Refractory cor pulmonale under extracorporeal membrane oxygenation for acute respiratory distress syndrome: the role of conversion to veno-pulmonary arterial assist-a case series.

Introduction: Pulmonary vascular dysfunction during severe acute respiratory distress syndrome (ARDS) may lead to right ventricle (RV) dysfunction and acute cor pulmonale (ACP). The occurrence/persistence of ACP despite conventional extracorporeal membrane oxygenation (ECMO) is a challenging situation. We explored the usefulness of a specific dual-lumen cannula that bypasses the RV, and on which a veno-pulmonary arterial assist (V-P ECMO) was mounted, in ARDS patients. Methods: We report a case-series of ARDS patients put on conventional veno-arterial or veno-venous ECMO and presented refractory ACP as an indication for a reconfiguration to V-P ECMO using the ProtekDuo cannula. The primary endpoint was the mitigation of RV and pulmonary vascular dysfunction as assessed by the change in end-diastolic RV/left ventricle (LV) surface ratio. Results: Six patients had their conventional ECMO reconfigured to V-P ECMO to treat refractory ACP. There was a decrease in end-diastolic RV/LV surface ratio, as well as end-systolic LV eccentricity index, and lactatemia immediately after V-P ECMO initiation. The resolution of refractory ACP was immediately achieved in four of our six (66%) patients. The V-P ECMO was weaned after a median of 26 [8-93] days after implantation. All but one patient were discharged home. We detected one case of severe hemolysis with V-P ECMO and two suspected cases of right-sided infective endocarditis. Conclusion: V-P ECMO is useful to mitigate RV overload and to improve hemodynamics in case of refractory ACP despite conventional ECMO.

Association between pulmonary artery pulsatility and mortality after implantation of left ventricular assist device.

AIMS: Right ventricular failure after left ventricular assist device (LVAD) implantation is a major concern that remains challenging to predict. We sought to investigate the relationship between preoperative pulmonary artery pulsatility index (PAPi) and mortality after LVAD implantation. METHODS AND RESULTS: A retrospective analysis of the ASSIST-ICD multicentre registry allowed the assessment of PAPi before LVAD according to the formula [(systolic pulmonary artery pressure - diastolic pulmonary artery pressure)/central venous pressure]. The primary endpoint was survival at 3 months, according to the threshold value of PAPi determined by the receiver operating characteristic (ROC) curve. A multivariate analysis including demographic, echographic, haemodynamic, and biological variables was performed to identify predictive factors for 2 year mortality. One hundred seventeen patients were included from 2007 to 2021. The mean age was 58.45 years (±13.16), with 15.4% of women (sex ratio 5.5). A total of 53.4% were implanted as bridge to transplant and 43.1% as destination therapy. Post-operative right ventricular failure was observed in 57 patients (48.7%), with no significant difference between survivors and non-survivors at 1 month (odds ratio 1.59, P = 0.30). The median PAPi for the whole study population was 2.83 [interquartile range 1.63-4.69]. The threshold value of PAPi determined by the ROC curve was 2.84. Patients with PAPi ≥ 2.84 had a higher survival rate at 3 months [PAPi < 2.84: 58.1% [46.3-72.8%] vs. PAPi ≥ 2.84: 89.1% [81.1-97.7%], hazard ratio (HR) 0.08 [0.02-0.28], P < 0.01], with no significant difference after 3 months (HR 0.67 [0.17-2.67], P = 0.57). Other predictors of 2 year mortality were systemic hypertension (HR 4.22 [1.49-11.97], P < 0.01) and diabetes mellitus (HR 4.90 [1.83-13.14], P < 0.01). LVAD implantation as bridge to transplant (HR 0.18 [0.04-0.74], P = 0.02) and heart transplantation (HR 0.02 [0.00-0.18], P < 0.01) were associated with a higher survival rate at 2 years. CONCLUSIONS: Preoperative PAPi < 2.84 was associated with a higher risk of early mortality after LVAD implantation without impacting 2 year outcomes among survivors.

Light-induced Trpin/Metout Switching During BLUF Domain Activation in ATP-bound Photoactivatable Adenylate Cyclase OaPAC.

The understanding of signal transduction mechanisms in photoreceptor proteins is essential for elucidating how living organisms respond to light as environmental stimuli. In this study, we investigated the ATP binding, photoactivation and signal transduction process in the photoactivatable adenylate cyclase from Oscillatoria acuminata (OaPAC) upon blue light excitation. Structural models with ATP bound in the active site of native OaPAC at cryogenic as well as room temperature are presented. ATP is found in one conformation at cryogenic- and in two conformations at ambient-temperature, and is bound in an energetically unfavorable conformation for the conversion to cAMP. However, FTIR spectroscopic experiments confirm that this conformation is the native binding mode in dark state OaPAC and that transition to a productive conformation for ATP turnover only occurs after light activation. A combination of time-resolved crystallography experiments at synchrotron and X-ray Free Electron Lasers sheds light on the early events around the Flavin Adenine Dinucleotide (FAD) chromophore in the light-sensitive BLUF domain of OaPAC. Early changes involve the highly conserved amino acids Tyr6, Gln48 and Met92. Crucially, the Gln48 side chain performs a 180° rotation during activation, leading to the stabilization of the FAD chromophore. Cryo-trapping experiments allowed us to investigate a late light-activated state of the reaction and revealed significant conformational changes in the BLUF domain around the FAD chromophore. In particular, a Trpin/Metout transition upon illumination is observed for the first time in the BLUF domain and its role in signal transmission via α-helix 3 and 4 in the linker region between sensor and effector domain is discussed.

Predictive value of the TRI-SCORE for in-hospital mortality after redo isolated tricuspid valve surgery.

OBJECTIVES: The TRI-SCORE reliably predicts in-hospital mortality after isolated tricuspid valve surgery (ITVS) on native valve but has not been tested in the setting of redo interventions. We aimed to evaluate the predictive value of the TRI-SCORE for in-hospital mortality in patients with redo ITVS and to compare its accuracy with conventional surgical risk scores. METHODS: Using a mandatory administrative database, we identified all consecutive adult patients who underwent a redo ITVS at 12 French tertiary centres between 2007 and 2017. Baseline characteristics and outcomes were collected from chart review and surgical scores were calculated. RESULTS: We identified 70 patients who underwent a redo ITVS (54±15 years, 63% female). Prior intervention was a tricuspid valve repair in 51% and a replacement in 49%, and was combined with another surgery in 41%. A tricuspid valve replacement was performed in all patients for the redo surgery. Overall, in-hospital mortality and major postoperative complication rates were 10% and 34%, respectively. The TRI-SCORE was the only surgical risk score associated with in-hospital mortality (p=0.005). The area under the receiver operating characteristic curve for the TRI-SCORE was 0.83, much higher than for the logistic EuroSCORE (0.58) or EuroSCORE II (0.61). The TRI-SCORE was also associated with major postoperative complication rates and survival free of readmissions for heart failure. CONCLUSION: Redo ITVS was rarely performed and was associated with an overall high in-hospital mortality and morbidity, but hiding important individual disparities. The TRI-SCORE accurately predicted in-hospital mortality after redo ITVS and may guide clinical decision-making process (www.tri-score.com).

Hybrid Androgen Receptor Inhibitors Outperform Enzalutamide and EPI-001 in in†vitro Models of Prostate Cancer Drug Resistance.

Androgen receptor targeted therapies for prostate cancer have serious limitations in advanced stages of the disease. While resistance to the FDA-approved enzalutamide is extensively documented, novel therapies based on epichlorohydrin scaffolds (EPI) are currently in clinical trials, but display suboptimal pharmacokinetics. Herein, we report the synthesis and biological characterisation of a novel class of compounds designed through covalently linking enzalutamide and EPI-001 through various triazole based linkers. The compounds display an 18 to 53 fold improvement in the cell killing potency towards C4-2b prostate cancer (PCa) cells compared to the gold standards of therapy, enzalutamide and EPI-001. The most promising compounds were proven to exhibit their toxicity exclusively through androgen receptor (AR) mediated pathways. This work sets the basis for the first class of hybrid AR inhibitors which successfully combine two drug moieties - EPI-001 and enzalutamide - into the same molecule.

Heart Transplantation, Either Alone or Combined With Liver and Kidney, a Viable Treatment Option for Selected Patients With Severe Cardiac Amyloidosis.

Heart transplantation in cardiac amyloidosis (CA) patients is possible and generally considered for transplantation if other organs are not affected. In this study, we aimed to describe and assess outcome in patients following heart transplantations at our CA referral center. Methods: We assessed all CA patients that had heart transplantations at our center between 2005 and 2018. Patients with New York Heart Association status 3 out of 4, with poor short-term prognosis due to heart failure, despite treatment, and without multiple myeloma, systemic disease, severe neuropathic/digestive comorbidities, cancer, or worsening infections were eligible for transplantation. Hearts were transplanted by bicaval technique. Standard induction and immunosuppressive therapies were used. Survival outcome of CA patients after transplantation was compared with recipients with nonamyloid pathologies in France. Results: Between 2005 and 2018, 23 CA patients had heart transplants: 17 (74%) had light chain (light chain amyloidosis [AL]) and 6 (26%) had hereditary transthyretin (hereditary transthyretin amyloidosis [ATTRv]) CA. Also, 13 (57%) were male, and the mean age at diagnosis was 56.5 y (range, 47.7-62.8). Among AL patients, 13 had heart-only and 5 had heart-kidney transplantations. Among ATTRv patients, 1 had heart-only and 5 had heart-liver transplantations. The 1-y survival rate after transplantation was 78%, 70% with AL, and 100% with ATTRv. At 2 y, 74% were alive: 65% with AL and 100% with ATTRv. Conclusion: After heart transplantation, French CA and nonamyloid patients have similar survival outcomes. Among CA patients, ATTRv patients have better prognosis than those with AL, possibly due to the combined heart-liver transplantation. Selected CA patients should be considered for heart transplantations.

Outcome of Temporary Circulatory Support As a Bridge-to-Left Ventricular Assist Device Strategy in Cardiogenic Shock Patients.

OBJECTIVES: Temporary circulatory support (TCS) as a bridge-to-left ventricular assist device (BTL) in cardiogenic shock patients has been increasing, but limited data exists on this BTL strategy. We aimed at analyzing the outcome of BTL patients in a population of cardiogenic shock patients compared with those without TCS at the time of the left ventricular assist device (LVAD) surgery and identify predictors of postoperative mortality in this specific population. DESIGN: A multicenter retrospective observational study conducted in 19 centers from 2006 to 2016. SETTING: Nineteen French centers. PATIENTS: A total of 329 cardiogenic shock patients at the time of LVAD implantation were analyzed. Patients were divided in three groups: those under TCS at the time of LVAD implantation (n = 173), those with TCS removal before LVAD surgery (n = 24), and those who did not undergo a bridging strategy (n = 152). Primary endpoint was 30-day mortality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the BTL group, 68 (39.3%), 18 (10.4%), and 15 (8.7%) patients were under venoarterial extracorporeal membrane oxygenation, Impella, and IABP support alone, and 72 patients (20.6%) were under multiple TCS support. BTL patients presented similar 30 days survival compared with the TCS removal and non-BTL groups. However, BTL group had a significantly longer ICU duration stay, with two-fold duration of mechanical ventilation time, but the three groups experienced similar postoperative complications. Multivariate analysis identified three independent predictors of mortality in the BTL group: combined surgery with LVAD, body mass index (BMI), and heart failure (HF) duration. BTL strategy was not an independent predictor of mortality in cardiogenic shock patients who underwent LVAD. CONCLUSIONS: BTL strategy is not associated with a lower survival among cardiogenic shock patients with LVAD implantation. Predictors of mortality are combined surgery with LVAD, higher BMI, and HF duration.

Percutaneous angio-guided versus surgical veno-arterial ECLS implantation in patients with cardiogenic shock or cardiac arrest.

BACKGROUND: Veno-arterial Extracorporeal Life Support (V-A ECLS) has gained increasing place into the management of patients with refractory cardiogenic shock or cardiac arrest. Both surgical and percutaneous approach can be used for cannulation, but percutaneous approach has been associated with fewer complications. Angio-guided percutaneous cannulation and decannulation may further decrease the rate of complication. We aimed to compare outcome and complication rates in patients supported with V-A ECLS through percutaneous angio-guided versus surgical approach. METHODS: We included all patients with emergent peripheral femoro-femoral V-A ECLS implantation for refractory cardiogenic shock or cardiac arrest in our center from March 2018 to March 2021. Survival and major complications (major bleeding, limb ischemia and groin infection) rates were compared between the percutaneous angio-guided and the surgical groups. RESULTS: One hundred twenty patients received V-A ECLS, 59 through surgical approach and 61 through angio-guided percutaneous approach. Patients' baseline characteristics and severity scores were equally balanced between the 2 groups. Thirty-day mortality was not significantly different between the 2 approaches. However, angio-guided percutaneous cannulation was associated with fewer major vascular complications (42% vs. 11%, p > 0.0001) and a higher rate of V-A ECLS decannulation. In multivariate analysis, percutaneous angio-guided implantation of V-A ECLS was independently associated with a lower probability of major complications. CONCLUSION: Compared to surgical approach, angio-guided percutaneous V-A ECLS implantation is associated with fewer major vascular complications. Larger studies are needed to confirm those results and address their impact on mortality.

Dysregulated Phenylalanine Catabolism Plays a Key Role in the Trajectory of Cardiac Aging.

BACKGROUND: Aging myocardium undergoes progressive cardiac hypertrophy and interstitial fibrosis with diastolic and systolic dysfunction. Recent metabolomics studies shed light on amino acids in aging. The present study aimed to dissect how aging leads to elevated plasma levels of the essential amino acid phenylalanine and how it may promote age-related cardiac dysfunction. METHODS: We studied cardiac structure and function, together with phenylalanine catabolism in wild-type (WT) and p21-/- mice (male; 2-24 months), with the latter known to be protected from cellular senescence. To explore phenylalanine's effects on cellular senescence and ectopic phenylalanine catabolism, we treated cardiomyocytes (primary adult rat or human AC-16) with phenylalanine. To establish a role for phenylalanine in driving cardiac aging, WT male mice were treated twice a day with phenylalanine (200 mg/kg) for a month. We also treated aged WT mice with tetrahydrobiopterin (10 mg/kg), the essential cofactor for the phenylalanine-degrading enzyme PAH (phenylalanine hydroxylase), or restricted dietary phenylalanine intake. The impact of senescence on hepatic phenylalanine catabolism was explored in vitro in AML12 hepatocytes treated with Nutlin3a (a p53 activator), with or without p21-targeting small interfering RNA or tetrahydrobiopterin, with quantification of PAH and tyrosine levels. RESULTS: Natural aging is associated with a progressive increase in plasma phenylalanine levels concomitant with cardiac dysfunction, whereas p21 deletion delayed these changes. Phenylalanine treatment induced premature cardiac deterioration in young WT mice, strikingly akin to that occurring with aging, while triggering cellular senescence, redox, and epigenetic changes. Pharmacological restoration of phenylalanine catabolism with tetrahydrobiopterin administration or dietary phenylalanine restriction abrogated the rise in plasma phenylalanine and reversed cardiac senescent alterations in aged WT mice. Observations from aged mice and human samples implicated age-related decline in hepatic phenylalanine catabolism as a key driver of elevated plasma phenylalanine levels and showed increased myocardial PAH-mediated phenylalanine catabolism, a novel signature of cardiac aging. CONCLUSIONS: Our findings establish a pathogenic role for increased phenylalanine levels in cardiac aging, linking plasma phenylalanine levels to cardiac senescence via dysregulated phenylalanine catabolism along a hepatic-cardiac axis. They highlight phenylalanine/PAH modulation as a potential therapeutic strategy for age-associated cardiac impairment.

Comparison of Outcomes and Mortality in Patients Having Left Ventricular Assist Device Implanted Early -vs- Late After Diagnosis of Cardiomyopathy.

LVAD implantation in patients with a recently diagnosed cardiomyopathy has been poorly investigated. This work aims at describing the characteristics and outcomes of patients receiving a LVAD within 30 days following the diagnosis of cardiomyopathy. Patients from the ASSIST-ICD study was divided into recently and remotely diagnosed cardiomyopathy based on the time from initial diagnosis of cardiomyopathy to LVAD implantation using the cut point of 30 days. The primary end point of the study was all-cause mortality at 30-day and during follow-up. A total of 652 patients were included and followed during a median time of 9.1 (2.5 to 22.1) months. In this population, 117 (17.9%) had a recently diagnosed cardiomyopathy and had LVAD implantation after a median time of 15.0 (9.0 to 24.0) days following the diagnosis. This group of patients was significantly younger, with more ischemic cardiomyopathy, more sudden cardiac arrest (SCA) events at the time of the diagnosis and were more likely to receive temporary mechanical support before LVAD compared with the remotely diagnosed group. Postoperative in-hospital survival was similar in groups, but recently diagnosed patients had a better long-term survival after hospital discharge. SCA before LVAD and any cardiac surgery combined with LVAD implantation were identified as 2 independent predictors of postoperative mortality in recently diagnosed patients. In conclusion, rescue LVAD implantation for recently diagnosed severe cardiomyopathy is common in clinical practice. Such patients experience a relatively low postoperative mortality and have a better long-term survival compared with remotely diagnosed patients.

Left Ventricle Unloading Through Pulmonary Artery in Patients With Venoarterial Extracorporeal Membrane Oxygenation.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) initiation for patients with cardiogenic shock or cardiac arrest is an attractive strategy since it provides a quick restoration of organ perfusion. One major limitation of VA-ECMO is left ventricle (LV) distension which is associated with poor prognosis. To prevent or treat LV distension, LV decompression may be required. Current strategies for LV decompression have some contraindications, carry a high risk of complications and, for some of them concerns remain regarding their effectiveness. We here describe our experience in two adult patients treated with VA-ECMO in whom indirect LV unloading using pulmonary artery venting was performed for the prevention and the treatment of LV distension, respectively. The placement of the venting cannula in the pulmonary trunk was quick, easy and safe and was associated with the resolution of LV distension. These results suggest that pulmonary artery venting may be an attractive strategy for indirect LV decompression during VA-ECMO.

Septuagenarian population has similar survival and outcomes to younger patients after left ventricular assist device implantation.

BACKGROUND: Left ventricular assist device (LVAD) implantation may be an attractive alternative therapeutic option for elderly patients with heart failure who are ineligible for heart transplantation. AIM: We aimed to describe the characteristics and outcomes of elderly patients (i.e. aged≥70 years) receiving an LVAD. METHODS: This observational study was conducted in 19 centres between 2006 and 2016. Patients were divided into two groups-younger (aged<70 years) and elderly (aged≥70 years), based on age at time of LVAD implantation. RESULTS: A total of 652 patients were included in the final analysis, and 74 patients (11.3%) were aged≥70 years at the time of LVAD implantation (maximal age 77.6 years). The proportion of elderly patients receiving an LVAD each year was constant, with a median of 10.6% (interquartile range 8.0-15.4%) per year, and all were implanted as destination therapy. Elderly and younger patients had similar durations of hospitalization in intensive care units and total lengths of hospital stays. Both age groups experienced similar rates of LVAD-related complications (i.e. stroke, bleeding, driveline infection and LVAD exchange), and the occurrence of LVAD complications did not impact survival in the elderly group compared with the younger group. Lastly, when compared with younger patients implanted as destination therapy, the elderly group also exhibited similar mid-term survival. CONCLUSION: This work strongly suggests that selected elderly adults can be scheduled for LVAD implantation.

Relation of Body Mass Index to Outcomes in Patients With Heart Failure Implanted With Left Ventricular Assist Devices.

We aimed at characterizing the impact of low and high body mass index (BMI) on outcomes after left-ventricular assist device (LVAD) surgery and define the predictors of mortality in patients with abnormal BMI (low/high). This study was conducted in 19 centers from 2006 to 2016. Patients were divided based on their baseline BMI into 3 groups of BMI: low (BMI ≤18.5 kg/m²); normal (BMI = 18.5 to 24.99 kg/m²) and high (BMI ≥25 kg/m²) (including overweight (BMI = 25 to 29.99 kg/m²), and obesity (BMI ≥30 Kg/m²)). Among 652 patients, 29 (4.4%), 279 (42.8%) and 344 (52.8%) had a low-, normal-, and high BMI, respectively. Patients with high BMI were significantly more likely men, with more co-morbidities and more history of ventricular/supra-ventricular arrhythmias before LVAD implantation. Patients with abnormal BMI had significantly lower survival than those with normal BMI. Notably, those with low BMI experienced the worst survival whereas overweight or obese patients had similar survival. Four predictors of mortality for LVAD candidates with abnormal BMI were defined: total bilirubin ≥16 µmol/L before LVAD, hypertension, destination therapy, and cardiac surgery with LVAD. Depending on the number of predictor per patients, those with abnormal BMI may be divided in 3 groups of 1-year mortality risk, i.e., low (0 to 1 predictor: 29% and 31%), intermediate (2 to 3 predictors, 51% and 52%, respectively), and high (4 predictors: 83%). In conclusion, LVAD recipients with abnormal BMI experience lower survival, especially underweight patients. Four predictors of mortality have been identified for LVAD population with abnormal BMI, differentiating those a low-, intermediate-, and high risks of death.

Current results of left ventricular assist device therapy in France: the ASSIST-ICD registry.

OBJECTIVES: Our goal was to provide a picture of left ventricular assist device (LVAD) activity in France between 2007 and 2016 based on the multicentric ASSIST-ICD registry. METHODS: We retrospectively collected 136 variables including in-hospital data, follow-up survival rates and adverse events from 671 LVAD recipients at 20 out of 24 LVAD implant centres in France. The average follow-up time was 1.2 years (standard deviation: 1.4); the total follow-up time was 807.5 patient-years. RESULTS: The included devices were the HeartMate II®, HeartWare LVAS® or Jarvik 2000®. The overall likelihood of being alive while on LVAD support or having a transplant (primary end point) at 1, 2, 3 and 5 years postimplantation was 65.2%, 59.7%, 55.9% and 47.7%, respectively, given a cumulative incidence of 29.2% of receiving a transplant at year 5. At implantation, 21.5% of patients were on extracorporeal life support. The overall rate of cardiogenic shock at implantation was 53%. The major complications were driveline infection (26.1%), pump pocket or cannula infection (12.6%), LVAD thrombosis (12.2%), ischaemic (12.8%) or haemorrhagic stroke (5.4%; all strokes 18.2%), non-cerebral haemorrhage (9.1%) and LVAD exchange (5.2%). The primary end point (survival) was stratified by age at surgery and by the type of device used, with inference from baseline profiles. The primary end point combined with an absence of complications (secondary end point) was also stratified by device type. CONCLUSIONS: The ASSIST-ICD registry provides a real-life picture of LVAD use in 20 of the 24 implant centres in France. Despite older average age and a higher proportion of patients chosen for destination therapy, survival rates improved compared to those in previous national registry results. This LVAD registry contrasts with other international registries because patients with implants have more severe disease, and the national policy for graft attribution is distinct. We recommend referring patients for LVAD earlier and suggest a discussion of the optimal timing of a transplant for bridged patients (more dismal results after the second year of support?).

Late cardiovascular complication after varicose vein endovascular ablation.

Venous insufficiency of the lower limbs is one of the most common vascular disorders affecting millions of people worldwide. Endovascular techniques are considered by current guidelines as simple, safe and effective. Persistence or even migration of foreign bodies after varicose vein endovascular surgery is a rare and unfeared complication. Herein, we present the case of a 39-year-old woman who underwent endoluminal treatment of varicose veins >2 years ago and she was admitted to our department for late cardiovascular complication caused by catheter or guidewire rupture and the dissemination of its fragments in the inferior vena cava, right heart chambers, liver and pulmonary arteries. A systematic verification of the length and integrity of the devices should be performed at the end of every endovascular procedure.

Extracorporeal membrane oxygenation support in acute circulatory failure: A plea for regulation and better organization.

Emergent implantation of temporary mechanical circulatory support using venoarterial ECMO (ECLS for extracorporeal Life Support) is increasingly adopted in various indications of acute circulatory failure refractory to optimal medical treatment. To implant such devices, but also to provide appropriate daily management, expertise and adapted technical platform are required. Organization, coordination and regulation of such program are not clearly established in our country. We propose a dedicated territorial organization to improve and facilitate management of these specific and most severe patients.

Causes and consequences of cardiac fibrosis in patients referred for surgical aortic valve replacement.

AIMS: Cardiac fibrosis is associated with left ventricular (LV) remodelling and contractile dysfunction in aortic stenosis (AS). The fibrotic process in this condition is still unclear. The aim of this study was to determine the role of both local and systemic inflammation as underlying mechanisms of LV fibrosis and contractile dysfunction. The diagnostic values of 2D-strain echocardiography and serum biomarkers in the evaluation of cardiac fibrosis in this condition were assessed through correlation analyses. METHODS AND RESULTS: Patients with AS referred for surgical valve replacement were prospectively and consecutively included. They all had a comprehensive echocardiography including 2D strain. Blood samples were collected to measure cytokines and inflammatory biomarkers using Luminex bead-based assays. A per-surgical myocardial biopsy of the basal antero-septal segment (S1) was performed. Serial sections of each biopsy were stained with Sirius red. Digital image analysis was used to quantify fibrosis. Immunostainings using specific antibodies against macrophage, glycoprotein (gp) 130, and interleukin 6 (IL-6) were also performed. Patients were divided into tertiles reflecting the severity of fibrosis: mild, moderate, and severe load (TF1 to TF3). The mean age of the 58 included patients was 73 ± 11 years. Twenty-four (43%) were in New York Heart Association III-IV. Mean aortic valve area was 0.8 ± 0.2 cm2 . Mean aortic stenosis peak velocity and mean gradient were respectively 4.5 ± 0.8 m/s and 54 ± 15 mmHg. The mean LV ejection fraction was 54 ± 12%, and the global LV longitudinal strain was -15 ± 4%. The mean S1 strain, corresponding to the biopsied region, was -10 ± 6% and was strongly correlated to fibrosis load (R = 0.83, P < 0.0001). TF3 was associated with higher mortality (P = 0.009), higher serum C-reactive protein and IL-6, and lower gp130 compared with the other tertiles (P < 0.05). IL-6 and gp130 were expressed in the heart and respectively in the plasma membrane of macrophages and in the cytoplasm of both macrophages and cardiomyocytes. During follow-up, three patients died and were all in the third fibrosis tertile. CONCLUSIONS: We found a positive correlation between elevated inflammatory markers and degree of fibrosis load. These two parameters were associated with worse outcomes in patients with severe AS. Our results may be of interest especially in patients for whom a transcatheter aortic valve implantation is indicated and myocardial biopsy is not possible. Strategies aiming at preventing inflammation might be considered to decrease or limit the progression of cardiac fibrosis in patients followed for AS.

Predictors and Clinical Impact of Late Ventricular Arrhythmias in Patients With Continuous-Flow Left Ventricular Assist Devices.

OBJECTIVES: This study aimed to evaluate the incidence, clinical impact, and predictors of late ventricular arrhythmias (VAs) in left ventricular assist device (LVAD) recipients aiming to clarify implantable cardioverter-defibrillator (ICD) indications. BACKGROUND: The arrhythmic risk and need for ICD in patients implanted with an LVAD are not very well known. METHODS: This observational study was conducted in 19 centers between 2006 and 2016. Late VAs were defined as sustained ventricular tachycardia or fibrillation occurring >30 days post-LVAD implantation, without acute reversible cause and requiring appropriate ICD therapy, external electrical shock, or medical therapy. RESULTS: Among 659 LVAD recipients, 494 (median 58.9 years of age; mean left ventricular ejection fraction 20.7 ± 7.4%; 73.1% HeartMate II, 18.6% HeartWare, 8.3% Jarvik 2000) were discharged alive from hospital and included in the final analysis. Late VAs occurred in 133 (26.9%) patients. Multivariable analysis identified 6 independent predictors of late VAs: VAs before LVAD implantation, atrial fibrillation before LVAD implantation, idiopathic etiology of the cardiomyopathy, heart failure duration >12 months, early VAs (<30 days post-LVAD), and no angiotensin-converting enzyme inhibitors during follow-up. The "VT-LVAD score" was created, identifying 4 risk groups: low (score 0 to 1), intermediate (score 2 to 4), high (score 5 to 6), and very high (score 7 to 10). The rates of VAs at 1 year were 0.0%, 8.0%, 31.0% and 55.0%, respectively. CONCLUSIONS: Late VAs are common after LVAD implantation. The VT-LVAD score may help to identify patients at risk of late VAs and guide ICD indications in previously nonimplanted patients. (Determination of Risk Factors of Ventricular Arrhythmias [VAs] after implantation of continuous flow left ventricular assist device with continuous flow left ventricular assist device [CF-LVAD] [ASSIST-ICD]; NCT02873169).

A New Three-Dimensional Echocardiography Method to Quantify Aortic Valve Calcification.

BACKGROUND: Aortic valve calcification (AVC) quantification is computed from multidetector computed tomography (MDCT). The aim of this study was to test the hypothesis that three-dimensional (3D) transthoracic echocardiography can be used to provide a bedside method to assess AVC. METHODS: The study included 94 patients (mean age, 78 ± 12 years; mean aortic valve [AV] area, 1.0 ± 0.6 cm2) referred for MDCT and echocardiography for AV assessment. Apical 3D full-volume data sets focused on the AV region were acquired during transthoracic echocardiography, and a region-growing algorithm was applied offline to compute 3D transthoracic echocardiographic AVC (AVC-3DEcho). AVC-3DEcho was compared with AVC by MDCT and with calcium weight in the subgroup of patients referred for surgery, with explanted AVs analyzed by a pathologist (n = 22). RESULTS: In the explanted valve group, AVC-3DEcho score exhibited fair correlations with MDCT score (r = 0.85, P < .001), calcium load (r = 0.81, P < .001), and peak AV velocity (r = 0.64, P < .001). In the overall population, AVC-3DEcho score correlated modestly with MDCT score (r = 0.61, P < .001) but had similar accuracy to identify severe aortic stenosis (area under the curve = 0.94). AVC-3DEcho > 1,054 mm3 identified severe aortic stenosis with specificity of 100% and sensitivity of 76%. In addition, AVC-3DEcho was associated with the presence of significant paravalvular regurgitation after transcatheter aortic valve implantation. Finally, intraobserver and interobserver variability for AVC-3DEcho score was 4.2% and 8.9%, respectively. CONCLUSIONS: AVC-3DEcho correlated with calcium weight obtained from pathologic analysis and MDCT. These data suggest that a bedside method for quantifying AV calcification with ultrasound is feasible.

Exercise Training in a Patient With a Left Ventricular Assist Device and Large Aortic Valve Thrombus.

DETAILS OF THE CLINICAL CASE: An aortic valve thrombus (AVT) is a rare complication after HeartMate II implantation. In a 44-year-old man, a large AVT was discovered 6 weeks after implantation of a HeartMate II for severe dilated cardiomyopathy. The aortic valve was permanently closed. DISCUSSION: After a followup of 3 months without embolic events, the patient started a cardiac rehabilitation (CR) program involving aerobic exercise, resistance exercises, group gymnastics, and relaxation exercise, and completed the program without any complications, resulting in a significant functional benefit. SUMMARY: CR might not be systematically contraindicated in patients with HeartMate II and an AVT, in particular, if there is no opening of the aortic valve at rest.