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We demonstrated that the end tidal CO2 oscillation causes oscillations of delta and alpha bands. The analysis of the regional field power showed that different cortical areas respond with different time delays to CO2 challenges. An opposite behavior was found for the end-tidal O2. We can suppose that the different cortical time delay response likely expresses specific ascending pathways to the cortex generated by chemoreceptor nuclei in the brainstem.

Bakground The aim of this study was to evaluate both analytical characteristics and clinical results of a new chemiluminescent method for the measurement of cardiac troponin I (cTnI), named VITROS ® High Sensitivity Troponin I Assay, using the VITROS® 3600 automated platform. The results found with this new method were compared to those observed with hs-cTnI ARCHITECT and ECLIA hs-cTnT ELECSYS methods. Methods For evaluation of analytical performance and comparison of clinical results, plasma samples (lithium-heparin), were collected from apparently healthy subjects and patients with cardiovascular diseases. Results The hs-cTnI VITROS method showed values for limit of blank (LoB 0.33 ng/L), limit of detection (LoD, 0.91 ng/L), limit of quantifications at 20% (LoQ 20% CV, 1.82 ng/L), and 10% (LoQ 10% CV, 4,74 ng/L), which are comparable to those previously reported for other hs-cTnI methods. Moreover, the clinical results of the hs-cTnI VITROS method were found to be closely correlated to those of hs-cTnI ARCHITECT (R = 0,9883, N = 198) and ECLIA hs-cTnT Elecsys (R = 0,9704, N = 293) methods. Conclusions The hs-cTnI VITROS method shows analytical performance comparable to other cTnI and cTnT assay. The results of this study confirm that there are significant systematic differences among hs-cTnI methods. Further multicenter studies using larger reference populations are needed in order to obtain a better estimation, especially of the 99° percentile URL values categorized for sex and age of hs-cTnI and hs-cTnT methods.

ObjectiveWe analysed the circulating levels and prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP), norepinephrine (NE), epinephrine (E), plasma renin activity (PRA) and aldosterone in patients with systolic heart failure (HF) receiving therapies that target the sympathetic system and the renin-angiotensin-aldosterone axis.MethodsWe retrieved data from consecutive HF outpatients with left ventricular ejection fraction (LVEF) ResultsPatients (n=1477) were aged 66±13 years, 75% were men, median LVEF was 32% (IQR 25–38), 77% had LVEF ConclusionsIn patients with HF with LVEF

Chemotherapy with anthracycline-based regimens remains a cornerstone of treatment of many solid and blood tumors but is associated with a significant risk of cardiotoxicity, which can manifest as asymptomatic left ventricular dysfunction or overt heart failure. These effects are typically dose-dependent and cumulative and may require appropriate screening strategies and cardioprotective therapies in order to minimize changes to anticancer regimens or even their discontinuation. Our current understanding of cardiac damage by anthracyclines includes a central role of oxidative stress and inflammation. The identification of these processes through circulating biomarkers or imaging techniques might then be helpful for early diagnosis and risk stratification. Furthermore, therapeutic strategies relieving oxidative stress and inflammation hold promise to prevent heart failure development or at least to mitigate cardiac damage, although further evidence is needed on their efficacy, either alone or as part of combination therapies with neurohormonal antagonists, which are the current adopted standard.

American journal of respiratory and critical care medicine : AJRCCM 204(4), 490-491 (2021). doi:10.1164/rccm.202104-0846LE, Published by American Thoracic Society, New York, NY

Prompt treatment may mitigate the adverse effects of congestion in the early phase of heart failure (HF) hospitalization, which may lead to improved outcomes. We analyzed 814 acute HF patients for the relationships between time to first intravenous loop diuretics, changes in biomarkers of congestion and multi-organ dysfunction, and 1-year composite endpoint of death or HF hospitalization. B-type natriuretic peptide (BNP), high sensitivity cardiac troponin I (hscTnI), urine and serum neutrophil gelatinase-associated lipocalin (NGAL), and galectin 3 were measured at hospital admission, hospital day 1, 2, 3 and discharge. Time to diuretics was not correlated with the timing of decongestion defined as BNP decrease = 30% compared to admission. Earlier BNP decreases but not time to diuretics were associated with earlier and greater decreases in hscTnI and urine NGAL, and lower incidence of the composite endpoint. After adjustment for confounders, only no BNP decrease at discharge was significantly associated with mortality but not the composite endpoint (p?=?0.006 and p?=?0.062, respectively). In conclusion, earlier time to decongestion but not the time to diuretics was associated with better biomarker trajectories. Residual congestion at discharge rather than the timing of decongestion predicted a worse prognosis.

Background and objective: The clinical relevance and interrelation of sleep-disordered breathing and nocturnal hypoxemia in patients with precapillary pulmonary hypertension (PH) is not fully understood. Methods: Seventy-one patients with PH (age 63 ± 15 years, 41% male) and 35 matched controls were enrolled. Patients with PH underwent clinical examination with assessment of sleep quality, daytime sleepiness, 6-minute walk distance (6MWD), overnight cardiorespiratory polygraphy, lung function, hypercapnic ventilatory response (HCVR; by rebreathing technique), amino-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and cardiac MRI (n = 34). Results: Prevalence of obstructive sleep apnea (OSA) was 68% in patients with PH (34% mild, apnea-hypopnea index [AHI] ≥5 to p < 0.01). Only 1 patient with PH showed predominant central sleep apnea (CSA). Nocturnal hypoxemia (mean oxygen saturation [SpO2] 2, self-reported sleep quality, 6MWD, HCVR, and lung and cardiac function between patients with moderate to severe OSA and those with mild or no OSA (all p > 0.05). Right ventricular (RV) end-diastolic (r = −0.39; p = 0.03) and end-systolic (r = −0.36; p = 0.04) volumes were inversely correlated with mean nocturnal SpO2 but not with measures of OSA severity or daytime clinical variables. Conclusion: OSA, but not CSA, is highly prevalent in patients with PH, and OSA severity is not associated with nighttime SpO2, clinical and functional status. Nocturnal hypoxemia is a frequent finding and (in contrast to OSA) relates to structural RV remodeling in PH.

Background Central apneas (CA) and obstructive apneas (OA) are highly prevalent in heart failure (HF) both with reduced and preserved systolic function. However, a comprehensive evaluation of apnea prevalence across HF according to ejection fraction (i.e HF with patients with reduced, mid-range and preserved ejection fraction- HFrEf, HFmrEF and HFpEF, respectively) throughout the 24 hours has never been done before. Materials and methods 700 HF patients were prospectively enrolled and then divided according to left ventricular EF (408 HFrEF, 117 HFmrEF, 175 HFpEF). All patients underwent a thorough evaluation including: 2D echocardiography; 24-h Holter-ECG monitoring; cardiopulmonary exercise testing; neuro-hormonal assessment and 24-h cardiorespiratory monitoring. Results In the whole population, prevalence of normal breathing (NB), CA and OA at daytime was 40%, 51%, and 9%, respectively, while at nighttime 15%, 55%, and 30%, respectively. When stratified according to left ventricular EF, CA prevalence decreased from HFrEF to HFmrEF and HFpEF: (daytime CA: 57% vs. 43% vs. 42%, respectively, p=0.001; nighttime CA: 66% vs. 48% vs. 34%, respectively, p When assessing moderte-severe apneas, defined with an apnea/hypopnea index >15 events/hour, prevalence of CA was again higher in HFrEF than HFmrEF and HFpEF both at daytime (daytime moderate-severe CA: 28% vs. 19% and 23%, respectively, p Conclusions Daytime and nighttime apneas, both central and obstructive in nature, are highly prevalent in HF regardless of EF. Across the whole spectrum of HF, CA prevalence increases and OA decreases as left ventricular systolic dysfunction progresses, both during daytime and nighttime. Funding Acknowledgement Type of funding source: None

Background Cardiac amyloidosis (CA) is caused by the extracellular deposition of misfolded proteins into insoluble amyloid fibrils, the 2 most common forms being transthyretin (ATTR) and immunoglobulin light chain (AL) amyloidosis. Chronic elevation of cardiac troponins and natriuretic peptides is common in CA and predicts worse outcome. The diagnostic yield of biomarkers of cardiac damage for CA has been less investigated. Purpose We aimed to evaluate the ruling-in/out values for the diagnosis of CA of high-sensitivity cardiac troponin T (hs-cTnT) and of N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP). Methods We studied 275 consecutive patients referred to two tertiary Centers in Italy (n=184) and France (n=91) with the clinical suspicion of CA due to the presence of a plasma cell dyscrasia or an unexplained left ventricular (pseudo)hypertrophy. CA was confirmed by the combination of suggestive features on imaging techniques (echocardiography, cardiac magnetic resonance, diphosphonate scintigraphy) and biopsy examination. All patients underwent a full baseline characterization including hs-cTnT and NT-proBNP. Biomarkers values corresponding to a negative likelihood ratio 10 were respectively chosen as rule-out and rule-in cut-offs for CA. Results CA was confirmed in 161 (59%) patients, who had either AL amyloidosis (n=96, 60%) or ATTR amyloidosis (n=65, 40%). At time of evaluation, 97 (35%) patients (34 CA vs. 63 controls, p=0.112) were hospitalized for decompensated heart failure. Patients with CA showed higher hs-cTnT (65 ng/L [44–122] vs. 31 [18–42], p Conclusions Plasma hs-cTnT and NT-proBNP have diagnostic value in patients with suspected CA. Stand-alone hs-cTnT levels Figure 1 Funding Acknowledgement Type of funding source: None

Background Reverse remodelling (RR) is the recovery from left ventricular (LV) dilation and dysfunction in response to treatment for heart failure (HF). RR is usually associated with improved prognosis. The impact of RR on indices of diastolic function, and the relative prognostic value of RR, changes in diastolic function and natriuretic peptide levels are currently unknown. Methods We analysed data from patients with stable systolic HF (LV ejection fraction [LVEF] Results 927 patients were evaluated (68±12 years; median LVEF 35% [interquartile interval 30–43%]; 27% women; 52% ischaemic aetiology). Patients experiencing RR (n=286, 31%) displayed more prominent positive changes in several parameters reflecting diastolic dysfunction, namely E/e' ratio, left atrial volume index (LAVi), and systolic pulmonary artery pressure (sPAP), as well as N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP; Figure). In the whole population, percent changes (Δ%) LVESVi displayed weak but significant correlations with Δ% E/e' (r=0.237, p Conclusions A recovery of LV geometry is accompanied by positive modifications in several indices related to diastolic function, as well as a decrease in NT-proBNP levels. Percent changes in NT-proBNP over 12 months are stronger predictors of outcome than variations in LV geometry or sPAP. Funding Acknowledgement Type of funding source: None

Background Early diagnosis of cardiac amyloidosis (CA) is warranted to initiate specific treatment and improve outcome. The amyloid light chain (AL) and inferior wall thickness (IWT) scores have been proposed to assess patients referred by hematologists or with unexplained left ventricular (LV) hypertrophy, respectively. These scores are composed of 4 or 5 variables, respectively, including strain data, and no decisional cut-offs were introduced. Methods Based on 2 variables common to the AL and IWT scores, we defined a simple score named AMYLoidosis Index (AMYLI) as the product of relative wall thickness (RWT) and E/e' ratio, and assessed its diagnostic performance. Optimal rule-out cut-offs were searched as those with negative likelihood ratio (LR−) Results In the derivation cohort (n=251), CA was ultimately diagnosed in 111 patients (44%). The 2.22 score value was selected as rule-out cut-off (LR- 0.0). In the hematology subset, AL CA was finally diagnosed in 32 patients (48%), with 2.36 as rule-out cut-off (LR− 0.0). In the hypertrophy subset, ATTR CA was diagnosed in 79 patients (43%), with 2.22 as best rule-out cut-off (LR− 0.0). In the validation cohort (n=691), where more patients were diagnosed with CA (94% and 68% in the hematology and in the hypertrophy subsets, respectively), the 2.22 rule-out cut-off had a LR− = ∞ (as no patient scoring Conclusions The AMYLI score (RWT* E/e') is simpler than those proposed and similarly accurate. A 2.22 cut-off value excludes CA diagnosis in patients undergoing a diagnostic screening for CA, while a Funding Acknowledgement Type of funding source: None

Background Cardiac magnetic resonance (CMR) is an important diagnostic technique for cardiac amyloidosis (CA). A deep learning (DL) approach to define the likelihood of CA based on automated interpretation of CMR images has never been attempted so far. Methods 187 subjects underwent standard 1.5 T CMR examination (GE-Healthcare, Milwaukee, USA) as part of a diagnostic workup for either unexplained left ventricular hypertrophy or blood dyscrasia with suspected light-chain (AL) amyloidosis. Patients were randomly assigned to 3 subgroups, which were used for training (n=121, 65%), internal validation (n=28, 15%), and model testing (n=38, 20%). LGE images in different orientations (short-axis, 2- and 4-chambers) were selected as the most informative CMR features. A deep convolutional neural network was trained to classify CMR examinations as “amyloidosis” (probability ≥50%) or “no amyloidosis” (probability Results CA was diagnosed in 101 subjects (54%; 45 AL, 56 transthyretin amyloidosis). A model including 2C, 4C and SA LGE images was created. In the test cohort, it allowed to diagnose CA with good diagnostic accuracy (84.2%), and an area under the curve (AUC) of 0.96 (Figure). The precision (positive predictive value), recall score (sensitivity), and F1 score (a measure of test accuracy) were 0.78, 0.94, and 0.86, respectively. An ML algorithm considering all available parameters (LV volumes and function, LGE presence and pattern, early darkening, pericardial and pleural effusion, etc.) displayed a similar diagnostic performance than the DL method (AUC 0.93 vs. 0.96; p=0.45). Conclusions The deep learning technique allowed to create an accurate diagnostic tool for CA based on LGE patterns, which could be easily converted into an online platform for automated image analysis. Funding Acknowledgement Type of funding source: None

Background Patients treated with ticagrelor often develop dyspnea of unknown origin. We aim to explore the contribution of central apneas to ticagrelor-related dyspnea in patients with acute coronary syndrome (ACS). Methods We consecutively enrolled patients with ACS, preserved left ventricular ejection fraction and no history of obstructive sleep apnea, treated either with ticagrelor 90 mg bid (n=30) or prasugrel 10 mg od (n=24). One week after ACS onset, all patients underwent, beyond thorough cardiovascular and respiratory assessment, 24-hour cardiorespiratory monitoring and assessment of chemosensitivity to hypercapnia. Results Patients treated with ticagrelor reported more frequently dyspnea than patients treated with prasugrel (43% versus 4%, p=0.001), despite no difference in demographic, clinical, echocardiographic and pulmonary data. Patients with dyspnea induced by ticagrelor showed higher apnea-hypopnea and central apnea index both at daytime and at nighttime compared to patients treated with ticagrelor but without dyspnea and patients treated with prasugrel (daytime AHI: 26 [7–34] vs 6 [4–14] and 6 [0–11] events/hour; nighttime AHI: 65 [17–72] vs 22 [8–37] and vs 11 [4–23] events/hour; daytime CAI: 5 [1–15] vs 1 [0–6] and 0 [0–1) events/hour; nighttime CAI 34 [2–55] vs 3 [0–9] and 0 [0–1], all p Conclusions Central apneas should be considered a likely mechanism of dyspnea in ACS patients treated with ticagrelor. A drug-related sensitization of the chemoreflex may be the cause of ventilatory instability in this setting. Funding Acknowledgement Type of funding source: None

Sacubitril/valsartan, vericiguat, and the sodium-glucose co-transporter-2 inhibitors (SGLT2i) dapagliflozin and empagliflozin proved effective in phase 3 trials on heart failure with reduced ejection fraction (HFrEF). We compared the treatment arms (sacubitril/valsartan, vericiguat, and SGLT2i) with the respective control arms (standard-of-care [SOC]) through a network meta-analysis of the phase 3 trials (PARADIGM-HF, VICTORIA, DAPA-HF, EMPEROR-Reduced), a phase 2 trial on vericiguat and the HFrEF subgroup of DECLARE-TIMI 58. There was a trend towards decreased risk of cardiovascular (CV) death or HF hospitalization with SGLT2i than sacubitril/valsartan (HR 0.92, 95% CI 0.81 to 1.05) and vericiguat (HR 0.83, 95% CI 0.73 to 0.94). A non-significant effect of SGLT2i on CV mortality compared to sacubitril/valsartan (HR 1.04, 95% CI 0.88 to 1.24) and vericiguat (HR 0.88, 95% CI 0.63 to 1.22) was found. SGLT2i demonstrated the greatest effect on HF hospitalization (HR 0.69, 95% CI 0.62 to 0.77) over the SOC, as well as a significant benefit over vericiguat (HR 0.77, 95% CI 0.66 to 0.89), but not over sacubitril/valsartan (HR 0.87, 95% CI 0.75 to 1.02). SGLT2i were ranked as the most effective therapy, followed by sacubitril/valsartan and vericiguat. Based on an indirect comparison, SGLT2i therapy is not associated with a significantly lower risk of CV death or HF hospitalization or CV death alone compared to sacubitril/valsartan or vericiguat. The risk of HF hospitalization does not differ significantly between patients on SGLT2i or sacubitril/valsartan, while dapagliflozin is superior to vericiguat. PROSPERO ID 186351.

ObjectivesTo evaluate the feasibility of a digital and continuous collection and reporting of patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) for chronic heart failure (CHF).DesignA single-site pilot study was settled for evaluating the feasibility of the intervention, both using qualitative and quantitative data (ie, workshop, surveys).SettingThe pilot has been implemented in a Tuscan specialised hospital (Italy).Participants162 patients were involved. Inclusion criteria were: a previous diagnosis of HF, age ≥18 years, absence of cognitive impairment or active tumours, ability to provide informed consent to study participation.InterventionThe continuous collection and reporting of PROMs and PREMs has been designed and implemented in 2018. PREMs questionnaires for patients were developed, while Kansas City Cardiomyopathy Questionnaire-12 was used for assessing PROMs. Questionnaires are administered at specific time points: discharge; 30 days, 7 and 12 months after the discharge. Enrolment of patients, administration and real-time reporting of questionnaires are carried on through a digital platform.Outcome measuresEnrolment, response and drop-out rates were considered to assess the feasibility of the intervention. Qualitative data were collected during meetings and workshops with health workers. The representativeness of the recruited sample with respect to the population characteristics was also evaluated.ResultsThe system has been successfully implemented during 2018. Response rates have been consistently above 50%, demonstrating patients’ transversal willingness to participate. All the involved stakeholders acknowledged the feasibility of the design. The recruited sample is significantly different in terms of age and educational level compared with the overall population characteristics.ConclusionIt is possible to run a web-based systematic collection and reporting system for CHF patient-reported data. Systematic collection and reporting of PROMs and PREMs data allows professionals to increasingly assume CHF patient perspective in their daily work. Limitations will be used to improve the system.

ObjectiveTo evaluate the performance of two available rapid immunological tests for identification of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) antibodies and their subsequent application to a regional screening of health care workers (HCW) in Tuscany (Italy).Designmeasures of accuracy and HCW serological surveillanceSetting6 major health facilities in Tuscany, Italy.Participants17,098 HCW of the Tuscany Region. Measures of accuracy were estimated to assess sensitivity in 176 hospitalized Covid-19 clinical subjects at least 14 days after a diagnostic PCR-positive assay result. Specificity was assessed in 295 sera biobanked in the pre-Covid-19 era in winter or summer 2013-14Main outcome measuresSensitivity and specificity, and 95% confidence intervals, were measured using two serological tests, named T-1 and T-2. Positive and Negative predictive values were estimated at different levels of prevalence. HCW of the health centers were tested using the serological tests, with a follow-up nasopharyngeal PCR-test swab in positive tested cases.ResultsSensitivity was estimated as 99% (95%CI: 95%-100%) and 97% (95% CI: 90%-100%), whereas specificity was the 95% and 92%, for Test T-1 and T-2 respectively. In the historical samples IgM cross-reactions were detected in sera collected during the winter period, probably linked to other human coronaviruses. Out of the 17,098 tested, 3.1% have shown the presence of SARS-CoV-2 IgG antibodies, among them 6.8% were positive at PCR follow-up test on nasopharyngeal swabs.ConclusionBased on the low prevalence estimate observed in this survey, the use of serological test as a stand-alone test is not justified to assess the individual immunity status. Serological tests showed good performance and might be useful in an integrated surveillance, for identification of infected subjects and their contacts as required by the policy of contact tracing, with the aim to reduce the risk of dissemination, especially in health service facilities.

All the latest international guidelines recommend that cardiac troponin (cTn) I and T should be considered the preferred biomarkers for diagnosis of acute myocardial infarction. However, only in the last 5 years, a progressive improvement in analytical performance of immunometric assays has allowed the measurement of circulating levels of cTnI and cTnT in the large part of apparently healthy adult subjects. The routine use of these high-sensitivity methods for cardiac troponin (hs-cTn) assay has in a short time demonstrated that cardiac troponin concentrations frequently increase after strenuous prolonged exercise in healthy athletes. This acute response of hs-cTn assay following exercise was at first considered to be physiological and without long-term adverse consequences. More recent studies have suggested that exercise-induced increases in hs-cTn values may not be always a physiological response to exercise, but, conversely, it should sometimes be considered as an early cardiovascular risk marker. The aim of this review is to provide an overview of acute and chronic effects of strenuous physical exercise on hs-cTn circulating levels and also to discuss the potential pathophysiological and clinical implications of biomarker responses.

Background The study aim was to evaluate whether is possible to harmonize the results of two hs-cTnI methods using a recalibration procedure based on linear regression models and measured values of external quality assessment (EQA) and clinical samples. Methods A two-step experimental approach was used. The preliminary step was performed using 16 EQA samples. The harmonization procedure was then validated by using 2530 heparinized plasma samples collected by 12 Italian University and Regional Hospitals from apparently healthy volunteers and patients admitted to emergency department with cardiac diseases. Two hs-cTnI methods were tested: Architect Stat High Sensitive Troponin-I, and the Access hs-cTnI using DxI platform. Linear regression models based on mean values measured with the two hs-cTni methods were used. Results A significant reduction in the measurement bias between the two methods was found after recalibration procedure. The agreement between-methods improved of about 2.5 folds after recalibration, as assessed by reduction in mean CV values from 38.4% (SD 25.9%) before recalibration to 15.0% (SD 10.6%) after recalibration for hs-cTnI values ≤ 500 ng/L (n = 13, P = 0.0111 by non-parametric test for paired data). Conclusions A recalibration procedure based on means of measured concentrations with hs-cTnI methods, which use monoclonal antibodies with similar binding characteristics, can be used to significantly reduce systematic bias and so to improve harmonization between methods. The results of this study can aid laboratorians and clinicians to better compare the concentrations respectively measured with the Architect and Access hs-cTnI methods.

In recent years, the formulation of some immunoassays with high-sensitivity analytical performance allowed the accurate measurement of cardiac troponin I (cTnI) and T (cTnT) levels in reference subjects. Several studies have demonstrated the association between the risk of major cardiovascular events and cardiac troponin concentrations even for biomarker values within the reference intervals. High-sensitivity cTnI and cTnT methods (hs-cTn) enable to monitor myocardial renewal and remodelling, and to promptly identify patients at highest risk ofheart failure. An early and effective treatment of individuals at higher cardiovascular risk may revert the initial myocardial remodelling and slow down heart failure progression. Specific clinical trials should be carried out to demonstrate the efficacy and efficiency of the general population screening by means of cost-benefit analysis, in order to better identify individuals at higher risk for heart failure (HF) progression with hs-cTn methods.

The hemodynamic impact of residual pulmonary regurgitation (PR) in repaired Tetralogy of Fallot (rTOF) has been well demonstrated. However, markers driving the decision making process to indicate the ideal timing of pulmonary valve replacement (PVR) are still uncertain. Furthermore, very few studies have included the right atrium (RA) dilatation as a preoperative risk factor for post-PVR clinical adverse outcome. The aim of this study was to investigate the impact of pre-PVR right atrial dilation on adverse outcomes in rTOF. We retrospectively reviewed from our CMR database all rTOF patients who underwent CMR study before and after PVR. Detailed clinical and surgical history were collected, in addition to imaging data. The composite primary and secondary post-PVR end points were also recorded. The study cohort consisted of 41 patients (mean age at PVR repair 27.4 ± 10 years). As expected, end-diastolic and end-systolic right ventricle (RV) volumes significantly decreased after PVR (p

Amyloidosis is a systemic disorder characterized by extracellular deposition of insoluble fibrils. The most common forms are amyloid light chain and amyloid transthyretin (ATTR) amyloidoses. Cardiac involvement may be found in both these forms, and is an important cause of morbidity and mortality. The clinical presentation of cardiac amyloidosis (CA) may be represented by congestive heart failure (HF), possibly progressing to end-stage HF, as well as atrial fibrillation with possible thromboembolic events, and also conduction disturbances related to amyloid infiltration of conduction fibres. Beyond therapies targeting the blood dyscrasia or the ATTR amyloidogenic cascade, a careful choice of drug therapies, need for device implantation, and possibly treatments for advanced HF is then warranted. In the present review, we try to provide a useful guide to clinicians treating patients with CA by enucleating 10 main questions and answering them based on the evidence available as well as expert opinion and our clinical experience.

Background Cheyne-Stokes respiration (CSR) is believed to only occur in supine and sleeping conditions, and thus, CSR treatment is applied to those specific states. Although CSR has also been described in patients with heart failure (HF) during wakefulness, its persistence in an upright position is still unknown. Objectives The purpose of this study was to assess the predictors, clinical correlates, and prognostic value of diurnal CSR in upright position. Methods Outpatients with systolic HF underwent a comprehensive evaluation, including short-term respiratory monitoring with a head-up tilt test to investigate the presence of upright CSR, assessment of chemoreflex response to hypoxia and hypercapnia, and 24-h cardiorespiratory recording. At follow-up, cardiac death was considered as the endpoint. Results Of 574 consecutive patients (left ventricular ejection fraction 32 ± 9%; age 65 ± 13 years; 80% men), 195 (34%) presented supine CSR only, 82 (14%) presented supine and upright CSR, and 297 patients (52%) had normal breathing. Patients with upright CSR had the greatest apnea-hypopnea and central apnea index (at daytime and nighttime), the worst hemodynamic profile and exercise performance, increased plasma norepinephrine and N-terminal pro–B-type natriuretic peptide, and chemosensitivity to hypercapnia, which was the only independent predictor of upright CSR (odds ratio: 3.96; 95% confidence interval [CI]: 1.45 to 10.76; p = 0.007 vs. normal breathing; odds ratio: 4.01; 95% CI: 1.54 to 10.46; p = 0.004 vs. supine CSR). At 8-year follow-up, patients with upright CSR had the worst outcome (log-rank = 14.05; p = 0.001) and the presence of upright CSR independently predicted 8-year cardiac death (hazard ratio: 2.39; 95% CI: 1.08 to 5.29; p = 0.032). Conclusions Upright CSR in HF patients is predicted by increased chemosensitivity to hypercapnia and is associated with worse clinical conditions and with a greater risk of cardiac death.

Sleep and breathing 25(2), 965-977 (2021). doi:10.1007/s11325-020-02144-8, Published by Springer, Berlin

Drug-induced cardiotoxicity is a major clinical problem; cardiotoxic drugs may induce both cardiac dysfunction and myocardial injury. Several recent studies reported that cardiac troponins measured with high-sensitivity methods (hs-cTn) can enable the early detection of myocardial injury related to chemotherapy or abuse of drugs that are potentially cardiotoxic. Several authors have some concerns about the standard definition of cardiotoxicity, in particular, regarding the early evaluation of chemotherapy cardiotoxicity in cancer patients. Several recent studies using the hs-cTn assay indicate that myocardial injury may precede by some months or years the diagnosis of heart failure (HF) based on the evaluation of left ventricular ejection fraction (LVEF). Accordingly, hs-cTn assay should considered to be a reliable laboratory test for the early detection of asymptomatic or subclinical cardiotoxic damage in patients undergoing cancer chemotherapy. In accordance with the Fourth Universal Definition of Myocardial Infarction and also taking into account the recent experimental and clinical evidences, the definition of drug-cardiotoxicity should be updated considering the early evaluation of myocardial injury by means of hs-cTn assay. It is conceivable that the combined use of hs-cTn assay and cardiac imaging techniques for the evaluation of cardiotoxicity will significantly increase both diagnostic sensitivity and specificity, and also better prevent chemotherapy-related left ventricular (LV) dysfunction and other adverse cardiac events. However, large randomized clinical trials are needed to evaluate the cost/benefit ratio of standardized protocols for the early detection of cardiotoxicity using hs-cTn assay in patients receiving chemotherapy for malignant diseases.

Aims Kidney impairment has been associated with worse outcomes in acute heart failure (AHF), although recent studies challenge this association. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel biomarker of kidney tubular injury. Its prognostic role in AHF has not been evaluated in large cohorts. The present study aimed to determine if serumNGAL (sNGAL) or urineNGAL (uNGAL) is superior to creatinine for predicting short-term outcomes in AHF Methods and results The study was conducted in an international, multicentre, prospective cohort consisting of 927 patients with AHF. Admission and peak values of sNGAL, uNGAL and uNGAL/urine creatinine (uCr) ratio were compared to admission and peak serum creatinine (sCr). The composite endpoints were death, initiation of renal replacement therapy, heart failure (HF) readmission and any emergent HF-related outpatient visit within 30 and 60 days, respectively. The mean age of the cohort was 69 years and 62% were male. The median length of stay was 6 days. The composite endpoint occurred in 106 patients and 154 patients within 30 and 60 days, respectively. Serum NGAL was more predictive than uNGAL and the uNGAL/uCr ratio but was not superior to sCr [area under the curve: admission sNGAL 0.61, 95% confidence interval (CI) 0.55- 0.67, and 0.59, 95% CI 0.54- 0.65; peak sNGAL: 0.60, 95% CI 0.54-0.66, and 0.57, 95% CI 0.52- 0.63; admission sCr: 0.60, 95% CI 0.54- 0.64, and 0.59, 95% CI 0.53- 0.64; peak sCr: 0.61, 95% CI 0.55-0.67, and 0.59, 95% CI 0.54- 0.64, at 30 and 60 days, respectively]. NGAL was not predictive of the composite endpoint in multivariate analysis. Conclusions Serum NGAL outperformed uNGAL but neither was superior to admission or peak sCr for predicting adverse events.

A regular intake of red grape juice has cardioprotective properties, but its role on the modulation of natriuretic peptides (NPs), in particular of C-type NP (CNP), has not yet been proven. The aims were to evaluate: (1) in vivo the effects of long-term intake of Tuscany Sangiovese grape juice (SGJ) on the NPs system in a mouse model of myocardial infarction (MI); (2) in vitro the response to SGJ small RNAs of murine MCEC-1 under physiological and ischemic condition; (3) the activation of CNP/NPR-B/NPR-C in healthy human subjects after 7 days’ SGJ regular intake. (1) C57BL/6J male and female mice (n = 33) were randomly subdivided into: SHAM (n = 7), MI (n = 15) and MI fed for 4 weeks with a normal chow supplemented with Tuscany SGJ (25% vol/vol, 200 µl/per day) (MI + SGJ, n = 11). Echocardiography and histological analyses were performed. Myocardial NPs transcriptional profile was investigated by Real-Time PCR. (2) MCEC-1 were treated for 24 h with a pool of SGJ small RNAs and cell viability under 24 h exposure to H2O2 was evaluated by MTT assay. (3) Human blood samples were collected from seven subjects before and after the 7 days’ intake of Tuscany SGJ. NPs and miRNA transcriptional profile were investigated by Real-Time PCR in MCEC-1 and human blood. Our experimental data, obtained in a multimodal pipeline, suggest that the long-term intake of SGJ promotes an adaptive response of the myocardium to the ischemic microenvironment through the modulation of the cardiac CNP/NPR-B/NPR-C system. Our results open new avenue in the development of functional foods aimed at enhancing cardioprotection of infarcted hearts through action on the myocardial epigenome.

Background Planar diphosphonate scintigraphy is an established diagnostic tool for amyloid transthyretin (ATTR) cardiomyopathy. Characterization of the amyloid burden up to the segmental level by single photon emission computed tomography (SPECT) has not been evaluated so far. Methods Data from consecutive patients undergoing cardiac 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) SPECT and diagnosed with ATTR cardiomyopathy at a tertiary referral center from June 2016 to April 2019 were collected. Results Thirty-eight patients were included (median age 81 years, 79% men, 92% with wild-type ATTR). In patients with Perugini score 1, the most intense diphosphonate regional uptake was found in septal segments, particularly in infero-septal segments. Among patients scoring 2, the amyloid burden in the septum became more significant, and extended to inferior and apical segments. Finally, patients scoring 3 displayed an intense and widespread tracer uptake. All patients with Perugini score 1 had LGE in at least one antero-septal, one infero-septal, and one infero-lateral segment. All patients with score 2 displayed LGE in infero-septal, inferior, and infero-lateral segments. LGE became extensive in patients scoring 3, with all patients having at least one LGE-positive segment in each region. Conclusions When assimilating different Perugini grades to evolutive stages of the disease, amyloid deposition seem to progress from the septum to the inferior wall and then to the other regions and from the basis to the apex. The potential of segmental analysis might be particularly relevant in patients with very limited cardiac uptake at planar scintigraphy (Perugini score 1). Funding Acknowledgement Type of funding source: None

Aging is associated not only with the reduction of psychophysical and sensory capacities but also with different types of neurodegenerative disorders up to dementia manifestations. Aging in health and self-sufficiency is strictly dependent on the prevention and correction of factors that may determine reduction of psychophysical capacities (e.g., cardiovascular, locomotor and neurodegenerative ones). To reach this goal, due to the dynamics of social and family changes and to the aging of the population, health professionals can be supported by technologies which provide noninvasive monitoring of physiologic parameters and rely on telemedicine, both instruments of support and care for better aging in the home setting. The authors, starting from the initial idea of a personalized monitoring of different psychophysical variables, defined a pilot study to assess the role of a 12-month individually tailored lifestyle counseling on parameters of mild cognitive impairment in a group of elderly subjects. Data derived from the applied approach appeared promising and may open the road to the possible implementation of individual counseling, based on multiparametric non-obtrusive technologies which take into consideration both psychological and physical aspects, to be followed in the home environment.

Background Heart failure with midrange ejection fraction (HFmrEF) represents a heterogeneous category where phenotype, as well as prognostic assessment, remains debated. The present study explores a specific HFmrEF subset, namely those who recovered from a reduced EF (rec-HFmrEF) and, particularly, it focuses on the possible additive prognostic role of cardiopulmonary exercise testing. Methods and Results We analyzed data from 4535 patients with HFrEF and 1176 patients with rec-HFmrEF from the Metabolic Exercise combined with Cardiac and Kidney Indexes database. The end point was cardiovascular death at 5 years. The median follow-up was 1343 days (25th–75th range 627–2403 days). Cardiovascular death occurred in 552 HFrEF and 61 rec-HFmrEF patients. The multivariate analysis confirmed an independent role of the MECKI score's variables in HFrEF (C-index = 0.744) whereas, in the rec-HFmrEF group, only age and peak oxygen uptake (pVO2) remained associated to the end point (C-index = 0.745). A peak oxygen uptake of ≤55% of predicted and a ventilatory efficiency of ≥31 resulted as the most accurate cut-off values in the outcome prediction. Conclusions: Present data support the cardiopulmonary exercise test and, particularly, the peak oxygen uptake, as a useful tool in the rec-HFmrEF prognostic assessment. A peak VO2 of ≤55% predicted and ventilatory efficiency of ≥31 might help to identify a high-risk rec-HFmrEF subgroup.

Myocardial fibrosis is an endogenous response to different cardiac insults that may become maladaptive over time and contribute to the onset and progression of heart failure (HF). Fibrosis is a direct and indirect target of established HF therapies, namely inhibitors of the renin-angiotensin-aldosterone system, but its resilience to therapy warrants a search for novel, more targeted approaches to myocardial fibrosis. Pirfenidone is a drug approved for idiopathic pulmonary fibrosis, a severe form of idiopathic interstitial pneumonias. Pirfenidone is a small synthetic molecule with high oral bioavailability, exerting an antifibrotic activity, but also anti-oxidant and anti-inflammatory effects. These effects have been attributed to the inhibition of several growth factors (in particular transforming growth factor-β, but also platelet-derived growth factor and beta fibroblast growth factor), matrix metalloproteinases, and pro-inflammatory mediators (such as interleukin-1β and tumour necrosis factor-α), and possibly also an improvement of mitochondrial function and modulation of lymphocyte activation. Given the activation of similar profibrotic pathways in lung and heart disease, the crucial role of fibrosis in several cardiac disorders, and the wide spectrum of activity of pirfenidone, this drug has been evaluated with interest as a potential treatment for cardiac disorders. In animal studies, pirfenidone has shown cardioprotective effects across different species and in a variety of models of cardiomyopathy. In the present review we summarize the pharmacological characteristics of pirfenidone and the data from animal studies supporting its cardioprotective effects.

Background Chronic obstructive pulmonary disease (COPD) is common in patients with chronic heart failure (CHF). Purpose We aimed to explore the impact of COPD on HF biomarkers (N-terminal fraction of pro-B-type natriuretic peptide [NT-proBNP], high-sensitivity troponin T [hs-TnT], and soluble suppression of tumorigenesis-2 [sST2]) and outcome. Methods Individual data from 14 cohorts of patients with stable chronic HF and NT-proBNP and hs-TnT values were analysed. Patients with known COPD status were evaluated. Results Patients (n=13,178) were aged 67 years (58–75), 75% males, and 76%, 11%, 13% with HF with reduced, mid-range, or preserved ejection fraction (HFrEF/HFmrEF/HFpEF), respectively. Patients with COPD were older than those without COPD (age 71 years [64–77] vs. 66 [57–75]; p Over a median follow-up of 2.1 years (1.5–3.7, range 0–18 years), 3,865/12,489 patients (31%) died; among them, 2,443/12,450 (20%) died for cardiovascular causes; 3,373/12,469 patients (27%) were hospitalized for HF over 35 months (15–63, range 0–216 months). Patients with COPD had a significantly higher all-cause mortality, cardiovascular mortality, and worse survival free from HF hospitalization (all p Conclusions COPD in HF is characterized by higher NT-proBNP, hs-TnT and sST2 levels. COPD adds prognostic significance over NT-proBNP alone, but not over the combination of NT-proBNP, hs-TnT, and sST2. Funding Acknowledgement Type of funding source: None

Background The study aim was to evaluate and compare analytical performances and clinical results of ADVIA BNP and PBNP methods using the Centaur XPT platform with those of Access BNP, using the DxI platform and the ECLIA NT-proBNP method, using the Cobas e411 platform, respectively. Methods Limits of blank (LoB), detection (LoD) and quantitation (LoQ) at 20% CV and 10% CV were evaluated according to international standardized protocols. The analytical parameters were assessed throughout a 90-working-day period using three curve calibrations. Results LoB, LoD and LoQ at 20% CV and 10% values of the ADVIA BNP method were 1.0 ng/L, 2.0 ng/L, 3.7 ng/L and 10.2 ng/L, respectively; while those of the ADVIA PBNP method were 1.3 ng/L, 3.0 ng/L, 9.7 ng/L and 22.3 ng/L, respectively. The ADVIA BNP and PBNP methods were able to measure the clinical decision values suggested by international guidelines for diagnosis of heart failure (HF) with an imprecision ≤6%. BNP concentrations measured with the ADVIA and Access methods showed a close linear regression (R=0.9923, n=200); a close linear regression was also found between NT-proBNP concentrations measured with the ADVIA and ECLIA methods (R=0.9954, n=202). However, the ADVIA method measured significantly lower BNP values than the Access method (on average −20.9%), while ADVIA PBNP method measured significantly higher NT-proBNP concentrations than the ECLIA method (on average +17.8%). Conclusions Analytical performances of the BNP and PBNP ADVIA methods are well in accordance with the quality specifications required by international guidelines for diagnosis and follow-up of patients with HF.

Objectives The aims of this paper were to evaluate the levels of Vitamin D (VitD) in patients with heart failure (HF), compared to a control group, to assess the effects of VitD on HF outcome and to compare VitD measurement between LIAISON immunoassay and HPLC-MS-MS methods in this population. Design and Methods We collected clinical, biochemical and outcome data from 247 patients with HF and in a subgroup of 151 patients, we measured VitD both with LIAISON and HPLC-MS-MS. Results HF patients had statistically lower 25OHD levels (45.2 ± 23.7 nmol/L vs 58.2 ± 24.0 nmol/L, P P P P = 0.02), confirmed in a multivariate adjusted analysis. Kaplan–Meier survival analyses showed that VitD insufficiency was associated with reduced survival in HF patients (log rank P = 0.017). There was a good agreement between LIAISON and HPLC-MS-MS (Cohen’s kappa coefficient 0.70), but the prevalence of VitD insufficiency was significantly higher with the former compared to the latter method (58.3%, n = 88 vs 55.6%, n = 84, P Conclusions 25OHD levels adequately measured by HPLC-MS-MS showed to be low in HF population and to be correlated with HF-related risk of death.

AIMS Mineralocorticoid receptor antagonists (MRAs) have been demonstrated to improve outcomes in reduced ejection fraction heart failure (HFrEF) patients. However, MRAs added to conventional treatment may lead to worsening of renal function and hyperkalaemia. We investigated, in a population-based analysis, the long-term effects of MRA treatment in HFrEF patients. METHODS AND RESULTS We analysed data of 6046 patients included in the Metabolic Exercise Cardiac Kidney Index score dataset. Analysis was performed in patients treated (n = 3163) and not treated (n = 2883) with MRA. The study endpoint was a composite of cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation. Ten years' survival was analysed through Kaplan-Meier, compared by log-rank test and propensity score matching. At 10 years' follow-up, the MRA-untreated group had a significantly lower number of events than the MRA-treated group (P

Aims Risk stratification in heart failure (HF) is crucial for clinical and therapeutic management. A multiparametric approach is the best method to stratify prognosis. In 2012, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score was proposed to assess the risk of cardiovascular mortality and urgent heart transplantation. The aim of the present study was to compare the prognostic accuracy of MECKI score to that of HF Survival Score (HFSS) and Seattle HF Model (SHFM) in a large, multicentre cohort of HF patients with reduced ejection fraction. Methods and results We collected data on 6112 HF patients and compared the prognostic accuracy of MECKI score, HFSS, and SHFM at 2- and 4-year follow-up for the combined endpoint of cardiovascular death, urgent cardiac transplantation, or ventricular assist device implantation. Patients were followed up for a median of 3.67 years, and 931 cardiovascular deaths, 160 urgent heart transplantations, and 12 ventricular assist device implantations were recorded. At 2-year follow-up, the prognostic accuracy of MECKI score was significantly superior [area under the curve (AUC) 0.781] to that of SHFM (AUC 0.739) and HFSS (AUC 0.723), and this relationship was also confirmed at 4 years (AUC 0.764, 0.725, and 0.720, respectively). Conclusion In this cohort, the prognostic accuracy of the MECKI score was superior to that of HFSS and SHFM at 2- and 4-year follow-up in HF patients in stable clinical condition. The MECKI score may be useful to improve resource allocation and patient outcome, but prospective evaluation is needed.

Background Familial hypercholesterolemia is the elective clinical condition that deserves the maximal personalisation in lipid-lowering therapy, especially in the presence of statin intolerance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a promising approach to lower low-density lipoprotein (LDL) cholesterol. Methods We enrolled 18 patients (mean age 62 ± 8 years, 72% men) affected by heterozygous familial hypercholesterolemia and cardiovascular disease, with a history of statin intolerance assigned to PCSK9 inhibitors. Six patients were also on LDL apheresis. Associated Lp(a)-hyperlipoproteinemia (defined as >60 mg/dl) was observed in two out of 18 subjects. PCSK9 inhibitor injectable monoclonal antibodies were administered, every 2 weeks, on top of patient therapy for 12 ± 4 weeks (evolocumab in 15 subjects, alirocumab in three subjects). Results After 3 months (12 ± 4 weeks) of therapy, a decrease in total cholesterol (–35%), LDL cholesterol (–51%) and Lp(a) levels (–20%) was observed. Five out of 18 patients reached LDL cholesterol levels of 100 mg/dl, three were already on LDL apheresis before the PCSK9 inhibitor treatment, while three were referred to LDL apheresis treatment. Adverse events were reported in two out of 18 patients on evolocumab: one presented with flu-like syndrome and the other reported episodes of mild difficulty in maintaining concentration. Conclusions PCSK9 inhibitors represent a novel therapeutic tool for patients with familial hypercholesterolemia who are intolerant to statins. However, more data are needed before cleaning up the old therapeutic armamentarium, such as LDL apheresis, which is likely to preserve its valuable role also in the new lipid-lowering era.

Objective Supplementation of glutathione (GSH) may be a positive strategy to improve the endogenous antioxidant defense required to counteract many acute and chronic diseases. However, the efficacy of GSH treatment seems to be closely related to type of administration, degree of absorption, and increase of its concentrations. The aim of this study was to test a new sublingual formulation of L-GSH, which enters directly the systemic circulation, to assess its efficacy on circulating biochemical markers of hepatic metabolism, lipid profile, and oxidative stress and on peripheral vascular function compared with placebo in patients with cardiovascular risk factors (CVRF). Methods We enrolled 16 healthy men with CVRF in a double-blinded, randomized placebo-controlled crossover study. At each visit, blood samples were collected for biochemistry analyses and peripheral endothelial function (reactive hyperemia index [RHI]) and stiffness were measured by Endo-PAT2000. Results In the overall population, a decrease in total and low-density lipoprotein cholesterol was highlighted after L-GSH supplementation compared with placebo (P = 0.023 and P = 0.04, respectively). On the contrary, no difference was observed in RHI and oxidative stress markers between L-GSH and placebo in the study population. However, seven participants with baseline abnormal RHI (≤1.67) compared with those with normal RHI showed a significant reduction of arterial stiffness after L-GSH administration, (P = 0.007 and P = 0.037, respectively). Conclusions Supplementation of L-GSH compared with placebo influences the lipid profile of patients with CVRF. Sublingual L-GSH may represent a valid prevention of vascular damage in patients with CVRF and endothelial dysfunction.

Objectives The purpose of this study was to perform the first meta-analysis of currently available data. Background Soluble suppression of tumorigenesis 2 (sST2) plasma concentration is elevated in chronic heart failure (CHF) and helps to predict prognosis in this setting, although the evidence is limited. Methods Three databases (Medline, Cochrane Library, and Scopus) were searched. Inclusion criteria were: follow-up studies; papers published in English; enrollment of CHF outpatients; available data on hazard ratio (HR) for the log2 ST2 (so that the reported HRs represent the risk per doubling of sST2) and 95% confidence interval (CI) for all-cause death, and possibly also for cardiovascular (CV) death; and use of standardized sST2 assay. Exclusion criteria were: sST2 considered only as an element of a prognostic score, and studies on patients with end-stage HF. Results Seven studies were finally included for all-cause death, with a global population of 6,372 patients; data on CV death were available for 5 studies, totaling 5,051 patients. The HR was 1.75 (95% CI: 1.37 to 2.22) for all-cause death and 1.79 (95% CI: 1.22 to 2.63) for CV death (both p Conclusions sST2 is a predictor of both all-cause and CV death in CHF outpatients. The present meta-analysis supports the use of sST2 for risk stratification in patients with stable CHF.

Aims: The use of β-blockers represents a milestone in the treatment of heart failure with reduced ejection fraction (HFrEF). Few studies have compared β-blockers in HFrEF, and there is little data on the effects of different doses. The present study aimed to investigate in a large database of HFrEF patients (MECKI score database) the association of β-blocker treatment with a composite outcome of cardiovascular death, urgent heart transplantation or left ventricular assist device implantation, addressing the role of β-selectivity and dosage regimens. Methods and results: In 5242 HFrEF patients, we investigated the role of: (i) β-blocker treatment vs. non-β-blocker treatment, (ii) β1-/β2-receptor-blockers vs. β1-selective blockers, and (iii) daily β-blocker dose. Patients were followed for 3.58 years, and 1101 events (18.3%) were observed; 4435 patients (86.8%) were on β-blockers, while 807 (13.2%) were not. At 5 years, β-blocker-patients showed a better outcome than non-β-blocker-subjects [hazard ratio (HR) 0.48, P 2 5 mg carvedilol equivalent daily dose, n = 1005) patients than in both medium dose (12.5–25 mg, n = 1431) and low dose (

AIMS Mitochondrial disease (MD) is a genetic disorder affecting skeletal muscles, with possible myocardial disease. The ergoreflex, sensitive to skeletal muscle work, regulates ventilatory and autonomic responses to exercise. We hypothesized the presence of an increased ergoreflex sensitivity in MD patients, its association with abnormal ventilatory and autonomic responses, and possibly with subclinical cardiac involvement. METHODS AND RESULTS Twenty-five MD patients (aged 46 ± 3 years, 32% male) with skeletal myopathy but without known cardiac disease, underwent a thorough evaluation including BNPs, galectin-3, soluble suppression of tumorigenesis 2 (sST2), high sensitivity troponin T/I, catecholamines, ECG, 24-h ECG recording, cardiopulmonary exercise testing, echocardiography, cardiac/muscle magnetic resonance (C/MMR), and ergoreflex assessment. Thirteen age- and sex-matched healthy controls were chosen. Among these myopathic patients, subclinical cardiac damage was detected in up to 80%, with 44% showing fibrosis at CMR. Ergoreflex sensitivity was markedly higher in patients than in controls (64% vs. 37%, P < 0.001), and correlated with muscle fat to water ratio and extracellular volume at MMR (both P < 0.05). Among patients, ergoreflex sensitivity was higher in those with cardiac involvement (P = 0.034). Patients showed a lower peak oxygen consumption (VO2 /kg) than controls (P < 0.001), as well as ventilatory inefficiency (P = 0.024). Ergoreflex sensitivity correlated with reduced workload and peak VO2 /kg (both P < 0.001), and several indicators of autonomic imbalance (P < 0.05). Plasma norepinephrine was the unique predictor of myocardial fibrosis at univariate analysis (P < 0.05). CONCLUSIONS Skeletal myopathy in MD is characterized by enhanced ergoreflex sensitivity, which is associated with a higher incidence of cardiac involvement, exercise intolerance, and sympathetic activation.

We thank Drs. Fudim and Soloveva for their speculations on the relevance of pre-load and baroreflex as pathophysiological determinants of the persistence of Cheyne-Stokes respiration (CSR) in the upright position, described in our large series of patients with chronic systolic heart failure (n =

Background A thorough analysis of noncardiac determinants of mortality in heart failure ( HF ) is missing. Furthermore, evidence conflicts on the outcome of patients with HF and no or mild systolic dysfunction. We aimed to investigate the prevalence of noncardiac and cardiac causes of death in a cohort of chronic HF patients, covering the whole spectrum of systolic function. Methods and Results We enrolled 2791 stable HF patients, classified into HF with reduced ejection fraction ( HF r EF ; left ventricular ejection fraction [EF] HF mr EF ; left ventricular EF 41–49%), or HF with preserved EF ( HF p EF ; left ventricular EF ≥50%), and followed up for all‐cause, cardiac, and noncardiac mortality (adjudicated as due to cancer, sepsis, respiratory disease, renal disease, or other causes). Over follow‐up of 39 months, adjusted mortality was lower in HF p EF and HF mr EF versus HF r EF (hazard ratio: 0.75 [95% CI, 0.67–0.84], P HF p EF ; hazard ratio: 0.78 [95% CI , 0.63–0.96], P =0.017 for HF mr EF ). HF r EF had the highest rates of cardiac death, whereas noncardiac mortality was similar across left ventricular EF categories. Noncardiac causes accounted for 62% of deaths in HF p EF , 54% in HF mr EF and 35% in HF r EF ; cancer was twice as frequent as a cause of death in HF p EF and HF mr EF versus HF r EF . Yearly rates of noncardiac death exceeded those of cardiac death since the beginning of follow‐up in HF p EF and HF mr EF . Conclusions Noncardiac death is a major determinant of outcome in stable HF , exceeding cardiac‐related mortality in HF p EF and HF mr HF . Comorbidities should be regarded as main therapeutic targets and objects of dedicated quality improvement initiatives, especially in patients with no or mild systolic dysfunction.

Background Natriuretic peptides are established biomarkers of heart failure (HF). The existence of gender-related differences in circulating levels and prognostic value are still controversial. Methods Individual patient data from studies assessing cardiac biomarkers (N-terminal fraction of pro-B-type natriuretic peptide - NT-proBNP - and high-sensitivity troponin T) for risk prediction in stable chronic HF were analysed. Results Women (n=1964, 23%) had higher median [interquartile interval] NT-proBNP concentrations than men (1678 [659–4215] vs. 1294 [522–2973] ng/L, p Over a 2.4-year follow-up (1.6–3.2), 2351 patients (27%) died, and cardiovascular death occurred in 1558/8271 (19%). HF hospitalization was recorded in 2088/7944 (26%) over 2.0 years (1.3–2.6). Women and men had similar areas under the curve for the 3 endpoints, with higher cut-offs among women: all-cause death, 2328 ng/L vs. 1319 ng/L; cardiovascular death, 2328 ng/L vs. 1413 ng/L; HF hospitalization, 1265 ng/L vs. 907 ng/L. In the prognostic model above, the risk of the three endpoints increased by 32%, 35%, and 17%, respectively, per doubling of NT-proBNP in women, and by 41%, 45%, and 30% in men. Conclusions Women with chronic HF display higher NT-proBNP levels than men in the whole population as well as across many patient subgroups. This difference is not entirely explained by heterogeneity in age, BMI, or renal function. NT-proBNP holds independent prognostic significance in both genders, although alternative prognostic cut-offs might be considered for women.

Background High-sensitivity troponin T (hs-TnT) reflects the severity of ongoing myocardial damage and holds independent prognostic significance in chronic heart failure (HF). In acute HF (AHF), its additive prognostic value over natriuretic peptides is unclear. Methods Individual data of 1571 AHF patients with admission hs-TnT were collected from 3 cohorts. Results Patients were aged 78±10 years, and 51% were men. Median hs-TnT and N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP) concentrations were 43 ng/L (interquartile interval 26–69) and 5660 (2693–12466), respectively. Patients experiencing in-hospital death (n=187, 13%) had significantly higher hs-TnT and NT-proBNP on admission (both p Conclusions The risk of in-hospital death is almost 3 folds higher with admission hs-TnT ≥43 ng/L and NT-proBNP ≥5660 ng/L, and hs-TnT ≥43 ng/L holds strong independent prognostic significance for post-discharge outcome.

Background Obesity defined by body mass index (BMI) is characterized by better prognosis and lower plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure (HF). We assessed whether another anthropometric measure, percent body fat (PBF), reveals different associations with outcome and HF biomarkers (NT-proBNP, high-sensitivity troponin T [hs-TnT], soluble suppression of tumorigenesis-2 [sST2]). Methods In an individual patient dataset, BMI was calculated as weight (kg)/height (m)2, and PBF through the Jackson-Pollock and Gallagher equations. Results Out of 6468 patients (median 68 years, 78% men, 76% ischaemic HF, 90% reduced EF), 24% died over 2.2 years (1.5–2.9), 17% from cardiovascular death. Median PBF was 26.9% (22.4–33.0%) with the Jackson-Pollock equation, and 28.0% (23.8–33.5%) with the Gallagher equation, with an extremely strong correlation (r=0.996, p Conclusion Patient prognosis improves with either BMI or PBF. Obesity, assessed with BMI or PBF, is associated with lower NT-proBNP but not hs-TnT or sST2. hs-TnT or sST2 are stronger prognostic predictors than NT-proBNP among obese patients.

Background Increased chemosensitivity to carbon dioxide (CO2) is an important trigger of central apneas in heart failure (HF), contributing to HF progression and mortality. We hypothesized that buspirone, a 5HT1A receptor agonist that inhibits serotonergic chemoreceptor neuron firing in animals, can decrease CO2 chemosensitivity, thus preventing CA in patients with HF. Methods Sixteen patients with systolic HF (age 71.3±5.8 years, left ventricular ejection fraction 29.8±7.8%) and moderate-severe central apneas (nighttime apnea/hypopnea index AHI≥15 events/hour) underwent a double-blind, placebo-controlled, cross over, randomized study of oral buspirone administration (45 mg/day for 1 week). Results Buspirone reduced CO2 chemosensitivity compared to placebo (1.2 IR [1.1–1.5] vs. 2.0 [1.6–2.2] L/min/mmHg, p=0.008). Furthermore, buspirone improved: the AHI at nighttime (16.5 [8.5–24.7] vs. 27.5 [23.0–37.3] events/hour, p=0.002), and daytime (8.0 [2.3–11.5] vs. 11.5 [6.3–18.8] events/hour, p=0.006); the central apnea index at nighttime (4.0 [1.0–19.0] vs. 12.5 [8.3–27.3] events/hour, p=0.01) and daytime (1.0 [0.0–3.0] vs. 4.0 [1.3–6.0] events/hour, p=0.009); and the oxygen desaturation index at nighttime (4.7 [1.0–11.0] vs. 20.0 [8.7–26.5] events/hour, p=0.004) and daytime (0.2 [0.1–0.7] vs. 1.2 [0.3–4.8] events/hour, p=0.005). Buspirone showed a good safety profile and had no effect on neurohormones, arrhythmias, exercise capacity and mood/daytime sleepiness. Conclusion Buspirone reduces CO2 chemosensitivity and inhibits central apneas both during the day and the night in patients with systolic HF.

Background Although Cheyne-Stokes respiration (CSR) is an oscillatory phenomenon, the direct effects of cyclical hyperventilation and apnea on cardiopulmonary hemodynamics have been poorly investigated. The aim of the study was to examine the echocardiographic changes associated with CSR phases in a group of patients with systolic heart failure (HF) and daytime CSR. Methods 14 HF patients (age 70 ± 9 years, LVEF 24 ± 5) underwent a thorough clinical evaluation, 24-h respiratory polygraphy, chemoreflex evaluation by rebreathing technique and neuro-hormonal assessment. Furthermore, they received a simultaneous echocardiographic and respiratory monitoring embedding the respiratory signal in the echocardiographic machine. Results All patients had daytime CSR (diurnal apnea-hypopnea index, AHI: 18.5, interquartile range: 15.3–39.5 events/h). Systolic pulmonary artery pressure and pulmonary vascular resistances (PVR) increased from hyperventilation to apnea (H 45.3 ± 11.4 vs A 52.4 ± 13.8 mmHg, p = 0.004, and H 3.3 ± 2.5 vs A 5.1 ± 3.2 Wood units, p = 0.0003, respectively), while acceleration time of the pulmonary artery decreased (H 110.1 ± 19.8 vs A 92.0 ± 19.9 ms, p = 0.001). During apnea a reduction of right and left ventricular outflow tract VTI (H 12.8 ± 4.9 versus A 9.9 ± 3.1, p = 0.002 and H 26.9 ± 8.8 versus A 22.8 ± 7.9 mm, p = 0.006, respectively), and a reduction in tricuspid annular plane systolic excursion (H 15.9 ± 4.4 versus A 14.4 ± 4.1 mm, p = 0.005) were also observed. Notably, PVR variation strongly correlated with chemosensitivity to hypercapnia (R = 0.89, p = 0.0004) and plasma norepinephrine level (R = 0.78, p = 0.003). Conclusions In HF patients with CSR, an increase in pulmonary pressure and pulmonary vascular resistances was observed during apnea. Pulmonary vasoconstriction strongly correlated with chemosensitivity to hypercapnia and indexes of adrenergic activation.