Abstract Degeneration of the biologic aortic valve prosthesis represents an increasingly important issue. This process often affects frail elderly patients who are not candidates for cardiac re–intervention. TAVI valve–in–valve implantation therefore probably remains the only viable option in such patients.We report the clinical case of Mrs. Luciana F., currently 94 years old, who underwent biological aortic valve replacement in 2016. In charge of the Elderly Patient‘s Heart Failure Outpatient Clinic (SOD Geriatrics–UTIG) since January 2023.At first evaluation,89 years old, widowed, living alone; MMSE 29/30. SPPB 7/12. Totally autonomous in BADL, and partially in IADL.She complained of decreased exercise tolerance (NYHA Class III). No alterations in left ventricular kinetics. Calcified and degenerated aortic valve prosthesis with markedly reduced box opening and severe stenosis (Vel 4.7 m/s; Grad max/med (86/55 mmHg) mild insufficiency. May 2023 access to DEA for syncopal episode, complicated by fall down stairs and head injury; on echocardiogram relief of further degeneration of aortic bioprosthesis (moderate–grade intra–prosthetic insufficiency at 2 jets with PTH 300 msec and severe stenosis, Gmax/Gmed 88/55 mmHg, DVI 0.20 June 2023 worsening of dyspnea that appeared even at rest NYHA IV. At echocolordoppler confirmed severe aortic stenosis severe bioprosthesis degeneration. She was evaluated in Heart Team: low overall risk (MPI 0.31) therefore percutaneous implantation of Medtronic Evolut R aortic bioprosthesis has been performed. At discharge asymptomatic, eupnoic, walking independently without aids for short stretches. At subsequent follow–up.–1 month: substantial clinical well–being in the absence of dyspnea on ordinary exertion (NYHA II), no orthopnea or paroxysmal nocturnal dyspnea; denies angor, heart palp or syncopal episodes. She has resumed household chores and leaves the house almost every day –6 months: clinical stability. She walks long distances every day in the absence of symptomatology. –1 years (turned 90 years old): clinical stability with dyspnea for moderate exertion continues active life. Trans prosthetic gradient max/medium 22/12 mmHg, VD–AD 30 mmHg. In conclusion TAVI procedure on degenerated biological prosthesis should be an option to be considered in the elderly patient selected and evaluated by a multidisciplinary Heart Team to achieve improvement of cardiovascular symptoms and concomitantly recovery of functional autonomy.

Abstract Background Dapagliflozin is a sodium–glucose cotransporter–2 inhibitor (SGLT2i) approved for the treatment of Heart Failure (HF); however, real–world data on the use of dapagliflozin in the setting of HF with reduced Ejection Fraction (HFrEF) are scarce. EVOLUTION–HF Italy is part of a wider initiative aimed at filling these gaps with Real–World Evidence studies in 13 European countries. Aims The primary aim of the study is to describe characteristics of patients starting dapagliflozin for HFrEF and treatment patterns including discontinuation of dapagliflozin. Patient Reported Outcomes (PROs) are investigated as secondary aims, including Kansas City Cardiomyopathy Questionnaire (KCCQ), Medication Adherence Report Scale (MARS–5), and 6–Minutes Walking Test (6MWT). This abstract reports interim analysis (IA) results after 6 months of follow–up. Methods EVOLUTION–HF is a descriptive, observational, longitudinal study, which enrolled patients ≥18 years of age initiating dapagliflozin according to the approved HFrEF label; those with previous SGLT2i treatment were excluded. The enrollment window was 14–45 days after dapagliflozin initiation, and follow–up lasts up to 1 year. Results 256 participants (mean age 68.5±11.6 years, 75.8% males) were enrolled in 11 Italian sites between April 2022 and April 2023; baseline clinical characteristics are reported in Figure 1. On average, Left Ventricular Ejection Fraction (LVEF) was 31.9%. Most participants had HF in NYHA class II (69.1%) and with ischaemic aetiology (55.7%); 31.7% were hospitalised for HF in the previous year. Cardiovascular treatments at baseline are detailed in Figure 2: 66.4% of patients were treated according to guideline–directed medical therapy for HFrEF (ARNI or ARB or ACEi + BB + MRA + SGLT2i). Follow–up visits at Month 6 were completed by 99 patients at the time of the IA (Figure 3). At 6 months, when compared with baseline, NTproBNP values lower and clinical status (as assessed by KCCQ score) improved, with patients being highly adherent to HF therapies. Conclusions The interim analysis presented in this abstract indicates signs of clinical improvement 6 months after initiation of dapagliflozin. At study completion (April 2024), EVOLUTION–HF Italy will generate robust evidence on real–world use of dapagliflozin among Italian patients with HFrEF, including relevant information on treatment pattern, clinical parameters, and quality of life.

Abstract Background SGLT2 inhibitors have dramatically improved the outcome of heart failure patients with both preserved (HFpEF), mildly reduced (HFmrEF) and reduced (HFrEF) ejection fraction. Cancer patients have been excluded (or not enrolled) from pivotal trials so data on safety in such population are lacking. We aimed to collect evidence on safety and activity of empagliflozin and dapagliflozin in active cancer patients. Study Design TOSCA is a retrospective/prospective multicentre observational trial now enrolling cancer patients receiving SGLT2i for both HFpEF, HFmrEF and HFrEF. Inclusion criteria included active cancer (histologically confirmed current cancer or history of cancer in previous 3 yrs), heart failure (HF) and SGLT2i therapy for HF. Exclusion criteria were age <18yrs, non–melanoma skin cancer and localised cervical cancer undergone radical treatment. Primary objective is assessing the safety of SGLT2i in active cancer patients expressed as percentage of toxicity (in particular hypoglycaemia, genital and urinary infections, acute renal failure, fractures, diabetic ketoacidosis and thromboembolic events) compared to side effects reported in phase III RCTs. Secondary objective is assessing the efficacy (change in EF, NYHA class variation, hospital/ER admissions for HF, need for diuretics) and exploratory objectives are time course variation of cardiac biomarkers, efficacy in the treatment of cardiac toxicity and drug–drug interactions with anticancer or supportive care drugs. A three months minimum follow–up will be required for every enrolled patient. Planned sample size is 80 patients (to be increased to a maximum of 200 cases) equally distributed between the two study cohorts. Relevance of expected results: SGLT2i are one of the pillars of HF treatment; the proof of safety (and activity) in active cancer patients could allow a wider cancer population to benefit of their efficacy in reducing cardiovascular mortality and could provide the rational basis for RCTs testing their role as cardio–protective strategy.

Abstract Background Amphotericin B (AmB) is an antifungal drug commonly used in a broad spectrum of infections, including leishmaniasis. Leishmaniasis, transmitted through insect bites, has cutaneous, mucocutaneous, or visceral (particularly liver and spleen) involvement. The main adverse effects of AmB are cardiotoxicity and nephrotoxicity, often reversible, but with yet unclear pathophysiology. Reversible dilated cardiomyopathy is a rare disease with very few cases described in the literature (less than 10). The Case A 41–year–old man with a silent cardiological history (only cocaine and alcohol abuse in past) is admitted for visceral leishmaniasis. Cardiological evaluation: LBBB in ECG (none previous available); no abnormality detected on ECOCG (EF 55%). Ten days after the AmB cycle, onset of worsening dyspnoea needing hospital treatment after a further two weeks for heart failure (HF). At ECOCG severe left ventricular dysfunction (EF 30%), no rise of cardiac enzymes was detected. Coronary angiography showed 50–75% stenosis on RCA and LAD, treated by angioplasty and stenting. Cardiac MRI showed: dilated left ventricle with diffuse biventricular hypokinesis (FE 16% left and 22% right), areas of LGE of non–ischemic appearance. HFrEF GDMTs were prescribed, with progressive clinical improvement over the next four weeks; at cardiac MRI performed one month later, partially recovery of biventricular function (FE sn 41% right 48%) was found. The ECG showed regression of LBBB. No myocardial biopsy was performed, so it is not possible to get to an unequivocal cardiac dysfunction’s cause. However, the time relationship between the use of AmB and the clinical findings evolution, consistently with the few literature available, suggests a probable diagnosis of AmB toxic cardiomyopathy. An ischaemic cause of the dysfunction is unlikely by the MRI feature and by coronary angiography findings. Literature data suggest that the presence of predisposing factors for cardiac dysfunction, rather than the duration of treatment or preparation used, is the most relevant factor in the development of AmB–related cardiomyopathy. It’s important to perform cardiac monitoring in all patients receiving AmB therapy. In all reported cases, cardiac function recovered substantially after cessation of AmB treatment.

Abstract Introduction SGLT2-i have been shown to improve prognosis in patients with reduced ejection fraction heart failure (HFrEF) in randomized clinical trials (RCTs). However, we have little data on the use of these drugs in clinical practice, both in terms of safety and efficacy profile, especially in elderly patients. Objectives To describe the characteristics of HFrEF outpatients who started SGLT2-I and evaluate tolerability and effect of therapy. Results We evaluated 42 patients, 32 M and 10 F, with a mean age of 78±8.2 years (62.1% over 75). At baseline, the mean EF was 34.5%± 6.0 and the patients' renal function calculated with CKD-EPI was 56.3±18.6 ml/min/m2. We followed at 6 months 36 patients. After 6 months of SGLT2i therapy, there was a significant reduction in NYHA class (NYHA I 30.6% vs 9.8%, NYHA III 13.9% vs 31.7%), a slight recovery in EF (38% vs 33% p-value = 0.039) and a decrease in diuretic dose (34 mg/day vs 64 mg/day, p-value 0.033). Despite a slight initial reduction in eGFR, like RCTs, there was recovery of renal function at 6 months. At 6 months, only 2 patients discontinued SGLT2i therapy due to urinary infection. Conclusions In our analysis after 6 months of SGLT2-i therapy in elderly patients, there was clinical improvement as evidenced by improvement in NYHA class and reduction in diuretic therapy. SGLT2-i have been shown to be relatively safe, with no adverse effects occurring and no significant worsening of renal function.

Abstract Background Loeys–Dietz syndrome (LDS) is a rare autosomal dominant genetic disorder of connective tissue, characterised by a broad spectrum of craniofacial, vascular (arterial tortuosity and aneurysms) and skeletal clinical signs. Four subtypes have been described, related to mutations in genes encoding for components of the transforming growth factor beta signalling pathway (TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3). Diagnosis is based on the evaluation of clinical manifestations and family history. Therefore, many radiologists remain unfamiliar with the imaging and clinical findings in LDS. The Case 75–year–old woman, history of surgery for ruptured gastric a. aneurysm and ectasia of visceral arterial vessels. One year onset of worsening dyspnoea and asthenia, at echocardiography (ECOCG) severe aortic insufficiency has been detected and patient underwent aortic valve replacement with bioprosthesis. Cardiac surgery was complicated by aortic dissection (Stanford A; DeBakey I type) treated with replacement of ascending aorta and anterior hemiarch with tubular prosthesis. On that occasion a family diagnosis of SMAD3 gene mutation was made (both sister and nephew typed), compatible with Loeys–Dietz syndrome type 3. At the control angioTC evidence of proximal and distal anastomosis in order, in the absence of signs of periprosthetic leak. At ECOCG (FE 55%), thickened septum with marked postcardiac dyskinesia. No abnormality detected on ECG. Due to persistence of dyspnoea on mild exertion (NYHA class III) and reduced tolerance to orthostatism, cardiac rehabilitation program was undertaken on an outpatient basis for three months, providing an improvement in exertion tolerance (NYHA II) and a benefit on functional autonomy. LDS is a multisystem connective tissue disorder that is associated with a high burden of complications, a correct diagnosis will allow clinicians to appropriately establish the best therapeutic strategy, especially in cardiac surgery, taking into account the intraoperative and perioperative potential risks.

Abstract Introduction Heart failure (HF) is a risk factor for postoperative mortality in major non–cardiac surgery. Collaboration between the Multimodal Preoperative Prehabilitation unit (MPP) and Heart Failure Clinic (HFC) could allow optimization of heart failure therapy and negative prognostic factors such as reduced functional capacity (FC), malnutrition, and sarcopenia to improve the prognosis of these patients. Case report: Mrs. C.M. is a 58–year–old patient who presents to the MPP unit in anticipation of total colectomy for drug–refractory ulcerative colitis. Mrs. C.M. has a past medical history significant for heart failure with reduced ejection fraction (EF 25%) of presumably valvular–arrhythmic etiology. She underwent tricuspid annuloplasty and mitral replacement surgery some years ago and is affected by atrial fibrillation. At the MPP unit, Mrs. C.M. had a reduced FC and was malnourished and sarcopenic. Blood tests showed iron deficiency anemia. Heart failure therapy (NYHA II) was not optimized according to guidelines. Therefore, the patient started multimodal prehabilitation consisting of aerobic and resistance exercise, nutritional intervention, intravenous iron infusion, and optimization of HF therapy. After the patient was evaluated at the HFC, she started empagliflozin, sacubitril/valsartan, and ranolazine; intermittent levosimendan therapy was also performed. She also underwent cardiac NMR, which showed non–ischemic fibrosis, and coronary angiography, which was negative. Finally, she underwent PM–ICD implantation. After six months of multimodal prehabilitation, there was an increase in EF (38% vs. 25%), a reduction in NT–proBNP (700 vs 4988 pg/mL), and mitigation of HF symptoms. There was also a marked improvement in FC (383 vs 269 meters at 6–minute walking test), nutritional status (stage B vs stage C at PG–SGA test), and muscle strength (handgrip strength test 14.6 vs 8.5 kg). Considering the excellent preoperative optimization response, it was decided to proceed with surgery after a collegial discussion (anesthetist, heart failure cardiologist, surgeon, and patient). Conclusions Multimodal preoperative prehabilitation, based on the collaboration between the Multimodal Preoperative Prehabilitation Unit and Heart Failure Clinic, can effectively improve the preoperative functional capacity of HF patients.

Abstract Heart failure (HF), despite new therapeutic strategies, remains a condition characterized by an inauspicious prognosis and poor quality of life. The management of advanced and then terminal SC proves to be a current challenge, especially in elderly patients. A.C, 87 years old is autonomous and cognitively intact (BADL preserved 5/6, MMSE 28/30). In June ‘21 femur fracture complicated by cerebral hemorrhage (no relics) and anterior STEMI (FE 25%). Not performed coronarography (contraindication to antiplatelet therapy). Discharged to NYHA II with ARNI, MRA and beta blocker. After 1 month hospitalized for HF in the course of AF, performed infusion of levosimendan. In September ‘21 taken over by our "HF clinic" with progressive titration of therapy and insertion of SGLT2–i. In January ‘22 due to precarious clinical compensation (NYHA III–IV) progressive increase in furosemide dosage and undertaken sequential nephron blockade with metolazone, with good response. Given advanced–HF situation, performed Levosimendan infusions under DH regimen (8 h; 0.05–>0.2 mcg/Kg/min; three times every 2 weeks) with clinical stabilization. In April, hospitalization for decompensation flare–up with worsening creatinine (0.8 >>>2 mg/dL). On discharge, given the precarious compensation, activated the "Hospital–Territory Rapid Intervention Group" with home diuretic infusions and stabilization of the clinical picture and subsequent new referral from the "heart failure clinic" with monthly FU. By November 2022, clinical (NYHA IV with diuretic resistance), cognitive and functional (MMSE 22/30, BADL preserved 2/6) worsening. Evaluated as an end–stage scenario (in the absence of further treatment options), family interview was performed, home nursing service activated for infusions of furosemide, and referred to the palliative care service to assist the patient in the terminal phase of illness at home (Fig. 1). Conclusion in order to ensure the best quality of life in the terminal phase of the disease, the management of advanced SC in the elderly patient must involve individualization of the care pathway, through multidimensional assessment of the patient and sharing of goals at the different stages: from intensive FU with optimization of therapy in the early stages to early activation of home and palliative care services in the more advanced stages.

Abstract Background Given the relevance and the growing complexity of the management of cardio–oncology (CO) outpatients, a common care pathway has been recently proposed by ANMCO and AIOM Tuscany. Materials and methods: The proposal: 1) defined 3 categories of patients to be entered into the pathway (A: known cardiac disease needing active oncology treatment; B: undergoing cancer treatments with potential cardiac toxicity; C: experiencing cardiac toxicity and/or worsening of cardiovascular risk profile); 2) proposed two standard request forms for oncology (ONCO) and hematology (HEM); 3) set the minimum requirements for a cardio–oncology path; 4) indicated follow–up strategies during and after oncological treatments. Given the short observation interval we focused on points 1 and 2. Medical records of all cancer patients for whom a CO examination was required were analized to check if proposed forms have been used and if cases fulfilled into appropriate categories. Observation period was retrospectively set to 1 year starting from October 2022. Minimum appropriateness threshold for each process index was set to 80%. Results A total of 480 requests for a CO visit were retrospectively identified, 322 out of 480 (67%) from medical oncology and 158 out of 480 (33%) from hematology units. Appropriate request form was used in 95% of cases (456 out of 480) with no difference between ONCO and HEM units. All patients but 20 (460 out of 480, 95.8%) fulfilled (at least) one of the 3 pre–defined categories with no difference between ONCO and HEM units. Categories distribution was: A group 25%, B group 60%, and C group 15%. Patients from medical oncology were more likely to belong to A and B groups while cases from hematology to B and C groups. Conclusions Our data indicate that minimum thresholds were met for both index 1 and 2 (with values that are approaching to 100%) so supporting the use of the proposed clinical CO pathway.

Abstract Hyperkalimia (HK) is a condition that occurs very frequently in patients with heart failure (HF). HK often limits and discourages the implementation and optimization of RAASI therapy in patients with HFrEF. The introduction of the new K–binders drugs has made it possible to overcome this obstacle by allowing optimization of therapy even in patients with persistent hyperkalemia. Mr. AB aged 83 years cognitively intact and autonomous ( Katz‘s BADL and Lawton‘s IADL preserved; MMSE 29/30). February 2022 accessed DEA for aggravating exertional dyspnea; at that time echocardiogram finding reduced left ventricular systolic function, FE 35%. March 2022 performed elective coronarography: coronary tree free of critical lesions, confirmed on echocardiogram reduced FE. Post indication to undertake Sacubitril/Valsartan, beta blocker and SGLT2i therapy. For moderate CKD (eGFR 33 ml/min) with tendency to hyperkalemia not initiated MRA. April 2022 the patient was taken to our Heart Failure Outpatient Clinic–UTIG– AOU Careggi. June 2022 considered improvement in renal function and Kaliemia in optimized range GDMTs therapy with Potassium Canreonate 25 mg/day. At control EEs in July 2022 found hyperKalemia with K values 5.5 mEq/L but stability of renal function. Reduced therefore the dosage of Potassium Canreonate (25 mg every other day) with indication to repeat blood tests soon. September 2022 despite reduction in MRA dosage further increase in Kaliemia values to 5.8 mEq/L. Suspended Potassium Canreonate and started Sodium Zirconium Cyclosilicate therapy initially at loading dosage of 10 g three times daily for two days then continued with maintenance dosage of 5 g. At follow–up performed the following week K 4.5 mEq/L. Re–introduced Potassium Canreonate 25 mg/day with initial tight control of potassium values that remained stably at optimal values. Hyperkalemia is an obstacle in titrating HFrEF, especially in elderly patients with CKD. However, we have new drugs available that may allow the implementation of guideline–recommended treatments by controlling potassium values.

Abstract SGLT2–i have been shown to improve prognosis in patients with heart failure with reduced ejection fraction (HFrEF) in randomized clinical trials (RCTs). However, at the moment, we have little data on the use of these drugs in clinical practice, both in terms of safety and efficacy profile. Objectives To describe the characteristics of HFrEF outpatients who started SGLT2–i in clinical practice; evaluate tolerability and the effect on clinical and biohumoral parameters. Methods We prospectively analyzed patients who started SGLT2–i in our Heart Failure clinic. The baseline characteristics, the variations of bio–humoral and clinical parameters were recorded, as well as the onset of adverse effects leading to drug suspension after one month. Results We evaluated 37 patients, with a mean age of 77.7± 8.5 years (65% over 75). The baseline characteristics of the population compared to that of the treatment arms of the RCTs are shown in Fig.1. Most patients were in NYHA II (62%), with ischemic etiology (65%), with reduced EF (mean 34.7± 5.1%) and nearly half of the patients received ICD or CRT–D (43.2%). At the one month follow–up, there was a significant reduction in NYHA class (Fig. 2)and furosemide dose (36.3 vs 53.2 mg, p<0.001), without a significant change in NTproBNP values ​​(2499 vs 2431 pg /mL, p=0.804). Furthermore, there was a reduction in systolic blood pressure (115 vs 120 mmHg, p=0.029) with no significant increase in the incidence of orthostatic hypotension (27% vs 21%, p=0.48). In line with the trials, there was a slight, non–significant worsening of renal function (CKD–EPI 52.9 vs 55.9 mL/min, p=0.10). At one month, no patients experienced any adverse effects leading to SGLT2–i discontinuation. Conclusions In this preliminary analysis, after one month of SGLT2–i therapy in elderly patients, there was a clinical and hemodynamic improvement as demonstrated by the improvement of the NYHA class and the reduction of the diuretic therapy. SGLT2–i have been shown to be relatively safe, with no adverse effects and no increased risk of orthostatic hypotension or significant worsening of renal function.

Abstract Background Heart Failure (HF) is a relevant issue for public health issue: it affects more than 64 million people worldwide1, and its burden is anticipated to increase as the population ages. Dapagliflozin is an inhibitor of the sodium–glucose cotransporter–2 (SGLT2i). In the DAPA–HF trial, dapagliflozin reduced the risk of hospitalisation for HF and death in patients with HFrEF (with or without Type 2 Diabetes) compared to placebo2,3,4. Currently, there is a lack of data on characteristics, treatment profiles, and patient reported outcomes (PROs) of patients initiated on dapagliflozin for HFrEF in clinical practice: the EVOLUTION–HF programme is aimed at answering those questions by collecting real–world data in 13 European Countries, including Italy. The primary objective is to characterise patients initiated on dapagliflozin for the treatment of HFrEF and to estimate occurrence of treatment discontinuations. Secondary objectives include an assessment of Health–related Quality of Life (HR–QoL) by means of the Kansas City Cardiomyopathy Questionnaire (KCCQ), patient–reported adherence to prescriptions of pharmacological treatments for HF (Medication Adherence Report Scale – 5 Item), performance on 6–Minutes Walking Test. Methods The study has an observational, longitudinal, descriptive design. To be enrolled, patients must be 18 years old or older and have initiated treatment with dapagliflozin according to the approved HFrEF label. Patients with a diagnosis of Type 1 Diabetes or previously treated with any SGLT2i are excluded from the study. Follow–up lasts one year from start of treatment. Sample size has been estimated in 250 patients, that will be enrolled in 11 centres. Results The study is currently ongoing, and it will generate evidences on the use and tolerability of dapagliflozin, as well as on treatment patterns of other pharmacological therapies for HF and diabetes. Also, the study will generate data from PROs regarding change of KCCQ across time, adherence to HF therapies in clinical practice, and 6–Minutes Walking Tesst. Multivariate analyses will evaluate association between patients’ characteristics and interruption of treatment, adherence and HR–QoL. The interim analysis will be available in the first months of 2023. Conclusions The EVOLUTION–HF Italy study Il programma di studio EVOLUTION–HF supporterà la pratica clinica con dati originali sull‘uso nel mondo reale delle nuove terapie farmacologiche per l‘HFrEF.

Abstract In July 2022 C.M., a 58–year–old woman, was admitted to our Heart Failure Outpatient Clinic. Patient with permanent AF undergoing DOAC therapy, previous double mitral and tricuspid valve replacement with bioprosthesis. As comorbidities she had stage IIIb CKD, previous ischemic stroke without outcome, multifactorial anaemia, asthma, ulcerative rectocolitis non–responsive to biological therapy. Since April 2022 progressive reduction in exercise tolerance with dyspnoea for previously well–tolerated exertion, with finding of severe left ventricular systolic dysfunction (FE 25%) due to widespread hypokinesia previously unknown. In September angiographic control confirmed the absence of coronary artery disease. Amiodarone therapy was started for frequent runs of VT. Cardiac MRI confirmed FE 27% with fibrosis of the interventricular septum and lower basal wall of non–ischemic appearance. In view of the clinical–instrumental findings, a single–chamber ICD pacemaker was implanted and the therapy for heart failure with reduced FE was optimised with the introduction of Sacubitril/Valsartan (later discontinued due to hypotension), MRA and SGLT2–I (Empagliflozin). Due to the persistence of labile haemodynamic compensation, an indication was given to perform three cycles of Levosimendan infusion at our Day Hospital. The routine EGA taken during the first infusion cycle showed metabolic acidosis in the absence of significant worsening of renal function (Fig. 1) with mild hypobicarbonatemia and electrolytes in the normal range. On the assumption that the acidosis was secondary to the introduction of SGLT2–I (about two months earlier), Empagliflozin was discontinued. One week after discontinuation, the control EGA (Fig. 1) showed resolution of the acidosis, with a substantially stable glomerular filtrate, so that discontinuation of the drug was confirmed. Conclusions In the literature there are reviews and case reports of euglycaemic diabetic ketoacidosis (euDKA) in DM2 patients on SGLT2–I therapy although there are currently only hypotheses regarding the pathophysiological mechanism. The possibility of inducing acidosis with hypobicarbonatemia in the absence of worsening renal function is unclear. A ‘Fanconi–like‘ mechanism could be hypothesised with induction of type 2 tubular acidosis with bicarbonate loss due to glycosuria.

Pharmacotherapy of chronic heart failure with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF) remains challenging. We aimed to assess whether combined neuro-humoral modulation (NHM) (renin–angiotensin system inhibitors, betablockers, mineralocorticoid receptor antagonists) was differentially associated with outcome according to phenotype and age groups. Between 1999 and 2018 we recruited in a nationwide cardiology registry 4707 patients (HFmrEF n = 2298, HFpEF n = 2409) from three age groups: <65, 65–79 and 80+ years old. We analyzed clinical characteristics and 1 year all-cause mortality/cardiovascular hospitalization according to none/single, any double, or triple NHM. Prescription rates of no/single and triple NHM were 25.1% and 26.7% for HFmrEF; 36.5% and 17.9% for HFpEF patients, respectively. Older age was associated with higher prescription of no/single NHM in HFmrEF (ptrend = 0.001); the reverse was observed among HFpEF (ptrend = 0.005). Triple NHM increased over time in both phenotypes (all p for trend < 0.0001). Compared to no/single NHM, triple, but not double, NHM was associated with better outcomes in both HFmrEF (HR 0.700, 95%CI 0.505–0.969, p = 0.032) and HFpEF (HR 0.700, 95%CI 0.499–0.983, p = 0.039), with no interaction between NHM treatment and age groups (p = 0.58, p = 0.80, respectively). In a cardiology setting, among HF outpatients with EF > 40%, triple NHM treatment increased over time and was associated with better patient outcomes.

Because of the Coronavirus Disease 2019 (COVID-19) pandemic, we were forced to cancel scheduled visits for nearly 150 patients followed in our heart failure (HF) outpatient clinic. Therefore, we structured a telephone follow-up, developing a standardized 23-item questionnaire from which we obtained the Covid-19-HF score. The questionnaire was built to reproduce our usual clinical evaluation investigating a patient's social and functional condition, mood, adherence to pharmacological and nonpharmacological recommendations, clinical and hemodynamic status, pharmacological treatment, and need to contact emergency services. The score was used as a clinical tool to define patients' clinical stability and timing of the following telephone contact on the basis of the assignment to progressively increasing risk score groups: green (0–3), yellow (4–8), and red (≥9).Here we present our experience applying the score in the first 30 patients who completed the 4-week follow-up, describing baseline clinical characteristics and events that occurred in the period of observation.

Evidence has emerged demonstrating an association between treatment with certain tyrosine kinase inhibitors (TKIs) and vascular adverse events (VAEs) in chronic myeloid leukemia (CML). An increase in VAEs has been documented with ponatinib, nilotinib, and dasatinib but not with imatinib and bosutinib. We used an endothelial cell (HUVEC) model and an in-vivo hindlimb ischemia mouse model to study TKI-associated VAEs. We show that compared with control-treated cells, ponatinib increased HUVEC apoptosis by 9 7 % and inhibited their VEGF-induced migration by 35%. HUVEC tube formation was signifi cantly abrogated by ponatinib as evidenced by an 8 7 % reduction in tube number, 68% reduction in segment length, 50% reduction in junction number, and 55% increase in the occurrence of isolated segments. Ponatinib’s suppressive effect on tube formation was partially rescued by VEGFR2 overexpression, a known ponatinib off-target. Dasatinib also dramatically disrupted tube formation as evidenced by a 9 7 % reduction in tube number, 95% reduction in segment length, 88% reduction in junction number, and 300% increase in the occurrence of isolated segments. Nilotinib was associated with reduced cell viability, whereas imatinib and bosutinib did not affect these processes. Furthermore, HUVECs treated with ponatinib, dasatinib, and nilotinib revealed a differential angiogenesis-related gene expression pattern. The expression profi le of imatinib- and bosutinib-treated cells was similar to that of control-treated cells. In our in-vivo model, unilateral femoral artery excision was performed to induce ischemia and stimulate new blood vessel formation in TKI-treated mice. Imatinib-treated mice showed a similar recovery pattern to that of control mice as assessed via Doppler imager. Bosutinib- and dasatinib-treated mice showed an initial delayed recovery but reached an overall recovery of 85% within 28 days. In contrast, ponatinib-treated mice reached overall perfusion of 60% around day 7 without further improvement. These results are in line with the clinical VAE profi les of ponatinib, dasatinib, and nilotinib, implicating endothelial toxicity related to these TKIs and supporting a direct effect of these TKIs on vascular cells. However, the in-vivo effect of these TKIs on endothelial pathogenesis requires further investigation. Understanding TKI-induced VAE pathogenesis could contribute to the future development of safer next-generation TKIs and could potentially infl uence TKI-personalized tailoring for CML patients. tio n : Prohibitin level was measured using an enzyme-linked immunosorbent assay. Mai n Outco m e Measures: We reported a signifi cant value of prohibtin level in CML patients and a signifi cant correlation between its level and disease activity and response to treatment. Results: We have demonstrated that prohibitin levels were signifi cantly higher in patients with CML than in the control participants (P=0.002). Prohibitin levels were signifi cantly higher in CML patients with an active disease status (P=0.001). In addition, signifi cantly higher levels of prohibitin in CML patients were associated with poor response to fi rst-generation TKIs (P=0.001). A serum level of prohibitin higher than 289 is a good predictor of poor response to fi rst-generation TKIs as per response assessment by PCR for BCR-ABL (area under the curve=0.6 7 , sensitivity and specifi city 58.33 and 80.56, respectively). Co n clusio n s: Prohibitin is overexpressed in CML patients and has a possible impact on disease activity and response to treatment in CML patients that warrants further investigations. antibodies by a semi-quantitative immunoassay (ELISA) which was considered positive at cut-off index (CI)>1. Other available tests for antibody detection were allowed as well. Results: Nighty-fi ve chronic phase CML patients with a median (Me) age 54 years (range 29-89), received Sputnik V (DEC.2020–JUL.2021), 40(42%) were males. Me CML duration was 8 years (range 0-20), 7 5( 7 9%) patients received TKIs at vaccination, 20(21%) were off-therapy: 1 7 (18%) in treatment-free remission, 3(3%) with CML onset. Seventeen (18%) patients had a prior history of COVID-19. AEs were reported in 53(56%) patients: local pain/discomfort -30(31.5%), weakness/drowsiness -29 (30.5%), fever and/or chills -28(29%), other AEs -10(12%): headache, heartbeat, limbs/back pain, herpes reactivation. General reactions stopped in 1-2 days. No severe or life-threatening AEs were observed. Antibodies were detected in 66(93%) of 7 1 patients by any method, Me time after 2nd injection was 31 days (range 5-1 7 9). ELISA test was positive in 48(94%) of 55 tested patients with Me CI 7 . 7 (range 1.1-12), consistent with values of healthy people. Three of 7 negative by ELISA patients (Me age 58 years (range 40- 7 0)) revealed antibodies by other tests with levels slightly above threshold. A very weak reverse correlation of the antibody levels with post-vaccination time (r =- 0.32) and with age (r =- 0.28) was observed. Co n clusio n s: Sputnik V vaccine showed no unexpected or severe AEs in CML patients. Seroconversion rate of about 93-94% was close to the 3-phase trial data (94-9 7 %). No strong age-dependent/time-dependent correlation of antibody levels was found in the tested time period. Sputnik V vaccination is safe and acceptable in CML patients. vaccination, 9, n=22), intermediate-risk (score 10-15, n=2 7 ) and high risk (score  16, n=24). The low-risk group had a signifi cantly higher rate of CCyR on TKI-3L compared to intermediate or high-risk groups (14/22[64%] vs 7 /2 7 [26%] vs 1/24[4%], p<0.05). There were 19(26%) deaths. Estimated 1-year and 5-year OS was 95% and 65% respectively. All CML-related deaths(n=14), as well as transformation to BC (n=13), occurred in intermediate- and high-risk groups. Co n clusio n s: Nearly a third of pts obtained CCyR on TKI-3L in our study. Most pts were alive at 5 years. Younger pts with any CyR on previous TKIs and at baseline had favorable prognosis. The use of TKI-3L is justifi ed in low-risk groups and may be used in transplant-eligible pts.

Abstract Background Although older patients with heart failure (HF) with reduced ejection fraction enrolled in PARADIGM–HF showed a good tolerance to sacubitril/valsartan (Sa/Va), more real–word data are needed to define their tolerability in this population. Aim: To describe the Sa/Va tolerability and titration in older HFrEF patients followed by our HF outpatient. Methods HFrEF patients aged ≥65 years and treated with Sa/Va from November 2016 to June 2021 were enrolled, assessing Sa/Va tolerability at six months and its clinical and hemodynamic effects. Results We enrolled 101 patients with a mean age of 78 years (⁓20% female). The aetiology was ischemic in 59% of cases while the mean ejection fraction was 31%. Sa/Va was prescribed at the starting dose (24/26mg) and intermediate dose (49/51mg) in 91% and 9% of cases, respectively. After six months, 9 of the 100 patients still alive had discontinued treatment with Sa/Va (4 for symptomatic hypotension, 3 for suspected allergic reaction and 2 for worsening renal function). Of the 91 patients still on therapy, only 17 had reached the target dose (97/103mg) while 28 were at the intermediate dose (Figure 1). Symptomatic hypotension (62%), hyperkalaemia (15%) and worsening of renal function (4%) were the main causes of maintaining Sa/Va therapy at the starting dose; note, in 15% of cases a specific cause of non–titration was not identified. Comparing HF treatment between starting dose vs higher–dose patients, after six months in low–dose patients there was a slight improvement in mineralcorticosteroid receptor antagonist (MRA) prescription and in combination therapy (Sa/Va, beta–blocker and MRA) while in patients at higher–doses there was a significant decrease (Figure 2). In patients still receiving Sa/Va, significant clinical improvement was observed while renal function, K+ levels and systolic blood pressure remained stable (Figure 3). Conclusions After six months of treatment, Sa/Va was well tolerated in most of our older patients and used in combination with a beta–blocker and an MRA in a high percentage of cases, although a reduction in MRA prescription is observed in patients taking higher dosages of Sa/Va. In addition, there was a marked improvement in the clinical variables.

Abstract Background Non-ST-elevation myocardial infarction (NSTEMI) is a condition that is associated with a high morbidity and mortality burden. The aim of the present study is to analyze clinical characteristics and outcomes of a large contemporary population of NSTEMI patients according to treatment strategy in a large administrative database. Methods This retrospective observational study included patients living in the region of Tuscany, aged 18 years or older who were discharged from a regional hospital with a diagnosis of NSTEMI (principal diagnosis ICD-9-CM codes 410.7 or 411.1 in HDA) between January 2016 and December 2018. According to management strategy patients were classified in two main groups: a conservative strategy (CON) group and an invasive strategy (INV) group which was further categorized in three subgroups: a PCI group, a CABG group and a group were patients were invasively managed but medically treated. Results The study population was composed by 15.208 patients. Mean age was 76±9 years, with 50% aged 75+ years, females were 38.5%. Management strategies groups composition was: CON strategy 24.9% and among INV strategy (75.1%) 67.3% were treated by PCI, 8.8% by CABG and 24% were invasively managed but medically treated. Compared to INV managed patients, patients in the CON group were older (mean age 85 vs 72 years, p<0.0001), more frequently female (54% vs 33%, p<0.0001), had a higher cardiovascular and non-cardiovascular comorbidity burden (eg. hypertension, diabetes, heart failure, atrial fibrillation, renal insufficiency, cancer, dementia and COPD, all <0.0001). In-hospital, 30-days and 1-year all-cause mortality rates (Figure) were 3%, 4.9% and 15.3% resulting significantly higher in the CON management strategy group compared to the INV strategy group: 8.9% vs 1.1; 14.0 vs 1.9%; all p<0.0001. Analyzing all-cause mortality rates among the three INV subgroups we found no differences both in-hospital and at 30 days, while at 1-year we found, all-cause mortality there was a significant difference among the three groups with a slightly higher mortality rate in the INV medically treated group compared to the PCI and the CABG subgroups: 8.9% vs 7.2% vs 7.5% respectively, p=0.011. Conclusions Real-world evidence show that patients with NSTEMI have significantly different characteristics and outcomes according to management strategy. Patients managed non-invasively have more complex features and worse outcomes both in-hospital and post-discharge. Patients which were managed invasively but medically treated represent an interesting subgroup which may deserve further evaluation. Funding Acknowledgement Type of funding sources: None.