Empagliflozin: Primus Inter Pares Among Sodium-Glucose Cotransporter-2 Inhibitors?

ABSTRACT: Sodium/glucose cotransporter-2 (SGLT2) inhibitors are a novel class of antidiabetic medications which have proved capable of providing breakthrough cardiovascular (CV) benefits in a variety of clinical scenarios, including patients with heart failure or obesity, irrespective of diabetic status. Several SGLT2 inhibitors are available, but the most prominent ones are canagliflozin, dapagliflozin, and empagliflozin. Several studies have focused on empagliflozin and its effects on the risk of heart failure incidence and recurrences. Most recently, empagliflozin has been recently tested in patients with recent myocardial infarction in the EMPAgliflozin on Hospitalization for Heart Failure and Mortality in Patients With aCuTe Myocardial Infarction randomized trial, with apparently ambiguous findings. The present viewpoint succinctly illustrates the main features of SGLT2 inhibitors as a pharmacologic class, their ever expanding role as a CV medication, and the comparative effectiveness of different individual SGLT2 inhibitors, explicitly commenting on the recent data on empagliflozin in patients with acute myocardial infarction. The reader will find in this article a poignant perspective on this novel avenue for CV prevention and treatment, which greatly expands the management armamentarium of CV practitioners. Indeed, we make the case that SGLT2 inhibitors have a clearly favorable class effect, with differences between individual agents mainly suitable for personalization of care and minimization of side effects.

Different Techniques of Surgical Left Atrial Appendage Closure and Their Efficacy: A Systematic Review.

Background: Atrial fibrillation has been identified as an independent risk factor for thromboembolic events. Since 1948 different surgical techniques have described the feasibility and the rationale of left atrial surgical appendage closure. The aim of this systematic review is to evaluate the reported patency rates of different surgical techniques. Methods: This systematic review was conducted according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Two independent investigators searched the PubMed, Scopus, Web of Science, Cochrane Central Register of Controlled Trials, and OVID® (Wolters Kluwer, Alphen aan den Rijn, Netherlands) to identify relevant studies. Consecutively, a PICO (Population, Intervention, Comparison and Outcomes) strategy assessment of literature was performed to search eventual other relevant studies that may have been ignored. Results: A total of 42 studies were included in our analysis. The total number of patients who underwent surgical left atrial appendage closure was 5671, and in 61.2% an imaging follow up was performed, mostly with transesophageal echocardiographic evaluation. Success rate for the different techniques was: Clip deployment 98%; Lariat procedure 88%; Surgical amputation 91%; Endocardial suture 74.3%, Epicardial suture 65%; Left atrial appendage closure (LAAC) ligation 60.9%; Stapler technique with excision of left atrial appendage (LAA) 100%; Stapler without excision 70%. Conclusions: To date, data on surgical left atrial appendage closure are poor and not standardized, even if reported rates are acceptable and comparable to transcatheter procedures. If validated on large-scale non-retrospective and multicentric studies, these promising developments may offer a valuable alternative for patients with atrial fibrillation (AF) and ineligible for oral anticoagulation therapy.

Progressive stages of dysmetabolism are associated with impaired biological features of human cardiac stromal cells mediated by the oxidative state and autophagy.

Cardiac stromal cells (CSCs) are the main players in fibrosis. Dysmetabolic conditions (metabolic syndrome-MetS, and type 2 diabetes mellitus-DM2) are strong pathogenetic contributors to cardiac fibrosis. Moreover, modulation of the oxidative state (OxSt) and autophagy is a fundamental function affecting the fibrotic commitment of CSCs, that are adversely modulated in MetS/DM2. We aimed to characterize CSCs from dysmetabolic patients, and to obtain a beneficial phenotypic setback from such fibrotic commitment by modulation of OxSt and autophagy. CSCs were isolated from 38 patients, stratified as MetS, DM2, or controls. Pharmacological modulation of OxSt and autophagy was obtained by treatment with trehalose and NOX4/NOX5 inhibitors (TREiNOX). Flow-cytometry and real-time quantitative polymerase chain reaction (RT-qPCR) analyses showed significantly increased expression of myofibroblasts markers in MetS-CSCs at baseline (GATA4, ACTA2, THY1/CD90) and after starvation (COL1A1, COL3A1). MetS- and DM2-CSCs displayed a paracrine profile distinct from control cells, as evidenced by screening of 30 secreted cytokines, with a significant reduction in vascular endothelial growth factor (VEGF) and endoglin confirmed by enzyme-linked immunoassay (ELISA). DM2-CSCs showed significantly reduced support for endothelial cells in angiogenic assays, and significantly increased H2 O2 release and NOX4/5 expression levels. Autophagy impairment after starvation (reduced ATG7 and LC3-II proteins) was also detectable in DM2-CSCs. TREiNOX treatment significantly reduced ACTA2, COL1A1, COL3A1, and NOX4 expression in both DM2- and MetS-CSCs, as well as GATA4 and THY1/CD90 in DM2, all versus control cells. Moreover, TREiNOX significantly increased VEGF release by DM2-CSCs, and VEGF and endoglin release by both MetS- and DM2-CSCs, also recovering the angiogenic support to endothelial cells by DM2-CSCs. In conclusion, DM2 and MetS worsen microenvironmental conditioning by CSCs. Appropriate modulation of autophagy and OxSt in human CSCs appears to restore these features, mostly in DM2-CSCs, suggesting a novel strategy against cardiac fibrosis in dysmetabolic patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Effects of two-month treatment with a mixture of natural activators of autophagy on oxidative stress and arterial stiffness in patients with essential hypertension: A pilot study.

BACKGROUND AND AIMS: Trehalose, spermidine, nicotinamide, and polyphenols are natural substances that exert pro-autophagic and antioxidant properties. Their role in blood pressure (BP) regulation and preservation of vascular function in essential hypertension is unknown. The aim of this study was to evaluate the effect of a mixture of these agents on BP level, markers of oxidative stress, autophagy, endothelial function, and vascular stiffness in outpatients with grade 1 uncomplicated essential hypertension. METHODS AND RESULTS: A single-centre, open-label, case-control, pilot study was conducted in adult outpatients (aged ≥18 years) receiving or not the mixture for two months along with the standard therapies. Both at baseline and at the end of the treatment the following clinical parameters were evaluated: brachial seated office BP level, central aortic pressure, pulse wave velocity, augmentation index (AI@75). Both at baseline and at the end of the treatment, a blood sample was drawn for the measurement of: H2O2, HBA%, levels of sNOX2-dp, Atg 5, P62, endothelin 1, and NO bioavailability. The mixture of nutraceuticals did not influence BP levels. Patients receiving the mixture showed a significant decrease of oxidative stress, stimulation of autophagy, increased NO bioavailability and no increase of the AI@75, in contrast to what observed in hypertensive patients not receiving the mixture. CONCLUSIONS: The supplementation of the trehalose, spermidine, nicotinamide, and polyphenols mixture counteracted hypertension-related arterial stiffness through mechanisms likely dependent on oxidative stress downregulation and autophagy stimulation. These natural activators of autophagy may represent favourable adjuvants for prevention of the hypertensive cardiovascular damage.

Impact of chronic use of heat-not-burn cigarettes on oxidative stress, endothelial dysfunction and platelet activation: the SUR-VAPES Chronic Study.

Tobacco habit still represents the leading preventable cause of morbidity and mortality worldwide. Heat-not-burn cigarettes (HNBCs) are considered as an alternative to traditional combustion cigarettes (TCCs) due to the lack of combustion and the absence of combustion-related specific toxicants. The aim of this observational study was to assess the effect of HNBC on endothelial function, oxidative stress and platelet activation in chronic adult TCC smokers and HNBC users. The results showed that both HNBC and TCC display an adverse phenotype in terms of endothelial function, oxidative stress and platelet activation. Future randomised studies are strongly warranted to confirm these data.

Profiling the Acute Effects of Modified Risk Products: Evidence from the SUR-VAPES (Sapienza University of Rome-Vascular Assessment of Proatherosclerotic Effects of Smoking) Cluster Study.

PURPOSE OF REVIEW: Modified risk products (MRP) are promoted as a safer alternative to traditional combustion cigarettes (TCC) in chronic smokers. Evidence for their lower hazardous profile is building, despite several controversies. Yet, it is unclear whether individual responses to MRP differ among consumers. We hypothesized that different clusters of subjects exist in terms of acute effects of MRP. RECENT FINDINGS: Pooling data from a total of 60 individuals, cluster analysis identified at least three clusters (labelled 1 to 3) of subjects with different electronic vaping cigarettes (EVC) effects and at least two clusters (labelled 4 to 5) of subjects with different heat-not-burn cigarettes (HNBC) effects. Specifically, oxidative stress, platelet aggregation, and endothelial dysfunction after EVC were significantly different cluster-wise (all p < 0.05), and oxidative stress and platelet aggregation after HNBC were significantly different (all p < 0.05). In particular, subjects belonging to Cluster 1 appeared to have less detrimental responses to EVC usage than subjects in Cluster 2 and 3, as shown by non-significant changes in flow-mediated dilation (FMD) and less marked increase in Nox2-derived peptide (NOX). Conversely, those assigned to Cluster 3 had the worst reaction in terms of changes in FMD, NOX, and P-selectin. Furthermore, individuals belonging to Cluster 4 responded unfavorably to both HNBC and EVC, whereas those in Cluster 5 interestingly showed less adverse results after using HNBC than EVC. Results for main analyses were consistent employing different clusters, tests, and bootstrap. Individual responses to MRP differ and smokers aiming at using EVC or HNBC as a risk reduction strategy should consider trying different MRP aiming at finding the one which is less detrimental, with subjects resembling those in Cluster 1 preferably using EVC and those resembling Cluster 5 preferably using HNBC.

On the Road to Regeneration: "Tools" and "Routes" Towards Efficient Cardiac Cell Therapy for Ischemic Cardiomyopathy.

PURPOSE OF REVIEW: Cardiac regenerative medicine is a field bridging together biotechnology and surgical science. In this review, we present the explored surgical roads to cell delivery and the known effects of each delivery method on cell therapy efficiency. We also list the more recent clinical trials, exploring the safety and efficacy of delivery routes used for cardiac cell therapy approaches. RECENT FINDINGS: There is no consensus in defining which way is the most suitable for the delivery of the different therapeutic cell types to the damaged heart tissue. In addition, it emerged that the "delivery issue" has not been systematically addressed in each clinical trial and for each and every cell type capable of cardiac repair. Cardiac damage occurring after an ischemic insult triggers a cascade of cellular events, eventually leading to heart failure through fibrosis and maladaptive remodelling. None of the pharmacological or medical interventions approved so far can rescue or reverse this phenomenon, and cardiovascular diseases are still the leading cause of death in the western world. Therefore, for nearly 20 years, regenerative medicine approaches have focused on cell therapy as a promising road to pursue, with numerous preclinical and clinical testing of cell-based therapies being studied and developed. Nonetheless, consistent clinical results are still missing to reach consensus on the most effective strategy for ischemic cardiomyopathy, based on patient selection, diagnosis and stage of the disease, therapeutic cell type, and delivery route.

What We Have Learned from the Recent Meta-analyses on Diagnostic Methods for Atherosclerotic Plaque Regression.

PURPOSE OF REVIEW: Atherosclerosis has major morbidity and mortality implications globally. While it has often been considered an irreversible degenerative process, recent evidence provides compelling proof that atherosclerosis can be reversed. Plaque regression is however difficult to appraise and quantify, with competing diagnostic methods available. Given the potential of evidence synthesis to provide clinical guidance, we aimed to review recent meta-analyses on diagnostic methods for atherosclerotic plaque regression. RECENT FINDINGS: We identified 8 meta-analyses published between 2015 and 2017, including 79 studies and 14,442 patients, followed for a median of 12 months. They reported on atherosclerotic plaque regression appraised with carotid duplex ultrasound, coronary computed tomography, carotid magnetic resonance, coronary intravascular ultrasound, and coronary optical coherence tomography. Overall, all meta-analyses showed significant atherosclerotic plaque regression with lipid-lowering therapy, with the most notable effects on echogenicity, lipid-rich necrotic core volume, wall/plaque volume, dense calcium volume, and fibrous cap thickness. Significant interactions were found with concomitant changes in low density lipoprotein cholesterol, high density lipoprotein cholesterol, and C-reactive protein levels, and with ethnicity. Atherosclerotic plaque regression and conversion to a stable phenotype is possible with intensive medical therapy and can be demonstrated in patients using a variety of non-invasive and invasive imaging modalities.

The Biological Mechanisms of Action of Cardiac Progenitor Cell Therapy.

PURPOSE OF REVIEW: Cell therapy for cardiovascular diseases is regarded as a rapidly growing field within regenerative medicine. Different cellular populations enriched for cardiac progenitor cells (CPCs), or derivate a-cellular products, are currently under preclinical and clinical evaluation. Here, we have reviewed the described mechanisms whereby resident post-natal CPCs, isolated in different ways, act as a therapeutic product on the damaged myocardium. RECENT FINDINGS: Several biological mechanisms of action have been described which can explain the multiple therapeutic effects of CPC treatment observed on cardiac function and remodelling. These mechanisms span from direct cardiovascular differentiation, through induction of resident progenitor proliferation, to paracrine effects on cardiac and non-cardiac cells mediated by exosomes and non-coding RNAs. All the reported mechanisms of action support an integrated view including cardiomyogenesis, cardioprotection, and anti-fibrotic effects. Moreover, future developments of CPC therapy approaches may support cell-free strategies, exploiting effective pleiotropic cell-derived products, such as exosomes.

What We Learned with Recent Network Meta-analyses on Atherosclerosis Prevention and Treatment.

PURPOSE OF REVIEW: The management of atherosclerosis requires a complex integration of the knowledge on its pathophysiology, patient values, and the synthesis of the global scientific evidence informing on its prevention and treatment. Novel statistical methods such as umbrella reviews and network meta-analyses (NMAs) offer a unique opportunity for integrating different sources of evidence stemming from randomized controlled trials (RCTs) or internally valid observational studies. We aimed to provide an updated perspective on the most important contributions of recent network meta-analyses on atherosclerosis prevention and treatment. RECENT FINDINGS: We identified and appraised in detail 9 NMAs on atherosclerosis prevention, all published in 2016, whereas a total of 12 NMAs on atherosclerosis treatment published between 2014 and 2016 were identified. Most NMAs focused on RCTs only, with primary prevention analyses including on average more trials and patients than those focusing on secondary prevention. In most cases, conclusive findings for clinically relevant outcomes could be provided. Yet, several inconclusive findings were reported, suggesting thus that NMAs can also guide new research by emphasizing where new evidence is most needed. NMAs provide a unique opportunity for poignant synthesis of high-quality evidence. In particular, they seem particularly promising when the evidence base has reached a sufficient level of maturity, and several competing interventions require comprehensive and comparative risk-benefit appraisal.

Impact of coronary revascularization vs medical therapy on ischemia among stable patients with or suspected coronary artery disease undergoing serial myocardial perfusion scintigraphy.

BACKGROUND: Randomized trials have challenged the role of revascularization in stable coronary artery disease. We aimed to appraise the impact of revascularization on ischemia in patients undergoing serial myocardial perfusion scintigraphy (MPS). METHODS: We queried our institutional database for stable subjects undergoing serial MPS and appraised the impact of revascularization on changes in ischemia. RESULTS: A total of 3631 patients were included: 967 (27%) undergoing revascularization and 2664 (73%) receiving medical therapy only. Patients treated with revascularization had a significantly lower burden of myocardial ischemia at follow-up (odds ratio = 0.577 [95% confidence interval 0.483-0.689] vs medical therapy, P < .001). Among all those having moderate or severe ischemia at baseline, revascularization was associated with a follow-up prevalence of 80% for no, minimal, or mild ischemia and 20% for moderate or severe ischemia, vs 43% and 57% for medical therapy (P < .001). Even at multivariable analysis and propensity-adjusted, and propensity-matched analyses, revascularization was associated with a significantly lower prevalence of moderate or severe ischemia at follow-up (respectively P < .001, P = .001, and P = .042). CONCLUSIONS: Revascularization appears superior to medical therapy in reducing ischemic burden and normalizing myocardial perfusion among subjects with moderate or severe ischemia at baseline.

The Light and Shadow of Senescence and Inflammation in Cardiovascular Pathology and Regenerative Medicine.

Recent epidemiologic studies evidence a dramatic increase of cardiovascular diseases, especially associated with the aging of the world population. During aging, the progressive impairment of the cardiovascular functions results from the compromised tissue abilities to protect the heart against stress. At the molecular level, in fact, a gradual weakening of the cellular processes regulating cardiovascular homeostasis occurs in aging cells. Atherosclerosis and heart failure are particularly correlated with aging-related cardiovascular senescence, that is, the inability of cells to progress in the mitotic program until completion of cytokinesis. In this review, we explore the intrinsic and extrinsic causes of cellular senescence and their role in the onset of these cardiovascular pathologies. Additionally, we dissect the effects of aging on the cardiac endogenous and exogenous reservoirs of stem cells. Finally, we offer an overview on the strategies of regenerative medicine that have been advanced in the quest for heart rejuvenation.

The Positive Effects of Exercise in Chemotherapy-Related Cardiomyopathy.

Anthracyclines such as doxorubicin, daunorubicin, epirubicin, mitoxantrone and idarubicin, are powerful chemotherapeutic drugs used both in children and adult populations. Their properties made them particularly suitable for a large variety of neoplasms including breast adenocarcinoma, small cell lung cancer and acute leukemia. Early and late anthracycline-induced cardiotoxicity is a well-known phenomenon, and the incidence of heart failure in patients receiving doxorubicin is 2.2%, with a mortality rate over 60% at 2 years. Prognosis can be improved by prevention, early detection and treatment. A specific treatment for anthracycline-induced cardiotoxicity is not yet available, but non-pharmacological measures such as exercise, lifestyle changes and control of risk factors have shown a cardioprotective effect. Exercise training represents a viable non-pharmacological treatment as it increases cardiovascular reserve and endothelial function, regulates proapoptotic signaling, protects against reactive oxygen species (ROS), and decreases autophagy/lysosomal signaling. However, no current guidelines are available for prevention management in cancer patients. Pharmacological measures both for prevention and treatment are those used for heart failure (ß-blockers, angiotensin-receptor blockers, angiotensin-converting enzyme inhibitors, statins, dexrazoxane and aldosteron antagonists). In this chapter, we will discuss how the evaluation, monitoring and prevention of chemotherapy-related cardiomyopathy is correlated with physical exercise.

Comparative Impact of Hypoglycemic Agents on Severity and Extent of Myocardial Ischemia in Patients With Type 2 Diabetes Mellitus Undergoing Myocardial Perfusion Scintigraphy.

BACKGROUND: Hypoglycemic agents differ in mechanism, efficacy, and profile. However, there is uncertainty on their impact on myocardial perfusion. We thus aimed to investigate whether individuals with type 2 diabetes mellitus treated with different drug classes exhibit different perfusion patterns at myocardial perfusion scintigraphy (MPS). METHODS AND RESULTS: We queried our administrative database for patients with diabetes mellitus without prior or recent myocardial infarction. The primary objective was to compare the severity and extent of ischemia at MPS, distinguishing patients according to management strategy. A total of 7592 patients were included [2336 (31%) on diet, 3611 (48%) on metformin, 749 (10%) on sulfonylureas, 449 (6%) on metformin plus sulfonylureas, 447 (6%) on metformin plus insulin]. Unadjusted analyses and analyses adjusting for baseline features suggested that sulfonylureas alone or in combination were associated with more severe ischemia than nonsulfonylurea regimens (P < 0.05), whereas combination regimens including metformin were associated with more extensive myocardial ischemia than the other regimens (P < 0.05 for both). However, no significant difference disfavoring either metformin or sulfonylurea regimens persisted after multivariable adjustment for baseline, stress, and angiographic characteristics (all P > 0.05). CONCLUSION: Several significant differences in baseline, stress, and scintigraphic features appear evident in patients with diabetes mellitus receiving different hypoglycemic agents or regimens.

Long-term home noninvasive mechanical ventilation increases systemic inflammatory response in chronic obstructive pulmonary disease: a prospective observational study.

BACKGROUND: Long-term home noninvasive mechanical ventilation (NIV) is beneficial in COPD but its impact on inflammation is unknown. We assessed the hypothesis that NIV modulates systemic and pulmonary inflammatory biomarkers in stable COPD. METHODS: Among 610 patients referred for NIV, we shortlisted those undergoing NIV versus oxygen therapy alone, excluding subjects with comorbidities or non-COPD conditions. Sputum and blood samples were collected after 3 months of clinical stability and analyzed for levels of human neutrophil peptides (HNP), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha). Patients underwent a two-year follow-up. Unadjusted, propensity-matched, and pH-stratified analyses were performed. RESULTS: Ninety-three patients were included (48 NIV, 45 oxygen), with analogous baseline features. Sputum analysis showed similar HNP, IL-6, IL-10, and TNF-alpha levels (P > 0.5). Conversely, NIV group exhibited higher HNP and IL-6 systemic levels (P < 0.001) and lower IL-10 concentrations (P < 0.001). Subjects undergoing NIV had a significant reduction of rehospitalizations during follow-up compared to oxygen group (P = 0.005). These findings were confirmed after propensity matching and pH stratification. CONCLUSIONS: These findings challenge prior paradigms based on the assumption that pulmonary inflammation is per se detrimental. NIV beneficial impact on lung mechanics may overcome the potential unfavorable effects of an increased inflammatory state.

Total adiponectin is inversely associated with platelet activation and CHA2DS2-VASc score in anticoagulated patients with atrial fibrillation.

BACKGROUND: Adiponectin (APN) possesses anti-inflammatory and antiatherogenic effects. Atrial fibrillation (AF) is burdened by enhanced systemic inflammation and platelet activation, as documented by increased blood levels of soluble CD40L (sCD40L). The interplay between APN and platelet activation in AF is still undefined. MATERIALS AND METHODS: Circulating levels of APN and sCD40L were measured in 257 anticoagulated nonvalvular AF patients. Exclusion criteria were as follows: prosthetic heart valves, cardiac revascularization in the previous year, severe cognitive impairment, chronic infectious or autoimmune diseases, and active cancer. RESULTS: Mean age was 72.9 (±8.7) years and 41.6% were female. Serum APN and plasmatic sCD40L were inversely correlated (R -0.626, P < 0.001). A progressive increase of sCD40L across tertiles of CHA2DS2-VASc score was observed (rS 0.473, P < 0.001), whilst APN was inversely correlated (rS -0.463, P < 0.001). A multivariable linear regression analysis showed that CHA2DS2-VASc score (B -0.227, P < 0.001) and sCD40L (B -0.524, P < 0.001) correlated to APN. CONCLUSIONS: AF patients at high risk of stroke disclose low and high levels of APN and sCD40L, respectively, suggesting a role for APN if it favors platelet activation in vivo in this clinical setting. Enhancing APN levels may be a future goal to reduce the risk of vascular outcomes in AF patients.