Pirfenidone as a novel cardiac protective treatment.

Myocardial fibrosis is a common feature of several heart diseases. 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. Some drugs (like renin-angiotensin-aldosterone system inhibitors) have been shown to reduce extracellular matrix deposition, but no primarily anti-fibrotic medications are currently used to treat patients with heart failure (HF). Pirfenidone is an oral antifibrotic agent approved for the treatment of idiopathic pulmonary fibrosis. Although its exact mechanism of action is not fully understood, pirfenidone might reduce the expression of profibrotic factors such as transforming growth factor-ß (TGF-ß), and proinflammatory cytokines, like tumor necrosis factor-α (TNF-α), interleukin (IL)-4, and IL-13, which could modulate the inflammatory response and inhibit collagen synthesis in lung tissue. There is some evidence that pirfenidone has antifibrotic activity in various animal models of cardiac disease. Furthermore, the positive results of the PIROUETTE trial, evaluating pirfenidone in patients with HF with preserved ejection fraction, have been very recently announced. This review summarizes the data about pirfenidone as a potential cardioprotective treatment.

Angio-Based Fractional Flow Reserve, Functional Pattern of Coronary Artery Disease, and Prediction of Percutaneous Coronary Intervention Result: a Proof-of-Concept Study.

PURPOSE: Wire-based coronary physiology pullback performed before percutaneous coronary intervention (PCI) discriminates coronary artery disease (CAD) distribution and extent, and is able to predict functional PCI result. No research investigated if quantitative flow ratio (QFR)-based physiology assessment is able to provide similar information. METHODS: In 111 patients (120 vessels) treated with PCI, QFR was measured both before and after PCI. Pre-PCI QFR trace was used to discriminate functional patterns of CAD (focal, serial lesions, diffuse disease, combination). Functional CAD patterns were identified analyzing changes in the QFR virtual pullback trace (qualitative method) or after computation of the QFR virtual pullback index (QVPindex) (quantitative method). QVPindex calculation was based on the maximal QFR drop over 20 mm and the length of epicardial coronary segment with QFR most relevant drop. Then, the ability of the different functional patterns of CAD to predict post-PCI QFR value was tested. RESULTS: By qualitative method, 51 (43%), 20 (17%), 15 (12%), and 34 (28%) vessels were classified as focal, serial focal lesions, diffuse disease, and combination, respectively. QVPindex values >0.71 and ≤0.51 predicted focal and diffuse patterns, respectively. Suboptimal PCI result (post-PCI QFR value ≤0.89) was present in 22 (18%) vessels. Its occurrence differed across functional patterns of CAD (focal 8% vs. serial lesions 15% vs. diffuse disease 33% vs. combination 29%, p=0.03). Similarly, QVPindex was correlated with post-PCI QFR value (r=0.62, 95% CI 0.50-0.72). CONCLUSION: Our results suggest that functional patterns of CAD based on pre-PCI QFR trace can predict the functional outcome after PCI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , number NCT02811796. Date of registration: June 23, 2016.

Incidence of vasoplegic syndrome after cardiac transplantation in patients treated with sacubitril/valsartan.

Vasoplegic syndrome (VS) is associated with poor outcomes after heart transplantation (HT). Our aim was to determine whether SAC/VALS is associated with VS after HT. We retrospectively analyzed all consecutive HT performed in three centers between January 2017 and August 2018. VS was defined as vasopressor need (norepinephrine or epinephrine >.5 mcg/kg/min or vasopressin) for more than 24 hours to maintain a mean arterial pressure >70 mm Hg. Ninety-six recipients underwent HT in the study period: 60 elective HT with no LVAD, 5 elective HT on long term LVAD, and 31 emergent HT: 3 on long-term LVAD and 28 on temporary mechanical circulatory support. Fourteen patients were on SAC/VALS treatment at the time of transplant, and 82 were not. The global incidence of VS was 15.6%, with no significant differences between the groups (7.14% in with SAC/VALS vs 17.07% in no-SAC/VALS). In conclusion, in our small cohort SAC/VALS was not associated with VS development.

Advanced remote care for heart failure in times of COVID-19 using an implantable pulmonary artery pressure sensor: the new normal.

Heart failure (HF) is a major public health problem and a leading cause of hospitalization in western countries. Over the past decades, the goal has been to find the best method for monitoring congestive symptoms to prevent hospitalizations. Addressing this task through regular physician visits, blood tests, and imaging has proven insufficient for optimal control and has not decreased enough HF-related hospitalization rates. In recent years, new devices have been developed for this reason and CardioMEMS is one of the therapeutic monitoring options. CardioMEMS has shown to be effective in preventing and reducing HF hospitalizations in patients both with HF with reduced ejection fraction and HF with preserved ejection fraction. CardioMEMS' versatility has made it a great option for pulmonary artery pressure monitoring, both during the coronavirus disease-19 (COVID-19) pandemic and when the clinic visits have (partially) resumed. CardioMEMS is the remote haemodynamic monitoring system with the most evidence-driven efficacy, and COVID-19 has put it in the spot as a centre-stage technology for HF monitoring. In a few months of the COVID-19 epidemic, CardioMEMS has grown to maturity, making it the new normal for high-quality, high-value remote HF care.

Comparison of Verapamil versus Heparin as Adjunctive Treatment for Transradial Coronary Procedures: The VERMUT Study.

OBJECTIVE: We sought to demonstrate that the combination of a local vasodilator (verapamil), modern materials, patent hemostasis, and intravenous anticoagulant only in the case of percutaneous coronary intervention, as compared to default heparin administration after sheath insertion, may optimize a combined endpoint, including radial artery oc-clusion (RAO), radial artery spasm (RAS), and access site complication. METHODS: This is a prospective, single-center, double-blind randomized trial. Overall, 418 patients undergoing a transradial approach (TRA) for coronary procedures were randomized 1: 1 to receive intraradial verapamil (5 mg) or heparin (5,000 IU) after a 6-Fr sheath insertion. The primary outcome was the 24-h occurrence of RAO (ultrasound confirmation), access site complication, and RAS requiring the bailout administration of vasodilators. RESULTS: The combined primary outcome occurred in 127 (30%) patients. It was significantly lower in patients randomized to verapamil as compared to others (26 vs. 35%, p = 0.03). This was mainly due to a significant reduction in RAS (3 vs. 10%, p = 0.006). The 24-h and 30-day occurrence of RAO did not differ between the study groups. CONCLUSION: Local administration of verapamil versus heparin reduces RAS, without increasing RAO, which appears to be strictly related to radial artery diameter and hemostasis time.

Amino terminal pro brain natriuretic peptide predicts all-cause mortality in patients with chronic obstructive pulmonary disease: Systematic review and meta-analysis.

Natriuretic peptides (NPs) are a family of prognostic biomarkers in patients with heart failure (HF). HF is one of the most frequent comorbidities in patients with chronic obstructive pulmonary disease (COPD). However, the prognostic role of NP in COPD patients remains unclear. The aim of this meta-analysis was to evaluate the relation between NP and all-cause mortality in COPD patients. We performed a systematic review and meta-analysis of observational studies assessing prognostic implications of elevated NP levels on all-cause mortality in COPD patients. Nine studies were considered for qualitative analysis for a total of 2788 patients. Only two studies focused on Mid Regional-pro Atrial Natriuretic Peptide (MR-proANP) and brain natriuretic peptide (BNP), respectively, but seven studies focused on pro-BNP (NT-proBNP) and were included in the quantitative analysis. Elevated NT-proBNP values were related to increased risk of all-cause mortality in COPD patients both with and without exacerbation (hazard ratio (HR): 2.87, p < 0.0001 and HR: 3.34, p = 0.04, respectively). The results were confirmed also after meta-regression analysis for confounding factors (previous cardiovascular history, hypertension, HF, forced expiratory volume at 1 second and mean age). NT-proBNP may be considered a reliable predictive biomarker of poor prognosis in patients with COPD.

Prospective Identification of Stent Fracture by Enhanced Stent Visualization System During Percutaneous Coronary Intervention.

BACKGROUND: No study has evaluated the clinical consequences of stent fracture (SF) detected during the index percutaneous coronary intervention (PCI). Thus, we sought to investigate the relationship between SF detected during PCI and clinical outcome.Methods and Results:We consecutively enrolled 832 patients with SF-predisposing factors undergoing 2nd-generation drug-eluting stent implantation and enhanced stent visualization (ESV) system evaluation to detect SF at index PCI. The primary endpoint was a 9-month device-oriented endpoint (DOCE, including cardiac death, target vessel myocardial infarction, and target lesion revascularization). We observed 136 SF in 115 patients (14% of study population). SF I-II was present in 78 patients (68% of patients with SF), and SF III-IV occurred in 37 patients (32%). DOCE at 9 months occurred in 135 patients (16% of the overall population). There was a significant difference in DOCE occurrence between the 3 groups (P=0.006 at log-rank), driven by the SF III-IV group (P=0.001 vs. no SF group, and P=0.01 vs. SF I-II group). In 23 cases of SF III-IV (62%) a further stent was implanted. DOCE occurrence was significantly higher in patients with "untreated" type III-IV SF as compared with the "treated" ones (9% vs. 79%, P<0.01). CONCLUSIONS: The ESV system is helpful in detecting SF during the index PCI. Type III-IV SFs are associated with a higher incidence of DOCE.

Effect of a Fourth Dose of mRNA Vaccine and of Immunosuppression in Preventing SARS-CoV-2 Breakthrough Infections in Heart Transplant Patients.

Patients with heart transplantation (HT) have an increased risk of COVID-19 disease and the efficacy of vaccines on antibody induction is lower, even after three or four doses. The aim of our study was to assess the efficacy of four doses on infections and their interplay with immunosuppression. We included in this retrospective study all adult HT patients (12/21-11/22) without prior infection receiving a third or fourth dose of mRNA vaccine. The endpoints were infections and the combined incidence of ICU hospitalizations/death after the last dose (6-month survival rate). Among 268 patients, 62 had an infection, and 27.3% received four doses. Following multivariate analysis, three vs. four doses, mycophenolate (MMF) therapy, and HT < 5 years were associated with an increased risk of infection. MMF ≥ 2000 mg/day independently predicted infection, together with the other variables, and was associated with ICU hospitalization/death. Patients on MMF had lower levels of anti-RBD antibodies, and a positive antibody response after the third dose was associated with a lower probability of infection. In HT patients, a fourth dose of vaccine against SARS-CoV-2 reduces the risk of infection at six months. Mycophenolate, particularly at high doses, reduces the clinical effectiveness of the fourth dose and the antibody response to the vaccine.

Global warming, renal function and heart failure over 20 years.

BACKGROUND: The impact of increasing temperatures on renal function in heart failure (HF) outpatients has never been specifically analyzed. METHODS: We retrieved creatinine and estimated glomerular filtration rate (eGFR) values of all HF outpatients followed at a HF clinic and temperature data from 2002 to 2021. For each patient and each year we averaged values of creatinine, eGFR and monthly temperatures during summer and the rest of the year. RESULTS: The study cohort included 2167 HF patients undergoing 25,865 elective visits, with a median of 14 visits for each patient (interquartile range 7-23). At the first visit, patients (70% men) had an age of 67 ± 13 years, and a left ventricular ejection fraction of 35 ± 14%. Creatinine was 1.25 ± 0.51 mg/dL, and eGFR was 65 ± 25 mL/min/1.73 m2. When pooling together all average values of creatinine and eGFR measured during summer or in the rest of the year, creatinine was significantly higher in summer (difference 0.04, 95% confidence interval [CI] 0.04 to 0.05, p < 0.001), and eGFR was slightly lower (difference - 2.0, 95% CI -2.3 to -1.8, p < 0.001). Temperature rise during summer increased from 2002 to 2021. The absolute (Δ) and percent (Δ%) elevation in temperature during summer displayed independent associations with Δ and Δ% creatinine and eGFR after adjusting for age, sex, plasma creatinine, and HF therapies. CONCLUSIONS: The magnitude of temperature elevation during summer has increased over 20 years. This elevation correlates with the decline in renal function during summer. This might be an example of how global warming is affecting human health.

Pirfenidone for Idiopathic Pulmonary Fibrosis and Beyond.

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.

Role of Quantitative Flow Ratio in Predicting Future Cardiac Allograft Vasculopathy in Heart Transplant Recipients.

BACKGROUND: Coronary angiography is the gold standard for cardiac allograft vasculopathy (CAV) diagnosis, but it usually detects the disease at an advanced stage. We investigated the role of quantitative flow ratio (QFR), a noninvasive tool to identify potentially flow-limiting lesions, in predicting CAV development in heart transplant recipients. METHODS: Consecutive heart transplant recipients with no evidence of angiographic CAV at baseline coronary angiography were retrospectively included between January 2010 and December 2015, and QFR computation was performed. The relationship between vessel QFR and the occurrence of angiographic vessel-related CAV (≥50% stenosis) was assessed. RESULTS: One hundred forty-three patients were included and QFR computation was feasible in 241 vessels. The median value of QFR at baseline coronary angiography was 0.98 (interquartile range, 0.94-1.00). During a median follow-up of 6.0 years (interquartile range, 4.6-7.8 years), vessel-related CAV occurred in 25 (10.4%) vessels. Receiver-operating characteristic curve analysis identified a QFR best cutoff of ≤0.95 (area under the curve, 0.81 [95% CI, 0.71-0.90]; P<0.001). QFR≤0.95 was associated with an increased risk of vessel-related CAV (adjusted hazard ratio, 20.87 [95% CI, 5.35-81.43]; P<0.001). In an exploratory analysis, QFR≤0.95 in at least 2 vessels was associated with higher incidence of cardiovascular death or late graft dysfunction (71.4% in recipients with 2-3 vessels affected versus 5.1% in recipients with 0-1 vessels affected, P<0.001). CONCLUSIONS: In a cohort of heart transplant recipients, QFR computation at baseline coronary angiography may be a safe and reliable tool to predict vessel-related CAV and clinical outcomes at long-term follow-up.

Cause of Death in Heart Failure Based on Etiology: Long-Term Cohort Study of All-Cause and Cardiovascular Mortality.

We assessed differences in long-term all-cause and cardiovascular (CV) mortality in heart failure (HF) outpatients based on the etiology of HF. Consecutive patients admitted to the HF Clinic from August 2001 to September 2019 (N = 2587) were considered for inclusion. HF etiology was divided into ischemic heart disease (IHD), dilated cardiomyopathy (DCM), hypertensive heart disease, alcoholic cardiomyopathy, drug-induced cardiomyopathy (DICM), valvular heart disease, and hypertrophic cardiomyopathy. All-cause death and CV death were the primary end points. Among 2387 patients included in the analysis (mean age 66.5 ± 12.5 years, 71.3% men), 1317 deaths were recorded (731 from CV cause) over a maximum follow-up of 18 years (median 4.1 years, interquartile range (IQR) 2-7.8). Considering IHD as the reference, only DCM had a lower risk of all-cause death (adjusted hazard ratio (aHR) 0.68, 95% confidence interval (CI) 0.56-0.83, p < 0.001), and only DICM had a higher risk of all-cause death (aHR 1.47, 95% CI 1.02-2.11, p = 0.04). However, almost all etiologies had a significantly lower risk of CV death than IHD. Among the studied HF etiologies, DCM and DICM have the lowest and highest risk of all-cause death, respectively, whereas IHD has the highest adjusted risk of CV death.

Sacubitril/valsartan affects pulmonary arterial pressure in heart failure with preserved ejection fraction and pulmonary hypertension.

AIMS: Prior studies have not fully characterized the haemodynamic effects of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan in heart failure with preserved ejection fraction and pulmonary hypertension (HFpEF-PH). The aim of the Treatment of PH With Angiotensin II Receptor Blocker and Neprilysin Inhibitor in HFpEF Patients With CardioMEMS Device (ARNIMEMS-HFpEF) study is to assess pulmonary artery pressure (PAP) dynamics by means of implanted PAP monitors in patients with HFpEF-PH treated with sacubitril/valsartan. METHODS AND RESULTS: This single-arm, investigator-initiated, interventional study included 14 consecutive ambulatory symptomatic HFpEF-PH patients who underwent CardioMEMS implantation prior to enrolment [mean ejection fraction 60.4 ± 7.2%, baseline mean PAP (mPAP) 33.9 ± 7.6 mmHg]. Daily PAP values were examined during three periods: a 6 week period after CardioMEMS implantation and before sacubitril/valsartan treatment (pre-ARNI), a 6 week period with sacubitril/valsartan treatment (ARNI ON), and a 6 week period of sacubitril/valsartan withdrawal (ARNI OFF). The primary endpoint was change in mPAP with and without sacubitril/valsartan. Secondary endpoints included changes in 6 min walking distance, B-line sum in lung ultrasound, and quality of life (QoL). During the study period, 1717 mPAP measurements were recorded. Between pre-ARNI vs. ARNI ON, mPAP significantly declined by -4.99 mmHg [95% confidence interval (CI) -5.55 to -4.43]. Between ARNI ON vs. ARNI OFF, mPAP significantly increased by +2.84 mmHg [95% CI +2.26 to +3.42]. Between pre-ARNI vs. ARNI ON, we found an improvement in 6 min walking distance, B-lines, and QoL. Mean loop diuretic management did not differ between periods. CONCLUSIONS: Sacubitril/valsartan significantly reduced mPAP in patients with HFpEF-PH, independent of loop diuretic management, together with improvement in functional capacity, lung congestion, and QoL. Sacubitril/valsartan may be a therapeutic alternative in HFpEF-PH.

Impact of trans-stent gradient on outcome after PCI: results from a HAWKEYE substudy.

To test whether quantitative flow ratio (QFR)-based trans-stent gradient (TSG) is associated with adverse clinical events at follow-up. A post-hoc analysis of the multi-center HAWKEYE study was performed. Vessels post-PCI were divided into four groups (G) as follows: G1: QFR ≥ 0.90 TSG = 0 (n = 412, 54.8%); G2: QFR ≥ 0.90, TSG > 0 (n = 216, 28.7%); G3: QFR < 0.90, TSG = 0 (n = 37, 4.9%); G4: QFR < 0.90, TSG > 0 (n = 86, 11.4%). Cox proportional hazards regression model was used to analyze the effect of baseline and prognostic variables. The final reduced model was obtained by backward stepwise variable selection. Receiver operating characteristic (ROC) was plotted and area under the curve (AUC) was calculated and reported. Overall, 449 (59.8%) vessels had a TSG = 0 whereas (40.2%) had TSG > 0. Ten (2.2%) vessel-oriented composite endpoint (VOCE) occurred in vessels with TSG = 0, compared with 43 (14%) in vessels with TSG > 0 (p < 0.01). ROC analysis showed an AUC of 0.74 (95% CI: 0.67 to 0.80; p < 0.001). TSG > 0 was an independent predictor of the VOCE (HR 2.95 [95% CI 1.77-4.91]). The combination of higher TSG and lower final QFR (G4) showed the worst long-term outcome while low TSG and high QFR showed the best outcome (G1) while either high TSG or low QFR (G2, G3) showed intermediate and comparable outcomes. Higher trans-stent gradient was an independent predictor of adverse events and identified a subgroup of patients at higher risk for poor outcomes even when vessel QFR was optimal (> 0.90).

Mortality Risk Prediction Dynamics After Heart Failure Treatment Optimization: Repeat Risk Assessment Using Online Risk Calculators.

Objectives: Heart 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 Methods: Out 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. Results: A 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). Conclusion: Mortality 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.

Circulating neprilysin hypothesis: A new opportunity for sacubitril/valsartan in patients with heart failure and preserved ejection fraction?

BACKGROUND: Circulating Neprilysin (sNEP) has emerged as a potential prognostic biomarker in heart failure (HF). In PARAGON-HF benefit of sacubitril/valsartan was only observed in patients with left ventricular ejection fraction (LVEF) ≤57%. We aimed to assess the prognostic value of sNEP in outpatients with HF and LVEF >57%, in comparison with patients with LVEF ≤57%. METHODS: Consecutive HF outpatients were included from May-2006 to February-2016. The primary endpoint was the composite of all-cause death or HF hospitalization and the main secondary endpoint was the composite of cardiovascular death or HF hospitalization. For the later competing risk methods were used. RESULTS: sNEP was measured in 1428 patients (age 67.7±12.7, 70.3% men, LVEF 35.8% ±14), 144 of which had a LVEF >57%. sNEP levels did not significantly differ between LVEF groups (p = 0.31). During a mean follow-up of 6±3.9 years, the primary endpoint occurred in 979 patients and the secondary composite endpoint in 714 (in 111 and 84 of the 144 patients with LVEF >57%, respectively). sNEP was significantly associated with both composite endpoints. Age- and sex- adjusted Cox regression analyses showed higher hazard ratios for sNEP in patients with LVEF >57%, both for the primary (HR 1.37 [1.16-1.61] vs. 1.04 [0.97-1.11]) and the secondary (HR 1.38 [1.21-1.55] vs. 1.11 [1.04-1.18]) composite endpoints. CONCLUSIONS: sNEP prognostic value in patients with HF and LVEF >57% outperforms that observed in patients with lower LVEF. Precision medicine using sNEP may identify HF patients with preserved LVEF that may benefit from treatment with sacubitril/valsartan.

Decoding empagliflozin's molecular mechanism of action in heart failure with preserved ejection fraction using artificial intelligence.

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-ß1 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.

Caval Valve Implantation (CAVI): An Emerging Therapy for Treating Severe Tricuspid Regurgitation.

Severe tricuspid regurgitation remains a challenging heart-valve disease to effectively treat with high morbidity and mortality at mid-term. Currently guideline-directed medical treatment is limited to escalating dose of diuretics, and the rationale and timing of open-heart surgery remains controversial. Emerging percutaneous therapies for severe tricuspid regurgitation continue to show promising results in early feasibility studies. However, randomized trial data is lacking. Additionally, many patients are deemed unsuitable for these emerging therapies due to anatomical or imaging constraints. Given the technical simplicity of the bicaval valve implantation (CAVI) technique compared to other transcatheter devices, CAVI is postulated as a suitable alternative for a wide variety of patients affected with severe+ tricuspid regurgitation. In this review we illustrate the current evidence and ongoing uncertainties of CAVI, focusing on the novel CAVI-specific devices.

Lung ultrasound in outpatients with heart failure: the wet-to-dry HF study.

AIMS: In ambulatory patients with chronic heart failure (HF), congestion and decongestion assessment may be challenging. The aim of this study is to assess the value of lung ultrasound (LUS) in outpatients with HF in characterizing decompensation and recompensation, and in outcomes prediction. METHODS AND RESULTS: Heart failure outpatients attended to establish HF decompensation were included. LUS was blindly performed at baseline (LUS1) and at clinical recompensation (LUS2). B-lines were counted in eight scanned areas. Diagnosis of no HF decompensation vs. right-sided, left-sided, or global HF decompensation, and patients' management were performed by physicians blinded to LUS1. Outcome was the composite of all-cause death or HF-related hospitalization. Two hundred and thirty-three suspicions of HF decompensation were included in 187 patients (71.4 ± 11.3 years, 66.8% men). Mean B-line (LUS1) was 17.6 ± 11.2 vs. 3.7 ± 4.5 for episodes with and without HF decompensation, respectively (P < 0.001). Global HF decompensation showed the highest number of B-lines (20.6 ± 11), followed by left-sided (19.7 ± 11.6) and right-sided (13.5 ± 9.8). B-lines declined to 6.9 ± 6.7 (LUS2) (P < 0.001 vs. LUS1) after treatment, within a mean time of 24.2 ± 23.7 days [median 13.5 days (interquartile range 6-40)]. B-lines were significantly associated with the composite endpoint at 30 days (hazard ratio [HR] 1.04 [95% confidence interval 1.01-1.07], P = 0.02), but not at 60 (P = 0.22) or 180 days (P = 0.54). In multivariable analysis, B-line number remained as an independent predictor of the composite endpoint at 30 days, [HR 1.04 (1.01-1.07), P = 0.014], with a 4% increase risk per B-line added. B-lines correlated significantly with CA125 (R = 0.30, P = 0.001). CONCLUSIONS: Lung ultrasound supports the diagnostic work-up of congestion and decongestion in chronic HF outpatients and identifies patients at high risk of short-term events.