Heart failure (HF) is not confined to contractile failure of cardiomyocytes or myocardial fibrosis. Coronary and systemic vascular dysfunction contributes to the initiation and progression of HF with or without reduced e...Heart failure (HF) is not confined to contractile failure of cardiomyocytes or myocardial fibrosis. Coronary and systemic vascular dysfunction contributes to the initiation and progression of HF with or without reduced ejection fraction. Furthermore, HF compromises vascular function, creating and sustaining a vicious cycle with deranging effects on coronary blood flow, cardiac metabolism and cardiac function. In HF, systemic arterial dysfunction, characterized by increased arterial stiffness and resistance, raises cardiac afterload and impedes myocardial contractile function. Reduced coronary blood flow impairs myocardial oxygen delivery and consequently cardiomyocyte metabolism and function. Coronary microvascular dysfunction is heterogeneous in its pathogenesis and manifestations, complicating the diagnosis and management across different HF phenotypes. Understanding the alterations in function in different segments of the vasculature, from the aorta to the capillary level, offers mechanistic insights into disease drivers and therapeutic interventions. Interventional approaches can improve vascular haemodynamics, whereas established and emerging pharmacotherapies target the neurohumoral axis and reduce extravascular compression, inflammation, and oxidative stress, thereby improving vascular function and HF-related outcomes. In this Review, we provide a mechanistic framework of vascular dysfunction in the pathogenesis of HF with or without reduced ejection fraction, pointing towards integrated therapies that consider the vascular implications of contemporary HF management across HF phenotypes.
Iliodromitis K, Seyfarth M, Balogh Z
… +3 more, Bogossian H, Iliodromitis E, Triposkiadis F
Basic Res Cardiol
· 2025 Aug · PMID 40504384
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Inflammation has a key role in coronary atherosclerotic disease (CAD), as it contributes to the development, progression, instability and rupture of the atherosclerotic plaque. The long-term treatment and continuous supp...Inflammation has a key role in coronary atherosclerotic disease (CAD), as it contributes to the development, progression, instability and rupture of the atherosclerotic plaque. The long-term treatment and continuous suppression of inflammation is a therapeutic goal for patients with increased cardiovascular risk and chronic CAD syndromes. In contrast, in acute myocardial infarction (MI), the presence of inflammation is necessary for smooth healing, tissue neovascularization, and limitation of left ventricular remodeling, rendering a "controlled amount" of inflammation desirable in this context. As a result, the use of nonselective, broad-spectrum anti-inflammatory drugs does not offer any beneficial effect and may turn out to be harmful. Nevertheless, the possibility that modification of a usual inflammatory response in MI with selective anti-inflammatory agents cannot be excluded. Conversely, an excessive, uncontrolled, and prolonged inflammatory response after an acute MI may result in extensive irreversible myocardial damage and should be timely recognized and treated, preferably with a selective anti-inflammatory agent. In the present review we highlight the key role of inflammation in chronic and acute CAD, discuss the underlying pathophysiology, and present the results of representative experimental and clinical studies evaluating the pharmaceutical modification of the inflammatory response in this context.
Cardiovascular diseases are the leading cause of death globally, with cardiac arrhythmias contributing substantially to this burden. Gene therapy, which directly targets the underlying disease pathobiology, offers an app...Cardiovascular diseases are the leading cause of death globally, with cardiac arrhythmias contributing substantially to this burden. Gene therapy, which directly targets the underlying disease pathobiology, offers an appealing treatment strategy for cardiac arrhythmias owing to its potential as a one-time, curative solution. Over the past two decades, substantial efforts have been made to develop new gene therapy approaches that overcome the limitations of conventional treatments. In this Review, we describe the rationale for gene therapy to treat cardiac arrhythmias; discuss advantages and disadvantages of gene silencing, gene replacement, gene suppression-and-replacement and gene editing technologies; summarize vector modalities and delivery approaches used in the field; present examples of gene therapy strategies used for atrial and ventricular arrhythmias; and highlight the current challenges and limitations in the gene therapy field.
Wang M, Preckel B, Zuurbier CJ
… +1 more, Weber NC
Basic Res Cardiol
· 2025 Aug · PMID 40366385
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Heart failure (HF) is a life-threatening cardiovascular disease associated with high mortality, diminished quality of life, and a significant economic burden on both patients and society. The pathogenesis of HF is closel...Heart failure (HF) is a life-threatening cardiovascular disease associated with high mortality, diminished quality of life, and a significant economic burden on both patients and society. The pathogenesis of HF is closely related to the endothelium, where endothelial ion channels play an important role in regulating intracellular Ca signals. These ion channels are essential to maintain vascular function, including endothelium-dependent vascular tone, inflammation response, and oxidative stress. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promising cardiovascular benefits in HF patients, reducing mortality risk and hospitalization in several large clinical trials. Clinical and preclinical studies indicate that the cardioprotective effects of SGLT2i in HF are mediated by endothelial nitric oxide (NO) pathways, as well as by reducing inflammation and reactive oxygen species in cardiac endothelial cells. Additionally, SGLT2i may confer endothelial protection by lowering intracellular Ca level through the inhibition of sodium-hydrogen exchanger 1 (NHE1) and sodium-calcium exchanger (NCX) in endothelial cells. In this review, we discuss present knowledge regarding the expression and role of Ca-related ion channels in endothelial cells in HF, focusing on the effects of SGLT2i on endothelial NHE1, NCX as well as on vascular tone.
Endothelial cells are multifunctional cells that form the inner layer of blood vessels and have a crucial role in vasoreactivity, angiogenesis, immunomodulation, nutrient uptake and coagulation. Endothelial cells have un...Endothelial cells are multifunctional cells that form the inner layer of blood vessels and have a crucial role in vasoreactivity, angiogenesis, immunomodulation, nutrient uptake and coagulation. Endothelial cells have unique metabolism and are metabolically heterogeneous. The microenvironment and metabolism of endothelial cells contribute to endothelial cell heterogeneity and metabolic specialization. Endothelial cell dysfunction is an early event in the development of several cardiovascular diseases and has been shown, at least to some extent, to be driven by metabolic changes preceding the manifestation of clinical symptoms. Diabetes mellitus, hypertension, obesity and chronic kidney disease are all risk factors for cardiovascular disease. Changes in endothelial cell metabolism induced by these cardiometabolic stressors accelerate the accumulation of dysfunctional endothelial cells in tissues and the development of cardiovascular disease. In this Review, we discuss the diversity of metabolic programmes that control endothelial cell function in the cardiovascular system and how these metabolic programmes are perturbed in different cardiovascular diseases in a disease-specific manner. Finally, we discuss the potential and challenges of targeting endothelial cell metabolism for the treatment of cardiovascular diseases.
The variation of heart rate in phase with breathing, known as 'respiratory sinus arrhythmia' (RSA), is a physiological phenomenon present in all air-breathing vertebrates. RSA arises from the interaction of several physi...The variation of heart rate in phase with breathing, known as 'respiratory sinus arrhythmia' (RSA), is a physiological phenomenon present in all air-breathing vertebrates. RSA arises from the interaction of several physiological mechanisms but is primarily mediated by rhythmic changes in cardiac parasympathetic (vagal) activity, increasing heart rate during inspiration and decreasing heart rate during expiration. RSA amplitude is an indicator of autonomic and cardiac health; RSA is diminished or absent in common pathological conditions such as chronic heart failure and hypertension. In this Expert Recommendation, we argue that the term 'RSA', although historically important, is semantically inaccurate and carries misleading pathological connotations, contributing to misunderstanding and misinterpretation of the origin and the physiological importance of the phenomenon. We propose replacing 'RSA' with the term 'respiratory heart rate variability' (RespHRV), which avoids pathological connotations and emphasizes the specific respiratory contribution to heart rate variability. We clarify that RespHRV encompasses respiratory-related heart rate variations in both the low-frequency and high-frequency bands traditionally defined in heart rate variability analysis, and that its amplitude should not be misconstrued as a measure of vagal tone. Adopting the proposed term 'RespHRV' is expected to unify understanding and stimulate further experimental and clinical research into the physiological mechanisms and functional importance of this phenomenon.
JAMA Cardiol
· 2025 Jun · PMID 40305039
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IMPORTANCE: Patients with atrial fibrillation (AF), a common morbid arrhythmia, are more likely to carry rare genetic variants associated with inherited cardiomyopathies. Prior studies on rare pathogenic variants in AF r...IMPORTANCE: Patients with atrial fibrillation (AF), a common morbid arrhythmia, are more likely to carry rare genetic variants associated with inherited cardiomyopathies. Prior studies on rare pathogenic variants in AF relied on small, hospital referral populations, and knowledge on clinical outcomes remains limited. OBJECTIVE: To evaluate the prevalence and prognostic implications of cardiomyopathy-associated pathogenic or likely pathogenic (CMP-PLP) genetic variants in patients with AF. DESIGN, SETTING, AND PARTICIPANTS: In 2 prospective cohort studies, the prevalence of CMP-PLP variants was assessed in the population of patients with AF and early-onset AF. The association between carrying a CMP-PLP variant and the risk of incident cardiomyopathy or heart failure (CMP/HF) after AF diagnosis was evaluated. Finally, the joint contributions of CMP-PLP variants, clinical risk, and polygenic risk were assessed. Included in this study were 2 large longitudinal cohort studies, the UK Biobank (UKB) (data 2006-2023) and the All of Us Research Program (AllofUs) (2018-2022). The UKB and AllofUs cohorts, respectively, contained 393 768 and 193 232 unrelated genotyped participants. EXPOSURES: CMP-PLP variants. MAIN OUTCOMES AND MEASURES: Prevalence of CMP-PLP variants and risk of incident CMP/HF after AF diagnosis. RESULTS: In the UKB cohort, 32 281 participants (8%) had AF (mean [SD] age, 62 [6] years; 20 459 male [63.4%]). In the AllofUs cohort, 11 901 participants (6%) had AF (mean [SD] age, 67 [12] years; 6576 male [55.3%]). Compared with the biobank populations, CMP-PLP variants were twice as prevalent in patients with AF (UKB, 2.04%; 95% CI, 1.89%-2.20%; AllofUs, 2.52%; 95% CI, 2.25%-2.82%) and 5 times as prevalent in AF with onset before age 45 years (UKB, 4.99%; 95% CI, 3.07%-7.91%; AllofUs, 4.66%; 3.40%-6.32%). Cumulative incidence of CMP/HF was high in patients with AF (18%) compared with patients without AF (3%). Still, among patients with AF without prior CMP/HF (UKB, 20 226; AllofUs, 8330), carrying a CMP-PLP variant was associated with 1.6-fold risk of incident CMP/HF (meta-analysis, 95% CI, 1.32-1.90). Finally, CMP-PLP variants, a polygenic score, and clinical risk factors were independent estimators of CMP/HF. CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that the prevalence of CMP-PLP variants was substantial in patients with early-onset AF. Patients with AF carrying a CMP-PLP variant had an associated increased risk of future CMP/HF, independent of clinical and polygenic risk. These results indicate that genetic testing in patients with AF may identify individuals at higher risk for developing CMP/HF.
Hørsdal OK, Larsen AM, Wethelund KL
… +10 more, Dalsgaard FF, Seefeldt JM, Helgestad OKL, Moeslund N, Møller JE, Ravn HB, Nielsen RR, Wiggers H, Berg-Hansen K, Gopalasingam N
Basic Res Cardiol
· 2025 Jun · PMID 40220139
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Cardiogenic shock (CS) is characterized by reduced cardiac output (CO), reduced end-organ perfusion, and high mortality. Medical therapies have failed to improve survival. The ketone body 3-hydroxybutyrate (3-OHB) enhanc...Cardiogenic shock (CS) is characterized by reduced cardiac output (CO), reduced end-organ perfusion, and high mortality. Medical therapies have failed to improve survival. The ketone body 3-hydroxybutyrate (3-OHB) enhances cardiac function in heart failure and CS. We aimed to elucidate the cardiovascular and cardiometabolic effects of 3-OHB treatment during CS. In a randomized, assessor-blinded crossover design, we studied 16 female pigs (60 kg, 5 months of age). CS was induced by left main coronary artery microsphere injections. Predefined criteria for CS were a 30% reduction in CO or mixed venous saturation (SvO). Intravenous 3-OHB infusion and a matching control solution were administered for 120 min in random order. Hemodynamic measurements were obtained by pulmonary artery catheterization and a left ventricular (LV) pressure-volume catheter. Myocardial mitochondrial function was assessed using high resolution respirometry. During CS, infusion with 3-OHB increased CO by 0.9 L/min (95%CI 0.4-1.3 L/min) compared with control infusion. SvO (P = 0.026) and heart rate (P < 0.001) increased. Stroke volume (P = 0.6) was not altered. LV contractile function as determined by LV end-systolic elastance improved during 3-OHB infusion compared with control infusion (P = 0.004). Systemic and pulmonary vascular resistance decreased, and diuresis increased. LV mitochondrial function was higher after 3-OHB infusion compared with control. We conclude that 3-OHB infusion enhances cardiac function by increasing contractility and reducing vascular resistance, while also preserving myocardial mitochondrial respiratory function in a large animal model of ischemic CS. These novel findings support the therapeutic potential of exogenous ketone supplementation in CS management.
Gyöngyösi M, Guthrie J, Hasimbegovic E
… +9 more, Han E, Riesenhuber M, Hamzaraj K, Bergler-Klein J, Traxler D, Emmert MY, Hackl M, Derdak S, Lukovic D
Basic Res Cardiol
· 2025 Jun · PMID 40205177
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The unsuccessful translation of cardiac regeneration and cardioprotection from animal experiments to clinical applications in humans has raised the question of whether microRNA bioinformatics can narrow the gap between a...The unsuccessful translation of cardiac regeneration and cardioprotection from animal experiments to clinical applications in humans has raised the question of whether microRNA bioinformatics can narrow the gap between animal and human research outputs. We reviewed the literature for the period between 2000 and 2024 and found 178 microRNAs involved in cardioprotection and cardiac regeneration. On analyzing the orthologs and annotations, as well as downstream regulation, we observed species-specific differences in the diverse regulation of the microRNAs and related genes and transcriptomes, the influence of the experimental setting on the microRNA-guided biological responses, and database-specific bioinformatics results. We concluded that, in addition to reducing the number of in vivo experiments, following the 3R animal experiment rules, the bioinformatics approach allows the prediction of several currently unknown interactions between pathways, coding and non-coding genes, proteins, and downstream regulatory elements. However, a comprehensive analysis of the miRNA-mRNA-protein networks needs a profound bioinformatics and mathematical education and training to appropriately design an experimental study, select the right bioinformatics tool with programming language skills and understand and display the bioinformatics output of the results to translate the research data into clinical practice. In addition, using in-silico approaches, a risk of deviating from the in vivo processes exists, with adverse consequences on the translational research.
Jarabicová I, Horváth C, Hrdlička J
… +15 more, Boroš A, Olejníčková V, Zábrodská E, Hubáčková SŠ, Šutovská HM, Molčan Ľ, Kopkan L, Chudý M, Kura B, Kaločayová B, Goncalvesová E, Neckář J, Zeman M, Kolář F, Adameová A
Basic Res Cardiol
· 2025 Apr · PMID 40088261
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Since cell dying in heart failure (HF) may vary based on the aetiology, we examined the main forms of regulated necrosis, such as necroptosis and pyroptosis, in the hearts damaged due to myocardial infarction (MI) or pre...Since cell dying in heart failure (HF) may vary based on the aetiology, we examined the main forms of regulated necrosis, such as necroptosis and pyroptosis, in the hearts damaged due to myocardial infarction (MI) or pressure overload. We also investigated the effects of a drug inhibiting RIP3, a proposed convergent point for both these necrosis-like cell death modes. In rat hearts, left ventricular function, remodelling, pro-cell death, and pro-inflammatory events were investigated, and the pharmacodynamic action of RIP3 inhibitor (GSK'872) was assessed. Regardless of the HF aetiology, the heart cells were dying due to necroptosis, albeit the upstream signals may be different. Pyroptosis was observed only in post-MI HF. The dysregulated miRNAs in post-MI hearts were accompanied by higher levels of a predicted target, HMGB1, its receptors (TLRs), as well as the exacerbation of inflammation likely originating from macrophages. The RIP3 inhibitor suppressed necroptosis, unlike pyroptosis, normalised the dysregulated miRNAs and tended to decrease collagen content and affect macrophage infiltration without affecting cardiac function or structure. The drug also mitigated the local heart inflammation and normalised the higher circulating HMGB1 in rats with post-MI HF. Elevated serum levels of HMGB1 were also detected in HF patients and positively correlated with C-reactive protein, highlighting pro-inflammatory axis. In conclusion, in MI-, but not pressure overload-induced HF, both necroptosis and pyroptosis operate and might underlie HF pathogenesis. The RIP3-targeting pharmacological intervention might protect the heart by preventing pro-death and pro-inflammatory mechanisms, however, additional strategies targeting multiple pro-death pathways may exhibit greater cardioprotection.
Hernandez-Resendiz S, Vilskersts R, Aluja D
… +28 more, Andreadou I, Bencsik P, Dambrova M, Efentakis P, Gao F, Giricz Z, Brenner GB, Sayour NV, Gergely TG, Makkos A, Inserte J, Kelly-Laubscher R, Kiss A, Krieg T, Kwak BR, Lecour S, Lopaschuk G, Mączewski M, Waszkiewicz M, Oknińska M, Pagliaro P, Podesser B, Prag HA, Ruiz-Meana M, Szabados T, Zuurbier CJ, Ferdinandy P, Hausenloy DJ
Basic Res Cardiol
· 2025 Apr · PMID 40072549
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Although many cardioprotective interventions have been shown to limit infarct size (IS), in preclinical animal studies of acute myocardial ischemia/reperfusion injury (IRI), their clinical translation to patient benefit...Although many cardioprotective interventions have been shown to limit infarct size (IS), in preclinical animal studies of acute myocardial ischemia/reperfusion injury (IRI), their clinical translation to patient benefit has been largely disappointing. A major factor is the lack of rigor and reproducibility in the preclinical studies. To address this, we have established the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) small animal multisite acute myocardial infarction (AMI) network, with centralized randomization and blinded core laboratory IS analysis, and have validated the network using ischemic preconditioning (IPC). Eight sites from the COST Innovators Grant (IG16225) network participated in the IMPACT AMI study. Mice and rats were randomly allocated into Sham, Control, or IPC groups. The IRI group underwent 45 min (mice) or 30 min (rats) of left coronary artery occlusion followed by 24 h reperfusion. IPC comprised three cycles of 5 min occlusion/reperfusion before IRI. IS was determined by a blinded core lab. The majority of site showed significant cardioprotection with IPC. In pooled mouse data, IPC (N = 42) reduced IS/AAR by 35% compared to control (N = 48) (30 ± 16% versus 46 ± 13%; p < 0.005), and in rat data, IPC (N = 36) reduced IS/AAR by 29% when compared to control (N = 39) (32 ± 19% versus 45 ± 14%; p < 0.01). The IMPACT multisite mouse and rat AMI networks, with centralized randomization and blinded core IS analysis, were established to improve the reproducibility of cardioprotective interventions in preclinical studies and to facilitate the translation of these therapies for patient benefit.
Kelm N, Kespohl M, Smagurauskaite G
… +12 more, Vales S, Karuppanan K, Mburu P, Thiele A, Pinkert S, Bukur T, Mülleder M, Berndt N, Klingel K, Gaida MM, Bhattacharya S, Beling A
Basic Res Cardiol
· 2025 Apr · PMID 40009121
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Myocarditis, an inflammatory disease of the heart muscle, is often triggered by viral infections. This inflammation, which can lead to severe cardiac dysfunction and adverse outcomes, is mediated by various CC and CXC ch...Myocarditis, an inflammatory disease of the heart muscle, is often triggered by viral infections. This inflammation, which can lead to severe cardiac dysfunction and adverse outcomes, is mediated by various CC and CXC chemokines that interact with receptors in a "one-to-many" fashion. Ticks have evolved chemokine-binding salivary proteins known as Evasins, which efficiently suppress inflammation. This study explores a tailored Evasin-derived CC chemokine-targeting strategy using a 17-mer synthetic dimeric peptide, BK1.3. This peptide inhibits the inflammatory chemokines CCL2, CCL3, CCL7, and CCL8 in murine Coxsackievirus B3 (CVB3) infection, a viral trigger of myocarditis. Administered at a dose of 5 mg/kg twice daily, BK1.3 effectively maintains virus control without exacerbating CVB3-induced morbidity markers, such as hemodynamic compromise, multiorgan failure with hepatitis and pancreatitis, hypothermia, hypoglycemia, and weight loss. Metabolic profiling combined with proteomics reveals preserved reprogramming of lipid storage and gluconeogenesis capacity in the liver, alongside sustained energy production in the injured heart muscle. In survivors of acute CVB3 infection exhibiting manifestations of the subacute phase, BK1.3 enhances virus control, reduces myeloid cell infiltration in the heart and liver, improves markers of liver injury, and alleviates cardiac dysfunction, as evidenced by echocardiographic global longitudinal strain analysis. These findings affirm the safety profile of BK1.3 peptide therapeutics in a preclinical mouse model of acute CVB3 infection and emphasize its potential for therapeutic advancement in addressing virus-induced inflammation in the heart.
Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulato...Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.
Crooijmans C, Jansen TPJ, Meeder JG
… +28 more, Woudstra J, Meuwissen M, De Vos AMJ, Paradies V, Olde Bijvank EGM, Winkler P, Vos NS, Arkenbout K, Woudstra P, Stoel MG, Van de Hoef TP, Van den Oord SCH, Widdershoven JWMG, Remkes W, Cetinyurek-Yavuz A, Den Ruijter HM, Onland-Moret NC, Boersma E, Beijk MAM, Appelman Y, Piek JJ, Konst RE, Maas AHEM, Van Royen N, Dimitriu-Leen AC, Elias-Smale SE, Damman P, NL-CFT Investigators
JAMA Cardiol
· 2025 Apr · PMID 39969865
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IMPORTANCE: Patients with angina and no obstructive coronary artery disease frequently have coronary vasomotor dysfunction as underlying pathophysiological mechanism, comprising epicardial spasm, microvascular spasm, and...IMPORTANCE: Patients with angina and no obstructive coronary artery disease frequently have coronary vasomotor dysfunction as underlying pathophysiological mechanism, comprising epicardial spasm, microvascular spasm, and/or microcirculatory dysfunction. These endotypes can be diagnosed by invasive coronary function testing which has previously shown to be safe in tertiary and expert centers. OBJECTIVE: To determine the prevalence of vasomotor dysfunction in patients with angina and no obstructive coronary artery disease who were clinically referred for a coronary function test (CFT); and assess safety and feasibility of a CFT. DESIGN, SETTING, AND PARTICIPANTS: This quality improvement study was performed using the Netherlands Registry of Invasive Coronary Vasomotor Function Testing (NL-CFT), a prospective, observational registry, in 15 participating hospitals (2 tertiary and 13 nontertiary). Patients with angina and no obstructive coronary artery disease who were referred for a clinically indicated CFT between December 2020 and January 2024 were included. MAIN OUTCOMES AND MEASURES: A complete CFT consisted of acetylcholine spasm provocation testing and assessment of microcirculatory function. Prevalence of different endotypes based on test results and overall safety were assessed. RESULTS: Among a total of 1207 patients included, 978 (81%) were female; and the mean (SD) age was 60 (10) years. The prevalence of coronary vasomotor dysfunction was very high (78%). There were 11 (0.9%) major and 10 (0.8%) minor complications reported. Of them, 3 major and all minor were definitely related to the coronary function test. No procedural death, myocardial infarction, or stroke was observed. No differences were found in the occurrence of complications between tertiary and nontertiary centers. CONCLUSIONS AND RELEVANCE: This study found that a CFT was feasible and safe to perform in both tertiary and nontertiary centers with a high diagnostic yield.
Gustafsson F, Uriel N, Netuka I
… +20 more, Katz JN, Pagani FD, Connors JM, Jorde UP, Zimpfer D, Pya Y, Conway J, Anyanwu A, Scandroglio AM, Sulemanjee N, Atluri P, Keebler M, Selzman CH, Alexis JD, Hayward C, Henderson J, Dirckx N, Gazzola C, Mehra MR, ARIES Investigators
JAMA Cardiol
· 2025 Mar · PMID 39774588
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IMPORTANCE: The Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart Failure (ARIES-HM3) study demonstrated that aspirin may be safely eliminated from the antithrombotic regimen af...IMPORTANCE: The Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart Failure (ARIES-HM3) study demonstrated that aspirin may be safely eliminated from the antithrombotic regimen after HeartMate 3 (HM3 [Abbott Cardiovascular]) left ventricular assist device (LVAD) implantation. This prespecified analysis explored whether conditions requiring aspirin (prior percutaneous coronary intervention [PCI], coronary artery bypass grafting [CABG], stroke, or peripheral vascular disease [PVD]) would influence outcomes differentially with aspirin avoidance. OBJECTIVE: To analyze aspirin avoidance on hemocompatibility-related adverse events (HRAEs) at 1 year after implant in patients with a history of CABG, PCI, stroke, or PVD. DESIGN, SETTING, AND PARTICIPANTS: This was an international, multicenter, prospective, double-blind, placebo-controlled, randomized clinical trial including patients implanted with a de novo HM3 LVAD across 51 centers. Data analysis was conducted from April to July 2024. INTERVENTIONS: Patients were randomized in a 1:1 ratio to receive aspirin (100 mg per day) or placebo, in addition to a vitamin K antagonist (VKA) targeted to an international normalized ratio of 2 to 3 in both groups. MAIN OUTCOMES AND MEASURES: Primary end point (assessed for noninferiority) was a composite of survival free of any nonsurgical (>14 days after implant) HRAEs including stroke, pump thrombosis, bleeding, and arterial peripheral thromboembolism at 12 months. Secondary end points included nonsurgical bleeding, stroke, and pump thrombosis events. RESULTS: Among 589 of 628 patients (mean [SD] age, 57.1 [13.7] years; 456 male [77.4%]) who contributed to the primary end point analysis, a history of PCI, CABG, stroke, or PVD was present in 41% (240 of 589 patients). There was no interaction between the presence of an atherosclerotic vascular condition and effect of aspirin compared with placebo (P for interaction= .23). The preset 10% noninferiority margin was not crossed for the studied subgroup of patients. Thrombotic events were rare, with no differences between aspirin and placebo in patients with and without vascular disease (P for interaction = .77). Aspirin treatment was associated with a higher rate of nonsurgical major bleeding events in the group with prior vascular condition history compared with those without aspirin (rate ratio for placebo compared with aspirin, 0.52; 95% CI, 0.35-0.79). CONCLUSIONS AND RELEVANCE: Results of this prespecified analysis of the ARIES-HM3 randomized clinical trial demonstrate that in patients with advanced heart failure who have classical indications for antiplatelet therapy use at the time of LVAD implantation, aspirin avoidance was safe and not associated with increased thrombosis risk. Importantly, elimination of aspirin was associated with no increased thrombosis but a reduction in nonsurgical bleeding events in patients with a history of PCI, CABG, stroke, or PVD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04069156.
Bellini B, Romano V, Zanda G
… +15 more, Iannopollo G, De Ferrari T, Bijlsma E, Napoli F, Vella C, Gentile D, Ghizzoni G, Ferri LA, Russo F, Ancona MB, Ancona F, Agricola E, Palmisano A, Esposito A, Montorfano M
Can J Cardiol
· 2025 May · PMID 39667491
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BACKGROUND: Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve (BAV) disease is still burdened by a non-negligible rate of stroke and permanent pacemaker implantation (PPI). These subopt...BACKGROUND: Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve (BAV) disease is still burdened by a non-negligible rate of stroke and permanent pacemaker implantation (PPI). These suboptimal results, possibly related to the unique BAV anatomy, may suggest the use of a different sizing method in this setting. The aim of our study is to evaluate whether the application of the supra-annular LIRA method may improve clinical outcomes in this population. METHODS: In this single-center retrospective study, we enrolled consecutive patients with severe aortic stenosis and raphe-type BAV undergone TAVR with the implantation of supra-annular self-expanding prostheses sized according to the LIRA method. The primary endpoint was the device success. Secondary endpoints were in-hospital and 30-day safety outcomes and 1-year clinical efficacy. All study endpoints were adjudicated according to the Valve Academic Research Consortium 3 criteria. RESULTS: A total of 104 patients (mean age, 79.8 ± 5.83 years) were enrolled in our study. The mean Society of Thoracic Surgeons score was 4.96 ± 4.73%. Use of the LIRA method led to prosthesis downsizing in 85.6% of patients. Device success was 94.2%. All-cause death was 0%, conversion to surgery was 0%, and an extremely low rate of stroke (1.9%) and PPI (9.6%) was observed. The intended performance of the valve was attained in 96.1% of patients and it was maintained at 1-year follow-up. Clinical efficacy at 1 year was reached in 90.6% of patients. CONCLUSIONS: The LIRA method represents an alternative option for prosthesis sizing in patients with type 1 and type 2 BAV undergoing TAVR with promising early and midterm outcomes.
Stevic N, Pinède A, Mewton N
… +6 more, Ovize M, Argaud L, Lecour S, Boiteux C, Bochaton T, Cour M
Basic Res Cardiol
· 2024 Dec · PMID 39579225
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Ventricular fibrillation (VF)-induced cardiac arrest frequently complicates ST-segment elevation myocardial infarction (STEMI). Although larger infarct sizes (IS) correlate with a higher risk of VF, the influence of VF i...Ventricular fibrillation (VF)-induced cardiac arrest frequently complicates ST-segment elevation myocardial infarction (STEMI). Although larger infarct sizes (IS) correlate with a higher risk of VF, the influence of VF itself on IS has remained poorly investigated. To address this knowledge gap, we analyzed the effect of VF on IS in patients and two experimental models. From a prospective cohort, 30 STEMI patients with VF were matched 1:2 with STEMI patients without VF on the common determinants of IS. The primary endpoint was IS, assessed using the 48-h area under the curve (AUC) for troponin. We also compared IS in pigs with/without spontaneous VF during STEMI (n = 15/group), and in an isolated rat heart model of myocardial infarction with/without electrically induced VF (n = 7/group). After matching, the patient characteristics, including the area at risk (AR), were similar. IS was 33% lower in the VF group compared to the control group (troponin AUC 1.6 [0.5-3.3] 10 arbitrary units vs. 2.4 [0.9-4.1] 10 arbitrary units; p < 0.05), but infarct scar size (assessed using MRI and ECG) did not differ between the groups at 1 and 6 months. In both experimental models, IS, expressed as a percentage of AR, was lower (p < 0.05) in the VF group than in the control group. When common determinants of IS are comparable, VF occurring prior to myocardial infarction reperfusion appears to be associated with smaller IS. Nevertheless, this finding, observed under specific experimental conditions and in a highly selected group of patients, was not associated with reduced infarct scar size.Registration (HIBISCUS-STEMI cohort): ClinicalTrials.gov NCT05794022.
Trenkwalder T, Maj C, Al-Kassou B
… +64 more, Debiec R, Doppler SA, Musameh MD, Nelson CP, Dasmeh P, Grover S, Knoll K, Naamanka J, Mordi IR, Braund PS, Dreßen M, Lahm H, Wirth F, Baldus S, Kelm M, von Scheidt M, Krefting J, Ellinghaus D, Small AM, Peloso GM, Natarajan P, Thanassoulis G, Engert JC, Dufresne L, Franke A, Görg S, Laudes M, Nowak-Göttl U, Vaht M, Metspalu A, Stoll M, Berger K, Pellegrini C, Kastrati A, Hengstenberg C, Lang CC, Kessler T, Hovatta I, Nickenig G, Nöthen MM, Krane M, Schunkert H, Samani NJ, Schumacher J, Kals M, Reigo A, Teder-Laving M, Gehlen J, Webb TR, Giel AS, Koebbe LL, Feirer N, Billmann M, Srinivasan S, Zimmer S, Palmer CNA, Li L, Yang C, Borisov O, Adam M, Veulemans V, Joner M, Xhepa E, TARGET Consortium; Estonian Biobank; and the European Consortium for Genetics of Aortic Stenosis (EGAS)
JAMA Cardiol
· 2025 Feb · PMID 39504041
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IMPORTANCE: Aortic stenosis (AS) and coronary artery disease (CAD) frequently coexist. However, it is unknown which genetic and cardiovascular risk factors might be AS-specific and which could be shared between AS and CA...IMPORTANCE: Aortic stenosis (AS) and coronary artery disease (CAD) frequently coexist. However, it is unknown which genetic and cardiovascular risk factors might be AS-specific and which could be shared between AS and CAD. OBJECTIVE: To identify genetic risk loci and cardiovascular risk factors with AS-specific associations. DESIGN, SETTING, AND PARTICIPANTS: This was a genomewide association study (GWAS) of AS adjusted for CAD with participants from the European Consortium for the Genetics of Aortic Stenosis (EGAS) (recruited 2000-2020), UK Biobank (recruited 2006-2010), Estonian Biobank (recruited 1997-2019), and FinnGen (recruited 1964-2019). EGAS participants were collected from 7 sites across Europe. All participants were of European ancestry, and information on comorbid CAD was available for all participants. Follow-up analyses with GWAS data on cardiovascular traits and tissue transcriptome data were also performed. Data were analyzed from October 2022 to July 2023. EXPOSURES: Genetic variants. MAIN OUTCOMES AND MEASURES: Cardiovascular traits associated with AS adjusted for CAD. Replication was performed in 2 independent AS GWAS cohorts. RESULTS: A total of 18 792 participants with AS and 434 249 control participants were included in this GWAS adjusted for CAD. The analysis found 17 AS risk loci, including 5 loci with novel and independently replicated associations (RNF114A, AFAP1, PDGFRA, ADAMTS7, HAO1). Of all 17 associated loci, 11 were associated with risk specifically for AS and were not associated with CAD (ALPL, PALMD, PRRX1, RNF144A, MECOM, AFAP1, PDGFRA, IL6, TPCN2, NLRP6, HAO1). Concordantly, this study revealed only a moderate genetic correlation of 0.15 (SE, 0.05) between AS and CAD (P = 1.60 × 10-3). Mendelian randomization revealed that serum phosphate was an AS-specific risk factor that was absent in CAD (AS: odds ratio [OR], 1.20; 95% CI, 1.11-1.31; P = 1.27 × 10-5; CAD: OR, 0.97; 95% CI 0.94-1.00; P = .04). Mendelian randomization also found that blood pressure, body mass index, and cholesterol metabolism had substantially lesser associations with AS compared with CAD. Pathway and transcriptome enrichment analyses revealed biological processes and tissues relevant for AS development. CONCLUSIONS AND RELEVANCE: This GWAS adjusted for CAD found a distinct genetic risk profile for AS at the single-marker and polygenic level. These findings provide new targets for future AS research.
Kleinbongard P, Arriola CG, Badimon L
… +17 more, Crisostomo V, Giricz Z, Gyöngyösi M, Heusch G, Ibanez B, Kiss A, de Kleijn DPV, Podesser BK, Carracedo RR, Rodríguez-Sinovas A, Ruiz-Meana M, Sanchez Margallo FM, Vilahur G, Zamorano JL, Zaragoza C, Ferdinandy P, Hausenloy DJ
Basic Res Cardiol
· 2024 Dec · PMID 39422732
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Numerous cardioprotective interventions have been reported to reduce myocardial infarct size (IS) in pre-clinical studies. However, their translation for the benefit of patients with acute myocardial infarction (AMI) has...Numerous cardioprotective interventions have been reported to reduce myocardial infarct size (IS) in pre-clinical studies. However, their translation for the benefit of patients with acute myocardial infarction (AMI) has been largely disappointing. One reason for the lack of translation is the lack of rigor and reproducibility in pre-clinical studies. To address this, we have established the European IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) pig AMI network with centralized randomization and blinded core laboratory IS analysis and validated the network with ischemic preconditioning (IPC) as a positive control. Ten sites in the COST Innovators Grant (IG16225) network participated in the IMPACT network. Three sites were excluded from the final analysis through quality control of infarct images and use of pre-defined exclusion criteria. Using a centrally generated randomization list, pigs were allocated to myocardial ischemia/reperfusion (I/R, N = 5/site) or IPC + I/R (N = 5/site). The primary endpoint was IS [% area-at-risk (AAR)], as quantified by triphenyl-tetrazolium-chloride (TTC) staining in a centralized, blinded core laboratory (5 sites), or IS [% left-ventricular mass (LV)], as quantified by a centralized, blinded cardiac magnetic resonance (CMR) core laboratory (2 sites). In pooled analyses, IPC significantly reduced IS when compared to I/R (57 ± 14 versus 32 ± 19 [%AAR] N = 25 pigs/group; p < 0.001; 25 ± 13 versus 14 ± 8 [%LV]; N = 10 pigs/group; p = 0.021). In site-specific analyses, in 4 of the 5 sites, IS was significantly reduced by IPC when compared to I/R when quantified by TTC and in 1 of 2 sites when quantified by CMR. A pig AMI multicenter European network with centralized randomization and core blinded IS analysis was established and validated with the aim to improve the reproducibility of cardioprotective interventions in pre-clinical studies and the translation of cardioprotection for patient benefit.