Fate mapping and scRNA sequencing reveal origin and diversity of lymph node stromal precursors.

Lymph node (LN) stromal cells play a crucial role in LN development and in supporting adaptive immune responses. However, their origin, differentiation pathways, and transcriptional programs are still elusive. Here, we used lineage-tracing approaches and single-cell transcriptome analyses to determine origin, transcriptional profile, and composition of LN stromal and endothelial progenitors. Our results showed that all major stromal cell subsets and a large proportion of blood endothelial cells originate from embryonic Hoxb6+ progenitors of the lateral plate mesoderm (LPM), whereas lymphatic endothelial cells arise from Pax3+ progenitors of the paraxial mesoderm (PXM). Single-cell RNA sequencing revealed the existence of different Cd34+ and Cxcl13+ stromal cell subsets and showed that embryonic LNs contain proliferating progenitors possibly representing the amplifying populations for terminally differentiated cells. Taken together, our work identifies the earliest embryonic sources of LN stromal and endothelial cells and demonstrates that stromal diversity begins already during LN development.

Electrical transport and persistent photoconductivity in monolayer MoS2 phototransistors.

We study electrical transport properties in exfoliated molybdenum disulfide (MoS2) back-gated field effect transistors at low drain bias and under different illumination intensities. It is found that photoconductive and photogating effect as well as space charge limited conduction can simultaneously occur. We point out that the photoconductivity increases logarithmically with the light intensity and can persist with a decay time longer than 104 s, due to photo-charge trapping at the MoS2/SiO2 interface and in MoS2 defects. The transfer characteristics present hysteresis that is enhanced by illumination. At low drain bias, the devices feature low contact resistance of [Formula: see text] ON current as high as [Formula: see text] 105 ON-OFF ratio, mobility of ∼1 cm2 V-1 s-1 and photoresponsivity [Formula: see text].

Macrophage polarization at the crossroad between HIV-1 infection and cancer development.

Mononuclear phagocytes play a fundamental role in the tissue homeostasis and innate defenses against viruses and other microbial pathogens. In addition, they are likely involved in several steps of cancer development. Circulating monocytes and tissue macrophages are target cells of viral infections, including human cytomegalovirus, human herpes virus 8, and the HIV, and alterations of their functional and phenotypic properties are likely involved in many tissue-degenerative diseases, including atherosclerosis and cancer. Different tissue microenvironments as well as their pathological alterations can profoundly affect the polarization state of macrophages toward the extreme phenotypes conventionally termed M1 and M2. Thus, targeting disease-associated macrophages is considered a potential approach particularly in the context of cancer-associated tumor-associated macrophages, supporting malignant cell growth and progression toward a metastatic phenotype. Of note is the fact that tumor-associated macrophages isolated from established tumors display phenotypic and functional features similar to those of in vitro-derived M2-polarized cells. Concerning HIV-1 infection, viral eradication strategies in the context of combination antiretroviral therapy should also consider the possibility to deplete, at least transiently, certain mononuclear phagocytes subsets, although the possibility of distinguishing those that are either infected or pathogenically altered remains a goal of future research. In the present review, we will focus on the recent literature concerning the role of human macrophage polarization in viral infections and cancer.

Worldwide impact of COVID-19 on hospital admissions for non-ST-elevation acute coronary syndromes (NSTACS): a systematic review with meta-analysis of 553,038 cases.

BACKGROUND: How COVID-19 impacted non-ST-segment elevation acute coronary syndromes (NSTACS) is object of controversial reports. AIM: To systematically review studies reporting NSTACS hospitalizations during COVID-19 pandemic, and analyze whether differences in COVID-19 epidemiology, methodology of report, or public health-related factors could contribute to discrepant findings. METHODS: Comprehensive search (MedLine, Embase, Scopus, Web-of-Science, Cochrane Register), of studies reporting NSTACS hospitalizations during COVID-19 pandemic compared with a reference period, following Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Data were independently extracted by multiple investigators and pooled using a random-effects model. Health-related metrics were from publicly available sources, and analyzed through multiple meta-regression modelling. RESULTS: We retrieved 102 articles (553 038 NSTACS cases, 40 countries). During peak COVID-19 pandemic, overall Incidence Rate-Ratio (IRR) of NSTACS hospitalizations over reference period decreased (0.70, 95% CI 0.66-0.75; p < 0.00001). Significant heterogeneity was detected among studies (I2= 98%; p < 0.00001). Importantly, wide variations were observed among, and within, countries. No significant differences were observed by study quality, whereas comparing different periods within 2020 resulted in greater decrease ((IRR: 0.61; CI: 0.53-0.71) than comparing 2020 vs previous years (IRR: 0.74; CI 0.69-0.79). Among many variables, major predictors of heterogeneity were: Sars-Cov-2 reproduction rate/country, number of hospitals queried, reference period length; country stringency index and socio-economical indicators did not significantly contribute. CONCLUSIONS: During COVID-19 pandemic NSTACS hospitalizations decreased significantly worldwide. However, substantial heterogeneity emerged among countries, and within the same country. Factors linked to public health management, but also to methodologies to collect results may have contributed to this heterogeneity. Trial registration: The protocol was registered in PROSPERO International Prospective Register of Systematic Reviews (ID: CRD42022308159).

Neratinib as extended adjuvant therapy in patients with copositive early breast cancer: German health technology assessment-driven analyses from the ExteNET study.

BACKGROUND: Neratinib is approved in the European Union for extended adjuvant treatment of human epidermal growth factor receptor 2-positive/hormone receptor-positive (copositive) early breast cancer ≤1 year of completion of prior trastuzumab-based therapy. Here, we report analyses of the hormone receptor-positive subgroup (N = 1631) from the ExteNET trial performed for the German health technology assessment (HTA). RESULTS: With 2 years of median follow-up, HTA analyses revealed a significant advantage in disease-free survival (DFS) for neratinib vs. placebo (absolute/relative risk reduction: 4.1/48.2%; hazard ratio [HR] [95% confidence interval {CI}]: 0.45 [0.29; 0.69]; p = 0.0002), consistent with distant DFS (absolute/relative risk reduction: 3.1/46.3%; HR [95% CI]: 0.52 [0.32; 0.84]; p = 0.0082). The 5-year follow-up confirmed this outcome.Quality of life analyses did not show clinically relevant differences over all time points. Only at month 1, the Functional Assessment of Cancer Therapy - General total score revealed a statistically relevant difference to the disadvantage of neratinib classified as clinically relevant. The tolerability profile of neratinib was dominated by gastrointestinal events, mainly diarrhoea (all grades: 94.4%; grade III: 39.4%; no systematic antidiarrhoeal prophylaxis), nausea (all grades/grade III: 43.9/1.6%), vomiting (26.6/3.2%), abdominal pain (23.8/1.9%), fatigue (28.1/1.9%) and rash (14.3/0.4%). No cumulative or irreversible toxicities were observed. As shown in the CONTROL study and instituted via a risk management plan, diarrhoea management can reduce frequency, cumulative duration and severity of diarrhoea. CONCLUSION: Extended adjuvant neratinib provides a clinically relevant benefit with further incremental reduction of relapse risk in the curative setting. Accordingly, the German HTA authority has granted an added benefit for this new treatment option.

Therapeutic Regeneration of Lymphatic and Immune Cell Functions upon Lympho-organoid Transplantation.

Lymph nodes (LNs) are secondary lymphoid tissues that play a critical role in filtering the lymph and promoting adaptive immune responses. Surgical resection of LNs, radiation therapy, or infections may damage lymphatic vasculature and compromise immune functions. Here, we describe the generation of functional synthetic lympho-organoids (LOs) using LN stromal progenitors and decellularized extracellular matrix-based scaffolds, two basic constituents of secondary lymphoid tissues. We show that upon transplantation at the site of resected LNs, LOs become integrated into the endogenous lymphatic vasculature and efficiently restore lymphatic drainage and perfusion. Upon immunization, LOs support the activation of antigen-specific immune responses, thus acquiring properties of native lymphoid tissues. These findings provide a proof-of-concept strategy for the development of functional lympho-organoids suitable for restoring lymphatic and immune cell functions.

A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression.

In chronic lymphocytic leukemia (CLL), the non-hematopoietic stromal microenvironment plays a critical role in promoting tumor cell recruitment, activation, survival, and expansion. However, the nature of the stromal cells and molecular pathways involved remain largely unknown. Here, we demonstrate that leukemic B lymphocytes induce the activation of retinoid acid synthesis and signaling in the microenvironment. Inhibition of RA-signaling in stromal cells causes deregulation of genes associated with adhesion, tissue organization and chemokine secretion including the B-cell chemokine CXCL13. Notably, reducing retinoic acid precursors from the diet or inhibiting RA-signaling through retinoid-antagonist therapy prolong survival by preventing dissemination of leukemia cells into lymphoid tissues. Furthermore, mouse and human leukemia cells could be distinguished from normal B-cells by their increased expression of Rarγ2 and RXRα, respectively. These findings establish a role for retinoids in murine CLL pathogenesis, and provide new therapeutic strategies to target the microenvironment and to control disease progression.

I-V and C-V Characterization of a High-Responsivity Graphene/Silicon Photodiode with Embedded MOS Capacitor.

We study the effect of temperature and light on the I-V and C-V characteristics of a graphene/silicon Schottky diode. The device exhibits a reverse-bias photocurrent exceeding the forward current and achieves a photoresponsivity as high as 2.5 A / W . We show that the enhanced photocurrent is due to photo-generated carriers injected in the graphene/Si junction from the parasitic graphene/SiO2/Si capacitor connected in parallel to the diode. The same mechanism can occur with thermally generated carriers, which contribute to the high leakage current often observed in graphene/Si junctions.

Clinical predictors of marked improvement in left ventricular performance after cardiac resynchronization therapy in patients with chronic heart failure.

BACKGROUND: Previous studies have shown that cardiac resynchronization therapy (CRT) improves cardiac performance and decreases mortality and hospital admission rates. However, it is not yet clear which patients will benefit from the procedure the most. The purpose of the study was to identify the pre-implant characteristics that better predict which patients will have the best outcome after CRT. METHODS: In this observational study, 156 patients were studied with echocardiography and a 6-minute walking test at baseline and 12 months after CRT. RESULTS: After CRT, we observed an increase in left ventricular ejection fraction (+29.6%, P < .0001), a decrease in left ventricular end systolic volume (-26.4%, P < .0001), in the proportion of patients with grade 2-4 mitral regurgitation (from 47.1% to 34.0%, P = .002), and with NYHA functional class III-IV (from 83.2% to 11.6%, P < .0001), an increase in exercise tolerance (+31.1%, P < .0001). Sixty-two patients had a marked increase in left ventricular ejection fraction (> 10 units); the only independent predictor of a marked effect of CRT was the nonischemic etiology of heart failure. In patients with ischemic cardiomyopathy, the benefit on ejection fraction correlates inversely with the extension of the ischemic damage. CONCLUSIONS: CRT improves left ventricular function and exercise tolerance in the long term. The nonischemic etiology of the cardiomyopathy is the only independent predictor of a marked effect of CRT; this is probably due to the absence of ischemic, nonviable scar tissue in these patients.

Lymphoid Tissue Mesenchymal Stromal Cells in Development and Tissue Remodeling.

Secondary lymphoid organs (SLOs) are sites that facilitate cell-cell interactions required for generating adaptive immune responses. Nonhematopoietic mesenchymal stromal cells have been shown to play a critical role in SLO function, organization, and tissue homeostasis. The stromal microenvironment undergoes profound remodeling to support immune responses. However, chronic inflammatory conditions can promote uncontrolled stromal cell activation and aberrant tissue remodeling including fibrosis, thus leading to tissue damage. Despite recent advancements, the origin and role of mesenchymal stromal cells involved in SLO development and remodeling remain unclear.

Insight On Colorectal Carcinoma Infiltration by Studying Perilesional Extracellular Matrix.

The extracellular matrix (ECM) from perilesional and colorectal carcinoma (CRC), but not healthy colon, sustains proliferation and invasion of tumor cells. We investigated the biochemical and physical diversity of ECM in pair-wised comparisons of healthy, perilesional and CRC specimens. Progressive linearization and degree of organization of fibrils was observed from healthy to perilesional and CRC ECM, and was associated with a steady increase of stiffness and collagen crosslinking. In the perilesional ECM these modifications coincided with increased vascularization, whereas in the neoplastic ECM they were associated with altered modulation of matrisome proteins, increased content of hydroxylated lysine and lysyl oxidase. This study identifies the increased stiffness and crosslinking of the perilesional ECM predisposing an environment suitable for CRC invasion as a phenomenon associated with vascularization. The increased stiffness of colon areas may represent a new predictive marker of desmoplastic region predisposing to invasion, thus offering new potential application for monitoring adenoma with invasive potential.

Human Prostate Tissue-derived Extracellular Matrix as a Model of Prostate Microenvironment.

BACKGROUND: Clinical experience highlights the wide heterogeneity of primary prostate cancer (PPCa), even when potentially related to the same grade and stage. Currently available prediction tools and biomarkers do not always allow for early recognition of PPCa aggressive phenotype, sometimes making it impossible to distinguish among men harbouring indolent tumours or life-threatening disease. OBJECTIVE: To establish a novel ex vivo/in vitro model suitable to estimate the invasive phenotype of PPCa cells (PPCaC). DESIGN, SETTING, AND PARTICIPANTS: The ability of PPCaC to infiltrate the prostate extracellular matrix (ECM) was used as an index of invasion. ECM was obtained by decellularising 24 NT-prostate specimens from radical prostatectomy. PPCaC were obtained from six tumours with different Gleason patterns and pathological stages. Invasion ability was estimated in direct-cocolture experiments. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The extent of ECM invasion by PPCaC was quantified by counting the number of infiltrated cells. Mann-Whitney test was utilised for statistical comparisons. RESULTS AND LIMITATIONS: Samples of ECM resulted to be free of cells and DNA and with a preserved three-dimensional structure and stromal protein content. The system resulted to be reliable since well characterised normal-, benign-, and malignant-prostate cell lines either re-epitheliased or invaded the matrices, according to their specific nature. Similarly, PPCaC invaded the ECMs consistently with their stage and biochemical recurrence. Of notice, this model was able to identify a different invasive phenotype even among tumours with equal Gleason patterns and pathological stages. The small sample size represents a limitation. CONCLUSIONS: We developed an ex vivo/in vitro model able to reproduce the original PPCa-microenvironment and suitable to recognise the inherent invasive behaviour of PPCaC. PATIENT SUMMARY: We developed a novel ex vivo/in vitro system which enables us to uncover which prostate tumours host potentially aggressive cancer cells. The identification of cancer cells with different invasive abilities will likely lead to the identification of new biomarkers to safely predict disease progression.

Renal function impairment predicts mortality in patients with chronic heart failure treated with resynchronization therapy.

BACKGROUND: The use of cardiac resynchronization therapy (CRT) and implantable cardioverter- defibrillator (ICD) for advanced heart failure (HF) is increasing. Renal dysfunction is a common condition in HF which is associated with a worse survival. The study aims at identifying in patients with advanced HF treated with CRT the effect of baseline glomerular filtration rate (GFR), GFR improvement and left ventricular ejection fraction (LVEF) change, after 6-months of CRT implant, on survival. METHODS: The study population consisted of 375 advanced HF patients who received a CRT between 1999 and 2009, of these 277 received also an ICD implant. Clinical characteristics (New York Heart Association [NYHA] functional class, ischemic vs. non-ischemic etiology, atrial fibrillation, diabetes, hypertension, LVEF, QRS duration and GFR were recorded. The use of common used drugs was evaluated. Cox proportional hazards analysis was calculated in order to evaluate variables associated to mortality. RESULTS: During a median follow-up of 43.0 months, 93 (24.8%) patients died. Patients deceased during the study had at baseline higher NYHA class and lower LVEF and GFR. In Cox regression analysis, GFR predicts long-term mortality (hazard ratio [HR] 0.983; 95% confidence interval [CI] 0.969-0.998; p = 0.023) independently from the effect of others covariates. In addition, a positive GFR improvement 6 months after CRT implant is significantly associated with a lower hazard of mortality (for each 10 mL/min of GFR improvement HR 0.86; 95% CI 0.75-0.99; p = 0.038). CONCLUSIONS: GFR is a significant predictor of mortality in advanced HF patients who received CRT. A GFR improvement 6 months after CRT implant is significantly associated with a lower hazard of mortality.

Cellular localization, invasion, and turnover are differently influenced by healthy and tumor-derived extracellular matrix.

The interplay between tumor cells and the microenvironment has been recognized as one of the hallmarks of cancer biology. To assess the role of extracellular matrix (ECM) in the modulation of tissue homeostasis and tumorigenesis, we developed a protocol for the purification of tissue-derived ECM using mucosae from healthy human colon, perilesional area, and colorectal carcinoma (CRC). Matched specimens were collected from the left colon of patients undergoing CRC resection surgery. ECMs were obtained from tissues that were decellularized with hypotonic solutions containing ionic and nonionic detergents, hypertonic solution, and endonuclease in the absence of denaturing agents. Mucosae-derived ECMs maintained distribution and localization of proteins and glycoproteins typical of the original tissues, and showed different three-dimensional (3D) structures among normal versus perilesional and tumor-derived stroma. The three types of ECM differentially regulated the localization and organization of seeded monocytes and cancer cells that were located and organized as in the original tissue. Specifically, healthy, perilesional, and CRC-derived ECMs sustained differentiation and polarization of cancer epithelial cells. In addition, healthy, but not perilesional and CRC-derived ECM constrained invasion of cancer cells. All three ECMs sustained turnover between cell proliferation and death up to 40 days of culture, although each ECM showed different ability in supporting cell proliferation, with tumor>perilesional>healthy-derived ECMs. Healthy-, perilesional- and CRC-derived ECM differently modulated cell homeostasis, spreading in the stroma and turnover between proliferation and death, and equally supported differentiation and polarization of cancer epithelial cells, thus highlighting the contribution of different ECMs modulating some features of tissue homeostasis and tumorigenesis. Moreover, these ECMs provide competent scaffolds useful to assess efficacy of antitumor drugs in a 3D setting that more closely recapitulates the native microenvironment. Further, ECM-based scaffolds may also be beneficial for future studies seeking prognostic and diagnostic stromal markers and targets for antineoplastic drugs.

Cell-Mediated Immunity in Elite Controllers Naturally Controlling HIV Viral Load.

The natural course of human immunodeficiency virus (HIV) infection is characterized by high viral load, depletion of immune cells, and immunodeficiency, ultimately leading to acquired immunodeficiency syndrome phase and the occurrence of opportunistic infections and diseases. Since the discovery of HIV in the early 1980s a naturally selected population of infected individuals has been emerged in the last years, characterized by being infected for many years, with viremia constantly below detectable level and poor depletion of immune cells. These individuals are classified as "elite controllers (EC) or suppressors" and do not develop disease in the absence of anti-retroviral therapy. Unveiling host factors and immune responses responsible for the elite status will likely provide clues for the design of therapeutic vaccines and functional cures. Scope of this review was to examine and discuss differences of the cell-mediated immune responses between HIV+ individuals with disease progression and EC.

HIV-1 infected lymphoid organs upregulate expression and release of the cleaved form of uPAR that modulates chemotaxis and virus expression.

Cell-associated receptor for urokinase plasminogen activator (uPAR) is released as both full-length soluble uPAR (suPAR) and cleaved (c-suPAR) form that maintain ability to bind to integrins and other receptors, thus triggering and modulating cell signaling responses. Concerning HIV-1 infection, plasma levels of suPAR have been correlated with the severity of disease, levels of immune activation and ineffective immune recovery also in individuals receiving combination anti-retroviral therapy (cART). However, it is unknown whether and which suPAR forms might contribute to HIV-1 induced pathogenesis and to the related state of immune activation. In this regard, lymphoid organs represent an import site of chronic immune activation and virus persistence even in individuals receiving cART. Lymphoid organs of HIV-1(+) individuals showed an enhanced number of follicular dendritic cells, macrophages and endothelial cells expressing the cell-associated uPAR in comparison to those of uninfected individuals. In order to investigate the potential role of suPAR forms in HIV-1 infection of secondary lymphoid organs, tonsil histocultures were established from HIV-1 seronegative individuals and infected ex vivo with CCR5- and CXCR4-dependent HIV-1 strains. The levels of suPAR and c-suPAR were significantly increased in HIV-infected tonsil histocultures supernatants in comparison to autologous uninfected histocultures. Supernatants from infected and uninfected cultures before and after immunodepletion of suPAR forms were incubated with the chronically infected promonocytic U1 cell line characterized by a state of proviral latency in unstimulated conditions. In the contest of HIV-conditioned supernatants we established that c-suPAR, but not suPAR, inhibited chemotaxis and induced virus expression in U1 cells. In conclusion, lymphoid organs are an important site of production and release of both suPAR and c-suPAR, this latter form being endowed with the capacity of inhibiting chemotaxis and inducing HIV-1 expression.

The Shc family protein adaptor, Rai, negatively regulates T cell antigen receptor signaling by inhibiting ZAP-70 recruitment and activation.

Rai/ShcC is a member of the Shc family of protein adaptors expressed with the highest abundance in the central nervous system, where it exerts a protective function by coupling neurotrophic receptors to the PI3K/Akt survival pathway. Rai is also expressed, albeit at lower levels, in other cell types, including T and B lymphocytes. We have previously reported that in these cells Rai attenuates antigen receptor signaling, thereby impairing not only cell proliferation but also, opposite to neurons, cell survival. Here we have addressed the mechanism underlying the inhibitory activity of Rai on TCR signaling. We show that Rai interferes with the TCR signaling cascade one of the earliest steps--recruitment of the initiating kinase ZAP-70 to the phosphorylated subunit of the TCR/CD3 complex, which results in a generalized dampening of the downstream signaling events. The inhibitory activity of Rai is associated to its inducible recruitment to phosphorylated CD3, which occurs in the physiological signaling context of the immune synapse. Rai is moreover found as a pre-assembled complex with ZAP-70 and also constitutively interacts with the regulatory p85 subunit of PI3K, similar to neuronal cells, notwithstanding the opposite biological outcome, i.e. impairment of PI-3K/Akt activation. The data highlight the ability of Rai to establish interactions with the TCR and key signaling mediators which, either directly (e.g. by inhibiting ZAP-70 recruitment to the TCR or sequestering ZAP-70/PI3K in the cytosol) or indirectly (e.g. by promoting the recruitment of effectors responsible for signal extinction) prevent full triggering of the TCR signaling cascade.

Is the left ventricular lateral wall the best lead implantation site for cardiac resynchronization therapy?

Short-term hemodynamic studies consistently report greater effects of cardiac resynchronization therapy (CRT) in patients stimulated from a LV lateral coronary sinus tributary (CST) compared to a septal site. The aim of the study was to compare the long-term efficacy of CRT when performed from different LV stimulation sites. From October 1999 to April 2002, 158 patients (mean age 65 years, mean LVEF 0.29, mean QRS width 174 ms) underwent successful CRT, from the anterior (A) CST in 21 patients, the anterolateral (AL) CST in 37 patients, the lateral (L) CST in 57 patients, the posterolateral (PL) CST in 40 patients, and the middle cardiac vein (MCV) CST in 3 patients. NYHA functional class, 6-minute walk test, and echocardiographic measurements were examined at baseline, and at 3, 6, and 12 months. Comparisons were made among all pacing sites or between lateral and septal sites by grouping AL + L + PL CST as lateral site (134 patients, 85%) and A + MC CST as septal site (24 patients, 15%). In patients stimulated from lateral sites, LVEF increased from 0.30 to 0.39 (P < 0.0001), 6-minute walk test from 323 to 458 m (P < 0.0001), and the proportion of NYHA Class III-IV patients decreased from 82% to 10% (P < 0.0001). In patients stimulated from septal sites, LVEF increased from 0.28 to 0.41 (P < 0.0001), 6-minute walk test from 314 to 494 m (P < 0.0001), and the proportion of NYHA Class III-IV patients decreased from 75% to 23% (P < 0.0001). A significant improvement in cardiac function and increase in exercise capacity were observed over time regardless of the LV stimulation sites, either considered singly or grouped as lateral versus septal sites.

Beneficial effects of biventricular pacing in patients with a "narrow" QRS.

Congestive heart failure (CHF) patients with LBBB and QRS duration > 150 ms are considered the best candidates to biventricular pacing (Biv-P). However, patients with a narrow (120-150 ms) QRS may also benefit from Biv-P since true ventricular dyssynchrony may be underestimated by considering only QRS enlargement. From October 1999 to April 2002, 158 CHF patients (121 men, mean age 65 years, mean LVEF 0.29, mean QRS width 174 ms) underwent successful Biv-P implantation and were then followed for a mean time of 11.2 months. According to basal QRS duration, patients were divided in two groups, with wide QRS (> or = 150 ms, 128 patients, 81%) and with narrow QRS (< 150 ms, 30 patients, 19%). In the wide QRS group, LVEF improved from 29% to 39% (P < 0.0001), 6-minute walk test from 311 to 463 m (P < 0.0001), while NYHA Class III-IV patients decreased from 86% to 8% (P < 0.0001). In the narrow QRS group LVEF improved from 30% to 38% (P < 0.0001), 6-minute walk test from 370 to 506 m (P < 0.0001), and NYHA Class III-IV patients decreased from 60% to 0% (P < 0.0001). The data showed that in wide and narrow QRS patients, Biv-P significantly improved clinical parameters (NYHA class, 6-minute walk test, quality-of-life, and hospitalization rate) and main echocardiographic indicators. Furthermore, narrow QRS patients had a better survival rate, rapidly regained left ventricular function, and only a few patients remained in a higher NYHA class during follow-up. These patients should not be excluded "a priori" from cardiac resynchronization therapy.