The Flt3-inhibitor quizartinib augments apoptosis and promotes maladaptive remodeling after myocardial infarction in mice.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) targeting fms-like tyrosine kinase 3 (Flt3) such as quizartinib were specifically designed for acute myeloid leukemia treatment, but also multi-targeting TKIs applied to solid tumor patients inhibit Flt3. Flt3 is expressed in the heart and its activation is cytoprotective in myocardial infarction (MI) in mice. OBJECTIVES: We sought to test whether Flt3-targeting TKI treatment aggravates cardiac injury after MI. METHODS AND RESULTS: Compared to vehicle, quizartinib (10 mg/kg/day, gavage) did not alter cardiac dimensions or function in healthy mice after four weeks of therapy. Pretreated mice were randomly assigned to MI or sham surgery while receiving quizartinib or vehicle for one more week. Quizartinib did not aggravate the decline in ejection fraction, but significantly enhanced ventricular dilatation one week after infarction. In addition, apoptotic cell death was significantly increased in the myocardium of quizartinib-treated compared to vehicle-treated mice. In vitro, quizartinib dose-dependently decreased cell viability in neonatal rat ventricular myocytes and in H9c2 cells, and increased apoptosis as assessed in the latter. Together with H2O2, quizartinib potentiated the phosphorylation of the pro-apoptotic mitogen activated protein kinase p38 and augmented H2O2-induced cell death and apoptosis beyond additive degree. Pretreatment with a p38 inhibitor abolished apoptosis under quizartinib and H2O2. CONCLUSION: Quizartinib potentiates apoptosis and promotes maladaptive remodeling after MI in mice at least in part via a p38-dependent mechanism. These findings are consistent with the multi-hit hypothesis of cardiotoxicity and make cardiac monitoring in patients with ischemic heart disease under Flt3- or multi-targeting TKIs advisable.

Comprehensive vasodilatation in women with acute heart failure: Novel insights from the GALACTIC randomized controlled trial.

AIMS: Sex-specific differences in acute heart failure (AHF) are both relevant and underappreciated. Therefore, it is crucial to evaluate the risk/benefit ratio and the implementation of novel AHF therapies in women and men separately. METHODS AND RESULTS: We performed a pre-defined sex-specific analysis in AHF patients randomized to a strategy of early intensive and sustained vasodilatation versus usual care in an international, multicentre, open-label, blinded endpoint trial. Inclusion criteria were AHF with increased plasma concentrations of natriuretic peptides, systolic blood pressure ≥100 mmHg, and plan for treatment in a general ward. Among 781 eligible patients, 288 (37%) were women. Women were older (median 83 vs. 76 years), had a lower body weight (median 64.5 vs. 77.6 kg) and lower estimated glomerular filtration rate (median 48 vs. 54 ml/min/1.73 m2 ). The primary endpoint, a composite of all-cause mortality or rehospitalization for AHF at 180 days, showed a significant interaction of treatment strategy and sex (p for interaction = 0.03; hazard ratio adjusted for female sex 1.62, 95% confidence interval 1.05-2.50; p = 0.03). The combined endpoint occurred in 53 women (38%) in the intervention group and in 35 (24%) in the usual care group. The implementation of rapid up-titration of renin-angiotensin-aldosterone system (RAAS) inhibitors was less successful in women versus men in the overall cohort and in patients with heart failure with reduced ejection fraction (median discharge % target dose in patients randomized to intervention: 50% in women vs. 75% in men). CONCLUSION: Rapid up-titration of RAAS inhibitors was less successfully implemented in women possibly explaining their higher rate of all-cause mortality and rehospitalization for AHF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, unique identifier NCT00512759.

Echocardiographic pattern of left ventricular function recovery in tachycardia-induced cardiomyopathy patients.

AIMS: Tachycardia-induced cardiomyopathy (TCM) represents a partially reversible type of cardiomyopathy (CM) that is often underdiagnosed and cardiac chamber remodelling in TCM remains incompletely understood. We aim to explore differences in the dimensions of the left ventricle and functional recovery in patients with TCM compared with patients with other forms of CM. METHODS AND RESULTS: We identified patients with reduced ejection fraction (≤50%) and/or atrial fibrillation or flutter with a left ventricular ejection fraction that improved from baseline (≥15% in left ventricular ejection fraction at follow-up or normalization of cardiac function with at least 10% improvement). Patients were then divided into two groups: (A) TCM patients and (B) patients with other forms of CM (controls). Two hundred thirty-eight patients were included (31% female, 70 years median age), 127 patients had TCM, and 111 had other forms of CM. Patients with TCM did not significantly improve indexed left ventricular volume (LVEDVI) after treatment (60 [45, 84] mL/m2 versus 56 [45, 70] mL/m2 , P = ns) compared with controls (67 [54, 81] mL/m2 versus 52 [42, 69] mL/m2 , P < 0.001). Patients with TCM patients had significantly worse fractional shortening at baseline than controls (15.5 [12, 23] vs. 20 [13, 30], P = 0.01) and higher indexed left atrial volume (LAVI) at baseline than controls (48 [37, 58] vs. 41 [33, 51], P = 0.01) that remained dilated at follow-up (follow-up LAVI 41 [33, 52] mL/m2 ). Good predictors of TCM were: normal LVEDVI (LVEDVI < 58 mL/m2 (M) and < 52 mL/m2 (F)) (odds ratio [OR] 5.2; 95% confidence interval [CI] 2.2-13.3, P < 0.001), fractional shortening < 30% (OR 3.5; 95% CI 1.4-9.2, P = 0.009), LAVI >40 mL/m2 (OR 3.4; 95% CI 1.6-7.3, P = 0.001) and normal wall thickness left ventricle (OR 3.2; 95% CI 1.4-7.8, P = 0.008). 54% of patients with TCM demonstrated diastolic dysfunction at follow-up, without differences from controls (54% vs. 43%, P = ns). 21% of patients with TCM showed persistent heart failure symptoms at follow-up compared with 4.5% of controls, P = 0.004. CONCLUSIONS: TCM patients have a specific pattern of functional recovery with persistent remodelling of the left atria and left ventricle. Several echocardiographic parameters might help identify TCM before treatment.

Bone Morphogenetic Protein 10-A Novel Biomarker to Predict Adverse Outcomes in Patients With Atrial Fibrillation.

Background Patients with atrial fibrillation (AF) face an increased risk of death and major adverse cardiovascular events (MACE). We aimed to assess the predictive value of the novel atrial-specific biomarker BMP10 (bone morphogenetic protein 10) for death and MACE in patients with AF in comparison with NT-proBNP (N-terminal prohormone of B-type natriuretic peptide). Methods and Results BMP10 and NT-proBNP were measured in patients with AF enrolled in Swiss-AF (Swiss Atrial Fibrillation Study), a prospective multicenter cohort study. A total of 2219 patients were included (median follow-up 4.3 years [interquartile range 3.9, 5.1], mean age 73±9 years, 73% male). In multivariable Cox proportional hazard models, the adjusted hazard ratio (aHR) associated with 1 ng/mL increase of BMP10 was 1.60 (95% CI, 1.37-1.87) for all-cause death, and 1.54 (95% CI, 1.35-1.76) for MACE. For all-cause death, the concordance index was 0.783 (95% CI, 0.763-0.809) for BMP10, 0.784 (95% CI, 0.765-0.810) for NT-proBNP, and 0.789 (95% CI, 0.771-0.815) for both biomarkers combined. For MACE, the concordance index was 0.732 (95% CI, 0.715-0.754) for BMP10, 0.747 (95% CI, 0.731-0.768) for NT-proBNP, and 0.750 (95% CI, 0.734-0.771) for both biomarkers combined. When grouping patients according to NT-proBNP categories (<300, 300-900, >900 ng/L), higher aHRs were observed in patients with high BMP10 in the categories of low NT-proBNP (all-cause death aHR, 2.28 [95% CI, 1.15-4.52], MACE aHR, 1.88 [95% CI, 1.07-3.28]) and high NT-proBNP (all-cause death aHR, 1.61 [95% CI, 1.14-2.26], MACE aHR, 1.38 [95% CI, 1.07-1.80]). Conclusions BMP10 strongly predicted all-cause death and MACE in patients with AF. BMP10 provided additional prognostic information in low- and high-risk patients according to NT-proBNP stratification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.

A Comprehensive Secondary Prevention Benchmark (2PBM) Score Identifying Differences in Secondary Prevention Care in Patients After Acute Coronary Syndrome.

PURPOSE: The objective of this study was to quantify secondary prevention care by creating a secondary prevention benchmark (2PBM) score for patients undergoing ambulatory cardiac rehabilitation (CR) after acute coronary syndrome (ACS). METHODS: In this observational cohort study, 472 consecutive ACS patients who completed the ambulatory CR program between 2017 and 2019 were included. Benchmarks for secondary prevention medication and clinical and lifestyle targets were predefined and combined in the comprehensive 2PBM score with maximum 10 points. The association of patient characteristics and achievement rates of components and the 2PBM were assessed using multivariable logistic regression analysis. RESULTS: Patients were on average 62 ± 11 yr of age and predominantly male (n = 406; 86%). The types of ACS were ST-elevation myocardial infarction (STEMI) in 241 patients (51%) and non-ST-elevation myocardial infarction in 216 patients (46%). Achievement rates for components of the 2PBM were 71% for medication, 35% for clinical benchmark, and 61% for lifestyle benchmark. Achievement of medication benchmark was associated with younger age (OR = 0.979: 95% CI, 0.959-0.996, P = .021), STEMI (OR = 2.05: 95% CI, 1.35-3.12, P = .001), and clinical benchmark (OR = 1.80: 95% CI, 1.15-2.88, P = .011). Overall ≥8 of 10 points were reached by 77% and complete 2PBM by 16%, which was independently associated with STEMI (OR = 1.79: 95% CI, 1.06-3.08, P = .032). CONCLUSIONS: Benchmarking with 2PBM identifies gaps and achievements in secondary prevention care. ST-elevation myocardial infarction was associated with the highest 2PBM scores, suggesting best secondary prevention care in patients after ST-elevation myocardial infarction.

Achievement of Low-Density Lipoprotein Cholesterol Targets in Cardiac Rehabilitation: Impact of the 2019 ESC/EAS Dyslipidaemia Guidelines.

In 2019 the European Society of Cardiology (ESC) lowered the target values for low-density lipoprotein cholesterol (LDL-C) from <1.8 mmol/L to <1.4 mmol/L for secondary prevention of cardiovascular disease (CVD). The aim of this study was to determine the clinical impact of the 2019 ESC/EAS dyslipidaemia guidelines on lipid-lowering therapies and achievement rates of LDL-C targets in a contemporary cohort of CAD patients participating in an ambulatory cardiac rehabilitation (CR) program.We conducted a retrospective analysis of prospectively collected data from the Swiss Secondary Prevention Registry (SwissPR) in patients with Coronary Artery Disease (CAD), who completed the ambulatory cardiovascular rehabilitation program (CR) of the University Hospital Basel, Switzerland from January 2017 to April 2021. To evaluate the impact of the guideline publication, the cohort was split into a pre-Guideline 2019 group (A) and a post-Guideline 2019 group (B). In total 1320 patients were screened leaving 875 patients for analysis. At discharge, more patients in group B were on maximal statin doses (20% vs. 9%, p < 0.0001) and on combination therapy with ezetimibe (51% vs. 17%, p < 0.0001) than in group A, which resulted in 53% of patients reaching the LDL-C target of <1.4 mmol/L in group B. Regression analysis revealed that dyslipidaemia and positive smoking history represent independent predictors for intensified lipid-lowering medication, whereas absolving CR after publication of the 2019 guidelines was the only significant predictor for reduced LDL-C at CR discharge. We found a significant difference in prescription rates of lipid-lowering medication, especially combination therapies and statin doses, after publication of the 2019 ESC/EAS dyslipidaemia guidelines resulting in an achievement rate of >50% of the LDL-C target <1.4 mmol/L in CAD patients participating in ambulatory CR.

Evaluation of Speech and Pause Alterations in Patients With Acute and Chronic Heart Failure.

Background Acute heart failure is the most frequent cause of unplanned hospital admission in elderly patients. Various biomarkers have been evaluated to better assess the status of these patients and prevent decompensation. Recently, voice has been suggested as a cost-effective and noninvasive way to monitor disease progression. This study evaluates speech and pause alterations in patients with acute decompensated and stable heart failure. Specifically, we aim to identify a vocal biomarker that could be used to monitor patients with heart failure and to prevent decompensation. Methods and Results Speech and pause patterns were evaluated in 68 patients with acute and 36 patients with stable heart failure. Voice recordings were performed using a web-browser based application that consisted of 5 tasks. Speech and pause patterns were automatically extracted and compared between acute and stable patients and with clinical markers. Compared with stable patients, pause ratio was up to 14.9% increased in patients with acute heart failure. This increase was largely independent of sex, age, and ejection fraction and persisted in patients with lower degrees of edema or dyspnea. Furthermore, pause ratio was positively correlated with NT-proBNP (N-terminal pro-B-type natriuretic peptide) after controlling for acute versus stable heart failure. Collectively, our findings indicate that the pause ratio could be useful in identifying acute heart failure, particularly in patients who do not display traditional indicators of decompensation. Conclusions Speech and pause patterns are altered in patients with acute heart failure. Particularly, we identified pause ratio as an easily interpretable vocal biomarker to support the monitoring of heart failure decompensation.

Case report of elevation of high-sensitivity cardiac troponin T in the absence of cardiac involvement in immune checkpoint inhibitor-associated myositis.

Background: Immune checkpoint inhibitors (ICIs) have markedly improved outcome in various types of cancer. ICI-associated myocarditis is one of the most severe immune-related adverse events. In particular, high concentrations of cardiac troponin T (cTnT) are associated with a high risk of death and early detection and vigorous therapy with high-dose steroids may improve survival. However, chronic skeletal muscle disorders have been suggested as a non-cardiac source of elevated high-sensitivity cardiac troponin T (hs-cTnT) concentrations. Case summary: Here, we present the case of a 72-year-old patient with metastatic melanoma treated with nivolumab and ipilimumab, who developed symptomatic myositis [creatine kinase (CK) max. 3113 U/L]. Due to substantially elevated concentrations of hs-cTnT (max. 1128 ng/L, normal <14 ng/L, Elecsys), the patient was referred to the cardio-oncology unit for evaluation of concomitant myocarditis. The patient did not report any cardiac symptoms and there were no clinical signs of congestion or rhythm abnormalities. Concentrations of NT-proBNP were within the normal range. Echocardiography showed normal cardiac dimensions and normal systolic and diastolic function. Cardiac magnetic resonance imaging confirmed these findings and also showed no evidence of acute or post-inflammatory myocardial tissue changes. Absence of relevant cardiomyocyte injury was supported by determination of normal levels of cardiac troponin I concentrations and made endomyocardial biopsy in this severely ill patient unnecessary. Discussion: Our observation documents ICI-induced myositis as an alternative non-cardiac cause of hs-cTnT elevation. A global cardiologic approach employing clinical and cardiac magnetic resonance imaging data as well as NT-proBNP and cardiac troponin I helps to identify false positive hs-TnT elevation under ICI therapy.

Inpatient Specialist Palliative Care in Patients With Left Ventricular Assist Devices (LVAD): A Retrospective Case Series.

Background: Repeat hospitalizations, complications, and psychosocial burdens are common in patients with left ventricular assist devices (LVAD). Specialist palliative care (sPC) involvement supports patients during decision-making until end-of-life. In the United States, guidelines recommend early specialist palliative care (esPC) involvement prior to implantation. Yet, data about sPC and esPC involvement in Europe are scarce. Materials and Methods: This is a retrospective descriptive study of deceased LVAD patients who had received sPC during their LVAD-related admissions to two university hospitals in Duesseldorf, Germany and Basel, Switzerland from 2010 to 2021. The main objectives were to assess: To which extent have LVAD patients received sPC, how early is sPC involved? What are the characteristics of those, how did sPC take place and what are key challenges in end-of-life care? Results: In total, 288 patients were implanted with a LVAD, including 31 who received sPC (11%). Twenty-two deceased LVAD patients (19 male) with sPC were included. Mean patient age at the time of implantation was 67 (range 49-79) years. Thirteen patients (59%) received LVAD as destination therapy, eight patients (36%) were implanted as bridge to transplantation (BTT), and one as an emergency LVAD after cardiogenic shock (5%). None of the eight BTT patients received a heart transplantation before dying. Most (n = 13) patients lived with their family and mean Eastern Cooperative Oncology Group (ECOG) performance status was three. Mean time between LVAD implantation and first sPC contact was 1.71 years, with a range of first sPC contact from 49 days prior to implantation to more than 6 years after. Two patients received esPC before implantation. In Duesseldorf, mean time between first sPC contact and in-hospital death was 10.2 (1-42) days. In Basel, patients died 16 (0.7-44) months after first sPC contact, only one died on the external sPC unit. Based on thorough examination of two case reports, we describe key challenges of sPC in LVAD patients including the necessity for sPC expertise, ethical and communicative issues as well as the available resources in this setting. Conclusion: Despite unequivocal recommendations for sPC in LVAD patients, the integration of sPC for these patients is yet not well established.

Practical Guidance for Diagnosing and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and How?

Iron deficiency (ID) is a comorbid condition frequently seen in patients with heart failure (HF). Iron has an important role in the transport of oxygen, and is also essential for skeletal and cardiac muscle, which depend on iron for oxygen storage and cellular energy production. Thus, ID per se, even without anaemia, can be harmful. In patients with HF, ID is associated with a poorer quality of life (QoL) and exercise capacity, and a higher risk of hospitalisations and mortality, even in the absence of anaemia. Despite its negative clinical consequences, ID remains under-recognised. However, it is easily diagnosed and managed, and the recently revised 2021 European Society of Cardiology (ESC) guidelines on HF provide specific recommendations for its diagnosis and treatment. Prospective randomised controlled trials in patients with symptomatic HF with reduced ejection fraction (HFrEF) show that correction of ID using intravenous iron (principally ferric carboxymaltose [FCM]) provides improvements in symptoms of HF, exercise capacity and QoL, and a recent trial demonstrated that FCM therapy following hospitalisation due to acute decompensated HF reduced the risk of subsequent HF hospitalisations. This review provides a summary of the epidemiology and pathophysiology of ID in HFrEF, and practical guidance on screening, diagnosing, and treating ID.

Budget Impact of Intravenous Iron Therapy with Ferric Carboxymaltose in Patients with Chronic Heart Failure with Reduced Ejection Fraction (HFrEF) and Iron Deficiency in Switzerland.

AIMS: A budget impact analysis compared treating patients with heart failure (HF) and reduced ejection fraction (HFrEF) and iron deficiency (ID) in Switzerland with intravenous ferric carboxymaltose (FCM) or placebo. METHODS: Clinical data from four international randomized trials showed that FCM versus placebo treatment was associated with a reduced hospitalization rate due to HF. The budget impact of this was modelled over 1 year. Hospital treatment costs for HFrEF, FCM drug costs, and estimated patient numbers were based on published data, official tariffs, specially commissioned analyses of SwissDRG data, and clinical and diagnosis-related groups (DRG) coding expert opinion. The original cost year was 2015. Sensitivity analyses were conducted including updated unit costs from 2019/2020. RESULTS: FCM treatment was associated with average cost savings of Swiss Francs (SFr) 503 per patient per year from the perspective of the Swiss mandatory health insurance system. Extrapolating across all eligible HFrEF patients with ID in Switzerland, this amounted to estimated savings of SFr 23,336,873. Sensitivity analyses showed these results to be robust in the face of changes to input parameters like treatment costs, different hospital settings, updated unit costs, and including outpatient treatment and patient co-payments in the analysis. CONCLUSIONS: The present analysis shows that using FCM to treat HFrEF patients with ID in line with current guideline recommendations resulted not only in medical benefits but also in significant cost savings. The analysis also provides an example of the pitfalls of transferring economic evaluation results, even between countries with similar hospital reimbursement systems.

Quantification of metabolic equivalents (METs) by the MET-REPAIR questionnaire: A validation study in patients with a high cardiovascular burden.

STUDY OBJECTIVE: Quantifying functional capacity is a core component of preoperative cardiovascular risk assessment. Lower metabolic equivalents (METs) are associated with higher morbidity/mortality in non-surgical and surgical populations. However, actually measuring METs preoperatively is rare. We sought to determine the correlation of self-reported METs using the questionnaire of the MET: REevaluation for Perioperative cArdIac Risk (MET-REPAIR) study and objectively measured METs by gold-standard cardiopulmonary exercise testing (CPET). DESIGN: Single-center prospective validation study. SETTING: University hospital. PATIENTS: We enrolled adult patients aged ≥45 undergoing out-patient cardiac rehabilitation. INTERVENTION: Patients completed the MET-REPAIR Questionnaire and the Duke Activity Status Index (DASI), had blood samples drawn, and underwent undergoing routine CPET. MEASUREMENTS: We compared measured METs by CPET to 1) self-reported METs (the MET-REPAIR Questionnaire), 2) the DASI score, 3) stand-alone questions, and 4) N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations. MAIN RESULTS: 140 patients were recruited. Measured METs by CPET correlated with 1) self-reported METs by the MET-REPAIR Questionnaire (ρ = 0.489, "fair"), 2) self-reported physical activity by the DASI (ρ = 0.487, "fair"), 3) the self-reported continual stair climbing ability (one of the stand-alone questions; ρ = 0.587, "fair") and 4) NT-proBNP concentrations (ρ = -0.353, "poor"). The area under the receiver operating characteristic curve (AUROC) for the ability to perform more than 4 METs were: highest for flights of stairs (0.841 [95%CI 0.735-0.948], p < 0.05 to rest, optimum: 3 flights), not significantly different between MET-REPAIR Questionnaire and DASI (0.666 [95%CI 0.551-0.781], optimum: 6 METs vs. 0.704 [95%CI 0.578-0.829], optimum: 32.2 points or 6.7 METs, p = 0.405), and not significant for NT-proBNP: (0.623 [95%CI 0.483-0.763]). CONCLUSIONS: The MET-REPAIR Questionnaire correlates with measured METs; all utilized forms of self-reported physical activity overestimate measured METs. NT-proBNP correlates poorly with measured METs.

Fms-like tyrosine kinase 3 is a regulator of the cardiac side population in mice.

Fms-like tyrosine kinase 3 (Flt3) is a regulator of hematopoietic progenitor cells and a target of tyrosine kinase inhibitors. Flt3-targeting tyrosine kinase inhibitors can have cardiovascular side effects. Flt3 and its ligand (Flt3L) are expressed in the heart, but little is known about their physiological functions. Here, we show that cardiac side population progenitor cells (SP-CPCs) from mice produce and are responsive to Flt3L. Compared with wild-type, flt3L-/- mice have less SP-CPCs with less contribution of CD45-CD34+ cells and lower expression of genes related to epithelial-to-mesenchymal transition, cardiovascular development and stem cell differentiation. Upon culturing, flt3L-/- SP-CPCs show increased proliferation and less vasculogenic commitment, whereas Akt phosphorylation is lower. Notably, proliferation and differentiation can be partially restored towards wild-type levels in the presence of alternative receptor tyrosine kinase-activating growth factors signaling through Akt. The lower vasculogenic potential of flt3L-/- SP-CPCs reflects in decreased microvascularisation and lower systolic function of flt3L-/- hearts. Thus, Flt3 regulates phenotype and function of murine SP-CPCs and contributes to cellular and molecular properties that are relevant for their cardiovasculogenic potential.

NOX1 mediates metabolic heart disease in mice and is upregulated in monocytes of humans with diastolic dysfunction.

AIMS: Microvascular inflammation plays an important role in the pathogenesis of diastolic dysfunction (DD) and metabolic heart disease. NOX1 is expressed in vascular and immune cells and has been implicated in the vascular pathology of metabolic disease. However, its contribution to metabolic heart disease is less understood. METHODS AND RESULTS: NOX1-deficient mice (KO) and male wild-type (WT) littermates were fed a high-fat high-sucrose diet (HFHS) and injected streptozotocin (75 mg/kg i.p.) or control diet (CTD) and sodium citrate. Despite similar weight gain and increase in fasting blood glucose and insulin, only WT-HFHS but not KO-HFHS mice developed concentric cardiac hypertrophy and elevated left ventricular filling pressure. This was associated with increased endothelial adhesion molecule expression, accumulation of Mac-2-, IL-1ß-, and NLRP3-positive cells and nitrosative stress in WT-HFHS but not KO-HFHS hearts. Nox1 mRNA was solidly expressed in CD45+ immune cells isolated from healthy mouse hearts but was negligible in cardiac CD31+ endothelial cells. However, in vitro, Nox1 expression increased in response to lipopolysaccharide (LPS) in endothelial cells and contributed to LPS-induced upregulation of Icam-1. Nox1 was also upregulated in mouse bone marrow-derived macrophages in response to LPS. In peripheral monocytes from age- and sex-matched symptomatic patients with and without DD, NOX1 was significantly higher in patients with DD compared to those without DD. CONCLUSIONS: NOX1 mediates endothelial activation and contributes to myocardial inflammation and remodelling in metabolic disease in mice. Given its high expression in monocytes of humans with DD, NOX1 may represent a potential target to mitigate heart disease associated with DD.

Comparison of V̇O2-Kinetic Parameters for the Management of Heart Failure.

Objective: The aim of this study was to analyze whether V̇O2-kinetics during cardiopulmonary exercise testing (CPET) is a useful marker for the diagnosis of heart failure (HF) and to determine which V̇O2-kinetic parameter distinguishes healthy participants and patients with HF. Methods: A total of 526 healthy participants and 79 patients with HF between 20 and 90 years of age performed a CPET. The CPET was preceded by a 3-min low-intensity warm-up and followed by a 3-min recovery bout. V̇O2-kinetics was calculated from the rest to exercise transition of the warm-up bout (on-kinetics), from the exercise to recovery transition following ramp test termination (off-kinetics) and from the initial delay of V̇O2 during the warm-up to ramp test transition (ramp-kinetics). Results: V̇O2 off-kinetics showed the highest z-score differences between healthy participants and patients with HF. Furthermore, off-kinetics was strongly associated with V̇O2peak. In contrast, ramp-kinetics and on-kinetics showed only minimal z-score differences between healthy participants and patients with HF. The best on- and off-kinetic parameters significantly improved a model to predict the disease severity. However, there was no relevant additional value of V̇O2-kinetics when V̇O2peak was part of the model. Conclusion: V̇O2 off-kinetics appears to be superior for distinguishing patients with HF and healthy participants compared with V̇O2 on-kinetics and ramp-kinetics. If V̇O2peak cannot be determined, V̇O2 off-kinetics provides an acceptable substitute. However, the additional value beyond that of V̇O2peak cannot be provided by V̇O2-kinetics.

Aortic Root Thrombus Directly After Left Ventricular Assist Device Implantation.

A 70-year-old female heart failure patient could not be weaned from temporary left ventricular mechanical support with Impella CP (Abiomed Inc, Danvers, MA) after myocardial infarction; therefore, she underwent left ventricular assist device implantation (HeartMate 3; Abbott, Chicago, IL). After uneventful surgery, the patient had an early postoperative thrombus in the aortic root, and surgical thrombectomy on extracorporeal circulation was performed on the seventh postoperative day. The patient recovered well and presented in good condition with no neurologic symptoms at the 6-month follow-up visit. Surgical excision of aortic root thrombus is a feasible option even for frail patients with a left ventricular assist device.

Après un infarctus du myocarde, une patiente de 70 ans présentant une insuffisance cardiaque n'a pas pu être sevrée d'une assistance mécanique temporaire pour le ventricule gauche par dispositif Impella CP (Abiomed Inc, Danvers, MA); elle a donc subi l'implantation d'un dispositif d'assistance ventriculaire gauche (HeartMate 3; Abbott, Chicago, IL). Après une intervention sans incident, la patiente a présenté un thrombus postopératoire précoce dans l'anneau aortique, et une thrombectomie chirurgicale sous circulation extracorporelle a été réalisée le septième jour suivant l'intervention. La patiente s'est bien rétablie et semblait en bonne santé, sans symptômes neurologiques, au moment de la visite de suivi six mois plus tard. L'excision chirurgicale du thrombus de l'anneau aortique est une option réaliste même chez les patients fragiles ayant un dispositif d'assistance ventriculaire gauche.

Management of transthyretin amyloidosis.

Transthyretin amyloidosis (ATTR amyloidosis) is a disease caused by deposition of transthyretin fibrils in organs and tissues, which causes their dysfunction. The clinical heterogeneity of ATTR amyloidosis and the variable presentation of symptoms at early disease stages, historically meant treatment delays. Diagnostic tools and therapy options of ATTR amyloidosis have markedly improved in recent years. The first Swiss Amyloidosis Network (SAN) meeting (Zurich, Switzerland, January 2020) aimed to define a consensus statement regarding the diagnostic work-up and treatment for systemic amyloidosis, tailored to the Swiss healthcare system. A consortium of 45 clinicians and researchers from all Swiss regions and universities was selected by the SAN committee to represent all sub-specialty groups involved in care of patients with amyloidosis. A steering committee conducted the literature search and analysis, wrote the critical synthesis and elaborated a list of statements that were evaluated by all the participants. These recommendations will improve outcomes and quality of life for patients with ATTR amyloidosis. A global review of these guidelines is planned every 3 years with a formal meeting of all the involved experts.

Influence of Antihypertensive Treatment on RAAS Peptides in Newly Diagnosed Hypertensive Patients.

(1) Background: Recently, influences of antihypertensive treatment on the renin-angiotensin-aldosterone system (RAAS) has gained attention, regarding a possible influence on inflammatory and anti-inflammatory pathways. We aimed to study the effects of newly initiated antihypertensive drugs on angiotensin (Ang) II and Ang (1-7) as representers of two counter-regulatory axes. (2) Methods: In this randomized, open-label trial investigating RAAS peptides after the initiation of perindopril, olmesartan, amlodipine, or hydrochlorothiazide, Ang II and Ang (1-7) equilibrium concentrations were measured at 8 a.m. and 12 a.m. at baseline and after four weeks of treatment. Eighty patients were randomized (1:1:1:1 fashion). (3) Results: Between the four substances, we found significant differences regarding the concentrations of Ang II (p < 0.0005 for 8 a.m., 12 a.m.) and Ang (1-7) (p = 0.019 for 8 a.m., <0.0005 for 12 a.m.) four weeks after treatment start. Ang II was decreased by perindopril (p = 0.002), and increased by olmesartan (p < 0.0005), amlodipine (p = 0.012), and hydrochlorothiazide (p = 0.001). Ang (1-7) was increased by perindopril and olmesartan (p = 0.008/0.002), but not measurably altered by amlodipine and hydrochlorothiazide (p = 0.317/ 0.109). (4) Conclusion: The initiation of all first line antihypertensive treatments causes early and distinct alterations of equilibrium angiotensin levels. Given the additional AT1R blocking action of olmesartan, RAAS peptides shift upon initiation of perindopril and olmesartan appear to work in favor of the anti-inflammatory axis compared to amlodipine and hydrochlorothiazide.