Proenkephalin Improves Cardio-Renal Risk Prediction in Acute Coronary Syndromes: The KID-ACS Score.

BACKGROUND AND AIMS: Circulating proenkephalin (PENK) is a stable endogenous polypeptide with fast response to glomerular dysfunction and tubular damage. This study examined the predictive value of PENK for renal outcomes and mortality in patients with acute coronary syndromes (ACS). METHODS: Proenkephalin was measured in plasma in a prospective multicentre ACS cohort from Switzerland (n=4787) and in validation cohorts from the UK (n=1141), Czechia (n=927), and Germany (n=220). A biomarker-enhanced risk score (KID-ACS score) for simultaneous prediction of in-hospital acute kidney injury (AKI) and 30-day mortality was derived and externally validated. RESULTS: On multivariable adjustment for established risk factors, circulating PENK remained associated with in-hospital AKI (per log2 increase: adjusted odds ratio [OR] 1.53, 95% confidence interval [CI] 1.13-2.09, P=0.007) and 30-day mortality (adjusted hazard ratio [HR] 2.73, 95% CI 1.85-4.02, P<0.001). The KID-ACS score integrates PENK and showed an area under the receiver operating characteristic curve (AUC) of 0.72 (95% CI 0.68-0.76) for in-hospital AKI, and of 0.91 (95% CI 0.87-0.95) for 30-day mortality in the derivation cohort. Upon external validation, KID-ACS achieved similarly high performance for in-hospital AKI (Zurich: AUC 0.73, 95% CI 0.70-0.77; Czechia: AUC 0.75, 95% CI 0.68-0.81; Germany: AUC 0.71, 95% CI 0.55-0.87) and 30-day mortality (UK: AUC 0.87, 95% CI 0.83-0.91; Czechia: AUC 0.91, 95% CI 0.87-0.94; Germany: AUC 0.96, 95% CI 0.92-1.00) outperforming the CA-AKI score and the GRACE 2.0 score, respectively. CONCLUSIONS: Circulating PENK offers incremental value for predicting in-hospital AKI and mortality in ACS. The simple 6-item KID-ACS risk score integrates PENK and provides a novel tool for simultaneous assessment of renal and mortality risk in patients with ACS.

Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.

BACKGROUND: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. METHODS: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (Bgn), Tlr3, and IFN-α/ß receptor alpha chain (Ifnar1)-deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. RESULTS: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn-/-, Tlr3-/-, and Ifnar1-/- mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/ß receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. CONCLUSIONS: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.

Cardiac troponin elevation and mortality in takotsubo syndrome: New insights from the international takotsubo registry.

BACKGROUND: The clinical relevance of cardiac troponin (cTn) elevation in takotsubo syndrome (TTS) remains uncertain. The present study sought to investigate the role of cardiac troponin (cTn) elevations in mortality prediction of patients with Takotsubo syndrome (TTS). METHODS: Patients enrolled in the International Takotsubo (InterTAK) Registry from January 2011 to February 2020 with available data on peak cTn levels were included in the analysis. Peak cTn levels during the index hospitalization were used to define clinically relevant myocardial injury. The threshold at which clinically relevant myocardial injury drives mortality at 1 year was identified using restricted cubic spline analysis. RESULTS: Out of 2'938 patients, 222 (7.6%) patients died during 1-year follow-up. A more than 28.8-fold increase of cTn above the upper reference limit was identified as threshold for clinically relevant myocardial injury. The presence of clinically relevant myocardial injury was significantly associated with an increased risk of mortality at 5 years (adjusted HR 1.58, 95% CI 1.18-2.12, p =.002). Clinically relevant myocardial injury was related to an increased 5-year mortality risk in patients with apical TTS (adjusted HR 1.57, 95% CI 1.21-2.03, p =.001), in presence of physical stressors (adjusted HR 1.60, 95% CI 1.22-2.11, p =.001), and in absence of emotional stressors (adjusted HR 1.49, 95% CI, 1.17-1.89, p =.001). CONCLUSION: This study for the first time determined a troponin threshold for the identification of TTS patients at excess risk of mortality. These findings advance risk stratification in TTS and assist in identifying patients in need for close monitoring and follow-up.

Long-term outcomes after echocardiography versus fluoroscopy-guided left atrial appendage closure: Is there still a role for a simplified approach?

BACKGROUND: Left atrial appendage closure (LAAC) represents an alternative to oral anticoagulation for stroke prevention in patients with non-valvular atrial fibrillation (AF). While transoesophageal echocardiography is the current standard for guiding LAAC procedures, several centers have employed fluoroscopic guidance alone. However, data on long-term outcomes are lacking. METHODS: A total of 536 patients with AF undergoing LAAC and with available data on long-term follow-up were included in the retrospective, single-center analysis. Outcomes of patients undergoing fluoroscopy-guided LAAC were compared with those undergoing echocardiography guided LAAC. Time-dependent analysis was performed with the Kaplan-Meier method. RESULTS: A total of 234 (44%) and 302 (56%) patients were treated with echocardiography and fluoroscopy guidance, respectively. Baseline characteristics did not differ between the two groups. Procedural success rates were high in both groups (97% of fluoroscopy vs. 98% of echocardiography guided procedures; p = 0.92) and rates of relevant peri-device leaks (p = 0.50) and device-related thrombus formation (p = 0.22) did not differ between groups. Median clinical follow-up time was 48 (IQR 19-73) months. Rates of all-cause mortality (p = 0.15, HR 0.83, CI 0.64-1.07) and stroke (p = 0.076, HR 2.23, CI 0.90-5.54) were comparable among groups. CONCLUSION: LAAC with fluoroscopy guidance alone is equally safe and leads to similar clinical outcome compared to LAAC with additional echocardiography guidance.

Long-term Outcome of Patients with Atrial Fibrillation and High Risk of Stroke treated with Oral Anticoagulation or Left Atrial Appendage-Occlusion - A Cardinality Matched Analysis.

INTRODUCTION: Atrial fibrillation (AF) poses a significant risk of stroke. Left atrial appendage occlusion (LAAO) is an alternative for patients with contraindications to oral anticoagulation (OAC) or with high risk of bleeding. This study aims to compare the outcomes of LAAO versus conventional stroke prevention in high-risk AF-patients. METHODS: This secondary analysis incorporates data from the prospective Swiss-AF and Beat-AF cohorts, and the Zurich LAAO Registry. Cardinality matching was performed to create two comparable cohorts: conventional treatment (92% OAC) and LAAO. The primary endpoint was a composite of stroke, cardiovascular (CV) death, and clinically relevant bleeding. Kaplan-Meier method with competing risk analysis was used. RESULTS: Each group included 468 patients (age 76.4 [70.5, 82.0] years, 33% female). The LAAO group exhibited higher baseline bleeding risk (HAS BLED 2.0 [1.0 to 3.0] versus 3.0 [3.0 to 4.0]; p<0.001). Median follow-up time: 6.0 [4.7 to 7.0] years in conventional treatment group and 4.0 [1.5 to 6.1] in LAAO group. No significant difference in the primary composite endpoint (HR 0.87, 95% CI: 0.72 to 1.06, p=0.18), stroke risk (HR 1.14, 95% CI: 0.66 to 1.97, p=0.64), or CV mortality (HR 1.08, 95% CI: 0.82 to 1.42, p=0.60) was observed between groups. LAAO correlated with a significantly lower risk of clinically relevant bleeding (HR 0.61, 95% CI: 0.47 to 0.80, p<0.001). CONCLUSION: In this cardinality matched analysis with long-term follow-up, LAAO showed similar stroke and CV death rates but lower clinically relevant bleeding risk compared to conventional therapy in high-risk AF-patients.

Athletes and Hypertension.

PURPOSE OF REVIEW: We reviewed most current medical literature in order to describe the epidemiology, clinical manifestation, outcome, and management of hypertension in athletes. RECENT FINDINGS: An estimated quarter of the world's population is suffering from hypertension and this prevalence is also reflected in athletes and in individuals involved in leisure time sport activities. Several studies found an inverse relationship between physical activity and blood pressure. Therefore, physical exercise is recommended to prevent, manage, and treat hypertension. On the other hand, the prevalence of hypertension may vary by sport and in some cases may even be higher in athletes competing in certain disciplines than in the general population. Hypertension is the most common medical condition in athletes and may raise concerns about its management and the individual's eligibility for competitive sports. A thorough clinical evaluation should be performed to correctly diagnose or rule out hypertension in athletes, describe the individual's risk profile, rule out secondary causes, and detect possible hypertension-mediated organ damage caused by hypertension at an early stage. Based on most recent clinical research and international consensus documents, we propose a diagnostic algorithm as well the non-pharmacological and pharmacological management of hypertension in athletes. Although elevated blood pressure levels are less common in the active population, athletes are not protected from hypertension. A thorough diagnostic approach may help to identify individual at risk for adverse cardiovascular events and to address the optimal treatment as well as sport recommendations.

Non-Coding RNAs in Stem Cell Regulation and Cardiac Regeneration: Current Problems and Future Perspectives.

Although advances in rapid revascularization strategies following acute myocardial infarction (AMI) have led to improved short and long-term outcomes, the associated loss of cardiomyocytes and the subsequent remodeling result in an impaired ventricular function that can lead to heart failure or death. The poor regenerative capacity of the myocardium and the current lack of effective regenerative therapies have driven stem cell research in search of a possible solution. One approach involves the delivery of stem cells to the site of injury in order to stimulate repair response. Although animal studies initially delivered promising results, the application of similar techniques in humans has been hampered by poor target site retention and oncogenic considerations. In response, several alternative strategies, including the use of non-coding RNAs (ncRNAs), have been introduced with the aim of activating and regulating stem cells or inducing stem cell status in resident cells. Circular RNAs (circRNAs) and microRNAs (miRNAs) are ncRNAs with pivotal functions in cell proliferation and differentiation, whose role in stem cell regulation and potential significance for the field of cardiac regeneration is the primary focus of this review. We also address the general advantages of ncRNAs as promising drivers of cardiac regeneration and potent stem cell regulators.

Clinical course of pregnancy-associated spontaneous coronary artery dissection: a case series.

Background: Spontaneous coronary artery dissection (SCAD) is the most important cause of acute coronary syndromes during pregnancy and in the post-partum period and involves a spontaneous intimal tear or intramural haematoma of a coronary artery. Pregnancy-associated SCAD accounts for a minority of SCAD cases but is associated with a high rate of adverse events. Case summary: We present a series of three cases with pregnancy-associated SCAD. All patients presented with acute coronary syndromes in the post-partum period, between 12 days and 5 months after delivery. They all had additional conditions that are associated with SCAD, such as fibromuscular dysplasia and migraine. The management of one patient was uncomplicated, however, the courses of the other two were characterized by adverse events. One presented after an out-of-hospital cardiac arrest, the other presented with multivessel SCAD and developed progression and recurrence of SCAD during follow-up. In conclusion, the patients could be successfully treated conservatively and were in good condition at their latest follow-ups. Discussion: This case series highlights the wide range of clinical courses that could exist in pregnancy-associated SCAD, from a benign manifestation to a life-threatening condition. Importantly, those patients are at an increased risk for acute and late adverse events.

A novel score to predict in-hospital mortality for patients with acute coronary syndrome and out-of-hospital cardiac arrest: the FACTOR study.

INTRODUCTION: Acute coronary syndromes (ACS) represent a substantial global healthcare challenge. In its most severe form, it can lead to out-of-hospital cardiac arrest (OHCA). Despite medical advancements, survival rates in OHCA patients remain low. Further, the prediction of outcomes in these patients poses a challenge to all health care providers involved. This study aims at developing a score with variables available on admission to assess in-hospital mortality of patients with OHCA undergoing coronary angiography. METHOD: All patients with OHCA due to ACS admitted to a tertiary care center were included. A multivariate logistic regression analysis was conducted to explore the association between clinical variables and in-hospital all-cause mortality. A scoring system incorporating variables available upon admission to assess individual patients' risk of in-hospital mortality was developed (FACTOR score). The score was then validated. RESULTS: A total of 291 patients were included in the study, with a median age of 65 [56-73] years, including 47 women (16.2%). The in-hospital mortality rate was 41.2%. A prognostic model was developed in the derivation cohort (n = 138) and included the following variables: age, downtime, first detected rhythm, and administration of epinephrine. The area under the curve for the FACTOR score was 0.823 (95% CI 0.737-0.894) in the derivation cohort and 0.828 (0.760-0.891) in the validation cohort (n = 153). CONCLUSION: The FACTOR score demonstrated a reliable prognostic tool for health care providers in assessing in-hospital mortality of OHCA patients. Early acknowledgement of a poor prognosis may help in patient management and allocation of resources.

Effect of a Hypertensive Response During Exercise on Growth Rates of Aortic Diameters.

BACKGROUND: Aortic diameters are related to age, sex, and body size. There is a scarcity of data on the long-term sequelae of a hypertensive response to exercise (HRE) on aortic diameters. In this retrospective cohort study, we aimed to evaluate the relationship between the growth rates of the aorta in individuals with a HRE. METHODS: Our analysis included follow-up data of 649 patients recruited between January 2009 and December 2014 with a HRE. Participants with known connective tissue disease or a history of acute aortic syndrome were excluded. Sinus of Valsalva (SoV) and ascending aorta (AscAo) diameters were measured by transthoracic echocardiography using leading edge to leading edge convention at end-diastole. RESULTS: At baseline, median age, maximum systolic blood pressure (BP), body mass index (BMI), diameter of the SoV, and AscAo were 62 years, 208 mm Hg, 26.9 kg/m2, 35 mm, and 35 mm respectively. 32% of patients were female and 67% had hypertension. After a median follow-up of 7.1 years, mean yearly growth rates (±SD) of the SoV and AscAo were 0.09 (0.41) mm and 0.13 (0.56) mm, respectively. No significant associations were observed between growth rates of aortic diameters and maximum systolic and diastolic BP or when considering only individuals with a baseline diameter >40 mm. CONCLUSIONS: In this large cohort study, maximum systolic and diastolic BP during exercise showed no association with growth rates of aortic diameters. Furthermore, the mean growth rates of aortic diameters in this population were in line with growth rates in a normal population.

Blood pressure behavior during exercise in patients with diastolic dysfunction and a hypertensive response to exercise.

A hypertensive response to exercise is a precursor leading to hypertension, which is a major risk factor for the development of heart failure and diastolic dysfunction. Herein, we aimed to assess blood pressure (BP) in patients with a hypertensive response to exercise and different degrees of diastolic dysfunction. Between January 2009 and December 2014, 373 patients with a hypertensive response to exercise (HRE) and echocardiographic data assessing diastolic function were enrolled at the University Hospital of Zurich. ANCOVA was used to assess the changes in BP response during exercise testing in individuals with different degrees of diastolic dysfunction. Normalization of systolic BP was blunted in patients with grade II and III diastolic dysfunction after 3 min of recovery in univariable [ß (95%) - 9.2 (-13.8 to - 4.8) p < .001, -16.0 (-23.0 to 9.0) p < .001, respectively] and adjusted models. In fully adjusted models, when taking maximal effort into account, there were no differences with regard to systolic BP during exercise. Patients without diastolic dysfunction achieved higher heart rates (HRs) [both in absolute terms (p < .001) and as a percentage of the calculated maximum (p = .003)] and greater wattage (p < .001) at maximum exertion. The findings of this cross-sectional study suggest that exercise capacity is compromised in patients with diastolic dysfunction. A hypertensive response to exercise and the finding of a blunted BP recovery may help identify patients at risk of developing heart failure.

Twenty-five-year trends in incidence, angiographic appearance, and management of spontaneous coronary artery dissection.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) has been described as an infrequent cause of acute coronary syndrome (ACS). Knowledge about the disease is still limited and SCAD might still be underdiagnosed. OBJECTIVES: Trends in incidence, presentation, angiographic appearance, management, and outcomes of SCAD over 25 years were analyzed. METHODS: Patients with SCAD between 1997 and 2021 at the University Hospital Zurich, Switzerland, were included. Incidences were assessed as total numbers and proportions of ACS cases. Clinical data were collected from medical records and angiographic findings were reviewed. Major adverse cardiac events (MACE) were defined as the composite of all-cause death, cardiac arrest, SCAD recurrence or progression, other myocardial infarction, and stroke. RESULTS: One hundred fifty-six SCAD cases were included in this study. The incidence increased significantly in total (p < 0.001) and relative to ACS cases (p < 0.001). This was based on an increase of shorter lesions (p = 0.004), SCAD type 2 (p < 0.001), and lesions in side branches (p = 0.014), whereas lesions in the left main coronary artery and proximal segments were decreasing (p-values 0.029 and < 0.001, respectively). There was an increase in conservative therapy (p < 0.001). The rate of MACE (24%) was stable, however, there was a reduced proportion of patients with a need for intensive care treatment (p = 0.017). CONCLUSIONS: SCAD represents an important entity of ACS that still might be underappreciated. The increasing incidence of SCAD is likely based on better awareness and familiarity with the disease. A lower need for intensive care treatment suggests positive effects of the increasing implementation of conservative management.

Temporal Trends in Takotsubo Syndrome: Results From the International Takotsubo Registry.

BACKGROUND: The perception of takotsubo syndrome (TTS) has evolved significantly over the years, primarily driven by increased recognition of acute complications and mortality. OBJECTIVES: This study aimed to explore temporal trends in demographic patterns, risk factors, clinical presentations, and outcomes in patients with TTS. METHODS: Patients diagnosed with TTS between 2004 and 2021 were enrolled from the InterTAK (International Takotsubo) registry. To assess temporal trends, patients were divided into 6 groups, each corresponding to a 3-year interval within the study period. RESULTS: Overall, 3,957 patients were included in the study. There was a significant demographic transition, with the proportion of male patients rising from 10% to 15% (P = 0.003). Although apical TTS remained the most common form, the diagnosis of midventricular TTS increased from 18% to 28% (P = 0.018). The prevalence of physical triggers increased from 39% to 58% over the years (P < 0.001). There was a significant increase in 60-day mortality over the years (P < 0.001). However, a landmark analysis excluding patients who died within the first 60 days showed no differences in 1-year mortality (P = 0.150). CONCLUSIONS: This study of temporal trends in TTS highlights a transition in patients demographic with a growing prevalence among men, increasing recognition of midventricular TTS type, and increased short-term mortality and rates of cardiogenic shock in recent years. This transition aligns with the rising prevalence of physical triggers, as expression of increased recognition of TTS in association with acute comorbidities.

Effectiveness of radiation protection systems in the cardiac catheterization laboratory: a comparative study.

BACKGROUND: As numbers and complexity of percutaneous coronary interventions are constantly increasing, optimal radiation protection is required to ensure operator safety. Suspended radiation protection systems (SRPS) and protective scatter-radiation absorbing drapes (PAD) are novel methods to mitigate fluoroscopic scattered radiation exposure. The aim of the study was to investigate the effectiveness regarding radiation protection of a SRPS and a PAD in comparison with conventional protection. METHODS: A total of 229 cardiac catheterization procedures with SRPS (N = 73), PAD (N = 82) and standard radiation protection (N = 74) were prospectively included. Real-time dosimeter data were collected from the first operator and the assistant. Endpoints were the cumulative operator exposure relative to the dose area product [standardized operator exposure (SOE)] for the first operator and the assistant. RESULTS: For the first operator, the SRPS and the PAD significantly decreased the overall SOE compared to conventional shielding by 93.9% and 66.4%, respectively (P < 0.001). The protective effect of the SRPS was significantly higher compared to the PAD (P < 0.001). For the assistant, the SRPS and the PAD provided a not statistically significant reduction compared to conventional shielding in the overall SOE by 38.0% and 30.6%, respectively. CONCLUSIONS: The SRPS and the PAD enhance radiation protection significantly compared to conventional protection. In most clinical scenarios, the protective effect of SRPS is significantly higher than the additional protection provided by the PAD. Comparison of the additional radiation protection provided by protective scatter-radiation absorbing drapes (PAD) and the suspended radiation protection system (SRPS) system over standard protection with lead aprons.

Is spontaneous coronary artery dissection (SCAD) related to local anatomy and hemodynamics? An exploratory study.

AIMS: Spontaneous coronary artery dissection (SCAD) is an increasingly diagnosed cause of myocardial infarction with unclear pathophysiology. The aim of the study was to test if vascular segments site of SCAD present distinctive local anatomy and hemodynamic profiles. METHODS: Coronary arteries with spontaneously healed SCAD (confirmed by follow-up angiography) underwent three-dimensional reconstruction, morphometric analysis with definition of vessel local curvature and torsion, and computational fluid dynamics (CFD) simulations with derivation of time-averaged wall shear stress (TAWSS) and topological shear variation index (TSVI). The (reconstructed) healed proximal SCAD segment was visually inspected for co-localization with curvature, torsion, and CFD-derived quantities hot spots. RESULTS: Thirteen vessels with healed SCAD underwent the morpho-functional analysis. Median time between baseline and follow-up coronary angiograms was 57 (interquartile range [IQR] 45-95) days. In seven cases (53.8%), SCAD was classified as type 2b and occurred in the left anterior descending artery or near a bifurcation. In all cases (100%), at least one hot spot co-localized within the healed proximal SCAD segment, in 9 cases (69.2%) ≥ 3 hot spots were identified. Healed SCAD in proximity of a coronary bifurcation presented lower TAWSS peak values (6.65 [IQR 6.20-13.20] vs. 3.81 [2.53-5.17] Pa, p = 0.008) and hosted less frequently TSVI hot spots (100% vs. 57.1%, p = 0.034). CONCLUSION: Vascular segments of healed SCAD were characterized by high curvature/torsion and WSS profiles reflecting increased local flow disturbances. Hence, a pathophysiological role of the interaction between vessel anatomy and shear forces in SCAD is hypothesized.

A CircRNA-miRNA-mRNA Network for Exploring Doxorubicin- and Myocet-Induced Cardiotoxicity in a Translational Porcine Model.

Despite the widespread use of doxorubicin (DOX) as a chemotherapeutic agent, its severe cumulative cardiotoxicity represents a significant limitation. While the liposomal encapsulation of doxorubicin (Myocet, MYO) reduces cardiotoxicity, it is crucial to understand the molecular background of doxorubicin-induced cardiotoxicity. Here, we examined circular RNA expression in a translational model of pigs treated with either DOX or MYO and its potential impact on the global gene expression pattern in the myocardium. This study furthers our knowledge about the regulatory network of circRNA/miRNA/mRNA and its interaction with chemotherapeutics. Domestic pigs were treated with three cycles of anthracycline drugs (DOX, n = 5; MYO, n = 5) to induce cardiotoxicity. Untreated animals served as controls (control, n = 3). We applied a bulk mRNA-seq approach and the CIRIquant algorithm to identify circRNAs. The most differentially regulated circRNAs were validated under cell culture conditions, following forecasting of the circRNA-miRNA-mRNA network. We identified eight novel significantly regulated circRNAs from exonic and mitochondrial regions in the porcine myocardium. The forecasted circRNA-miRNA-mRNA network suggested candidate circRNAs that sponge miR-17, miR-15b, miR-130b, the let-7 family, and miR125, together with their mRNA targets. The identified circRNA-miRNA-mRNA network provides an updated, coherent view of the mechanisms involved in anthracycline-induced cardiotoxicity.

Effect of monovalent COVID-19 vaccines on viral interference between SARS-CoV-2 and several DNA viruses in patients with long-COVID syndrome.

Epstein-Barr virus (EBV) reactivation may be involved in long-COVID symptoms, but reactivation of other viruses as a factor has received less attention. Here we evaluated the reactivation of parvovirus-B19 and several members of the Herpesviridae family (DNA viruses) in patients with long-COVID syndrome. We hypothesized that monovalent COVID-19 vaccines inhibit viral interference between SARS-CoV-2 and several DNA viruses in patients with long-COVID syndrome, thereby reducing clinical symptoms. Clinical and laboratory data for 252 consecutive patients with PCR-verified past SARS-CoV-2 infection and long-COVID syndrome (155 vaccinated and 97 non-vaccinated) were recorded during April 2021-May 2022 (median 243 days post-COVID-19 infection). DNA virus-related IgG and IgM titers were compared between vaccinated and non-vaccinated long-COVID patients and with age- and sex-matched non-infected, unvaccinated (pan-negative for spike-antibody) controls. Vaccination with monovalent COVID-19 vaccines was associated with significantly less frequent fatigue and multiorgan symptoms (p < 0.001), significantly less cumulative DNA virus-related IgM positivity, significantly lower levels of plasma IgG subfractions 2 and 4, and significantly lower quantitative cytomegalovirus IgG and IgM and EBV IgM titers. These results indicate that anti-SARS-CoV-2 vaccination may interrupt viral cross-talk in patients with long-COVID syndrome (ClinicalTrials.gov Identifier: NCT05398952).

Coronary microvascular dysfunction in Takotsubo syndrome: an analysis using angiography-derived index of microcirculatory resistance.

BACKGROUND: Coronary microvascular dysfunction (CMD) has been proposed as a crucial factor in the pathophysiology of Takotsubo syndrome (TTS). The angiography-derived index of microcirculatory resistance (caIMR) offers an alternative to conventional hyperemic wire-based IMR to assess CMD. We aimed to evaluate CMD's prevalence, transience, and impact on in-hospital outcomes in TTS. METHODS: All three coronary arteries of 96 patients with TTS were assessed for their coronary angiography derived Index of microcirculatory Resistance (caIMR) and compared to non-obstructed vessels of matched patients with ST-elevation myocardial infarction. Further, the association between caIMR and the TTS-specific combined in-hospital endpoint of death, cardiac arrest, ventricular arrhythmogenic events and cardiogenic shock was investigated. RESULTS: Elevated IMR was present in all TTS patients, with significantly elevated caIMR values in all coronary arteries compared to controls. CaIMR did not differ between apical and midventricular TTS types. CaIMR normalized in TTS patients with follow-up angiographies performed at a median of 28 months (median caIMR at event vs follow-up: LAD 34.8 [29.9-41.1] vs 20.3 [16.0-25.3], p < 0.001; LCX: 38.7 [32.9-50.1] vs 23.7 [19.4-30.5], p < 0.001; RCA: 31.7 [25.0-39.1] vs 19.6 [17.1-24.0], p < 0.001). The extent of caIMR elevation significantly correlated with the combined in-hospital endpoint (p = 0.036). CONCLUSION: TTS patients had evidence of elevated caIMR in at least one coronary artery with a trend towards higher LAD caIMR in apical type TTS and normalization after recovery. Furthermore, extent of caIMR elevation was associated with increased risk of in-hospital MACE of TTS patients.

Machine learning-based prediction of in-hospital death for patients with takotsubo syndrome: The InterTAK-ML model.

AIMS: Takotsubo syndrome (TTS) is associated with a substantial rate of adverse events. We sought to design a machine learning (ML)-based model to predict the risk of in-hospital death and to perform a clustering of TTS patients to identify different risk profiles. METHODS AND RESULTS: A ridge logistic regression-based ML model for predicting in-hospital death was developed on 3482 TTS patients from the International Takotsubo (InterTAK) Registry, randomly split in a train and an internal validation cohort (75% and 25% of the sample size, respectively) and evaluated in an external validation cohort (1037 patients). Thirty-one clinically relevant variables were included in the prediction model. Model performance represented the primary endpoint and was assessed according to area under the curve (AUC), sensitivity and specificity. As secondary endpoint, a K-medoids clustering algorithm was designed to stratify patients into phenotypic groups based on the 10 most relevant features emerging from the main model. The overall incidence of in-hospital death was 5.2%. The InterTAK-ML model showed an AUC of 0.89 (0.85-0.92), a sensitivity of 0.85 (0.78-0.95) and a specificity of 0.76 (0.74-0.79) in the internal validation cohort and an AUC of 0.82 (0.73-0.91), a sensitivity of 0.74 (0.61-0.87) and a specificity of 0.79 (0.77-0.81) in the external cohort for in-hospital death prediction. By exploiting the 10 variables showing the highest feature importance, TTS patients were clustered into six groups associated with different risks of in-hospital death (28.8% vs. 15.5% vs. 5.4% vs. 1.0.8% vs. 0.5%) which were consistent also in the external cohort. CONCLUSION: A ML-based approach for the identification of TTS patients at risk of adverse short-term prognosis is feasible and effective. The InterTAK-ML model showed unprecedented discriminative capability for the prediction of in-hospital death.