Brisk walking can be a maximal effort in heart failure patients: a comparison of cardiopulmonary exercise and 6 min walking test cardiorespiratory data

Aims Cardiopulmonary exercise test (CPET) and 6 min walking test (6MWT) are frequently used in heart failure (HF). CPET is a maximal exercise, whereas 6MWT is a self-selected constant load test usually considered a submaximal, and therefore safer, exercise, but this has not been tested previously. The aim of this study was to compare the cardiorespiratory parameters collected during CPET and 6MWT in a large group of healthy subjects and patients with HF of different severity.Methods and results Subjects performed a standard maximal CPET and a 6MWT wearing a portable device allowing breath-by-breath measurement of cardiorespiratory parameters. HF patients were grouped according to their CPET peak oxygen uptake (peak(V) over-dotO(2)). One hundred and fifty-five subjects were enrolled, of whom 40 were healthy (59 +/- 8 years; male 67%) and 115 were HF patients (69 +/- 10 years; male 80%; left ventricular ejection fraction 34.6 +/- 12.0%). CPET peak(V) over-dotO(2) was 13.5 +/- 3.5 ml/kg/min in HF patients and 28.1 +/- 7.4 mL/kg/min in healthy subjects (P < 0.001). 6MWT-(V) over-dotO(2) was 98 +/- 20% of the CPET peak(V) over-dotO(2) values in HF patients, while 72 +/- 20% in healthy subjects (P < 0.001). 6MWT-(V) over-dot was >110% of CPET peak(V) over-dotO(2) in 42% of more severe HF patients (peak(V) over-dotO(2) < 12 mL/kg/min). Similar results have been found for ventilation and heart rate. Of note, the slope of the relationship between (V) over-dotO(2) at 6MWT, reported as a percentage of CPET peak(V) over-dotO(2) vs. 6MWT (V) over-dotO(2) reported as the absolute value, progressively increased as exercise limitation did.Conclusions In conclusion, the last minute of 6MWT must be perceived as a maximal or even supramaximal exercise activity in patients with more severe HF. Our findings should influence the safety procedures needed for the 6MWT in HF

Impact of Sacubitril/Valsartan on Circulating microRNA in Patients with Heart Failure

Sacubitril/Valsartan, used for the treatment of heart failure (HF), is a combination of two drugs, an angiotensin receptor inhibitor, and a neprilysin inhibitor, which activates vasoactive peptides. Even though its beneficial effects on cardiac functions have been demonstrated, the mechanisms underpinning these effects remain poorly understood. To achieve more mechanistic insights, we analyzed the profiles of circulating miRNAs in plasma from patients with stable HF with reduced ejection function (HFrEF) and treated with Sacubitril/Valsartan for six months. miRNAs are short (22–24 nt) non-coding RNAs, which are not only emerging as sensitive and stable biomarkers for various diseases but also participate in the regulation of several biological processes. We found that in patients with high levels of miRNAs, specifically miR-29b-3p, miR-221-3p, and miR-503-5p, Sacubitril/Valsartan significantly reduced their levels at follow-up. We also found a significant negative correlation of miR-29b-3p, miR-221-3p, and miR-503-5p with VO2 at peak exercise, whose levels decrease with HF severity. Furthermore, from a functional point of view, miR-29b-3p, miR-221-3p, and miR-503-5p all target Phosphoinositide-3-Kinase Regulatory Subunit 1, which encodes regulatory subunit 1 of phosphoinositide-3-kinase. Our findings support that an additional mechanism through which Sacubitril/Valsartan exerts its functions is the modulation of miRNAs with potentially relevant roles in HFrEF pathophysiology

The double anaerobic threshold in heart failure: MECKI score database overview

Abstract Aims In heart failure (HF), anaerobic threshold (AT) may be indeterminable but its value held a relevant prognostic role. AT is evaluated joining three methods: V‐slope, ventilatory equivalent, and end‐tidal methods. The possible non‐concordance between the V‐slope (met AT) and the other two methods (vent AT) has been highlighted in healthy individuals and named double threshold (DT). Methods and results We reanalysed 1075 cardiopulmonary exercise tests of HF patients recruited in the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score database. We identified DT in 43% of cases. Met AT precedes vent AT being met–ventΔVO2 221 (interquartile range: 129–319) mL/min. Peak VO2, 1307 ± 485 vs. 1343 ± 446 mL/min (63 ± 17 vs. 63 ± 17 percentage of predicted), was similar between DT+ and DT− patients. Differently, DT+ showed a lower ventilatory vs. carbon dioxide production (VE/VCO2) slope (29.6 ± 6.1 vs. 31.0 ± 6.3), a lower peak exercise end‐tidal oxygen tension (PetO2) 115.3 (111.5–118.9) vs. 116.4 (112.4–120.2) mmHg, and a higher carbon dioxide tension (PetCO2) 34.2 (30.9–37.1) vs. 32.4 (28.7–35.5) mmHg. Vent AT showed a significant higher VO2, 957 ± 318 vs. 719 ± 252 mL/min, VCO2, 939 ± 319 vs. 627 ± 226 mL/min, ventilation, 31.0 ± 8.3 vs. 22.5 ± 6.3 L/min, respiratory exchange ratio, 0.98 ± 0.08 vs. 0.87 ± 0.07, PetO2, 108 (104–112) vs. 105 (101–109) mmHg, PetCO2, 37 (34–40) vs. 36 (33–39) mmHg, and VE/VO2 ratio, 33.5 ± 6.7 vs. 32.6 ± 6.9, but lower VE/VCO2 ratio, 33 (30–37) vs. 36 (32–41), compared with met AT. At 2 year survival by Kaplan–Meier analysis, even adjusted for confounders, DT resulted not associated with survival. Conclusions Double threshold is frequently observed in HF patients. DT+ is associated to a decreased ventilatory response during exercise

Prognostic radiomic signature for head and neck cancer: Development and validation on a multi-centric MRI dataset

BACKGROUND AND PURPOSE: Prognosis in locally advanced head and neck cancer (HNC) is currently based on TNM staging system and tumor subsite. However, quantitative imaging features (i.e., radiomic features) from magnetic resonance imaging (MRI) may provide additional prognostic info. The aim of this work is to develop and validate an MRI-based prognostic radiomic signature for locally advanced HNC. MATERIALS AND METHODS: Radiomic features were extracted from T1- and T2-weighted MRI (T1w and T2w) using the segmentation of the primary tumor as mask. In total 1072 features (536 per image type) were extracted for each tumor. A retrospective multi-centric dataset (n = 285) was used for features selection and model training. The selected features were used to fit a Cox proportional hazard regression model for overall survival (OS) that outputs the radiomic signature. The signature was then validated on a prospective multi-centric dataset (n = 234). Prognostic performance for OS and disease-free survival (DFS) was evaluated using C-index. Additional prognostic value of the radiomic signature was explored. RESULTS: The radiomic signature had C-index = 0.64 for OS and C-index = 0.60 for DFS in the validation set. The addition of the radiomic signature to other clinical features (TNM staging and tumor subsite) increased prognostic ability for both OS (HPV- C-index 0.63 to 0.65; HPV+ C-index 0.75 to 0.80) and DFS (HPV- C-index 0.58 to 0.61; HPV+ C-index 0.64 to 0.65). CONCLUSION: An MRI-based prognostic radiomic signature was developed and prospectively validated. Such signature can successfully integrate clinical factors in both HPV+ and HPV- tumors

Influence of exertional oscillatory breathing and its temporal behavior in patients with heart failure and reduced ejection fraction

Background: Exertional oscillatory breathing (EOV) represents an emerging prognostic marker in heart failure (HF) patients, however little is known about EOV meaning with respect to its disappearance/persistence during cardiopulmonary exercise test (CPET). The present single-center study evaluated EOV clinical and prognostic impact in a large cohort of reduced ejection fraction HF patients (HFrEF) and, contextually, if a specific EOV temporal behavior might be an addictive risk predictor. Methods and results: Data from 1.866 HFrEF patients on optimized medical therapy were analysed. The primary cardiovascular (CV) study end-point was cardiovascular death, heart transplantation or LV assistance device (LVAD) implantation at 5-years. For completeness a secondary end-point of total mortality at 5- years was also explored. EOV presence was identified in 251 patients (13%): 142 characterized by EOV early cessation (Group A) and 109 by EOV persistence during the whole CPET (Group B). The entire EOV Group showed worse clinical and functional status than NoEOV Group (n = 1.615) and, within the EOV Group, Group B was characterized by a more severe HF. At CV survival analysis, EOV patients showed a poorer outcome than the NoEOV Group (events 27.1% versus 13.1%, p < 0.001) both unpolished and after matching for main confounders. Instead, no significant differences were found between EOV Group A and B with respect to CV outcome. Conversely the analysis for total mortality failed to be significant. Conclusions: Our analysis, albeit retrospective, supports the inclusion of EOV into a CPET-centered clinical and prognostic evaluation of the HFrEF patients. EOV characterizes per se a more advanced HFrEF stage with an unfavorable CV outcome. However, the EOV persistence, albeit suggestive of a more severe HF, does not emerge as a further prognostic marker

Echocardiographic Screening for Rheumatic Heart Disease in a Ugandan Orphanage: Feasibility and Outcomes

Background: Rheumatic heart disease (RHD) is a major cause of cardiovascular disease in developing nations, leading to more than 230,000 deaths annually. Most patients seek medical care only when long-term structural and hemodynamic complications have already occurred. Echocardiographic screenings ensure the early detection of asymptomatic subjects who could benefit from prophylaxis, monitoring and intervention, when appropriate. The aim of this study is to assess the feasibility of a screening program and the prevalence of RHD in a Ugandan orphanage. Methods: We performed an RHD-focused echocardiogram on all the children (5–14 years old) living in a north Ugandan orphanage. Exams were performed with a portable machine (GE Vivid-I). All the time intervals were recorded (minutes). Results: A total of 163 asymptomatic children were screened over 8 days (medium age 9.1; 46% male; 17% affected by severe motor impairment). The feasibility rate was 99.4%. An average of 20.4 exams were performed per day, with an average of 15.5 images collected per subject. Pathological mitral regurgitation (MR) was found in 5.5% of subjects, while at least two morphological features of RHD were found in 4.3%, leading to 1 “definite RHD” (0.6%) case and 13 “borderline RHD” cases (8.1%). Six congenital heart defects were also noted (3.7%): four atrial septal defects, one coronary artery fistula and one Patent Ductus Arteriosus. Conclusions: We demonstrated the feasibility of an echocardiographic screening for RHD in an orphanage in Uganda. A few factors, such as good clinical and hygienic care, the availability of antibiotics and closeness to a big hospital, may account for the low prevalence of the disease in our population

Exercise oxygen pulse kinetics in patients with hypertrophic cardiomyopathy

19Objectives Reduced cardiac output (CO) has been considered crucial in symptoms' genesis in hypertrophic cardiomyopathy (HCM). Absolute value and temporal behaviour of O-2-pulse (oxygen uptake/heart rate (VO2/HR)), and the VO2/work relationship during exercise reflect closely stroke volume (SV) and CO changes, respectively. We hypothesise that adding O-2-pulse absolute value and kinetics, and VO2/work relationship to standard cardiopulmonary exercise testing (CPET) could help identify more exercise-limited patients with HCM. Methods CPETs were performed in 3 HCM dedicated clinical units. We retrospectively enrolled non-end-stage consecutive patients with HCM, grouped according to left ventricle outflow tract obstruction (LVOTO) at rest or during Valsalva manoeuvre (72% of patients with LVOTO = 50 mm Hg). We evaluated the CPET response in HCM focusing on parameters strongly associated with SV and CO, such as O-2-pulse and VO2, respectively, considering their absolute values and temporal behaviour during exercise. Results We included 312 patients (70% males, age 49 +/- 18 years). Peak VO2 (percentage of predicted), O-2-pulse and ventilation to carbon dioxide production (VE/VCO2) slope did not change across LVOTO groups. Ninety-six (31%) patients with HCM presented an abnormal O-2-pulse temporal behaviour, irrespective of LVOTO values. These patients showed lower peak systolic pressure, workload (106 +/- 45 vs 130 +/- 49 W), VO2 (21.3 +/- 6.6 vs 24.1 +/- 7.7 mL/min/kg; 74%+/- 17% vs 80%+/- 20%) and O-2-pulse (12 (9-14) vs 14 (11-17) mL/beat), with higher VE/VCO2 slope (28 (25-31) vs 27 (24-31)) (p<0.005 for all). Only 2 patients had an abnormal VO2/work slope. Conclusion None of the frequently used CPET parameters, either as absolute values or dynamic relationships, were associated with LVOTO. Differently, an abnormal temporal behaviour of O-2-pulse during exercise, which is strongly related to inadequate SV increase, correlates with reduced functional capacity (peak and anaerobic threshold VO2 and workload) and increased VE/VCO2 slope, identifying more advanced disease irrespectively of LVOTO.nonenoneMapelli, Massimo; Romani, Simona; Magrì, Damiano; Merlo, Marco; Cittar, Marco; Masè, Marco; Muratori, Manuela; Gallo, Giovanna; Sclafani, Matteo; Carriere, Cosimo; Zaffalon, Denise; Salvioni, Elisabetta; Mattavelli, Irene; Vignati, Carlo; De Martino, Fabiana; Rovai, Sara; Autore, Camillo; Sinagra, Gianfranco; Agostoni, PiergiuseppeMapelli, Massimo; Romani, Simona; Magrì, Damiano; Merlo, Marco; Cittar, Marco; Masè, Marco; Muratori, Manuela; Gallo, Giovanna; Sclafani, Matteo; Carriere, Cosimo; Zaffalon, Denise; Salvioni, Elisabetta; Mattavelli, Irene; Vignati, Carlo; De Martino, Fabiana; Rovai, Sara; Autore, Camillo; Sinagra, Gianfranco; Agostoni, Piergiusepp

Symptomatic post COVID patients have impaired alveolar capillary membrane function and high VE/VCO2

Abstract Background Post COVID-19 syndrome is characterized by several cardiorespiratory symptoms but the origin of patients’ reported symptomatology is still unclear. Methods Consecutive post COVID-19 patients were included. Patients underwent full clinical evaluation, symptoms dedicated questionnaires, blood tests, echocardiography, thoracic computer tomography (CT), spirometry including alveolar capillary membrane diffusion (DM) and capillary volume (Vcap) assessment by combined carbon dioxide and nitric oxide lung diffusion (DLCO/DLNO) and cardiopulmonary exercise test. We measured surfactant derive protein B (immature form) as blood marker of alveolar cell function. Results We evaluated 204 consecutive post COVID-19 patients (56.5 ± 14.5 years, 89 females) 171 ± 85 days after the end of acute COVID-19 infection. We measured: forced expiratory volume (FEV1) 99 ± 17%pred, FVC 99 ± 17%pred, DLCO 82 ± 19%, DM 47.6 ± 14.8 mL/min/mmHg, Vcap 59 ± 17 mL, residual parenchymal damage at CT 7.2 ± 3.2% of lung tissue, peakVO2 84 ± 18%pred, VE/VCO2 slope 112 [102–123]%pred. Major reported symptoms were: dyspnea 45% of cases, tiredness 60% and fatigability 77%. Low FEV1, Vcap and high VE/VCO2 slope were associated with persistence of dyspnea. Tiredness was associated with high VE/VCO2 slope and low PeakVO2 and FEV1 while fatigability with high VE/VCO2 slope. SPB was fivefold higher in post COVID-19 than in normal subjects, but not associated to any of the referred symptoms. SPB was negatively associated to Vcap. Conclusions In patients with post COVID-19, cardiorespiratory symptoms are linked to VE/VCO2 slope. In these patients the alveolar cells are dysregulated as shown by the very high SPB. The Vcap is low likely due to post COVID-19 pulmonary endothelial/vasculature damage but DLCO is only minimally impaired being DM preserved

Development of a multiomics database for personalized prognostic forecasting in head and neck cancer: The Big Data to Decide EU Project

27Despite advances in treatments, 30% to 50% of stage III-IV head and neck squamous cell carcinoma (HNSCC) patients relapse within 2 years after treatment. The Big Data to Decide (BD2Decide) project aimed to build a database for prognostic prediction modeling.nonenoneCavalieri, Stefano; De Cecco, Loris; Brakenhoff, Ruud H; Serafini, Mara Serena; Canevari, Silvana; Rossi, Silvia; Lanfranco, Davide; Hoebers, Frank J P; Wesseling, Frederik W R; Keek, Simon; Scheckenbach, Kathrin; Mattavelli, Davide; Hoffmann, Thomas; López Pérez, Laura; Fico, Giuseppe; Bologna, Marco; Nauta, Irene; Leemans, C René; Trama, Annalisa; Klausch, Thomas; Berkhof, Johannes Hans; Tountopoulos, Vasilis; Shefi, Ron; Mainardi, Luca; Mercalli, Franco; Poli, Tito; Licitra, LisaCavalieri, Stefano; De Cecco, Loris; Brakenhoff, Ruud H; Serafini, Mara Serena; Canevari, Silvana; Rossi, Silvia; Lanfranco, Davide; Hoebers, Frank J P; Wesseling, Frederik W R; Keek, Simon; Scheckenbach, Kathrin; Mattavelli, Davide; Hoffmann, Thomas; López Pérez, Laura; Fico, Giuseppe; Bologna, Marco; Nauta, Irene; Leemans, C René; Trama, Annalisa; Klausch, Thomas; Berkhof, Johannes Hans; Tountopoulos, Vasilis; Shefi, Ron; Mainardi, Luca; Mercalli, Franco; Poli, Tito; Licitra, Lis