Journal Of Clinical & Experimental Cardiology[JOURNAL]
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200 papers
From kidney injury to cardiac dysfunction: the central role of oxidative stress in diabetes and CKD.
Sen P, Sittig T, Hamers J … +14 more , d'Ambrosio L, Ornek I, Zhang J, Shashikadze B, Stöckl JB, Bachter M, Bierschenk S, Renner S, Wolf E, Clauss S, Fröhlich T, Nickel AG, Maack C, Merkus D
Basic Res Cardiol · 2026 Feb · PMID 41419687 · Full text
Both diabetes mellitus (DM) and chronic kidney disease (CKD) predispose to cardiac remodeling and coronary microvascular dysfunction, which is proposed to be mediated through increased oxidative stress. To link oxidative...
Both diabetes mellitus (DM) and chronic kidney disease (CKD) predispose to cardiac remodeling and coronary microvascular dysfunction, which is proposed to be mediated through increased oxidative stress. To link oxidative stress and cardiac remodeling in DM and CKD, CKD was induced in genetically modified DM swine (INS transgenic) at 10-12 weeks of age via renal microembolization, while non-embolized DM and wild-type (WT) swine served as controls. Compared to WT, 1) DM animals displayed modest LV dilation and a slight decline in ejection fraction, with increased end-systolic pressures and coronary blood flow. Addition of CKD did not further aggravate these alterations, but increased the pressure and diastolic wall stress compared to WT. 2) Proteomic analysis revealed enrichment in metabolic pathways involving fatty acids and glutamate, thus highlighting substantial metabolic reprogramming in both DM and DM_CKD groups. Re-analysis of proteomic data from human HFpEF patients showed differential regulation of similar pathways as well as anti-oxidant enzymes. 3) Isolated mitochondrial respiration was reduced in DM and DM_CKD hearts across multiple substrates (fatty acids, pyruvate-malate, glutamate-malate, and succinate), implicating broad mitochondrial dysfunction. 4) DM_CKD animals showed heightened oxidative stress in both coronary vasculature and myocardium as compared to both WT and DM [13 ± 3 (WT), 14 ± 3 (DM) and 39 ± 10% positive nuclei (DM_CKD)]. 5) LV-interstitial fibrosis was increased in DM_CKD (3.72 ± 0.50%) vs WT (1.70 ± 0.29%), with DM having an intermediate phenotype (2.82 ± 0.37%). Thus, even mild CKD in the presence of DM is accompanied by oxidative stress and ECM deposition. Our findings highlight the critical role of CKD in accelerating cardiac pathology and underscore the importance of targeting the cardiorenal axis in future therapeutic strategies.
Serum amyloid A in HFpEF and cardiometabolic diseases.
Liu L, Wang R, Strocchi S … +5 more , Eroglu T, Nambiar N, Liévano Contreras SV, Diezel SA, Schiattarella GG
Basic Res Cardiol · 2026 Feb · PMID 41313351 · Full text
Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of all heart failure cases, and its prevalence is projected to rise further. Among its heterogeneous subtypes, cardiometabolic HFpEF, whi...
Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of all heart failure cases, and its prevalence is projected to rise further. Among its heterogeneous subtypes, cardiometabolic HFpEF, which is driven by metabolic dysfunction, represents a globally predominant form. Recent advances in preclinical models have highlighted metabolic disturbances and systemic inflammation as key contributors to HFpEF pathogenesis. While much attention has focused on classical inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), the full spectrum of upstream inflammatory drivers and the therapeutic strategies targeting inflammation in cardiometabolic HFpEF remain incompletely defined. Among emerging candidates, serum amyloid A (SAA) family proteins, highly inducible acute-phase proteins, have attracted growing attention due to their elevated levels in chronic metabolic diseases. Here, we summarize clinical associations between elevated SAA levels and major cardiometabolic conditions-including obesity, diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), and hypertension-and discuss potential mechanisms based on preclinical studies. We place particular emphasis on the known and potential pathogenetic role of SAA in cardiometabolic HFpEF, where it may contribute to systemic inflammation, endothelial dysfunction, and myocardial fibrosis. Overall, this review aims to advance understanding of SAA in HFpEF and cardiometabolic disease, and to support translational efforts toward improved diagnosis and treatment.
Impairment of local metabolic coronary control involves perfusion-contraction matching not supply-demand imbalance.
Essajee SI, Dick GM, Tucker SM … +5 more , Warne CM, Figueroa CA, Beard DA, Duncker DJ, Tune JD
Basic Res Cardiol · 2026 Feb · PMID 41266900 · Full text
Understanding of local metabolic control of coronary flow remains stifled by debate around data interpretation and anticipated outcomes. To address this question we performed experiments in a cannulated coronary preparat...
Understanding of local metabolic control of coronary flow remains stifled by debate around data interpretation and anticipated outcomes. To address this question we performed experiments in a cannulated coronary preparation in swine to precisely control flow as myocardial oxygen consumption (MVO) and contractile function were modulated by dobutamine (1-10 μg/kg/min, iv), reductions in coronary perfusion pressure (CPP), and the inhibition of voltage-gated K channels with 4-aminopyridine (4-AP; 1 mM, ic). Reduction of CPP to 40 mmHg diminished coronary flow (~ 55%; P < 0.001) and systolic wall thickening (~ 35%; P < 0.001). 4-AP-mediated reductions in coronary flow (~ 35%; P = 0.01) and wall thickening (~ 40%; P < 0.05) were restored by returning coronary flow to normal baseline levels. Dobutamine increased heart rate and coronary flow ~ 65% (P < 0.001) and coronary flow remained tightly coupled with MVO. Inhibition of coronary responses to dobutamine was associated with an ~ 35% reduction in wall thickening and an ~ 50% increase in MVO. Reductions in CPP, administration of 4-AP, and diminished flow during dobutamine infusion were associated with proportional decreases in coronary flow and MVO. Wall thickening progressively decreased as coronary flow was reduced below ~ 5.0-7.5 μL/g/beat regardless of whether the decrease was due to diminished "supply" (CPP, 4-AP) or limitations during increased "demand" (flow clamp or restriction with dobutamine). These findings demonstrate that impairments in local metabolic control of coronary flow are reliably demonstrated by decreases in contractile function as a consequence of reductions in the volume of myocardial perfusion per beat.
Efficacy and Safety of Sglt-2 Inhibitors In Renal Allograft Recipients: an Open-Label, Single-Center Prospective Study.
Novikova MS, Minushkina LO, Allazova SS … +8 more , Zateyshchikov DA, Boeva OI, Kotenko ON, Vinogradov VE, Shilov EM, Antsiferov MB, Koteshkova OM, Molina LP
Kardiologiia · 2025 Oct · PMID 41129246 · Publisher ↗
Aim To evaluate the safety and efficacy of sodium-glucose cotransporter-2 inhibitor (SGLT-2i) inhibitor therapy in kidney transplant recipients (KTRs) with and without post-transplant diabetes mellitus (PTDM).Material...
Aim To evaluate the safety and efficacy of sodium-glucose cotransporter-2 inhibitor (SGLT-2i) inhibitor therapy in kidney transplant recipients (KTRs) with and without post-transplant diabetes mellitus (PTDM).Material and methods KTRs (n=2146, with PTDM n=303, or 14%) who had undergone transplantation more than one year ago, with stable graft function (estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2), after excluding patients with combined kidney and pancreas transplantation (n=57), type 1 diabetes mellitus (DM) (n=124), and type 2 DM diagnosed before kidney allotransplantation (KAT) (n=74), were prescribed SGLT-2i (empagliflozin 25 mg/day or dapagliflozin 10 mg/day; n=107), the rest of the KTRs (n=1784) did not receive SGLT-2i. After pseudo-randomization, two groups were formed and included in an open, single-center prospective study: an experimental group with SGLT-2i (n=78; with PTDM n=45) and a control group, without SGLT-2i (n=78; n=45 with PTDM). The groups were comparable in the PTDM duration and the period from KAT to inclusion in the study, as well as in clinical characteristics, including gender, age, history of acute myocardial infarction (AMI) before KAT, levels of glycated hemoglobin (HbA1c), systolic blood pressure (SBP) and diastolic blood pressure (DBP), GFR, microalbuminuria (MAU), blood uric acid concentration, blood lipid profile (total cholesterol (TC), low-density lipoproteins (LDL)), basal blood concentration (C0) of calcineurin inhibitors (CNI), and therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), statins, and metformin (p >0.05).Results The relative risk (RR) of all-cause death in the experimental group was reduced by 60% compared with the control group (RR 0.40; 95% confidence interval (CI) 0.17-0.98 vs. RR 2.44; 95% CI 1.01-5.86; p=0.04). The RR of adverse coronary outcomes in the experimental group was reduced by 75% compared with the control group (RR 0.25; 95% CI 0.06-0.89 vs. 4.0; 95% CI 1.11-14.42; p=0.03). The RR of adverse renal outcomes in the experimental group was reduced by 72% compared with the control group (RR 0.28; 95% CI 0.09-0.85 vs. 3.50; 95% CI 1.16-10.49; p=0.02). In addition, in the experimental group, compared to the control group, the GFR decline was slower (-1.29±0.763 ml/min/1.73 m2/year vs. -3.33±0.767 ml/min/1.73 m2/year; p=0.047). Also, a pronounced advantage in the dynamic decline in GFR was observed throughout the entire study period (-3.10±1.73 ml/min/1.73 m2 vs. -7.87±1.87 ml/min/1.73 m2; p=0.040).Conclusion SGLT2i effectively reduce cardiovascular and renal mortality, the risk of adverse renal and coronary outcomes, and slow the progression of chronic kidney disease in KTRs, regardless of the presence of PTDM. A large-scale study evaluating the efficacy of SGLT2i in KTRs is warranted to formulate appropriate clinical recommendations.
Multimodal, device-based therapeutic targeting of the cardiovascular autonomic nervous system.
Paton JFR, Żera T, Vadigepalli R … +2 more , Herring N, Paterson DJ
Nat Rev Cardiol · 2026 Apr · PMID 41034673 · Publisher ↗
The miniaturization of implantable sensors and actuators, combined with advances in interactive modelling and high-resolution imaging, is propelling the use of medical devices for counteracting impaired neural control of...
The miniaturization of implantable sensors and actuators, combined with advances in interactive modelling and high-resolution imaging, is propelling the use of medical devices for counteracting impaired neural control of the cardiovascular system. In this Review, we discuss the current effectiveness of this technology for modulating autonomic activity in numerous cardiovascular conditions, including high blood pressure, heart failure and cardiac arrhythmias. We advocate for smarter closed-loop bionic devices fitted with feedback from multiple sensors to allow adaptive, state-dependent control, and discuss how the adoption of artificial intelligence technology would facilitate auto-personalization to meet the needs of patients. We also describe how transcriptomics of autonomic circuits can guide device-based approaches. Finally, the use of stem cell therapies to target sympathetic circuits more precisely will help to optimize the therapeutic effects of autonomic modulation for the treatment of arrhythmia. For bioelectronic medicine to achieve clinical utility in neurocardiology, these innovations must demonstrate improved efficacy beyond that offered by contemporary interventions.
Polygenic Susceptibility in Peripartum, Alcohol-Induced, and Cancer Therapy-Related Cardiomyopathies.
Maamari DJ, Biddinger KJ, Jurgens SJ … +18 more , Rämö JT, Gaziano L, Zheng A, Challa SP, Hayes D, Gongora CA, Choi SH, Chang KM, Tsao PS, Arany Z, Thavendiranathan P, Huffman JE, Fahed AC, Sarma AA, Neilan TG, Khera AV, Ellinor PT, Aragam KG
JAMA Cardiol · 2025 Nov · PMID 41032333 · Full text
IMPORTANCE: Rare monogenic variants linked to nonischemic dilated cardiomyopathy (DCM) are enriched among individuals with secondary cardiomyopathies, such as peripartum (PPCM), alcohol-induced (ACM), and cancer therapy-...
IMPORTANCE: Rare monogenic variants linked to nonischemic dilated cardiomyopathy (DCM) are enriched among individuals with secondary cardiomyopathies, such as peripartum (PPCM), alcohol-induced (ACM), and cancer therapy-related (CCM) cardiomyopathies. However, it remains unclear whether a polygenic predisposition to DCM also contributes to these conditions. OBJECTIVE: To assess the association of a DCM polygenic score with PPCM, ACM, and CCM, and to evaluate the contributions of monogenic and polygenic susceptibilities to these secondary cardiomyopathies. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective genetic association analysis of data from the Mass General Brigham (MGB) Biobank (n = 42 137, 2008-2025), with replication in the UK Biobank (n = 295 160, 2005-2010), FinnGen (n = 417 950, 2017-2025), and the Veterans Affairs Million Veteran Program (n = 516 066, 2011-2025). In MGB Biobank, medical records were reviewed to ascertain secondary cardiomyopathy cases and antecedent clinical risk factors. EXPOSURES: DCM polygenic risk score and DCM monogenic variants. MAIN OUTCOMES AND MEASURES: The primary outcomes were the association of the DCM polygenic risk score with PPCM, ACM, and CCM and the prevalence of monogenic variants and a high polygenic score among individuals with cardiomyopathy. RESULTS: The mean (SD) age in the MGB Biobank was 55.7 (17.0) years at enrollment, and 24 551 (58.3%) were female. Across the 4 study cohorts, 3414 individuals with secondary cardiomyopathy were identified, including 70 with PPCM, 2281 with ACM, and 1063 with CCM. The DCM polygenic score was associated with PPCM (odds ratio [OR], 1.82 per SD; 95% CI, 1.43-2.30), ACM (OR, 1.56; 95% CI,1.34-1.82), and CCM (OR, 1.64; 95% CI,1.24-2.15) (all with P < .001). Monogenic variants were enriched but present in 7 of 113 individuals with medical record-reviewed cardiomyopathy in MGB, while 66 had a high polygenic score, which conferred an approximately 3-fold increased odds of cardiomyopathy. Most individuals with cardiomyopathy lacked antecedent clinical risk factors. CONCLUSIONS AND RELEVANCE: In this cohort study, individuals with PPCM, ACM, and CCM were enriched for monogenic DCM variants and a high DCM polygenic score, suggesting a shared genetic susceptibility influenced by distinct environmental precipitants. These findings support a shared genetic architecture between secondary cardiomyopathies and DCM, although additional work with larger numbers of individuals with cardiomyopathy is needed to confirm these findings.
The CNP analogue vosoritide mediates PDE2-sensitive anti-arrhythmogenic effects in mouse hearts with STZ-induced type 1 diabetes.
Firneburg R, Tergau K, Cachorro E … +7 more , Schubert M, Dhara A, Luo X, Klapproth E, Guan K, El-Armouche A, Kämmerer S
Basic Res Cardiol · 2025 Dec · PMID 40965622 · Full text
Diabetes mellitus induces adverse structural, electrophysiological and autonomic remodelling increasing the risk for life-threatening arrhythmias, particularly after acute myocardial infarction. Natriuretic peptides (NPs...
Diabetes mellitus induces adverse structural, electrophysiological and autonomic remodelling increasing the risk for life-threatening arrhythmias, particularly after acute myocardial infarction. Natriuretic peptides (NPs) show increasing evidence of antagonising arrhythmia. Our previous study demonstrated that C-type NP (CNP) reduces arrhythmia after ischaemia-reperfusion injury (I/R) via the cGMP-dependent phosphodiesterase 2 (PDE2) in healthy mice. However, the clinical use of CNP is challenging due to its short plasma half-life. To address this, we investigated whether the more stable CNP analogue vosoritide (VO) reduces arrhythmia at cellular and organ levels in mice with STZ-induced type 1 diabetes (50 µg/g, i.p. for 5 days). After 5 weeks, STZ treatment led to elevated blood glucose and HbA1c levels, impaired cardiac function, and an increased incidence of arrhythmia after I/R in ex vivo perfused hearts. Cardiac PDE2 expression was similarly increased in diabetic mice and diabetic patients with dilated cardiomyopathy. Notably, cGMP-mediated PDE2 activation via VO clearly reduced arrhythmia generation after I/R in ex vivo perfused hearts from diabetic mice (Cohen's d = 2.3). In cardiomyocytes, VO significantly decreased pro-arrhythmic signals upon β-adrenergic stress, such as spontaneous Ca waves and sparks (Cohen's d = 1.0) or L-type Ca current amplitudes (Cohen's d = 1.6). Specific PDE2 inhibition with BAY 60-7550 or genetic cardiomyocyte-specific PDE2 deletion prevented the anti-arrhythmic VO effects. Importantly, VO did not affect the QT interval, action potential duration, or contraction of cardiomyocytes from diabetic mice. Thus, the modified natriuretic peptide VO may serve as a promising therapeutic option to prevent lethal arrhythmias in susceptible diabetic patients.
Downregulation of TCF19 and ATAD2 causes endothelial cell cycle arrest at the transition from cardiac hypertrophy to heart failure.
Erny E, Koentges C, Mukherjee D … +6 more , Wirth L, Kamaras C, Zell F, Hossfeld M, Groß O, Lother A
Basic Res Cardiol · 2025 Dec · PMID 40962957 · Full text
Cardiac hypertrophy is a key mechanism that allows the heart to adapt to increased load, but in the long term is associated with a higher risk for heart failure, arrhythmia, and death. During hypertrophic growth, cardiac...
Cardiac hypertrophy is a key mechanism that allows the heart to adapt to increased load, but in the long term is associated with a higher risk for heart failure, arrhythmia, and death. During hypertrophic growth, cardiac myocytes signal to endothelial cells via vascular endothelial growth factor (VEGF) to promote angiogenesis and maintain myocardial oxygen supply. Insufficient angiogenesis leads to a decline in capillary density and drives the progression from compensated cardiac hypertrophy to heart failure. Here, we studied the time course of endothelial cell gene expression during heart failure development and identified transcriptional regulators of cell proliferation and angiogenesis. We applied transverse aortic constriction (TAC) in mice and isolated cardiac endothelial cells for RNA sequencing after 6 h and 1, 3, 7, or 28 days to create an inventory of gene expression during the course of cardiac hypertrophy and failure. Echocardiography revealed that decompensated heart failure occurred between days 7 and 28 after TAC. At the same time, we observed a switch in endothelial cell gene expression with an upregulation of proliferation markers in the hypertrophy state but downregulation in decompensated heart failure. Of note, endothelial cell cycle arrest occurred despite strong VEGF signaling from cardiac myocytes, indicating VEGF resistance. To investigate how endothelial cell proliferation is transcriptionally regulated, we performed a weighted gene co-expression network analysis and identified a module of 180 cell cycle-related genes. We predicted transcription factor 19 (TCF19), ATPase family AAA domain containing 2 (ATAD2), and transcription factor Dp-1 (TFDP1) to be central regulators of this gene module. Knockdown of TCF19 and ATAD2 by siRNA in HUVECs led to a downregulation of the marker of proliferation MKI67 and repressed cell proliferation, tube formation, and cell migration, confirming their regulatory function. In heart tissue biopsies from patients with aortic stenosis, TCF19 and ATAD2 abundance were positively correlated with endothelial cell proliferation. TCF19 or ATAD2 control the expression of a gene network involved in endothelial cell proliferation and angiogenesis. Downregulation of TCF19 and ATAD2 is associated with endothelial cell cycle arrest and an impaired angiogenic response to VEGF signaling that may promote the transition from compensated cardiac hypertrophy to heart failure.
Distal Radial Artery Access With 6F and 7F Thin-Walled Sheaths for Coronary Intervention: A Multicentre, Randomized, DRAWS Trial Protocol.
Liu M, Du Y, Cui C … +29 more , Li C, Yu W, Wang H, Song Y, Gao Z, Song L, Zhai J, Yang Y, Yang W, Wu Y, Liu D, Guo J, Heisha N, Liu H, Zhao Y, Zhang F, Tang Y, Zhao Y, Yu M, Zhang B, Yang J, Li R, Li H, Xiong X, Guo X, Li H, Song Y, Duan F, Gao L
Can J Cardiol · 2025 Dec · PMID 40953816 · Publisher ↗
Distal radial artery access (dTRA) reduces radial artery occlusion (RAO) and improves safety compared with conventional transradial access, yet its use in complex coronary interventions necessitating larger guiding cathe...
Distal radial artery access (dTRA) reduces radial artery occlusion (RAO) and improves safety compared with conventional transradial access, yet its use in complex coronary interventions necessitating larger guiding catheters remains limited. Thin-walled 7F sheaths with reduced external diameter may overcome this barrier. We present the protocol for a multicentre, randomized, open-label, noninferiority trial enrolling 574 patients aged 18 to 80 years with distal radial artery diameter ≥ 1.7 mm who are scheduled for elective percutaneous coronary intervention (PCI) across 5 Chinese centres. Participants are centrally randomized 1:1 to receive either a 7F thin-walled sheath (experimental) or a 6F thin-walled sheath (control) via dTRA. The primary endpoint is RAO and distal RAO at 24 hours, evaluated by Doppler ultrasound. Secondary endpoints include cannulation and procedural success, crossover to alternative access, RAO and distal RAO at 30 days, hematoma (EASY scale), major bleeding (BARC), pain (VAS), functional status (Barthel Index), length of stay, and total hospitalization costs. Data are collected pre-, intra-, and postprocedure, with follow-up at 24 hours and 30 days. Results will provide robust evidence on the safety and efficacy of 7F thin-walled sheaths in dTRA for complex PCI, informing optimal equipment selection and procedural strategies. CLINICAL TRIAL REGISTRATION: NCT06585917.
In vitro and ex vivo Flow Models for Arterial Thrombosis: A Systematic Review.
Eyisoylu H, Cagnazzo R, Koenderink GH … +2 more , de Maat MPM, van Beusekom HMM
Cardiology · 2025 Sep · PMID 40924657 · Publisher ↗
INTRODUCTION: Arterial thrombosis is a multifaceted process characterized by platelet aggregation and fibrin deposition, leading to the occlusion of blood vessels. It plays a central role in cardiovascular conditions suc...
INTRODUCTION: Arterial thrombosis is a multifaceted process characterized by platelet aggregation and fibrin deposition, leading to the occlusion of blood vessels. It plays a central role in cardiovascular conditions such as myocardial infarction and ischemic stroke. Gaining insight into the mechanisms underlying arterial thrombosis is essential for developing effective treatments aimed at preventing thrombotic events and reducing associated health burdens. In vitro and ex vivo models serve as critical tools for investigating the pathophysiology of arterial thrombosis by providing controlled environments to study thrombus formation and characteristics. This systematic review provides a comprehensive overview of in vitro and ex vivo flow-based models used to study arterial thrombosis, classifying them by scale (macro vs. micro) and evaluating their design principles, physiological relevance, and experimental utility. METHODS: A systematic search of Medline, Embase, and Web of Science was conducted using broad and specific terms related to arterial thrombosis models incorporating flow or shear stress. Articles were screened by two independent reviewers. Studies were included if they described in vitro or ex vivo models with dynamic flow; models limited to static or venous conditions or in vivo studies were excluded. In total, 82 studies met the inclusion criteria. RESULTS: Macro-scale models can mimic complex flow patterns in larger arterial conditions and enable the formation of thrombi comparable in size to clinical specimens. Microfluidic models allow precise control over shear conditions and geometry with minimal blood volumes and are suitable for high-resolution imaging and customization, including endothelialization and patient-specific designs. While, both model types present limitations in replicating complex in vivo hemodynamics, standardization, and scalability, they offer valuable, controllable platforms for mechanistic studies and drug testing in arterial thrombosis. CONCLUSIONS: While no single model fully recapitulates the in vivo environment, ongoing innovations, particularly in microfabrication and model standardization, continue to improve physiological relevance and clinical translatability.
MicroRNA Expression Pre-Trastuzumab Treatment in HER-2+ Early Breast Cancer Patients as a Predictor of Cancer Therapy-Related Cardiac Dysfunction: A Pilot Cohort Study.
Pivatto Júnior F, Santos ÂBS, Englert EF … +7 more , Mazzutti G, Costa GOM, Saffi MAL, Siebert M, Liedke PER, Fritsch VH, Biolo A
Cardiology · 2025 Sep · PMID 40920621 · Publisher ↗
INTRODUCTION: At present, existing risk scores together with traditional biomarkers such as troponin and brain natriuretic peptide are still unable to accurately predict cancer therapy-related cardiac dysfunction (CTRCD)...
INTRODUCTION: At present, existing risk scores together with traditional biomarkers such as troponin and brain natriuretic peptide are still unable to accurately predict cancer therapy-related cardiac dysfunction (CTRCD). MicroRNAs (miRNAs) have emerged as promising biomarkers for improved identification of high-risk patients; however, limited studies have been performed in patients with HER2-positive breast cancer. This study aimed to investigate the predictive potential of six serum-derived circulating miRNAs for CTRCD occurrence in patients with early-stage HER2-positive breast cancer receiving trastuzumab (TTZ). METHODS: A prospective cohort study was conducted involving consecutive female patients aged 18 years or older with HER2-positive early breast cancer, who attended the breast oncology outpatient clinic of the institution between March 2019 and March 2022. Blood samples were obtained prior to the initiation of TTZ therapy. CTRCD was defined as a reduction in left ventricular ejection fraction >10 percentage points, resulting in a value <53%. Quantification of miRNAs - including let-7f-5p, miR-1-3p, miR-20a-5p, miR-126-3p, miR-130-3p, and miR-210a-3p - was performed using quantitative real-time polymerase chain reaction. The optimal miRNA cutoff points were determined using the Youden index. CTRCD-free survival was analyzed using Kaplan-Meier curves, with group comparisons conducted via the log-rank test. RESULTS: A total of 47 patients (mean age 53.1 ± 13.2 years) were included and followed for a median of 14.2 months (IQR 10.9-24.5), corresponding to 71.5 patient-years of follow-up. Doxorubicin was administered as part of the treatment regimen in 22 patients (46.8%). Six patients (12.8%) developed CTRCD. Patients exhibiting high baseline expression levels of miR-20a-5p, miR-126-3p, miR-130-3p, and miR-210-3p prior to TTZ treatment demonstrated significantly reduced CTRCD-free survival (all p < 0.05). Elevated levels of miR-126-3p and miR-130-3p showed 100% sensitivity and specificities of 53.7% and 48.8%, respectively, for predicting the development of CTRCD. CONCLUSION: This pilot study suggests that elevated expression of some miRNA prior to TTZ treatment may be associated with lower CTRCD-free survival, but these findings require confirmation in larger, prospective studies. While high levels of miR-126-3p and miR-130a-3p were observed in all patients who developed CTRCD, their potential role as biomarkers of cardiotoxicity risk should be further explored in future research with broader patient cohorts.
Hyperpolarized-MRI in Hypertrophic Cardiomyopathy: A Narrative Review.
Malik A, Kundur SP, Sivalokanathan S
Clin Med Insights Cardiol · 2025 · PMID 40895840 · Full text
Hypertrophic cardiomyopathy is a genetically inherited cardiac disorder that presents with diverse clinical phenotypes. It is associated with significant adverse outcomes, including arrhythmias and sudden cardiac death....
Hypertrophic cardiomyopathy is a genetically inherited cardiac disorder that presents with diverse clinical phenotypes. It is associated with significant adverse outcomes, including arrhythmias and sudden cardiac death. Current gold-standard diagnostic methods include echocardiography and cardiac magnetic resonance imaging. These imaging modalities are the cornerstone in identifying structural abnormalities and aiding risk stratification. However, they fail to capture the preceding cellular and metabolic disturbances that underpin disease progression. Hyperpolarized magnetic resonance imaging (HP-MRI) is an emerging imaging technique that enables non-invasive and non-ionizing visualization of metabolic pathways. HP-MRI enhances the signal of metabolites like [1-C]pyruvate, providing insights into metabolic pathways. Alterations in the metabolic pathways of cardiomyocytes are central to HCM pathophysiology. HP-MRI may be able to delineate the metabolic consequences of sarcomere mutations and distinguish HCM from phenocopies such as glycogen storage disorders or cardiac amyloidosis. More importantly, it has the potential to detect early metabolic shifts and thus play a role in early diagnosis, personalized risk stratification, and monitoring therapeutic response. Although still in experimental stages with technical challenges, HP-MRI has demonstrated considerable potential in preclinical and small-scale studies, exhibiting effectiveness in the diagnosis and monitoring of malignancies across a substantial number of investigations. Further research focusing on larger cohorts and integrating HP-MRI with traditional cardiovascular imaging may pave the way for its clinical use, as well as risk stratification, in HCM.
Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.
Glazer AM, Tabet DR, Parikh VN … +13 more , Kroncke BM, Cote AG, Yamamoto Y, Wang Q, Muhammad A, Lancaster MC, O'Neill MJ, Weile J, Yang T, Macrae CA, Ashley EA, Roth FP, Roden DM
Nat Rev Cardiol · 2026 Mar · PMID 40890511 · Full text
Cardiovascular diseases are leading global causes of death and disability, often presenting as interrelated phenotypes of atherosclerotic vascular disease, heart failure and arrhythmias. Cardiovascular diseases arise fro...
Cardiovascular diseases are leading global causes of death and disability, often presenting as interrelated phenotypes of atherosclerotic vascular disease, heart failure and arrhythmias. Cardiovascular diseases arise from interactions between environmental factors and predisposing genotypes and include common Mendelian lipid disorders, cardiomyopathies and arrhythmia syndromes. The identification of a pathogenic variant through genetic testing can inform disease diagnosis, risk prediction, treatment and family screening. However, a major roadblock in genomic medicine is that for many variants, especially missense variants, we lack sufficient evidence to enable a definitive classification, and therefore these variants are deemed as 'variants of uncertain significance'. In this Review, we describe how multiplexed assays of variant effects can enable the functional assessment of nearly all coding variants in a target sequence, potentially offering a proactive approach to identifying the functional significance of gene variants that are observed later in a patient. We discuss validation, including the role of in silico variant effect predictors, and how multiplexed experimental methods are informing cardiovascular disease biology and ultimately resolving the problem of variants of uncertain significance at scale.
Calcific aortic valve disease augments vesicular microRNA-145-5p to regulate the calcification of valvular interstitial cells via cellular crosstalk.
Goody PR, Christmann D, Goody D … +19 more , Hildebrand S, Billig H, Nehl D, Chennupati R, Gladka M, Wilhelm-Jüngling K, Uchida S, Iris-Bibli S, Moore JB, Hamdani N, Paneni F, Pullamsetti SS, Zimmer S, Jansen F, Bakhtiary F, Aikawa E, Pfeifer A, Nickenig G, Hosen MR
Basic Res Cardiol · 2025 Oct · PMID 40847220 · Full text
Calcific aortic valve disease (CAVD) is one of the leading causes of cardiovascular death in the elderly population worldwide. MicroRNAs (miRNAs) are highly dysregulated in patients with CAVD undergoing surgical aortic v...
Calcific aortic valve disease (CAVD) is one of the leading causes of cardiovascular death in the elderly population worldwide. MicroRNAs (miRNAs) are highly dysregulated in patients with CAVD undergoing surgical aortic valve replacement (SAVR). However, the miRNA-dependent mechanisms regulating inflammation and calcification or miRNA-mediated cell-cell crosstalk during the pathogenesis of CAVD remain poorly understood. Here, we investigated the role of extracellular vesicle (EV)-associated miR-145-5p, which we showed to be strongly upregulated in CAVD in mice and humans during valve calcification. Human TaqMan miRNA arrays identified dysregulated miRNAs in CAVD tissue explants from patients compared to non-calcified (patients with aortic insufficiency) heart valve tissue explants from patients undergoing SAVR. Echocardiographic parameters were measured in conjunction with the quantification of dysregulated miRNAs in a murine CAVD model. In vitro calcification experiments were performed to investigate the effects of EV-miR-145-5p on calcification and crosstalk in heart valve cells. Integrated OMICS analyses were performed to analyze molecular miRNA signatures and their effects on signaling pathways-associated with CAVD. RNA sequencing, high-throughput transcription factor (TF) activity assays, and osteogenesis arrays revealed that a number of genes, miRNAs, TFs are critical for calcification and apoptosis involved in the pathogenesis of CAVD. Among several miRNAs dysregulated in valve explants from CAVD patients, miR-145-5p was the most highly sex-independently upregulated miRNA (AUC, 0.780, p value, 0.01) in patient plasma. Large EV population (170-800 nm) isolated from aortic valve tissues explanted from patients with CAVS (calcific aortic valve stenosis) after SAVR demonstrated a significantly higher level of miR-145-5p expression in comparison to control (vesicle-free plasma). MiRNA arrays utilizing with aortic stenosis samples from patients and mice showed that the expression of miR-145-5p is significantly upregulated and positively correlated with cardiac function based on echocardiography. In vitro experiments confirmed that miR-145-5p is encapsulated in EVs and transported into interstitial cells of the aortic valve. The results of integrated OMICs show that miR-145-5p is related to markers of inflammation, calcification, and apoptosis. In vitro calcification experiments demonstrated that miR-145-5p regulates the ALPL gene, a hallmark of calcification in vascular and heart valve cells. Mechanistically, EV-mediated shuttling of miR-145-5p suppressed the expression of ZEB2, a negative regulator of the ALPL gene, by binding to its 3' untranslated region to inhibit its translation, thereby diminishing the calcification of valvular interstitial cells. Elevated levels of pro-calcific and pro-apoptotic EV-associated miR-145-5p contribute to the progression of CAVD via the ZEB2-ALPL axis, which could potentially be therapeutically targeted to minimize the burden of CAVD.
Sex differences in a murine model of infective endocarditis.
Bartsch B, Jamin RN, Schott A … +8 more , Al Zaidi M, Lübbering N, Billig H, Kurts C, Nickenig G, Parcina M, Zimmer S, Weisheit CK
Basic Res Cardiol · 2025 Oct · PMID 40770580 · Full text
Infective endocarditis (IE) is a highly lethal disease with a notable male predominance, yet the biological basis for this sex disparity remains unclear. We established a murine IE model in C57BL6 mice in which aortic va...
Infective endocarditis (IE) is a highly lethal disease with a notable male predominance, yet the biological basis for this sex disparity remains unclear. We established a murine IE model in C57BL6 mice in which aortic valve injury was induced via wire-injury and followed by intravenous injection of Staphylococcus aureus. Infection was confirmed by blood and valve cultures, and cardiac function was evaluated by echocardiography. Systemic cytokine levels were measured, and immune cell infiltration in valve tissue was assessed by flow cytometry and immunofluorescence. In the murine model, IE was induced in 77/85 animals. Male mice exhibited significantly higher bacterial loads in blood and valves, greater valve cusp enlargement, increased ventricular volumes, and more frequent aortic regurgitation. Both sexes showed strong neutrophilic responses, but males had markedly elevated systemic IL-1α, IL-1β, IL-6, and TNF-α levels. Females demonstrated earlier and more robust recruitment of CD68⁺ and CD206⁺ macrophages, as well as Ly6G⁺ neutrophils, to the injured valve, correlating with reduced bacterial vegetations. This murine model mirrors the clinical sex disparity in IE: males develop more severe disease and systemic inflammation, while females benefit from a rapid, localized immune response. These findings provide a platform for dissecting molecular drivers of sex-specific susceptibility in IE.
European guidelines for hypertension in 2024: a comparison of key recommendations for clinical practice.
Lauder L, Weber T, Böhm M … +18 more , Brouwers S, Bruno RM, Gerdts E, Kreutz R, Lüscher TF, Mancia G, McEvoy JW, McManus RJ, Ntsekhe M, Parati G, Pathak A, de Pinho R, Rahimi K, Sarafidis P, Schutte AE, Williams B, Touyz RM, Mahfoud F
Nat Rev Cardiol · 2025 Sep · PMID 40691360 · Publisher ↗
Hypertension is the most prevalent modifiable risk factor for cardiovascular disease and for cardiovascular and all-cause mortality globally. Suboptimal control of elevated blood pressure places a substantial burden on h...
Hypertension is the most prevalent modifiable risk factor for cardiovascular disease and for cardiovascular and all-cause mortality globally. Suboptimal control of elevated blood pressure places a substantial burden on health-care systems worldwide. Several factors contribute to this suboptimal control, such as limited awareness of hypertension, lack of appropriate diagnosis and poor control of blood pressure among those with a diagnosis. These factors can be due to patient non-adherence to treatment, inertia among health-care professionals and low uptake and implementation of clinical guideline recommendations. From 2003 to 2018, the European Society of Hypertension and the European Society of Cardiology jointly published four sets of guidelines on hypertension. However, the two societies released separate guidelines on hypertension in 2023 and 2024, respectively. These two sets of European guidelines agree on most recommendations, but some differences have been identified. In this Expert Recommendation, we highlight the key consensus recommendations from the two guidelines; compare differing approaches to the definition, classification, diagnosis and treatment of hypertension; and aim to help health-care professionals in their decision-making to improve the management of hypertension and to reduce the burden of hypertension-associated outcomes and premature deaths.
The Pump and the Pipes: Another Step towards the Non-Invasive Evaluation of Left Ventricular-Arterial Coupling in the Spectrum of Heart Failure.
De Biase N, Pugliese NR, Kopeva K
Cardiology · 2026 · PMID 40639364 · Publisher ↗
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Challenges and opportunities in assessing right ventricular structure and function: a Roadmap for standardization, clinical implementation and research.
Kovács A, Magunia H, Nicoara A … +8 more , Oxborough D, Keller M, Augustine DX, Thijssen D, van Dijk A, Denault A, Haddad F, Surkova E
Nat Rev Cardiol · 2026 Jan · PMID 40562802 · Publisher ↗
Given its crucial role in determining patient symptoms and outcomes in various cardiopulmonary diseases, the thorough and accurate assessment of right ventricular function is essential for both diagnosis and ongoing pati...
Given its crucial role in determining patient symptoms and outcomes in various cardiopulmonary diseases, the thorough and accurate assessment of right ventricular function is essential for both diagnosis and ongoing patient monitoring. In the era of precision medicine, a more detailed characterization of patients with cardiopulmonary diseases is needed, especially with the emergence of novel pharmacological and device-based therapies, such as transcatheter tricuspid valve intervention, gene therapy in patients with cardiomyopathy and anti-obesity interventions for patients with heart failure. Precise and reproducible quantification of right ventricular morphology and function are crucial for risk stratification, the selection of different therapies for the appropriate patients and the evaluation of treatment outcomes. As our understanding of right ventricular pathophysiology expands, the need for sensitive markers of functional deterioration, reliable prognostic indicators and more precise surrogates for clinical trials becomes increasingly important. In this Roadmap, we address current challenges in the standardization of image acquisition, analysis and interpretation across different modalities. We explore the factors limiting the clinical adoption of more advanced approaches and provide expert recommendations to overcome these barriers. Additionally, we outline potential next steps for incorporating parameters of right ventricular function as surrogate end points in multicentre clinical trials of new drugs or devices, and highlight new research opportunities, including the integration of artificial intelligence technologies. Finally, we issue a call for international collaboration on selected priority areas.
Potassium as an electro-metabolic signal for local coronary vasodilation.
Tune JD, Duncker DJ, Goodwill AG … +10 more , Warne CM, Essajee SI, Tucker SM, Romero SA, Bender SB, Beard DA, Figueroa CA, Sorop O, Merkus D, Dick GM
Basic Res Cardiol · 2025 Aug · PMID 40560298 · Full text
This study tested the hypothesis that K serves as an in vivo signal coupling coronary blood flow with the oxidative requirements of the myocardium. Experiments were performed in swine in which coronary parameters and art...
This study tested the hypothesis that K serves as an in vivo signal coupling coronary blood flow with the oxidative requirements of the myocardium. Experiments were performed in swine in which coronary parameters and arterial and coronary venous [K] were measured under baseline conditions, during exogenous administration of K (1-5 mM; n = 4), during increases in myocardial oxygen consumption (MVO) to dobutamine (n = 7) and exercise (n = 6), alterations in coronary perfusion pressure (CPP; n = 8), and systemic hypoxemia (PaO to ~ 30 mmHg; n = 7). Exogenous intracoronary K increased blood flow (~ 20%) in direct proportion to the coronary venous [K] up to the lethal limit of ~ 10 mM. Dobutamine increased coronary flow and MVO ~ threefold but the coronary venous-arterial [K] gradient (i.e., a surrogate index of myocardial release of K into the coronary circulation) did not change. Similarly, exercise increased coronary flow and MVO ~ 2.5-fold without a change in the coronary venous-arterial [K] gradient. The coronary venous-arterial [K] gradient did not change over the CPP range of 140-40 mmHg. Hypoxemia increased coronary blood flow ~ twofold and coronary vascular resistance was weakly associated with < 0.5 mM change in the coronary venous-arterial [K] gradient. Intracoronary glibenclamide dose-dependently (1-3 mg/min; n = 4) increased coronary resistance but did not affect the coronary venous-arterial [K] gradient. Intracoronary pinacidil dose-dependently (0.3-3.0 µg/kg/min; n = 3) increased coronary blood flow but did not affect the coronary venous-arterial [K] gradient. Similarly, intravenous glibenclamide (3 mg/kg; n = 6) increased coronary resistance but did not affect the coronary venous-arterial [K] gradient in exercising swine. These findings fail to support the concept that myocardial interstitial [K] couples coronary blood flow to MVO during physiologic increases in cardiac work or when oxygen delivery is constrained.
Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets.
Mericskay M, Zuurbier CJ, Heather LC … +7 more , Karlstaedt A, Inserte J, Bertrand L, Kararigas G, Ruiz-Meana M, Maack C, Schiattarella GG
Nat Rev Cardiol · 2025 Oct · PMID 40544173 · Publisher ↗
The number of patients with heart failure is expected to rise sharply owing to ageing populations, poor dietary habits, unhealthy lifestyles and improved survival rates from conditions such as hypertension and myocardial...
The number of patients with heart failure is expected to rise sharply owing to ageing populations, poor dietary habits, unhealthy lifestyles and improved survival rates from conditions such as hypertension and myocardial infarction. Heart failure is classified into two main types: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). These forms fundamentally differ, especially in how metabolism is regulated, but they also have shared features such as mitochondrial dysfunction. HFrEF is typically driven by neuroendocrine activation and mechanical strain, which demands a higher ATP production to sustain cardiac contraction. However, the primary energy source in a healthy heart (fatty acid β-oxidation) is often suppressed in HFrEF. Although glucose uptake increases in HFrEF, mitochondrial dysfunction disrupts glucose oxidation, and glycolysis and ketone oxidation only partially compensate for this imbalance. Conversely, HFpEF, particularly in individuals with metabolic diseases, such as obesity or type 2 diabetes mellitus, results from both mechanical and metabolic overload. Elevated glucose and lipid levels overwhelm normal metabolic pathways, leading to an accumulation of harmful metabolic byproducts that impair mitochondrial and cellular function. In this Review, we explore how disruptions in cardiac metabolism are not only markers of heart failure but also key drivers of disease progression. We also examine how metabolic intermediates influence signalling pathways that modify proteins and regulate gene expression in the heart. The growing recognition of the role of metabolic alterations in heart failure has led to groundbreaking treatments that target these metabolic disruptions, offering new hope for these patients.
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