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The administration of extracellular vesicles (EV) from mesenchymal stromal cells (MSC) is a promising cell-free nanotherapy for tissue repair after myocardial infarction (MI). However, the optimal EV delivery strategy remains undetermined. Here, we designed a novel MSC-EV delivery, using 3D scaffolds engineered from decellularised cardiac tissue as a cell-free product for cardiac repair. EV from porcine cardiac adipose tissue-derived MSC (cATMSC) were purified by size exclusion chromatography (SEC), functionally analysed and loaded to scaffolds. cATMSC-EV markedly reduced polyclonal proliferation and pro-inflammatory cytokines production (IFNγ, TNFα, IL12p40) of allogeneic PBMC. Moreover, cATMSC-EV recruited outgrowth endothelial cells (OEC) and allogeneic MSC, and promoted angiogenesis. Fluorescently labelled cATMSC-EV were mixed with peptide hydrogel, and were successfully retained in decellularised scaffolds. Then, cATMSC-EV-embedded pericardial scaffolds were administered in vivo over the ischemic myocardium in a pig model of MI. Six days from implantation, the engineered scaffold efficiently integrated into the post-infarcted myocardium. cATMSC-EV were detected within the construct and MI core, and promoted an increase in vascular density and reduction in macrophage and T cell infiltration within the damaged myocardium. The confined administration of multifunctional MSC-EV within an engineered pericardial scaffold ensures local EV dosage and release, and generates a vascularised bioactive niche for cell recruitment, engraftment and modulation of short-term post-ischemic inflammation.

Abstract Aims This study aimed to evaluate psychometric properties of the Spanish version of the Thirst Distress Scale for patients with Heart Failure (TDS‐HF) and to describe thirst distress‐associated factors in outpatients at a heart failure (HF) clinic in Spain. Thirst is common in patients with HF, but thirst distress has rarely been addressed and may significantly decrease quality of life. Methods and results A cross‐sectional study was performed assessing perceived thirst distress by patients with HF during the preceding 3 days, with the TDS‐HF (scores 8 to 40). Univariable and multivariable linear regression analyses were performed to identify variables independently associated with thirst distress. Three‐hundred two HF outpatients were included (age 67 ± 12 years, 74% male, HF duration 82 ± 75 months, left ventricular ejection fraction 42 ± 14%). Most patients were on treatment with fluid restriction (99%), sodium restriction (99%), and diuretics (70%). The psychometric evaluation of the Spanish version of the TDS‐HF showed satisfactory item‐total and inter‐item correlations (range from 0.77 to 0.85 and 0.60 to 0.84, respectively), and internal consistency was 0.95 (Cronbach's alpha). The majority perceived mild to moderate thirst distress, and 18% perceived it as high or severe. The mean score obtained was 16.2 ± 9.3 (median 13, Q1–Q3 8–20). Higher serum urea {beta coefficient 1.6 [95% confidence interval (CI) 0.267 to 2.92], P = 0.019} and lower potassium [beta coefficient −3.63 (85% CI −6.32 to −0.93), P = 0.009] remained significantly associated with thirst distress in the multivariable analysis, together with the dose of diuretics [beta coefficient 2.98 (95% CI 1.37 to 4.59), P

Abstract Aims Reverse remodelling (RR) is the recovery from left ventricular (LV) dilatation and dysfunction. Many arbitrary criteria for RR have been proposed. We searched the criteria with the strongest prognostic yield for the hard endpoint of cardiovascular death. Methods and results We performed a systematic literature search of diagnostic criteria for RR. We evaluated their prognostic significance in a cohort of 927 patients with LV ejection fraction (LVEF) 10 U and (ii) LVEF increase ≥1 category [severe (LVEF ≤ 30%), moderate (LVEF 31–40%), mild LV dysfunction (LVEF 41–55%), and normal LV function (LVEF ≥ 56%)]. The same two criteria yielded independent prognostic significance and improved risk reclassification even in patients with more severe systolic dysfunction, namely, those with LVEF 10 U and LVEF increase ≥1 category displayed a greater prognostic value than LVESV reduction ≥15%, both in the whole cohort and in the subgroups with LVEF 10 U independently predicted cardiovascular death over Model 1 and LVESV reduction ≥15% (hazard ratio 0.40, 95% confidence interval 0.18–0.90, P = 0.026), while LVESV reduction ≥15% did not independently predict cardiovascular death (P = 0.112). Conclusions Left ventricular ejection fraction increase >10 U and LVEF increase ≥1 category are stronger predictors of cardiovascular death than the most commonly used criterion for RR, namely, LVESV reduction ≥15%.

ObjectiveTo assess the arrhythmic safety profile of the adipose graft transposition procedure (AGTP) and its electrophysiological effects on post-myocardial infarction (MI) scar.BackgroundMyocardial repair is a promising treatment for patients with MI. The AGTP is a cardiac reparative therapy that reduces infarct size and improves cardiac function. The impact of AGTP on arrhythmogenesis has not been addressed.MethodsMI was induced in 20 swine. Contrast-enhanced magnetic resonance (ce-MRI), electrophysiological study (EPS), and left-ventricular endocardial high-density mapping were performed 15 days post-MI. Animals were randomized 1:1 to AGTP or sham-surgery group and monitored with ECG-Holter. Repeat EPS, endocardial mapping, and ce-MRI were performed 30 days post-intervention. Myocardial SERCA2, Connexin-43 (Cx43), Ryanodine receptor-2 (RyR2), and cardiac troponin-I (cTnI) gene and protein expression were evaluated.ResultsThe AGTP group showed a significant reduction of the total infarct scar, border zone and dense scar mass by ce-MRI (p = 0.04), and a decreased total scar and border zone area in bipolar voltage mapping (p < 0.001). AGTP treatment significantly reduced the area of very-slow conduction velocity (

Abstract The use of sodium-glucose co-transporter 2 inhibitors to treat heart failure with preserved ejection fraction (HFpEF) is under investigation in ongoing clinical trials, but the exact mechanism of action is unclear. Here we aimed to use artificial intelligence (AI) to characterize the mechanism of action of empagliflozin in HFpEF at the molecular level. We retrieved information regarding HFpEF pathophysiological motifs and differentially expressed genes/proteins, together with empagliflozin target information and bioflags, from specialized publicly available databases. Artificial neural networks and deep learning AI were used to model the molecular effects of empagliflozin in HFpEF. The model predicted that empagliflozin could reverse 59% of the protein alterations found in HFpEF. The effects of empagliflozin in HFpEF appeared to be predominantly mediated by inhibition of NHE1 (Na+/H+ exchanger 1), with SGLT2 playing a less prominent role. The elucidated molecular mechanism of action had an accuracy of 94%. Empagliflozin’s pharmacological action mainly affected cardiomyocyte oxidative stress modulation, and greatly influenced cardiomyocyte stiffness, myocardial extracellular matrix remodelling, heart concentric hypertrophy, and systemic inflammation. Validation of these in silico data was performed in vivo in patients with HFpEF by measuring the declining plasma concentrations of NOS2, the NLPR3 inflammasome, and TGF-β1 during 12 months of empagliflozin treatment. Using AI modelling, we identified that the main effect of empagliflozin in HFpEF treatment is exerted via NHE1 and is focused on cardiomyocyte oxidative stress modulation. These results support the potential use of empagliflozin in HFpEF.

AimsCardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort.Methods and resultsThis multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death.ConclusionThe primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

BackgroundLeft ventricular (LV) remodeling consists in maladaptive changes in cardiac geometry and function following an insult such as ST-segment elevation myocardial infarction (STEMI). Interventions able to prevent LV remodeling after a STEMI are expected to improve the outcome of this condition. Paroxetine has inhibitory effects on GRK2, also known as beta-adrenergic receptor kinase 1 (ADRBK1). This drug does not yield beneficial effects on LV remodeling in patients with STEMI and LV ejection fraction ≤ 45%.MethodsWe compared the molecular effects of paroxetine and drugs for neurohormonal antagonism (beta-blockers, angiotensin converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoid receptor antagonists), using a bioinformatic approach integrating transcriptomic data in a swine model of post-MI and available evidence from the literature and massive public databases.ResultsAmong standard therapies for MI, beta-blockers are the only ones acting directly upon GKR2, but the mechanism of action overlaps with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with respect to the AT2R-mediated anti-hypertensive response. Moreover, beta-blockers could have anti-fibrotic and anti-inflammatory effects through the regulation of myocyte-specific enhancer factors, endothelins and chemokines.ConclusionThe additive benefit of paroxetine on the background of the standard therapy for STEMI, which includes beta-blockers, is expected to be limited. Nonetheless, paroxetine becomes particularly interesting when a beta-blocker is contraindicated (for example, in hypotensive individuals) or poorly tolerated.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disorder developing from multiple aetiologies with overlapping pathophysiological mechanisms. HFpEF diagnosis may be challenging, as neither cardiac imaging nor physical examination are sensitive in this situation. Here, we review biomarkers of HFpEF, of which the best supported are related to myocardial stretch and injury, including natriuretic peptides and cardiac troponins. An overview of biomarkers of inflammation, extracellular matrix derangements and fibrosis, senescence, vascular dysfunction, anaemia/iron deficiency and obesity is also provided. Finally, novel biomarkers from -omics technologies, including plasma metabolites and circulating microRNAs, are outlined briefly. A cardiac-centred approach to HFpEF diagnosis using natriuretic peptides seems reasonable at present in clinical practice. A holistic approach including biomarkers that provide information on the non-cardiac components of the HFpEF syndrome may enrich our understanding of the disease and may be useful in classifying HFpEF phenotypes or endotypes that may guide patient selection in HFpEF trials.

Abstract A higher neprilysin activity has been suggested in women. In this retrospective analysis, we evaluated the association of sex and body mass index (BMI) with soluble neprilysin (sNEP) and recurrent admissions among 1021 consecutive HF outpatients. The primary and secondary endpoints were the number of HF hospitalizations and all-cause mortality, respectively. The association between sNEP with either endpoint was evaluated across sex and BMI categories (≥ 25 kg/m2 vs.

Abstract Evidence regarding any association of HDL-particle (HDL-P) derangements and HDL-cholesterol content with cardiovascular (CV) death in chronic heart failure (HF) is lacking. To investigate the prognostic value of HDL-P size (HDL-Sz) and the number of cholesterol molecules per HDL-P for CV death in HF patients. Outpatient chronic HF patients were enrolled. Baseline HDL-P number, subfractions and HDL-Sz were measured using 1H-NMR spectroscopy. The HDL-C/P ratio was calculated as HDL-cholesterol over HDL-P. Endpoint was CV death, with non-CV death as the competing event. 422 patients were included and followed-up during a median of 4.1 (0–8) years. CV death occurred in 120 (30.5%) patients. Mean HDL-Sz was higher in CV dead as compared with survivors (8.39 nm vs. 8.31 nm, p

Subjects with type 2 diabetes mellitus (T2D) are at increased risk for heart failure (HF). The cardiac-specific (FABP3) and adipose-tissue-specific (FABP4) types of the fatty acid binding proteins have been associated with both all-cause and cardiovascular (CV) mortality. The aim of this study was to explore the prognosis value of FABP3 and FABP4 in ambulatory subjects with chronic HF (CHF), with and without T2D. A prospective study involving 240 ambulatory CHF subjects was performed. Patients were followed-up for a mean of 5.78 ± 3.30 years and cause of death (if any) was recorded. Primary endpoints were defined as all-cause and CV death, and a composite endpoint that included CV death or hospitalization for HF was included as a secondary endpoint. Baseline serum samples were obtained and the serum FABP3 and FABP4 concentrations were assessed by sandwich enzyme-linked immunosorbent assay. Survival analysis was performed with multivariable Cox regressions, using Fine and Gray competing risks models when needed, to explore the prognostic value of FABP3 and FABP4 concentrations, adjusting for potential confounders. Type 2 diabetes mellitus was highly prevalent, accounting for 47.5% for total subjects with CHF. Subjects with T2D showed higher mortality rates (T2D: 69.30%; non-T2D: 50.79%, p = 0.004) and higher serum FABP3 (1829.3 (1104.9–3440.5) pg/mL vs. 1396.05 (820.3–2362.16) pg/mL, p = 0.007) and FABP4 (45.5 (27.6–79.8) ng/mL vs. 34.1 (24.09–55.3) ng/mL, p = 0.006) concentrations compared with non-T2D CHF subjects. In the whole study cohort, FABP3 was independently associated with all-cause death, and both FABP3 and FABP4 concentrations were associated with CV mortality. The predictive values of these two molecules for all-cause (FABP3: HR 1.25, 95% CI 1.09–1.44; p = 0.002. FABP4: HR 2.21, 95% CI 1.12–4.36; p = 0.023) and CV mortality (FABP3: HR 1.28, 95% CI 1.09–1.50; p = 0.002. FABP4: HR 4.19, 95% CI 2.21–7.95; p < 0.001) were only statistically significant in the subgroup of subjects with T2D. Notably, FABP4 (HR 2.07, 95% CI 1.11–3.87; p = 0.022), but not FABP3, also predicted the occurrence of the composite endpoint (death or hospitalization for HF) only in subjects with T2D. All these associations were not found in CHF subjects without T2D. Our findings support the usefulness of serum FABP3 and FABP4 concentrations as independent predictors for the occurrence of all-cause and CV mortality in ambulatory subjects with CHF with T2D.

Aims: Recent guidelines recommend four core drug classes (renin–angiotensin system inhibitor/angiotensin receptor–neprilysin inhibitor [RASi/ARNi], beta‐blocker, mineralocorticoid receptor antagonist [MRA], and sodium–glucose cotransporter 2 inhibitor [SGLT2i]) for the pharmacological management of heart failure (HF) with reduced ejection fraction (HFrEF). We assessed physicians' perceived (i) comfort with implementing the recent HFrEF guideline recommendations; (ii) status of guideline‐directed medical therapy (GDMT) implementation; (iii) use of different GDMT sequencing strategies; and (iv) barriers and strategies for achieving implementation. Methods and results: A 26‐question survey was disseminated via bulletin, e‐mail and social channels directed to physicians with an interest in HF. Of 432 respondents representing 91 countries, 36% were female, 52% were aged <50 years, and 90% mainly practiced in cardiology (30% HF). Overall comfort with implementing quadruple therapy was high (87%). Only 12% estimated that >90% of patients with HFrEF without contraindications received quadruple therapy. The time required to initiate quadruple therapy was estimated at 1–2 weeks by 34% of respondents, 1 month by 36%, 3 months by 24%, and ≥6 months by 6%. The average respondent favoured traditional drug sequencing strategies (RASi/ARNi with/followed by beta‐blocker, and then MRA with/followed by SGLT2i) over simultaneous initiation or SGLT2i‐first sequences. The most frequently perceived clinical barriers to implementation were hypotension (70%), creatinine increase (47%), hyperkalaemia (45%) and patient adherence (42%). Conclusions: Although comfort with implementing all four core drug classes in patients with HFrEF was high among physicians, a majority estimated implementation of GDMT in HFrEF to be low. We identified several important perceived clinical and non‐clinical barriers that can be targeted to improve implementation. [ABSTRACT FROM AUTHOR]

Abstract To assess mortality trends at 1 and 3 years from 2001 to 2018 in a real-life cohort of HF outpatients from different etiologies with depressed and preserved LVEF. A total of 2368 consecutive patients with HF (mean age 66.4 ± 12.9 years, 71% men, 15.4% with preserved LVEF) admitted to a HF clinic from August 2001 to September 2018 were included in the study. Patients were divided into five quintiles (Q) according to the period of admission. Trends for all-cause and cardiovascular mortality from Q1 to Q5 were assessed by linear regression. Patients with LVEF

ObjectivesHeart failure (HF) management has significantly improved over the past two decades, leading to better survival. This study aimed to assess changes in predicted mortality risk after 12 months of management in a multidisciplinary HF clinic.Materials and MethodsOut of 1,032 consecutive HF outpatients admitted from March-2012 to November-2018, 357 completed the 12-months follow-up and had N-terminal pro-B-type natriuretic peptide (NTproBNP), high sensitivity troponin T (hs-TnT), and interleukin-1 receptor-like-1 (known as ST2) measurements available both at baseline and follow-up. Three contemporary risk scores were used: MAGGIC-HF, Seattle HF Model (SHFM), and the Barcelona Bio-HF (BCN Bio-HF) calculator, which incorporates the three above mentioned biomarkers. The predicted risk of all-cause death at 1 and 3 years was calculated at baseline and re-evaluated after 12 months.ResultsA significant decline in predicted 1-and 3-year mortality risk was observed at 12 months: MAGGIC ~16%, SHFM ~22% and BCN Bio-HF ~15%. In the HF with reduced ejection fraction (HFrEF) subgroup guideline-directed medical therapy led to a complete normalization of left ventricular ejection fraction (≥50%) in almost a third of the patients and to a partial normalization (41–49%) in 30% of them. Repeated risk assessment after 12 months with SHFM and BCN Bio-HF provided adequate discrimination for all-cause 3-year mortality (C-Index: MAGGIC-HF 0.762, SHFM 0.781 and BCN Bio-HF 0.791).ConclusionMortality risk declines in patients with HF managed for 12 months in a multidisciplinary HF clinic. Repeating the mortality risk assessment after optimizing the HF treatment is recommended, particularly in the HFrEF subgroup.

Pirfenidone (PFD) slows the progression of idiopathic pulmonary fibrosis (IPF) by inhibiting the exaggerated fibrotic response and possibly through additional mechanisms, such as anti-inflammatory effects. PFD has also been evaluated in other fibrosing lung diseases. Myocardial fibrosis is a common feature of several heart diseases and the progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may trigger a vicious cycle that leads to persistent structural and functional alterations of the myocardium. No primarily antifibrotic medications are used to treat patients with heart failure. There is some evidence that PFD has antifibrotic actions in various animal models of cardiac disease and a phase II trial on patients with heart failure and preserved ejection fraction has yielded positive results. This review summarises the evidence about the possible mechanisms of IPF and modulation by PFD, the main results about IPF or non-IPF interstitial pneumonias and also data about PFD as a potential protective cardiac drug.

Compelling evidence supports the therapeutic benefit of extracellular vesicles (EVs). EVs are nanostructures with a lipid bilayer membrane that are secreted by multiple cells, including mesenchymal stromal cells (MSCs), as means of cellular communication. MSC-EVs, resembling their MSC origin, carry protected immunomodulatory and pro-regenerative cargoes to targeted neighboring or distant cells and tissues. Though treatments focused on MSC-EVs have emerged as greatly versatile approaches to modulate multiple inflammatory-related conditions, crucial concerns, including the possibility of increasing therapeutic outcomes by pre-conditioning parental MSCs or engineering derived EVs and clarification of the most relevant mechanisms of action, remain. Here, we summarize the large amount of preclinical research surrounding the modulation of beneficial effects by MSC-EVs.