman et al. reply in a separate comment.31
The editors hope that this issue of the European Heart Journal will be of interest to its readers.
Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca,BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work.
With thanks to Amelia Meier-Batschelet, Johanna Huggler, and MartinMeyer for help with compilation of this article.
