Iron deficiency and supplementation in patients with heart failure: Results from the IRON-HF international survey.

AIMS: Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, regardless of anaemia status. Iron supplementation has been demonstrated to improve exercise capacity and quality of life in patients with HF with an ejection fraction <50% and ID. This survey aimed to provide data on real-world practices related to ID screening and management. METHODS AND RESULTS: We designed and distributed an online survey (23 questions) regarding ID screening and management in the HF setting. Overall, 256 cardiologists completed the survey (59.8% male, mostly between 30 and 50 years). The majority of physicians defined ID according to the most recent HF recommendations (98.4%) and reported screening for ID in more than half of their patients (68.4%). However, only 54.3% of the respondents performed periodic screening (every 6 months to 1 year). A total of 93.0% of participants prescribed and/or administered iron supplementation, using intravenous iron as the preferred method of administration (86.3%). After iron supplementation, 96.1% of the respondents reassessed ID, most frequently at 3-6 months (67.6%). Most physicians (93.8%) perceived ID as an underestimated comorbidity in HF. Cardiologists' age, training status, subspecialty and work setting (academic vs. non-academic hospitals) were associated with heterogeneity in the answers. CONCLUSIONS: The results of this survey highlight the need for more consistent strategies of ID screening and treatment for patients with HF.

Blood pressure response during exercise testing in individuals with and without hypertension: The value of the recovery phase.

BACKGROUND: Hypertension and exercise testing are essential for cardiovascular risk assessment. However, an exact description of blood pressure (BP) in patients with a hypertensive response during exercise (HRE), especially in the recovery phase is lacking. Herein, we aimed to analyse BP and heart rate during exercise testing and recovery in patients with an HRE. METHODS: 800 patients aged 17-90 with an HRE during a standardized bicycle ergometry test were recruited. The BP behaviour during exercise testing was correlated with clinical data. Furthermore, data were analysed according to the presence of pre-existent hypertension. RESULTS: Of the 800 patients included in this study 497 (62%) were previously diagnosed with hypertension. Analysis of covariance showed a significantly faster systolic (ß [95% CI] 8.0 [4.9-11.1]) and diastolic (2.4 [0.4-4.4]) BP recovery 3 min after maximal exercise in patients without hypertension in univariable models. These results remained robust in fully adjusted models taking into account age, sex, body mass index, cardiovascular disease, and antihypertensive treatment for systolic (5.3 [1.2-9.4]) and diastolic BP (4.5 [1.9-7.0]). Furthermore, patients with hypertension displayed higher systolic BP during maximal exercise in univariable (3.8 [0.1-7.5]) and fully adjusted (5.5 [1.1-10.0]) models. There was no difference in maximum diastolic BP between groups. CONCLUSION: In this large cohort study, patients without hypertension showed a faster systolic and diastolic BP recovery and lower maximal systolic BP compared to patients with hypertension. Overall, this study provides new insights into cardiovascular health during recovery phase.

Valgus stress knee radiographs accurately anticipate the bone resection in medial unicompartmental knee arthroplasty: Protocol validation using an image-based robotic system.

PURPOSE: The objective of this study was to describe a planning method for medial unicompartmental knee arthroplasty (UKA) implantation using preoperative stress radiographs to measure the thickness of tibial and femoral bone resections and to validate this method with data from an image-based robotic surgery system. Having such method for preoperative planning would be of interest for surgeons performing UKA in order to anticipate optimal bone resection on both tibia and femoral sides. METHODS: A new planning method for medial UKA based on valgus stress knee radiographs validated it with an image-based robotic surgery system (Restoris MCK, MAKO®, Stryker Corporation) was proposed. This retrospective study involved radiographic measurements of 76 patients who underwent image-based robotic medial UKA between April 2022 and February 2023. Preoperative anteroposterior stress radiographs of the knee were used to simulate UKA implantation. The UKA technique was based on Cartier's angle and aimed at restoring the joint line. The total dimension measured was 14 mm (8 mm for minimal tibial component and polyethylene insert + 4 mm for femoral component + 2 mm for safety laxity). Bone resections were measured in the preoperative valgus stress radiographs and then against the intraoperative bone resection data provided by the robotic system. Inter- and intra-observer reliability was assessed using 25 measurements. RESULTS: The mean planned tibial resection measured in the radiographs was 4.3 ± 0.4 [2.9-5.8], while the mean robotic resection was 4.2 ± 0.5 [2.7-5.8] (mean difference = 0.15 mm, 95% confidence interval [CI] [-0.27 to 0.57]). There was a strong correlation between these two values (Pearson's rank R = 0.79, p < 0.001). Intra- and inter-observer reliability were also very strong (Pearson's rank R = 0.91, p < 0.001, and Pearson's rank R = 0.82, p < 0.001, respectively). The mean planned femoral bone resection measured in the radiographs was 2.7 ± 0.7 mm [1-4.5], while the mean robotic resection was 2.5 ± 0.9 [1-5] (mean difference = 0.21 mm, 95% CI [-0.66 to 1.08]). There was a strong correlation between these two values (Pearson's rank R = 0.82, p < 0.001). Intra- and inter-observer reliability were also strong (Pearson's rank R = 0.88, p < 0.001, and Pearson's rank R = 0.84, p < 0.001, respectively). CONCLUSION: This study describes and validates with robotic information a simple and reproducible preoperative planning method to determine femoral and tibial bone resection for medial UKA implantation using antero-posterior valgus stress knee radiographs, leaving a medial safety laxity of 2 mm. It represents a very valuable contribution to the understanding of UKA principles, which can serve to extend its indications and increase reproducibility of the surgical technique. LEVEL OF EVIDENCE: III. Retrospective cohort study.

Phenotype clustering of hospitalized high-risk patients with COVID-19 - a machine learning approach within the multicentre, multinational PCHF-COVICAV registry.

IMTRODUCTION: The high-risk population of patients with cardiovascular (CV) disease or risk factors (RF) suffering from COVID-19 is heterogeneous. Several predictors for impaired prognosis have been identified. However, with machine learning (ML) approaches, certain phenotypes may be confined to classify the affected population and to predict outcome. This study aimed to phenotype patients using unsupervised ML technique within the International Postgraduate Course Heart Failure Registry for patients hospitalized with COVID-19 and Cardiovascular disease and/or RF (PCHF-COVICAV). MATERIAL AND METHODS: Patients from the eight centres with follow-up data available from the PCHF-COVICAV registry were included in this ML analysis (K-medoids algorithm). RESULTS: Out of 617 patients included into the prospective part of the registry, 458 [median age: 76 (IQR:65-84) years, 55% male] were analyzed and 46 baseline variables, including demographics, clinical status, comorbidities and biochemical characteristics were incorporated into the ML. Three clusters were extracted by this ML method. Cluster 1 (n = 181) represents mainly women with the least number of overall comorbidities and cardiovascular RF. Cluster 2 (n = 227) is characterized mainly by men with non-CV conditions and less severe symptoms of infection. Cluster 3 (n=50) mainly represents men with the highest prevalence of cardiac comorbidities and RF, more extensive inflammation and organ dysfunction with the highest 6-month all-cause mortality risk. CONCLUSIONS: The ML process has identified three important clinical clusters from hospitalized COVID-19 CV and/or RF patients. The cluster of males with severe CV disease, particularly HF, and multiple RF presenting with increased inflammation had a particularly poor outcome.

Evaluating nutrition in advanced ovarian cancer: which biomarker works best?

BACKGROUND: Advanced epithelial ovarian cancer (OC) patients often present with malnutrition; however, the ideal nutritional evaluation tool is unclear. We aimed to evaluate the role of preoperative albumin, Prognostic Nutritional Index [PNI], neutrophil-to-lymphocyte ratio [NLR], and platelet-to-lymphocyte ratio [PLR] as independent predictors of severe postoperative complications and 90-day mortality in OC patients who underwent primary cytoreductive surgery to identify the ideal tool. METHODS: OC patients who underwent surgery at Mayo Clinic (2003-2018) were included; biomarkers were retrospectively retrieved and established cut-offs were utilized. Outcomes included severe complications (Accordion grade ≥ 3) and 90-day mortality. Univariate and multivariable logistic regression models were performed. Biomarkers were evaluated in separate models adjusted for age and American Society of Anesthesiologists (ASA) score for 90-day mortality, and adjusted for age, ASA score, stage, and surgical complexity for severe complications. RESULTS: Albumin <3.5 g/dL, PNI < 45, NLR > 6 and PLR ≥ 200 were univariately associated with 90-day mortality (all p < 0.05) in 627 patients that met inclusion criteria. Each marker remained significant in adjusted models with albumin having the highest OR: 6.04 [95% CI:2.80-13.03] and AUC (0.83). Univariately, PNI <45, NLR >6, and PLR ≥200 were significant predictors of severe complications(all p < 0.05), however failed to reach significance in adjusted models. Albumin was not associated with severe complications. CONCLUSION: All biomarkers were associated with 90-day mortality in adjusted models, with albumin being the easiest predictor to attain clinically; none with severe complications. Future research should focus less on methods of nutritional assessment and more on strategies to improve nutrition during OC tumor-directed therapy.

Pathophysiological Link and Treatment Implication of Heart Failure and Preserved Ejection Fraction in Patients with Chronic Kidney Disease.

Heart failure with preserved ejection fraction (HFpEF) results from a complex interplay of age, genetic, cardiac remodeling, and concomitant comorbidities including hypertension, obesity, diabetes, and chronic kidney disease (CKD). Renal failure is an important comorbidity of HFpEF, as well as a major pathophysiological mechanism for those patients at risk of developing HFpEF. Heart failure (HF) and CKD are intertwined conditions sharing common disease pathways; the so-called "kidney tamponade", explained by an increase in intracapsular pressure caused by fluid retention, is only the latest model to explain renal injury in HF. Recognizing the different phenotypes of HFpEF remains a real challenge; the pathophysiological mechanisms of renal dysfunction may differ across the HF spectrum, as well as the prognostic role. A better understanding of the role of cardiorenal interactions in patients with HF in terms of symptom status, disease progression, and prognosis remains essential in HF management. Historically, patients with HF and CKD have been scarcely represented in clinical trial populations. Current concerns affect the practical approach to HF treatment, and, in this context, physicians are frequently hesitant to prescribe and titrate both new and old treatments. Therefore, the extensive application of HF drugs in diverse HF subtypes with numerous comorbidities and different renal dysfunction etiologies remains a controversial matter of discussion. Numerous recently introduced drugs, such as sodium-glucose-linked transporter 2 inhibitors (SGLT2i), constitute a new therapeutic option for patients with HF and CKD. Because of their protective vascular and hormonal actions, the use of these agents may be safely extended to patients with renal dysfunction in the long term. The present review delves into the phenotype of patients with HFpEF and CKD from a pathophysiological perspective, proposing a treatment approach that suggests a practical stepwise algorithm for the proper application of life-saving therapies in clinical practice.

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.

Venous Thromboembolism Management throughout the COVID-19 Era: Addressing Acute and Long-Term Challenges.

Background: COVID-19 increases the risk of venous thromboembolism (VTE) through a complex interplay of mechanisms collectively referred to as immunothrombosis. Limited data exist on VTE challenges in the acute setting throughout a dynamic long-term follow-up of COVID-19 patients compared to non-COVID-19 patients. The aim of the study was to investigate acute and long-term management and complications in VTE patients with and without COVID-19. Methods: A prospective, observational, single-center cohort study on VTE patients followed from the acute care stage until 24 months post-diagnosis. Results: 157 patients, 30 with COVID-19-associated VTE and 127 unrelated to COVID-19, were enrolled. The mean follow-up was 10.8 (±8.9) months. COVID-19 patients had fewer comorbidities (1.3 ± 1.29 vs. 2.26 ± 1.68, p < 0.001), a higher proportion of pulmonary embolism at baseline (96.7% vs. 76.4%, p = 0.01), and had a lower probability of remaining on anticoagulant therapy after three months (p < 0.003). The most used initial therapy was low-molecular-weight heparin in 130/157 cases, followed by long-term treatment with direct oral anticoagulants in 123/157. Two (6.7%) COVID-19 vs. three (2.4%) non-COVID-19 patients (p = 0.243) had major hemorrhagic events, all of them within the first three months. Four (3.1%) non-COVID-19 patients had VTE recurrence after six months. Three (2.4%) non-COVID-19 patients developed chronic thromboembolic pulmonary hypertension. There were no fatalities among patients with COVID-19, compared to a mortality of 12/127 (9.4%) in the non-COVID-19 subgroup (p = 0.027). Discussion: Our study offers a comprehensive overview of the evolving nature of VTE management, emphasizing the importance of personalized risk-based approaches, including a limited course of anticoagulation for most COVID-19-associated VTE cases and reduced-dose extended therapy for high-risk subsets.

Is the Number of Citations Related to the Study Methodology in Shoulder Arthroplasty Literature? A Bibliometric and Statistical Analysis of Current Evidence.

Background: We reviewed the shoulder arthroplasty (SA) literature to correlate citations, methodological characteristics and quality of most-cited articles in this field. We hypothesized that a greater number of citations would be found for high-quality clinical studies. Methods: We searched the Web of Knowledge database for the 50 most-cited articles about SA and collected author name, publication year, country of origin, journal, article type, level of evidence (LoE), subject of paper, type of arthroplasty and metrics (number of citations and citation rate). Coleman Methodology Score (CMS) was computed for clinical articles. Statistical analysis of variance and correlation coefficients were used to investigate the relationship between different variables. Results: Out of the selected 50 studies on SA, 26% were nonclinical. There were 15,393 citations overall (mean 307.8), with a mean 19.5 citations per year (range 48.3-6.7). Thirty or 60% of all articles were LoE IV. All studies were published between 1984 and 2011 in 8 journals. Reverse SA (RSA) was the most common subject (36% of studies). The United States was the country responsible for most contributions (50% of studies). CMS ranged from 81 to 38 (mean 59.6). RSA received the highest number of citations (P < .001), independently from country of origin (P = .137) and LoE (P = .723). CMS correlated with citation rate (r = 0.397; P = .013) and publication year (tau = 0.397; P = .013), but not with LoE (P = .204). Conclusion: In SA literature, citation rate positively correlates with methodological quality of a study, independently from publication country and LoE. Among most-cited papers, RSA is the most common standalone subject.

Prolonging the stability of cetuximab (Erbitux®) and panitumumab (Vectibix®): An orthogonal assessment of physicochemical, biological and microbiological properties of original opened glass vials and diluted saline preparations.

The two anti-epidermal growth factor receptor monoclonal antibodies (mAbs) cetuximab and panitumumab are the pillars for the treatment of EGFR-positive, KRAS wild-type metastatic colorectal cancers. However, stability data of these mAbs are generally missing or incomplete. Here, we report for the first time an orthogonal analysis of the stability of cetuximab (Erbitux®) and panitumumab (Vectibix®), either undiluted vial leftovers or saline dilutions in polyolefin/polyamide infusion bags. All samples were stored at 2-8 °C protected from light, according to their summary of product characteristics (SmPCs). Alternatively, opened vials and preparations were maintained at 25 °C for 15 h, and then stored again at 2-8 °C protected from light to mimic a temporary interruption of the cold chain. Vial leftovers proved stable up to 180 days when stored according to their SmPCs, while compounded preparations in infusion bags maintained their physiochemical, biological and microbiological stability up to 30 days. Additionally, no changes were detected up to 30 days for the same samples undergoing a thermal excursion. Our results provide additional rationale to the SmPCs, crucial especially in the case of reassignment and pre-preparation of bags. This information will allow hospitals to achieve significant cost savings, and better organization of the entire therapeutic process.

Impaired retinal micro-vascular function in patients with atrial fibrillation.

BACKGROUND: Cardiovascular (CV) risk factors and CV diseases, in particular heart failure, are strongly associated with impaired microvascular retinal endothelial function. Whether atrial fibrillation (AF) contributes to vascular dysfunction is not clear. Therefore, the aim of this study was to investigate the impact of AF on retinal microvascular function. METHODS: In this study, vascular function was measured non-invasively with flicker-light induced vasodilatation of retinal arterioles (FIDart%). Patients with a history of AF and risk factors for heart failure (HF) or heart failure (n = 69; age 67.9 ± 9.2 years, 71% male, 35% HFrEF, 56% paroxysmal, 25% persistent, 19% permanent AF), as well as age, sex and ejection fraction matched patients with absent history of AF (n = 66; age 63.4 ± 10.6 years, 67% male, 47% HFrEF) were included. Patients with AF were further divided into those with paroxysmal AF (in sinus rhythm - AFSR: n = 38, age 71.4 ± 9.2, 73% male), and those with AF at the time of the study visit. RESULTS: Retinal microvascular function was impaired in patients with AF compared to patients without AF (FIDart% 1.1% [0.3-2.8] vs. 2.7% [1.3-5.1], p < 0.001). Patients currently in AF have poorer retinal microvascular function (FIDart% 0.8% [0.1-1.9) compared to patients with a history of AF but currently in SR at the time of retinal function measurement (1.5% [0.6-4.9] p = 0.017). In patients with AF, impaired retinal vascular function was independently associated with larger left atrial volume (mean 49.8 ± 18.4), even after correction for confounding factors in different models (SCR = -0. 251 to -0.256, p = 0.035-0.01). CONCLUSIONS: AF in patients with heart failure is associated with impaired vascular function, even if currently in sinus rhythm. The association of retinal microvascular dysfunction with left atrial volume, a surrogate for elevated cardiac filling pressures, may further highlight the important interplay between the vasculature and elevated filling pressures in the development of AF.

Diverging role of epicardial adipose tissue across the entire heart failure spectrum.

AIMS: Epicardial adipose tissue (EAT) is a metabolically highly active tissue modulating numerous pathophysiological processes. The aim of this study was to investigate the association between EAT thickness and endothelial function in patients with heart failure (HF) across the entire ejection fraction spectrum. METHODS AND RESULTS: A total of 258 patients with HF with an ejection fraction across the entire spectrum [HF with reduced ejection fraction (HFrEF), n = 168, age 60.6 ± 11.2 years; HF with preserved ejection fraction (HFpEF), n = 50, mean age 65.1 ± 11.9 years; HF with mildly reduced ejection fraction (HFmrEF), n = 32, mean age 65 ± 12] were included. EAT was measured with transthoracic echocardiography. Vascular function was assessed with flicker-light-induced vasodilation of retinal arterioles (FIDart%) and flow-mediated dilatation (FMD%) in conduit arteries. Patients with HFrEF have less EAT compared with patients with HFpEF (4.2 ± 2 vs. 5.3 ± 2 mm, respectively, P < 0.001). Interestingly, EAT was significantly associated with impaired microvascular function (FIDart%; r = -0.213, P = 0.012) and FMD% (r = -0.186, P = 0.022), even after multivariate correction for confounding factors (age, body mass index, hypertension, and diabetes; standardized regression coefficient (SRC) = -0.184, P = 0.049 for FIDart% and SRC = -0.178, P = 0.043 for FMD%) in HFrEF but not in HFpEF. CONCLUSIONS: Although less EAT is present in HFrEF than in HFpEF, only in HFrEF EAT is associated with vascular dysfunction. The diverging role of EAT in HF and its switch to a functionally deleterious tissue promoting HF progression provide the rationale to specifically target EAT, in particular in patients with reduced ejection fraction.

Regulation of cellular contractile force, shape and migration of fibroblasts by oncogenes and Histone deacetylase 6.

The capacity of cells to adhere to, exert forces upon and migrate through their surrounding environment governs tissue regeneration and cancer metastasis. The role of the physical contractile forces that cells exert in this process, and the underlying molecular mechanisms are not fully understood. We, therefore, aimed to clarify if the extracellular forces that cells exert on their environment and/or the intracellular forces that deform the cell nucleus, and the link between these forces, are defective in transformed and invasive fibroblasts, and to indicate the underlying molecular mechanism of control. Confocal, Epifluorescence and Traction force microscopy, followed by computational analysis, showed an increased maximum contractile force that cells apply on their environment and a decreased intracellular force on the cell nucleus in the invasive fibroblasts, as compared to normal control cells. Loss of HDAC6 activity by tubacin-treatment and siRNA-mediated HDAC6 knockdown also reversed the reduced size and more circular shape and defective migration of the transformed and invasive cells to normal. However, only tubacin-mediated, and not siRNA knockdown reversed the increased force of the invasive cells on their surrounding environment to normal, with no effects on nuclear forces. We observed that the forces on the environment and the nucleus were weakly positively correlated, with the exception of HDAC6 siRNA-treated cells, in which the correlation was weakly negative. The transformed and invasive fibroblasts showed an increased number and smaller cell-matrix adhesions than control, and neither tubacin-treatment, nor HDAC6 knockdown reversed this phenotype to normal, but instead increased it further. This highlights the possibility that the control of contractile force requires separate functions of HDAC6, than the control of cell adhesions, spreading and shape. These data are consistent with the possibility that defective force-transduction from the extracellular environment to the nucleus contributes to metastasis, via a mechanism that depends upon HDAC6. To our knowledge, our findings present the first correlation between the cellular forces that deforms the surrounding environment and the nucleus in fibroblasts, and it expands our understanding of how cells generate contractile forces that contribute to cell invasion and metastasis.

Lactate Can Modulate the Antineoplastic Effects of Doxorubicin and Relieve the Drug's Oxidative Damage on Cardiomyocytes.

BACKGROUND: Doxorubicin (DOXO) is currently administered as the first-choice therapy for a variety of malignancies. Cancer cells exhibit enhanced glycolysis and lactate production. This metabolite affects gene expression and can play a role in chemoresistance. AIM OF THIS STUDY: We investigated whether the enhanced lactate levels that characterize neoplastic tissues can modify the response of cancer cells to DOXO. METHODS: After exposing cancer cells to increased lactate levels, we examined whether this metabolite could interfere with the principal mechanisms responsible for the DOXO antineoplastic effect. RESULTS: Increased lactate levels did not affect DOXO-induced topoisomerase poisoning but offered protection against the oxidative damage caused by the drug. This protection was related to changes in gene expression caused by the combined action of DOXO and lactate. Oxidative damage significantly contributed to the heavy cardiotoxicity following DOXO treatment. In cultured cardiomyocytes, we confirmed that DOXO-induced DNA damage and oxidative stress can be significantly mitigated by exposing the cells to increased lactate levels. CONCLUSIONS: In addition to contributing to elucidating the effects of the combined action of DOXO and lactate, our results suggest a possible method to reduce the heavy drug cardiotoxicity, a major side effect leading to therapy discontinuation.

The Different Pathways of Epicardial Adipose Tissue across the Heart Failure Phenotypes: From Pathophysiology to Therapeutic Target.

Epicardial adipose tissue (EAT) is an endocrine and paracrine organ constituted by a layer of adipose tissue directly located between the myocardium and visceral pericardium. Under physiological conditions, EAT exerts protective effects of brown-like fat characteristics, metabolizing excess fatty acids, and secreting anti-inflammatory and anti-fibrotic cytokines. In certain pathological conditions, EAT acquires a proatherogenic transcriptional profile resulting in increased synthesis of biologically active adipocytokines with proinflammatory properties, promoting oxidative stress, and finally causing endothelial damage. The role of EAT in heart failure (HF) has been mainly limited to HF with preserved ejection fraction (HFpEF) and related to the HFpEF obese phenotype. In HFpEF, EAT seems to acquire a proinflammatory profile and higher EAT values have been related to worse outcomes. Less data are available about the role of EAT in HF with reduced ejection fraction (HFrEF). Conversely, in HFrEF, EAT seems to play a nutritive role and lower values may correspond to the expression of a catabolic, adverse phenotype. As of now, there is evidence that the beneficial systemic cardiovascular effects of sodium-glucose cotransporter-2 receptors-inhibitors (SGLT2-i) might be partially mediated by inducing favorable modifications on EAT. As such, EAT may represent a promising target organ for the development of new drugs to improve cardiovascular prognosis. Thus, an approach based on detailed phenotyping of cardiac structural alterations and distinctive biomolecular pathways may change the current scenario, leading towards a precision medicine model with specific therapeutic targets considering different individual profiles. The aim of this review is to summarize the current knowledge about the biomolecular pathway of EAT in HF across the whole spectrum of ejection fraction, and to describe the potential of EAT as a therapeutic target in HF.

Arrhythmic Manifestations of Cardiac Amyloidosis: Challenges in Risk Stratification and Clinical Management.

Amyloidosis is a systemic disease characterized by extracellular deposits of insoluble amyloid in various tissues and organs. Cardiac amyloidosis is a frequent feature of the disease, causing a progressive, restrictive type of cardiomyopathy, and is associated with adverse clinical outcomes and increased mortality. The typical clinical presentation in patients with cardiac amyloidosis is heart failure (HF) with preserved ejection fraction. Most patients present with typical symptoms and signs of HF, such as exertional dyspnea, pretibial edema, pleural effusions and angina pectoris due to microcirculatory dysfunction. However, patients may also frequently encounter various arrhythmias, such as atrioventricular nodal block, atrial fibrillation and ventricular tachyarrhythmias. The management of arrhythmias in cardiac amyloidosis patients with drugs and devices is often a clinical challenge. Moreover, predictors of life-threatening arrhythmic events are not well defined. This review intends to give a deepened insight into the arrhythmic features of cardiac amyloidosis by discussing the pathogenesis of these arrhythmias, addressing the challenges in risk stratification and strategies for management in these patients.

Value of troponin T versus I in the diagnosis of immune checkpoint inhibitor-related myocarditis and myositis: rechallenge?

A 54-year old patient with metastatic melanoma presented with asymptomatic myositis and myocarditis after combined immune checkpoint inhibitors (ICI) therapy (anti-programmed cell death receptor-1, anti-lymphocyte activating gene-3, and anti-indoleamine 2,3-dioxygenase-1). The diagnosis was based on the typical time window after ICI, recurrence upon re-challenge, elevations of CK, high-sensitive troponin T (hs-TnT) and I (hs-TnI), mild NT-proBNP increase, and positive magnetic resonance imaging criteria. Notably, hsTnI was found to more rapidly increase and fall and to be more heart-specific than TnT in the context of ICI-related myocarditis. This led to ICI therapy withdrawal and switch to a less effective systemic therapy. This case report highlights the differential value of hs-TnT and hs-TnI for diagnosis and monitoring of ICI-related myositis and myocarditis.

Hypertensive response to exercise, hypertension and heart failure with preserved ejection fraction (HFpEF)-a continuum of disease?

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) has been shown to be a long-term consequence of uncontrolled arterial hypertension (aHT). Other than that, hypertensive response to exercise (HRE) precedes aHT. We aim to evaluate the available evidence for a continuum of HRE, aHT and HFpEF. METHODS: A literature search on PubMed was conducted to assembly the most recent data on the topic. After collecting the data, a qualitative analysis was instrumented. RESULTS: 10 studies including 16,165 subjects were analyzed with respect to the association between HRE and the future risk of developing aHT. With the exception of one study, all reported on a positive association between HRE and the future development of aHT despite methodological issues related to different definitions for HRE. Furthermore, HRE was associated with an increased risk of coronary artery disease. Moreover, we analysed 6 studies including overall 1366 subjects investigating the association between HRE and HFpEF. In these studies, increased left atrial volume index (LAVI), elevated E/e' (as surrogate parameters of increased LV end-diastolic filling pressure and of diastolic dysfunction) and higher LV mass index have been proposed as independent predictor of HRE in patients with no known HFpEF diagnosis. DISCUSSION AND CONCLUSION: The literature search revealed suggestive data on a connection of HRE, aHT and HFpEF. HRE seems to be an independent risk factor for aHT and aHT in turn is one of the main risk factors for HFpEF. However, further research is needed to improve our knowledge of a possible continuum of disease.