No relationship between left ventricular radial wall motion and longitudinal velocity and the extent and severity of noncompaction cardiomyopathy

<p>Abstract</p> <p>Background</p> <p>Noncompaction cardiomyopathy (NCCM) is characterized by a prominent trabecular meshwork and deep intertrabecular recesses. Although systolic dysfunction is common, limited information is available on differences in wall motion of the normal compacted and noncompacted segments. The purpose of this study was to assess radial wall motion and longitudinal wall velocity in patients with NCCM, according to the extent and severity of noncompaction.</p> <p>Methods</p> <p>The study comprised 29 patients in sinus rhythm (age 41 ± 15 years, 15 men), who fulfilled stringent diagnostic criteria for NCCM and compared to 29 age and gender matched healthy controls. Segmental radial wall motion of all compacted and noncompacted segments was assessed with the standard visual wall motion score index and longitudinal systolic (Sm) wall velocity with tissue Doppler imaging of the mitral annulus. For each LV wall a normalized Sm value was calculated. The extent and severity of NC in each LV segment was assessed both in a qualitative and quantitative manner.</p> <p>Results</p> <p>Heart failure was the primary clinical presentation in half of the patients. NCCM patients had a wall motion score index of 1.68 ± 0.43 and a normalized Sm of 82 ± 20%. The total and maximal noncompaction scores were not related to the wall motion score index and the normalized Sm. NCCM patients with and without heart failure had similar total and maximal noncompaction scores.</p> <p>Conclusions</p> <p>In NCCM patient's radial wall motion and longitudinal LV wall velocity is impaired but not related to the extent or severity of noncompaction.</p

Left ventricular non-compaction: clinical features and cardiovascular magnetic resonance imaging

Background: It is apparent that despite lack of family history, patients with the morphological characteristics of left ventricular non-compaction develop arrhythmias, thrombo-embolism and left ventricular dysfunction. METHODS: Forty two patients, aged 48.7 +/- 2.3 yrs (mean +/- SEM) underwent cardiovascular magnetic resonance (CMR) for the quantification of left ventricular volumes and extent of non-compacted (NC) myocardium. The latter was quantified using planimetry on the two-chamber long axis LV view (NC area). The patients included those referred specifically for CMR to investigate suspected cardiomyopathy, and as such is represents a selected group of patients. RESULTS: At presentation, 50% had dyspnoea, 19% chest pain, 14% palpitations and 5% stroke. Pulmonary embolism had occurred in 7% and brachial artery embolism in 2%. The ECG was abnormal in 81% and atrial fibrillation occurred in 29%. Transthoracic echocardiograms showed features of NC in only 10%. On CMR, patients who presented with dyspnoea had greater left ventricular volumes (both p < 0.0001) and a lower left ventricular ejection fraction (LVEF) (p < 0.0001) than age-matched, healthy controls. In patients without dyspnoea (n = 21), NC area correlated positively with end-diastolic volume (r = 0.52, p = 0.0184) and end-systolic volume (r = 0.56, p = 0.0095), and negatively with EF (r = -0.72, p = 0.0001). CONCLUSION: Left ventricular non-compaction is associated with dysrrhythmias, thromboembolic events, chest pain and LV dysfunction. The inverse correlation between NC area and EF suggests that NC contributes to left ventricular dysfunction

Isolated ventricular noncompaction: a case report

Isolated ventricular noncompaction is an extremely rare cardiomyopathy, not fully clarified

Landscape of immune-related signatures induced by targeting of different epigenetic regulators in melanoma: implications for immunotherapy

Background Improvement of efficacy of immune checkpoint blockade (ICB) remains a major clinical goal. Association of ICB with immunomodulatory epigenetic drugs is an option. However, epigenetic inhibitors show a heterogeneous landscape of activities. Analysis of transcriptional programs induced in neoplastic cells by distinct classes of epigenetic drugs may foster identification of the most promising agents. Methods Melanoma cell lines, characterized for mutational and differentiation profile, were treated with inhibitors of DNA methyltransferases (guadecitabine), histone deacetylases (givinostat), BET proteins (JQ1 and OTX-015), and enhancer of zeste homolog 2 (GSK126). Modulatory effects of epigenetic drugs were evaluated at the gene and protein levels. Master molecules explaining changes in gene expression were identified by Upstream Regulator (UR) analysis. Gene set enrichment and IPA were used respectively to test modulation of guadecitabine-specific gene and UR signatures in baseline and on-treatment tumor biopsies from melanoma patients in the Phase Ib NIBIT-M4 Guadecitabine + Ipilimumab Trial. Prognostic significance of drug-specific immune-related genes was tested with Timer 2.0 in TCGA tumor datasets. Results Epigenetic drugs induced different profiles of gene expression in melanoma cell lines. Immune-related genes were frequently upregulated by guadecitabine, irrespective of the mutational and differentiation profiles of the melanoma cell lines, to a lesser extent by givinostat, but mostly downregulated by JQ1 and OTX-015. GSK126 was the least active drug. Quantitative western blot analysis confirmed drug-specific modulatory profiles. Most of the guadecitabine-specific signature genes were upregulated in on-treatment NIBIT-M4 tumor biopsies, but not in on-treatment lesions of patients treated only with ipilimumab. A guadecitabine-specific UR signature, containing activated molecules of the TLR, NF-kB, and IFN innate immunity pathways, was induced in drug-treated melanoma, mesothelioma and hepatocarcinoma cell lines and in a human melanoma xenograft model. Activation of guadecitabine-specific UR signature molecules in on-treatment tumor biopsies discriminated responding from non-responding NIBIT-M4 patients. Sixty-five % of the immune-related genes upregulated by guadecitabine were prognostically significant and conferred a reduced risk in the TCGA cutaneous melanoma dataset. Conclusions The DNMT inhibitor guadecitabine emerged as the most promising immunomodulatory agent among those tested, supporting the rationale for usage of this class of epigenetic drugs in combinatorial immunotherapy approaches. © 2022, The Author(s)

Evaluation of left atrial systolic function in noncompaction cardiomyopathy by real-time three-dimensional echocardiography

Background Noncompaction cardiomyopathy (NCCM) is a rare disorder with persistance of the embryonic pattern of myoarchitecture. NCCM is characterized by loosened, spongy myocardium associated with a high incidence of systolic and diastolic left ventricular (LV) dysfunction and heart failure (HF). It is known that LV dysfunction contributes to elevated left atrial (LA) and pulmonary vascular pressures, however atrial function has not been examined in NCCM. The objective of the present study was to assess LA systolic function characterized by LA ejection force (LAEF) in NCCM patients using real-time three-dimensional echocardiography (RT3DE) and to compare to control subjects. Methods The study comprised 17 patients with an established diagnosis of NCCM and their results were compared to 17 healthy age-matched controls with no evidence of cardiovascular disease. Forty-one percent of NCCM patients were in NYHA functional class II / III HF. Previously proposed echocardiographic diagnostic criteria for NCCM were used. All patients underwent conventional two-dimensional echocardiography and RT3DE. LAEF was measured based on MA annulus diameter (LAEF3D-MAD) and area (LAEF3D-MAA) using RT3DE. Results The presence and severity of mitral regurgitation were more frequent in NCCM patients than in control subjects. LV diameters and mitral annulus were significantly increased in NCCM patients. Compared with control subjects, both LAEF3D-MAD (3.8 ± 2.2 vs 2.3 ± 1.0 kdyne, P < 0.05) and LAEF3D-MAA (12.7 ± 7.6 vs 4.9 ± 2.1 kdyne, P < 0.01) were significantly increased in NCCM patients. Conclusions LAEF as a characteristic of LA systolic function is increased in NCCM patients compared to normal individuals. These results can suggest compensating left atrial work against the dysfunctional LV in NCCM patients

An Integrated Environment for Application-Dependent Testing of FPGA Device

Targeting only the portion of an FPGA actually used in a given application, the so-called application-dependent test (ADT) can be used to reduce testing efforts and time as well as to enable defect tolerance and improve the manufacturing yield, since it excludes those faults that do not affect the design for which the FPGA will be used. In spite of its inherent advantages, ADT has very limited support, if any, in both academic and commercial tools currently available. To address this limitation, this work introduces an integrated software environment for application-dependent test of FPGAs. The environment architecture is comprised of a variety of tools, such as a SAT solver, a fault simulator, a package for visual inspection of the networks, a custom benchmark generator, and various custom fault list generators and test configuration generators. The architecture is highly modular and extensively based on a plug-in approach, enabling third-party test strategies and configuration generation logic to be easily integrated. To demonstrate the potential of the environment, we developed a complete suite of plug-ins, based on both state-of-the-art and novel ADT techniques. The test configuration generation module addresses some limitations of existing approaches, related to the exhaustiveness of the faults covered (with special regard to feedback bridging faults) as well as some convergence issues caused by existing techniques. The experimental results presented at the end of the paper, obtained from a set of real-world benchmarks, confirm the effectiveness of the environment architecture as well as the impact of the new ADT techniques implemented in the proof-of-concept plug-ins