General consensus on multimodal functions and validation analysis of perinatal derivatives for regenerative medicine applications.

Perinatal tissues, such as placenta and umbilical cord contain a variety of somatic stem cell types, spanning from the largely used hematopoietic stem and progenitor cells to the most recently described broadly multipotent epithelial and stromal cells. As perinatal derivatives (PnD), several of these cell types and related products provide an interesting regenerative potential for a variety of diseases. Within COST SPRINT Action, we continue our review series, revising and summarizing the modalities of action and proposed medical approaches using PnD products: cells, secretome, extracellular vesicles, and decellularized tissues. Focusing on the brain, bone, skeletal muscle, heart, intestinal, liver, and lung pathologies, we discuss the importance of potency testing in validating PnD therapeutics, and critically evaluate the concept of PnD application in the field of tissue regeneration. Hereby we aim to shed light on the actual therapeutic properties of PnD, with an open eye for future clinical application. This review is part of a quadrinomial series on functional/potency assays for validation of PnD, spanning biological functions, such as immunomodulation, anti-microbial/anti-cancer, anti-inflammation, wound healing, angiogenesis, and regeneration

Echocardiographically defined haemodynamic categorization predicts prognosis in ambulatory heart failure patients treated with sacubitril/valsartan

Aim: Echo-derived haemodynamic classification, based on forward-flow and left ventricular (LV) filling pressure (LVFP) correlates, has been proposed to phenotype patients with heart failure and reduced ejection fraction (HFrEF). To assess the prognostic relevance of baseline echocardiographically defined haemodynamic profile in ambulatory HFrEF patients before starting sacubitril/valsartan. Methods and results: In our multicentre, open-label study, HFrEF outpatients were classified into 4 groups according to the combination of forward flow (cardiac index; CI:< or ≥2.0 L/min/m2 ) and early transmitral Doppler velocity/early diastolic annular velocity ratio (E/e': ≥ or <15): Profile-A: normal-flow, normal-pressure; Profile-B: low-flow, normal-pressure; Profile-C: normal-flow, high-pressure; Profile-D: low-flow, high-pressure. Patients were started on sacubitril/valsartan and followed-up for 12.3 months (median). Rates of the composite of death/HF-hospitalization were assessed by multivariable Cox proportional-hazards models. Twelve sites enrolled 727 patients (64 ± 12 year old; LVEF: 29.8 ± 6.2%). Profile-D had more comorbidities and worse renal and LV function. Target dose of sacubitril/valsartan (97/103 mg BID) was more likely reached in Profile-A (34%) than other profiles (B: 32%, C: 24%, D: 28%, P < 0.001). Event-rate (per 100 patients per year) progressively increased from Profile-A to Profile-D (12.0%, 16.4%, 22.9%, and 35.2%, respectively, P < 0.0001). By covariate-adjusted Cox model, profiles with low forward-flow (B and D) remained associated with poor outcome (P < 0.01). Adding this categorization to MAGGIC-score and natriuretic peptides, provided significant continuous net reclassification improvement (0.329; P < 0.001). Intermediate and high-dose sacubitril/valsartan reduced the event's risk independently of haemodynamic profile. Conclusions: Echocardiographically-derived haemodynamic classification identifies ambulatory HFrEF patients with different risk profiles. In real-world HFrEF outpatients, sacubitril/valsartan is effective in improving outcome across different haemodynamic profiles

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Previsione in fase acuta del rimodellamento ventricolare sinistro post-infartuale nel paziente con STEMI.

SCOPO. Verificare, mediante ecocardiografia trans toracica, se le variazioni di spessore della parete infartuata in pazienti con STEMI trattati con PCI primaria entro 12 h dall’evento, possono rappresentare un parametro indicativo di danno da ischemia-riperfusione, al fine di stimarne il ruolo predittivo nei confronti dell’outcome funzionale ventricolare e del rimodellamento cardiaco post-infartuale a 1 mese. MATERIALI E METODI. È stato condotto uno studio clinico prospettico nel quale sono stati arruolati 48 pazienti (37 maschi, 11 femmine, età media 62± 13 anni) con STEMI, trattato con p-PCI entro 12 ore dall’insorgenza dei sintomi, e che non avevano infarto pregresso o precedenti interventi di rivascolarizzazione coronarica. I pazienti sono stati sottoposti a ecocardiogramma transtoracico entro 12 ore dall’angioplastica primaria, in pre-dimissione e a un mese di follow-up. Fra i vari parametri ecocardiografici, sono stati in particolare valutati lo spessore telediastolico della parete miocardica infartuata (i-EDWT), lo spessore telediastolico della parete miocardica controlaterale irrorata da un’arteria coronaria angiograficamente indenne (c-EDWT), la frazione di eiezione (FE), il Wall MotionScore Index (WMSI) e il volume telediastolico del ventricolo sinistro (EDV).È stata inoltre rivalutato l’esame coronarografico eseguito in urgenza e sono stati valutati i flussi coronarici secondo il TIMI score. Mediante valutazione statistica si è giunti a prendere come riferimento un valore di cut- off di 3 mm di variazione di spessore delle parete tele diastolica e i pazienti sono stati suddivisi in due gruppi ( di 3 mm). E’ stata eseguita l’analisi statistica sui 2 sottogruppi valutando le modificazioni di EF, LVEDV e mettendole in correlazione con l’EDWT. RISULTATI. L’i-EDWT è aumentato significativamente in pre-dimissione, rispetto al valore evidenziato entro 12 ore dalla p-PCI, con un incremento (i-delta di 2.4 ± 1.9 mm (p3 mm, si nota come questi abbiano un valore assoluto di EF a 1 mese ridotta rispetto a quei pazienti in cui non è stata evidenziato tale incremento di spessore (i-DELTA 3 mm. Non è stata trovata una correlazione statisticamente significativa tra flusso coronarico post PCI primaria mediante la classificazione TIMI score e lo spessore della parete infartuata (iEDWT) ma si è evidenziato che i pazienti che hanno un TIMI<3 , tendono ad avere uno spessore predimissione aumentato. CONCLUSIONI. Nei pazienti con STEMI trattato con p-PCI, l’aumento di spessore della parete miocardica, rilevato mediante ecocardiografia transtoracica, si realizza soltanto nella regione infartuata, fornendo un semplice,ripetibile e non invasivo biomarker di danno da riperfusione. Il fatto che l’aumento di spessore telediastolico della parete miocardica nel paziente con STEMI trattati con p-PCI, si osservi soltanto nella regione infartuata, avvalora l’ipotesi che esso sia espressione di edema intramiocardico secondario a danno da ischemia-riperfusione. La variazione di spessore della parete infartuata (i-DELTA) correla inversamente con la frazione d’eiezione a un mese. Un incremento di spessore > 3 mm si associa a una maggiore compromissione della funzione sistolica ventricolare sinistra. I pazienti con TIMI score < 3 tendono ad avere un ispessimento parietale telediastolico maggiore in fase di predimissione

Transcatheter edge-to-edge mitral valve repair with PASCAL system: early results of a single-centre experience.

Mitral regurgitation (MR) is the second most frequent heart valve disease in the general population. Data suggest that only a minority of affected patients undergoes surgical treatment. The most important patient characteristics associated with a decision to refuse the surgery are increased operative risk due to age, comorbidities and impaired left ventricular function. In the past two decades transcatheter mitral valve edge-to-edge repair (TEER) has become a valuable and established treatment option in this high-risk population. The MitraClip system is the most widely used technology for TEER. Nevertheless, percutaneous repair in more complex valve pathologies beyond anatomic criteria tested in clinical trials has resulted in a considerable number of patients who need re-intervention. Recently, the PASCAL Transcatheter Valve Repair System has been added to the armamentarium of TEER therapies and is expected to expand the treatable patient population by offering unique features. Data on the real-world performance of the PASCAL system outside of clinical studies are limited. The aim of the present study is to characterize the real-world performance and clinical outcomes of TEER with the PASCAL System in a cohort of patients with functional and degenerative mitral regurgitations. A total of 45 consecutive patients with symptomatic moderate-to-severe and severe MR were treated in our Institute using the PASCAL device. Primary performance endpoint included procedural success and clinical success. The primary safety endpoint was the rate of MAEs at 30 days and 6 months. Between January 2020 and June 2021, 45 patients with symptomatic moderate-to-severe and severe MR were enrolled. The mean age was 79 years old. Patients were in New York Heart Association (NYHA) functional class III or IV, with 78% functional and 22% degenerative MR aetiology. At 30 days the MAE rate was 4%, 25 patients (56%) were in NYHA functional class I and 18 patients (40%) were in NYHA functional class II (p < 0.0001 vs baseline). The average six-minute walk distance (6MWD) increased 65 metres (p < 0.001 vs baseline). After six months of follow-up, the MAE rate was 5% with an all-cause mortality rate of 7% with no occurrence of stroke. The improvement of symptoms and functional capacity in the overall population and in both aetiologies, was maintained at 6 months with 40/42 (95%) patients in NYHA functional class I or II (p < 0.001 vs baseline) and by 80 metres (p < 0.0001) increase in mean 6-minute walking distance. The EQ-5D Health Questionnaire scores improved significantly from baseline to 6 months (p < 0.0001). In conclusion, in a real-world population, the treatment of severe MR can be successfully and safely treated with the PASCAL device regardless of aetiologies. This intervention resulted in a sustained MR reduction, improvement in exercise capacity and quality of life on a short-term follow-up

Left atrial stiffness predicts cardiac events in patients with heart failure and reduced ejection fraction : The impact of diabetes

Background: The aim of this study was to investigate the relationship between diabetes mellitus (DM) and left atrial (LA) remodelling in a group of patients with heart failure and reduced ejection fraction (HFrEF), and their combined impact on cardiac events (CE). Methods: This study included 136 consecutive HFrEF patients (65 +/- 11 years), 36 had DM, and 86 had increased LA stiffness (LASt). All patients underwent complete conventional and tissue Doppler echocardiographic measurements were made including LA volumes and function. LASt was calculated using the formula: LASt = E/e' ratio / PALS. Results: At 55 +/- 37 months follow-up, free survival from CE was 69% in patients without DM and 44.4% in those with DM (p &lt; .0001). The CE free survival was lower in patients with increased LASt compared to normal LASt, (50 versus. 80%, p &lt; .001), irrespective of the presence of DM (27 versus. 71%, p &lt; .001).The best cut-off value of LASt for predicting CE in the group as a whole was &gt;= 0.82% [81% sensitivity, 72% specificity and AUC 0.82 (p &lt; .001)]. LASt &gt;= 0.82% also predicted CE in no DM patients [78% sensitivity, 71% specificity and AUC 0.80 (p &lt; .001)] and was a stronger predictor in DM patients [85% sensitivity, 71% specificity and AUC = 0.847 (p &lt; .001)]. Conclusion: High LA stiffness is associated with poor clinical outcome in patients with HFrEF. Diabetes has an additional incremental value in determining clinical outcome in those patients

Combining echo-derived haemodynamic phenotypes and myocardial strain for risk stratification of chronic heart failure with reduced ejection fraction

Echocardiography has shown to categorize heart failure (HF) patients according to haemodynamic profiles. Whether left ventricular (LV) global longitudinal strain (LV-GLS) could integrate echo-derived haemodynamic profiles to risk stratify chronic HF patients is still unknown

Echocardiography of right ventricular-arterial coupling predicts survival of elderly patients with heart failure and reduced to mid-range ejection fraction

Echocardiography of right ventricular (RV)-arterial coupling obtained by the estimation of the ratio of the longitudinal annular systolic excursion of the tricuspid annular plane and pulmonary artery systolic pressure (TAPSE/PASP) has been found to be a remarkable prognostic indicator in patients with HF. Our aim was to evaluate the impact of TAPSE, PASP and their ratio in the prognostic stratification of outpatients with HF aged ≥70 years and reduced to mid-range ejection fraction (EF). A complete echocardiographic examination was performed in 400 outpatients with chronic HF and left ventricular (LV) EF ≤50% who averaged 77 years in age. During a median follow-up period of 25 months (interquartile range: 8-46), there were 135 cardiovascular deaths. Two different Cox regression models were evaluated, one including TAPSE and PASP, separately, and the other with TAPSE/PASP. In the first model, LV end-systolic volume index, age, no angiotensin converting enzyme (ACE) inhibitor use, TAPSE, PASP and gender were found to be independently associated with the outcome after adjustment for demographics, clinical, biochemical, echocardiographic data. In the second model, TAPSE/PASP resulted the most important independent predictor of outcome (hazard ratio [HR]:0.07, p<0.0001) followed by LV end-systolic volume index, no ACE inhibitor use, age and gender. The use of the variable TASPE/PASP improved the predictive value of the new multivariable model (area under the curve [AUC] of 0.74 vs AUC of 0.71; p<0.05). TASPE/PASP improved the net reclassification (NRI = 14.7%; p<0.01) and the integrated discrimination (IDI = 0.04; p<0.01). In conclusion, the study findings showed that assessment of RV-arterial coupling by TAPSE/PASP was of major importance to assess the prognosis of patients with chronic HF and LV EF ≤50% aged ≥70 years

The added value of exercise stress echocardiography in patients with heart failure

Doppler echocardiography can provide reliable and repeatable measures of cardiac index (CI), whereas lung ultrasound (LUS) represents a quantitative approach to assess pulmonary congestion. We tested the hypothesis that simultaneous assessment of CI and LUS during exercise stress echocardiography (ESE) may define heart failure (HF) outpatients with different risk of adverse outcome. Standard transthoracic echocardiography and LUS (B-lines) evaluation were assessed during semisupine ESE. CI and B-lines were measured at baseline and peak exercise. Resting plasma B-type natriuretic peptide levels were also evaluated. We enrolled 105 HF patients (87 males; age 62 ± 11 years; New York Heart Association class I to III) with reduced left ventricular ejection fraction (30 ± 7%). Patients were classified into 4 profiles: (1) peak CI ≥4.0 l/min/m 2 and peak B-lines &lt;15 (no evidence of congestion or hypoperfusion, n = 47); (2) peak CI ≥4.0 l/min/m 2 and peak B-lines ≥15 (congestion with adequate perfusion, n = 23); (3) peak CI &lt;4.0 l/min/m 2 and peak B-lines &lt;15 (hypoperfusion without congestion, n = 13); and (4) peak CI &lt;4.0 l/min/m 2 and peak B-lines ≥15 (congestion and hypoperfusion, n = 22). There were 21 cardiovascular deaths and 18 hospitalizations for worsening HF during a median follow-up of 29 months. Multivariate predictors of the combined end point were peak hemodynamic profiles (hazard ratio [HR] 1.62, 95% confidence interval [CI] 1.19 to 2.21; p = 0.002), B-type natriuretic peptide (HR 1.00, 95% CI 1.00 to 1.01; p = 0.001), and rest E/e’ (HR 1.09, 95% CI 1.03 to 1.15; p = 0.002). Survival analysis showed a worse survival in patients with ESE-derived D profile, followed by patients with C, B, and A profile (log-rank: chi-square = 40.5; p &lt;0.0001). In conclusion, dual evaluation of CI and LUS during ESE is useful for risk stratification of HF patients with reduced ejection fraction. Evidence of pulmonary congestion and low CI at peak ESE identifies a subgroup with a very high risk of adverse outcome

Speckle Tracking-Derived Left Atrial Stiffness Predicts Clinical Outcome in Heart Failure Patients with Reduced to Mid-Range Ejection Fraction

Background and Aim: Left atrial stiffness (LASt) is an important marker of cardiac function, especially in patients with heart failure (HF); it explains symptoms on the basis of pressure transfer to the pulmonary circulation. The aim of this study was to evaluate the relationship between LASt and cardiac events (CE) in HF patients with reduced to mid-range ejection fraction. Methods: The study included 215 consecutive ambulatory HF patients with ejection fraction (EF) &lt; 50% (162 HF reduced EF and 53 HF mid-range EF) of mean age 66 +/- 11 years and 24.4% females. Peak LA strain (PALS) was measured by speckle tracking echocardiography and E/e' recorded from the apical four-chamber view. Non-invasive LASt was calculated using the equation: LASt = E/e' ratio/PALS. Documented cardiac events (CE) were HF hospitalization and cardiac death. Results: During a median follow up of 41 +/- 34 months, 65 patients (30%) had CE. In multivariate analysis model, only raised LV filling pressure (E/e') (OR = 0.292, (95% CI 0.099 to 0.859), p = 0.02), peak pulmonary artery pressure (PAP) (OR = 1.050 (1.009 to 1.094), p = 0.01), PALS (OR = 0.932 (0.873 to 0.994), p = 0.02) and LASt (OR = 3.781 (1.144 to 5.122), p = 0.001) independently predicted CE. LASt &gt;= 0.76% was the most powerful predictor of CE, with 80% sensitivity and 73% specificity (AUC 0.82, CI = 0.73 to 0.87, p &lt; 0.001) followed by PALS &lt;= 16%, with 74% sensitivity and 72% specificity (AUC 0.77, CI = 0.71 to 0.84, p &lt; 0.001). These results were consistent irrespective of EF (p &lt; 0.05). Conclusion: In this cohort of ambulatory HFrEF and HFmrEF patients, LASt proved the most powerful predictor of clinical outcome