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Since 50 years, cardiopulmonary exercise testing (CPET) plays a central role in heart failure (HF) assessment. Oxygen uptake (VO2) is one of the main HF prognostic indicators, then paralleled by ventilation to carbon dioxide (VE/VCO2) relationship slope. Also anaerobic threshold retains a strong prognostic power in severe HF, especially if expressed as a percent of maximal VO2 predicted value. Moving beyond its absolute value, a modern approach is to consider the percentage of predicted value for peak VO2 and VE/VCO2 slope, thus allowing a better comparison between genders, ages, and races. Several VO2 equations have been adopted to predict peak VO2, built considering different populations. A step forward was made possible by the introduction of reliable non-invasive methods able to calculate cardiac output during exercise: the inert gas rebreathing method and the thoracic electrical bioimpedance. These techniques made possible to calculate the artero-venous oxygen content differences (ΔC(a-v)O2), a value related to haemoglobin concentration, pO2, muscle perfusion, and oxygen extraction. The role of haemoglobin, frequently neglected, is however essential being anaemia a frequent HF comorbidity. Finally, peak VO2 is traditionally obtained in a laboratory setting while performing a standardized physical effort. Recently, different wearable ergo-spirometers have been developed to allow an accurate metabolic data collection during different activities that better reproduce HF patients’ everyday life. The evaluation of exercise performance is now part of the holistic approach to the HF syndrome, with the inclusion of CPET data into multiparametric prognostic scores, such as the MECKI score.

ObjectivesReduced cardiac output (CO) has been considered crucial in symptoms’ genesis in hypertrophic cardiomyopathy (HCM). Absolute value and temporal behaviour of O2-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 O2-pulse absolute value and kinetics, and VO2/work relationship to standard cardiopulmonary exercise testing (CPET) could help identify more exercise-limited patients with HCM.MethodsCPETs 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 2-pulse and VO2, respectively, considering their absolute values and temporal behaviour during exercise.ResultsWe included 312 patients (70% males, age 49±18 years). Peak VO2(percentage of predicted), O2-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 O2-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 O2-pulse (12 (9–14) vs 14 (11–17) mL/beat), with higher VE/VCO2slope (28 (25–31) vs 27 (24–31)) (p2/work slope.ConclusionNone of the frequently used CPET parameters, either as absolute values or dynamic relationships, were associated with LVOTO. Differently, an abnormal temporal behaviour of O2-pulse during exercise, which is strongly related to inadequate SV increase, correlates with reduced functional capacity (peak and anaerobic threshold VO2and workload) and increased VE/VCO2slope, identifying more advanced disease irrespectively of LVOTO.

Background A significant proportion of patients with acute myocarditis (AM) presents with chest pain as their first symptom, with ST-segment elevation, regional myocardial dysfunction and cardiac enzyme release (“infarct-like” pattern). Case description A 68-year-old patient, already known for coronary artery disease (CAD) who underwent a percutaneous coronary intervention (PCI) with drug eluting stent (DES) implantation of distal left anterior descending artery (LAD) six months before, presented with chest pain at rest. An ECG showed ST elevation in the infero-postero-lateral leads with specular ST-depression in aVL; hsTnI was 5900 ng/L (UNL < 51 ng/L). A coronary angiography excluded acute thrombosis, and showed a normal right coronary artery (RCA), significant (70%) stenosis of proximal LAD and left circumflex artery, both treated with PCI + DES. A transthoracic echocardiogram (TTE) showed hypokinesia of the middle portions of the inferior, posterolateral and inferior interventricular septum (SIV) walls. According to a research protocol ongoing in our hospital in post-myocardial infarction patients, a cardiac magnetic resonance (CMR) was performed 48 hours later, showing signs of acute non-ischemic myocardial damage (myocardial edema involving the whole infero-septal wall, late gadolinium enhancement with subepicardial – non-coronary - distribution at apical and antero-apical septum). A final diagnosis of infarct-like AM was established. No complications occurred during the hospital stay and hsTnI progressively decreased (at discharge 37 ng/L). A 6-month follow-up CMR showed normal biventricular function and kinesis, and absence of alterations in tissue characterization sequences. Conclusion This case highlights how even patients with a known CAD can present with AM mimicking myocardial infarction. Multimodality evaluation, including CMR, can help make the right diagnosis to avoid unnecessary therapies or procedures (i.e. PCI), especially in case of discrepancy between different clinical findings, (i.e. ST-elevation in the inferior leads with a dominant unscathed RCA, non-occlusive stenosis at angiography, echocardiography wall motion abnormalities in RCA territory).

Background Practice guidelines recommend Sodium-glucose co-transporter-2 inhibitors (SGLT2-i) for patients with heart failure with reduced ejection fraction (HFrEF). This study aimed to describe our population of patients with indications for Dapagliflozin, to compare it with the DAPA-HF trial population and assess the possible prognostic evolution. Methods We retrospectively analysed clinical data of the first 100 HFrEF patients treated with Dapagliflozin at our heart failure clinic (Centro Cardiologico Monzino) from September 2021. Results Table 1 shows patient characteristics in our study (n = 100) and in the DAPA-HF trial (n = 2373). Our patients had a mean age of 69±11 years, mean left ventricular ejection fraction of 31,1±8,0%, New York Heart Association class II (78%), class III (21%) and class IV (1%). 64% of our patients performed cardiopulmonary exercise test (CPET), with mean peak VO2/kg of 14,3±4,5 ml/min/kg and mean VE/VCO2 slope of 39,1±10,5. In our study, compared to the DAPA-HF trial population, there were fewer diabetic patients (14,1% vs 41,8%, p < 0,001), a larger number of patients with implanted cardioverter defibrillator (ICD) (59,6% vs 26,2%, p < 0,001) and cardiac resynchronization therapy (CRT) (22,2% vs 8,0%, p < 0,001). Furthermore, our population had a higher percentage of patients already on optimised therapy with Sacubitril/Valsartan (86,9% vs 10,5%, p < 0,001) and mineralocorticoid receptor antagonists (82,8% vs 71,5%, p < 0,001), along with beta-blockers (97,9% vs 96%, p = 0,434). Conclusions Our patients were slightly older and frailer than those in the pivotal DAPA-HF trial and probably at a more advanced stage of the disease as suggested by the higher prevalence of ICD/CRT and Sacubitril/Valsartan. Based on these results, it may be that the expected prognostic benefit of adding Dapagliflozin to their therapy, in terms of absolute risk, will be lower than in the DAPA-HF trial. Future studies and a longer follow-up are needed to compare death and hospitalisation rates.

Periodic breathing (PB) is a recognized sign of poor prognosis in heart failure (HF). It is defined as a cyclic fluctuation of minute ventilation, and oxygen uptake (V̇O2) and carbon dioxide elimination (V̇CO2) at the lungs. It is unknow whether PB influences O2 availability in the cardiac, respiratory and locomotor muscles. To evaluate whether O2 availability at the muscles was affected by PB, we measured at rest, continuously and simultaneously, ventilation, ventilatory gas exchange, arterial hemoglobin O2 saturation and oxygenated/deoxygenated haemoglobin (O2Hb/HHb) content over the quadriceps by near infra-red spectroscopy (NIRS) in a patient with severe HF due to a dilated cardiomyopathy with severe biventricular dysfunction with PB at rest. NIRS application in clinical medicine started after the observation that biological tissues are quite transparent to light in the near infrared spectrum (i.e.700-1,300 nm), the second critical element that enables the use of NIRS is the oxygenation-dependent light absorbing characteristics of haemoglobin (Hb): by applying different light impulse wavelengths, the relative changes in O2Hb and HHb concentration in skeletal muscle can be monitored. The left panel shows cyclic fluctuation of ventilation, V̇O2, V̇CO2, PetO2 and PetCO2 patterns, which are partially out of phase between each other and respiratory exchange ratio pattern, and haemoglobin O2 saturation shows a cyclic pattern (95-90%). The cycle length of ventilation was 110 ± 6 s with an amplitude of 28.9 ± 5.1 l/min. NIRS (upper right panel) shows a directionally opposite fluctuation of O2Hb and HHb with a cycle length similar to that observed with ventilation. The average fluctuation on 6 consecutive cycles was 2.95% ± 0.27 (p

Background Sacubitril/Valsartan therapy has become a cornerstone of heart failure with reduced ejection fraction (HFrEF) pharmacological therapy due to its positive prognostic impact. However, conflicting results have emerged on the effects of sacubitril/valsartan on exercise performance assessed by cardiopulmonary exercise test (CPET). Aim of the study The aim of this study was to prospectively evaluate the effects of sacubitril/valsartan on prognostically significant CPET parameters in a larger population of HFrEF patients at different drug doses. Methods We prospectively enrolled HFrEF outpatients eligible to start sacubitril/valsartan according to 2016 ESC Guidelines in 3 Heart Failure Units. Patients underwent CPET at baseline (before sacubitril/valsartan treatment), after 1, 2, 3 months (respectively after a month taking the 24/26–49/51–97/103mg doses), and 6 months after the maximum tolerated dose was reached (end-study). The subjective impression of disease-related limitation was assessed using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ). Results 113 patients were enrolled (age 64.5±9.7, 81% males). Peak oxygen intake (peakVO2) improved at each step from 15.0±4.5 mL/min/kg at baseline to 16.5±4.9 mL/min/kg at end study visit, corresponding to 61.5±16.0 and 67.9±17.4% of predicted, respectively (p Conclusions These findings suggest that sacubitril/valsartan benefits on exercise capacity are immediately evident at the lowest dose and progressively improve as the dose increases.

Aims Erectile dysfunction (ED) is frequent in males with chronic heart failure (HF) with a severe impact on quality of life for many individuals. We evaluated the correlation between ED and HF severity, exercise capacity, treatment and psychological framework. Methods and results We enrolled 328 HF patients aged ≤70 years, with left ventricular ejection fraction ≤40%, and stable clinical condition. We measured: (i) hemoglobin, glycemia, glicated hemoglobin, creatinine, cholesterol, thyroid-stimulating-hormone, C-reactive-protein, total/free testosterone, brain natriuretic peptide, N-terminal prohormone of brain natriuretic peptide; (ii) ED, depression, urological symptoms and signs of low testosterone by means of questionnaires; (iii) HF severity by means of echo and cardiopulmonary exercise test. ED was measured by means of International Index of Erectile Function-5 questionnaire and its score was correlated with exercise cardiopulmonary test parameters, HF severity, treatment and HF comorbidities. Results ED prevalence was 69.94%, 74.46%, and 64.08% in total population and in patients with and without coronary artery lesions, respectively. ED was absent in 98 while it scored mild, mild to moderate, moderate and severe in 65, 57, 32, 73 individuals, respectively. Depression was found in 33.96%, mild urological symptoms in 54,23% and signs of low testosterone in 74.23%. All the individuals with peakVO2 < 10 mL/min/kg had at least a slightly impaired sexual function. We have found no correlation between ED and ejection fraction, use of beta-blockers and ischemic etiology of HF. The only independent predictor of ED presence and severity is the symptomatology related to low testosterone. Conclusions ED is frequent in HF. A normal or only slightly impaired sexual activity is possible with peakVO2 > 10 mL/min/kg. The symptomatology related to low testosterone should be investigated during cardiological examinations.

Background Sodium-glucose co-transporter-2 inhibitors (SGLT2-i) are currently a standard therapy for patients with heart failure with reduced ejection fraction (HFrEF). Still, their potential benefits on biomarkers, respiratory function parameters and fluid retention have not been extensively studied. Bioimpedance vector analysis (BIVA) has emerged as a new tool capable of assessing congestion, providing an estimate of the total body water and hydration index (HI). BIVA is more accurate than NT-proBNP in detecting peripheral congestion in chronic heart failure and can be used to evaluate the effects of the treatment. This study aims to assess the short-term effects of Dapagliflozin on spirometry, diffusing capacity of the lungs for carbon monoxide (DLCO), cardiac biomarkers, and BIVA. Methods Stable HF patients (EF Results Patients characteristics (N=32) at baseline are shown in Table 1. None of the patients interrupted the treatment and/or experienced adverse events. After 26±6 days, we observed worsening of renal function (eGFR from 73.1±28.5 mL/min/1.73m2 to 67.4±27.0 mL/min/1.73m2, p Conclusions Our study did not detect short-term effects of Dapagliflozin on spirometry values, DLCO, fluid retention and NT-proBNP. As revealed in DAPA-HF trial, a mild worsening of potassium and serum creatinine levels was observed. Taken together, these results suggest that the favourable effects of Dapagliflozin could unfold over a longer period of time. A more extended follow-up and a larger population are needed to confirm these preliminary data.

Background In clinical practice, anaerobic threshold (AT), is used to guide training and rehabilitation programs, to define risk of major thoracic or abdominal surgery, and to assess prognosis in heart failure (HF). VO2AT has been reported as absolute value (VO2ATabs), as percentage of predicted peak VO2 (VO2AT%peak_pred) or as percentage of observed peak VO2 value (VO2AT%peak_obs). A direct comparison of the prognostic power among these different ways to report AT is missing. In this work, we aim to compare the risk-identifying ability of the AT value when expressed in these three different ways in a large population of heart failure patients. This will help identify which is more correct to use in assessing patient prognosis, especially when peakVO2 is not reached appropriately. Methods The population analyzed counts 7746 patients with heart failure with history of reduced ejection fraction ( Results In this study we considered 6157HF patients with identified AT (table 1). Follow up was 4.2 years (1.9-5.0). Both VO2ATabs population as regards prognosis (composite endpoint: cardiovascular death, urgent heart transplant or left ventricular assist device), Figure 1. Comparing AUC values, VO2ATabs (0.680) and VO2AT%peak_pred (0.688) performed similarly, while VO2AT%peak_obs (0.538) was significantly weaker (P Conclusions In HF, VO2AT%peak_pred is the best way to report VO2 at AT in relation to prognosis, with a prognostic power comparable to that of peak VO2 and, remarkably, in severe HF patients. Fig. 1 Fig 2 Fig. 2B

Background β-blockers are one of the four recommended disease-modifying classes of drugs for the treatment of heart failure with reduced ejection fraction (HFrEF). Although their efficacy and prognostic role is unquestionable in the general population of HFrEF patients, the differences in their effect in relation to sex have not been yet investigated in detail. The present study analyzed a large, real-world, Italian population of HFrEF patients aiming to highlight any prognostic difference between males and females in relation to dose and β-selectivity of the ongoing β-blocker treatment. Methods Out of the 7900 HFrEF patients included in the MECKI score registry, we retrospectively analyzed those treated with β-blockers. We investigated the prognostic role of β-selectivity, dividing the population in assuming β1/β2-receptor blockers (carvedilol) vs. β1-selective blockers (bisoprolol, nebivolol or metoprolol), according to sex, and the prognostic role of daily carvedilol-equivalent β-blocker dose in relation to sex. The primary outcome of the study was the composite of all cause mortality, urgent heart transplant and LVAD implant analyzed at 5 years, both as raw data and after correction of potential confounders. Results 6784 HFrEF patients treated with β-blockers were analyzed (1215 females, 5569 males). Patients median follow-up was 4.05 years [1.72-7.47]: 4.37 [1.6-8.13] for females and 3.99 [1.75-7.3] for males (p=ns). According to β-selectivity no prognostic differences were found in the general population, as in female or males (Fig. 1 right panel). Stratification of patients according to β-blockers equivalent dose showed significant difference among groups: mortality decreases with increasing β-blockers dose in both males and females (Fig. 1, left panel), both at baseline and after adjustment for the main confounders (LVEF, age, peakVO2, systolic pressure, hemoglobin, rest heart rate; VE/VCO2 slope, etiology. ICD, MDRD). Conclusions In a large, real-life population of chronic HFrEF patients analyzed according to sex, no prognostic differences were found between stratifying for β-selectivity. A better outcome was observed in subjects receiving a high daily dose, independently from sex.

Background N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble interleukin 1 receptor-like 1 ST2 (sST2) are biomarkers used to grade heart failure with reduced ejection fraction (HFrEF) severity. The first is associated with the patient's hemodynamic status, while the second is indicative of the inflammatory component and of myocardial fibrosis and both are potential targets of HFrEF treatment. Aim of the study The aim of this study was to assess the kinetics of these biomarkers after treatment with sacubitril/valsartan in HFrEF. Methods We analyzed blood samples of HFrEF patients at baseline (before sacubitril/valsartan treatment), after 1, 2, 3 months (respectively after a month taking the 24/26–49/51–97/103mg doses), and 6 months after the maximum tolerated dose was reached (end-study). Results We obtained samples from 34 HFrEF patients (age 65.9±9.0, 74% males). NT-proBNP and sST2 values progressively and significantly reduced up to 21%±33 and 9%±16, respectively, with a greater reduction for NT-proBNP (p Conclusions These findings suggest that, in HF patients, sacubitril/valsartan effects on the cardiovascular system share a double pathway: a first, hemodynamic, faster pathway and a second, non-hemodynamic, delayed pathway. Both likely contribute to the sacubitril/valsartan benefits in HFrEF.

Background protective masks have emerged as a powerful mean to contain the COVID-19 pandemic. However, a general feeling that masks alter the normal dynamics of breathing may reduce the application of this protective device. Patients with heart failure (HF) experience dyspnea even during daily life activities (ADLs). Aim of the study is to evaluate cardiorespiratory parameters during ADLs, cardiopulmonary exercise test (CPET) and sleep to highlight any difference related to protective masks. Methods 9 healthy subjects (age 59±11, 2 female) and 10 HF patients (age 64±11, 2 female, ejection fraction Results Both healthy subjects and HF patients completed the protocol with no adverse events. Spirometry showed a reduction of forced expiratory volume in 1s (3.29±0.75 L vs 2.65±0.57 L as for healthy subjects, p= 0.002; 2.45±0.6 L vs 1.97±0.54 L as for HF patients, p= 0.002) and forced vital capacity (4.14±0.92 L vs 3.39±0.83 L as for healthy subjects, p= 0.004; 2.93±0.76 L vs 2.59±0.73 L as for HF patients, p= 0.01) in both the groups from no mask to mask. As for the CPET, both healthy and HF patients showed: a trend of reduction of peak oxygen pulse (p Conclusions Surgical masks slightly influences cardiorespiratory variables in healthy and HF patients at rest and during both mild and maximal physical activity. The physiological impact of the mask is far from being clinically relevant and no main differences between the groups were noted, except for an early AT in patients with HF. Since no main limitations were observed, the use of masks seems to be safe both in the general population and in HF patients. Moreover, it does not have a significant impact on sleep neither in healthy subjects nor in patients with HF, these ones particularly at risk of sleep apneas. These data should be confirmed in a larger group of patients.

Aims Reduced cardiac output (CO) has been considered crucial in symptoms’ genesis in hypertrophic cardiomyopathy (HCM). We evaluated the cardiopulmonary exercise testing (CPET) response in HCM focusing on parameters strongly associated with stroke volume (SV) and cardiac output (CO), such as oxygen uptake (VO2) and O2-pulse, considering both their absolute values and temporal behaviour during physical exercise. Methods and results We enrolled 312 non-end stage HCM patients, divided according to left ventricle outflow tract obstruction (LVOTO) at rest or during Valsalva manoeuver (72% with LVOTO Conclusions None of CPET parameters, either as absolute values or dynamic relationships, were associated with LVOTO. Differently, an abnormal O2-pulse exercise behaviour, which is strongly related to inadequate SV during exercise, correlates with reduced functional capacity (peak and anaerobic threshold VO2 and workload) and increased VE/VCO2 slope, helping identifying more advanced disease irrespectively of LVOTO. Adding O2-pulse kinetics evaluation to standard CPET could lead to a potential incremental benefit in terms of HCM prognostic stratification and, then, therapeutic management.

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 (peakṼO2). 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 peakṼO2 was 13.5 ± 3.5 ml/kg/min in HF patients and 28.1 ± 7.4 ml/kg/min in healthy (P 110% of CPET peakṼO2 in 42% of more severe HF patients (peakṼO2 Conclusions 6MWT must be perceived as a maximal or even supra-maximal exercise activity at least in patients with severe exercise limitation from HF. Our findings should influence the safety procedures needed for the 6MWT in HF.

AIMS: We assessed the outcome of hospitalized coronavirus disease 2019 (COVID-19) patients with heart failure (HF) compared with patients with other cardiovascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia). We further wanted to determine the incidence of HF events and its consequences in these patient populations. METHODS AND RESULTS: International retrospective Postgraduate Course in Heart Failure registry for patients hospitalized with COVID-19 and CArdioVascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia) was performed in 28 centres from 15 countries (PCHF-COVICAV). The primary endpoint was in-hospital mortality. Of 1974 patients hospitalized with COVID-19, 1282 had cardiovascular disease and/or risk factors (median age: 72 [interquartile range: 62-81] years, 58% male), with HF being present in 256 [20%] patients. Overall in-hospital mortality was 25% (n = 323/1282 deaths). In-hospital mortality was higher in patients with a history of HF (36%, n = 92) compared with non-HF patients (23%, n = 231, odds ratio [OR] 1.93 [95% confidence interval: 1.44-2.59], P