Predictors of failed left bundle branch pacing implant in heart failure with reduced ejection fraction: importance of left ventricular diameter and QRS morphology.

BACKGROUND: Left bundle branch pacing (LBBP) is considered an alternative to cardiac resynchronization therapy (CRT). However, LBBP is not suitable for all heart failure patients. OBJECTIVE: The aim of our study was to identify predictors of unsuccessful LBBP implantation in CRT candidates. METHODS: A cohort of consecutive patients with indications for CRT were included. Clinical, echocardiography and electrocardiography variables were prospectively recorded. RESULTS: A total of 187 patients were included in the analysis. LBBP implantation was successful in 152/187 (81.2%) patients and failed in 35/187 (18.7%) patients. The causes of unsuccessful implantation were unsatisfactory paced QRS (28/35; 80%), inability to screw the helix (4/35; 11.4%), lead instability (2/35; 5.7%), and high pacing thresholds (1/35; 2.8%). The left ventricular end diastolic diameter (LVEDD), non-LBBB (left bundle branch block) QRS morphology, and QRS width were predictors of failed implantation according to the univariate analysis. According to the multivariable regression analysis, LVEDD [OR 1.31 per 5 mm increase (95% CI 1.05, 1.63) p=0.02] and non-LBBB [OR 3.07 (95% CI 1.08, 8.72) p=0.03] were found to be independent predictors of unsuccessful LBBP implantation. An LVEDD of 60 mm has 60% sensitivity and 71% specificity for predicting LBBP implant failure. CONCLUSIONS: When LBBP was used as CRT, LVEDD and non-LBBB QRS morphology predicted unsuccessful implantation. Non-LBBB triples the likelihood of failed implantation independent of LVEDD. Caution should be taken when considering these parameters to plan the best pacing strategy for patients.

Longitudinal comparison of dyssynchrony correction and strain improvement by conduction system pacing: LEVEL-AT trial secondary findings.

Longitudinal dyssynchrony correction and strain improvement by comparable cardiac resynchronization therapy techniques is unreported. AIMS: Our purpose was to compare echocardiographic dyssynchrony correction and strain improvement by conduction system pacing (CSP) vs. biventricular pacing (BiVP) as a marker of contractility improvement during one-year follow-up. METHODS AND RESULTS: A treatment-received analysis was performed in patients included in the LEVEL-AT trial (NCT04054895), randomized to CSP or BiVP, and evaluated at baseline (ON and OFF programming) and at 6 and 12 months (n = 69, 32% women). Analysis included intraventricular (septal flash), interventricular (difference between left and right ventricular outflow times), and atrioventricular (diastolic filling time) dyssynchrony and strain parameters (septal bounce, global longitudinal strain [GLS], left bundle branch block pattern and mechanical dispersion).Baseline left ventricular ejection fraction (LVEF) was 27.5 ± 7% and left ventricular end-systolic volume (LVESV) was 138 ± 77 ml, without differences between groups. Longitudinal analysis showed LVEF and LVESV improvement (p < 0.001), without between-group differences. At 12-month follow-up, adjusted mean LVEF was 46% with CSP (95%CI 42.2%, 49.3%) vs. 43% with BiVP (95%CI 39.6%, 45.8%) (p = 0.31) and LVESV was 80 ml (95%CI 55.3 ml, 104.5 ml) vs. 100 ml (95%CI 78.7 ml, 121.6 ml), respectively (p = 0.66).Longitudinal analysis showed a significative improvement of all dyssynchrony parameters and GLS over time (p < 0.001), without differences between groups. Baseline GLS significantly correlated with LVEF and LVESV at 12-month follow-up. CONCLUSION: CSP and BiVP provided similar dyssynchrony and strain correction over time. Baseline global longitudinal strain correction predicted ventricular remodeling at 12-month follow-up.

Stepwise application of ECG and electrogram-based criteria to ensure electrical resynchronization with left bundle branch pacing.

AIMS: To define a stepwise application of left bundle branch pacing (LBBP) criteria that will simplify implantation and guarantee electrical resynchronization. Left bundle branch pacing has emerged as an alternative to biventricular pacing. However, a systematic stepwise criterion to ensure electrical resynchronization is lacking. METHODS AND RESULTS: A cohort of 24 patients from the LEVEL-AT trial (NCT04054895) who received LBBP and had electrocardiographic imaging (ECGI) at 45 days post-implant were included. The usefulness of ECG- and electrogram-based criteria to predict accurate electrical resynchronization with LBBP were analyzed. A two-step approach was developed. The gold standard used to confirm resynchronization was the change in ventricular activation pattern and shortening in left ventricular activation time, assessed by ECGI. Twenty-two (91.6%) patients showed electrical resynchronization on ECGI. All patients fulfilled pre-screwing requisites: lead in septal position in left-oblique projection and W paced morphology in V1. In the first step, presence of either right bundle branch conduction delay pattern (qR or rSR in V1) or left bundle branch capture Plus (QRS ≤120 ms) resulted in 95% sensitivity and 100% specificity to predict LBBP resynchronization, with an accuracy of 95.8%. In the second step, the presence of selective capture (100% specificity, only 41% sensitivity) or a spike-R <80 ms in non-selective capture (100% specificity, sensitivity 46%) ensured 100% accuracy to predict resynchronization with LBBP. CONCLUSION: Stepwise application of ECG and electrogram criteria may provide an accurate assessment of electrical resynchronization with LBBP (Graphical abstract).

Conduction System Pacing vs Biventricular Pacing in Heart Failure and Wide QRS Patients: LEVEL-AT Trial.

BACKGROUND: Conduction system pacing (CSP) has emerged as an alternative to biventricular pacing (BiVP). Randomized studies comparing both therapies are scarce and do not include left bundle branch pacing. OBJECTIVES: This study aims to compare ventricular resynchronization achieved by CSP vs BiVP in patients with cardiac resynchronization therapy indication. METHODS: LEVEL-AT (Left Ventricular Activation Time Shortening with Conduction System Pacing vs Biventricular Resynchronization Therapy) was a randomized, parallel, controlled, noninferiority trial. Seventy patients with cardiac resynchronization therapy indication were randomized 1:1 to BiVP or CSP, and followed up for 6 months. Crossover was allowed when primary allocation procedure failed. Primary endpoint was the change in left ventricular activation time, measured using electrocardiographic imaging. Secondary endpoints were left ventricular reverse remodeling and the combined endpoint of heart failure hospitalization or death at 6-month follow-up. RESULTS: Thirty-five patients were allocated to each group. Eight (23%) patients crossed over from CSP to BiVP; 2 patients (6%) crossed over from BiVP to CSP. Electrocardiographic imaging could not be performed in 2 patients in each group. A similar decrease in left ventricular activation time was achieved by CSP and BiVP (-28 ± 26 ms vs -21 ± 20 ms, respectively; mean difference -6.8 ms; 95% CI: -18.3 ms to 4.6 ms; P < 0.001 for noninferiority). Both groups showed a similar change in left ventricular end-systolic volume (-37 ± 59 mL CSP vs -30 ± 41 mL BiVP; mean difference: -8 mL; 95% CI: -33 mL to 17 mL; P = 0.04 for noninferiority) and similar rates of mortality or heart failure hospitalizations (2.9% vs 11.4%, respectively) (P = 0.002 for noninferiority). CONCLUSIONS: Similar degrees of cardiac resynchronization, ventricular reverse remodeling, and clinical outcomes were attained by CSP as compared to BiVP. CSP could be a feasible alternative to BiVP. (LEVEL-AT [Left Ventricular Activation Time Shortening With Conduction System Pacing vs Biventricular Resynchronization Therapy]; NCT04054895).

Changes in Pulmonary Function in Patients With Advanced Heart Failure Listed for Heart Transplantation.

BACKGROUND: Pulmonary function tests (PFTs) are often impaired in patients with advanced heart failure. There is limited data about their impact on survival after heart transplantation (HT). We sought to assess the prevalence and type of PFT abnormalities in patients on HT waiting list and their impact on outcomes. METHODS: We performed a retrospective analysis of a prospective registry of consecutive patients undergoing HT between 2012 and 2018. Patients were classified into 4 groups according to pre-HT PFT results: 1. normal pattern: forced vital capacity (FVC) ≥ 80% and forced expiratory volume in 1 second (FEV1) to FVC ratio (FEV1/FVC) ≥ 0.7; 2. obstructive: FEV1/FVC < 0.7; 3. nonobstructive: FEV1/FVC ≥ 0.7 and FVC < 80% when total lung capacity value was not available; and 4. restrictive: FEV1/FVC ≥ 0.7 and total lung capacity < 80%. The prevalence of impaired carbon monoxide diffusing capacity corrected for hemoglobin < 80% and FEV1 < 70% was also analyzed. High-urgency HT patients and those referred from other centers without quantitative pulmonary evaluation were excluded. RESULTS: Among 123 patients who underwent HT, 83 patients with complete PFT were included. Median follow-up was 2.7 ± 1.9 years. Of these, 29 (34.9%) had an obstructive pattern, 20 (24.1%) a nonobstructive, 18 (21.7%) a restrictive, and 16 (19.3%) a normal pattern. Fifty-one (61.4%) patients had FEV1 < 70% and 58 (69.9%) a carbon monoxide diffusing capacity corrected for hemoglobin < 80%. There was a tendency to lower survival in all altered PFT groups compared with normal (P = .054) but not within the other groups. Patients with an impaired FEV1 had significantly higher mortality than patients with normal values (P = .008). Area under receiver operating characteristic curve for FEV1 was 0.73 (95% confidence interval [0.60-0.86]). A cutoff value of FEV1 (60.5) predicts mortality with 66% sensitivity and 64% specificity. CONCLUSIONS: PFT alterations have a very high prevalence on HT waiting list patients. Patients with impaired FEV1 had worse outcomes after heart transplantation.

[Primary central nervous system lymphoma following immunotherapy for metastatic melanoma]. / Lymphome cérébral primitif après immunothérapie d'un mélanome métastatique.

BACKGROUND: Anti-PD-1 and anti-CTLA-4 monoclonal antibodies are used in melanoma, while anti-PD-1 are also used in Hodgkin's lymphoma. Primary central nervous system lymphoma is a rare form of non-Hodgkin's lymphoma with few effective treatments. However, several recent studies have reported multiple cases of non-Hodgkin's lymphoma and primary central nervous system lymphoma treated by anti-PD-1 antibodies with favourable responses. PATIENTS AND METHODS: This study focuses on the case of a 59-year-old man with metastatic melanoma treated by immunotherapy (anti-CTLA-4 followed by anti-PD-1). He underwent 28 courses of therapy with pembrolizumab. Treatment was stopped after clinical and radiological remission. The patient presented left hemiparesis and a primary central nervous system lymphoma was diagnosed two months after discontinuation of immunotherapy. He started urgent high-dose methotrexate chemotherapy but without significant results. Despite second-line chemotherapy with R-ICE (rituximab-ifosfamide, carboplatin and etoposide), the patient died. DISCUSSION: Several hypotheses may be advanced regarding a possible relationship between immunotherapy and the occurrence of this primary central nervous system lymphoma. The lymphoma may have been pre-existing and controlled by immunotherapy, but progressing rapidly after treatment, or it may have been induced by the immunotherapy. However, immunotherapy may have played no role; the relationship between melanoma and lymphoma is well known. CONCLUSION: While immunotherapy cannot be unequivocally incriminated in primary central nervous system lymphoma, this case raises many questions about the imputability of immunotherapy in the occurrence of secondary cancers, including lymphomas.

Sexual acquisition of HIV infection after solid organ transplantation: Late presentation and potentially fatal complications.

INTRODUCTION: While the growing knowledge on HIV among solid organ transplant recipients (SOT) is limited to either pretransplant infection or allograft transmission, there are only sparse reports describing HIV-infection after transplantation through sexual route, the primary mode of transmission in the general population. METHODS: From two different centers, we report nine new cases of HIV infection in SOT recipients attributed to sexual acquisition: eight cases of kidney-transplant recipients and one heart-transplant recipient. FINDINGS: There were nine cases of post-transplant HIV-infection detected among 14 526 transplants performed 1998 to 2015. In 6/9 cases, infection was contracted 5 years after SOT. All but one patient had stable allograft function under immunosuppressive therapy. The main trigger to diagnosis was late CMV disease and sexually transmitted diseases; five patients had CDC-stage 3 HIV infection. In 7/9 patients, virologic response and CD4 recovery were achieved within 3 months after starting antiretroviral therapy (ART). After an average of 3.6 years post diagnosis, 5/9 patients remained alive with well-controlled infection and functioning allograft. CONCLUSION: Sexual acquisition of HIV infection after SOT represents a difficult challenge, as it may occur in any kind of transplant and at any time. The course of infection resembles that of the general population, with life-threatening infectious complications, but good response to ART. Assessment of lifestyle and risk behavior is paramount, as indications may be not disclosed without direct questioning.

Alginate/chitosan polyelectrolyte complexes: A comparative study of the influence of the drying step on physicochemical properties.

Polyelectrolyte complexes (PECs) based on Alginate and Chitosan were prepared for biomedical application. These two biopolymers are valuable resources for biomedical applications. In the present work, three PECs materials were produced using three different drying techniques: hot air drying, lyophilization and supercritical CO2 drying. The choice of the drying technique allowed producing different type of structures, with different porosity scale. In order to evaluate their potential as intra-abdominal wound dressings, swelling ability in various media, enzymatic resistance and drug release behavior of the resulting materials was studied. It was shown that the increase of the porosity improved the swelling ability, without altering the resistance of the materials, whereas drug release studies revealed that the majority of the drug was released within the first 24h whatever the drying process.

Data on clinical characteristics of a heart failure patients' cohort with reduced ejection fraction and analysis of the circulating values of five different heart failure biomarkers; high sensitivity troponin T, galectin-3, C-terminal propeptide of type I procollagen, soluble AXL and BNP.

In this article, the full description of a heart failure with reduced ejection fraction (HF_REF) cohort of 192 patients is provided. Tables with the baseline demographic, prior history, ECG parameters, echocardiographic parameters, laboratory values and pharmacological treatment of these patients are included. Also, the quartile values of the analyzed circulating biomarkers: high sensitivity Troponin T (hs-TnT), galectin-3 (Gal-3), C-terminal propeptide of type I procollagen (CICP), soluble AXL (sAXL) and Brain Natriuretic Peptide (BNP) are given. The main demographic and clinical features of the patients' subgroups that have hs-TnT, Gal-3, CICP or BNP above the third quartile are described. Tables with Pearson correlation analysis of the HF_REF patients' biomarker levels are included. And Pearson correlation analysis of the HF_REF patients' hs-TnT, Gal-3, CICP levels with patients' biochemical parameters, blood count and inflammation parameters are also described. These data are related to the research articles (AXL receptor tyrosine kinase is increased in patients with heart failure (M. Batlle, P. Recarte-Pelz, E. Roig, M.A. Castel, M. Cardona, M. Farrero, et al., 2014) [1] and Use of serum levels of high sensitivity troponin T, galectin-3 and C-terminal propeptide of type I procollagen at long term follow-up in Heart Failure patients with reduced ejection fraction: comparison with soluble AXL and BNP (M. Batlle, B. Campos, M. Farrero, M. Cardona, B. González, M.A. Castel, et al., 2016) [2].

Use of serum levels of high sensitivity troponin T, galectin-3 and C-terminal propeptide of type I procollagen at long term follow-up in heart failure patients with reduced ejection fraction: Comparison with soluble AXL and BNP.

BACKGROUND: Prognostic biomarkers are needed to improve the management of the heart failure (HF) epidemic, being the brain natriuretic peptides the most valuable. Here we evaluate 3 biomarkers, high sensitivity troponin T (hs-TnT), galectin-3 (Gal-3) and C-terminal propeptide of type I procollagen (CICP), compare them with a recently described new candidate (sAXL), and analyze their relationship with BNP. METHODS: HF patients with reduced ejection fraction (n=192) were included in this prospective observational study, with measurements of candidate biomarkers, functional, clinical and echocardiographic variables. A Cox regression model was used to determine predictors for clinical events, i.e. all-cause mortality and heart transplantation. RESULTS: Hs-TnT circulating values were correlated to clinical characteristics indicative of more advanced HF. When analyzing the event-free survival at a mean follow-up of 3.6years, patients in the higher quartile of either BNP, hs-TnT, CICP and sAXL had increased risk of suffering a clinical event, but not Gal-3. Combination of high sAXL and BNP values had greater predictive value (HR 6.8) than high BNP alone (HR 4.9). In a multivariate Cox regression analysis, BNP, sAXL and NYHA class were independent risk factors for clinical events. CONCLUSIONS: In this HF cohort, hs-TnT is a good HF marker and has a very significant prognostic value. The prognostic value of CICP and sAXL was of less significance. However, hs-TnT did not add predictive value to BNP, while sAXL did. This suggests that elevated troponin has a common origin with BNP, while sAXL could represent an independent pathological mechanism.

A New Quantitative Approach to Assessing Noncompliance With Medical Recommendations in Heart Transplant Recipients.

BACKGROUND: Failure of compliance with medical regimen is one of the major risk factors associated with morbidity and mortality in heart transplant (HT) recipients. Nevertheless, to date, there is no specific, gold-standard, comprehensive set of tools for assessing compliance in these patients. OBJECTIVE: The objective of the present study was to develop a specific instrument for the assessment of noncompliance with medical recommendations in HT recipients. METHODS: This prospective observational study used a nonprobability sampling method, which was performed from January 2006 to December 2012. All of the patients met clinical criteria for being included on the waiting list for a HT. We designed a scale for measuring the compliance degree at 12 months after heart transplantation. This scale included the most important aspects of the medical regimen, using nine discrete quantitative variables. The total score was described as the patient's Noncompliance Factor (NCF). The results were analysed by mean, ranks, and percentages. RESULTS: The sample was constituted of 61 participants who underwent surgical HT intervention and completed the 12-month follow-up assessment. The overall incidence of noncompliance was around 30% and only 43.1% of the recipients had an acceptable degree of compliance. CONCLUSIONS: The overall incidence of noncompliance in HT recipients is high and this can generate worse clinical outcomes. Evaluation by specific screening instruments like the one proposed in the present study can be useful for a systematic detection of this phenomenon.

An Update on Heart Transplantation in Human Immunodeficiency Virus-Infected Patients.

Cardiovascular diseases have become a significant cause of morbidity in patients with human immunodeficiency virus (HIV) infection. Heart transplantation (HT) is a well-established treatment of end-stage heart failure (ESHF) and is performed in selected HIV-infected patients in developed countries. Few data are available on the prognosis of HIV-infected patients undergoing HT in the era of combined antiretroviral therapy (cART) because current evidence is limited to small retrospective cohorts, case series, and case reports. Many HT centers consider HIV infection to be a contraindication for HT; however, in the era of cART, HT recipients with HIV infection seem to achieve satisfactory outcomes without developing HIV-related events. Consequently, selected HIV-infected patients with ESHF who are taking effective cART should be considered candidates for HT. The present review provides epidemiological data on ESHF in HIV-infected patients from all published experience on HT in HIV-infected patients since the beginning of the epidemic. The practical management of these patients is discussed, with emphasis on the challenging issues that must be addressed in the pretransplant (including HIV criteria) and posttransplant periods. Finally, proposals are made for future management and research priorities.

Plasma tissue inhibitor of matrix metalloproteinase-1 a predictor of long-term mortality in patients treated with cardiac resynchronization therapy.

AIMS: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in cardiac remodelling. Available information regarding their prognostic utility in heart failure (HF) and cardiac resynchronization therapy (CRT) is controversial. The aim of this study was to analyse MMP-2 and TIMP-1 levels as predictors of long-term mortality in HF patients treated with CRT. METHODS AND RESULTS: We prospectively included 42 consecutive patients with successfully implanted CRT. Matrix metalloproteinase-2 and TIMP-1 assays were performed prior to implant. Patients were evaluated at baseline and at the outpatient clinic at 6-month intervals. Clinical response, left ventricular (LV) remodelling, and mortality were analysed. During a mean follow-up of 60 ± 34 months, long-term mortality from any cause was 36% (15 patients). The cause of death was end stage of HF in 12 patients, sudden death in 2 patients, and 1 unknown. After adjustment using a Cox regression model, the independent predictors of long-term mortality were baseline TIMP-1, hazard ratio (HR) 1.18 (95% confidence interval (95% CI) [1.05-1.33], P = 0.007), baseline glomerular filtration rate (GFR), HR 0.97 (95% CI [0.94-1.00], P = 0.05), and permanent atrial fibrillation (AF), HR 3.14 (95% CI [1.02-9.67], P = 0.04). Area under receiver operating characteristic curve for TIMP-1 was 0.79 (95% CI [0.63-0.94]). Tissue inhibitor of matrix metalloproteinase-1 ≥ 248 ng/mL predicts mortality with 80% sensitivity and 71% specificity. CONCLUSION: Tissue inhibitor of matrix metalloproteinase-1 is a powerful predictor of long-term mortality in HF patients treated with CRT.

Pharmacokinetics of Ferrous Sulphate (Tardyferon®) after Single Oral Dose Administration in Women with Iron Deficiency Anaemia.

Iron-containing preparations available on the market vary in dosage, salt, and chemical state of iron contained in the preparation, as well as in the iron delivery process (immediate or prolonged-release). The present study aimed at characterizing the serum pharmacokinetics of iron in non pregnant women with iron deficiency anaemia (IDA) following a single oral administration of a prolonged-release ferrous sulphate tablet. This multicenter, single dose, open-label study was conducted in 30 women aged between 18 and 45 years with IDA. A single 160 mg oral dose of ferrous sulphate was given as 2 tablets of 80 mg of Tardyferon(®) under fasting conditions. Blood samples were collected before dosing and until 24 h post-dosing. Serum iron concentrations were determined using a routine colorimetric analytical method. Pharmacokinetic parameters were determined from the serum concentration profiles using a non compartmental approach. Serum profiles showed elevated levels of iron up to 12 h after drug intake. The median time to maximum serum concentrations (Tmax) occurred 4 h post-dosing. Between 2 and 8 h post-dosing, mean serum iron concentrations fluctuated by only 20%. Additionally, C8h and C12h represented on average 78.6% and 47.5% of the Cmax, respectively. This study demonstrates that a single oral dose of 160 mg Tardyferon(®) administered under fasting condition to 30 women with IDA leads to an optimal long-lasting release of iron in the gastrointestinal tract in the targeted population. This allows the attainment and maintenance of elevated serum iron levels for up to 12 h after administration.

Pulmonary hypertension is related to peripheral endothelial dysfunction in heart failure with preserved ejection fraction.

BACKGROUND: Pulmonary hypertension (PH) and collagen metabolism abnormalities are prevalent in patients with heart failure with preserved ejection fraction (HFpEF). Peripheral endothelial dysfunction (PED) has been described in HF and in pulmonary arterial hypertension. Our aim is to determine whether PH is associated with PED and impaired collagen metabolism in patients with HFpEF.; METHODS AND RESULTS: Flow-mediated dilation of the brachial artery, matrix metalloproteinase-2 and matrix metalloproteinase-9, tissue metalloproteinase inhibitor 1, and C-terminal propeptide of type I procollagen were determined in 28 patients with HFpEF and 42 hypertensive controls. Patients with systolic pulmonary artery pressure >35 mm Hg on echocardiogram underwent a right heart catheterization. Patients with HFpEF had more severe PED than controls: flow-mediated dilation 1.95% (-0.81 to 4.92) versus 5.02% (3.90 to 10.12), P=0.002. Twenty patients with PH underwent right heart catheterization: mean pulmonary artery pressure 38 (27-52) mm Hg, wedge capillary pressure 18 (16-22) mm Hg, pulmonary vascular resistance 362 (235-603) dyn s cm(-5). There was a significant inverse correlation between flow-mediated dilation and pulmonary vascular resistance in patients with HFpEF and PH (r=-0.679; P=0.002). Patients with HFpEF showed higher matrix metalloproteinase-2 and C-terminal propeptide of type I procollagen values than hypertensive controls. Patients with HFpEF and higher C-terminal propeptide of type I procollagen values also had higher mean pulmonary artery pressure (r=0.553; P=0.014), transpulmonary gradient (r=0.560; P=0.013), and pulmonary vascular resistance (r=0.626; P=0.004). CONCLUSIONS: In patients with HFpEF, there is a significant correlation between PED and pulmonary vascular resistance. Collagen metabolism was more impaired in patients with HFpEF and PH. PED and collagen metabolism assessment could be useful tools to identify patients with HFpEF at risk of developing PH.