Sodium-glucose cotransporter 2 inhibitors induce anti-inflammatory and anti-ferroptotic shift in epicardial adipose tissue of subjects with severe heart failure.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure. METHODS: 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed. RESULTS: SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects. CONCLUSIONS: Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.

Interposition of right internal iliac artery free-graft for left coronary artery reimplantation in adults with anomalous left coronary artery originating from the pulmonary artery: case series and long-term results.

Anomalous left coronary artery originating from the pulmonary artery (ALCAPA) is an infrequent congenital anomaly. Presentation of this syndrome is rare in adults. Nevertheless, adult patients are at risk of ischaemia, arrhythmias or sudden cardiac death and always require surgical intervention. At our institution, a specific technique of interposition of the right internal iliac artery as a free-graft for left coronary artery reimplantation was used in adult ALCAPA patients. The aim of this report is to determine long-term results and experiences with this surgical technique.

Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart Failure: The ARIES-HM3 Randomized Clinical Trial.

IMPORTANCE: Left ventricular assist devices (LVADs) enhance quality and duration of life in advanced heart failure. The burden of nonsurgical bleeding events is a leading morbidity. Aspirin as an antiplatelet agent is mandated along with vitamin K antagonists (VKAs) with continuous-flow LVADs without conclusive evidence of efficacy and safety. OBJECTIVE: To determine whether excluding aspirin as part of the antithrombotic regimen with a fully magnetically levitated LVAD is safe and decreases bleeding. DESIGN, SETTING, and PARTICIPANTS: This international, randomized, double-blind, placebo-controlled study of aspirin (100 mg/d) vs placebo with VKA therapy in patients with advanced heart failure with an LVAD was conducted across 51 centers with expertise in treating patients with advanced heart failure across 9 countries. The randomized population included 628 patients with advanced heart failure implanted with a fully magnetically levitated LVAD (314 in the placebo group and 314 in the aspirin group), of whom 296 patients in the placebo group and 293 in the aspirin group were in the primary analysis population, which informed the primary end point analysis. The study enrolled patients from July 2020 to September 2022; median follow-up was 14 months. Intervention: Patients were randomized in a 1:1 ratio to receive aspirin (100 mg/d) or placebo in addition to an antithrombotic regimen. MAIN OUTCOMES AND MEASURES: The composite primary end point, assessed for noninferiority (-10% margin) of placebo, was survival free of a major nonsurgical (>14 days after implant) hemocompatibility-related adverse events (including stroke, pump thrombosis, major bleeding, or arterial peripheral thromboembolism) at 12 months. The principal secondary end point was nonsurgical bleeding events. RESULTS: Of the 589 analyzed patients, 77% were men; one-third were Black and 61% were White. More patients were alive and free of hemocompatibility events at 12 months in the placebo group (74%) vs those taking aspirin (68%). Noninferiority of placebo was demonstrated (absolute between-group difference, 6.0% improvement in event-free survival with placebo [lower 1-sided 97.5% CI, -1.6%]; P < .001). Aspirin avoidance was associated with reduced nonsurgical bleeding events (relative risk, 0.66 [95% confidence limit, 0.51-0.85]; P = .002) with no increase in stroke or other thromboembolic events, a finding consistent among diverse subgroups of patient characteristics. CONCLUSIONS AND RELEVANCE: In patients with advanced heart failure treated with a fully magnetically levitated LVAD, avoidance of aspirin as part of an antithrombotic regimen, which includes VKA, is not inferior to a regimen containing aspirin, does not increase thromboembolism risk, and is associated with a reduction in bleeding events. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04069156.

Bioprosthetic Total Artificial Heart Implantation Does Not Induce Chronic Inflammation.

The Aeson total artificial heart (A-TAH) has been developed for patients at risk of death from biventricular failure. We aimed to assess the inflammatory status in nine subjects implanted with the A-TAH in kinetics over one year. Laboratory assessment of leukocyte counts, inflammatory cytokines assay, and peripheral blood mononuclear cell collection before and after A-TAH implantation. Leukocyte counts were not significantly modulated according to time after A-TAH implantation (coefficient of the linear mixed effect model with 95% CI, -0.05 (-0.71 to -0.61); p = 0.44). We explored inflammatory cytokine after A-TAH and did not observe, at any time, a modified profile compared to pre-implantation values (all p -values > 0.05). Finally, we compared the distribution of circulating immune cell subpopulations identified based on sequential expression patterns for multiple clusters of differentiation. None of the population explored had significant modulation during the 12-month follow-up (all p -values > 0.05). In conclusion, using a cytokine multiplex assay combined with a flow cytometry approach, we demonstrated the absence of inflammatory signals in peripheral blood over a period of 12 months following A-TAH implantation.

Decreased Epicardial CTRP3 mRNA Levels in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease Undergoing Elective Cardiac Surgery: A Possible Association with Coronary Atherosclerosis.

(1) Background: C1q TNF-related protein 3 (CTRP3) is an adipokine with anti-inflammatory and cardioprotective properties. In our study, we explored changes in serum CTRP3 and its gene expression in epicardial (EAT) and subcutaneous (SAT) adipose tissue in patients with and without coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) undergoing elective cardiac surgery. (2) Methods: SAT, EAT, and blood samples were collected at the start and end of surgery from 34 patients: (i) 11 without CAD or T2DM, (ii) 14 with CAD and without T2DM, and (iii) 9 with both CAD and T2DM. mRNA levels of CTRP3 were assessed by quantitative reverse transcription PCR. Circulating levels of CTRP3 and other factors were measured using ELISA and Luminex Multiplex commercial kits. (3) Results: Baseline plasma levels of TNF-α and IL6 did not differ among the groups and increased at the end of surgery. Baseline circulating levels of CTRP3 did not differ among the groups and decreased after surgery. In contrast, baseline CTRP3 mRNA levels in EAT were significantly decreased in CAD/T2DM group, while no differences were found for TNF-α and IL6 gene expression. (4) Conclusions: Our data suggest that decreased EAT mRNA levels of CTRP3 could contribute to higher risk of atherosclerosis in patients with CAD and T2DM.

Bioprosthetic Total Artificial Heart in Autoregulated Mode Is Biologically Hemocompatible: Insights for Multimers of von Willebrand Factor.

BACKGROUND: Carmat bioprosthetic total artificial heart (Aeson; A-TAH) is a pulsatile and autoregulated device. The aim of this study is to evaluate level of hemolysis potential acquired von Willebrand syndrome after A-TAH implantation. METHODS: We examined the presence of hemolysis and acquired von Willebrand syndrome in adult patients receiving A-TAH support (n=10) during their whole clinical follow-up in comparison with control subjects and adult patients receiving Heartmate II or Heartmate III support. We also performed a fluid structure interaction model coupled with computational fluid dynamics simulation to evaluate the A-TAH resulting shear stress and its distribution in the blood volume. RESULTS: The cumulative duration of A-TAH support was 2087 days. A-TAH implantation did not affect plasma free hemoglobin over time, and there was no association between plasma free hemoglobin and cardiac output or beat rate. For VWF (von Willebrand factor) evaluation, A-TAH implantation did not modify multimers profile of VWF in contrast to Heartmate II and Heartmate III. Furthermore, fluid structure interaction coupled with computational fluid dynamics showed a gradually increase of blood damage according to increase of cardiac output (P<0.01), however, the blood volume fraction that endured significant shear stresses was always inferior to 0.03% of the volume for both ventricles in all regimens tested. An inverse association between cardiac output, beat rate, and high-molecular weight multimers ratio was found. CONCLUSIONS: We demonstrated that A-TAH does not cause hemolysis or AWVS. However, relationship between HMWM and cardiac output depending flow confirms relevance of VWF as a biological sensor of blood flow, even in normal range.

Elevated Circulating Stem Cells Level is Observed One Month After Implantation of Carmat Bioprosthetic Total Artificial Heart.

The Aeson® total artificial heart (A-TAH) has been developed as a total heart replacement for patients at risk of death from biventricular failure. We previously described endothelialization of the hybrid membrane inside A-TAH probably at the origin of acquired hemocompatibility. We aimed to quantify vasculogenic stem cells in peripheral blood of patients with long-term A-TAH implantation. Four male adult patients were included in this study. Peripheral blood mononuclear cells were collected before A-TAH implantation (T0) and after implantation at one month (T1), between two and five months (T2), and then between six and twelve months (T3). Supervised analysis of flow cytometry data confirmed the presence of the previously identified Lin-CD133+CD45- and Lin-CD34+ with different CD45 level intensities. Lin-CD133+CD45-, Lin-CD34+CD45- and Lin-CD34+CD45+ were not modulated after A-TAH implantation. However, we demonstrated a significant mobilization of Lin-CD34+CD45dim (p = 0.01) one month after A-TAH implantation regardless of the expression of CD133 or c-Kit. We then visualized data for the resulting clusters on a uniform manifold approximation and projection (UMAP) plot showing all single cells of the live Lin- and CD34+ events selected from down sampled files concatenated at T0 and T1. The three clusters upregulated at T1 are CD45dim clusters, confirming our results. In conclusion, using a flow cytometry approach, we demonstrated in A-TAH-transplanted patients a significant mobilization of Lin-CD34+CD45dim in peripheral blood one month after A-TAH implantation. Using a flow cytometry approach, we demonstrated in A-TAH transplanted patients a significant mobilization of Lin-CD34+CD45dim in peripheral blood one month after A-TAH implantation. This cell population could be at the origin of newly formed endothelial cells on top of hybrid membrane in Carmat bioprosthetic total artificial heart.

Association of thrombophilia prospective detection with hemocompatibility related outcomes in left ventricular assist device patients.

INTRODUCTION: Inherited thrombophilias represent a concerning risk factor due to a proclivity to an aberrant clot formation. However, in patients with left ventricular assist device (LVAD), their impact on bleeding and thrombotic complications remains still poorly understood. The aim of the present study was to evaluate the effect of thrombophilic mutation directed anticoagulation therapy on adverse clinical outcomes in LVAD patients. MATERIALS AND METHODS: About 138 consecutive patients indicated for LVAD implant (HeartMate II, Abbott, Plymouth, USA) were prospectively screened for three major thrombophilic mutations: factor II (prothrombin), factor V Leiden, and homozygous methylenetetrahydrofolate reductase (MTHFR). Subsequently, discordant individualized anticoagulation targets of INR 2.5-3.0 in thrombophilia positive and INR 1.8-2.2 in negative patients were established; notably without anti-platelet agents given the center standard of care. RESULTS: Mean age was 50 ± 12.7 years, 83% male. Mean duration of support was 464.5 days (SD 482.9; SEM 41.1) and median of 310 days (IQR 162; 546). Full thrombophilia positive cohort analysis has not revealed any significant impact on event free survival. In contrast, detailed analysis of specific thrombophilias subsets has revealed Factor II prothrombin mutation as a significant predisposition for the pump thrombosis risk (SHR 10.48; p = 0.001) despite more aggressive prespecified anticoagulation target. Moreover, the incidence of bleeding events in prothrombin group was also significantly increased (SHR 6.0; p = 0.03). CONCLUSIONS: Our observations suggest that specific thrombophilias in LVAD patients may pose different intensity predisposition for thrombotic complications. Factor II (prothrombin) positive mutation was identified as significant risk factor associated with the pump thrombosis.

Increased pulsatility index is associated with adverse outcomes in left ventricular assist device recipients.

AIMS: Recipients of left ventricular assist devices (LVAD) are exposed to increased risk of adverse clinical events. One of the potential contributing factors is non-pulsatile flow generated by LVAD. We evaluated the association of flow patterns in carotid arteries and of increased arterial stiffness with death and cerebrovascular events in LVAD recipients. METHODS AND RESULTS: We analysed data from 83 patients [mean age 54 ± 15 years; 12 women; HeartMate II (HMII), n = 34; HeartMate 3 (HM3), n = 49]. Pulsatile and resistive indexes, atherosclerotic changes in carotid arteries (measured by duplex ultrasound), and arterial stiffness [measured by Endo-PAT 2000 as the augmentation index standardized for heart rate (AI@75)] were evaluated 3 and 6 months after LVAD implantation. Sixteen patients died during follow-up (27.3 months; interquartile range 15.7-44.3). After adjusting for the main variables examined, the pulsatility index measured at 3 months was positively associated with increased hazard ratios (HR) for death and cerebrovascular events [HR 9.8, 95% confidence interval (CI) 1.62-59.42], with HR increasing after adding AI@75 to the model (HR 18.8, 95% CI 2.44-145.50). In HM3 recipients, HR was significantly lower than in HMII recipients (HR 0.31, 95% CI 0.11-0.91), but the significance disappeared after adding AI@75 to the model (HR 0.33, 95% CI 0.09-1.18). CONCLUSIONS: The risk of death and cerebrovascular events in LVAD recipients is associated with increased pulsatility index in carotid arteries and potentiated by increased arterial stiffness. The same risk is attenuated by HM3 LVAD implantation, but this effect is weakened by increased arterial stiffness.

Implantation of durable left ventricular assist device in patient with postmyocardial infarction ventricular septal defect.

Ventricular septal defect (VSD) is a severe complication of myocardial infarction (MI) with a high mortality rate. We report a case of a large post-MI VSD treated with percutaneous venoarterial extracorporeal membrane oxygenation (VA-ECMO) to restore hemodynamic stability and to avoid surgery in the acute setting. VSD closure with endoventricular patch and implantation of biventricular assist device (BiVAD) was arranged sixteen days after MI. Because of no signs of myocardial recovery, implantation of durable left ventricular assist device (LVAD) as a bridge to transplant was provided, leaving right ventricular assist device (RVAD) to right ventricle recovery. RVAD was explanted 18 days after durable LVAD placement and the patient was discharged home two months after MI. The use of durable LVAD is a unique solution that can be applied in selected patients with MI-VSD and heart failure.

The effect of long-term left ventricular assist device support on flow-sensitive plasma microRNA levels.

BACKGROUND: Implantation of current generation left ventricular assist devices (LVADs) in the treatment of end-stage heart failure (HF), not only improves HF symptoms and end-organ perfusion, but also leads to cellular and molecular responses, presumably in response to the continuous flow generated by these devices. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression in multiple biological processes, including the pathogenesis of HF. In our study, we examined the influence of long-term LVAD support on changes in flow-sensitive miRNAs in plasma. MATERIALS AND METHODS: Blood samples from patients with end-stage heart failure (N = 33; age = 55.7 ± 11.6 years) were collected before LVAD implantation and 3, 6, 9, and 12 months after implantation. Plasma levels of the flow-sensitive miRNAs; miR-10a, miR-10b, miR-146a, miR-146b, miR-663a, miR-663b, miR-21, miR-155, and miR-126 were measured using quantitative PCR. RESULTS: Increasing quantities of miR-126 (P < 0.03) and miR-146a (P < 0.02) was observed at each follow-up visit after LVAD implantation. A positive association between miR-155 and Belcaro score (P < 0.04) and an inverse correlation between miR-126 and endothelial function, measured as the reactive hyperemia index (P < 0.05), was observed. CONCLUSIONS: Our observations suggest that after LVAD implantation, low pulsatile flow up-regulates plasma levels of circulating flow-sensitive miRNAs, contributing to endothelial dysfunction and vascular remodeling.

An Integrative Study of Aortic mRNA/miRNA Longitudinal Changes in Long-Term LVAD Support.

Studying the long-term impact of continuous-flow left ventricular assist device (CF-LVAD) offers an opportunity for a complex understanding of the pathophysiology of vascular changes in aortic tissue in response to a nonphysiological blood flow pattern. Our study aimed to analyze aortic mRNA/miRNA expression changes in response to long-term LVAD support. Paired aortic samples obtained at the time of LVAD implantation and at the time of heart transplantation were examined for mRNA/miRNA profiling. The number of differentially expressed genes (Pcorr < 0.05) shared between samples before and after LVAD support was 277. The whole miRNome profile revealed 69 differentially expressed miRNAs (Pcorr < 0.05). Gene ontology (GO) analysis identified that LVAD predominantly influenced genes involved in the extracellular matrix and collagen fibril organization. Integrated mRNA/miRNA analysis revealed that potential targets of miRNAs dysregulated in explanted samples are mainly involved in GO biological process terms related to dendritic spine organization, neuron projection organization, and cell junction assembly and organization. We found differentially expressed genes participating in vascular tissue engineering as a consequence of LVAD duration. Changes in aortic miRNA levels demonstrated an effect on molecular processes involved in angiogenesis.

First Clinical Experience With the Pressure Sensor-Based Autoregulation of Blood Flow in an Artificial Heart.

The CARMAT-Total Artificial Heart (C-TAH) is designed to provide heart replacement therapy for patients with end-stage biventricular failure. This report details the reliability and efficacy of the autoregulation device control mechanism (auto-mode), designed to mimic normal physiologic responses to changing patient needs. Hemodynamic data from a continuous cohort of 10 patients implanted with the device, recorded over 1,842 support days in auto-mode, were analyzed with respect to daily changing physiologic needs. The C-TAH uses embedded pressure sensors to regulate the pump output. Right and left ventricular outputs are automatically balanced. The operator sets target values and the inbuilt algorithm adjusts the stroke volume and beat rate, and hence cardiac output, automatically. Auto-mode is set perioperatively after initial postcardiopulmonary bypass hemodynamic stabilization. All patients showed a range of average inflow pressures of between 5 and 20 mm Hg during their daily activities, resulting in cardiac output responses of between 4.3 and 7.3 L/min. Operator adjustments were cumulatively only required on 20 occasions. This report demonstrates that the C-TAH auto-mode effectively produces appropriate physiologic responses reflective of changing patients' daily needs and represents one of the unique characteristics of this device in providing almost physiologic heart replacement therapy.

European registry of type A aortic dissection (ERTAAD) - rationale, design and definition criteria.

BACKGROUND: Acute Stanford type A aortic dissection (TAAD) is a life-threatening condition. Surgery is usually performed as a salvage procedure and is associated with significant postoperative early mortality and morbidity. Understanding the patient's conditions and treatment strategies which are associated with these adverse events is essential for an appropriate management of acute TAAD. METHODS: Nineteen centers of cardiac surgery from seven European countries have collaborated to create a multicentre observational registry (ERTAAD), which will enroll consecutive patients who underwent surgery for acute TAAD from January 2005 to March 2021. Analysis of the impact of patient's comorbidities, conditions at referral, surgical strategies and perioperative treatment on the early and late adverse events will be performed. The investigators have developed a classification of the urgency of the procedure based on the severity of preoperative hemodynamic conditions and malperfusion secondary to acute TAAD. The primary clinical outcomes will be in-hospital mortality, late mortality and reoperations on the aorta. Secondary outcomes will be stroke, acute kidney injury, surgical site infection, reoperation for bleeding, blood transfusion and length of stay in the intensive care unit. DISCUSSION: The analysis of this multicentre registry will allow conclusive results on the prognostic importance of critical preoperative conditions and the value of different treatment strategies to reduce the risk of early adverse events after surgery for acute TAAD. This registry is expected to provide insights into the long-term durability of different strategies of surgical repair for TAAD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04831073 .

The Effect of Artificial Pulsatility on the Peripheral Vasculature in Patients With Continuous-Flow Ventricular Assist Devices.

BACKGROUND: Implantation of left-ventricular assist systems (LVASs) has become the standard of care for advanced heart failure (HF). The absence of pulsatility in previous devices contributes to vascular and endothelial dysfunction related to atherosclerotic or vascular complications. We hypothesized that the artificial pulsatility provided by the HeartMate 3 (HM3) (Abbott, Chicago, IL) LVAS would exert a favourable effect on the vasculature. METHODS: In 32 patients implanted with HM3 (5 female patients, mean age 55 ± 13.6 years), the reactive hyperemia index (RHI) and peripheral augmentation index (AI), markers of endothelial function and arterial stiffness, were measured with an EndoPAT2000 before and in the third and sixth month after implantation. RHI and AI data from 30 HeartMate II (HM II) (Abbott) recipients in the third and sixth month after implantation, from 15 patients with advanced HF without LVASs and from 13 healthy volunteers were also analyzed. RESULTS: In HM3 recipients, the mean RHI significantly decreased at 3 and 6 months after implantation. The RHI was substantially lower at baseline than that of healthy or the HF reference group. Increasing AI values, indicating worsening arterial stiffness, were also observed. Similar trends were observed in HM II recipients between the third and sixth months but with higher absolute values of RHI and AI. CONCLUSIONS: We detected impaired vascular function in HM3 patients and provided additional evidence on the negative effect of low pulsatility on vascular function after LVAS implantation. The results suggest that the artificial pulsatility of the HM3 does not avert the progression of endothelial dysfunction.

Different Expression of Mitochondrial and Endoplasmic Reticulum Stress Genes in Epicardial Adipose Tissue Depends on Coronary Atherosclerosis.

The aim of our study was to analyze mitochondrial and endoplasmic reticulum (ER) gene expression profiles in subcutaneous (SAT) and epicardial (EAT) adipose tissue, skeletal muscle, and myocardium in patients with and without CAD undergoing elective cardiac surgery. Thirty-eight patients, 27 with (CAD group) and 11 without CAD (noCAD group), undergoing coronary artery bypass grafting and/or valvular surgery were included in the study. EAT, SAT, intercostal skeletal muscle, and right atrium tissue and blood samples were collected at the start and end of surgery; mRNA expression of selected mitochondrial and ER stress genes was assessed using qRT-PCR. The presence of CAD was associated with decreased mRNA expression of most of the investigated mitochondrial respiratory chain genes in EAT, while no such changes were seen in SAT or other tissues. In contrast, the expression of ER stress genes did not differ between the CAD and noCAD groups in almost any tissue. Cardiac surgery further augmented mitochondrial dysfunction in EAT. In our study, CAD was associated with decreased expression of mitochondrial, but not endoplasmic reticulum stress genes in EAT. These changes may contribute to the acceleration of coronary atherosclerosis.