Iron therapy and severe arrhythmias in HFrEF: rationale, study design, and baseline results of the RESAFE-HF trial.

AIMS: The Iron Intravenous Therapy in Reducing the burden of Severe Arrhythmias in HFrEF (RESAFE-HF) registry study aims to provide real-word evidence on the impact of intravenous ferric carboxymaltose (FCM) on the arrhythmic burden of patients with heart failure with reduced ejection fraction (HFrEF), iron deficiency (ID), and implanted cardiac implantable electronic devices (CIEDs). METHODS AND RESULTS: The RESAFE-HF (NCT04974021) study was designed as a prospective, single-centre, and open-label registry study with baseline, 3, 6, and 12 month visits. Adult patients with HFrEF and CIEDs scheduled to receive IV FCM as treatment for ID as part of clinical practice were eligible to participate. The primary endpoint is the composite iron-related endpoint of haemoglobin ≥ 12 g/dL, ferritin ≥ 50 ng/L, and transferrin saturation > 20%. Secondary endpoints include unplanned HF-related hospitalizations, ventricular tachyarrhythmias detected by CIEDs and Holter monitors, echocardiographic markers, functional status (VO2 max and 6 min walk test), blood biomarkers, and quality of life. In total, 106 patients with a median age of 72 years (14.4) were included. The majority were male (84.9%), whereas 92.5% of patients were categorized to New York Heart Association II/III. Patients' arrhythmic burden prior to FCM administration was significant-19 patients (17.9%) received appropriate CIED therapy for termination of ventricular tachyarrhythmia in the preceding 12 months, and 75.5% of patients have frequent, repetitive multiform premature ventricular contractions. CONCLUSIONS: The RESAFE-HF trial is expected to provide evidence on the effect of treating ID with FCM in HFrEF based on real-world data. Special focus will be given on the arrhythmic burden post-FCM administration.

The impact of atrial mechanical function on age-dependent presentation of neurocardiogenic syncope.

BACKGROUND: The contribution of atrial and ventricular function in neurocardiogenic syncope (NCS) pathophysiology is elusive. HYPOTHESIS: We assessed the influence of echocardiographic properties to the age of presentation and NCS recurrences. METHODS: We assigned 124 patients with symptoms suggesting NCS, to those with syncope initiation at age <35 (group A, n = 56) and >35 years (group B, n = 68). Echocardiographic indices were measured before head-up tilt test (HUTT). RESULTS: A total of 55 had positive HUTT (44%) with a trend favoring group A (p = .08). Group A exhibited lower left atrial (LA) volume index (17 ± 6 vs. 22 ± 11 ml/m2 , p = .015), higher LA ejection fraction (69 ± 10 vs. 63 ± 11%, p = .008), LA peak strain (reservoir phase 41 ± 13 vs. 31 ± 14%, p = .001, contraction phase 27 ± 11 vs. 15 ± 10%, p < .001) and LA peak strain rate (reservoir phase 1.83 ± 1.04 vs. 1.36 ± 0.96 1/s, p = .012, conduit phase 2.36 ± 1.25 vs. 1.36 ± 0.78 1/s, p = .001). Group A showed smaller minimum right atrial (RA) volume, better RA systolic function, superior left ventricular diastolic indices, and lower filling pressures. Group A patients were more likely to have >3 recurrences (82.0% vs. 50.1%, p < .05). CONCLUSIONS: Patients with younger age of NCS onset and more syncopal recurrences manifest smaller LA and RA dimensions with distinct patterns of systolic and diastolic function and better LA reservoir and contraction properties. These findings may indicate an increased susceptibility to preload reduction, thereby triggering the NCS mechanism.

Identification of acute myocardial infarction in elderly patients using optimized highly sensitive troponin I thresholds.

Purpose: Established diagnostic thresholds for high-sensitivity cardiac troponins (hs-cTn) might not apply for elderly patients as they are elevated irrespective of the presence of an acute myocardial infarction (AMI). Aim of the present study was to investigate hs-cTnI in elderly patients with suspected AMI and to calculate optimized diagnostic cutoffs. Material and methods: Data from a prospective multi-centre study and from a second independent prospective single-centre cohort study were analysed. A number of 2903 patients were eligible for further analysis. Patients > 70 years were classified as elderly. hs-cTnI was measured upon admission. Results: Around 34.7% of 2903 patients were classified as elderly. Around 22.5% of elderly patients were finally diagnosed with AMI. Elderly patients had higher hs-cTnI levels at admission irrespective of the final diagnosis (p < 0.001). According to the AUROC, hs-cTnI was a strong marker for detection of AMI in elderly patients. Application of the 99th percentile cutoffs showed a substantially lower specificity in elderly. By using optimized thresholds, specificity was improved to levels as in younger patients in both cohorts but accompanied with a decrease in sensitivity. Conclusions: hs-cTnI levels have a lower specificity for detecting AMI in elderly patients. This lower specificity can be improved by using hs-cTnI thresholds optimized for elderly patients.

Cardiac Troponins for the Diagnosis of Acute Myocardial Infarction in Chronic Kidney Disease.

Background Patients with chronic kidney disease ( CKD ) are at high risk of myocardial infarction. Cardiac troponins are the biomarkers of choice for the diagnosis of acute myocardial infarction ( AMI ) without ST -segment elevation ( NSTE ). In patients with CKD , troponin levels are often chronically elevated, which reduces their diagnostic utility when NSTE - AMI is suspected. The aim of this study was to derive a diagnostic algorithm for serial troponin measurements in patients with CKD and suspected NSTE - AMI . Methods and Results Two cohorts, 1494 patients from a prospective cohort study with high-sensitivity troponin I (hs- cTnI ) measurements and 7059 cases from a clinical registry with high-sensitivity troponin T (hs- cTnT ) measurements, were analyzed. The prospective cohort comprised 280 CKD patients (estimated glomerular filtration rate <60 mL/min/1.73 m2). The registry data set contained 1581 CKD patients. In both cohorts, CKD patients were more likely to have adjudicated NSTE - AMI than non- CKD patients. The specificities of hs- cTnI and hs- cTnT to detect NSTE - AMI were reduced with CKD (0.82 versus 0.91 for hs- cTnI and 0.26 versus 0.73 for hs- cTnT ) but could be restored by applying optimized cutoffs to either the first or a second measurement after 3 hours. The best diagnostic performance was achieved with an algorithm that incorporates serial measurements and rules in or out AMI in 69% (hs- cTnI ) and 55% (hs- cTnT ) of CKD patients. Conclusions The diagnostic performance of high-sensitivity cardiac troponins in patients with CKD with suspected NSTE - AMI is improved by use of an algorithm based on admission troponin and dynamic changes in troponin concentration.

Left atrial deformation as a potent predictor for paroxysmal atrial fibrillation in patients with end-stage renal disease.

It is widely known that various factors contribute to left atrial (LA) mechanical dysfunction in patients with end stage renal disease (ESRD). However, the connection between atrial dysfunction and arrhythmic events such as paroxysmal atrial fibrillation (PAF), in this group of patients, remains unclear. The purpose of our study was to evaluate prospectively the association between LA deformation indices and PAF in ESRD patients. 79 patients (41 men, mean age 57 ± 17) with ESRD and preserved left ventricular systolic function comprised the study population. All patients underwent a baseline comprehensive echocardiography study and were followed for a mean period of 16 ± 5 months. PAF episodes, first and the following events, were reported. LA longitudinal strain reflecting LA reservoir function and LA longitudinal strain rate reflecting LA pump function were specifically evaluated as LA deformation indices of interest, using 2D speckle tracking echocardiography. At the end of follow up period nine patients died. 15 of the rest 70 reported one or more episodes of PAF. LA indexed volumes were significantly higher in patients with PAF (32 ± 26 vs. 21.5 ± 9 ml/m2, p = 0.002), mean LA strain was significantly reduced (17 ± 7 vs. 27 ± 9%, p < 0.001) as well as mean LA stain rate (- 1.19 ± 0.5 vs. - 1.95 ± 0.5 1/s, p < 0.001). Multivariate analysis showed that LA strain rate when adjusted with age together with PAF history remained the single most significant echocardiographic parameter for PAF prediction. Impaired LA strain and LA strain rate are associated with PAF in ESRD patients. LA strain rate might be a better independent predictor of PAF, compared to standard echocardiographic indices. Further prospective studies are needed to validate its relevance in routine clinical practice.

Urinary neutrophil gelatinase-associated lipocalin and cystatin C compared to the estimated glomerular filtration rate to predict risk in patients with suspected acute myocardial infarction.

INTRODUCTION: Impaired renal function, reflected by estimated glomerular filtration rate (eGFR) or cystatin C, is a strong risk predictor in the presence of acute myocardial infarction (AMI). Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is an early marker of acute kidney injury. uNGAL might also be a good predictor of outcome in patients with cardiovascular disease. Aim of the present study was to evaluate the prognostic value of uNGAL compared to eGFR and cystatin C in patients with suspected AMI. METHODS: 1818 patients were enrolled with suspected AMI. Follow-up information on the combined endpoint of death or non-fatal myocardial infarction was obtained 6months after enrolment and was available in 1804 patients. 63 events (3.5%) were registered. RESULTS: While cystatin C and eGFR were strong risk predictors for the primary endpoint even adjusted for several variables, uNGAL was not independently associated with outcome: When applied continuously uNGAL was associated with outcome but did not remain a statistically significant predictor after several adjustments (i.e. eGFR). By adding cystatin C or uNGAL to GRACE risk score variables, only cystatin C could improve the predictive value while uNGAL showed no improvement. CONCLUSION: We could show that cystatin C is an independent risk predictor in patients with suspected AMI and cystatin C can add improvement to the commonly used GRACE risk score. In contrast uNGAL is not independently associated with outcome and seems not to add further prognostic information to GRACE risk score.

Diagnosis of tuberous sclerosis complex in a patient referred for uncontrolled hypertension and renal dysfunction: a case highlighting the importance of proper diagnostic work-up of hypertensive patients.

: We report a case of a 39-year-old woman with resistant hypertension and renal dysfunction. The patient was hospitalized 3 months earlier for dyspnea at the Department of Cardiology, where she was diagnosed with heart failure (left ventricle injection fraction: 25-30%), pulmonary hypertension, chronic kidney disease (serum creatinine: 1.58 mg/dl), and resistant hypertension and discharged with optimal heart failure treatment. At presentation to our clinic, apart from uncontrolled hypertension for more than 10 years and history of pre-eclampsia and fetal loss, the patient had obesity (BMI: 38 kg/m) and facial fibromas. The first diagnostic steps proposed by the European Society of Hypertension/European Society of Cardiology (ESH/ESC) Guidelines to identify other target-organ damage and causes of secondary hypertension revealed typical proteinuric hypertensive nephropathy, hypertensive retinopathy, and sleep-apnea syndrome. Furthermore, a renal ultrasound showed multiple bilateral renal angiomyolipomas, confirmed by an MRI scan. Following consultation with the Neurology and Dermatology Departments, the diagnosis of tuberous sclerosis complex, based on presence of six major criteria, was confirmed. During the following 10 months, careful adjustments in the patient's antihypertensive treatment, reinforcement of lifestyle interventions, and improved compliance enabled her to reduce her body weight, control blood pressure, improve her heart (left ventricle injection fraction: >40%), and renal injury (creatinine urine clearance: 125 ml/min, urine protein: 178 mg/24 day) and serum triglycerides (153 mg/dl). These improvements enabled the start of everolimus, required for a slight increase in angiomyolipomas' size (3.46 cm) in the repeated examinations.

Increased myeloperoxidase plasma levels in patients with Alzheimer's disease.

BACKGROUND: Increasing evidence supports the role of cardiovascular risk factors in the development of Alzheimer's disease (AD). OBJECTIVE: In the present pilot study, we investigated plasma concentrations of myeloperoxidase (MPO) and its possible association with plasma amyloid-ß (Aß)1-42/1-40 ratio in AD patients and elderly healthy controls. METHODS: The study sample included 28 AD patients and 27 elderly individuals with a normal cognitive status as a control group. The Mini-Mental Status Examination was used to determine the global cognition. MPO, Aß1-40, and Aß1-42 plasma concentrations were measured by enzyme linked immunoabsorbent assays. RESULTS: AD patients showed significantly higher plasma concentrations of MPO in comparison to healthy elderly controls (AD versus healthy elderly controls (mean ± SD): 132.8 ± 114.8 ng/mL versus 55.0 ± 42.6 ng/mL; p = 0.002). MPO plasma concentrations showed a significant positive correlation in the whole sample with the presence of AD (ρ = 0.428, p < 0.001) and its stage (ρ = 0.331; p = 0.013) as well as with plasma concentrations of Aß1-42 (ρ = 0.406; p = 0.004) and Aß1-42/1-40 ratio (ρ = 0.354; p = 0.013). In a binary logistic regression model, plasma MPO concentrations were independently associated with the presence of AD (p = 0.014). CONCLUSION: AD patients showed significantly increased plasma levels of MPO, which could be an important molecular link between atherosclerosis and AD. Further studies should evaluate whether MPO may also be a useful biomarker and potential new treatment target in AD.

Midregional pro-atrial natriuretic peptide in the general population/Insights from the Gutenberg Health Study.

BACKGROUND: The use of biomarkers is firmly established for the assessment of cardiovascular disease. Emerging biomarkers such as midregional pro-atrial natriuretic peptide (MR-proANP) challenge established markers regarding risk prediction and stratification ability. The aim of the present study was to describe the distribution of a contemporary MR-proANP assay in a large population-representative sample and to evaluate the association with prevalent cardiac diseases and cardiovascular risk factors. METHODS: MR-proANP was determined by the use of a contemporary commercially available assay (BRAHMS GmbH, Hennigsdorf, Germany) in a representative sample of 5000 participants from the large population-based Gutenberg Health Study. N-terminal pro B-type natriuretic peptide (NT-proBNP) was used as a comparator. RESULTS: Mean age was 55.5 ± 10.9 years. Coronary artery disease (CAD) was documented in 4.6%, heart failure (HF) in 1.5% of the study participants. We observed a moderate to strong correlation of the biomarkers with age, diabetes, hypertension, smoking, renal function, prevalence of CAD and HF. Males showed lower MR-proANP concentrations than females. MR-proANP showed no relevant correlation with BMI (ρ=-0.030) and CRP (ρ=0.039). Reference limits for MR-proANP representing the 95th/97.5th/99th percentile were determined for healthy individuals with 116/132/169 pmol/mL. CONCLUSIONS: The current analysis in a large population-based sample elucidates the correlations and distribution of MR-proANP. Its concentration in healthy individuals depends on prevalent cardiovascular diseases and classical risk factors. The reported population-based reference values might be useful for distinguishing between healthy and diseased individuals, thus improving risk stratification and triaging in various clinical settings.

Cystatin C and cardiovascular mortality in patients with coronary artery disease and normal or mildly reduced kidney function: results from the AtheroGene study.

AIMS: Chronic kidney disease is associated with increased risk of cardiovascular disease. Cystatin C is a promising marker to reliably mirror renal function. The role of cystatin C in patients with coronary artery disease (CAD) and normal or mildly reduced kidney function is the subject of current investigation. METHODS AND RESULTS: In 2162 patients, over the whole spectrum of CAD, baseline cystatin C concentrations were measured. Patients with an estimated glomerular filtration rate of < or =60 mL/min per 1.73 m(2) (n = 295) were excluded. In patients with complete follow-up information (n = 1827), 66 cardiovascular deaths were registered during a median follow-up of 3.65 years. Logarithmically transformed, standardized cystatin C was associated with cardiovascular death [hazard ratio: 1.94, 95% confidence interval (CI): 1.59-2.37, P < 0.001]. A potential threshold effect was observed; patients in the upper quartile had a 3.87-fold (95% CI: 2.33-6.42; P < 0.001) risk of mortality compared with the pooled lower quartiles. This risk association remained robust after adjustment for potential confounders including classical risk factors and N-terminal pro B-type natriuretic peptide. Serum creatinine was not associated with the outcome in this group of patients with normal renal function. CONCLUSION: Results of this prospective study show that cystatin C is a potent predictor of cardiovascular mortality beyond classical risk factors in patients with CAD and normal or mildly reduced kidney function.